Dihydrochromene derivatives

Abstract

The present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 1A , R 1B , R 1C and R 1D is a hydrogen atom, etc. 2A and R 2B is a hydrogen atom, etc. 3A , R 3B , R 3C and R 3 is a hydrogen atom, etc., L is a bond, etc., V is C 1‑6 The alkylene group, Q being an optionally substituted imidazole, is a novel antitumor agent targeting CSCs, which are believed to be closely related to the sustained proliferation of malignant tumors, the metastasis or recurrence of cancer, and the resistance to antitumor agents.

Description

Technical Field

[0001] The present invention relates to dihydrochromene derivatives and pharmaceutically acceptable salts thereof which can be used as medicines, and to antitumor agents containing the derivatives as effective ingredients. Background Art

[0002] Even if conventional cancer treatments are able to induce tumor regression, they are sometimes not expected to bring meaningful survival effects, partly because it has been proposed that cancer stem cells (hereinafter referred to as "CSCs" when necessary) are closely related to the continued proliferation of malignant tumors, metastasis or recurrence of cancer, and resistance to antitumor agents. CSCs have been identified in almost all types of major human cancers (such as breast cancer, colon cancer, lung cancer, and hematological malignancies) (Non-Patent Document 1). Moreover, CSCs differ greatly in biological characteristics from normal cancer cells obtained by differentiation of CSCs, and thus the development of antitumor agents targeting CSCs is expected to lead to new cancer treatment strategies (Non-Patent Document 2).

[0003] One of the characteristics of CSCs is self-renewal ability (Non-Patent Document 3). Established reliable methods for measuring the self-renewal ability of cells include, for example, a method for measuring the spheroidization ability of cancer cells under non-adherent conditions in the absence of serum (Non-Patent Document 4).

[0004] There is no document disclosed so far that the compounds of the present invention represented by the formula (1) shown below can exhibit anticancer effects or inhibitory effects on the spheroidization ability of cancer cells.

[0005] Prior art

[0006] (Non-patent reference)

[0007] [Non-patent document 1] Boman et al., Journal of Clinical Oncology 26(17): 2795-2799. 2008

[0008] [Non-patent document 2] Lobo et al., Annu Rev Cell Dev Biol 23: 675-99. 2007

[0009] [Non-patent document 3] Al-Hajj et al., Oncogene 23(43): 7274-82. 2004

[0010] [Non-patent document 4] Ponti et al., Cancer Res 65(13): 5506-11. 2005. Summary of the invention

[0011] (Technical issue)

[0012] An object of the present invention is to provide a compound that can be used as a novel antitumor agent targeting CSCs, which are considered to be closely related to the continuous proliferation of malignant tumors, metastasis or recurrence of cancer, and resistance to antitumor agents.

[0013] (Solution to the problem)

[0014] The present inventors have conducted extensive studies to achieve the above-mentioned object, and have subsequently found that a compound of the following formula (1) or a pharmaceutically acceptable salt thereof (hereinafter referred to as "the compound of the present invention" when necessary) has an effective inhibitory effect on the spheroidization ability of cancer cells and is very useful as a novel antitumor agent. Based on the above-mentioned findings, the present invention has been achieved.

[0015] The present invention is described as follows.

[0016] (Item 1) A compound of formula (I):

[0017]

[0018] or a pharmaceutically acceptable salt thereof, wherein

[0019] R 1A , R 1B , R 1C and R 1D are each independently a hydrogen atom, a halogen atom, an azido group or a cyano group, provided that R 1A , R 1B , R 1C and R 1D Not all of them are hydrogen atoms.

[0020] R 2A and R 2B are independently a hydrogen atom or a C 1-6 alkyl,

[0021] R 3A , R 3B , R 3C and R 3D are independently a hydrogen atom, a halogen atom, a hydroxyl group, a C 1-6 Alkyl, C 1-6 Alkoxy, -CO2R 4 、-NR 5 R 6 or -NR 7 COR 8 , or R 3A , R 3B , R 3C and R 3D Any two of them can be joined together to form =O at the common carbon atom to which they are attached,

[0022] L is a bond or -C(O)-,

[0023] V is 1 to 3 independently selected from fluorine atoms, hydroxyl groups, C 1-6 Alkoxy, C 3-7 The C substituted with a cycloalkyl, a 3- to 7-membered saturated heterocyclic group, a cyano group, and an azido group 1-6 Alkylene,

[0024] Q is an optionally substituted imidazolyl group,

[0025] R 4 and R 8 Each independently is C 1-3 Alkyl, and

[0026] R 5 , R 6 and R 7 are independently a hydrogen atom or a C 1-3 Alkyl, or when R 5 and R 6 Both C 1-3 When alkyl groups are present, they may combine with the nitrogen atom to which they are attached to form a 3- to 6-membered nitrogen-containing saturated heterocyclic group,

[0027] Provided that the following compounds of formula (Z-1) and (Z-2) are not included:

[0028] .

[0029] (Item 2) The compound of Item 1 or a pharmaceutically acceptable salt thereof, wherein

[0030] Q is 1 to 3 independently selected from halogen atoms, cyano, C 1-6 Alkyl (which may be independently selected from halogen atoms, cyano, hydroxyl, C 1-6 Alkoxy, -NR 5a R 6a and-NR 7a COR 8a Substituents), C 2-6 Alkenyl (which may be substituted with 1 to 3 hydroxyl groups), -CO2R 4a and-CONR 9 R 10 The substituents of imidazolyl substituted by

[0031] R 5a , R 6a , R 7a , R 9 and R 10 are independently a hydrogen atom or a C 1-3 Alkyl, or

[0032] When R5a and R 6a Both C 1-3 alkyl, they may combine with the nitrogen atom to which they are attached to form a 3- to 6-membered nitrogen-containing saturated heterocyclic group, and

[0033] When R 9 and R 10 Both C 1-3 alkyl, they may combine with the nitrogen atom to which they are attached to form a 3- to 6-membered nitrogen-containing saturated heterocyclic group, and

[0034] R 4a and R 8a Independently for C 1-3 alkyl.

[0035] (Item 3) The compound of Item 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R 3A , R 3B , R 3C and R 3D It's a hydrogen atom.

[0036] (Item 4) The compound or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 3, wherein R 2A and R 2B are independently a hydrogen atom or a C 1-3 alkyl.

[0037] (Item 5) The compound or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 3, wherein R 2A and R 2B Each independently is C 1-3 alkyl.

[0038] (Item 6) The compound or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 3, wherein R 2A and R 2B It's methyl.

[0039] (Item 7) The compound or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 6, wherein L is a bond.

[0040] (Item 8) The compound or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 6, wherein L is -CO-.

[0041] (Item 9) The compound or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 8, wherein V is C 1-6 Alkylene.

[0042] (Item 10) The compound or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 8, wherein V is C 1-3 Alkylene.

[0043] (Item 11) The compound or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 8, wherein V is ethylene.

[0044] (Item 12) The compound or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 8, wherein V is a methylene group.

[0045] (Item 13) The compound or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 12, wherein R 1A , R 1B , R 1C and R 1D are each independently a hydrogen atom, a fluorine atom or a chlorine atom, provided that R 1A , R 1B , R 1C and R 1D Not all are hydrogen atoms.

[0046] (Item 14) The compound or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 13, wherein Q is of the formula (Q-1) or (Q-2):

[0047]

[0048] in

[0049] R 11A , R 11B , R 11C , R 11D and R 11E are each independently a hydrogen atom, a halogen atom, a cyano group, a C 1-6 Alkyl (which may be independently selected from halogen atoms, cyano, hydroxyl, C 1-6 Alkoxy, -NR 5a R 6a and-NR 7a COR 8a Substituents), C 2-6 Alkenyl (which may be substituted with 1 to 3 hydroxyl groups), -CO2R 4a or-CONR 9 R 10 ,

[0050] R 5a , R 6a , R 7a , R 9 and R 10 are independently a hydrogen atom or a C 1-3 Alkyl, or

[0051] When R 5a and R 6a Both C 1-3alkyl, they may combine with the nitrogen atom to which they are attached to form a 3- to 6-membered nitrogen-containing saturated heterocyclic group, and

[0052] When R 9 and R 10 Both C 1-3 When alkyl groups are present, they may combine with the nitrogen atom to which they are attached to form a 3- to 6-membered nitrogen-containing saturated heterocyclic group,

[0053] R 4a and R 8a Independently for C 1-3 alkyl,

[0054] R 12 is a hydrogen atom or C 1-6 Alkyl, and

[0055] The asterisk (*) is the junction with V.

[0056] (Item 15) The compound according to Item 14 or a pharmaceutically acceptable salt thereof, wherein R 11A , R 11B , R 11C , R 11D and R 11E are independently a hydrogen atom, a cyano group, a C 1-6 Alkyl (which may be 1 to 3 independently selected from fluorine atoms, hydroxyl groups and -NR 7a COR 8a Substituents), C 2-6 Alkenyl (which may be substituted with a hydroxyl group) or -CO2R 4a .

