Pharmaceutical including amine derivative

Abstract

To provide a pharmaceutical having DYRK inhibitory action.SOLUTION: The present invention provides a pharmaceutical that includes an amine derivative represented by the following formula (1) (where A1, A2, L1, L2, X, Z, R1, and R4 are as defined in the specifications), or a pharmaceutically acceptable salt thereof as an active ingredient.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a medicine, particularly to a medicine containing a novel amine derivative having DYRK inhibitory activity or a pharmaceutically acceptable salt thereof. [Background technology]

[0002] DYRK (Dual-specificity tyrosine-phosphorylation Regulated protein kinase) is a type of dual-specificity protein kinase that phosphorylates tyrosine, serine, and threonine. DYRK functions as a tyrosine kinase only in the case of autophosphorylation, but catalyzes the phosphorylation of serine or threonine residues for exogenous substrates. Five members of the DYRK family are known in humans: DYRK1A, DYRK1B, DYRK2, DYRK3, and DYRK4 (Non-Patent Document 1).

[0003] DYRK1A has been reported to be associated with many neuropsychiatric disorders. For example, in patients with Alzheimer's disease, the expression of β-amyloid and DYRK1A are significantly correlated (Non-Patent Document 2). Furthermore, DYRK1A is thought to be involved in the abnormal phosphorylation of tau protein (Tau), which is thought to be one of the causes of Alzheimer's disease (Non-Patent Document 3).

[0004] Parkinson's disease is a neurodegenerative disease caused by the degeneration of dopamine neurons, which are important for motor function, and mitochondrial dysfunction is thought to be one of its causes (Non-Patent Document 4). Parkin, an enzyme involved in protein degradation, is known to metabolize abnormal mitochondria and suppress their abnormal accumulation, and DYRK1A has been reported to suppress the activity of this parkin protein (Non-Patent Document 5).

[0005] The DYRK1A gene is located in the critical region for Down syndrome, and it has been reported that mice overexpressing DYRK1A exhibit abnormalities in neuropsychiatric functions and exhibit Down syndrome-like symptoms (Non-Patent Document 6). It has also been reported that DYRK1A expression is elevated in the brains of Down syndrome patients and Down syndrome-like model mice (Non-Patent Document 7). These findings suggest that DYRK1A is involved in the onset of neurological symptoms in Down syndrome patients (Non-Patent Document 8).

[0006] Furthermore, it has been reported that early-onset Alzheimer's disease occurs frequently in patients with Down's syndrome, which indicates that DYRK1A is closely related to Alzheimer's disease (Non-Patent Document 8).

[0007] Therefore, compounds that inhibit DYRK1A are believed to be useful in the treatment of neuropsychiatric disorders such as Alzheimer's disease, Down's syndrome, mental retardation, memory impairment, amnesia, and Parkinson's disease.

[0008] Recently, it has been reported that DYRK1A is highly expressed in brain tumors such as glioblastoma, and that DYRK1A regulates the expression of epidermal growth factor receptor (EGFR) (Non-Patent Document 9). Therefore, compounds that inhibit DYRK1A are thought to suppress the proliferation of cancer cells in EGFR-dependent brain tumors and other tumors, and to be useful in the treatment of EGFR-dependent tumors.

[0009] Compounds that inhibit the family enzymes DYRK1B, DYRK2, and DYRK3 are also expected to have various pharmaceutical applications. For example, it has been reported that DYRK1B is highly expressed in cancer cells in the dormant phase (G0 phase) and contributes to resistance to various chemotherapeutic agents (Non-Patent Document 10). It has also been reported that inhibition of DYRK1B promotes exit from the G0 phase and improves sensitivity to chemotherapeutic agents (Non-Patent Document 11). Therefore, compounds that inhibit DYRK1B are thought to be useful in the treatment of pancreatic cancer, ovarian cancer, osteosarcoma, colon cancer, and lung cancer (Non-Patent Documents 11, 12, 13, 14, 15).

[0010] DYRK2 has been suggested to regulate p53 and induce apoptosis in response to DNA damage (Non-Patent Document 16). Furthermore, compounds that inhibit DYRK3 have been reported to be useful in the treatment of sickle cell anemia and chronic kidney disease (Non-Patent Document 17).

[0011] Compounds that inhibit DYRK are reported in Patent Document 1, and DYRK1A and DYRK1B inhibitors are reported in Patent Document 2. However, there is no description of the amine derivatives contained in the medicament of the present invention. [Prior art documents] [Patent documents]

[0012] [Patent Document 1] WO2010 / 10797 publication [Patent Document 2] WO2013 / 26806 publication [Non-patent literature]

[0013] [Non-Patent Document 1] Becker W. et al., J. Biol. Chem., 1998, 273, 25893-25902 [Non-patent document 2] Kimura R. et al.,Hum.Mol.Genet.,2007,16,15-23 [Non-patent document 3] Ryoo SR. et al.,J.Biol.Chem.,2007,282,34850-34857 [Non-patent document 4] Narendra D. et al.,J.Cell.Biol.,2008,183,795-803 [Non-Patent Document 5] Im E.,J.Neurochem.,2015,134,756-768 [Non-patent document 6] Branchi I. et al.,J.Neuropathol.Exp.Neurol.,2004,63,429-440

Non-licensed Document 7

[0014]

Non-licensed literature 9

Non-licensed literature 10

Non-licensed Document 11

Non-licensed Document 12

Non-licensed Document 13

Non-licensed Document 14

Non-licensed Document 15

Non-licensed Document 16

Non-licensed Document 17

[0015] An objective of the present invention is to provide a medicine, particularly a medicine containing a novel amine derivative having DYRK inhibitory activity or a pharmaceutically acceptable salt thereof. [Means for solving the problem]

[0016] That is, the present invention is as follows.

[0017] [Section 1] The following formula (1): [ka] [In the formula, A 1 represents an oxygen atom or a nitrogen atom (=N-), A 2 is CR B , C.R. C R D , an oxygen atom or NR A1 represents L 1 is an optionally substituted methylene, an optionally substituted ethylene, an optionally substituted methine, an optionally substituted ethanediylidene, ═N—, or NR A2 represents R A1 , R A2 , R B , R C and R D are each independently a hydrogen atom or an optionally substituted C 1-6 represents alkyl, R 1 represents a hydrogen atom, a halogen atom, or an optionally substituted C 1-6 represents alkyl, X represents a carbon atom or a nitrogen atom; L 2 may be substituted C 1-4 represents alkylene, R Emay be substituted C 1-6 represents alkyl, Z is -NR 2 R 3 -OR 7 represents R 7 may be substituted C 1-6 Alkyl, or R 4 and optionally substituted C 1-7 represents alkylene, wherein R 4 and R 7 together with the carbon atom and oxygen atom to which they are attached form an optionally substituted 5- to 11-membered saturated heterocyclic ring; R 2 is a hydrogen atom, optionally substituted C 1-6 Alkyl, C(O)-R E , C 3-10 Cycloalkyl, C 2-6 represents an alkynyl or 4- to 11-membered saturated heterocyclic ring group; R 3 is a hydrogen atom, optionally substituted C 1-6 Alkyl or C(O)-R E represents R 4 may be substituted C 1-6 represents alkyl, Here, R 2 and R 3 may be taken together with the nitrogen atom to which they are attached to form an optionally substituted 4- to 11-membered saturated heterocyclic ring, or R 3 and R 4 may form an optionally substituted 4- to 11-membered saturated heterocyclic ring together with the nitrogen atom and carbon atom to which they are attached, or 2 , R 3 and any carbon atom on a saturated heterocycle consisting of a nitrogen atom and R 4 may be taken together to form a 4- to 11-membered saturated heterocycle (sometimes referred to herein as "compound (1)" or "compound represented by formula (1)") or a pharmaceutically acceptable salt thereof.

[0018] [Section 2] Z is -NR 2 R 3 represents R 2 and R 3 are each independently a hydrogen atom, an optionally substituted C 1-6 Alkyl or C(O)-R E where R 2 and R 3 may be taken together with the nitrogen atom to which they are attached to form an optionally substituted 4- to 8-membered saturated heterocycle.

[0019] [Section 3] Z is -NR 2 R 3 represents R 3 and R 4 Item 3. The pharmaceutical agent according to Item 1, wherein, together with the nitrogen atom and carbon atom to which each is attached, form an optionally substituted 4- to 8-membered saturated heterocycle.

[0020] [Section 4] R 1 The medicine according to any one of Items 1 to 3, wherein is a hydrogen atom.

[0021] [Section 5] The pharmaceutical agent according to any one of Items 1 to 4, wherein X is a carbon atom.

[0022] [Section 6] A 1 is an oxygen atom, and A 2 is methylene, and L 1 Item 6. The pharmaceutical composition according to Item 5, wherein is methylene.

[0023] [Section 7] Formula (1) is changed to the following formula (1a): [ka] [In the formula, A 2 represents an optionally substituted methylene or oxygen atom, L 1 represents an optionally substituted methylene or an optionally substituted ethylene, L 2 may be substituted C 1-4 represents alkylene, R 2 and R 3 are each independently a hydrogen atom, an optionally substituted C 1-6 Alkyl or C(O)-R E where R 2 and R 3 may be taken together with the nitrogen atom to which they are attached to form an optionally substituted 4- to 8-membered saturated heterocycle, R E may be substituted C 1-6 represents alkyl, R 4 may be substituted C 1-6 Item 7. A medicine containing the compound according to item 1, 2, 4, 5 or 6, or a pharmaceutically acceptable salt thereof, wherein:

[0024] [Section 8] R 2 and R 3 each independently represents an optionally substituted C 1-6 Item 8. The pharmaceutical composition according to Item 7, wherein the compound is alkyl.

[0025] [Section 9] R 2 and R 3 and R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form an optionally substituted 4- to 8-membered saturated heterocycle.

[0026] [Section 10] L 2 But C 1-3 The pharmaceutical agent according to any one of items 7 to 9, wherein the alkylene is alkylene.

[0027] [Section 11] Formula (1) is changed to the following formula (1b): [ka] [In the formula, A 2 represents an optionally substituted methylene or oxygen atom, L 1 represents an optionally substituted methylene or an optionally substituted ethylene, l and m each independently represent 1, 2, or 3, and the sum of l and m is 5 or less; n represents 1, 2, 3 or 4; R 2 is a hydrogen atom, optionally substituted C 1-6 Alkyl, C 3-10 Cycloalkyl or C(O)-R E represents R E may be substituted C 1-6 represents alkyl, R F represents a hydrogen atom, a halogen atom, or an optionally substituted C 1-6 represents alkyl, When n is 2, 3, or 4, R F may be the same or different, and two R F may be joined together with the carbon atoms to which they are attached to form a spiro ring consisting of a 4- to 8-membered saturated heterocycle or a 3- to 8-membered saturated carbocycle, or two R F may be bonded to form a bridge.] or a pharmaceutically acceptable salt thereof.

[0028] [Section 12] R 2 is a hydrogen atom, optionally substituted C 1-6 Alkyl or C 3-10 Item 12. The pharmaceutical agent according to Item 11, wherein the compound is cycloalkyl.

[0029] [Section 13] R 2 may be substituted C 1-6 Item 12. The pharmaceutical composition according to Item 11, wherein the compound is alkyl.

[0030] [Section 14] Item 14. The pharmaceutical composition according to any one of Items 11 to 13, wherein l and m are each independently 1 or 2.

[0031] [Section 15] Z is -OR 7 and R 4 and R 7 Item 3. The pharmaceutical agent according to Item 1, wherein, together with the carbon atom and oxygen atom to which each is attached, form an optionally substituted 5- to 8-membered saturated heterocycle.

[0032] [Section 16] Formula (1) is changed to the following formula (1c): [ka] [In the formula, A 2 represents an optionally substituted methylene or oxygen atom, L 1 represents an optionally substituted methylene or an optionally substituted ethylene, p and q each independently represent 1, 2, or 3, where the sum of p and q is 5 or less; t represents 1, 2, 3 or 4; R G is a hydrogen atom, a halogen atom, or an optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 represents an alkoxy or CN group, When t is 2, 3, or 4, R G may be the same or different, and two R G may be joined together with the carbon atoms to which they are attached to form a spiro ring consisting of a 4- to 8-membered saturated heterocycle or a 3- to 8-membered saturated carbocycle, or two R G Item 16. The pharmaceutical composition according to item 1 or 15, wherein:

[0033] [Section 17] Item 17. The pharmaceutical composition according to any one of items 1 to 16, comprising a compound selected from the group consisting of the following compounds or a pharmaceutically acceptable salt thereof: cis-3-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-5-methyloctahydro-2H-imidazo[4,5-c]pyridin-2-one (Example 7); cis-3-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-5-(2-methoxyethyl)octahydro-2H-imidazo[4,5-c]pyridin-2-one (Example 8); cis-1-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-5-methyloctahydro-2H-imidazo[4,5-c]pyridin-2-one (Example 9); cis-3-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-5-ethyloctahydro-2H-imidazo[4,5-c]pyridin-2-one (Example 11); cis-1-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-5-methylhexahydropyrrolo[3,4-d]imidazol-2(1H)-one (Example 14); cis-3-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-5-(propan-2-yl)octahydro-2H-imidazo[4,5-c]pyridin-2-one (Example 15); cis-3-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-5-methyloctahydroimidazo[4,5-c]azepin-2(1H)-one (Example 17); (3aS,7aS)-3-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-5-(oxetan-3-yl)octahydro-2H-imidazo[4,5-c]pyridin-2-one (Example 19); (3aR,7aR)-1-(2H-[1,3]dioxolo[4,5-e][1,3]benzothiazol-7-yl)hexahydropyrano[3,4-d]imidazol-2(3H)-one (Example 21); (4S,5R)-1-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-4-methyl-5-[(morpholin-4-yl)methyl]imidazolidin-2-one (Example 23); (4R,5R)-1-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-4-methyl-5-[(morpholin-4-yl)methyl]imidazolidin-2-one (Example 24); (3aR,7aS)-3-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-5-methyloctahydro-2H-imidazo[4,5-c]pyridin-2-one (Example 28); (3aR,7aS)-5-cyclopropyl-3-(7,8-dihydro[1,4]dioxino[2,3-e][1,3]benzothiazol-2-yl)octahydro-2H-imidazo[4,5-c]pyridin-2-one (Example 34); (3aR,7aS)-5-cyclopropyl-3-(2H-[1,3]dioxolo[4,5-e][1,3]benzothiazol-7-yl)octahydro-2H-imidazo[4,5-c]pyridin-2-one (Example 36); (3aR,7aR)-1-(7,8-dihydro[1,4]dioxino[2,3-e][1,3]benzothiazol-2-yl)hexahydropyrano[3,4-d]imidazol-2(3H)-one (Example 37); (3aR,6S,7aR)-1-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-6-methylhexahydropyrano[3,4-d]imidazol-2(3H)-one (Example 38); (3aR,6S,7aR)-1-(7,8-dihydro[1,4]dioxino[2,3-e][1,3]benzothiazol-2-yl)-6-methylhexahydropyrano[3,4-d]imidazol-2(3H)-one (Example 39); (3aR,6R,7aR)-1-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-6-(fluoromethyl)hexahydropyrano[3,4-d]imidazol-2(3H)-one (Example 40); (3aR,6R,7aR)-1-(7,8-dihydro[1,4]dioxino[2,3-e][1,3]benzothiazol-2-yl)-6-(fluoromethyl)hexahydropyrano[3,4-d]imidazol-2(3H)-one (Example 41); (3aR,6S,7aR)-1-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-6-ethylhexahydropyrano[3,4-d]imidazol-2(3H)-one (Example 42); (3aR,6S,7aR)-1-(7,8-dihydro[1,4]dioxino[2,3-e][1,3]benzothiazol-2-yl)-6-ethylhexahydropyrano[3,4-d]imidazol-2(3H)-one (Example 43); (4S,5S)-1-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-5-(methoxymethyl)-4-methylimidazolidin-2-one (Example 44); (3aR,6aS)-1-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)tetrahydro-1H-furo[3,4-d]imidazol-2(3H)-one (Example 65); rac-(3aR,7aS)-3-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-5-(oxetan-3-yl)octahydro-2H-imidazo[4,5-c]pyridin-2-one (Example 71); rac-(3aR,7aS)-5-cyclobutyl-3-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)octahydro-2H-imidazo[4,5-c]pyridin-2-one (Example 72); rac-(3aR,8aS)-3-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-5-(oxetan-3-yl)octahydroimidazo[4,5-c]azepin-2(1H)-one (Example 73); rac-(3aR,7aS)-3-(7,8-dihydro[1,4]dioxino[2,3-e][1,3]benzothiazol-2-yl)-5-methyloctahydro-2H-imidazo[4,5-c]pyridin-2-one (Example 76); rac-(3aR,7aS)-1-(7,8-dihydro[1,4]dioxino[2,3-e][1,3]benzothiazol-2-yl)-5-methyloctahydro-2H-imidazo[4,5-c]pyridin-2-one (Example 77); rac-(3aR,7aS)-1-(2H-[1,3]dioxolo[4,5-e][1,3]benzothiazol-7-yl)-5-methyloctahydro-2H-imidazo[4,5-c]pyridin-2-one (Example 78); rac-(3aR,7aS)-3-(2H-[1,3]dioxolo[4,5-e][1,3]benzothiazol-7-yl)-5-methyloctahydro-2H-imidazo[4,5-c]pyridin-2-one (Example 79); rac-(3aR,7aS)-3-(7,8-dihydro[1,4]dioxino[2,3-e][1,3]benzothiazol-2-yl)-5-(oxetan-3-yl)octahydro-2H-imidazo[4,5-c]pyridin-2-one (Example 80); rac-(3aR,7aS)-3-(2H-[1,3]dioxolo[4,5-e][1,3]benzothiazol-7-yl)-5-(oxetan-3-yl)octahydro-2H-imidazo[4,5-c]pyridin-2-one (Example 81); rac-(3aR,8aS)-3-(2H-[1,3]dioxolo[4,5-e][1,3]benzothiazol-7-yl)-5-methyloctahydroimidazo[4,5-c]azepin-2(1H)-one (Example 85); rac-(3aR,8aS)-3-(2H-[1,3]dioxolo[4,5-e][1,3]benzothiazol-7-yl)-5-(oxetan-3-yl)octahydroimidazo[4,5-c]azepin-2(1H)-one (Example 86); (3aS,6S,7aR)-1-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-5,6-dimethyloctahydro-2H-imidazo[4,5-c]pyridin-2-one (Example 93); rac-(3aR,7aS)-5-cyclopropyl-3-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)octahydro-2H-imidazo[4,5-c]pyridin-2-one (Example 98); rac-(3aR,7aS)-3-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-5-(2-propyn-1-yl)octahydro-2H-imidazo[4,5-c]pyridin-2-one (Example 99); rac-[(3aR,7aS)-3-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-2-oxooctahydro-5H-imidazo[4,5-c]pyridin-5-yl]acetonitrile (Example 100); rac-(3aR,6aS)-1-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-5-(2-propyn-1-yl)hexahydropyrrolo[3,4-d]imidazol-2(1H)-one (Example 102); rac-[(3aR,6aS)-1-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-2-oxohexahydropyrrolo[3,4-d]imidazol-5(1H)-yl]acetonitrile (Example 103); rac-(3aR,8aS)-5-cyclopropyl-3-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)octahydroimidazo[4,5-c]azepin-2(1H)-one (Example 104); rac-(3aR,8aS)-3-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-5-(2-propyn-1-yl)octahydroimidazo[4,5-c]azepin-2(1H)-one (Example 105); rac-[(3aR,8aS)-3-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-2-oxooctahydroimidazo[4,5-c]azepin-5(1H)-yl]acetonitrile (Example 106); rac-(3aR,7aS)-3-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-5-(2,2,2-trifluoroethyl)octahydro-2H-imidazo[4,5-c]pyridin-2-one (Example 107); rac-(3aR,7aS)-5-(2,2-difluoroethyl)-3-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)octahydro-2H-imidazo[4,5-c]pyridin-2-one (Example 108); (3aR,7aS)-5-cyclopropyl-3-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)octahydro-2H-imidazo[4,5-c]pyridin-2-one (Example 110); [(3aR,7aS)-3-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-2-oxooctahydro-5H-imidazo[4,5-c]pyridin-5-yl]acetonitrile (Example 112); (3aR,7aS)-3-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-5-(2-propyn-1-yl)octahydro-2H-imidazo[4,5-c]pyridin-2-one (Example 114); (4S,5R)-1-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-5-{[(3S)-3-fluoropyrrolidin-1-yl]methyl}-4-methylimidazolidin-2-one (Example 115); (4S,5R)-5-[(3,3-difluoroazetidin-1-yl)methyl]-1-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-4-methylimidazolidin-2-one (Example 116); (4S,5R)-5-[(3,3-difluoropyrrolidin-1-yl)methyl]-1-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-4-methylimidazolidin-2-one (Example 117); (4S,5R)-1-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-5-[(3-fluoroazetidin-1-yl)methyl]-4-methylimidazolidin-2-one (Example 118); rac-(3aR,7aR)-3-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)hexahydropyrano[3,4-d]imidazol-2(3H)-one (Example 120); rac-(3aR,7aR)-1-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)hexahydropyrano[3,4-d]imidazol-2(3H)-one (Example 121); (3aR,7aR)-1-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)hexahydropyrano[3,4-d]imidazol-2(3H)-one (Example 122); (3aR,7aR)-1-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-6,6-dimethylhexahydropyrano[3,4-d]imidazol-2(3H)-one (Example 124); (3aR,6R,7aR)-1-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-2-oxooctahydropyrano[3,4-d]imidazole-6-carbonitrile (Example 127); (3aR,6R,7aR)-1-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-6-methoxyhexahydropyrano[3,4-d]imidazol-2(3H)-one (Example 129); (3aR,6R,7aR)-1-(2H-[1,3]dioxolo[4,5-e][1,3]benzothiazol-7-yl)-2-oxooctahydropyrano[3,4-d]imidazole-6-carbonitrile (Example 131); (3aR,6R,7aR)-1-(7,8-dihydro[1,4]dioxino[2,3-e][1,3]benzothiazol-2-yl)-2-oxooctahydropyrano[3,4-d]imidazole-6-carbonitrile (Example 133); (3aR,8aR)-1-(7,8-dihydro[1,4]dioxino[2,3-e][1,3]benzothiazol-2-yl)hexahydro-1H-oxepino[3,4-d]imidazol-2(3H)-one (Example 135); (3aR,6S,7aR)-1-(2H-[1,3]dioxolo[4,5-e][1,3]benzothiazol-7-yl)-6-ethylhexahydropyrano[3,4-d]imidazol-2(3H)-one (Example 138); (3aR,6S,7aR)-1-(2H-[1,3]dioxolo[4,5-e][1,3]benzothiazol-7-yl]-6-methylhexahydropyrano[3,4-d]imidazol-2(3H)-one (Example 139); (3aR,6R,7aR)-1-(2H-[1,3]dioxolo[4,5-e][1,3]benzothiazol-7-yl]-6-(fluoromethyl)hexahydropyrano[3,4-d]imidazol-2(3H)-one (Example 140); (3aR,6R,7aR)-1-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-6-(hydroxymethyl)hexahydropyrano[3,4-d]imidazol-2(3H)-one (Example 144); (3aR,6R,7aR)-1-(7,8-dihydro[1,4]dioxino[2,3-e][1,3]benzothiazol-2-yl)-6-(hydroxymethyl)hexahydropyrano[3,4-d]imidazol-2(3H)-one (Example 146); (3aR,6R,7aR)-1-(2H-[1,3]dioxolo[4,5-e][1,3]benzothiazol-7-yl)-6-(hydroxymethyl)hexahydropyrano[3,4-d]imidazol-2(3H)-one (Example 147); (3aR,6R,7aR)-1-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-6-ethynylhexahydropyrano[3,4-d]imidazol-2(3H)-one (Example 149); (3aR,7aR)-1-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-6-fluorohexahydropyrano[3,4-d]imidazol-2(3H)-one (Example 151); (3aR,6S,6aS)-1-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-6-(hydroxymethyl)tetrahydro-1H-furo[3,4-d]imidazol-2(3H)-one (Example 157); (3aR,6S,6aS)-1-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-6-(fluoromethyl)tetrahydro-1H-furo[3,4-d]imidazol-2(3H)-one (Example 159); (3aR,6R,6aS)-1-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-6-methyltetrahydro-1H-furo[3,4-d]imidazol-2(3H)-one (Example 161); and [(3aS,4R,6aR)-3-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-2-oxohexahydro-1H-furo[3,4-d]imidazol-4-yl]acetonitrile (Example 162).

[0034] [Section 18] A medicine comprising any of the compounds described in Examples 1 to 162 or a pharmaceutically acceptable salt thereof.

[0035] [Section 19] A pharmaceutical composition comprising the compound according to any one of Items 1 to 17 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0036] [Section 20] Item 18. A therapeutic and / or preventive agent for a disease in which DYRK is involved, comprising the compound according to any one of Items 1 to 17 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0037] [Section 21] Item 21. The therapeutic and / or prophylactic agent according to Item 20, wherein the disease in which DYRK is involved is frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration, dementia with Lewy bodies, vascular dementia, traumatic brain injury, chronic traumatic encephalopathy, stroke, Alzheimer's disease, Parkinson's disease, Down's syndrome, depression, and mental retardation, memory disorder, memory loss, learning disability, intellectual disability, cognitive impairment, mild cognitive impairment, dementia symptoms associated with these diseases, or brain tumor, pancreatic cancer, ovarian cancer, osteosarcoma, colon cancer, lung cancer, bone resorption disease, osteoporosis, sickle cell anemia, chronic kidney disease, or bone resorption disease.

[0038] [Section 22] A method for treating and / or preventing a disease in which DYRK is involved, comprising administering to a patient in need of treatment a therapeutically effective amount of the compound according to any one of items 1 to 17 or a pharmaceutically acceptable salt thereof.

[0039] [Section 23] Use of the compound or a pharmaceutically acceptable salt thereof according to any one of items 1 to 17 for producing an agent for treating and / or preventing a disease in which DYRK is involved.

[0040] [Section 24] Item 18. The compound or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 17 for use in the treatment and / or prevention of a disease in which DYRK is involved.

[0041] [Section 25] A pharmaceutical comprising the pharmaceutical according to any one of Items 1 to 17 in combination with at least one drug selected from the group consisting of anticancer drugs, antipsychotic drugs, antidementia drugs, antiepileptic drugs, antidepressants, gastrointestinal drugs, thyroid hormone drugs, and antithyroid drugs.

[0042] [Section 26] Item 20. The pharmaceutical composition according to Item 19, for treating frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration, dementia with Lewy bodies, vascular dementia, traumatic brain injury, chronic traumatic encephalopathy, stroke, Alzheimer's disease, Parkinson's disease, Down's syndrome, depression and complications associated therewith, mental retardation, memory impairment, memory loss, learning disability, intellectual disability, cognitive impairment, mild cognitive impairment, progression of dementia symptoms, or prevention of the onset of dementia, or for treating brain tumor, pancreatic cancer, ovarian cancer, osteosarcoma, colon cancer, lung cancer, bone resorption disease, osteoporosis, sickle cell anemia, chronic kidney disease, or bone resorption disease, in combination with at least one or more drugs selected from the group consisting of anticancer agents, antipsychotic agents, antidementia agents, antiepileptic agents, antidepressants, gastrointestinal agents, thyroid hormone agents, and antithyroid agents. [Effects of the Invention]

[0043] The present inventors conducted extensive research to solve the above-mentioned problems and discovered that pharmaceuticals containing the amine derivatives represented by formula (1) and pharmaceutically acceptable salts thereof are an excellent group of drugs with excellent DYRK inhibitory activity, thereby completing the present invention. The pharmaceuticals provided by the present invention are useful as therapeutic agents for diseases known to be associated with abnormal cellular responses mediated by DYRK1A, such as psychiatric and neurological disorders such as Alzheimer's disease, Parkinson's disease, Down's syndrome, and depression, as well as the associated mental retardation, memory impairment, amnesia, learning disabilities, intellectual disability, cognitive impairment, mild cognitive impairment, and progression of dementia symptoms, or as preventive agents for the onset of dementia, as well as pharmaceuticals (or pharmaceutical compositions) for the prevention or treatment of tumors such as brain tumors. The pharmaceuticals provided by the present invention are useful as DYRK1B inhibitors and as pharmaceuticals (or pharmaceutical compositions) for the prevention or treatment of tumors such as pancreatic cancer, ovarian cancer, osteosarcoma, colon cancer, and lung cancer. Furthermore, the pharmaceuticals provided by the present invention are useful as pharmaceuticals (or pharmaceutical compositions) for preventing or treating bone resorption diseases and osteoporosis because they regulate p53 and induce apoptosis in response to DNA damage in DYRK2. Furthermore, the pharmaceuticals provided by the present invention are useful as DYRK3 inhibitors, and as pharmaceuticals (or pharmaceutical compositions) for preventing or treating sickle cell anemia, chronic kidney disease, bone resorption diseases, and osteoporosis. Furthermore, as DYRK-inhibiting compounds, they are useful as reagents for pathological imaging of the above-mentioned diseases, and as reagents for basic experiments and research. DETAILED DESCRIPTION OF THE INVENTION

[0044] The terms used in this specification are explained below.

[0045] "DYRK" stands for Dual-specificity tYrosine-phosphorylation Regulated protein Kinase and refers to one or more of the DYRK family (DYRK1A, DYRK1B, DYRK2, DYRK3, DYRK4).

[0046] Examples of "halogen atom" include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. A fluorine atom is preferred.

[0047] "C 1-6 "Alkyl" means a straight or branched chain saturated hydrocarbon group having 1-6 carbon atoms, and "C6 alkyl" means a straight or branched chain saturated hydrocarbon group having 6 carbon atoms, and similarly for other numbers. 1-6 As the alkyl, preferably "C 1-4 alkyl" and more preferably "C 1-3 "C alkyl" is an example. 1-3 Specific examples of "alkyl" include methyl, ethyl, propyl, 1-methylethyl, etc. 1-4 Specific examples of "alkyl" include the above-mentioned "C 1-3 In addition to the specific examples of "alkyl", butyl, 1,1-dimethylethyl, 1-methylpropyl, 2-methylpropyl, etc. are also included. 1-6 Specific examples of "alkyl" include the above-mentioned "C 1-4 In addition to the specific examples of "alkyl", pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylbutyl, 2-methylbutyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, hexyl, and the like can be mentioned.

[0048] "C 1-6 "Alkoxy" means "C 1-6 alkyloxy" and the "C 1-6 The "C alkyl" portion is 1-6 "C" is synonymous with "alkyl." 1-6 The "alkoxy" is preferably "C 1-4 Alkoxy" is preferred, and "C 1-3 "Alkoxy" is one example. 1-3 Specific examples of "alkoxy" include methoxy, ethoxy, propoxy, 1-methylethoxy, etc. 1-4 Specific examples of "alkoxy" include the above-mentioned "C 1-3In addition to the specific examples of "alkoxy", butoxy, 1,1-dimethylethoxy, 1-methylpropoxy, 2-methylpropoxy, etc. are also included. 1-6 Specific examples of "alkoxy" include the above-mentioned "C 1-4 In addition to the specific examples of "alkoxy", pentyloxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 1-methylbutoxy, 2-methylbutoxy, 4-methylpentyloxy, 3-methylpentyloxy, 2-methylpentyloxy, 1-methylpentyloxy, hexyloxy, and the like can be mentioned.

[0049] "C 1-6 "Alkoxycarbonyl" refers to the above "C 1-6 It is a "carbonyl" substituted with "alkoxy". 1-6 The "alkoxycarbonyl" is preferably "C 1-4 Alkoxycarbonyl" is preferred, and "C 1-3 "C alkoxycarbonyl" is an example. 1-3 Specific examples of "alkoxycarbonyl" include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1-methylethoxycarbonyl, etc. 1-4 Specific examples of "alkoxycarbonyl" include the above-mentioned "C 1-3 In addition to the specific examples of "alkoxycarbonyl," butoxycarbonyl, 1,1-dimethylethoxycarbonyl, 1-methylpropoxycarbonyl, 2-methylpropoxycarbonyl, etc. are also included. 1-6 Specific examples of "alkoxycarbonyl" include the above-mentioned "C 1-4 In addition to the specific examples of "alkoxycarbonyl," examples include pentyloxycarbonyl, 1,1-dimethylpropoxycarbonyl, 1,2-dimethylpropoxycarbonyl, 1-methylbutoxycarbonyl, 2-methylbutoxycarbonyl, 4-methylpentyloxycarbonyl, 3-methylpentyloxycarbonyl, 2-methylpentyloxycarbonyl, 1-methylpentyloxycarbonyl, hexyloxycarbonyl, and the like.

[0050] "C 1-7 alkylene," "C 1-4 alkylene" or "C 1-3 "Alkylene" means a straight or branched chain saturated divalent hydrocarbon group having 1-7, 1-4, or 1-3 carbon atoms, respectively. 1-7 As "alkylene", preferably "C 1-4 alkylene" and "C 1-4 As alkylene, preferably "C 1-3 Alkylene" and "C 1-3 As alkylene, preferably "C 1-2 "C alkylene" is an example. 1-2 Specific examples of "alkylene" include methylene and ethylene. 1-3 Specific examples of "alkylene" include the above-mentioned "C 1-2 In addition to the specific examples of "alkylene," propylene, 1-methylethylene, etc. are also included. 1-4 Specific examples of "alkylene" include the above-mentioned "C 1-3 In addition to the specific examples of "alkylene," butylene, 1,1-dimethylethylene, 1,2-dimethylethylene, 1-methylpropylene, 2-methylpropylene, etc. are also included. 1-7 Specific examples of "alkylene" include the above-mentioned "C 1-4In addition to the specific examples of "alkylene", pentylene, 1,1-dimethylpropylene, 2,2-dimethylpropylene, 1,2-dimethylpropylene, 1,3-dimethylpropylene, 1-methylbutylene, 2-methylbutylene, hexylene, 1,1-dimethylbutylene, 2,2-dimethylbutylene, 1,2-dimethylbutylene, 1,3-dimethylbutylene, 1,4-dimethylbutylene, 2,3-dimethylbutylene, 1-methylpentylene, 2-methylbutylene, Examples of pentylene include pentylene, 3-methylpentylene, heptylene, 1,1-dimethylpentylene, 2,2-dimethylpentylene, 3,3-dimethylpentylene, 1,2-dimethylpentylene, 1,3-dimethylpentylene, 1,4-dimethylpentylene, 1,5-dimethylpentylene, 2,3-dimethylpentylene, 2,4-dimethylpentylene, 2,5-dimethylpentylene, 1-methylhexylene, 2-methylhexylene, and 3-methylhexylene.

[0051] "C 2-6 "Alkynyl" means a straight or branched unsaturated hydrocarbon group having 2 to 6 carbon atoms and 1 to 3 triple bonds. "Alkynyl" is preferably "C 2-4 alkynyl" and more preferably "C 2-3 Specific examples of "alkynyl" include ethynyl, propargyl, 2-butynyl, etc.

[0052] "C 3-10 "Cycloalkyl" means a cyclic saturated hydrocarbon group having 3 to 10 carbon atoms, including those having a partially unsaturated bond and those having a bridged structure. 3-10 As "cycloalkyl", preferably "C 3-7 "Cycloalkyl" is an example. 3-7 Specific examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. 3-10 Specific examples of "cycloalkyl" include the above-mentioned "C 3-7In addition to the specific examples of "cycloalkyl", cyclooctyl, cyclononyl, cyclodecyl, adamantyl, etc. are included.

[0053] The term "4-11-membered saturated heterocycle" refers to a monocyclic or bicyclic saturated heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur atoms, and includes those having partially unsaturated bonds and those with bridged structures. The "4-11-membered saturated heterocycle" is preferably a "4-8-membered saturated heterocycle," more preferably a "5-8-membered saturated heterocycle," and even more preferably a "5-7-membered saturated heterocycle." Specific examples of the "4-8-membered saturated heterocycle" include an azetidine ring, a pyrrolidine ring, a piperidine ring, an azepane ring, an azocane ring, a morpholine ring, a piperazine ring, an oxazocane ring, an azabicycloheptane ring, an azabicyclooctane ring, an oxetane ring, a thietane ring, a tetrahydrofuran ring, a tetrahydrothiophene ring, a tetrahydropyran ring, a thiomorpholine ring, and a 1,4-dioxane ring. Specific examples of the "4-11-membered saturated heterocycle" include, in addition to the specific examples of the "4-8-membered saturated heterocycle", an azonane ring, an oxazonane ring, an azecane ring, an oxazecane ring, an azacycloundecane ring, an azabicyclononane ring, an azabicyclodecane ring, and the like.

[0054] The term "3- to 8-membered saturated carbocyclic ring" refers to a monocyclic or bicyclic saturated aliphatic carbocyclic ring, including those having a partial unsaturated bond and those having a bridged structure. A "3- to 8-membered saturated carbocyclic ring" is preferably a "4- to 8-membered saturated carbocyclic ring," more preferably a "5- to 8-membered saturated carbocyclic ring," and even more preferably a "5- to 7-membered saturated carbocyclic ring." Specific examples of a "3- to 8-membered saturated heterocyclic ring" include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, and bicycloheptane.

[0055] In the structural formula (1), A 1 , A 2 and L 1The tricyclic heterocycle formed by containing the following represents a chemically stable heterocycle, and includes one having a partial unsaturated bond. The tricyclic heterocycle is preferably a structure shown below. [ka]

[0056] "R 2 and R 3 "R" and "R 3 and R 4 together with the nitrogen atom to which it is bonded," and "R 2 , R 3 and any carbon atom on a saturated heterocycle consisting of a nitrogen atom and R 4 "A 4-11-membered saturated heterocyclic ring formed by combining R means a monocyclic or bicyclic saturated heterocyclic ring containing one or more heteroatoms other than the nitrogen atom as ring-constituting atoms, and includes those having a partially unsaturated bond and those having a bridged structure. 2 and R 3 "R" and "R 3 and R 4 together with the nitrogen atom to which it is bonded," and "R 2 , R 3 and any carbon atom on a saturated heterocycle consisting of a nitrogen atom and R 4are taken together" is preferably a "4-8-membered saturated heterocycle". Specific examples of the "4-8-membered saturated heterocycle" include an azetidine ring, a pyrrolidine ring, a piperidine ring, an azepane ring, an azocane ring, a morpholine ring, a piperazine ring, an oxazocane ring, an azabicycloheptane ring, and an azabicyclooctane ring. Specific examples of the "4-11-membered saturated heterocycle" include, in addition to the specific examples of the "4-8-membered saturated heterocycle", an azonane ring, an oxazonane ring, an azecane ring, an oxazecane ring, an azacycloundecane ring, an azabicyclononane ring, and an azabicyclodecane ring. Z is -OR 7 In the case of "R 4 and R 7 "5-11-membered saturated heterocyclic ring formed by the carbon atoms and oxygen atoms to which they are bonded" means a monocyclic or bicyclic saturated heterocyclic ring containing one or more heteroatoms other than the oxygen atom as ring-constituting atoms, and includes those having a partially unsaturated bond and those having a bridged structure. 4 and R 7 are bonded together with the carbon atom and oxygen atom to which they are bonded," a preferred example is a "5-8-membered saturated heterocycle." Specific examples of the "5-8-membered saturated heterocycle" include a tetrahydrofuran ring, a tetrahydropyran ring, an oxepane ring, and an oxocane ring. Specific examples of the "5-11-membered saturated heterocycle" include an oxonane ring, an oxecane ring, and an oxacycloundecane ring in addition to the specific examples of the "5-8-membered saturated heterocycle."

[0057] In this specification, for example, a bond of a substituent written across a pyrrolidine ring represented by the following formula (W) means that one substituent is substituted at any substitutable position on the pyrrolidine ring. Specifically, compounds represented by the following formula (W-1) or (W-2) are included in the compounds represented by the following formula (W). [ka]

[0058] In the compound represented by formula (1), A 1 , A 2 , L 1 , L 2 , R A1 , R A2 , R B , R C , R D , R E , R F , R 1 , R 2 , R 3 , R 4 ,X,l,m,n,Z,R 7 , p, q, t, R G The definitions and preferred ranges of each of the above are as follows, but the technical scope of the present invention is not limited to the range of the compounds listed below.

[0059] A 1 is an oxygen atom or a nitrogen atom (=N-), preferably an oxygen atom.

[0060] A 2 is CR B , C.R. C R D , an oxygen atom or NR A1 and preferably CR C R D or an oxygen atom, more preferably a methylene or oxygen atom.

[0061] L 1 represents optionally substituted methylene, optionally substituted ethylene, optionally substituted methine, optionally substituted ethanediylidene or =N-, preferably methylene.

[0062] L 2 may be substituted C 1-4 It is alkylene, preferably methylene, ethylene or propylene, more preferably methylene or ethylene.

[0063] RA1 , R A2 , R B , R C and R D is a hydrogen atom or an optionally substituted C 1-6 It is alkyl, preferably a hydrogen atom.

[0064] R E and R G may be substituted C 1-6 It is alkyl, preferably methyl.

[0065] R F represents a hydrogen atom, a halogen atom, or an optionally substituted C 1-6 alkyl, preferably a hydrogen atom or an optionally substituted C 1-6 It is alkyl.

[0066] R 1 represents a hydrogen atom, a halogen atom, or an optionally substituted C 1-6 It is alkyl, preferably a hydrogen atom or a halogen atom, more preferably a hydrogen atom.

[0067] R 2 is a hydrogen atom, optionally substituted C 1-6 Alkyl, C(O)-R E , C 3-10 Cycloalkyl, C 2-6 Alkynyl or a 4- to 11-membered saturated heterocyclic ring, preferably a hydrogen atom, optionally substituted C 1-6 Alkyl or C 3-10 cycloalkyl, more preferably a hydrogen atom or an optionally substituted C 1-6 It is alkyl.

[0068] R 3 is a hydrogen atom, optionally substituted C 1-6 Alkyl or C(O)-R E and preferably a hydrogen atom or an optionally substituted C 1-6 It is alkyl.

[0069] R 4 may be substituted C 1-6 alkyl, preferably optionally substituted C 1-4 It is alkyl, more preferably methyl or ethyl.

[0070] X is a carbon atom or a nitrogen atom, preferably a carbon atom.

[0071] l, m, p and q are 1, 2 or 3, preferably 1 or 2.

[0072] n and t are 1, 2, 3 or 4, preferably 1 or 2.

[0073] Z is -NR 2 R 3 -OR 7 and Z is -NR 2 R 3 When R 2 and R 3 together with the nitrogen atom to which they are attached form an optionally substituted 4- to 8-membered saturated heterocyclic ring, or R 3 and R 4 together with the nitrogen atom and carbon atom to which they are attached form an optionally substituted 4-8 membered saturated heterocyclic ring, and Z is -OR 7 When R 7 may be substituted C 1-6 Alkyl, or R 4 and optionally substituted C 1-7 alkylene, preferably optionally substituted methylene or optionally substituted ethylene, 4 and R 7 together with the carbon atom and oxygen atom to which each is attached form an optionally substituted 5-8 membered saturated heterocyclic ring.

[0074] As used herein, "optionally substituted C 1-6When "alkyl" is substituted, the substituents include a halogen atom, a hydroxyl group (the hydroxyl group may be substituted with a protecting group for the hydroxyl group), an optionally substituted C 3-10 Cycloalkyl and optionally substituted C 1-6 Alkoxy, C 2-6 Alkynyl group, nitrile, C 1-6 Alkoxycarbonyl, formyl and 4-11 membered saturated heterocyclic rings (the saturated heterocyclic rings are optionally substituted C 1-6 The aryl group may be substituted with one or more substituents selected from the group consisting of alkyl, halogen, and nitrogen-protecting groups, and is substituted at any substitutable position. The number of such substituents is preferably 1 to 5, and more preferably 1 to 3. When substituted with two or more substituents, the respective substituents may be the same or different.

[0075] As used herein, "optionally substituted C 3-10 When "cycloalkyl" is substituted, the substituents are halogen atoms, hydroxy, C 1-6 Alkyl, C 1-6 Alkoxy and C 3-10 The substituents are one or more selected from the group consisting of cycloalkyl groups, and are substituted at any substitutable position. The number of the substituents is preferably 1 to 5, more preferably 1 to 3. When substituted with two or more substituents, the respective substituents may be the same or different.

[0076] As used herein, "optionally substituted C 1-6 When "alkoxy" is substituted, the substituents include halogen atoms, hydroxy, C 1-6 Alkyl, C 1-6 Alkoxy and C 3-8 The substituents are one or more selected from the group consisting of cycloalkyl groups, and are substituted at any substitutable position. The number of the substituents is preferably 1 to 5, more preferably 1 to 3. When substituted with two or more substituents, the respective substituents may be the same or different.

[0077] As used herein, "optionally substituted C 1-7 alkylene," "optionally substituted C 1-4 "Alkylene" and "Optionally substituted C 1-3 When "alkylene" is substituted, the substituents are a halogen atom, hydroxy, C optionally substituted with a halogen atom or hydroxy. 1-6 alkyl (the hydroxy may be substituted with a hydroxy-protecting group), C 1-6 Alkoxy, C 3-8 Cycloalkyl groups, nitriles, C 1-6 Alkoxycarbonyl, Formyl, C 2-6 Alkynyl group, oxo group and 4-11 membered saturated heterocyclic ring (the saturated heterocyclic ring is optionally substituted C 1-6 and optionally substituted with an alkyl, halogen atom, or nitrogen atom-protecting group. These are one or more substituents selected from the group consisting of (a) and (b), and are substituted at any substitutable position. The number of such substituents is preferably 1 to 5, and more preferably 1 to 3. When substituted with two or more substituents, the respective substituents may be the same or different, and two substituents on the same carbon atom may, together with the carbon atoms to which they are attached, form a spiro ring consisting of a 4- to 8-membered saturated heterocycle or a 3- to 8-membered saturated carbocycle.

[0078] In the present specification, when "optionally substituted ethylene" is substituted, examples of the substituent include C 1-6 Alkyl (the hydroxy may be substituted with a hydroxy protecting group), nitrile, C 1-6 Alkoxycarbonyl, Formyl, C 2-6 Alkynyl groups and 4-11 membered saturated heterocyclic rings (the saturated heterocyclic rings are optionally substituted C 1-6It may be substituted with an alkyl, a halogen atom, or a nitrogen atom-protecting group. It is one or more substituents selected from the group consisting of an alkyl group, a halogen atom, and an oxo group, and is substituted at any substitutable position. The number of such substituents is preferably 1 to 4. When substituted with two or more substituents, the respective substituents may be the same or different, and two substituents on the same carbon atom may, together with the carbon atoms to which they are attached, form a spiro ring consisting of a 4- to 8-membered saturated heterocycle or a 3- to 8-membered saturated carbocycle.

[0079] In the present specification, when "optionally substituted methylene", "optionally substituted methine" and "optionally substituted ethanediylidene" are substituted, examples of the substituent include C optionally substituted with a halogen atom or hydroxy. 1-6 Alkyl (the hydroxy may be substituted with a hydroxy protecting group), nitrile, C 1-6 Alkoxycarbonyl, Formyl, C 2-6 Alkynyl group, oxo group and 4-11 membered saturated heterocyclic ring (the saturated heterocyclic ring is optionally substituted C 1-6 and optionally substituted with an alkyl, halogen atom, or nitrogen atom-protecting group.) and are substituted at any substitutable position. The number of such substituents is preferably 1 to 4. When substituted with two or more substituents, the respective substituents may be the same or different, and two substituents on the same carbon atom may, together with the carbon atoms to which they are attached, form a spiro ring consisting of a 4- to 8-membered saturated heterocycle or a 3- to 8-membered saturated carbocycle.

[0080] In the present specification, examples of the substituents that the "optionally substituted 4- to 11-membered saturated heterocyclic ring", the "optionally substituted 4- to 8-membered saturated heterocyclic ring", the "optionally substituted 5- to 8-membered saturated heterocyclic ring" and the "optionally substituted 5- to 11-membered saturated heterocyclic ring" may have include a halogen atom, hydroxy, a C 1-6 alkyl (the hydroxy may be substituted with a hydroxy-protecting group), C 1-6 Alkoxy, C3-8 Cycloalkyl, nitrile, C 1-6 Alkoxycarbonyl, Formyl, C 2-6 Alkynyl group, oxo group and 4-11 membered saturated heterocyclic ring (the saturated heterocyclic ring is optionally substituted C 1-6 and optionally substituted with an alkyl, halogen atom, or nitrogen atom-protecting group. These are one or more substituents selected from the group consisting of: (a) a substituted alkyl group, (b) a substituted halogen atom, (c) a substituted aryl group, (d) a substituted aryl group, (e) a substituted aryl group, (f) a substituted aryl group, (g) a substituted aryl group, (h) a substituted aryl group, (i) a substituted aryl group, (j ...

[0081] Among the compounds represented by formula (1), preferred compounds include the following compounds or pharmaceutically acceptable salts thereof:

[0082] A 1 is an oxygen atom, and A 2 is methylene, and L 1 is methylene, and L 2 optionally substituted C 1-4 alkylene, X is a carbon atom, and R 1 is a hydrogen atom, and R 2 , R 3 and R 4 optionally substituted C 1-6 A compound that is alkyl.