[0057] (Item 16) The compound according to Item 14 or a pharmaceutically acceptable salt thereof, wherein R 11A , R 11B , R 11C , R 11D and R 11E are independently a hydrogen atom, a cyano group, a C 1-3 Alkyl or C 2-6 Alkenyl, wherein the alkyl and the alkenyl may each independently be substituted with one hydroxyl group.

[0058] (Item 17) The compound according to Item 14 or a pharmaceutically acceptable salt thereof, wherein R 11A , R 11B , R 11C , R 11D and R 11E are independently a hydrogen atom or a C 1-3 alkyl.

[0059] (Item 18) The compound or a pharmaceutically acceptable salt thereof according to any one of Items 14 to 17, wherein R 12It's a hydrogen atom.

[0060] (Item 19) The compound according to any one of Items 1 to 18 or a pharmaceutically acceptable salt thereof, wherein Formula (I) is Formula (1-A):

[0061] .

[0062] (Item 20) The compound or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 18, wherein Formula (I) is Formula (1-B):

[0063] .

[0064] (Item 21) The compound of any one of Items 1 to 18 or a pharmaceutically acceptable salt thereof, wherein Formula (I) is Formula (1-C):

[0065] .

[0066] (Item 22) The compound according to Item 1 or a pharmaceutically acceptable salt thereof, which is selected from:

[0067] (4'aS, 10'bS)-8'-chloro-5', 5'-dimethyl-1-[(4-methyl-1H-imidazol-5-yl)methyl]-4'a, 10'b-dihydro-2'H, 4'H, 5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran] (Example 18),

[0068] (4'aR,10'bR)-8'-chloro-5',5'-dimethyl-1-[(4-methyl-1H-imidazol-5-yl)methyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran] (Example 18),

[0069] (4'aR,10'bR)-9'-chloro-5',5'-dimethyl-1-[(4-methyl-1H-imidazol-5-yl)methyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran] (Example 24),

[0070] (4'aS, 10'bS)-9'-chloro-5', 5'-dimethyl-1-[(4-methyl-1H-imidazol-5-yl)methyl]-4'a, 10'b-dihydro-2'H, 4'H, 5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran] (Example 24),

[0071] (4'aS, 10'bS)-9'-chloro-5', 5'-dimethyl-1-[(1-methyl-1H-imidazol-5-yl)methyl]-4'a, 10'b-dihydro-2'H, 4'H, 5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran] (Example 32),

[0072] (4'aR,10'bR)-9'-chloro-5',5'-dimethyl-1-[(1-methyl-1H-imidazol-5-yl)methyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran] (Example 32),

[0073] (4'aR,10'bR)-8'-chloro-5',5'-dimethyl-1-[(1-methyl-1H-imidazol-5-yl)methyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran] (Example 33),

[0074] (4'aS, 10'bS)-8'-chloro-5', 5'-dimethyl-1-[(1-methyl-1H-imidazol-5-yl)methyl]-4'a, 10'b-dihydro-2'H, 4'H, 5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran] (Example 33),

[0075] (4'aS, 10'bS)-7'-chloro-5', 5'-dimethyl-1-[(1-methyl-1H-imidazol-5-yl)methyl]-4'a, 10'b-dihydro-2'H, 4'H, 5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran] (Example 34),

[0076] (4'aR,10'bR)-7'-chloro-5',5'-dimethyl-1-[(1-methyl-1H-imidazol-5-yl)methyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran] (Example 34),

[0077] (4'aR,10'bR)-8'-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran] (Example 38),

[0078] (4'aS, 10'bS)-8'-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5',5'-dimethyl-4'a, 10'b-dihydro-2'H, 4'H, 5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran] (Example 38),

[0079] (4'aS, 10'bS)-9'-fluoro-1-[2-(1H-imidazol-1-yl)ethyl]-5',5'-dimethyl-4'a, 10'b-dihydro-2'H, 4'H, 5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran] (Example 39),

[0080] (4'aR,10'bR)-9'-fluoro-1-[2-(1H-imidazol-1-yl)ethyl]-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran] (Example 39),

[0081] (4'aR,10'bR)-9'-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran] (Example 40),

[0082] (4'aS, 10'bS)-9'-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5',5'-dimethyl-4'a, 10'b-dihydro-2'H, 4'H, 5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran] (Example 40),

[0083] (4'aS, 10'bS)-9'-fluoro-5', 5'-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4'a, 10'b-dihydro-2'H, 4'H, 5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran] (Example 43),

[0084] (4'aR,10'bR)-9'-fluoro-5',5'-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran] (Example 43),

[0085] (4'aR,10'bR)-9'-chloro-5',5'-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran] (Example 46),

[0086] (4'aS, 10'bS)-9'-chloro-5', 5'-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4'a, 10'b-dihydro-2'H, 4'H, 5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran] (Example 46),

[0087] (4'aS, 10'bS)-8'-chloro-5', 5'-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4'a, 10'b-dihydro-2'H, 4'H, 5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran] (Example 49),

[0088] (4'aR,10'bR)-8'-chloro-5',5'-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran] (Example 49),

[0089] (1-{2-[(4'aR,10'bR)-9'-fluoro-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran]-1-yl]ethyl}-1H-imidazol-2-yl)methanol (Example 52),

[0090] (1-{2-[(4'aS,10'bS)-9'-fluoro-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran]-1-yl]ethyl}-1H-imidazol-2-yl)methanol (Example 52),

[0091] (1-{2-[(4'aS,10'bS)-9'-chloro-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran]-1-yl]ethyl}-1H-imidazol-2-yl)methanol (Example 53),

[0092] (1-{2-[(4'aR,10'bR)-9'-chloro-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran]-1-yl]ethyl}-1H-imidazol-2-yl)methanol (Example 53),

[0093] (1-{2-[(4'aR,10'bR)-8'-chloro-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran]-1-yl]ethyl}-1H-imidazol-2-yl)methanol (Example 54),

[0094] (1-{2-[(4'aS,10'bS)-8'-chloro-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran]-1-yl]ethyl}-1H-imidazol-2-yl)methanol (Example 54),

[0095] (1-{2-[(4'aS,10'bS)-9'-chloro-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran]-1-yl]ethyl}-5-methyl-1H-imidazol-4-yl)methanol (Example 56),

[0096] (1-{2-[(4'aR,10'bR)-9'-chloro-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran]-1-yl]ethyl}-5-methyl-1H-imidazol-4-yl)methanol (Example 56),

[0097] (4'aS,10'bR)-8'-chloro-1-[(4-methyl-1H-imidazol-5-yl)methyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran] (Example 64), and

[0098] (4'aR,10'bS)-8'-chloro-1-[(4-methyl-1H-imidazol-5-yl)methyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidine-4,3'-pyrano[3,2-c][1]benzopyran] (Example 64).

[0099] (Item 23) The compound according to Item 1 or a pharmaceutically acceptable salt thereof, which is selected from:

[0100] (4'aS, 10'bS)-8'-chloro-5', 5'-dimethyl-1-[(4-methyl-1H-imidazol-5-yl)methyl]-4'a, 10'b-dihydro-2'H, 4'H, 5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran] (Example 18),

[0101] (4'aR,10'bR)-8'-chloro-5',5'-dimethyl-1-[(4-methyl-1H-imidazol-5-yl)methyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran] (Example 18),

[0102] (4'aR,10'bR)-9'-chloro-5',5'-dimethyl-1-[(4-methyl-1H-imidazol-5-yl)methyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran] (Example 24),

[0103] (4'aS, 10'bS)-9'-chloro-5', 5'-dimethyl-1-[(4-methyl-1H-imidazol-5-yl)methyl]-4'a, 10'b-dihydro-2'H, 4'H, 5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran] (Example 24),

[0104] (4'aS, 10'bS)-9'-chloro-5', 5'-dimethyl-1-[(1-methyl-1H-imidazol-5-yl)methyl]-4'a, 10'b-dihydro-2'H, 4'H, 5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran] (Example 32),

[0105] (4'aR,10'bR)-9'-chloro-5',5'-dimethyl-1-[(1-methyl-1H-imidazol-5-yl)methyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran] (Example 32),

[0106] (4'aR,10'bR)-8'-chloro-5',5'-dimethyl-1-[(1-methyl-1H-imidazol-5-yl)methyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran] (Example 33),

[0107] (4'aS, 10'bS)-8'-chloro-5', 5'-dimethyl-1-[(1-methyl-1H-imidazol-5-yl)methyl]-4'a, 10'b-dihydro-2'H, 4'H, 5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran] (Example 33),

[0108] (4'aS,10'bS)-7'-chloro-5',5'-dimethyl-1-[(1-methyl-1H-imidazol-5-yl)methyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran] (Example 34), and

[0109] (4'aR,10'bR)-7'-chloro-5',5'-dimethyl-1-[(1-methyl-1H-imidazol-5-yl)methyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran] (Example 34).