[0083] A 1 is an oxygen atom, and A 2 is methylene, and L 1 is methylene, and L 2 is methylene or ethylene, X is a carbon atom, and R 1 is a hydrogen atom, and R 2 and R 3 optionally substituted C 1-6 alkyl, and R4 is methyl or ethyl.

[0084] A 1 is an oxygen atom, and A 2 is methylene, and L 1 is methylene, and L 2 optionally substituted C 1-4 alkylene, X is a carbon atom, and R 1 is a hydrogen atom, and R 2 and R 3 together with the nitrogen atom to which it is attached form an optionally substituted 4- to 11-membered saturated heterocyclic ring, and R 4 optionally substituted C 1-6 A compound that is alkyl.

[0085] A 1 is an oxygen atom, and A 2 is methylene, and L 1 is methylene, and L 2 is methylene or ethylene, X is a carbon atom, and R 1 is a hydrogen atom, and R 2 and R 3 together with the nitrogen atom to which it is attached form an optionally substituted 4- to 8-membered saturated heterocyclic ring, and R 4 is methyl or ethyl.

[0086] A 1 is an oxygen atom, and A 2 is methylene, and L 1 is methylene, X is a carbon atom, and R 1 is a hydrogen atom, and R 2 is a hydrogen atom or an optionally substituted C 1-6 alkyl, and R 3 and R 4 together with the nitrogen atom and carbon atom to which they are attached to form an optionally substituted 4-11 membered saturated heterocyclic ring.

[0087] A 1 is an oxygen atom, and A 2 is methylene, and L1 is methylene, X is a carbon atom, and R 1 is a hydrogen atom, and R 2 optionally substituted C 1-6 alkyl, and R 3 and R 4 together with the nitrogen atom and carbon atom to which they are attached to form an optionally substituted 4-8 membered saturated heterocyclic ring.

[0088] A 1 and A 2 is an oxygen atom, and L 1 is methylene or ethylene, X is a carbon atom, and R 1 is a hydrogen atom, and L 2 optionally substituted C 1-4 alkylene, and R 2 , R 3 and R 4 optionally substituted C 1-6 A compound that is alkyl.

[0089] A 1 and A 2 is an oxygen atom, and L 1 is methylene or ethylene, X is a carbon atom, and L 2 optionally substituted C 1-4 alkylene, and R 1 is a hydrogen atom, and R 2 and R 3 together with the nitrogen atom to which it is attached form an optionally substituted 4- to 11-membered saturated heterocyclic ring, and R 4 optionally substituted C 1-6 A compound that is alkyl.

[0090] A 1 and A 2 is an oxygen atom, and L 1 is methylene or ethylene, X is a carbon atom, and R 1 is a hydrogen atom, and R 2 is a hydrogen atom or an optionally substituted C 1-6 alkyl, and R 3 and R4 together with the nitrogen atom and carbon atom to which they are attached to form an optionally substituted 4-11 membered saturated heterocyclic ring.

[0091] A 1 is an oxygen atom, and A 2 is methylene, and L 1 is methylene or ethylene, and L 2 optionally substituted C 1-4 alkylene, X is a carbon atom, and R 1 is a hydrogen atom and Z is -OR 7 and R 7 R 4 and optionally substituted C 1-7 alkylene, R 4 and R 7 are taken together with the carbon and oxygen atoms to which they are attached to form an optionally substituted 5-11 membered saturated heterocyclic ring.

[0092] A 1 is an oxygen atom, and A 2 is methylene, and L 1 is methylene or ethylene, and L 2 is methylene or ethylene, X is a carbon atom, and R 1 is a hydrogen atom and Z is -OR 7 and R 7 R 4 and optionally substituted C 1-7 alkylene, R 4 and R 7 are taken together with the carbon and oxygen atoms to which they are attached to form an optionally substituted 5-11 membered saturated heterocyclic ring.

[0093] A 1 and A 2 is an oxygen atom, and L 1 is methylene or ethylene, and L 2 optionally substituted C 1-4 alkylene, X is a carbon atom, and R 1is a hydrogen atom and Z is -OR 7 and R 7 R 4 and optionally substituted C 1-7 alkylene, R 4 and R 7 are taken together with the carbon and oxygen atoms to which they are attached to form an optionally substituted 5-11 membered saturated heterocyclic ring.

[0094] A 1 and A 2 is an oxygen atom, and L 1 is methylene or ethylene, and L 2 is methylene or ethylene, X is a carbon atom, and R 1 is a hydrogen atom and Z is -OR 7 and R 7 R 4 and optionally substituted C 1-7 alkylene, R 4 and R 7 are taken together with the carbon and oxygen atoms to which they are attached to form an optionally substituted 5-11 membered saturated heterocyclic ring.

[0095] Of the compounds represented by formula (1), preferred compounds specifically include the following compounds or pharmaceutically acceptable salts thereof:

[0096] cis-3-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-5-methyloctahydro-2H-imidazo[4,5-c]pyridin-2-one (Example 7); cis-3-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-5-(2-methoxyethyl)octahydro-2H-imidazo[4,5-c]pyridin-2-one (Example 8); cis-1-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-5-methyloctahydro-2H-imidazo[4,5-c]pyridin-2-one (Example 9); cis-3-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-5-ethyloctahydro-2H-imidazo[4,5-c]pyridin-2-one (Example 11); cis-1-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-5-methylhexahydropyrrolo[3,4-d]imidazol-2(1H)-one (Example 14); cis-3-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-5-(propan-2-yl)octahydro-2H-imidazo[4,5-c]pyridin-2-one (Example 15); cis-3-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-5-methyloctahydroimidazo[4,5-c]azepin-2(1H)-one (Example 17); (3aS,7aS)-3-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-5-(oxetan-3-yl)octahydro-2H-imidazo[4,5-c]pyridin-2-one (Example 19); (3aR,7aR)-1-(2H-[1,3]dioxolo[4,5-e][1,3]benzothiazol-7-yl)hexahydropyrano[3,4-d]imidazol-2(3H)-one (Example 21); (4S,5R)-1-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-4-methyl-5-[(morpholin-4-yl)methyl]imidazolidin-2-one (Example 23); (4R,5R)-1-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-4-methyl-5-[(morpholin-4-yl)methyl]imidazolidin-2-one (Example 24); (3aR,7aS)-3-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-5-methyloctahydro-2H-imidazo[4,5-c]pyridin-2-one (Example 28); (3aR,7aS)-5-cyclopropyl-3-(7,8-dihydro[1,4]dioxino[2,3-e][1,3]benzothiazol-2-yl)octahydro-2H-imidazo[4,5-c]pyridin-2-one (Example 34); (3aR,7aS)-5-cyclopropyl-3-(2H-[1,3]dioxolo[4,5-e][1,3]benzothiazol-7-yl)octahydro-2H-imidazo[4,5-c]pyridin-2-one (Example 36); (3aR,7aR)-1-(7,8-dihydro[1,4]dioxino[2,3-e][1,3]benzothiazol-2-yl)hexahydropyrano[3,4-d]imidazol-2(3H)-one (Example 37); (3aR,6S,7aR)-1-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-6-methylhexahydropyrano[3,4-d]imidazol-2(3H)-one (Example 38); (3aR,6S,7aR)-1-(7,8-dihydro[1,4]dioxino[2,3-e][1,3]benzothiazol-2-yl)-6-methylhexahydropyrano[3,4-d]imidazol-2(3H)-one (Example 39); (3aR,6R,7aR)-1-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-6-(fluoromethyl)hexahydropyrano[3,4-d]imidazol-2(3H)-one (Example 40); (3aR,6R,7aR)-1-(7,8-dihydro[1,4]dioxino[2,3-e][1,3]benzothiazol-2-yl)-6-(fluoromethyl)hexahydropyrano[3,4-d]imidazol-2(3H)-one (Example 41); (3aR,6S,7aR)-1-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-6-ethylhexahydropyrano[3,4-d]imidazol-2(3H)-one (Example 42); (3aR,6S,7aR)-1-(7,8-dihydro[1,4]dioxino[2,3-e][1,3]benzothiazol-2-yl)-6-ethylhexahydropyrano[3,4-d]imidazol-2(3H)-one (Example 43); (4S,5S)-1-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-5-(methoxymethyl)-4-methylimidazolidin-2-one (Example 44); (3aR,6aS)-1-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)tetrahydro-1H-furo[3,4-d]imidazol-2(3H)-one (Example 65); rac-(3aR,7aS)-3-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-5-(oxetan-3-yl)octahydro-2H-imidazo[4,5-c]pyridin-2-one (Example 71); rac-(3aR,7aS)-5-cyclobutyl-3-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)octahydro-2H-imidazo[4,5-c]pyridin-2-one (Example 72); rac-(3aR,8aS)-3-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-5-(oxetan-3-yl)octahydroimidazo[4,5-c]azepin-2(1H)-one (Example 73); rac-(3aR,7aS)-3-(7,8-dihydro[1,4]dioxino[2,3-e][1,3]benzothiazol-2-yl)-5-methyloctahydro-2H-imidazo[4,5-c]pyridin-2-one (Example 76); rac-(3aR,7aS)-1-(7,8-dihydro[1,4]dioxino[2,3-e][1,3]benzothiazol-2-yl)-5-methyloctahydro-2H-imidazo[4,5-c]pyridin-2-one (Example 77); rac-(3aR,7aS)-1-(2H-[1,3]dioxolo[4,5-e][1,3]benzothiazol-7-yl)-5-methyloctahydro-2H-imidazo[4,5-c]pyridin-2-one (Example 78); rac-(3aR,7aS)-3-(2H-[1,3]dioxolo[4,5-e][1,3]benzothiazol-7-yl)-5-methyloctahydro-2H-imidazo[4,5-c]pyridin-2-one (Example 79); rac-(3aR,7aS)-3-(7,8-dihydro[1,4]dioxino[2,3-e][1,3]benzothiazol-2-yl)-5-(oxetan-3-yl)octahydro-2H-imidazo[4,5-c]pyridin-2-one (Example 80); rac-(3aR,7aS)-3-(2H-[1,3]dioxolo[4,5-e][1,3]benzothiazol-7-yl)-5-(oxetan-3-yl)octahydro-2H-imidazo[4,5-c]pyridin-2-one (Example 81); rac-(3aR,8aS)-3-(2H-[1,3]dioxolo[4,5-e][1,3]benzothiazol-7-yl)-5-methyloctahydroimidazo[4,5-c]azepin-2(1H)-one (Example 85); rac-(3aR,8aS)-3-(2H-[1,3]dioxolo[4,5-e][1,3]benzothiazol-7-yl)-5-(oxetan-3-yl)octahydroimidazo[4,5-c]azepin-2(1H)-one (Example 86); (3aS,6S,7aR)-1-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-5,6-dimethyloctahydro-2H-imidazo[4,5-c]pyridin-2-one (Example 93); rac-(3aR,7aS)-5-cyclopropyl-3-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)octahydro-2H-imidazo[4,5-c]pyridin-2-one (Example 98); rac-(3aR,7aS)-3-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-5-(2-propyn-1-yl)octahydro-2H-imidazo[4,5-c]pyridin-2-one (Example 99); rac-[(3aR,7aS)-3-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-2-oxooctahydro-5H-imidazo[4,5-c]pyridin-5-yl]acetonitrile (Example 100); rac-(3aR,6aS)-1-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-5-(2-propyn-1-yl)hexahydropyrrolo[3,4-d]imidazol-2(1H)-one (Example 102); rac-[(3aR,6aS)-1-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-2-oxohexahydropyrrolo[3,4-d]imidazol-5(1H)-yl]acetonitrile (Example 103); rac-(3aR,8aS)-5-cyclopropyl-3-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)octahydroimidazo[4,5-c]azepin-2(1H)-one (Example 104); rac-(3aR,8aS)-3-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-5-(2-propyn-1-yl)octahydroimidazo[4,5-c]azepin-2(1H)-one (Example 105); rac-[(3aR,8aS)-3-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-2-oxooctahydroimidazo[4,5-c]azepin-5(1H)-yl]acetonitrile (Example 106); rac-(3aR,7aS)-3-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-5-(2,2,2-trifluoroethyl)octahydro-2H-imidazo[4,5-c]pyridin-2-one (Example 107); rac-(3aR,7aS)-5-(2,2-difluoroethyl)-3-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)octahydro-2H-imidazo[4,5-c]pyridin-2-one (Example 108); (3aR,7aS)-5-cyclopropyl-3-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)octahydro-2H-imidazo[4,5-c]pyridin-2-one (Example 110); [(3aR,7aS)-3-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-2-oxooctahydro-5H-imidazo[4,5-c]pyridin-5-yl]acetonitrile (Example 112); (3aR,7aS)-3-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-5-(2-propyn-1-yl)octahydro-2H-imidazo[4,5-c]pyridin-2-one (Example 114); (4S,5R)-1-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-5-{[(3S)-3-fluoropyrrolidin-1-yl]methyl}-4-methylimidazolidin-2-one (Example 115); (4S,5R)-5-[(3,3-difluoroazetidin-1-yl)methyl]-1-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-4-methylimidazolidin-2-one (Example 116); (4S,5R)-5-[(3,3-difluoropyrrolidin-1-yl)methyl]-1-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-4-methylimidazolidin-2-one (Example 117); (4S,5R)-1-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-5-[(3-fluoroazetidin-1-yl)methyl]-4-methylimidazolidin-2-one (Example 118); rac-(3aR,7aR)-3-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)hexahydropyrano[3,4-d]imidazol-2(3H)-one (Example 120); rac-(3aR,7aR)-1-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)hexahydropyrano[3,4-d]imidazol-2(3H)-one (Example 121); (3aR,7aR)-1-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)hexahydropyrano[3,4-d]imidazol-2(3H)-one (Example 122); (3aR,7aR)-1-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-6,6-dimethylhexahydropyrano[3,4-d]imidazol-2(3H)-one (Example 124); (3aR,6R,7aR)-1-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-2-oxooctahydropyrano[3,4-d]imidazole-6-carbonitrile (Example 127); (3aR,6R,7aR)-1-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-6-methoxyhexahydropyrano[3,4-d]imidazol-2(3H)-one (Example 129); (3aR,6R,7aR)-1-(2H-[1,3]dioxolo[4,5-e][1,3]benzothiazol-7-yl)-2-oxooctahydropyrano[3,4-d]imidazole-6-carbonitrile (Example 131); (3aR,6R,7aR)-1-(7,8-dihydro[1,4]dioxino[2,3-e][1,3]benzothiazol-2-yl)-2-oxooctahydropyrano[3,4-d]imidazole-6-carbonitrile (Example 133); (3aR,8aR)-1-(7,8-dihydro[1,4]dioxino[2,3-e][1,3]benzothiazol-2-yl)hexahydro-1H-oxepino[3,4-d]imidazol-2(3H)-one (Example 135); (3aR,6S,7aR)-1-(2H-[1,3]dioxolo[4,5-e][1,3]benzothiazol-7-yl)-6-ethylhexahydropyrano[3,4-d]imidazol-2(3H)-one (Example 138); (3aR,6S,7aR)-1-(2H-[1,3]dioxolo[4,5-e][1,3]benzothiazol-7-yl]-6-methylhexahydropyrano[3,4-d]imidazol-2(3H)-one (Example 139); (3aR,6R,7aR)-1-(2H-[1,3]dioxolo[4,5-e][1,3]benzothiazol-7-yl]-6-(fluoromethyl)hexahydropyrano[3,4-d]imidazol-2(3H)-one (Example 140); (3aR,6R,7aR)-1-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-6-(hydroxymethyl)hexahydropyrano[3,4-d]imidazol-2(3H)-one (Example 144); (3aR,6R,7aR)-1-(7,8-dihydro[1,4]dioxino[2,3-e][1,3]benzothiazol-2-yl)-6-(hydroxymethyl)hexahydropyrano[3,4-d]imidazol-2(3H)-one (Example 146); (3aR,6R,7aR)-1-(2H-[1,3]dioxolo[4,5-e][1,3]benzothiazol-7-yl)-6-(hydroxymethyl)hexahydropyrano[3,4-d]imidazol-2(3H)-one (Example 147); (3aR,6R,7aR)-1-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-6-ethynylhexahydropyrano[3,4-d]imidazol-2(3H)-one (Example 149); (3aR,7aR)-1-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-6-fluorohexahydropyrano[3,4-d]imidazol-2(3H)-one (Example 151); (3aR,6S,6aS)-1-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-6-(hydroxymethyl)tetrahydro-1H-furo[3,4-d]imidazol-2(3H)-one (Example 157); (3aR,6S,6aS)-1-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-6-(fluoromethyl)tetrahydro-1H-furo[3,4-d]imidazol-2(3H)-one (Example 159); (3aR,6R,6aS)-1-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-6-methyltetrahydro-1H-furo[3,4-d]imidazol-2(3H)-one (Example 161); and [(3aS,4R,6aR)-3-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-2-oxohexahydro-1H-furo[3,4-d]imidazol-4-yl]acetonitrile (Example 162).

[0097] Among the compounds represented by formula (1), more preferred compounds include the following compounds or pharmaceutically acceptable salts thereof:

[0098] (3aR,7aR)-1-(2H-[1,3]dioxolo[4,5-e][1,3]benzothiazol-7-yl)hexahydropyrano[3,4-d]imidazol-2(3H)-one (Example 21); (4S,5R)-1-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-4-methyl-5-[(morpholin-4-yl)methyl]imidazolidin-2-one (Example 23); (3aR,7aS)-5-cyclopropyl-3-(7,8-dihydro[1,4]dioxino[2,3-e][1,3]benzothiazol-2-yl)octahydro-2H-imidazo[4,5-c]pyridin-2-one (Example 34); (3aR,7aS)-5-cyclopropyl-3-(2H-[1,3]dioxolo[4,5-e][1,3]benzothiazol-7-yl)octahydro-2H-imidazo[4,5-c]pyridin-2-one (Example 36); (3aR,7aR)-1-(7,8-dihydro[1,4]dioxino[2,3-e][1,3]benzothiazol-2-yl)hexahydropyrano[3,4-d]imidazol-2(3H)-one (Example 37); (3aR,6S,7aR)-1-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-6-methylhexahydropyrano[3,4-d]imidazol-2(3H)-one (Example 38); (3aR,6S,7aR)-1-(7,8-dihydro[1,4]dioxino[2,3-e][1,3]benzothiazol-2-yl)-6-methylhexahydropyrano[3,4-d]imidazol-2(3H)-one (Example 39); (3aR,6R,7aR)-1-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-6-(fluoromethyl)hexahydropyrano[3,4-d]imidazol-2(3H)-one (Example 40); (3aR,6R,7aR)-1-(7,8-dihydro[1,4]dioxino[2,3-e][1,3]benzothiazol-2-yl)-6-(fluoromethyl)hexahydropyrano[3,4-d]imidazol-2(3H)-one (Example 41); (3aR,6S,7aR)-1-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-6-ethylhexahydropyrano[3,4-d]imidazol-2(3H)-one (Example 42); (3aR,6S,7aR)-1-(7,8-dihydro[1,4]dioxino[2,3-e][1,3]benzothiazol-2-yl)-6-ethylhexahydropyrano[3,4-d]imidazol-2(3H)-one (Example 43); (4S,5S)-1-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-5-(methoxymethyl)-4-methylimidazolidin-2-one (Example 44); rac-(3aR,8aS)-3-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-5-(oxetan-3-yl)octahydroimidazo[4,5-c]azepin-2(1H)-one (Example 73); rac-(3aR,7aS)-5-cyclopropyl-3-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)octahydro-2H-imidazo[4,5-c]pyridin-2-one (Example 98); rac-(3aR,8aS)-5-cyclopropyl-3-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)octahydroimidazo[4,5-c]azepin-2(1H)-one (Example 104); (3aR,7aS)-5-cyclopropyl-3-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)octahydro-2H-imidazo[4,5-c]pyridin-2-one (Example 110); [(3aR,7aS)-3-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-2-oxooctahydro-5H-imidazo[4,5-c]pyridin-5-yl]acetonitrile (Example 112); (3aR,7aS)-3-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-5-(2-propyn-1-yl)octahydro-2H-imidazo[4,5-c]pyridin-2-one (Example 114); (3aR,7aR)-1-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)hexahydropyrano[3,4-d]imidazol-2(3H)-one (Example 122); (3aR,7aR)-1-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-6,6-dimethylhexahydropyrano[3,4-d]imidazol-2(3H)-one (Example 124); (3aR,6R,7aR)-1-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-2-oxooctahydropyrano[3,4-d]imidazole-6-carbonitrile (Example 127); (3aR,6R,7aR)-1-(2H-[1,3]dioxolo[4,5-e][1,3]benzothiazol-7-yl)-2-oxooctahydropyrano[3,4-d]imidazole-6-carbonitrile (Example 131); (3aR,6R,7aR)-1-(7,8-dihydro[1,4]dioxino[2,3-e][1,3]benzothiazol-2-yl)-2-oxooctahydropyrano[3,4-d]imidazole-6-carbonitrile (Example 133); (3aR,6S,7aR)-1-(2H-[1,3]dioxolo[4,5-e][1,3]benzothiazol-7-yl)-6-ethylhexahydropyrano[3,4-d]imidazol-2(3H)-one (Example 138); (3aR,6S,7aR)-1-(2H-[1,3]dioxolo[4,5-e][1,3]benzothiazol-7-yl]-6-methylhexahydropyrano[3,4-d]imidazol-2(3H)-one (Example 139); (3aR,6R,7aR)-1-(2H-[1,3]dioxolo[4,5-e][1,3]benzothiazol-7-yl]-6-(fluoromethyl)hexahydropyrano[3,4-d]imidazol-2(3H)-one (Example 140) (3aR,6R,7aR)-1-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-6-ethynylhexahydropyrano[3,4-d]imidazol-2(3H)-one (Example 149); and (3aR,7aR)-1-(7,8-Dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-6-fluorohexahydropyrano[3,4-d]imidazol-2(3H)-one (Example 151).

[0099] The production method of the compound represented by formula (1) of the present invention will be explained below with examples, but the present invention is not limited to these.

[0100] The compound represented by formula (1) can be synthesized by the following production method or a method combining a known compound and a known synthesis method. The compounds in the reaction schemes may each form a salt, and examples of such salts include the same as those of compound (1). Note that these reactions are merely illustrative, and compounds may also be produced by other appropriate methods based on the knowledge of those skilled in organic synthesis.

[0101] In each of the production methods described below, even if the use of a protecting group is not specifically specified, when a functional group that requires protection is present, the functional group may be protected as necessary, and the target product may be obtained by deprotecting the functional group after completion of the reaction or after performing a series of reactions.

[0102] Examples of the protecting group include ordinary protecting groups described in the literature (T.W. Greene and P.G.M. Buts, "Protective Groups in Organic Synthesis," 3rd Ed., John Wiley and Sons, Inc., New York (1999)). More specifically, examples of protecting groups for amino groups include tert-butoxycarbonyl, benzyloxycarbonyl, dimethylformamide, p-toluenesulfonyl, o-nitrobenzenesulfonyl, and tetrahydropyranyl. Examples of protecting groups for hydroxy groups include trialkylsilyl, acetyl, benzyl, tetrahydropyranyl, and methoxymethyl. Examples of protecting groups for aldehyde groups include dialkyl acetals and cyclic alkyl acetals. Examples of protecting groups for carboxyl groups include tert-butyl esters, orthoesters, and acid amides. Compounds in which these functional groups are protected are also included in the compounds of the formula (1).

[0103] Introduction and removal of a protecting group can be carried out by a method commonly used in organic synthetic chemistry (e.g., the method described in T.W. Greene and P.G.M. Butts, "Protective Groups in Organic Synthesis", 3rd Ed., John Wiley and Sons, Inc., New York (1999)) or a method similar thereto.

[0104] Manufacturing method 1 The compound represented by formula (1-9) can be produced, for example, by the method shown below. [ka] [In the formula, R 1 , R 2 , R 3 , R 4 , A 1 , A 2 , L 1 , L 2 , R E , X is as defined in the above item 1; R 2a , R 3a may be substituted C 1-6 R represents alkyl; 5 may be substituted C 1-5 LG represents a leaving group (e.g., an iodine atom, a bromine atom, a chlorine atom, an -O-substituted sulfonyl group (e.g., a methanesulfonyl group, a p-toluenesulfonyl group, etc.)), and PG represents a protecting group (e.g., a tert-butoxycarbonyl group, a benzyloxycarbonyl group, a benzyl group, etc.).

[0105] Step 1-1: Production process of compound (1-3) Compound (1-3) can be obtained by reacting compound (1-1) with compound (1-2) by a method similar to a known synthetic method (e.g., Chemical & Pharmaceutical Bulletin, 1406, (2007), Advanced Synthesis & Catalysis, 1643, (2005), etc.). Compound (1-1) can be produced by a known synthetic method (e.g., Bioorganic & Medicinal Chemistry Letters, 28, (2007), J. Org. Chem. 2613, (1986), etc.) or a synthetic method similar thereto. Compound (1-2) can be a commercially available product or produced by a known synthetic method (e.g., Tetrahedron Letters, 946, (2015), Synlett, 426, (1999), etc.) or a synthetic method similar thereto.

[0106] Step 1-2: Preparation of Compound (1-4) Compound (1-4) is produced by cyclizing compound (1-3) by a method similar to known synthetic methods (for example, Journal of Organic Chemistry, 8693, (2003), WO2013043001, etc.).

[0107] Step 1-3: Preparation of Compound (1-5) Compound (1-5) is produced by cyclizing compound (1-4) by a method similar to known synthetic methods (e.g., Organic Letters, 5136, (2015), Bioorganic & Medicinal Chemistry, 822, (2008), etc.).

[0108] Step 1-4: Preparation of Compound (1-9) Compound (1-9) can be obtained by reacting compound (1-5) with compound (1-6) in an inert solvent, optionally in the presence of a boron hydride compound and an acid. Compound (1-6) can be a commercially available product or can be produced by a known synthesis method (e.g., US200619965, Journal of Medicinal Chemistry, 3680, (2003) etc.) or a synthesis method similar thereto.

[0109] Specific examples of the inert solvent include ether solvents such as tetrahydrofuran, tetrahydropyran, 1,4-dioxane, and 1,2-dimethoxyethane; halogenated hydrocarbons such as chloroform, dichloromethane, and 1,2-dichloroethane; protic polar solvents such as methanol, ethanol, 1-propanol, 2-propanol, and water; and mixed solvents thereof, etc. Preferred are tetrahydrofuran, dichloromethane, chloroform, and methanol.

[0110] Specific examples of the acid include carboxylic acids such as formic acid, propionic acid, acetic acid, and trifluoroacetic acid; and mineral acids such as hydrochloric acid.

[0111] Specific examples of the borohydride compound include sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, etc. Preferred are sodium triacetoxyborohydride and sodium cyanoborohydride.

[0112] The reaction temperature is not particularly limited, but is usually selected within the range of from 0° C. to the boiling point of the solvent used, preferably 0° C. to 20° C. The reaction time is usually 30 minutes to 72 hours.

[0113] Compound (1-9) can also be produced by reacting compound (1-7) with compound (1-5) using a base, optionally in the presence of a halogenating agent, in an inert solvent. Compound (1-7) can be a commercially available product or one produced by a known synthesis method (e.g., US2013 / 1503254, EP1679308, (2006), etc.) or a synthesis method analogous thereto.

[0114] Specific examples of the inert solvent include ether solvents such as tetrahydrofuran, tetrahydropyran, 1,4-dioxane, and 1,2-dimethoxyethane; aromatic hydrocarbons such as toluene, xylene, and pyridine; aprotic polar solvents such as acetonitrile, propionitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, and dimethyl sulfoxide; halogenated hydrocarbons such as chloroform, dichloromethane, and 1,2-dichloroethane; and mixed solvents thereof. Preferred are acetonitrile, N,N-dimethylacetamide, and dimethyl sulfoxide.

[0115] Specific examples of the base include organic bases such as triethylamine, diisopropylethylamine, and pyridine; and inorganic bases such as potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, and sodium hydroxide. Preferred are diisopropylethylamine, potassium carbonate, and cesium carbonate.

[0116] Specific examples of the halogenating agent include inorganic halides such as potassium iodide and sodium iodide; and organic halides such as tetrabutylammonium iodide.

[0117] The reaction temperature is not particularly limited, but is usually selected within the range of from 0° C. to the boiling point of the solvent used, preferably 0° C. to 100° C. The reaction time is usually 30 minutes to 72 hours.

[0118] Compound (1-9) can also be produced by reacting carboxylic acid (1-8) with compound (1-5) using a condensing agent or an acid anhydride corresponding to carboxylic acid (1-8) in the presence of a base and an additive, if necessary, in an inert solvent. Carboxylic acid (1-8) or the corresponding acid anhydride can be a commercially available product or one produced by a known synthetic method (e.g., Journal of Organic Chemistry 2564, (1999), Organic Letters 4739, (2004), etc.) or a synthetic method similar thereto.

[0119] Specific examples of the inert solvent include ether solvents such as tetrahydrofuran, tetrahydropyran, 1,4-dioxane, and 1,2-dimethoxyethane; aromatic hydrocarbons such as toluene, xylene, and pyridine; aprotic polar solvents such as acetonitrile, propionitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, and dimethyl sulfoxide; halogenated hydrocarbons such as chloroform, dichloromethane, and 1,2-dichloroethane; and mixed solvents thereof. Preferred are N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, chloroform, and dichloromethane.

[0120] Specific examples of condensing agents include dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide, benzotriazol-1-yl-tris(dimethylamino)phosphonium hexafluorophosphate, diphenylphosphonyldiamide, N,N-carbonyldiimidazole, O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate.

[0121] Specific examples of additives that can be used in the reaction include N-hydroxysuccinimide, 1-hydroxybenzotriazole, and 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine.

[0122] Specific examples of the base include organic bases such as triethylamine, diisopropylethylamine, and pyridine.

[0123] The reaction temperature is not particularly limited, but is usually selected from the range of about -20°C to the boiling point of the solvent used, preferably 0°C to 20°C. The reaction time is usually 10 minutes to 48 hours.

[0124] Manufacturing method 2 The compound represented by formula (2-7) can be produced, for example, by the method shown below. [ka] [In the formula, R 1 , R 2 , R 3 , R 4 , A 1 , A 2 , L 1 , L 2 X is as defined in the above item 1; LG represents a leaving group (e.g., an iodine atom, a bromine atom, a chlorine atom, an -O-substituted sulfonyl group (e.g., a methanesulfonyl group, a p-toluenesulfonyl group, etc.)); and PG represents a protecting group (e.g., a tert-butoxycarbonyl group, a benzyloxycarbonyl group, a benzyl group, etc.).

[0125] Step 2-1: Production process of compound (2-2) Compound (2-2) is produced using compound (1-1) and compound (2-1) according to the method described in step 1-1. Compound (2-1) can be produced by a known synthesis method (e.g., Chemical Communications 7693, (2015), WO2015061572, etc.) or a synthesis method similar thereto.

[0126] Step 2-2: Preparation of Compound (2-3) Compound (2-3) is produced using compound (2-2) according to the method described in step 1-2.

[0127] Step 2-3: Preparation of Compound (2-4) Compound (2-4) can be produced from compound (2-3) by deprotecting the protecting group and then following the method described in step 1-3.

[0128] Step 2-4: Preparation of Compound (2-5) When LG is a substituted sulfonyl group, compound (2-5) can be obtained by deprotecting compound (2-4) and then reacting with sulfonyl chloride in the presence of a base in an inert solvent.When LG is a halogen, compound (2-4) can be obtained by deprotecting compound (2-4) and then reacting with a halogenating agent in an inert solvent.

[0129] Specific examples of the inert solvent include ether solvents such as tetrahydrofuran, tetrahydropyran, 1,4-dioxane, and 1,2-dimethoxyethane; aromatic hydrocarbons such as toluene and xylene; halogenated hydrocarbons such as chloroform, dichloromethane, and 1,2-dichloroethane; aprotic polar solvents such as acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methyl-2-pyrrolidinone; and mixed solvents thereof. Tetrahydrofuran, chloroform, and dichloromethane are preferred.

[0130] Specific examples of the base include organic bases such as triethylamine, diisopropylethylamine, pyridine, 2,4,6-trimethylpyridine, and 4-dimethylaminopyridine, with triethylamine and diisopropylamine being preferred.

[0131] Specific examples of sulfonyl chloride include methanesulfonyl chloride, monochloromethanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride, o-nitrobenzenesulfonyl chloride, p-nitrobenzenesulfonyl chloride, etc. Methanesulfonyl chloride is preferred.

[0132] Specific examples of the halogenating agent include thionyl chloride, oxalyl dichloride, phosphorus tribromide, etc. Thionyl chloride and phosphorus tribromide are preferred.

[0133] The reaction temperature is not particularly limited, but is usually selected within the range of from −20° C. to the boiling point of the solvent used, preferably 0° C. to 60° C. The reaction time is usually 5 minutes to 24 hours.

[0134] Step 2-5: Preparation of Compound (2-7) Compound (2-7) can be obtained by reacting compound (2-5) with compound (2-6) in an inert solvent in the presence of a base and, if necessary, a halide. Compound (2-6) can be a commercially available product or one produced by a known synthesis method (e.g., WO20073965, US2010216812, etc.) or a synthesis method analogous thereto.

[0135] Specific examples of the inert solvent include ether solvents such as tetrahydrofuran, tetrahydropyran, 1,4-dioxane, and 1,2-dimethoxyethane; halogenated hydrocarbons such as chloroform, dichloromethane, and 1,2-dichloroethane; aprotic polar solvents such as acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, and dimethyl sulfoxide; and mixed solvents thereof, etc. Preferred are acetonitrile, tetrahydrofuran, dichloromethane, and N,N-dimethylformamide.

[0136] Specific examples of the base include organic bases such as triethylamine, diisopropylethylamine, pyridine, 2,4,6-trimethylpyridine, and 4-dimethylaminopyridine; and inorganic bases such as potassium carbonate, sodium carbonate, and cesium carbonate.

[0137] Specific examples of the halide include organic halides such as tetrabutylammonium iodide and tetrabutylammonium bromide; and inorganic halides such as potassium iodide, potassium bromide, sodium iodide and sodium bromide.

[0138] The reaction temperature is not particularly limited, but is usually selected within the range from −20° C. to the boiling point of the solvent used or compound (2-6), preferably 0° C. to 120° C. The reaction time is usually 30 minutes to 72 hours.

[0139] Manufacturing method 3 The compound represented by formula (1-4) can also be produced, for example, by the method shown below. [ka] [In the formula, R 1 , R 2 , R 3 , R 4 , A 1 , A 2 , L 1 , L 2 , X is as defined in the above item 1; R 3a may be substituted C 1-6 LG represents a leaving group (e.g., an iodine atom, a bromine atom, a chlorine atom, an -O-substituted sulfonyl group (e.g., a methanesulfonyl group, a p-toluenesulfonyl group, etc.)), and PG represents a protecting group (e.g., a tert-butoxycarbonyl group, a benzyloxycarbonyl group, a benzyl group, etc.).

[0140] Step 3-1: Preparation of Compound (3-2) Compound (3-2) is produced using compound (1-1) and compound (3-1) according to the method described in step 1-1. Compound (3-1) can be a commercially available product or one produced by a known synthesis method (e.g., WO2008136457, WO2014015905, etc.) or a synthesis method similar thereto.

[0141] Step 3-2: Preparation of Compound (3-3) Compound (3-3) is produced using compound (3-2) according to the method described in step 1-2.

[0142] Step 3-3: Preparation of Compound (3-4) Compound (3-4) is produced using compound (3-3) according to the method described in step 2-4.

[0143] Step 3-4: Preparation of Compound (3-5) Compound (3-5) can be produced by synthesizing compound (3-4) using a method similar to known synthetic methods (e.g., Journal of Medicinal Chemistry 3918, (1995), WO2015177326, etc.).

[0144] Step 3-5: Preparation of Compound (1-4) Compound (1-4) can also be produced by synthesizing compound (3-5) using a method similar to known synthetic methods (e.g., Bioorganic & Medicinal Chemistry Letters 5227 (2007), WO2016044641, etc.).

[0145] Manufacturing method 4 The compound represented by formula (4-5) can be produced, for example, by the method shown below. [ka] [In the formula, R 1 , A 1 , A 2 , L 1, X is as defined in the above item 1, and R G , p, q, and t are as defined in the above item 16; Y represents a halogen atom (e.g., iodine atom, bromine atom, chlorine atom, etc.); and PG represents a protecting group (e.g., tert-butoxycarbonyl group, benzyloxycarbonyl group, etc.).

[0146] Step 4-1: Preparation of Compound (4-3) Compound (4-3) is produced using compound (4-1) and compound (4-2) according to the method described in step 1-1. Compound (4-1) can be produced by a known synthesis method (e.g., Bioorganic & Medicinal Chemistry Letters, 28, (2007), Journal of Organic Chemistry 2613, (1986), etc.) or a synthesis method similar thereto. Compound (4-2) can be a commercially available product or produced by a known synthesis method (e.g., WO2012061418, WO2010097248, etc.) or a synthesis method similar thereto.

[0147] Step 4-2: Preparation of Compound (4-4) Compound (4-4) can be produced by cyclizing compound (4-3) in a manner similar to known synthetic methods (e.g., Chemical Communications 446, (2004), Journal of Organic Chemistry 8719, (2009), etc.).

[0148] Step 4-3: Preparation of Compound (4-5) Compound (4-5) can be produced from compound (4-4) by deprotecting the protecting group and then following the method described in step 1-3.

[0149] Manufacturing method 5 The compound represented by formula (5-4) can be produced, for example, by the method shown below. [ka] [In the formula, R 1 , A 1 , A 2 , L 1 , X is as defined in the above item 1, and R G , p, q, and t are as defined in the above item 16.]

[0150] Step 5-1: Preparation of Compound (5-2) Compound (5-2) is produced using compound (1-1) and compound (5-1) according to the method described in step 1-1. Compound (5-1) can be a commercially available product or one produced by a known synthesis method (e.g., Journal of the American Chemical Society, 12521, (1996), Green Chemistry 451, (2005), etc.) or a synthesis method similar thereto.

[0151] Step 5-2: Preparation of Compound (5-3) Compound (5-3) is produced using compound (5-2) according to the method described in step 1-2.

[0152] Step 5-3: Preparation of Compound (5-4) Compound (5-4) is produced using compound (5-3) according to the method described in step 1-3.

[0153] By appropriately combining the above-mentioned production methods, it is possible to obtain a compound having a desired functional group at a desired position. The intermediates and products in the above-mentioned production methods can be isolated and purified by appropriately combining methods used in ordinary organic synthesis, such as filtration, extraction, washing, drying, concentration, crystallization, various types of chromatography, etc. Furthermore, the intermediates can be subjected to the next reaction without any particular purification.

[0154] "Pharmaceutically acceptable salts" include acid addition salts and base addition salts. For example, acid addition salts include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, hydroiodide, nitrate, and phosphate, and organic acid salts such as citrate, oxalate, phthalate, fumarate, maleate, succinate, malate, acetate, formate, propionate, benzoate, trifluoroacetate, methanesulfonate, benzenesulfonate, para-toluenesulfonate, and camphorsulfonate. Base addition salts include inorganic base salts such as sodium salt, potassium salt, calcium salt, magnesium salt, barium salt, and aluminum salt, and organic base salts such as trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, tromethamine [tris(hydroxymethyl)methylamine], tert-butylamine, cyclohexylamine, dicyclohexylamine, and N,N-dibenzylethylamine. Furthermore, "pharmaceutically acceptable salts" also include amino acid salts with basic or acidic amino acids such as arginine, lysine, ornithine, aspartic acid, or glutamic acid.

[0155] Suitable salts of starting compounds and intermediates, and salts acceptable as pharmaceutical raw materials, are conventional non-toxic salts, including acid addition salts such as organic acid salts (e.g., acetate, trifluoroacetate, maleate, fumarate, citrate, tartrate, methanesulfonate, benzenesulfonate, formate, p-toluenesulfonate, etc.) and inorganic acid salts (e.g., hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, etc.); salts with amino acids (e.g., arginine, aspartic acid, glutamic acid, etc.); metal salts such as alkali metal salts (e.g., sodium salt, potassium salt, etc.) and alkaline earth metal salts (e.g., calcium salt, magnesium salt, etc.); ammonium salts; and organic base salts (e.g., trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.), which can be appropriately selected by those skilled in the art.

[0156] In the above-mentioned production methods, the starting compounds or intermediates may exist in the form of a salt such as a hydrochloride depending on the reaction conditions, etc., but can be used as is or in a free form. When the starting compound or intermediate is obtained in the form of a salt and it is desired to use or obtain the starting compound or intermediate in a free form, it can be converted to the free form by dissolving or suspending it in an appropriate solvent and neutralizing it with a base such as an aqueous solution of sodium bicarbonate.

[0157] Compound (1) or a pharmaceutically acceptable salt thereof may exist in the form of isomers such as tautomers (e.g., keto-enol forms), positional isomers, geometric isomers, or optical isomers. All possible isomers, including these, and mixtures of such isomers in any ratio are encompassed in the present invention. In addition, optical isomers can be separated by carrying out a known separation step such as a method using an optically active column, fractional crystallization, etc. in an appropriate step of the above-mentioned production method. Optically active substances can also be used as starting materials. In this specification, a compound whose structural formula indicates the configuration (S, R) means an optically active compound, and if no configuration is specified, it means a racemic compound. The cyclic urea moiety of the compound exists in cis and trans forms, and if no configuration is specified, it means a racemic compound.

[0158] When a salt of compound (1) is desired to be obtained, if a salt of compound (1) is obtained, it can be purified as is, or if compound (1) is obtained in a free form, compound (1) can be dissolved or suspended in an appropriate solvent and an acid or base can be added to form a salt. In addition, compound (1) or a pharmaceutically acceptable salt thereof may exist in the form of a solvate with water or various solvents, and these solvates are also encompassed by the present invention.

[0159] In the present invention, the term "hydrogen atom" includes 1 H and 2 H(D), and any one or more compounds represented by formula (1) 1 H 2Deuterium conversion products converted to H(D) are also included in the compounds represented by formula (1).

[0160] The pharmaceutical of the present invention can be administered orally or parenterally, either directly or after formulation using an appropriate dosage form. Examples of dosage forms include, but are not limited to, tablets, capsules, powders, granules, liquids, suspensions, injections, patches, and poultices. The formulations are prepared by known methods using pharmaceutically acceptable additives. Depending on the purpose, additives that can be used include excipients, disintegrants, binders, flow agents, lubricants, coating agents, solubilizers, solubilizers, thickeners, dispersants, stabilizers, sweeteners, and flavors. Specific examples of additives include lactose, mannitol, crystalline cellulose, low-substituted hydroxypropyl cellulose, corn starch, partially pregelatinized starch, carmellose calcium, croscarmellose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, magnesium stearate, sodium stearyl fumarate, polyethylene glycol, propylene glycol, titanium oxide, and talc.

[0161] The pharmaceutical agent of the present invention may be administered orally, parenterally, or rectally, and the daily dosage varies depending on the type of compound, the administration method, the symptoms and age of the patient, etc. For example, in the case of oral administration, the dosage is usually about 0.01 to 1000 mg, more preferably about 0.1 to 500 mg, per kg body weight of a human or mammal, administered once or in divided doses. In the case of parenteral administration such as intravenous injection, the dosage is usually about 0.01 to 300 mg, more preferably about 1 to 100 mg, per kg body weight of a human or mammal.

[0162] Furthermore, the pharmaceutical agent of the present invention can be used as a DYRK inhibitor, as a reagent for pathological imaging of the above-mentioned diseases, or as a reagent for basic experiments and research. [Example]

[0163] The present invention will be explained in more detail below with reference to Examples, Reference Examples, and Test Examples, but the present invention is not limited thereto. The names of compounds shown in the following Examples and Reference Examples do not necessarily conform to the IUPAC nomenclature.

[0164] The following abbreviations may be used in this specification: (Boc)2O: di-tert-butyl dicarbonate Cbz: benzyloxycarbonyl DIAD: Diisopropyl azodicarboxylate Boc: tert-butoxycarbonyl Bn: Benzyl TBDMS: tert-butyldimethylsilyl Ac: Acetyl Ms: methanesulfonyl DMSO: dimethyl sulfoxide Ts: p-toluenesulfonyl Tf: Trifluoromethanesulfonyl Rt: retention time

[0165] The physical property data of each compound in the Examples and Reference Examples were measured under the following conditions. Nuclear magnetic resonance spectrum ( 1 H-NMR): Equipment used: JEOL JNM-AL400;Brucker AVANCE 400 Spectrometer

[0166] Liquid chromatography / mass spectrometry (LC / MS): (1) Method A and Method B Detection equipment: ACQUITY (registered trademark) SQ detector (Waters) HPLC: ACQUITY UPLC® SYSTEM Column: Waters ACQUITY UPLC(registered trademark) BEH C18(1.7um, 2.1mm × 30mm) Flow rate: 0.8mL / min; Detection UV: 220nm and 254nm; Temperature: 40℃ [Table 1]

[0167] (2) Method C Detection equipment: ACQUITY (registered trademark) QDa detector (Waters) HPLC: ACQUITY UPLC® SYSTEM Column: Waters ACQUITY UPLC(registered trademark) BEH C18(1.7um, 2.1mm × 30mm) Flow rate: 0.6 mL / min; UV detection: 20-400 nm; Temperature: 40°C [Table 2]

[0168] (3) Method D Detector: ACQUITY (registered trademark) SQ detector 2 (Waters) HPLC: ACQUITY UPLC® SYSTEM Column: Waters ACQUITY UPLC® BEH C18 (1.7 μm, 2.1 mm × 50 mm) Flow rate: 0.6 mL / min; UV detection: 210 nm to 400 nm; Temperature: 35°C [Table 3]

[0169] (4) Method E Detection equipment: LCMS-2010A (Shimadzu Corporation) HPLC: Prominence® SYSTEM Column:Cadenza CD-C18(3.0um, 2.0mm × 50mm) Flow rate: 0.5 mL / min; UV detection: 215, 254 nm; Temperature: 40°C [Table 4]

[0170] The names of compounds in the Reference Examples and Examples were determined by ACD / Name (ACD / Labs 12.0, Advanced Chemistry Development Inc.).

[0171] Reference Example 1 and Reference Example 2 Reference Example 1: tert-Butyl cis-3-amino-4-{[(2,3-dihydro-1-benzofuran-4-yl)carbamothioyl]amino}piperidine-1-carboxylate Reference Example 2: tert-Butyl cis-4-amino-3-{[(2,3-dihydro-1-benzofuran-4-yl)carbamothioyl]amino}piperidine-1-carboxylate [ka] To a solution (20 mL) of cis-1-Boc-3,4-diaminopiperidine (1.08 g) and N,N-diisopropylethylamine (647 mg) in chloroform, 4-isothiocyanato-2,3-dihydrobenzofuran (886 mg) was added under ice-cooling, and the mixture was stirred for 2 hours under ice-cooling. The reaction mixture was directly purified by silica gel column chromatography (chloroform / methanol) to give the title compounds (Reference Example 1: 1.04 g, Reference Example 2: 680 mg). Reference example 1: LC-MS [M+H] + / Rt (min): 393.2 / 0.562 (Method B) Reference example 2: LC-MS [M+H] + / Rt (min): 393.2 / 0.559 (Method B)

[0172] Reference examples 3~7 According to the methods described in Reference Examples 1 and 2, the compounds of Reference Examples 3 to 7 were obtained using the corresponding starting compounds. [Table 5]

[0173] Reference example 8 tert-Butyl cis-4-amino-3-[(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)amino]piperidine-1-carboxylate [ka] To a chloroform solution (70 mL) of the compound of Reference Example 2 (2.71 g), sodium bicarbonate (580 mg) and benzyltrimethylammonium tribromide (2.69 g) were added and stirred for 1 hour. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (2.64 g). LC-MS [M+H] + / Rt (min): 391.2 / 0.600 (Method B)

[0174] Reference examples 9~13 According to the method described in Reference Example 8, the compounds of Reference Examples 9 to 13 were obtained using the corresponding starting compounds. [Table 6]

[0175] Reference example 14 tert-Butyl cis-3-(7,8-dihydrobenzofuro[3,2-e][1,3]benzothiazol-2-yl)-2-oxooctahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate [ka] To a chloroform solution (4 mL) of the compound of Reference Example 8 (151 mg), triethylamine (0.162 mL) and di(N-succinimidyl)carbonate (99 mg) were added and stirred for 0.5 hours. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (114 mg). LC-MS [M+H] + / Rt (min): 417.2 / 0.803 (Method B)

[0176] Reference examples 15~19 According to the method described in Reference Example 14, the compounds of Reference Examples 15 to 19 were obtained using the corresponding starting compounds. [Table 7]

[0177] Reference example 20 (2S,3R)-3-(benzylamino)-4-{[tert-butyl(dimethyl)silyl]oxy}butan-2-ol [ka] Triethylamine (2.4 mL), N,N-dimethylaminopyridine (1.3 mL), and TBDMS chloride were added to a chloroform solution (65 mL) of (2R,3S)-2-(benzylamino)butane-1,3-diol (4.46 g) under ice-cooling, and the mixture was stirred for 4 hours under ice-cooling. Saturated aqueous sodium bicarbonate was added to the reaction mixture, which was then extracted with chloroform. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to give the title compound (5.42 g). LC-MS [M+H] + / Rt (min): 310.3 / 0.872 (Method A)

[0178] Reference example 21 According to the method described in Reference Example 20, the compound of Reference Example 21 was obtained using the corresponding starting compound. [Table 8]

[0179] Reference example 22 Benzyl benzyl[(2R,3S)-1-{[tert-butyl(dimethyl)silyl]oxy}-3-hydroxybutan-2-yl]carbamate [ka] To a solution of the compound of Reference Example 20 (5.42 g) in tetrahydrofuran (45 mL) and water (30 mL), sodium carbonate (5.57 g) and benzyl chloroformate (2.96 mL) were added and stirred at room temperature for 14 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (6.61 g). LC-MS [M+H] + / Rt (min): 444.4 / 1.389 (Method A)

[0180] Reference example 23 According to the method described in Reference Example 22, the compound of Reference Example 23 was obtained using the corresponding starting compound. [Table 9]

[0181] Reference example 24 Benzyl benzyl[(2S,3R)-1-{[tert-butyl(dimethyl)silyl]oxy}-3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)butan-2-yl]carbamate [ka] To a toluene solution (60 mL) of the compound (6.61 g) of Reference Example 22, phthalimide (2.74 g), and triphenylphosphine (4.89 g), DIAD (3.81 mL) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 7 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (7.03 g). LC-MS [M+H] + / Rt (min): 573.4 / 1.488 (Method A).