[0110] (Item 24) The compound according to Item 1 or a pharmaceutically acceptable salt thereof, which is selected from:

[0111] (4'aR,10'bR)-8'-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran] (Example 38),

[0112] (4'aS, 10'bS)-8'-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5',5'-dimethyl-4'a, 10'b-dihydro-2'H, 4'H, 5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran] (Example 38),

[0113] (4'aS, 10'bS)-9'-fluoro-1-[2-(1H-imidazol-1-yl)ethyl]-5',5'-dimethyl-4'a, 10'b-dihydro-2'H, 4'H, 5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran] (Example 39),

[0114] (4'aR,10'bR)-9'-fluoro-1-[2-(1H-imidazol-1-yl)ethyl]-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran] (Example 39),

[0115] (4'aR,10'bR)-9'-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran] (Example 40),

[0116] (4'aS, 10'bS)-9'-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5',5'-dimethyl-4'a, 10'b-dihydro-2'H, 4'H, 5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran] (Example 40),

[0117] (4'aS, 10'bS)-9'-fluoro-5', 5'-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4'a, 10'b-dihydro-2'H, 4'H, 5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran] (Example 43),

[0118] (4'aR,10'bR)-9'-fluoro-5',5'-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran] (Example 43),

[0119] (4'aR,10'bR)-9'-chloro-5',5'-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran] (Example 46),

[0120] (4'aS, 10'bS)-9'-chloro-5', 5'-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4'a, 10'b-dihydro-2'H, 4'H, 5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran] (Example 46),

[0121] (4'aS, 10'bS)-8'-chloro-5', 5'-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4'a, 10'b-dihydro-2'H, 4'H, 5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran] (Example 49),

[0122] (4'aR,10'bR)-8'-chloro-5',5'-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran] (Example 49),

[0123] (1-{2-[(4'aR,10'bR)-9'-fluoro-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran]-1-yl]ethyl}-1H-imidazol-2-yl)methanol (Example 52),

[0124] (1-{2-[(4'aS,10'bS)-9'-fluoro-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran]-1-yl]ethyl}-1H-imidazol-2-yl)methanol (Example 52),

[0125] (1-{2-[(4'aS,10'bS)-9'-chloro-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran]-1-yl]ethyl}-1H-imidazol-2-yl)methanol (Example 53),

[0126] (1-{2-[(4'aR,10'bR)-9'-chloro-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran]-1-yl]ethyl}-1H-imidazol-2-yl)methanol (Example 53),

[0127] (1-{2-[(4'aR,10'bR)-8'-chloro-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran]-1-yl]ethyl}-1H-imidazol-2-yl)methanol (Example 54),

[0128] (1-{2-[(4'aS,10'bS)-8'-chloro-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran]-1-yl]ethyl}-1H-imidazol-2-yl)methanol (Example 54),

[0129] (1-{2-[(4'aS,10'bS)-9'-chloro-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran]-1-yl]ethyl}-5-methyl-1H-imidazol-4-yl)methanol (Example 56), and

[0130] (1-{2-[(4'aR,10'bR)-9'-chloro-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran]-1-yl]ethyl}-5-methyl-1H-imidazol-4-yl)methanol (Example 56).

[0131] (Item 25) The compound according to Item 1 or a pharmaceutically acceptable salt thereof, which is selected from:

[0132] (4'aS, 10'bS)-8'-chloro-5', 5'-dimethyl-1-[(4-methyl-1H-imidazol-5-yl)methyl]-4'a, 10'b-dihydro-2'H, 4'H, 5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran] (Example 18),

[0133] (4'aR,10'bR)-8'-chloro-5',5'-dimethyl-1-[(4-methyl-1H-imidazol-5-yl)methyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran] (Example 18),

[0134] (4'aR,10'bR)-8'-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran] (Example 38),

[0135] (4'aS, 10'bS)-8'-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5',5'-dimethyl-4'a, 10'b-dihydro-2'H, 4'H, 5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran] (Example 38),

[0136] (4'aS,10'bS)-9'-fluoro-5',5'-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran] (Example 43), and

[0137] (4'aR,10'bR)-9'-Fluoro-5',5'-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidine-4,3'-pyrano[3,2-c][1]benzopyran] (Example 43).

[0138] (Item 26) The compound according to Item 1 or a pharmaceutically acceptable salt thereof, which is selected from:

[0139] (4'aS,10'bS)-8'-chloro-5',5'-dimethyl-1-[(4-methyl-1H-imidazol-5-yl)methyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran] (Example 18).

[0140] (Item 27) The compound according to Item 1 or a pharmaceutically acceptable salt thereof, which is selected from:

[0141] (4'aR,10'bR)-8'-chloro-5',5'-dimethyl-1-[(4-methyl-1H-imidazol-5-yl)methyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran] (Example 18).

[0142] (Item 28) The compound according to Item 1 or a pharmaceutically acceptable salt thereof, which is selected from:

[0143] (4'aR,10'bR)-8'-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidine-4,3'-pyrano[3,2-c][1]benzopyran] (Example 38).

[0144] (Item 29) The compound according to Item 1 or a pharmaceutically acceptable salt thereof, which is selected from:

[0145] (4'aS,10'bS)-8'-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran] (Example 38).

[0146] (Item 30) The compound according to Item 1 or a pharmaceutically acceptable salt thereof, which is selected from:

[0147] (4'aS,10'bS)-9'-Fluoro-5',5'-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidine-4,3'-pyrano[3,2-c][1]benzopyran] (Example 43).

[0148] (Item 31) The compound according to Item 1 or a pharmaceutically acceptable salt thereof, which is selected from:

[0149] (4'aR,10'bR)-9'-Fluoro-5',5'-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidine-4,3'-pyrano[3,2-c][1]benzopyran] (Example 43).

[0150] (Item 32) The compound or its phosphate according to Item 1, which is selected from:

[0151] (4'aS, 10'bS)-8'-chloro-5', 5'-dimethyl-1-[(4-methyl-1H-imidazol-5-yl)methyl]-4'a, 10'b-dihydro-2'H, 4'H, 5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran] (Example 18),

[0152] (4'aR,10'bR)-8'-chloro-5',5'-dimethyl-1-[(4-methyl-1H-imidazol-5-yl)methyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran] (Example 18),

[0153] (4'aR,10'bR)-8'-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran] (Example 38),

[0154] (4'aS, 10'bS)-8'-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5',5'-dimethyl-4'a, 10'b-dihydro-2'H, 4'H, 5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran] (Example 38),

[0155] (4'aS,10'bS)-9'-fluoro-5',5'-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran] (Example 43), and

[0156] (4'aR,10'bR)-9'-Fluoro-5',5'-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidine-4,3'-pyrano[3,2-c][1]benzopyran] (Example 43).

[0157] (Item 33) The compound according to Item 1 or its fumarate, which is selected from:

[0158] (4'aS, 10'bS)-8'-chloro-5', 5'-dimethyl-1-[(4-methyl-1H-imidazol-5-yl)methyl]-4'a, 10'b-dihydro-2'H, 4'H, 5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran] (Example 18),

[0159] (4'aR,10'bR)-8'-chloro-5',5'-dimethyl-1-[(4-methyl-1H-imidazol-5-yl)methyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran] (Example 18),

[0160] (4'aR,10'bR)-8'-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran] (Example 38),

[0161] (4'aS, 10'bS)-8'-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5',5'-dimethyl-4'a, 10'b-dihydro-2'H, 4'H, 5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran] (Example 38),

[0162] (4'aS,10'bS)-9'-fluoro-5',5'-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran] (Example 43), and

[0163] (4'aR,10'bR)-9'-Fluoro-5',5'-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidine-4,3'-pyrano[3,2-c][1]benzopyran] (Example 43).

[0164] (Item 34) The compound according to Item 1 or its p-toluenesulfonate, which is selected from:

[0165] (4'aS, 10'bS)-8'-chloro-5', 5'-dimethyl-1-[(4-methyl-1H-imidazol-5-yl)methyl]-4'a, 10'b-dihydro-2'H, 4'H, 5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran] (Example 18),

[0166] (4'aR,10'bR)-8'-chloro-5',5'-dimethyl-1-[(4-methyl-1H-imidazol-5-yl)methyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran] (Example 18),

[0167] (4'aR,10'bR)-8'-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran] (Example 38),

[0168] (4'aS, 10'bS)-8'-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5',5'-dimethyl-4'a, 10'b-dihydro-2'H, 4'H, 5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran] (Example 38),

[0169] (4'aS,10'bS)-9'-fluoro-5',5'-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran] (Example 43), and

[0170] (4'aR,10'bR)-9'-Fluoro-5',5'-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidine-4,3'-pyrano[3,2-c][1]benzopyran] (Example 43).

[0171] (Item 35) A medicament comprising the compound according to any one of Items 1 to 34 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0172] (Item 36) An antitumor drug comprising the compound according to any one of Items 1 to 34 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0173] (Item 37) The anti-tumor drug of Item 36, wherein the tumor is acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, polycythemia vera, malignant lymphoma, myeloma, brain tumor, head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, breast cancer, gastric cancer, gallbladder / bile duct cancer, liver cancer, pancreatic cancer, colon cancer, rectal cancer, ovarian cancer, chorioepithelioma, uterine body cancer, cervical cancer, urothelial carcinoma, renal cell carcinoma, prostate cancer, testicular tumor, Wilms' tumor, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's sarcoma or soft tissue sarcoma.

[0174] (Item 38) A pharmaceutical composition comprising a compound of any one of Items 1 to 34 or a pharmaceutically acceptable salt thereof, used in combination with another agent or a pharmaceutically acceptable salt thereof, wherein the other agent is at least one agent selected from the following: anticancer alkylating agents, anticancer antimetabolites, anticancer antibiotics, plant-derived anticancer drugs, anticancer platinum complexes, anticancer camptothecin derivatives, anticancer tyrosine kinase inhibitors, anticancer serine / threonine kinase inhibitors, anticancer phospholipid kinase inhibitors, anticancer monoclonal antibodies, interferons, biological response modifiers, hormone preparations, angiogenesis inhibitors, immune checkpoint inhibitors, epigenetic-related molecule inhibitors, protein post-translational modification inhibitors, proteasome inhibitors and other anti-tumor drugs.

[0175] (Item 39) A compound according to any one of Items 1 to 34 or a pharmaceutically acceptable salt thereof for use in treating cancer, used in combination with another agent or a pharmaceutically acceptable salt thereof, wherein the other agent is at least one agent selected from the group consisting of anticancer alkylating agents, anticancer antimetabolites, anticancer antibiotics, plant-derived anticancer drugs, anticancer platinum complexes, anticancer camptothecin derivatives, anticancer tyrosine kinase inhibitors, anticancer serine / threonine kinase inhibitors, anticancer phospholipid kinase inhibitors, anticancer monoclonal antibodies, interferons, biological response modifiers, hormone preparations, angiogenesis inhibitors, immune checkpoint inhibitors, epigenetic-related molecule inhibitors, protein post-translational modification inhibitors, proteasome inhibitors and other anti-tumor drugs.

[0176] (Item 40) A method for treating cancer, comprising administering the compound of any one of Items 1 to 34 or a pharmaceutically acceptable salt thereof to a patient in need thereof.

[0177] (Item 41) Use of a compound according to any one of Items 1 to 34 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancer.

[0178] (Item 42) A pharmaceutical composition for treating cancer, comprising the compound according to any one of Items 1 to 34 or a pharmaceutically acceptable salt thereof.

[0179] (Effects of the Invention)

[0180] The compounds of the present invention may exhibit an inhibitory effect on the formation ability of CSCs, and thus they are useful as antitumor drugs. In an additional preferred embodiment, since the compounds of the present invention have a large deviation between the concentrations that inhibit cell proliferation and the concentrations that inhibit hERG current, they are expected to be highly safe. DETAILED DESCRIPTION

[0181] Hereinafter, terms used herein are explained as follows.

[0182] In case "optionally substituted" or "substituted" is used in the definition of a substituent, the number of substituents is not limited as long as the substitution is possible, ie it is one or more.

[0183] Unless stated otherwise, the definition of each substituent also extends to the case where the substituent is included as part of a moiety or is present on another substituent.

[0184] The "halogen atom" includes, for example, a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. It is preferably a fluorine atom or a chlorine atom.

[0185] “C 1-6 The term "alkyl group" refers to an alkyl group having 1 to 6 carbon atoms, and the same applies to the case of other carbon numbers.

[0186] “C 1-6 "Alkyl" refers to a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms. 1-6 The alkyl group preferably includes "C 1-4 Alkyl", more preferably "C 1-3 Alkyl". "C 1-3 "Alkyl" includes, for example, methyl, ethyl, propyl, 1-methylethyl, etc. In addition to the "C 1-3 In addition to the examples listed in "alkyl", "C 1-4 "Alkyl" also includes, for example, butyl, 1,1-dimethylethyl, 1-methylpropyl, 2-methylpropyl, etc. In addition to the "C 1-4 In addition to the examples listed in "alkyl", "C 1-6The term "alkyl" also includes, for example, pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylbutyl, 2-methylbutyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, hexyl and the like.

[0187] “C 2-6 "Alkenyl" refers to a straight or branched unsaturated hydrocarbon group having 2 to 6 carbon atoms and 1 to 3 double bonds. 2-6 "Alkenyl" preferably includes "C 2-4 "C 2-4 "Alkenyl" includes, for example, ethenyl, propenyl, methacryl, butenyl, etc. In addition to the "C 2-4 In addition to the examples listed in "alkenyl", "C 2-6 "Alkenyl" also includes, for example, pentenyl, hexenyl, etc.

[0188] “C 1-6 "Alkoxy" refers to "C 1-6 Alkyloxy", and "C 1-6 The "alkyl" part is as described in "C 1-6 "C 1-6 "Alkoxy" preferably includes "C 1-4 Alkoxy", more preferably "C 1-3 Alkoxy". "C 1-3 "Alkoxy" includes, for example, methoxy, ethoxy, propoxy, 1-methylethoxy, and the like. In addition to the "C 1-3 In addition to the examples listed in "alkoxy", "C 1-4 "Alkoxy" also includes, for example, butoxy, 1,1-dimethylethoxy, 1-methylpropoxy, 2-methylpropoxy, etc. In addition to the "C 1-4 In addition to the examples listed in "alkoxy", "C 1-6 The "alkoxy" also includes, for example, pentyloxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 1-methylbutoxy, 2-methylbutoxy, 4-methylpentyloxy, 3-methylpentyloxy, 2-methylpentyloxy, 1-methylpentyloxy, hexyloxy and the like.

[0189] “C 1-6 "Alkylene" refers to a divalent straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms. 1-6 "Alkylene" preferably includes "C 1-3 Alkylene". "C 1-3 The term "alkylene" includes, for example, methylene, ethylene, propylene, 1-methylethylene and the like.

[0190] “C 3-7 "Cycloalkyl" refers to a cyclic saturated hydrocarbon group having 3 to 7 carbon atoms, which may have a partially unsaturated bond or a bridge structure.3-7 The term "cycloalkyl" includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.

[0191] "3- to 7-membered saturated heterocyclic group" refers to a saturated heterocyclic ring composed of 3 to 7 atoms, wherein the atoms include carbon atoms and 1 to 2 atoms independently selected from nitrogen atoms, oxygen atoms and sulfur atoms, and may have a partially unsaturated bond and a bridged structure. "3- to 7-membered saturated heterocyclic group" generally includes "3- to 7-membered monocyclic saturated heterocyclic group", preferably "4- to 7-membered monocyclic saturated heterocyclic group", more preferably "5- or 6-membered monocyclic saturated heterocyclic group". "5- or 6-membered monocyclic saturated heterocyclic group" includes, for example, tetrahydrofuranyl, pyrrolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, cycloheximino, oxazolidinyl, thiazolidinyl, oxoimidazolidinyl, dioxoimidazolidinyl, oxooxazolidinyl, dioxooxazolidinyl, dioxothiazolidinyl, tetrahydrofuranyl, tetrahydropyranyl and the like. The "3- to 7-membered monocyclic saturated heterocyclic group" includes, for example, epoxy, aziridine, oxetanyl, azetidine and the like, in addition to the examples listed in the "5- or 6-membered monocyclic saturated heterocyclic group".

[0192] "Imidazole group" refers to an imidazole ring group, which may also be referred to as an imidazole group. The imidazole group should not be limited as long as the direct binding position is a carbon atom or a nitrogen atom constituting the imidazole ring, and includes the following formula. In the following formula, * represents the binding position. In the following formula, when the binding position is a carbon atom, a structure in which the NH group of the imidazole ring is substituted with a methyl group is exemplified.

[0193]

[0194] "Cancer" and "tumor" are used interchangeably and both refer to malignant neoplasms, which encompass cancer, sarcoma, and hematologic malignancies. "Cancer" and "tumor" include, for example, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, myelodysplastic syndrome, adult T-cell leukemia / lymphoma, polycythemia vera, malignant lymphoma, myeloma, brain tumor, head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, breast cancer, gastric cancer, gallbladder / bile duct cancer, liver cancer, pancreatic cancer, colon cancer, rectal cancer, ovarian cancer, chorioepithelioma, uterine corpus cancer, cervical cancer, urothelial carcinoma, renal cell carcinoma, prostate cancer, testicular tumor, Wilms' tumor, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's sarcoma, chondrosarcoma, soft tissue sarcoma, skin cancer, and the like.