[0182] Reference example 25 According to the method described in Reference Example 24, the compound of Reference Example 25 was obtained using the corresponding starting compound. [Table 10]

[0183] Reference example 26 2-[(2R,3S)-3-amino-4-{[tert-butyl(dimethyl)silyl]oxy}butan-2-yl]-1H-isoindole-1,3(2H)-dione [ka] Palladium hydroxide on carbon (1.63 g) was added to a solution (150 mL) of the compound of Reference Example 24 (7.03 g) in ethanol, and the mixture was stirred at room temperature under a hydrogen atmosphere for 35 hours. The reaction mixture was filtered through Celite and then concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (hexane / ethyl acetate, chloroform / methanol) to give the title compound (816 mg). LC-MS [M+H] + / Rt (min): 349.3 / 0.906 (Method A).

[0184] Reference example 27 According to the method described in Reference Example 26, the compound of Reference Example 27 was obtained using the corresponding starting compound. [Table 11]

[0185] Reference example 28 N-[(2S,3S)-1-{[tert-butyl(dimethyl)silyl]oxy}-3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)butan-2-yl]-N'-(2,3-dihydro-1-benzofuran-7-yl)thiourea [ka] To a chloroform solution (5 mL) of the compound of Reference Example 27 (444 mg), diisopropylethylamine (0.65 mL) and 4-isothiocyanato-2,3-dihydrobenzofuran (226 mg) were added under ice-cooling, and the mixture was stirred at room temperature for 3 hours. 4-Isothiocyanato-2,3-dihydrobenzofuran (22.6 mg) was added, and the mixture was stirred overnight. Saturated aqueous sodium bicarbonate and water were added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (660 mg). LC-MS [M+H] + / Rt (min): 526.3 / 1.251 (Method B).

[0186] Reference example 29 According to the method described in Reference Example 28, the compound of Reference Example 29 was obtained using the corresponding starting compound. [Table 12]

[0187] Reference example 30 2-{(2S,3S)-4-{[tert-butyl(dimethyl)silyl]oxy}-3-[(6,7-dihydrofuro[2,3-e][1,3]benzothiazol-2-yl)amino]butan-2-yl}-1H-isoindole-1,3(2H)-dione [ka] Sodium bicarbonate (105 mg) was added to a chloroform solution (7 mL) of the compound of Reference Example 28 (660 mg) at room temperature. Benzyltrimethylammonium tribromide (441 mg) was added under ice-cooling, and the mixture was stirred for 2 hours under ice-cooling. Saturated aqueous sodium bicarbonate and water were added to the reaction mixture, which was then extracted with chloroform. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Imidazole (129 mg) and TBDMS chloride (189 mg) were added to a chloroform / tetrahydrofuran solution (4 mL / 8 mL) of the residue, and the mixture was stirred for 4 hours. Imidazole (200 mg) and TBDMS chloride (190 mg) were further added, and the mixture was stirred for 1 hour. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (596 mg). LC-MS [M+H] + / Rt (min): 524.4 / 1.353 (Method A).

[0188] Reference example 31 According to the method described in Reference Example 30, the compound of Reference Example 31 was obtained using the corresponding starting compound. [Table 13]

[0189] Reference example 32 (2S,3S)-1-{[tert-butyl(dimethyl)silyl]oxy}-N 2 -(6,7-dihydrofuro[2,3-e][1,3]benzothiazol-2-yl)butane-2,3-diamine [ka] Hydrazine monohydrate (0.554 mL) was added to a solution of the compound of Reference Example 30 (596 mg) in methanol / tetrahydrofuran (10 mL / 10 mL), and the mixture was stirred at 70° C. for 4 hours. After cooling to room temperature, ethyl acetate (20 mL) was added to the reaction mixture, and the mixture was stirred for 20 minutes. The reaction mixture was filtered through Celite and concentrated under reduced pressure to give the title compound (490 mg). LC-MS [M+H] + / Rt (min): 394.3 / 0.948 (Method A).

[0190] Reference example 33 According to the method described in Reference Example 32, the compound of Reference Example 33 was obtained using the corresponding starting compound. [Table 14]

[0191] Reference example 34 (4S,5S)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1-(6,7-dihydrofuro[2,3-e][1,3]benzothiazol-2-yl)-4-methylimidazolidin-2-one [ka] To a chloroform solution (10 mL) of the compound of Reference Example 32 (490 mg), diisopropylethylamine (0.582 mL) and di(N-succinimidyl)carbonate (307 mg) were added and stirred for 2 hours. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to give the title compound (295 mg). LC-MS [M+H] + / Rt (min): 420.3 / 1.241 (Method A).

[0192] Reference example 35 According to the method described in Reference Example 34, the compound of Reference Example 35 was obtained using the corresponding starting compound. [Table 15]

[0193] Reference example 36 (4S,5S)-1-(6,7-dihydrofuro[2,3-e][1,3]benzothiazol-2-yl)-5-(hydroxymethyl)-4-methylimidazolidin-2-one [ka] To a methanol suspension (5 mL) of the compound of Reference Example 34 (295 mg), 2M hydrogen chloride ethanol solution (1 mL) was added and stirred for 1 hour. 2M hydrogen chloride ethanol solution (4 mL) was added and stirred for 5 hours. 2M hydrogen chloride ethanol solution (4 mL) was further added and stirred overnight. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium bicarbonate was added, and the mixture was extracted with chloroform / ethanol (3 / 1). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to give the title compound (235 mg). LC-MS [M+H] + / Rt (min): 306.1 / 0.600 (Method B).

[0194] Reference example 37 According to the method described in Reference Example 36, the compound of Reference Example 37 was obtained using the corresponding starting compound. [Table 16]

[0195] Reference example 38 [(4S,5S)-3-(6,7-dihydrofuro[2,3-e][1,3]benzothiazol-2-yl)-5-methyl-2-oxoimidazolidin-4-yl]methyl methanesulfonate [ka] To a solution (4 mL) of the compound of Reference Example 36 (46 mg) in tetrahydrofuran, triethylamine (0.063 mL) and methanesulfonyl chloride (0.017 mL) were added under ice-cooling, and the mixture was stirred at room temperature for 40 minutes. Triethylamine (0.063 mL) and methanesulfonyl chloride (0.023 mL) were added to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 3 hours. Saturated aqueous sodium bicarbonate and water were added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (122 mg). This was carried on to the next reaction without further purification. LC-MS [M+H] + / Rt (min): 306.1 / 0.600 (Method B).

[0196] Reference examples 39~41 According to the method described in Reference Example 38, the compounds of Reference Examples 39 to 41 were obtained using the corresponding starting compounds. [Table 17]

[0197] Reference example 42 tert-Butyl cis-3,4-diazidoazepane-1-carboxylate [ka] Sodium azide (1.41 g) was added to a solution (5 mL) of the compound of Reference Example 41 (1.25 g) in dimethylformamide, and the mixture was stirred at 65°C for 4 hours and at 70°C for 8 hours. Dimethyl sulfoxide (3 mL) was added, and the mixture was stirred at 90°C for 24 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (639 mg). LC-MS [M+H] + / Rt (min): 282.2 / 1.045 (Method B).

[0198] Reference example 43 According to the method described in Reference Example 42, the compound of Reference Example 43 was obtained using the corresponding starting compound. [Table 18]

[0199] Reference example 44 tert-Butyl cis-3,4-diaminoazepane-1-carboxylate [ka] Palladium hydroxide on carbon (130 mg) was added to a solution (15 mL) of the compound of Reference Example 42 (639 mg) in ethanol, and the mixture was stirred under a hydrogen atmosphere for 8 hours. The reaction mixture was filtered through Celite and then concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (chloroform / methanol) to give the title compound (380 mg). LC-MS [M+H] + / Rt (min): 230.2 / 0.276 (Method B).

[0200] Reference example 45 According to the method described in Reference Example 44, the compound of Reference Example 45 was obtained using the corresponding starting compound. [Table 19]

[0201] Reference example 46 5-Bromo-4-isothiocyanato-2H-1,3-benzodioxole [ka] Thiophosgene (17.8 mL) was added to a solution of 5-bromo-1,3-benzodioxol-4-amine (20 g) in water (40 mL) under ice-cooling, and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether) to give the title compound (10 g). 1 H-NMR (DMSO-D6) δ: 7.18 (1H, d, J = 8.4 Hz), 6.91 (1H, d, J = 8.4 Hz), 6.22 (2H, s).

[0202] Reference example 47 tert-Butyl {(3R,4R)-4-[(2H-[1,3]dioxolo[4,5-e][1,3]benzothiazol-7-yl)amino]oxan-3-yl}carbamate [ka] To a solution (23 mL) of the compound of Reference Example 7 (1.1 g) in acetonitrile, 1,10-phenanthroline (84 mg), cesium carbonate (1.51 g), and copper(I) iodide (22 mg) were added, followed by stirring at 95°C for 4 hours. The reaction mixture was filtered through Celite and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (759 mg). 1H-NMR (CDCl3) δ: 7.00 (1H, d, J = 8.2 Hz), 6.68 (1H, d, J = 8.2 Hz), 6.16 (1H, s), 6.07-5.99 (2H, m), 5.27 (1H, s), 4.21 (1H, d, J = 8.2 Hz), 4.05 (1H, s), 3.97 (1H, dd, J = 4.5, 11.9 Hz), 3.90-3.83 (1H, m), 3.69-3.61 (1H, m), 3.61-3.51 (1H, m), 2.38-2.25 (1H, m), 1.73 ((1H, dtd, J = 4.9, 12.0, 13.5 Hz), 1.47 (9H, s).

[0203] Reference example 48 5-Isothiocyanato-2,3-dihydro-1,4-benzodioxin [ka] 5-Amino-1,4-benzodioxane (2.75 g) was added to a chloroform solution (20 mL) of 1,1'-thiocarbonyldi-2(1H)-pyridone (4.43 g) at room temperature, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (3.38 g). 1 H-NMR (CDCl3) δ: 6.80-6.67 (3H, m), 4.37-4.33 (2H, m), 4.28-4.24 (2H, m).

[0204] Reference examples 49~57 According to the methods described in Reference Examples 1 and 2, the compounds of Reference Examples 49 to 57 were obtained using the corresponding starting compounds. [Table 20]

[0205] Reference examples 58~66 According to the method described in Reference Example 8, the compounds of Reference Examples 58 to 66 were obtained using the corresponding starting compounds. [Table 21]

[0206] Reference Examples 67 and 68 According to the method described in Reference Example 14, the compounds of Reference Examples 67 and 68 were obtained using the corresponding starting compounds. [Table 22]

[0207] Reference example 69 (3R,4S,6R)-6-Cyanooxane-3,4-diyl diacetate [ka] Trimethylsilyl cyanide (1.93 mL) and boron trifluoride diethyl ether complex (4.56 mL) were added to a dichloromethane solution (40 mL) of (2S,4S,5R)-tetrahydro-2H-pyran-2,4,5-triyl triacetate (3.12 g) under ice-cooling, and the mixture was stirred for 1 hour under ice-cooling. Saturated aqueous sodium bicarbonate was added to the reaction mixture, which was then extracted with chloroform. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (2.94 g). 1 H-NMR (CDCl3) δ: 5.38-5.28 (1H, m), 5.21-5.13 (1H, m), 4.84 (1H, t, J = 4.6 Hz), 4.01 (1H, dd, J = 2.5, 12.9 Hz), 3.93 (1H, dd, J = 4.5, 12.9 Hz), 2.42-2.29 (1H, m), 2.14-2.08 (4H, m), 2.07 (3H, s).

[0208] Reference example 70 Methyl 2,6-anhydro-3-deoxy-D-ribo-hexonate [ka] Reference Example 69 was added to a 5% solution of hydrogen chloride in methanol (30 mL) at room temperature and stirred overnight under reflux. The reaction mixture was cooled to 0°C, and the resulting insoluble matter was filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to give the title compound (2.82 g). 1 H-NMR (CDCl3) δ: 4.39 (1H, ddd, J = 0.7, 3.0, 10.8 Hz), 4.19-4.10 (1H, m), 3.94-3.87 (1H, m), 3.86-3.79 (1H, m), 3.77 (3H, s), 3.66 (1H, dd, J = 9.4, 10.8 Hz), 2.41 (1H, dd, J = 1.1, 2.9 Hz), 2.28-2.18 (2H, m), 1.97-1.86 (1H, m).

[0209] Reference example 71 Methyl 2,6-anhydro-4,5-O-benzylidene-3-deoxy-D-ribohexonate [ka] Benzaldehyde dimethyl acetal (5.55 mL) and p-toluenesulfonic acid hydrate (0.424 g) were added to a solution of Reference Example 70 (2.67 g) in dimethylformamide (30 mL) at room temperature, and the mixture was stirred overnight at 60-70°C. After cooling the reaction mixture to room temperature, water was added and the mixture was extracted with hexane / ethyl acetate (1:1). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (4.3 g) as a mixture of approximately 3:2. 1H-NMR (CDCl3) δ: 7.60-7.31 (5H, m), 6.35 (0.4H, s), 5.79 (0.6H, s), 4.58-3.98 (4H, m), 3.83-3.72 (3H, m), 3.72-3.47 (1H, m), 2.60-2.40 (1H, m), 2.15-1.96 (1H, m).

[0210] Reference example 72 2,6-Anhydro-4,5-O-benzylidene-3-deoxy-D-ribo-hexitol [ka] Sodium borohydride (2.25 g) was added to a methanol solution (40 mL) of Reference Example 71 (3.93 g) under ice-cooling, and the mixture was stirred under ice-cooling for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (3.08 g) as a mixture of approximately 3:2. 1 H-NMR (CDCl3) δ: 7.59-7.31 (5H, m), 6.34 (0.4H, s), 5.83 (0.6H, s), 4.54-4.20 (2H, m), 4.11-3.92 (2H, m), 3.84-3.62 (2H, m), 2.24-1.73 (3H, m).

[0211] Reference example 73 2,6-Anhydro-4,5-O-benzylidene-1,3-dideoxy-1-iodo-D-ribo-hexitol [ka] Triphenylphosphine (13.8 g), imidazole (8.96 g), and iodine (13.4 g) were added to a solution of Reference Example 72 (10.4 g) in tetrahydrofuran (210 mL) under ice-cooling, and the mixture was stirred for 30 minutes under ice-cooling and then at room temperature for 3.5 hours. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with 5% aqueous sodium thiosulfate solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (14.0 g) as a mixture of approximately 3:2. 1 H-NMR (CDCl3) δ: 7.61-7.31 (5H, m), 6.34 (0.4H, s), 5.75 (0.6H, s), 4.55-4.23 (2H, m), 4.14-3.94 (1H, m), 3.73-3.47 (2H, m), 3.34-3.10 (2H, m), 2.41-2.30 (1H, m), 1.94-1.67 (1H, m).

[0212] Reference example 74 2,6-anhydro-4,5-O-benzylidene-1,3-dideoxy-1-fluoro-D-ribo-hexitol [ka] To a dichloromethane solution (33 mL) of Reference Example 72 (10.4 g), diisopropylethylamine (3.44 mL) and diethylaminosulfur trifluoride (1.04 mL) were added under ice-cooling, and the mixture was stirred under reflux for 19 hours. Further diisopropylethylamine (1.72 mL) and diethylaminosulfur trifluoride (0.52 mL) were added at room temperature, and the mixture was stirred under reflux for 2 hours. Saturated aqueous sodium bicarbonate was added to the reaction mixture under ice-cooling, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (1.25 g) as a mixture of approximately 3:2. 1H-NMR (CDCl3) δ: 7.57-7.32 (5H, m), 6.38 (0.4H, s), 5.90 (0.6H, s), 4.57-4.26 (4H, m), 4.15-3.85 (2H, m), 3.63-3.49 (1H, m), 2.22-1.84 (2H, m).

[0213] Reference example 75 2,6-anhydro-4,5-O-benzylidene-3-deoxy-D-ribohexose [ka] To a dichloromethane solution (85 mL) of Reference Example 72 (2.00 g), Dess-Martin reagent (4.31 g) was added under ice-cooling, and the mixture was stirred overnight at room temperature. Saturated aqueous sodium bicarbonate and saturated aqueous sodium thiosulfate were added to the reaction mixture under ice-cooling, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (0.83 g). 1 H-NMR (CDCl3) δ: 9.70 (1H, s), 7.58-7.45 (2H, m), 7.43-7.37 (1H, m), 5.92 (1H, s), 4.57-4.43 (1H, s), 4.35-4.14 (2H, m), 4.01 (1H, dd, J = 5.3, 12.1 Hz), 3.64 (1H, dd, J = 7.2, 12.1 Hz), 2.44 (1H, ddd, J = 2.6, 3.8, 15.1 Hz), 1.92 (1H, ddd, J = 3.8, 11.9, 15.1 Hz).

[0214] Reference example 76 3,7-Anhydro-5,6-O-benzylidene-1,2,4-trideoxy-D-ribo-hept-1-ynitol [ka] Potassium carbonate (0.979 mg) and dimethyl (1-diazo-2-oxopropyl)phosphonate (0.638 mL) were added to a methanol solution (35 mL) of Reference Example 75 (0.83 g) at room temperature, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (0.415 mg). 1 H-NMR (CDCl3) δ: 7.57-7.46 (2H, m), 7.45-7.34 (3H, m), 5.91 (1H, s), 4.56-4.45 (2H, m), 4.27-4.23 (1H, m), 4.10 (1H, dd, J = 4.9, 12.5 Hz), 3.71 (1H, dd, J = 6.1, 12.5 Hz), 2.50 (1H, d, J = 2.2 Hz), 2.38-2.32 (1H, m), 2.20-2.13 (1H, m).

[0215] Reference example 77 2,6-Anhydro-4,5-O-benzylidene-1,3-dideoxy-D-ribo-hexitol [ka] Sodium borohydride (7.64 g) was added to a solution of Reference Example 73 (10.4 g) in dimethyl sulfoxide (200 mL) under ice-cooling, and the mixture was stirred overnight at room temperature. The reaction mixture was poured into ice water and then extracted with hexane / ethyl acetate (1:1). The organic layer was washed with water, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (7.34 g) as a mixture of approximately 3:2. 1H-NMR (CDCl3) δ: 7.60-7.32 (5H, m), 6.37 (0.4H, s), 5.78 (0.6H, s), 4.09-3.91 (1H, m), 3.82-3.64 (1H, m), 3.56-3.32 (1H, m), 2.32-2.11 (1H, m), 1.85-1.62 (1H, m), 1.24-1.14 (3H, m).

[0216] Reference example 78 2,6-anhydro-1,3-dideoxy-D-ribo-hexitol [ka] To a solution (160 mL) of Reference Example 77 (7.34 g) in methanol, p-toluenesulfonic acid hydrate (0.951 g) was added at room temperature, followed by stirring overnight at room temperature. Diisopropylethylamine (1.16 mL) was added to the reaction mixture at room temperature, followed by stirring for 15 minutes at room temperature, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to give the title compound (3.83 g). 1 H-NMR (CDCl3) δ: 4.18-4.02 (1H, m), 3.91-3.66 (3H, m), 3.64-3.44 (1H, m), 2.18 (1H, d, J = 3.1 Hz), 2.04-1.94 (1H, m), 1.90 (1H, ddd, J = 2.2, 3.8, 14.3 Hz), 1.54 (1H, dddd, J = 1.2, 2.7, 11.1, 14.1 Hz), 1.16 (3H, d, J = 6.3 Hz).

[0217] Reference example 79 According to the method described in Reference Example 78, the compound of Reference Example 79 was obtained using the corresponding starting compound. [Table 23]

[0218] Reference example 80 3,7-anhydro-1,2,4-trideoxy-D-ribo-heptitol [ka] To a solution (18 mL) of Reference Example 76 (410 mg) in methanol, 10% palladium on carbon (95 mg) was added at room temperature, and the mixture was stirred overnight under a hydrogen atmosphere at room temperature. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (240 mg). 1 H-NMR (CDCl3) δ: 4.16-4.07 (1H, m), 3.81-3.69 (2H, m), 3.62-3.49 (2H, m), 2.33-2.27 (1H, m), 2.16 (1H, d, J = 6.3 Hz), 1.91 (1H, ddd, J = 2.2, 3.8, 14.3 Hz), 1.59-1.34 (3H, m), 0.93 (3H, t, J = 7.5 Hz).

[0219] Reference examples 81~83 According to the method described in Reference Example 38, the compounds of Reference Examples 81 to 83 were obtained using the corresponding starting compounds. [Table 24]

[0220] Reference examples 84~86 According to the method described in Reference Example 42, the compounds of Reference Examples 84 to 86 were obtained using the corresponding starting compounds. [Table 25]

[0221] Reference examples 87~89 According to the method described in Reference Example 44, the compounds of Reference Examples 87 to 89 were obtained using the corresponding starting compounds. [Table 26]

[0222] Reference example 90 tert-Butyl 3-buten-1-yl(1-(hydroxymethyl)cyclopropyl)carbamate [ka] Potassium carbonate (4.56 g), sodium iodide (4.95 g), and 4-bromo-1-butene (3.02 mL) were added to a solution of (1-aminocyclopropyl)methanol in acetonitrile (50 mL) at room temperature, followed by stirring at 85°C for 12.5 hours. The reaction mixture was cooled to room temperature, filtered, and concentrated. Tetrahydrofuran (50 mL), triethylamine (8.36 mL), and (Boc)O (7.20 g) were added to the residue, followed by stirring at room temperature for 1.5 hours. Saturated aqueous sodium bicarbonate was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane / ethyl acetate) to give the title compound (3.52 g). LC-MS [M+H] + / Rt (min): 242.5 / 0.936 (Method B)

[0223] Reference example 91 tert-Butyl 3-buten-1-yl(1-formylcyclopropyl)carbamate [ka] A chloroform suspension (20 mL) of Dess-Martin reagent (2.80 g) was added to a chloroform solution (30 mL) of the compound of Reference Example 90 (1.52 g) at room temperature, followed by stirring at room temperature for 1 hour. Dess-Martin reagent (900 mg) was added to the reaction mixture at room temperature, followed by stirring for 40 minutes. Sodium bicarbonate (2.80 g) and diethyl ether were added to the reaction mixture, followed by stirring at room temperature, followed by filtration through Celite, and concentration under reduced pressure. The residue was purified by column chromatography (hexane / ethyl acetate) to give the title compound (1.35 g). LC-MS [M-56+H] + / Rt (min): 184.3 / 1.029 (Method B)

[0224] Reference example 92 tert-Butyl 3-buten-1-yl(1-vinylcyclopropyl)carbamate [ka] Potassium tert-butoxide (1.27 g) was added to a suspension (19 mL) of methyltriphenylphosphonium bromide (4.03 g) in tetrahydrofuran at room temperature, followed by stirring for 1 hour. A solution (9 mL) of the compound of Reference Example 91 (1.35 g) in tetrahydrofuran was added to the reaction mixture at room temperature, followed by stirring for 1 hour. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (hexane / ethyl acetate) to give the title compound (1.23 g). LC-MS [M-56+H] + / Rt (min): 182.3 / 1.282 (Method B)

[0225] Reference example 93 tert-Butyl 2-propen-1-yl[1-(2-propen-1-yl)cyclopropyl]carbamate [ka] Sodium hydride (60% in oil; 150 mg) and allyl bromide (0.318 mL) were added to a solution of tert-butyl (1-allylcyclopropyl)carbamate (2.90 mL) in dimethylformamide (10 mL) at 0°C, and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (0.68 g). 1 H-NMR (DMSO-d6) δ: 5.82-5.72 (2H, m), 5.21-4.80 (4H, m), 3.79 (2H, brs), 2.29 (2H, brs), 1.42 (9H, s), 0.85 (2H, brs), 0.64 (2H, brs).

[0226] Reference example 94 According to the method described in Reference Example 93, the compound of Reference Example 94 was obtained using the corresponding starting compound. [Table 27]

[0227] Reference example 95 tert-Butyl 4-azaspiro[2.5]-7-octene-4-carboxylate [ka] To a solution of the compound of Reference Example 93 (1.23 g) in toluene (52 mL), Grubbs second-generation catalyst (220 mg) was added at room temperature, and the mixture was stirred for 7.5 hours at 50° C. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (hexane / ethyl acetate) to obtain the title compound (1.04 g). LC-MS [M-56+H] + / Rt (min): 154.1 / 1.151 (Method B)

[0228] Reference Examples 96 and 97 According to the method described in Reference Example 95, the compounds of Reference Examples 96 and 97 were obtained using the corresponding starting compounds. [Table 28]

[0229] Reference example 100 tert-Butyl (2S)-2-methyl-4-[(trifluoromethanesulfonyl)oxy]-3,6-dihydropyridine-1(2H)-carboxylate Reference example 101 tert-Butyl (6S)-6-methyl-4-[(trifluoromethanesulfonyl)oxy]-3,6-dihydropyridine-1(2H)-carboxylate [ka] A solution of tert-butyl (S)-2-methyl-4-oxopiperidine-1-carboxylate (1.20 g) in tetrahydrofuran (7 mL) was added to a solution of lithium diisopropylamide (1.1 M in tetrahydrofuran, 6.6 mL) in tetrahydrofuran (7 mL) at 0°C, and the mixture was stirred at 0°C for 10 minutes. A solution of N-phenylbis(trifluoromethanesulfonimide) (2.60 g) in tetrahydrofuran (14 mL) was added dropwise over 5 minutes at 0°C, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (0.70 g) as a mixture with N-phenylbis(trifluoromethanesulfonimide). 1H-NMR (DMSO-d6) δ: 5.73-5.69 (1H, m), 4.64-3.60 (2H, m), 2.97-2.51 (1H, m), 2.23-2.02 (1H, m), 1.46 (s, 4.5H), 1.45 (s, 4.5H), 1.21 (1.5H, d, J = 6.8 Hz), 1.16 (1.5H, d, J = 6.8 Hz).

[0230] Reference Examples 102 and 103 According to the methods described in Reference Examples 100 and 101, the compounds of Reference Examples 102 and 103 were obtained using the corresponding starting compounds. [Table 29]

[0231] Reference example 104 tert-Butyl (2S)-2-methyl-3,6-dihydropyridine-1(2H)-carboxylate Reference example 105 tert-Butyl (6S)-6-methyl-3,6-dihydropyridine-1(2H)-carboxylate [ka] To a tetrahydrofuran solution (2 mL) of a mixture of Reference Example 100 and Reference Example 101 and N-phenylbis(trifluoromethanesulfonimide) (345 mg), triphenylphosphine (52.0 mg) and palladium acetate (22.0 mg) were added at room temperature, and the mixture was stirred at room temperature for 5 minutes. A tetrahydrofuran solution (4 mL) of formic acid (51.0 mg) and diisopropylethylamine (116 mg) was added dropwise at room temperature over 3 minutes, and the mixture was stirred under reflux for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (45.0 mg) as a mixture. 1H-NMR (DMSO-d6) δ: 5.78-5.55 (2H, m), 4.46-3.47 (2H, m), 2.80-1.78 (2H, m), 1.45 (s, 4.5H), 1.44 (s, 4.5H), 1.14 (1.5H, d, J = 6.8 Hz), 1.08 (1.5H, d, J = 6.8 Hz).

[0232] Reference Examples 106 and 107 According to the methods described in Reference Examples 104 and 105, the compounds of Reference Examples 106 and 107 were obtained using the corresponding starting compounds. [Table 30]

[0233] Reference example 108 According to the method described in Reference Example 20, the compound of Reference Example 108 was obtained using the corresponding starting compound. [Table 31]

[0234] Reference example 109 tert-Butyl rac-(3R,4R,5R)-3-{[tert-butyl(dimethyl)silyl]oxy}-4,5-dihydroxypiperidine-1-carboxylate [ka] To a solution of the compound of Reference Example 108 (4.76 g) in water / acetone / acetonitrile (15 mL / 15 mL / 15 mL), 4-methylmorpholine-4-oxide monohydrate (2.68 g) and osmium tetroxide (immobilized catalyst I) (2.06 g) were added at room temperature, and the mixture was stirred at room temperature for 16 hours. 4-Methylmorpholine 4-oxide monohydrate (3.48 g) and osmium tetroxide (immobilized catalyst I) (6.18 g) were added at room temperature, and the mixture was stirred at room temperature for 25 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (hexane / ethyl acetate) to give the title compound (4.80 g). LC-MS [M+H] + / Rt (min): 348.2 / 1.066 (Method B)

[0235] Reference example 110 1,6-anhydro-2,3-dideoxy-D-erythro-2-hexenitol [ka] A catalytic amount of 10% palladium on carbon was added to a solution (50 mL) of the compound of Reference Example 97 (2.36 g) in methanol, and the mixture was stirred overnight at room temperature under a hydrogen atmosphere at atmospheric pressure. The reaction mixture was filtered and concentrated under reduced pressure to give the title compound (1.00 g). 1 H-NMR (CDCl3) δ: 3.87-3.81 (1H, m), 3.79-3.71 (4H, m), 3.63-3.56 (1H, m), 1.95-1.81 (2H, m), 1.81-1.71 (1H, m), 1.72-1.56 (1H, m).

[0236] Reference examples 111~118 According to the method described in Reference Example 38, the compounds of Reference Examples 111 to 118 were obtained using the corresponding starting compounds. [Table 32]

[0237] Reference example 119 (2R,4S,5R)-2-cyano-5-[(4-methylbenzene-1-sulfonyl)oxy]oxan-4-yl 4-methylbenzene-1-sulfonate [ka] p-Toluenesulfonyl chloride (3.53 g) was added to a pyridine solution (15 mL) of (2R,4S,5R)-4,5-dihydroxytetrahydro-2H-pyran-2-carbonitrile (1.06 g) at 0°C, and the mixture was stirred at 50°C overnight. After the reaction mixture was cooled to room temperature, ice water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and saturated aqueous sodium bicarbonate, then filtered and concentrated under reduced pressure. Diethyl ether was added to the residue and the mixture was stirred. The resulting solid was collected by filtration to give the title compound (2.55 g). 1 H-NMR (CDCl3) δ: 7.74 (2H, d, J = 6.4 Hz), 7.71 (2H, d, J = 6.4 Hz), 7.39-7.32(4H, m), 4.78-4.68 (2H, m), 4.51 (1H, dt, J = 2.9, 5.6 Hz), 4.01 (1H, dd, J = 5.6, 12.9 Hz), 3.80 (1H, dd, J = 2.7, 12.9 Hz), 2.49-2.42 (1H, m), 2.47 (6H, s), 2.01-1.87 (1H, m).

[0238] Reference example 120 According to the method described in Reference Example 119, the compound of Reference Example 120 was obtained using the corresponding starting compound. [Table 33]

[0239] Reference examples 121~132 According to the method described in Reference Example 38, the compounds of Reference Examples 121 to 132 were obtained using the corresponding starting compounds. [Table 34-1] [Table 34-2]

[0240] Reference examples 133~146 According to the method described in Reference Example 42, the compounds of Reference Examples 133 to 146 were obtained using the corresponding starting compounds. [Table 35-1] [Table 35-2]

[0241] Reference example 147 tert-Butyl rac-(3R,4R,5S)-3,4-diazido-5-hydroxypiperidine-1-carboxylate [ka] To a solution (10 mL) of the compound of Reference Example 135 (798 mg) in tetrahydrofuran, tetrabutylammonium fluoride (1 M tetrahydrofuran solution, 3.01 mL) was added at room temperature and stirred for 1 hour. Methanol was added to the reaction mixture, which was then concentrated under reduced pressure. The residue was purified by column chromatography (hexane / ethyl acetate) to give the title compound (542 mg). LC-MS [M+H] + / Rt (min): 284.2 / 0.829 (Method B)

[0242] Reference example 148 tert-Butyl rac-(3R,4R,5R)-3,4-diazido-5-fluoropiperidine-1-carboxylate [ka] To a solution (10 mL) of the compound (442 mg) of Reference Example 147 in chloroform, bis(2-methoxyethyl)aminosulfur trifluoride (0.548 mL) was added at room temperature, and the mixture was stirred overnight at room temperature. The reaction mixture was directly purified by column chromatography (hexane / ethyl acetate) to give the title compound (343 mg). LC-MS [M+H] + / Rt (min): 286.1 / 0.944 (Method B)

[0243] Reference example 149 tert-Butyl 7-oxa-3-azaspiro[bicyclo[4.1.0]heptane-2,1'-cyclopropane]-3-carboxylate [ka] To a chloroform solution (10 mL) of the compound of Reference Example 95 (418 mg), m-chloroperbenzoic acid (592 mg) was added at 0°C, and the mixture was stirred at 0°C for 2 hours and at room temperature for 3 hours. Saturated sodium bicarbonate water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with a mixed solution of saturated sodium bicarbonate water and saturated aqueous sodium thiosulfate, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (hexane / ethyl acetate) to give the title compound (333 mg). LC-MS [M+H] + / Rt (min): 226.1 / 0.979 (Method B)

[0244] Reference example 150 tert-Butyl rac-(7R,8R)-8-azido-7-hydroxy-4-azaspiro[2.5]octane-4-carboxylate [ka] Sodium azide (115 mg) and ammonium chloride (95 mg) were added to a methanol / water solution (6 mL / 4 mL) of the compound of Reference Example 149 (333 mg) at room temperature, and the mixture was stirred at 65°C for 24 hours and at 100°C for 11 hours. Saturated sodium bicarbonate water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (hexane / ethyl acetate) to give the title compound (100 mg). LC-MS [M+H] + / Rt (min): 269.3 / 0.892 (Method A)

[0245] Reference example 151 tert-Butyl rac-(6R,7S)-6,7-diamino-4-azaspiro[2.5]octane-4-carboxylate [ka] To a solution of the compound of Reference Example 136 (530 mg) in tetrahydrofuran-water (10:1) (18 mL) was added triphenylphosphine (1.41 g) at room temperature, followed by stirring for 4 hours at 60° C. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / methanol) to obtain the title compound (380 mg). LC-MS [M+H] + / Rt (min): 242.2 / 0.241 (Method B)

[0246] Reference examples 152~166 According to the method described in Reference Example 44 or Reference Example 151, the compounds of Reference Examples 152 to 166 were obtained using the corresponding starting compounds. [Table 36-1] [Table 36-2]

[0247] Reference example 167 Di-tert-butyl (3R,4R)-2,3,4,7-tetrahydrooxepin-3,4-diylbis(rac-carbamate) [ka] To a dichloromethane solution (8 mL) of the compound of Reference Example 110 (1.00 g), triethylamine (6.33 mL) and methanesulfonyl chloride (1.77 mL) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated brine, then dried over sodium hydrogen sulfate, filtered, and concentrated under reduced pressure. Sodium azide (1.94 g) was added to a dimethylformamide solution (12 mL) of the obtained crude product at room temperature, and the mixture was stirred at 65°C for 18 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, then dried over sodium hydrogen sulfate, filtered, and concentrated under reduced pressure. 10% palladium carbon (0.10 g) was added to an ethanol solution (15 mL) of the obtained crude product at room temperature, and the mixture was stirred at room temperature for 3 days under a 35 bar hydrogen atmosphere. The reaction mixture was filtered and concentrated under reduced pressure. To a solution of the crude product in methanol (28 mL), triethylamine (1.59 mL) and (Boc)O (2.64 mL) were added at room temperature, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography (hexane / ethyl acetate) to give the title compound (314 mg). 1 H-NMR (CDCl3) δ: 5.26 (2H, s), 4.08-3.90 (1H, m), 3.89-3.71 (2H, m), 3.72-3.50 (3H, m), 1.92-1.62 (4H, m), 1.46 (9H, s), 1.45 (9H, s).

[0248] Reference examples 168~206 According to the methods described in Reference Examples 1, 2 and 24, the compounds of Reference Examples 168 to 206 were obtained using the corresponding starting compounds. [Table 37-1] [Table 37-2] [Table 37-3] [Table 37-4]

[0249] Reference example 207 tert-Butyl rac-{(3R,4S)-4-[(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)amino]oxolan-3-yl}carbamate [ka] To a chloroform suspension (30 mL) of the compound of Reference Example 188 (947 mg), benzyltrimethylammonium tribromide (1.30 g) was added at 0°C, and the mixture was stirred at 0°C for 15 minutes. Triethylamine (0.945 mL) and (Boc)2O (814 mg) were added at 0°C, and the mixture was stirred at room temperature for 3 hours. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane / ethyl acetate) to give the title compound (688 mg). LC-MS [M+H] + / Rt (min): 378.1 / 3.197 (Method C)

[0250] Reference examples 208~248 According to the methods described in Reference Examples 8, 26 and 47, the compounds of Reference Examples 208 to 248 were obtained using the corresponding starting compounds. [Table 38-1] [Table 38-2] [Table 38-3] [Table 38-4] [Table 38-5]

[0251] Reference examples 249~268 According to the method described in Reference Example 14, the compounds of Reference Examples 249 to 268 were obtained using the corresponding starting compounds. [Table 39-1] [Table 39-2] [Table 39-3]

[0252] Reference example 269 According to the method described in Reference Example 28, the compound of Reference Example 269 was obtained using the corresponding starting compound. [Table 40]

[0253] Reference example 270 tert-Butyl rac-(3aR,6aS)-3-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-2-oxohexahydro-1H-furo[3,4-d]imidazole-1-carboxylate [ka] To a solution (10 mL) of the compound of Example 119 (380 mg) in tetrahydrofuran, sodium hydride (60% in oil, 130 mg) and (Boc)2O (0.33 mL) were added at 0°C, and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate) to give the title compound (465 mg). LC-MS [M+H] + / Rt (min): 404.6 / 2.568 (Method D)

[0254] Reference example 271 tert-Butyl (3aS,6aR)-3-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-2-oxohexahydro-1H-furo[3,4-d]imidazole-1-carboxylate Reference example 272 tert-Butyl (3aR,6aS)-3-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-2-oxohexahydro-1H-furo[3,4-d]imidazole-1-carboxylate [ka] The compound of Reference Example 270 (465 mg) was subjected to optical separation under the following supercritical fluid chromatography conditions to obtain the title compound (Reference Example 271: 160 mg - first peak: 2.01 min, Reference Example 272: 160 mg - second peak: 4.03 min). Column: CHIRALCEL (registered trademark) OJ-H; Solvent: Solution A: carbon dioxide, Solution B: methanol; Mobile phase conditions: A / B (%) = 55 / 45; Flow rate: 90 mL / min (analysis: 3 mL / min); UV detection: 214 nm; Column temperature: 30°C [Table 41]

[0255] Reference example 273 tert-Butyl {(3R,4R)-4-[(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)amino]-6,6-dimethyloxan-3-yl}carbamate [ka] To a dichloromethane solution (4 mL) of (4S,5S)-5-amino-2,2-dimethyltetrahydro-2H-pyran-4-ol (56.0 mg), triethylamine (0.065 mL) and (Boc)2O (0.107 mL) were added at room temperature, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography (hexane / ethyl acetate) to obtain the Boc derivative (70.0 mg). To a dichloromethane solution (6 mL) of the obtained Boc derivative (70.0 mg), triethylamine (0.048 mL) and methanesulfonyl chloride (0.024 mL) were added under ice cooling, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product (106 mg). To a solution of the obtained crude product (106 mg) in dimethylformamide (5 mL), sodium azide (63.9 mg) and sodium acetate (53.8 mg) were added at room temperature, and the mixture was stirred at 80°C for 3 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. A catalytic amount of 10% palladium on carbon was added to a solution of the obtained crude product in methanol (10 mL) at room temperature, and the mixture was stirred overnight at room temperature under a hydrogen atmosphere at atmospheric pressure. The reaction mixture was filtered through Celite and concentrated under reduced pressure to obtain the crude product (84.0 mg). To a solution of the obtained crude product (84.0 mg) in tetrahydrofuran (3 mL), 4-isothiocyanato-2,3-dihydrobenzofuran (67.0 mg) was added at room temperature, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography (hexane / ethyl acetate) to obtain the title compound (18.0 mg). LC-MS [M+H] + / Rt (min): 420.2 / 2.273 (Method C)

[0256] Reference example 274 According to the method described in Reference Example 273, the compound of Reference Example 274 was obtained using the corresponding starting compound. [Table 42]

[0257] Reference example 275 1,4-Anhydro-5-O-[tert-butyl(dimethyl)silyl]-2,3-bis-O-(trifluoromethanesulfonyl)-D-ribitol [ka] Pyridine (7.81 mL) and trifluoromethanesulfonic anhydride (8.16 mL) were added to a dichloromethane solution (322 mL) of (2R,3S,4S)-2-[{(tert-butyldimethylsilyl)oxy}methyl]tetrahydrofuran-3,4-diol (4.00 g) under ice-cooling, and the mixture was stirred for 1 hour under ice-cooling. Ice water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over sodium hydrogen sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane / ethyl acetate) to give the title compound (7.04 g). 1 H-NMR (CDCl3) δ: 5.47-5.36 (2H, s), 4.34-4.25 (2H, m), 4.19-4.00 (1H, m), 3.87-3.70 (2H, m), 0.90 (9H, s), 0.09 (3H, s), 0.08 (3H, s).

[0258] Reference example 276 2,5-Anhydro-1-O-[tert-butyl(dimethyl)silyl]-D-arabinitol [ka] To a solution (92 mL) of the compound from Reference Example 275 (7.04 g) in dimethylformamide, 18-crown-6 (7.82 g) and cesium acetate (7.91 g) were added at room temperature, followed by stirring at 40°C for 13 hours. Cesium acetate (7.91 g) was added, and the mixture was further stirred at 40°C for 3 hours. The reaction mixture was concentrated under reduced pressure, and then ethyl acetate and water were added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium hydrogen sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane / ethyl acetate) to give the monoacetate derivatives (2.78 g) as a mixture. The obtained monoacetate derivatives (2.78 g) were dissolved in 7N ammonia methanol solution (70 mL) and stirred at room temperature for 10 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (hexane / ethyl acetate) to give the title compound (2.15 g). 1 H-NMR (DMSO-d6) δ: 4.80 (1H, d, J = 6.1 Hz), 4.58 (1H, d, J = 4.6 Hz), 4.17-4.07 (1H, m), 3.97-3.90 (1H, m), 3.82-3.74 (2H, m), 3.30 (1H, dd, J = 6.7, 8.2 Hz), 3.66-3.57 (1H, m), 3.45 (1H, dd, J = 6.8, 8.2 Hz), 0.86 (9H, s), 0.03 (3H, s), 0.03 (3H, s).

[0259] Reference example 277 According to the method described in Reference Example 38, the compound of Reference Example 277 was obtained using the corresponding starting compound. [Table 43]

[0260] Reference example 278 According to the method described in Reference Example 42, the compound of Reference Example 278 was obtained using the corresponding starting compound. [Table 44]

[0261] Reference example 279 According to the method described in Reference Example 44, the compound of Reference Example 279 was obtained using the corresponding starting compound. [Table 45]

[0262] Reference Examples 280 and 281 According to the methods described in Reference Examples 1 and 2, the compounds of Reference Examples 280 and 281 were obtained using the corresponding starting compounds. [Table 46]

[0263] Reference Examples 282 and 283 According to the method described in Reference Example 47, the compounds of Reference Examples 282 and 283 were obtained using the corresponding starting compounds. [Table 47] Reference Examples 284 and 285 According to the method described in Reference Example 38, the compounds of Reference Examples 284 and 285 were obtained using the corresponding starting compounds. [Table 48] Reference example 286 According to the method described in Reference Example 42, the compound of Reference Example 286 was obtained using the corresponding starting compound. [Table 49] Reference example 287 According to the method described in Reference Example 44, the compound of Reference Example 287 was obtained using the corresponding starting compound. [Table 50]

[0264] Reference example 288 According to the methods described in Reference Examples 1 and 2, the compound of Reference Example 288 was obtained using the corresponding starting compounds. [Table 51]

[0265] Reference example 289 According to the method described in Reference Example 47, the compound of Reference Example 289 was obtained using the corresponding starting compound. [Table 52]

[0266] Reference example 290 According to the method described in Reference Example 77, the compound of Reference Example 290 was obtained using the corresponding starting compound. [Table 53]

[0267] Example 1 cis-3-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)octahydro-2H-imidazo[4,5-c]pyridin-2-one [ka] Trifluoroacetic acid (3 mL) was added to the compound of Reference Example 14 (114 mg) and stirred for 11 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by aminosilica gel column chromatography (chloroform / methanol) to give the title compound (62 mg). LC-MS [M+H] + / Rt (min): 317.1 / 0.399 (Method B); 1 H-NMR (DMSO-d6) δ: 7.73 (1H, s), 7.57 (1H, d, J = 8.5 Hz), 6.72 (1H, d, J = 8.5 Hz), 4.64-4.56 (2H, m), 4.52-4.44 (1H, m), 4.04-3.99 (1H, m), 3.53-3.46 (1H, m), 3.39-3.33 (2H, m), 2.77-2.69 (1H, m), 2.62-2.51 (2H, m), 2.30-2.19 (1H, m), 1.81-1.69 (2H, m).

[0268] Examples 2 to 6 According to the method described in Example 1, the compounds of Examples 2 to 6 were obtained using the corresponding starting compounds. [Table 54]

[0269] Example 7 cis-3-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-5-methyloctahydro-2H-imidazo[4,5-c]pyridin-2-one [ka] To a solution of the compound of Example 1 (21.8 mg) in methanol (2 mL), 37% formaldehyde solution (0.02 mL) and methanol (1 mL) were added and stirred for 10 minutes. Sodium triacetoxyborohydride (50 mg) was added and stirred for 20 minutes. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol). Methanol was added to the resulting solid and the mixture was stirred. The solid was collected by filtration and dried to give the title compound (12 mg). LC-MS [M+H] + / Rt (min): 331.1 / 0.412 (Method B); 1 H-NMR (DMSO-d6) δ: 7.73 (1H, s), 7.58 (1H, d, J = 7.9 Hz), 6.73 (1H, d, J = 7.9 Hz), 4.69-4.56 (3H, m), 4.00-3.94 (1H, m), 3.43-3.27 (3H, m), 2.56-2.51 (1H, m), 2.16 (3H, s), 2.12-2.04 (1H, m), 1.96-1.75 (3H, m).

[0270] Example 8 cis-3-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-5-(2-methoxyethyl)octahydro-2H-imidazo[4,5-c]pyridin-2-one [ka] To a suspension of the compound of Example 1 (32 mg) in acetonitrile (1 mL), 2-chloroethyl methyl ether (0.036 mL), potassium iodide (66 mg), and potassium carbonate (111 mg) were added and stirred at 80°C for 15 hours. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (0.035% trifluoroacetic acid acetonitrile / 0.05% trifluoroacetic acid water) and amino silica gel column chromatography (chloroform / methanol). Ethyl acetate was added to the resulting solid, and the mixture was stirred. The solid was collected by filtration and dried to give the title compound (19 mg). LC-MS [M+H] + / Rt (min): 375.1 / 0.463 (Method B); 1 H-NMR (CDCl3) δ: 7.45 (1H, d, J = 8.2 Hz), 6.76 (1H, d, J = 8.2 Hz), 4.92-4.85 (1H, m), 4.77 (1H, s), 4.70-4.61 (2H, m), 4.09-4.05 (1H, m), 3.69-3.63 (1H, m), 3.51-3.38 (4H, m), 3.34 (3H, s), 2.82-2.76 (1H, m), 2.65-2.54 (2H, m), 2.34-2.26 (1H, m), 2.20-2.02 (2H, m), 1.91-1.87 (1H, m).