[0195] The compound shown herein is of the following formula (Y):

[0196]

[0197] Four stereoisomers may be included, which are derived from the stereochemistry of the two carbon atoms at the fused portion (two * portions) of the tetrahydropyranochromene ring. That is, the compound of formula (Y) encompasses at least one compound selected from the four stereoisomers having the following formulae (Y-1), (Y-2), (Y-3) and (Y-4):

[0198]

[0199] The stereochemistry of carbon atoms at the fused portion of formula (Y-1), (Y-2), (Y-3) and (Y-4) are shown in absolute configuration.

[0200] The racemate of the compound of formula (Y) includes the cis form and the trans form of the following formulae (Y-5) and (Y-6):

[0201]

[0202] The stereochemistry of the carbon atoms at the fused portion of formula (Y-5) and (Y-6) is shown in relative configuration, ie, one of two stereoisomers in each configuration is shown.

[0203] The stereochemistry of all compounds shown in this specification should be defined based on the stereochemistry of the specified chemical structure or chemical name. In the case where the stereochemistry is not explicitly defined, the stereochemistry may include multiple stereoisomers as in formula (Y) above.

[0204] In this specification, a "bonding rod" passing through a ring such as the following formula (W) means that a substituent "R" is attached to any substitutable position of the ring. For example, the following formula (W):

[0205]

[0206] Refers to the following formula (W-1), (W-2), (W-3) or (W-4):

[0207] .

[0208] In the compounds of the present invention of formula (1), preferably R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 3A , R 3B , R 3C , R 3D , R 4 , R 4a , R 5 , R 5a , R 6 , R6a , R 7 , R 7a , R 8 , R 8a , R 9 , R 10 , R 11A , R 11B , R 11C , R 11D , R 11E , R 12 , L, V and Q are as follows, but the technical scope of the present invention is not limited to the scope of the compounds listed below.

[0209] R 1A Preferred are hydrogen atoms, fluorine atoms, chlorine atoms and bromine atoms, and more preferred are hydrogen atoms.

[0210] R 1B It preferably includes a hydrogen atom, a fluorine atom, a chlorine atom and a bromine atom, more preferably a fluorine atom or a chlorine atom, and even more preferably a chlorine atom.

[0211] R 1C It preferably includes a hydrogen atom, a fluorine atom, a chlorine atom and a bromine atom, more preferably a fluorine atom or a chlorine atom, and even more preferably a chlorine atom.

[0212] R 1D Preferred are hydrogen atoms, fluorine atoms, chlorine atoms and bromine atoms, and more preferably hydrogen atoms.

[0213] In R 1A , R 1B , R 1C and R 1D In one embodiment, R 1A , R 1C and R 1D is a hydrogen atom, and R 1B is a fluorine atom. In another embodiment, R 1A , R 1C and R 1D is a hydrogen atom, and R 1B is a chlorine atom. 1A , R 1B , R 1C and R 1D In a different embodiment, R 1A , R 1B and R 1D is a hydrogen atom, and R 1C is a fluorine atom. In another embodiment, R 1A , R 1B and R 1D is a hydrogen atom, and R 1C It is a chlorine atom.

[0214] R 2A Preferably, it includes hydrogen atoms and C 1-3 It is more preferably methyl.

[0215] R 2B Preferably, it includes hydrogen atoms and C 1-3 It is more preferably methyl.

[0216] In one embodiment, R 2A and R 2B All are methyl.

[0217] R 3A , R 3B , R 3C and R 3D Preferred is a hydrogen atom.

[0218] R 4 and R 4a Preferably including C 1-3 It is more preferably methyl.

[0219] R 5 and R 5a Preferably, it includes hydrogen atoms and C 1-3 alkyl.

[0220] R 6 and R 6a Preferably, it includes hydrogen atoms and C 1-3 alkyl.

[0221] R 7 and R 7a Preferably, it includes hydrogen atoms and C 1-3 alkyl.

[0222] R 8 and R 8a Preferably including C 1-3 alkyl.

[0223] R 9 Preferably, it includes hydrogen atoms and C 1-3 alkyl.

[0224] R 10 Preferably, it includes hydrogen atoms and C 1-3 alkyl.

[0225] R 11A , R 11B and R 11C Preferably, it includes a hydrogen atom, a cyano group and a C 1-3 It is more preferably a hydrogen atom or a methyl group, and even more preferably a hydrogen atom.

[0226] R 11D Preferably, it includes hydrogen atoms and C1-3 It is more preferably methyl.

[0227] R 11E Preferably, it includes hydrogen atoms, C 1-3 Alkyl and C 2-6 It is more preferably a hydrogen atom.

[0228] R 12 Preferably, it includes hydrogen atoms and C 1-3 The alkyl group is more preferably a hydrogen atom.

[0229] In one embodiment, L is a bond. In another embodiment, L is -C(O)-.

[0230] V preferably includes C 1-3 Alkylene. It is more preferably methylene or ethylene. In one embodiment, V is methylene. In another embodiment, V is ethylene.

[0231] Q preferably includes 1 to 3 independently selected cyano groups; 1 to 3 independently selected hydroxyl groups and -NR 7a COR 8a Substituents substituted with C 1-3 Alkyl; and C which may be substituted with one hydroxyl group 2-6 In one embodiment, Q is of formula (Q-1). In another embodiment, Q is of formula (Q-2). In formula (Q-1), R 11A , R 11B and R 11C In one embodiment, R 11A , R 11B and R 11C In another embodiment, R 11A is a methyl group, and R 11B and R 11C are all hydrogen atoms. In formula (Q-2), R 11D , R 11E and R 12 In one embodiment, R 11D is a methyl group, and R 11E and R 12 It's a hydrogen atom.

[0232] The compound of formula (1) may include 4 stereoisomers derived from the stereochemistry of the two carbon atoms in the fused portion (the two * portions) of the tetrahydropyranochromene ring.

[0233]

[0234] More specifically, the compound of formula (1) encompasses four fused ring compounds having the above formulae (Y-1), (Y-2), (Y-3) and (Y-4).

[0235] The compounds of formula (1-A) and (1-B) shown below are trans-fused tetrahydropyranochromene rings, wherein the stereochemistry of two carbon atoms at the fused portion in formula (1-A) and (1-B) is shown in absolute configuration.

[0236]

[0237] The two compounds of formula (1-A) and (1-B) are enantiomers of each other, ie the stereochemistry of the two carbon atoms at the fused part of the tetrahydropyranochromene ring is opposite if no chiral carbon is present other than in the tetrahydropyranochromene ring.

[0238] The compounds of formula (1-C) are shown in relative configuration wherein the tetrahydropyranochromene ring is a trans-fused ring, although for convenience the structure of formula (1-C) below shows one stereochemistry with dashed and bold lines emanating from two carbon atoms.

[0239]

[0240] A compound containing equal amounts of two stereoisomers of formulae (1-A) and (1-B) can be represented by formula (1-C).

[0241] In one embodiment, the compound of the present invention of formula (1) comprises the following (A).

[0242] （A）

[0243] A compound or a pharmaceutically acceptable salt thereof, wherein

[0244] R 1A , R 1B , R 1C and R 1D are each independently a hydrogen atom, a fluorine atom or a chlorine atom, provided that R 1A , R 1B , R 1C and R 1D Not all of them are hydrogen atoms.

[0245] R 2A and R 2B are independently a hydrogen atom or a C 1-3 alkyl,

[0246] R 3A , R 3B , R 3C and R 3D are hydrogen atoms,

[0247] L is a bond or -C(O)-,

[0248] V is for C 1-3 an alkylene group, and

[0249] Q is 1 to 3 independently selected from cyano; 1 to 3 independently selected from hydroxyl and -NR 7a COR 8a Substituents substituted with C 1-3 Alkyl; and C which may be substituted with one hydroxyl group 2-6 The substituent of the alkenyl group is an imidazolyl group substituted with the alkenyl group.

[0250] In one embodiment, the compound of the present invention of formula (1) comprises the following (B).

[0251] （B）

[0252] A compound or a pharmaceutically acceptable salt thereof, wherein

[0253] R 1A , R 1B , R 1C and R 1D are each independently a hydrogen atom, a fluorine atom or a chlorine atom, provided that R 1A , R 1B , R 1C and R 1D Not all of them are hydrogen atoms.

[0254] R 2A and R 2B are each independently a hydrogen atom or a methyl group,

[0255] R 3A , R 3B , R 3C and R 3D are hydrogen atoms,

[0256] L is the key,

[0257] V is for C 1-3 an alkylene group, and

[0258] Q is 1 to 3 independently selected from cyano; 1 to 3 independently selected from hydroxyl and -NR 7a COR 8a Substituents substituted with C 1-3 Alkyl; and C which may be substituted with one hydroxyl group 2-6 The substituent of the alkenyl group is an imidazolyl group substituted with the alkenyl group.

[0259] In one embodiment, the compound of the present invention of formula (1) includes the following (C).