[0271] Examples 9 to 19 According to the method described in Example 7 or Example 8, the compounds of Examples 9 to 19 were obtained using the corresponding starting compounds. [Table 55-1] [Table 55-2] [Table 55-3]

[0272] Example 20 cis-5-Acetyl-3-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)octahydro-2H-imidazo[4,5-c]pyridin-2-one [ka] Triethylamine (0.028 mL) and acetic anhydride (0.011 mL) were added to a chloroform solution (2 mL) of the compound of Example 1 (32 mg), and the mixture was stirred overnight. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with chloroform / ethanol (3 / 1). The organic layer was dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (0.035% trifluoroacetic acid acetonitrile / 0.05% aqueous trifluoroacetic acid), amino silica gel column chromatography (chloroform / methanol), and silica gel column chromatography (chloroform / methanol) to give the title compound (27 mg). LC-MS [M+H] + / Rt (min): 359.1 / 0.566 (Method B); 1 H-NMR (DMSO-d6, 100℃) δ: 7.59 (1H, br s), 7.54 (1H, d, J = 7.9 Hz), 6.72 (1H, d, J = 7.9 Hz), 4.83-4.78 (1H, m), 4.62 (2H, t, J = 8.8 Hz), 4.30-4.17 (2H, m), 3.85-3.78 (1H, m), 3.52-3.41 (2H, m), 3.39 (2H, t, J = 8.8 Hz), 2.13-2.02 (1H, m), 1.94-1.68 (4H, m).

[0273] Example 21 (3aR,7aR)-1-(2H-[1,3]dioxolo[4,5-e][1,3]benzothiazol-7-yl)hexahydropyrano[3,4-d]imidazol-2(3H)-one [ka] To a solution (5 mL) of the compound of Reference Example 47 (759 mg) in ethyl acetate, a 4 M solution of hydrogen chloride in ethyl acetate (5 mL) was added, and the mixture was stirred overnight at room temperature. Hexane was added to the reaction mixture, and the resulting solid was collected by filtration. After washing with hexane, the mixture was dried under reduced pressure. Triethylamine (1.41 mL) and di(N-succinimidyl)carbonate (519 mg) were added to a solution (20 mL) of the resulting solid (668 mg) in dimethylformamide, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (364 mg). LC-MS [M+H] + / Rt (min): 320.0 / 1.990 (Method C); 1 H-NMR (DMSO-d6) δ: 7.96 (1H, s), 7.37 (1H, d, J = 8.2 Hz), 6.93 (1H, d, J = 8.2 Hz), 6.10 (2H, dd, J = 1.1, 5.0 Hz), 4.78 (1H, ddd, J = 6.1, 7.3, 8.6 Hz), 3.90-3.72 (3H, m), 3.67 (1H, dd, J = 2.7, 12.8 Hz), 3.44 (1H, ddd, J = 3.0, 10.2, 11.5), 2.46-2.28 (1H, m), 1.85-1.68 (1H, m).

[0274] Example 22 (4R,5R)-1-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-5-[(dimethylamino)methyl]-4-methylimidazolidin-2-one [ka] To a solution (3 mL) of the compound of Reference Example 39 (59.4 mg) in acetonitrile, dimethylamine (2.0 M tetrahydrofuran solution) (0.31 mL), potassium iodide (26.2 mg), and potassium carbonate (55.6 mg) were added, followed by stirring at 60°C for 15 hours. After the reaction mixture was cooled to room temperature, saturated aqueous sodium bicarbonate was added, and the mixture was extracted with chloroform-methanol (10:1). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) and aminosilica gel column chromatography (chloroform / methanol) to give the title compound (22.6 mg). LC-MS [M+H] + / Rt (min): 333.2 / 0.569 (Method A); 1 H-NMR (400 MHz, CDCl3) δ: 7.45 (1H, d, J = 7.9 Hz), 6.76 (1H, d, J = 7.9 Hz), 4.93 (1H, s), 4.66 (2H, t, J = 8.9 Hz), 4.40-4.34 (1H, m), 3.90-3.84 (1H, m), 3.44 (2H, dt, J = 2.0, 8.9 Hz), 2.87 (1H, dd, J = 2.4, 11.9 Hz), 2.34 (1H, dd, J = 10.1, 11.9 Hz), 2.34 (6H, s), 1.35 (3H, d, J = 7.3 Hz).

[0275] Examples 23 to 26 According to the method described in Example 22, the compounds of Examples 23 to 26 were obtained using the corresponding starting compounds. [Table 56]

[0276] Example 27 (3aS,7aR)-3-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-5-methyloctahydro-2H-imidazo[4,5-c]pyridin-2-one Example 28 (3aR,7aS)-3-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-5-methyloctahydro-2H-imidazo[4,5-c]pyridin-2-one [ka] The compound of Example 7 (30.0 mg) was subjected to optical separation under the following conditions to obtain the title compounds (Example 27: 12.2 mg - first peak: 15.3 min, Example 28: 8.1 mg - second peak: 16.4 min). Column: CHIRALPAK (registered trademark) IG; Solvent: Solution A: chloroform, Solution B: 2-propanol; Mobile phase conditions: A / B = 9 / 1; Flow rate: 5 mL / min; UV detection: 254 nm; Column temperature: 40 °C [Table 57]

[0277] Examples 29 and 30 According to the method described in Example 1, the compounds of Examples 29 and 30 were obtained using the corresponding starting compounds. [Table 58]

[0278] Example 31 cis-5-Cyclopropyl-3-(7,8-dihydro[1,4]dioxino[2,3-e][1,3]benzothiazol-2-yl)octahydro-2H-imidazo[4,5-c]pyridin-2-one [ka] To a solution of the compound of Example 29 (100 mg) in methanol / tetrahydrofuran (1.5 mL / 1.2 mL), (1-ethoxycyclopropoxy)trimethylsilane (0.121 mL), acetic acid (0.172 mL), and sodium cyanoborohydride (94 mg) were added and stirred at 60°C for 3 hours. After the reaction mixture was cooled to room temperature, saturated aqueous sodium bicarbonate was added and the mixture was extracted with chloroform / ethanol (3 / 1). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to give the title compound (77 mg). LC-MS [M+H] + / Rt (min): 373.3 / 0.585 (Method A); 1 H-NMR (DMSO-d6) δ: 7.72 (1H, s), 7.27 (1H, d, J = 8.5 Hz), 6.79 (1H, d, J = 8.5 Hz), 4.61-4.53 (1H, m), 4.41-4.25 (4H, m), 3.98-3.92 (1H, m), 3.49-3.41 (1H, m), 2.75-2.67 (1H, m), 2.45-2.36 (1H, m), 2.35-2.27 (1H, m), 1.86-1.75 (2H, m), 1.68-1.63 (1H, m), 0.43-0.37 (2H, m), 0.33-0.23 (2H, m).

[0279] Example 32 According to the method described in Example 31, the compound of Example 32 was obtained using the corresponding starting compound. [Table 59]

[0280] Example 33 (3aS,7aR)-5-Cyclopropyl-3-(7,8-dihydro[1,4]dioxino[2,3-e][1,3]benzothiazol-2-yl)octahydro-2H-imidazo[4,5-c]pyridin-2-one Example 34 (3aR,7aS)-5-Cyclopropyl-3-(7,8-dihydro[1,4]dioxino[2,3-e][1,3]benzothiazol-2-yl)octahydro-2H-imidazo[4,5-c]pyridin-2-one [ka] The compound of Example 31 (104 mg) was subjected to optical separation under the following conditions to obtain the title compounds (Example 33: 37 mg - first peak: 13.0 min, Example 34: 36 mg - second peak: 14.9 min). Column: CHIRALPAK (registered trademark) IG; Solvent: Solution A: chloroform, Solution B: methanol, Solution C: diethylamine; Mobile phase conditions: A / B / C = 99 / 1 / 0.001; Flow rate: 0.5 mL / min; UV detection: 280 nm; Column temperature: 25°C [Table 60]

[0281] Example 35 (3aS,7aR)-5-Cyclopropyl-3-(2H-[1,3]dioxolo[4,5-e][1,3]benzothiazol-7-yl)octahydro-2H-imidazo[4,5-c]pyridin-2-one Example 36 (3aR,7aS)-5-Cyclopropyl-3-(2H-[1,3]dioxolo[4,5-e][1,3]benzothiazol-7-yl)octahydro-2H-imidazo[4,5-c]pyridin-2-one [ka] The compound of Example 32 (85.0 mg) was subjected to optical separation under the following conditions to obtain the title compounds (Example 35: 37.1 mg - first peak: 10.7 min, Example 36: 36.4 mg - second peak: 12.3 min). Column: CHIRALPAK (registered trademark) IG; Solvent: Solution A: chloroform, Solution B: methanol, Solution C: diethylamine; Mobile phase conditions: A / B / C = 99 / 1 / 0.002; Flow rate: 5 mL / min; UV detection: 280 nm; Column temperature: 40 °C [Table 61]

[0282] Examples 37 to 43 According to the method described in Reference Example 14, the compounds of Examples 37 to 43 were obtained using the corresponding starting compounds. [Table 62-1] [Table 62-2]

[0283] Example 44 According to the method described in Reference Example 14, the compound of Example 44 was obtained using the corresponding starting compound. [Table 63]

[0284] Examples 45 to 66 According to the method described in Example 1, the compounds of Examples 45 to 66 were obtained using the corresponding starting compounds. [Table 64-1] [Table 64-2] [Table 64-3] [Table 64-4]

[0285] Examples 67 to 108 According to the method described in Example 7 or Example 8, the compounds of Examples 67 to 108 were obtained using the corresponding starting compounds. [Table 65-1] [Table 65-2] [Table 65-3] [Table 65-4] [Table 65-5] [Table 65-6] [Table 65-7] [Table 65-8]

[0286] Example 109 (3aS,7aR)-5-Cyclopropyl-3-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)octahydro-2H-imidazo[4,5-c]pyridin-2-one Example 110 (3aR,7aS)-5-Cyclopropyl-3-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)octahydro-2H-imidazo[4,5-c]pyridin-2-one [ka] The compound of Example 98 (12.0 mg) was subjected to optical separation under the following conditions to obtain the title compounds (Example 109: 1.5 mg - first peak: 9.40 min, Example 110: 1.1 mg - second peak: 10.8 min). Column: CHIRALPAK (registered trademark) IG; Solvent: Solution A: chloroform, Solution B: methanol, Solution C: diethylamine; Mobile phase conditions: A / B / C = 99 / 1 / 0.002; Flow rate: 7 mL / min; UV detection: 280 nm; Column temperature: 40 °C [Table 66]

[0287] Example 111 [(3aS,7aR)-3-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-2-oxooctahydro-5H-imidazo[4,5-c]pyridin-5-yl]acetonitrile Example 112 [(3aR,7aS)-3-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-2-oxooctahydro-5H-imidazo[4,5-c]pyridin-5-yl]acetonitrile [ka] The compound of Example 100 (30.0 mg) was optically resolved under the following conditions to obtain the title compounds (Example 111: 13.8 mg - First Peak: 13.0 min, Example 112: 12.2 mg - Second Peak: 14.5 min). Column: CHIRALPAK (registered trademark) IC; Solvent: Solution A: chloroform, Solution B: methanol, Solution C: diethylamine; Mobile phase conditions: A / B / C = 98 / 1 / 0.001; Flow rate: 10 mL / min; UV detection: 254 nm; Column temperature: 40 °C [Table 67]

[0288] Example 113 (3aS,7aR)-3-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-5-(2-propyn-1-yl)octahydro-2H-imidazo[4,5-c]pyridin-2-one Example 114 (3aR,7aS)-3-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-5-(2-propyn-1-yl)octahydro-2H-imidazo[4,5-c]pyridin-2-one [ka] The compound of Example 99 (30.0 mg) was optically resolved under the following conditions to obtain the title compounds (Example 113: 15.4 mg - First Peak: 10.2 min, Example 114: 13.7 mg - Second Peak: 11.3 min). Column: CHIRALPAK (registered trademark) IC; Solvent: Solution A: chloroform, Solution B: methanol, Solution C: diethylamine; Mobile phase conditions: A / B / C = 99 / 1 / 0.001; Flow rate: 10 mL / min; UV detection: 254 nm; Column temperature: 40 °C [Table 68]

[0289] Examples 115 to 118 According to the method described in Example 19, the compounds of Examples 115 to 118 were obtained using the corresponding starting compounds. [Table 69]

[0290] Examples 119 to 124 According to the method described in Example 21, the compounds of Examples 119 to 124 were obtained using the corresponding starting compounds. [Table 70]

[0291] Examples 125 to 140 According to the method described in Reference Example 14, the compounds of Examples 125 to 140 were obtained using the corresponding starting compounds. [Table 71-1] [Table 71-2] [Table 71-3]

[0292] Examples 141 to 143 According to the method described in Reference Example 70, the compounds of Examples 141 to 143 were obtained using the corresponding starting compounds. [Table 72]

[0293] Examples 144 to 147 According to the method described in Reference Example 72, the compounds of Examples 144 to 147 were obtained using the corresponding starting compounds. [Table 73]

[0294] Example 148 According to the method described in Reference Example 75, the compound of Example 148 was obtained using the corresponding starting compound. [Table 74]

[0295] Example 149 According to the method described in Reference Example 76, the compound of Example 149 was obtained using the corresponding starting compound. [Table 75]

[0296] Example 150 (3aR,7aR)-1-(7,8-Dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-6-hydroxyhexahydropyrano[3,4-d]imidazol-2(3H)-one [ka] To a solution (3 mL) of the compound of Example 129 (53.0 mg) in 1,4-dioxane, 1N hydrochloric acid (4 mL) was added at room temperature, and the mixture was stirred at room temperature for 1 hour and at 60°C for 2 hours. After cooling the reaction mixture to room temperature, saturated aqueous sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was washed with ethyl acetate to give the title compound (8.0 mg). LC-MS [M+H] + / Rt (min): 334.1 / 2.761 (Method C); 1H-NMR (DMSO-d6) δ: 7.95 (1H, s), 7.59 (1H, d, J = 8.4 Hz), 6.74 (1H, d, J = 8.4 Hz), 6.40 (1H, d, J = 4.9 Hz), 5.00-4.85 (1H, m), 4.81 (1H, td, J = 4.4, 9.1 Hz), 4.67-4.52 (2H, m), 3.98-3.84 (2H, m), 3.49-3.43 (1H, m), 3.42-3.34 (1H, m), 2.77-2.68 (1H, m), 2.00-1.90 (2H, m).

[0297] Example 151 (3aR,7aR)-1-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-6-fluorohexahydropyrano[3,4-d]imidazol-2(3H)-one [ka] Diethylaminosulfur trifluoride (0.041 mL) was added to a dichloromethane / 1,4-dioxane solution (6 mL / 9 mL) of Example 150 (69.0 mg) under ice-cooling, and the mixture was stirred under ice-cooling for 15 minutes. Saturated aqueous sodium bicarbonate was added to the reaction mixture under ice-cooling, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to give the title compound (20.0 mg). LC-MS [M+H] + / Rt (min): 336.1 / 2.123 (Method C); 1H-NMR (DMSO-d6) δ: 8.08 (1H, s), 7.60 (1H, d, J = 8.4 Hz), 6.75 (1H, d, J = 8.4 Hz), 5.67 (1H, ddd, J = 5.0, 6.9, 60.9 Hz), 4.94-4.83 (1H, m), 4.67-4.54 (2H, m), 4.13-3.96 (2H, m), 3.68 (1H, d, J = 12.6 Hz), 3.45-3.33 (2H, m), 3.22-3.02 (1H, m), 2.32-2.14 (1H, m).

[0298] Example 152 According to the method described in Reference Example 75, the compound of Example 152 was obtained using the corresponding starting compound. [Table 76]

[0299] Examples 153 and 154 According to the method described in Reference Example 147, the compounds of Examples 153 and 154 were obtained using the corresponding starting compounds. [Table 77]

[0300] Examples 155 and 156 According to the method described in Reference Example 14, the compounds of Examples 155 and 156 were obtained using the corresponding starting compounds. [Table 78]

[0301] Examples 157 and 158 According to the method described in Reference Example 147, the compounds of Examples 157 and 158 were obtained using the corresponding starting compounds. [Table 79]

[0302] Example 159 According to the method described in Reference Example 74, the compound of Example 159 was obtained using the corresponding starting compound. [Table 80]

[0303] Example 160 According to the method described in Reference Example 14, the compound of Example 160 was obtained using the corresponding starting compound. [Table 81]

[0304] Example 161 (3aR,6R,6aS)-1-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-6-methyltetrahydro-1H-furo[3,4-d]imidazol-2(3H)-one [ka] To a solution (3 mL) of Reference Example 290 (1.0 mg) in tetrahydrofuran, 1.0 M tetrabutylammonium fluoride solution (0.024 mL) was added at room temperature, and the mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (0.6 mg). LC-MS [M+H] + / Rt (min): 318.1 / 2.123 (Method C); 1H-NMR (DMSO-d6) δ: 8.17 (1H, s), 7.60 (1H, d, J = 8.4 Hz), 6.75 (1H, d, J = 8.4 Hz), 4.68 (1H, dd, J = 2.4, 8.7 Hz), 4.65-4.58 (2H, m), 4.46-4.38 (1H, m), 4.29-4.21 (1H, m), 4.02-3.94 (1H, m), 3.65 (1H, dd, J = 2.6, 9.9 Hz), 3.50-3.38 (2H, m), 1.38 (3H, d, J = 6.6 Hz).

[0305] Example 162 [(3aS,4R,6aR)-3-(7,8-dihydrofuro[3,2-e][1,3]benzothiazol-2-yl)-2-oxohexahydro-1H-furo[3,4-d]imidazol-4-yl]acetonitrile [ka] To a solution (2 mL) of Reference Example 285 (20.0 mg) in dimethyl sulfoxide, potassium cyanide (4.0 mg) was added at room temperature, followed by stirring at 80° C. for 1 hour. Potassium cyanide (16.5 mg) was further added, and the mixture was stirred at 80° C. for 35 minutes. Then, 1.0 M tetrabutylammonium fluoride solution (0.204 mL) in tetrahydrofuran was added at room temperature, followed by stirring at 70° C. for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (2.4 mg). LC-MS [M+H] + / Rt (min): 343.1 / 2.090 (Method C); 1H-NMR (DMSO-d6) δ: 8.27 (1H, s), 7.61 (1H, d, J = 8.4 Hz), 6.76 (1H, d, J = 8.4 Hz), 4.82 (1H, dd, J = 3.1, 8.9 Hz), 4.69-4.56 (2H, m), 4.49-4.56 (2H, m), 4.49-4.41 (1H, m), 4.37 (1H, dt, J = 3.1, 6.2 Hz), 4.13 (1H, dd, J = 5.2, 9.9 Hz), 3.72 (1H, dd, J = 3.3, 10.0 Hz) 3.45-3.36 (2H, m), 3.19-3.17 (2H, m).

[0306] Formulation Example 1: Tablet production The compound of Example 1 (250 g), cornstarch (54 g), carboxymethylcellulose calcium (40 g), crystalline cellulose (50 g), and magnesium stearate (6 g) are mixed and granulated by a conventional method, and compressed into 1,000 tablets, each weighing 400 mg.

[0307] Formulation Example 2: Powder Production The compound of Example 1 (500 g), lactose (470 g), hydroxypropyl cellulose (25 g) and light anhydrous silicic acid (5 g) are mixed in a conventional manner and then powdered. Test Example 1

[0308] [Inhibition of DYRK family members (DYRK1A, DYRK1B, DYRK2, DYRK3)] (Method for measuring kinase activity) Kinase activity was measured by mobility shift assay (MSA) using the QuickScout Screening Assist™ MSA kit (commercially available from Carna Biosciences). The FITC-labeled DYRKtide peptide provided with the kit was used as the substrate for the kinase reaction. A substrate mixture was prepared using assay buffer [20 mM HEPES, 0.01% Triton X-100™, 2 mM dithiothreitol, pH 7.5] containing the substrate (4 μM), MgCl2 (20 mM), and ATP (DYRK1A; 100 μM, DYRK1B; 200 μM, DYRK2; 40 μM, DYRK3; 20 μM). In addition, kinases (DYRK1A; Carna Biosciences, Catalog No. 04-130, DYRK1B; Carna Biosciences, Catalog No. 04-131, DYRK2; Carna Biosciences, Catalog No. 04-132, DYRK3; Carna Biosciences, Catalog No. 04-133) were diluted with assay buffer to prepare enzyme solutions (DYRK1A; 0.2 ng / μL, DYRK1B; 0.08 ng / μL, DYRK2; 0.04 ng / μL, DYRK3; 0.25 ng / μL). A 10 mM DMSO solution of the test compound was further diluted with DMSO to 10 concentrations (0.00003 mM, 0.0001 mM, 0.0003 mM, 0.001 mM, 0.003 mM, 0.01 mM, 0.03 mM, 0.1 mM, 0.3 mM, and 1 mM), and each was diluted 25-fold with assay buffer to prepare drug solutions (4% DMSO solutions). Five μL of the drug solution or control solution (4% DMSO-assay buffer), 5 μL of the substrate mixture, and 10 μL of the enzyme solution were mixed in a 384-well polypropylene plate and reacted at room temperature for 1 hour. The reaction was then terminated by adding 60 μL of the kit's termination buffer. Next, the amounts of the substrate (S) and phosphorylated substrate (P) in the reaction solution were measured using the LabChip EZ Reader II system (Caliper Life Sciences) according to the protocol of the assay kit.

[0309] (Method for evaluating inhibitory activity) The peak heights of the "substrate" and "phosphorylated substrate" were designated S and P, respectively, and a blank was also measured by adding assay buffer instead of the enzyme solution.

[0310] The inhibition rate (%) of the test compound was calculated according to the following formula. Inhibition rate (%) = (1-(CA) / (BA)) x 100 Here, A, B, and C respectively indicate P / (P+S) of blank wells, P / (P+S) of control solution wells, and P / (P+S) of compound-added wells.

[0311] Also, IC 50 The values ​​were calculated by regression analysis of the inhibition rate and the test compound concentration (logarithm). (Evaluation results) The inhibitory activity of representative compounds of compound (I) or pharmaceutically acceptable salts thereof contained in the pharmaceutical of the present invention against DYRK1A, DYRK1B, DYRK2, and DYRK3 is shown in Table 3. The kinase activity inhibitory effect was measured using IC 50 Values ​​less than 0.01 μM are indicated by ***, values ​​between 0.01 μM and 0.1 μM are indicated by **, values ​​between 0.1 μM and 1 μM are indicated by *, and values ​​greater than 1 μM are indicated by -. [Table 82] [Table 83] [Table 84] [Table 85] [Table 86] This result indicates that the test compound (compound (1)) has strong DYRK inhibitory activity. Test Example 2

[0312] [Hematological examination test using mice after oral administration] In this study, 8-12 week old mice (B6C3F1, female, Charles River Japan) were used. A 0.5% methylcellulose solution or a suspension of the example compound in 0.5% methylcellulose solution was orally administered to the mice at 10 mL / kg in a single or repeated dose. From the day after the final administration, blood was collected from the caudal vena cava under isoflurane anesthesia. The blood was anticoagulated in a blood collection tube containing EDTA-2K, and the reticulocyte count was quantified using a multi-parameter automated hematology analyzer (Sysmex). [Evaluation results] It has been confirmed that Compound (I) or a pharmaceutically acceptable salt thereof contained in the medicament of the present invention exhibits safety within its therapeutic range. [Industrial Applicability]

[0313] The pharmaceuticals provided by the present invention are useful as preventive or therapeutic agents for diseases known to be associated with abnormal cellular responses mediated by DYRK1A, such as psychiatric and neurological disorders such as Alzheimer's disease, Parkinson's disease, Down's syndrome, mental retardation, memory impairment, amnesia, and depression, as well as tumors such as brain tumors. Furthermore, as inhibitors of DYRK1B, they are useful as pharmaceuticals (or pharmaceutical compositions) for the prevention or treatment of tumors such as pancreatic cancer. Furthermore, since the pharmaceuticals provided by the present invention regulate p53 and induce apoptosis in response to DNA damage, they are useful as pharmaceuticals (or pharmaceutical compositions) for the prevention or treatment of bone resorption diseases and osteoporosis. Furthermore, as inhibitors of DYRK3, they are useful as pharmaceuticals (or pharmaceutical compositions) for the prevention or treatment of sickle cell anemia, chronic kidney disease, bone resorption diseases, and osteoporosis. Furthermore, as DYRK inhibitors, they are useful as reagents for pathological imaging of the above-mentioned diseases and as reagents for basic experiments and research.

Claims

1. The following formula (1): 【Chemistry 1】 [In the formula, A １ This represents an oxygen atom or a nitrogen atom (=N-), A ２ CR Ｂ CR Ｃ R Ｄ , oxygen atom or NR Ａ１ This represents, L １ may be substituted methylene, may be substituted ethylene, may be substituted methine, may be substituted ethanediylidene, =N- or NR Ａ２ This represents, R Ａ１ 、 R Ａ２ 、 R Ｂ 、 R Ｃ 以及 R Ｄ 各自独立地表示氢原子或可被取代的 C １－６ 烷基, R １ C is a hydrogen atom, a halogen atom, or a substituted C １－６ Represents alkyl, X represents a carbon atom or a nitrogen atom, L ２ C may be substituted. １－４ Represents alkylene, R Ｅ C may be substituted. １－６ Represents alkyl, Z is -NR ２ R ３ OR ７ This represents, R ７ C may be substituted. １－６ Alkyl, or R ４ A C which may be substituted, is formed together with １－７ Represents alkylene, and herein, R ４ and R ７ However, together with the carbon and oxygen atoms to which they are bonded, they form a saturated heterocycle of 5-11 members, which may be substituted. R ２ C is a hydrogen atom, which may be substituted. １－６ Alkyl, C(O)-R Ｅ , C ３－１０ Cycloalkyl, C ２－６ Represents an alkynyl or a cyclic group of a 4-11 member saturated heterocycle, R ３ C is a hydrogen atom, which may be substituted. １－６ Alkyl or C(O)-R Ｅ This represents, R ４ C may be substituted. １－６ Represents alkyl, Here, R ２ and R ３ However, together with the nitrogen atom to which they are bonded, they may form a substituted 4-11 member saturated heterocycle, or R ３ and R ４ However, together with the nitrogen and carbon atoms to which they are bonded, they may form a substituted 4-11 member saturated heterocycle, or the R ２ , R ３ and any carbon atom and R on a saturated heterocycle composed of nitrogen atoms ４ These may combine to form a 4-11 member saturated heterocycle. A pharmaceutical product containing a compound represented by [ ] or a pharmaceutically acceptable salt thereof.

2. Z is -NR ２ R ３ Represents R ２ and R ３ However, each can be considered independently: a hydrogen atom, or a carbon atom that may be substituted. １－６ Alkyl or C(O)-R Ｅ This represents, and here, R ２ and R ３ The pharmaceutical product according to claim 1, wherein these may, together with the nitrogen atom to which they are bonded, form a substituted or otherwise saturated 4-8 membered heterocycle.

3. Z is -NR ２ R ３ Represents R ３ and R ４ The pharmaceutical product according to claim 1, wherein each atom, together with the nitrogen and carbon atoms to which it is bonded, forms a substituted 4-8 member saturated heterocycle.

4. R １ The pharmaceutical product according to any one of claims 1 to 3, wherein the atom is a hydrogen atom.

5. The pharmaceutical product according to claim 1, wherein X is a carbon atom.

6. A １ However, it is an oxygen atom, A ２ It is methylene, L １ The pharmaceutical product according to claim 5, wherein is methylene.

7. Equation (1) is given by the following equation (1a): 【Chemistry 2】 [In the formula, A ２ This represents a methylene or oxygen atom that may be substituted, L １ represents optionally substituted methylene or optionally substituted ethylene, L ２ C may be substituted. １－４ Represents alkylene, R ２ and R ３ Each of these independently consists of a hydrogen atom and a C atom which may be substituted. １－６ Alkyl or C(O)-R Ｅ This represents, and here, R ２ and R ３ However, these may, together with the nitrogen atom to which they are bonded, form a substituted 4-8 member saturated heterocycle. R Ｅ C may be substituted. １－６ Represents alkyl, R ４ C may be substituted. １－６ A pharmaceutical product comprising the compound described in claim 1, represented by [], or a pharmaceutically acceptable salt thereof.

8. R ２ and R ３ However, each of them may be substituted independently. １－６ The pharmaceutical product according to claim 7, wherein it is alkyl.

9. R ２ and R ３ The pharmaceutical product according to claim 7, wherein these combine with the nitrogen atom to which they bond to form a saturated heterocycle of 4-8 members, which may be substituted.

10. L ２ However, C １－３ The pharmaceutical product according to claim 7, which is alkylene.

11. Equation (1) is given by the following equation (1b): 【Transformation 3】 [In the formula, A ２ This represents a methylene or oxygen atom that may be substituted, L １ represents optionally substituted methylene or optionally substituted ethylene, l and m each independently represent 1, 2, or 3, where the sum of l and m is 5 or less. n represents 1, 2, 3, or 4. R ２ C is a hydrogen atom, which may be substituted. １－６ Alkyl, C ３－１０ Cycloalkyl or C(O)-R Ｅ This represents, R Ｅ represents an optionally substituted C １－６ alkyl, R Ｆ C is a hydrogen atom, a halogen atom, or a substituted C １－６ Represents alkyl, If n is 2, 3, or 4, R Ｆ They may be the same or different, and two Rs on the same carbon atom Ｆ However, they may also form a spiro ring consisting of a 4-8 member saturated heterocycle or a 3-8 member saturated carbon ring together with the carbon atoms they bond to, or two R atoms on different carbon atoms. Ｆ A pharmaceutical product containing the compound described in claim 1, or a pharmaceutically acceptable salt thereof, which may be bonded together to form a crosslink.

12. R ２ is a hydrogen atom, optionally substituted C １－６ alkyl or C ３－１０ cycloalkyl, the medicament according to claim 11.

13. R ２ However, C may be substituted. １－６ The pharmaceutical product according to claim 11, wherein it is alkyl.

14. The pharmaceutical product according to claim 11, wherein l and m are each independently 1 or 2.

15. Z is - OR ７ And R ４ and R ７ The pharmaceutical product according to claim 1, wherein each atom, together with the carbon and oxygen atoms to which it is bonded, forms a substituted 5-8 member saturated heterocycle.

16. Equation (1) is given by the following equation (1c): 【Chemistry 4】 [In the formula, A ２ This represents a methylene or oxygen atom that may be substituted, L １ represents optionally substituted methylene or optionally substituted ethylene, p and q each independently represent 1, 2, or 3, where the sum of p and q is 5 or less. t represents 1, 2, 3, or 4. R Ｇ C may be a hydrogen atom, a halogen atom, or a substituted C １－６ Alkyl, optionally substituted C １－６ Represents an alkoxy or CN group, If t is 2, 3, or 4, R Ｇ They may be the same or different, and two Rs on the same carbon atom Ｇ However, they may also form a spiro ring consisting of a 4-8 member saturated heterocycle or a 3-8 member saturated carbon ring together with the carbon atoms they bond to, or two R atoms on different carbon atoms. Ｇ The pharmaceutical product according to claim 1, which is represented by [but may be bonded together to form a crosslink].

17. The pharmaceutical product according to claim 1, comprising a compound selected from the group consisting of the following compounds or a pharmaceutically acceptable salt thereof: cis-3-(7,8-dihydrofl[3,2-e][1,3]benzothiazole-2-yl)-5-methyloctahydro-2H-imidazo[4,5-c]pyridine-2-one (Example 7); cis-3-(7,8-dihydrofl[3,2-e][1,3]benzothiazole-2-yl)-5-(2-methoxyethyl)octahydro-2H-imidazo[4,5-c]pyridine-2-one (Example 8); cis-1-(7,8-dihydrofl[3,2-e][1,3]benzothiazole-2-yl)-5-methyloctahydro-2H-imidazo[4,5-c]pyridine-2-one (Example 9); cis-3-(7,8-dihydrofl[3,2-e][1,3]benzothiazole-2-yl)-5-ethyloctahydro-2H-imidazo[4,5-c]pyridine-2-one (Example 11); cis-1-(7,8-dihydrofl[3,2-e][1,3]benzothiazole-2-yl)-5-methylhexahydropyrrolo[3,4-d]imidazole l-2(1H)-one (Example 14); cis-3-(7,8-dihydrofl[3,2-e][1,3]benzothiazole-2-yl)-5-(propan-2-yl)octahydro-2H-imidazo[4,5-c]pyridine-2-one (Example 15); cis-3-(7,8-dihydrofl[3,2-e][1,3]benzothiazole-2-yl)-5-methyloctahydroimidazo[4,5-c]azepine-2(1H)-one (Example 17); (3aS,7aS)-3-(7,8-dihydrofl[3,2-e][1,3]benzothiazole-2-yl)-5-(oxetan-3-yl)octahydro-2H-imidazo[4,5-c]pyridine-2-one (Example 19); (3aR,7aR)-1-(2H-[1,3]dioxolo[4,5-e][1,3]benzothiazole-7-yl)hexahydropyrano[3,4-d]imidazole-2(3H)-one (Example 21); (4S,5R)-1-(7,8-dihydrofl[3,2-e][1,3]benzothiazole-2-yl)-4-methyl-5-[(morpholin-4-yl)methyl]imidazolidined-2-one (Example 23); (4R,5R)-1-(7,8-dihydrofl[3,2-e][1,3]benzothiazole-2-yl)-4-methyl-5-[(morpholin-4-yl)methyl]imidazolidinedione-2-one (Example 24); (3aR,7aS)-3-(7,8-dihydrofl[3,2-e][1,3]benzothiazole-2-yl)-5-methyloctahydro-2H-imidazo[4,5-c]pyridine-2-one (Example 28); (3aR,7aS)-5-cyclopropyl-3-(7,8-dihydro[1,4]dioxyno[2,3-e][1,3]benzothiazole-2-yl)octahydro-2H-imidazo[4,5-c]pyridine-2-one (Example 34); (3aR,7aS)-5-cyclopropyl-3-(2H-[1,3]dioxolo[4,5-e][1,3]benzothiazole-7-yl)octahydro-2H-imidazo[4,5-c]pyridine-2-one (Example 36); (3aR,7aR)-1-(7,8-dihydro[1,4]dioxyno[2,3-e][1,3]benzothiazole-2-yl)hexahydropyrano[3,4-d]imidazole-2(3H)-one (Example 37); (3aR,6S,7aR)-1-(7,8-dihydrofl[3,2-e][1,3]benzothiazole-2-yl)-6-methylhexahydropyrano[3,4-d]imidazole-2(3H)-one (Example 38); (3aR,6S,7aR)-1-(7,8-dihydro[1,4]dioxyno[2,3-e][1,3]benzothiazole-2-yl)-6-methylhexahydropyrano[3,4-d]imidazole-2(3H)-one (Example 39); (3aR,6R,7aR)-1-(7,8-dihydrofl[3,2-e][1,3]benzothiazole-2-yl)-6-(fluoromethyl)hexahydropyrano[3,4-d]imidazole-2(3H)-one (Example 40); (3aR,6R,7aR)-1-(7,8-dihydro[1,4]dioxyno[2,3-e][1,3]benzothiazole-2-yl)-6-(fluoromethyl)hexahydropyrano[3,4-d]imidazole-2(3H)-one (Example 41); (3aR,6S,7aR)-1-(7,8-dihydrofl[3,2-e][1,3]benzothiazole-2-yl)-6-ethylhexahydropyrano[3,4-d]imidazole-2(3H)-one (Example 42); (3aR,6S,7aR)-1-(7,8-dihydro[1,4]dioxyno[2,3-e][1,3]benzothiazole-2-yl)-6-ethylhexahydropyrano[3,4-d]imidazole-2(3H)-one (Example 43); (4S,5S)-1-(7,8-dihydrofl[3,2-e][1,3]benzothiazole-2-yl)-5-(methoxymethyl)-4-methylimidazolidined-2-one (Example 44); (3aR,6aS)-1-(7,8-dihydroflou[3,2-e][1,3]benzothiazole-2-yl)tetrahydro-1H-flou[3,4-d]imidazole-2(3H)-one (Example 65); rac-(3aR,7aS)-3-(7,8-dihydrofl[3,2-e][1,3]benzothiazole-2-yl)-5-(oxetan-3-yl)octahydro-2H-imidazo[4,5-c]pyridine-2-one (Example 71); rac-(3aR,7aS)-5-cyclobutyl-3-(7,8-dihydrofl[3,2-e][1,3]benzothiazole-2-yl)octahydro-2H-imidazo[4,5-c]pyridine-2-one (Example 72); rac-(3aR,8aS)-3-(7,8-dihydrofl[3,2-e][1,3]benzothiazole-2-yl)-5-(oxetan-3-yl)octahydroimidazo[4,5-c]azepine-2(1H)-one (Example 73); rac-(3aR,7aS)-3-(7,8-dihydro[1,4]dioxyno[2,3-e][1,3]benzothiazole-2-yl)-5-methyloctahydro-2H-imidazo[4,5-c]pyridine-2-one (Example 76); rac-(3aR,7aS)-1-(7,8-dihydro[1,4]dioxyno[2,3-e][1,3]benzothiazole-2-yl)-5-methyloctahydro-2H-imidazo[4,5-c]pyridine-2-one (Example 77); rac-(3aR,7aS)-1-(2H-[1,3]dioxolo[4,5-e][1,3]benzothiazole-7-yl)-5-methyloctahydro-2H-imidazo[4,5-c]pyridine-2-one (Example 78); rac-(3aR,7aS)-3-(2H-[1,3]dioxolo[4,5-e][1,3]benzothiazole-7-yl)-5-methyloctahydro-2H-imidazo[4,5-c]pyridine-2-one (Example 79); rac-(3aR,7aS)-3-(7,8-dihydro[1,4]dioxyno[2,3-e][1,3]benzothiazole-2-yl)-5-(oxetan-3-yl)octahydro-2H-imidazo[4,5-c]pyridine-2-one (Example 80); rac-(3aR,7aS)-3-(2H-[1,3]dioxolo[4,5-e][1,3]benzothiazole-7-yl)-5-(oxetan-3-yl)octahydro-2H-imidazo[4,5-c]pyridine-2-one (Example 81); rac-(3aR,8aS)-3-(2H-[1,3]dioxolo[4,5-e][1,3]benzothiazole-7-yl)-5-methyloctahydroimidazo[4,5-c]azepine-2(1H)-one (Example 85); rac-(3aR,8aS)-3-(2H-[1,3]dioxolo[4,5-e][1,3]benzothiazole-7-yl)-5-(oxetan-3-yl)octahydroimidazo[4,5-c]azepine-2(1H)-one (Example 86); (3aS,6S,7aR)-1-(7,8-dihydrofl[3,2-e][1,3]benzothiazole-2-yl)-5,6-dimethyloctahydro-2H-imidazo[4,5-c]pyridine-2-one (Example 93); rac-(3aR,7aS)-5-cyclopropyl-3-(7,8-dihydrofl[3,2-e][1,3]benzothiazole-2-yl)octahydro-2H-imidazo[4,5-c]pyridine-2-one (Example 98); rac-(3aR,7aS)-3-(7,8-dihydrofl[3,2-e][1,3]benzothiazole-2-yl)-5-(2-propyne-1-yl)octahydro-2H-imidazo[4,5-c]pyridine-2-one (Example 99); rac-[(3aR,7aS)-3-(7,8-dihydrofl[3,2-e][1,3]benzothiazole-2-yl)-2-oxooctahydro-5H-imidazo[4,5-c]pyridine-5-yl]acetonitrile (Example 100); rac-(3aR,6aS)-1-(7,8-dihydrofl[3,2-e][1,3]benzothiazole-2-yl)-5-(2-propyne-1-yl)hexahydropyrrolo[3,4-d]imidazole-2(1H)-one (Example 102); rac-[(3aR,6aS)-1-(7,8-dihydrofl[3,2-e][1,3]benzothiazole-2-yl)-2-oxohexahydropyrrolo[3,4-d]imidazole-5(1H)-yl]acetonitrile (Example 103); rac-(3aR,8aS)-5-cyclopropyl-3-(7,8-dihydrofl[3,2-e][1,3]benzothiazole-2-yl)octahydroimidazo[4,5-c]azepine-2(1H)-one (Example 104); rac-(3aR,8aS)-3-(7,8-dihydrofl[3,2-e][1,3]benzothiazole-2-yl)-5-(2-propin-1-yl)octahydroimidazo[4,5-c]azepine-2(1H)-one (Example 105); rac-[(3aR,8aS)-3-(7,8-dihydrofl[3,2-e][1,3]benzothiazole-2-yl)-2-oxooctahydroimidazo[4,5-c]azepine-5(1H)-yl]acetonitrile (Example 106); rac-(3aR,7aS)-3-(7,8-dihydrofl[3,2-e][1,3]benzothiazole-2-yl)-5-(2,2,2-trifluoroethyl)octahydro-2H-imidazo[4,5-c]pyridine-2-one (Example 107); rac-(3aR,7aS)-5-(2,2-difluoroethyl)-3-(7,8-dihydrofluoro[3,2-e][1,3]benzothiazole-2-yl)octahydro-2H-imidazo[4,5-c]pyridine-2-one (Example 108); (3aR,7aS)-5-cyclopropyl-3-(7,8-dihydrofl[3,2-e][1,3]benzothiazole-2-yl)octahydro-2H-imidazo[4,5-c]pyridine-2-one (Example 110); [(3aR,7aS)-3-(7,8-dihydrofl[3,2-e][1,3]benzothiazole-2-yl)-2-oxooctahydro-5H-imidazo[4,5-c]pyridine-5-yl]acetonitrile (Example 112); (3aR,7aS)-3-(7,8-dihydrofl[3,2-e][1,3]benzothiazole-2-yl)-5-(2-propyne-1-yl)octahydro-2H-imidazo[4,5-c]pyridine-2-one (Example 114); (4S,5R)-1-(7,8-dihydrofl[3,2-e][1,3]benzothiazole-2-yl)-5-{[(3S)-3-fluoropyrrolidine-1-yl]methyl}-4-methylimidazolidined-2-one (Example 115); (4S,5R)-5-[(3,3-difluoroazetidine-1-yl)methyl]-1-(7,8-dihydrofl[3,2-e][1,3]benzothiazole-2-yl)-4-methylimidazolidinedione-2-one (Example 116); (4S,5R)-5-[(3,3-difluoropyrrolinidine-1-yl)methyl]-1-(7,8-dihydrofl[3,2-e][1,3]benzothiazole-2-yl)-4-methylimidazolidined-2-one (Example 117); (4S,5R)-1-(7,8-dihydrofl[3,2-e][1,3]benzothiazole-2-yl)-5-[(3-fluoroazetidine-1-yl)methyl]-4-methylimidazolidined-2-one (Example 118); rac-(3aR,7aR)-3-(7,8-dihydrofl[3,2-e][1,3]benzothiazole-2-yl)hexahydropyrano[3,4-d]imidazole-2(3H)-one (Example 120); rac-(3aR,7aR)-1-(7,8-dihydrofl[3,2-e][1,3]benzothiazole-2-yl)hexahydropyrano[3,4-d]imidazole-2(3H)-one (Example 121); (3aR,7aR)-1-(7,8-dihydrofl[3,2-e][1,3]benzothiazole-2-yl)hexahydropyrano[3,4-d]imidazole-2(3H)-one (Example 122); (3aR,7aR)-1-(7,8-dihydrofl[3,2-e][1,3]benzothiazole-2-yl)-6,6-dimethylhexahydropyrano[3,4-d]imidazole-2(3H)-one (Example 124); (3aR,6R,7aR)-1-(7,8-dihydrofl[3,2-e][1,3]benzothiazole-2-yl)-2-oxooctahydropyrano[3,4-d]imidazole-6-carbonitrile (Example 127); (3aR,6R,7aR)-1-(7,8-dihydrofl[3,2-e][1,3]benzothiazole-2-yl)-6-methoxyhexahydropyrano[3,4-d]imidazole-2(3H)-one (Example 129); (3aR,6R,7aR)-1-(2H-[1,3]dioxolo[4,5-e][1,3]benzothiazole-7-yl)-2-oxooctahydropyrano[3,4-d]imidazole-6-carbonitrile (Example 131); (3aR,6R,7aR)-1-(7,8-dihydro[1,4]dioxyno[2,3-e][1,3]benzothiazole-2-yl)-2-oxooctahydropyrano[3,4-d]imidazole-6-carbonitrile (Example 133); (3aR,8aR)-1-(7,8-dihydro[1,4]dioxyno[2,3-e][1,3]benzothiazole-2-yl)hexahydro-1H-oxepino[3,4-d]imidazole-2(3H)-one (Example 135); (3aR,6S,7aR)-1-(2H-[1,3]dioxolo[4,5-e][1,3]benzothiazole-7-yl)-6-ethylhexahydropyrano[3,4-d]imidazole-2(3H)-one (Example 138); (3aR,6S,7aR)-1-(2H-[1,3]dioxolo[4,5-e][1,3]benzothiazole-7-yl]-6-methylhexahydropyrano[3,4-d]imidazole-2(3H)-one (Example 139); (3aR,6R,7aR)-1-(2H-[1,3]dioxolo[4,5-e][1,3]benzothiazole-7-yl]-6-(fluoromethyl)hexahydropyrano[3,4-d]imidazole-2(3H)-one (Example 140); (3aR,6R,7aR)-1-(7,8-dihydrofl[3,2-e][1,3]benzothiazole-2-yl)-6-(hydroxymethyl)hexahydropyrano[3,4-d]imidazole-2(3H)-one (Example 144); (3aR,6R,7aR)-1-(7,8-dihydro[1,4]dioxyno[2,3-e][1,3]benzothiazole-2-yl)-6-(hydroxymethyl)hexahydropyrano[3,4-d]imidazole-2(3H)-one (Example 146); (3aR,6R,7aR)-1-(2H-[1,3]dioxolo[4,5-e][1,3]benzothiazole-7-yl)-6-(hydroxymethyl)hexahydropyrano[3,4-d]imidazole-2(3H)-one (Example 147); (3aR,6R,7aR)-1-(7,8-dihydrofl[3,2-e][1,3]benzothiazole-2-yl)-6-ethinylhexahydropyrano[3,4-d]imidazole-2(3H)-one (Example 149); (3aR,7aR)-1-(7,8-dihydrofl[3,2-e][1,3]benzothiazole-2-yl)-6-fluorohexahydropyrano[3,4-d]imidazole-2(3H)-one (Example 151); (3aR,6S,6aS)-1-(7,8-dihydroflou[3,2-e][1,3]benzothiazole-2-yl)-6-(hydroxymethyl)tetrahydro-1H-flou[3,4-d]imidazole-2(3H)-one (Example 157); (3aR,6S,6aS)-1-(7,8-dihydroflou[3,2-e][1,3]benzothiazole-2-yl)-6-(fluoromethyl)tetrahydro-1H-flou[3,4-d]imidazole-2(3H)-one (Example 159); (3aR,6R,6aS)-1-(7,8-dihydroflou[3,2-e][1,3]benzothiazole-2-yl)-6-methyltetrahydro-1H-flou[3,4-d]imidazole-2(3H)-one (Example 161); and [(3aS,4R,6aR)-3-(7,8-dihydrofl[3,2-e][1,3]benzothiazole-2-yl)-2-oxohexahydro-1H-fl[3,4-d]imidazole-4-yl]acetonitrile (Example 162).

18. A pharmaceutical product containing any of the compounds described in Examples 1 to 162 or a pharmaceutically acceptable salt thereof.

19. A pharmaceutical composition comprising the compound described in claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

20. A therapeutic and / or prophylactic agent for diseases involving DYRK, comprising the compound described in claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

21. The therapeutic and / or prophylactic agent according to claim 20, wherein the disease in which DYRK is involved is frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration, Lewy body dementia, vascular dementia, traumatic brain injury, chronic traumatic encephalopathy, stroke, Alzheimer's disease, Parkinson's disease, Down syndrome, depression and associated mental retardation, memory impairment, memory loss, learning disability, intellectual disability, cognitive impairment, mild cognitive impairment, dementia symptoms, or brain tumor, pancreatic cancer, ovarian cancer, osteosarcoma, colorectal cancer, lung cancer, bone resorption disease, osteoporosis, sickle cell anemia, chronic kidney disease, or bone resorption disease.

22. The pharmaceutical composition according to claim 19, for use in the treatment and / or prevention of diseases involving DYRK.

23. A pharmaceutical product comprising the pharmaceutical product described in claim 1 and at least one drug selected from drugs classified as anticancer drugs, antipsychotic drugs, antidementia drugs, antiepileptic drugs, antidepressants, gastrointestinal drugs, thyroid hormone drugs, or antithyroid drugs.

24. The pharmaceutical composition according to claim 19, for use in combination with at least one drug selected from drugs classified as anticancer drugs, antipsychotic drugs, antidementia drugs, antiepileptic drugs, antidepressants, gastrointestinal drugs, thyroid hormone drugs, or antithyroid drugs, for treating frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration, Lewy body dementia, vascular dementia, traumatic brain injury, chronic traumatic encephalopathy, stroke, Alzheimer's disease, Parkinson's disease, Down syndrome, depression and its associated complications, intellectual disability, memory impairment, memory loss, learning disability, intellectual disability, cognitive impairment, mild cognitive impairment, progression of dementia symptoms, or prevention of dementia onset, or for treating brain tumors, pancreatic cancer, ovarian cancer, osteosarcoma, colorectal cancer, lung cancer, bone resorption disorders, osteoporosis, sickle cell anemia, or chronic kidney disease.

25. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic and / or prophylactic agent for diseases involving DYRK.

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