[0260] （C）

[0261] A compound or a pharmaceutically acceptable salt thereof, wherein

[0262] R 1A , R 1B , R 1C and R 1D are each independently a hydrogen atom, a fluorine atom or a chlorine atom, provided that R 1A , R 1B , R 1C and R 1D Not all of them are hydrogen atoms.

[0263] R 2A and R 2B are each independently a hydrogen atom or a methyl group,

[0264] R 3A , R 3B , R 3C and R 3D are hydrogen atoms,

[0265] L is the key,

[0266] V is a methylene group, and

[0267] Q is 1 to 2 independently selected from C 1-3 Alkyl and C 2-6 The substituent of the alkenyl group is an imidazolyl group substituted with the alkenyl group.

[0268] In one embodiment, the compound of the present invention of formula (1) includes the following (D).

[0269] （D）

[0270] A compound or a pharmaceutically acceptable salt thereof, wherein

[0271] R 1A , R 1B , R 1C and R 1D are each independently a hydrogen atom, a fluorine atom or a chlorine atom, provided that R 1A , R 1B , R 1C and R 1D Not all of them are hydrogen atoms.

[0272] R 2A and R 2B is a hydrogen atom or a methyl group,

[0273] R 3A , R 3B , R 3C and R 3Dare hydrogen atoms,

[0274] L is the key,

[0275] V is ethylene, and

[0276] Q is C which may be substituted by 1 to 3 independently selected cyano groups and 1 to 2 hydroxyl groups. 1-3 The substituent of the alkyl group is an imidazolyl group substituted with the alkyl group.

[0277] In one embodiment, the compound of the present invention of formula (1) includes the following (E).

[0278] （E）

[0279] A compound or a pharmaceutically acceptable salt thereof, wherein

[0280] R 1A , R 1B , R 1C and R 1D are each independently a hydrogen atom, a fluorine atom or a chlorine atom, provided that R 1A , R 1B , R 1C and R 1D Not all of them are hydrogen atoms.

[0281] R 2A and R 2B is a hydrogen atom or a methyl group,

[0282] R 3A , R 3B , R 3C and R 3D are hydrogen atoms,

[0283] L is the key,

[0284] V is ethylene,

[0285] Q is the formula (Q-1), and

[0286] R 11A , R 11B and R 11C are independently a hydrogen atom, a cyano group, a C 1-3 Alkyl or C 2-6 Alkenyl, wherein the alkyl and the alkenyl may each independently be substituted with one hydroxyl group.

[0287] In one embodiment, the compound of the present invention of formula (1) includes the following (F).

[0288] （F）

[0289] A compound or a pharmaceutically acceptable salt thereof, wherein

[0290] R 1A , R 1B , R 1C and R 1D are each independently a hydrogen atom, a fluorine atom or a chlorine atom, provided that R 1A , R 1B , R 1C and R 1D Not all of them are hydrogen atoms.

[0291] R 2A and R 2B is a hydrogen atom or a methyl group,

[0292] R 3A , R 3B , R 3C and R 3D are hydrogen atoms,

[0293] L is the key,

[0294] V is a methylene group,

[0295] Q is the formula (Q-2),

[0296] R 11D and R 11E are independently a hydrogen atom, a cyano group, a C 1-3 Alkyl or C 2-6 alkenyl, wherein the alkyl and the alkenyl may each independently be substituted with one hydroxyl group, and

[0297] R 12 is a hydrogen atom or C 1-6 alkyl.

[0298] The compound of formula (1) may exist as its tautomer. Therefore, the compound of the present invention also includes the tautomer of compound (1).

[0299] The compound of formula (1) may have at least one chiral carbon atom. Therefore, the compounds of the present invention also include the optically active compound (1) and the racemate of the compound (1).

[0300] Any one or more of 1 H atoms are 2 Compounds of formula (1) substituted with H(D) atoms are also within the scope of the present invention of formula (1).

[0301] The compound of formula (1) and its pharmaceutically acceptable salt may also be in the form of hydrate and / or solvate, and thus the compound of the present invention encompasses such hydrate and solvate thereof, such as ethanolate. In addition, the compound of the present invention also includes various embodiments of its crystal form.

[0302] When the compound of formula (1) has an acidic group, pharmaceutically acceptable salts of the compound include, for example, alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; inorganic metal salts such as zinc salts; and organic base salts such as triethylamine, triethanolamine, tris(hydroxymethyl)aminomethane and basic amino acids.

[0303] When the compound of formula (1) has a basic group, pharmaceutically acceptable salts of the compound include, for example, inorganic acid salts such as hydrochlorides, hydrobromides, sulfates, phosphates and nitrates; and organic acid salts such as acetates, propionates, succinates, lactates, malates, tartrates, citrates, maleates, fumarates, methanesulfonates, p-toluenesulfonates, benzenesulfonates, ascorbic acid salts and acidic amino acids.

[0304] Preferred salts of starting materials and intermediates, and acceptable salts as drug substances can be conventional salts. These salts include, for example, acid addition salts, such as organic acid salts (such as acetate, trifluoroacetate, maleate, fumarate, citrate, tartrate, methanesulfonate, benzenesulfonate, formates and toluenesulfonate) and inorganic acid salts (such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate and phosphate), salts with amino acids (such as arginine, aspartate and glutamate), metal salts such as alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as calcium and magnesium salts), ammonium salts and organic base salts (such as trimethylamine salts, triethylamine salts, pyridinium salts, picoline salts, dicyclohexylamine salts and N, N'-dibenzylethylenediamine salts), or can be suitably selected by the technician.

[0305] method

[0306] Hereinafter, methods for preparing the compounds of the present invention of formula (1) are illustrated together with examples, but the methods for preparing the compounds of the present invention should not be limited to these examples. The compounds used in the following methods may exist in the form of their salts unless they affect the reaction.

[0307] The compounds of the present invention can be prepared from known compounds as starting materials, for example, by the following method or a method analogous thereto, or optionally in combination with a synthetic method known to those skilled in the art.

[0308] In each method shown below, the functional group that needs to be protected can be optionally protected, and then can be deprotected after the reaction or a series of reactions are completed to obtain the desired compound, even if the use of the protecting group is not specifically described. The introduction and elimination of the protecting group can be carried out by a commonly used method in organic synthetic chemistry (for example, see "Protective Groups in Organic Synthesis", 3rd edition, John Wiley and Sons, inc., New York (1999)) or a similar method.

[0309] Method 1

[0310] The compound of the present invention of formula (1c) can be prepared, for example, by the following method:

[0311]

[0312] Where R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 3A , R 3B , R 3C , R 3D , V and Q are as defined in item 1, and LG 1 represents a leaving group and includes, for example, a halogen atom and a hydroxyl group.

[0313] Compound (1b) can be prepared in a known manner as described in, for example, Journal of Medicinal chemistry, 60(15):6678-6692 (2017), Journal of Medicinal chemistry, 60(22): 9376-9392 (2017), etc. or in a manner similar thereto, or is commercially available.

[0314] Step 1-1

[0315] Compound (1c) can be prepared by reacting compound (1a) prepared by the method below with compound (1b) (such as a carboxylic acid compound and an acid chloride compound) in the presence or absence of an appropriate condensing agent and / or an appropriate base in an appropriate solvent.

[0316] The base used herein includes amines such as triethylamine, diisopropylethylamine and pyridine, alkali metal carbonates such as potassium carbonate, sodium carbonate and sodium hydrogen carbonate, etc. It preferably includes triethylamine, diisopropylethylamine and pyridine.

[0317] The condensing agent used herein may be appropriately selected from condensing agents commonly used in organic synthetic chemistry, which preferably include 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 1-hydroxybenzotriazole.

[0318] The solvent used herein should not be limited unless the solvent reacts under the reaction conditions of this step, but includes, for example, ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, methylcyclopentyl ether, anisole and 1,4-dioxane; aromatic hydrocarbon solvents such as benzene, toluene, chlorobenzene and xylene; ester solvents such as ethyl acetate and methyl acetate; aprotic solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone, acetonitrile and dimethyl sulfoxide; and mixtures thereof. The solvent preferably includes tetrahydrofuran, toluene, N,N-dimethylformamide and acetonitrile.

[0319] The reaction time is generally 5 minutes to 72 hours, preferably 30 minutes to 24 hours.

[0320] The reaction temperature is usually -78°C to 200°C, preferably -78°C to 80°C.

[0321] Method 2

[0322] The compound of the present invention of formula (1c) can also be prepared, for example, by the following method:

[0323]

[0324] Where R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 3A , R 3B , R 3C , R 3D , V and Q are as defined in item 1, LG 1 As defined in Method 1, and LG 2 represents a leaving group and includes, for example, a halogen atom, a methanesulfonyloxy group, an ethanesulfonyloxy group, a p-toluenesulfonyloxy group and a trifluoromethanesulfonyloxy group.

[0325] Compound (2a) can be prepared in a known manner, for example, as described in ACS Chemical Biology, 12(8): 2124-2131 (2017) or in a manner similar thereto, or is commercially available.

[0326] Step 2-1

[0327] Compound (2b) can be prepared from Compound (1a) and Compound (2a) prepared in the following method according to the method described in Step 1-1 of Method 1 or a similar method.

[0328] Step 2-2

[0329] Compound (1c) can be prepared by reacting compound (2b) and an imidazole derivative (QH) in the presence or absence of an appropriate base in an appropriate solvent.

[0330] The base used herein includes, for example, organic bases such as triethylamine, diisopropylethylamine, tributylamine, 1.5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), pyridine, dimethylaminopyridine, picoline and N-methylmorpholine (NMM), and inorganic bases such as sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide and potassium hydroxide. It preferably includes triethylamine, diisopropylethylamine and potassium carbonate.

[0331] The solvent used herein should not be limited unless the solvent reacts under the reaction conditions of this step, but includes, for example, ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, methylcyclopentyl ether, anisole, 1,4-dioxane; aromatic hydrocarbon solvents such as benzene, toluene, chlorobenzene and xylene; ester solvents such as ethyl acetate and methyl acetate; aprotic solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone, acetonitrile and dimethyl sulfoxide; and mixtures thereof. The solvent preferably includes tetrahydrofuran, toluene, N,N-dimethylformamide and acetonitrile.

[0332] The reaction temperature is usually -80°C to reflux temperature, preferably 25°C to 90°C.

[0333] The reaction time is generally 30 minutes to 48 hours, preferably 6 to 12 hours.

[0334] Method 3

[0335] The compound of formula (3b) can be prepared, for example, by the following method:

[0336]

[0337] Where R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 3A, R 3B , R 3C , R 3D and Q is as defined in item 1.

[0338] Compound (3a) can be prepared in a known manner as described in, for example, RSC Advances, 4(76): 40561-40568 (2014), Journal of the American Chemical Society, 117(43): 10605-10613 (1995), etc., or in a manner similar thereto, or is commercially available.

[0339] Step 3-1

[0340] Compound (3b) can be prepared from compound (1a) and compound (3a) in a known manner as described in, for example, Journal of the American Chemical Society, 93(12):2897-2904 (1971), Journal of Organic Chemistry, 37(10):1673-1674 (1972), Journal of Organic Chemistry, 61(11):3849-3862 (1996), Tetrahedron, 60:7899-7906 (2004) and the like, or in a manner analogous thereto.

[0341] Method 4

[0342] The compound of formula (4b) can be prepared, for example, by the following method:

[0343]

[0344] Where R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 3A , R 3B , R 3C , R 3D , V and Q are as defined in item 1, and LG 2 As defined in Method 2.

[0345] Compound (4a) can be prepared by a known method described in, for example, Journal of Medicinal Chemistry, 39(19): 3806-3813 (1996), Advanced Synthesis & Catalysis, 356(9), 1955-1961 (2014), etc. or in a similar manner thereto, or is commercially available.

[0346] Step 4-1

[0347] Compound (4b) can be prepared from Compound (1a) and Compound (4a) prepared in the following method according to the method described in Step 2-2 of Method 2 or a similar method.

[0348] Method 5

[0349] The compound of formula (5c) can be prepared, for example, by the following method:

[0350]

[0351] Where R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 3A , R 3B , R 3C , R 3D , V and Q are as defined in item 1, and LG 2 Independently as defined in Method 2.

[0352] Compound (5a) can be produced in a known manner as described in, for example, Journal of Organic Chemistry, 25: 24-26 (1960) or the like, or in a manner analogous thereto, or is commercially available.

[0353] Step 5-1

[0354] Compound (5b) can be prepared from Compound (1a) and Compound (5a) prepared in the following method according to the method described in Step 2-1 of Method 2 or a similar method.

[0355] Step 5-2

[0356] Compound (5c) can be prepared from compound (5b) and compound Q according to the method described in Step 2-2 of Method 2 or a similar method.

[0357] Method 6

[0358] The production intermediate of formula (1a) can be prepared, for example, by the following method:

[0359]

[0360] Where R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 3A , R 3B , R 3C and R 3D As defined in item 1, and P is an amino protecting group including amino protecting groups described in Protective Groups in Organic Synthesis (edited by Theodora W. Greene, Peter G. M. Wuts, published by John Wiley & Sons, Inc. (1999)).

[0361] Step 6-1

[0362] Compound (6c) can be prepared in a known manner as described in, for example, Journal of the Chemical Society, Perkin Transactions 1, (11): 1401-1404 (2002), Chemistry Letters, (10): 889-890 (1996), Journal of Organic Chemistry, 64(26): 9507-9511 (1999), Synthesis, 44(23), 3579-3589 (2012), Tetrahedron Letters, 54(28), 3639-3642 (2013), Synlett, 26(15), 2151-2155 (2015), Organic Letters, 3(17), 2669-2672 (2001) or the like, or in a manner similar thereto from a commercially available compound (6a) and a compound (6b) obtained by the method shown below.

[0363] Step 6-2

[0364] Compound (1a) can be prepared by deprotecting the protecting group P in compound (6c). This step can be performed according to, for example, Protective Groups in Organic Synthesis (edited by Theodora W. Greene, Peter GM Wuts, published by John Wiley & Sons, Inc. (1999)).

[0365] Method 7

[0366] The production intermediate of formula (6b) can be prepared, for example, by the following method:

[0367]

[0368] Where R 2A , R 2B , R 3A , R 3B , R 3C and R 3D As defined in item 1, P is as defined in method 6, and LG 2 As defined in Method 2.

[0369] Step 7-1

[0370] Compound (7c) can be prepared from commercially available compounds (7a) and (7b) in a known manner as described in, for example, Journal of the American Chemical Society, 137(46): 14590-14593 (2015), European Journal of Medicinal Chemistry, 45(7): 2827-2840 (2010), Bioorganic & Medicinal Chemistry Letters, 14(14): 3675-3678 (2004), Bioorganic & Medicinal Chemistry Letters, 13(13): 2167-2172 (2003), Synthesis, (20): 3241-3246 (2011), Bioorganic & Medicinal Chemistry Letters, 20(22): 6375-6378 (2010), etc., or in a manner similar thereto.

[0371] Step 7-2

[0372] Compound (6b) can be prepared from compound (7c) in a known manner as described in, for example, Bioorganic & Medicinal Chemistry Letters, 25(22):5032-5035 (2015), Bioorganic & Medicinal Chemistry Letters, 14(17): 4453-4459(2004), Angewandte Chemie, International Edition, 56(4), 1152-1157 (2017), Tetrahedron Letters, 51(49), 6415-6417 (2010), Organic Process Research & Development, 17(2): 257-264 (2013), etc., or in a manner similar thereto.

[0373] The compounds of the present invention having the desired substituents at the desired positions can be given by appropriately combining the above methods. The intermediates and the desired compounds in the above methods can be separated / purified by purification methods commonly used in organic chemistry, such as filtering, extraction, washing, drying, concentrating, crystallization, various chromatography, etc., or a combination thereof. Some intermediates can be used in the next step without any purification.

[0374] The starting compound or intermediate in the above method may be in the form of a salt (such as hydrochloride), or directly in the free form, depending on the reaction conditions, etc. If it is necessary to use the starting compound or the free form of the intermediate in the form of a salt, the salt form can be dissolved or suspended in an appropriate solvent and neutralized with a base (such as aqueous sodium bicarbonate solution) or an acid to convert it into its free form.

[0375] The compound of formula (1) or its pharmaceutically acceptable salt may sometimes exist in the form of tautomers (such as keto-enol form), regioisomers, geometric isomers or optical isomers. All these possible isomers and mixtures thereof in any mixing ratio are also included in the present invention.

[0376] Optical isomers can be resolved by a known separation procedure (such as a method using an optically active column and a fractional crystallization method) in an appropriate step of the above methods. In addition, an optically active starting material may be used.

[0377] If the compound of formula (1) should be obtained in the form of a salt or when the compound of formula (1) is obtained in the form of a salt, it may be purified without further reaction, and when it is obtained in a free form, it may be dissolved or suspended in an appropriate organic solvent, and an acid or a base may be added thereto to form a salt. The compound of formula (1) or a pharmaceutically acceptable salt thereof may sometimes exist in the form of a solvate with water or various solvents. Such solvates are also included in the present invention.

[0378] As used herein, "treatment" refers to administering the active ingredient of the present invention to a person (ie, a patient) diagnosed by a doctor as suffering from a disease.

[0379] The compounds of the present invention can be directly administered orally or parenterally, or administered as a suitable pharmaceutical preparation. Dosage forms include, for example, tablets, capsules, powders, granules, liquids, suspensions, injections, patches, poultices, etc., but are not limited thereto. Pharmaceutical preparations are prepared by conventional methods using pharmaceutically acceptable additives.

[0380] As additives, excipients, disintegrants, binders, fluidizers, lubricants, coating agents, solubilizers, solubilization aids, thickeners, dispersants, stabilizers, sweeteners, flavors, etc. can be used depending on the purpose. Additives used herein include, for example, lactose, mannitol, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, corn starch, partially pregelatinized starch, carboxymethyl cellulose calcium, crosslinked carboxymethyl cellulose sodium, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl alcohol, magnesium stearate, sodium stearyl fumarate, polyethylene glycol, propylene glycol, titanium oxide, talc, and the like.

[0381] The route of administration should be selected as the most effective route for treatment, which includes oral administration and parenteral administration, such as intravenous injection, rubbing, inhalation and eye drops. Oral administration is preferred. Dosage forms include, for example, tablets and injections, and tablets are preferred. The dosage of the pharmaceutical composition and its administration frequency may depend on the route of administration, and the patient's disease, symptoms, age, body weight, etc., and therefore cannot be generalized. Typically, the compound of the present invention can be administered to adults at about 0.0001-about 5000 mg / day, preferably about 0.001-about 1000 mg / day, more preferably about 0.1-about 500 mg, and particularly preferably about 1-about 300 mg, which can be administered once a day or several times a day, preferably once to three times a day.

[0382] The compounds of the present invention can be used together or in combination with different drugs to enhance the effect and / or reduce side effects. Different drugs that can be used together or in combination with the compounds of the present invention include, for example, anticancer alkylating agents, anticancer antimetabolites, anticancer antibiotics, anticancer agents of plant origin, anticancer platinum complexes, anticancer camptothecin derivatives, anticancer tyrosine kinase inhibitors, anticancer serine / threonine kinase inhibitors, anticancer phospholipid kinase inhibitors, anticancer monoclonal antibodies, interferons, biological response modifiers, hormone preparations, angiogenesis inhibitors, immune checkpoint inhibitors, epigenetic-related molecule inhibitors, protein post-translational modification inhibitors, proteasome inhibitors and other anti-tumor drugs, or pharmaceutically acceptable salts thereof. In more detail, they include, for example, azacytidine, vorinostat, decitabine, romidepsin, idarubicin, daunorubicin, doxorubicin, enocitabine, cytarabine, mitoxantrone, thioguanine, etoposide, ifosfamide, cyclophosphamide, dacarbazine, temozolomide, nimustine, busulfan, procarbazine, melphalan, ranimustine, all-trans retinoic acid, tamibarotene, cisplatin, carboplatin, oxaliplatin, irinotecan, bleomycin, mitomycin C, methotrexate, paclitaxel, docetaxel, gemcitabine, tamoxifen, thiotepa, tegafur, fluorouracil, everolimus, temsirolimus, gefitinib, erlotinib, imatinib, Crizotinib, osimertinib, afatinib, dasatinib, bosutinib, vandetanib, sunitinib, axitinib, pazopanib, lenvatinib, lapatinib, nilotinib, ibrutinib, ceritinib, alectinib, tofacitinib, baricitinib, ruxolitinib, olaparib, sorafenib, vemurafenib, dabrafenib, trametinib, palbociclib, bortezomib, carfilzomib, rituximab, cetuximab, trastuzumab, bevacizumab, panitumumab, nivolumab, atuzumab, mogatuzumab, alemtuzumab, ofatumumab, ipilimumab, ramucirumab, brentuximab vedotin), gemtuzumab ozogamicin and inotuzumab ozogamicin. In addition, the above-mentioned different drugs that can be used together with the compounds of the present invention can also be cell drugs. The cell drugs used together include, for example, CAR-T cells. In more detail, they include, for example, tisagenlecleucel and axicabtagene ciloleucel.

[0383] The dosing interval of the compounds of this invention and the different drugs used together should not be limited. They can be applied to the object in need at the same time, or can be applied at intervals of a period of time. In addition, the compounds of this invention and different drugs can be mixed as a combination drug. The dosage of the different drugs used together can be appropriately determined according to the clinical dosage. The mixing ratio of the compounds of this invention and the different drugs used together can be appropriately determined according to the disease, symptom, combination, etc. of the object, route of administration, and object to be treated. When the object to be treated is human, the different drugs used together can be used, for example, with a dosage of 0.01-100 parts by weight per portion of the compounds of this invention.

[0384] Protective groups, condensing agents and the like used herein are sometimes shown with abbreviations based on IUPAC-IUB, which are conventionally used in this technical field. However, the names of compounds herein should not always be based on the IUPAC nomenclature system. Example

[0385] The present invention is explained in more detail below by referring to Reference Examples, Examples and Tests; however, the technical scope of the present invention should not be limited thereto. The compound names used in Reference Examples and Examples should not always be based on the IUPAC nomenclature system.

[0386] In this specification, the abbreviations shown below are sometimes used.

[0387] Hex: Hexane

[0388] IPA: Isopropyl alcohol

[0389] THF: Tetrahydrofuran

[0390] TFA: trifluoroacetic acid

[0391] MeCN: Acetonitrile

[0392] Me:Methyl

[0393] Et: Ethyl

[0394] Pr:propyl

[0395] Ph: phenyl

[0396] Boc: tert-butoxycarbonyl.

[0397] NMR data used to identify the compounds were obtained using a JEOL JNM-AL series AL400.

[0398] The symbols used in NMR represent the following meanings: s is singlet, d is doublet, dd is doublet of doublets, t is triplet, td is triplet of doublets, q is quartet, m is multiplet, br is broad, brs is broad singlet, brm is broad multiplet, and J is coupling constant.

[0399] The LC / MS analysis conditions used to identify the compounds are as follows. Mass spectra [MS (m / z)] are expressed as [M+H] + or [M+2H] 2+ The retention time is shown as Rt (minutes).

[0400] LC / MS analysis method (condition 1):

[0401] Testing equipment: ACQUITY TM SQ detector (Waters Corporation)

[0402] HPLC: ACQUITY TM UPLC System

[0403] Column: Waters ACQUITY TM UPLC BEH C18 (1.7 μm, 2.1 mm × 30 mm)

[0404] Solvent: A: 0.06% formic acid / H2O, B: 0.06% formic acid / MeCN

[0405] Gradient conditions: Linear gradient from B 2% to B 96% in 0.0 to 1.3 min

[0406] Flow rate: 0.8 mL / min

[0407] UV: 220 nm and 254 nm.

[0408] LC / MS analysis method (condition 2):

[0409] LCMS-2020 system (Shimadzu Corporation)

[0410] Column: Kinetex TM 1.7 μm Minibore column, C18 (30 mm × 2.1 mm)

[0411] Solvent: A: 0.05% TFA / H2O, B: MeCN

[0412] Gradient conditions: Linear gradient from B 10% to B 99% from 0.0 to 1.7 min, B 99% in 1.9 min

[0413] Flow rate: 0.50 mL / min

[0414] UV: 220 nm and 254 nm.

[0415] The optical activities of the compounds of the present invention and their synthetic intermediates were analyzed under the following conditions.

[0416] HPLC systems for optical resolution

[0417] Pump: LC-20AD (Shimadzu Corporation)

[0418] Detector: SPD-20A (Shimadzu Corporation)

[0419] Pump: SIL-20A (Shimadzu Corporation).

[0420] Condition A

[0421] Column: CHIRALPAK IE

[0422] Dimensions: 0.46 cm ID × 25 cm L

[0423] Mobile phase: n-Hex / EtOH / i-PrNH2= 90 / 10 / 0.1 <v v>

[0424] Flow rate: 1.0 mL / min

[0425] Temperature: 40℃

[0426] Wavelength: 287 nm.

[0427] Condition B

[0428] Column: CHIRALPAK IE

[0429] Dimensions: 0.46 cm ID × 25 cm L

[0430] Mobile phase: n-Hex / IPA / i-PrNH2 = 80 / 20 / 0.1 <v v>

[0431] Flow rate: 1.0 mL / min

[0432] Temperature: 40℃

[0433] Wavelength: 285 nm.

[0434] Condition C

[0435] Column: CHIRALPAK IE

[0436] Dimensions: 0.46 cm ID × 25 cm L

[0437] Mobile phase: MeOH / i-PrNH2 = 100 / 0.1 <v v>

[0438] Flow rate: 1.0 mL / min

[0439] Temperature: 40℃

[0440] Wavelength: 280 nm.

[0441] Condition D

[0442] Column: CHIRALPAK AD-H

[0443] Dimensions: 0.46 cm ID × 25 cm L

[0444] Mobile phase: n-Hex / IPA / EtOH / i-PrNH2 = 85 / 5 / 10 / 0.1 <v v>

[0445] Flow rate: 1.0 mL / min

[0446] Temperature: 40℃

[0447] Wavelength: 280 nm.

[0448] Condition E

[0449] Column: CHIRALPAK AD-H

[0450] Dimensions: 0.46 cm ID × 25 cm L

[0451] Mobile phase: MeOH / Et2NH = 100 / 0.1 <v v>

[0452] Flow rate: 1.0 mL / min

[0453] Temperature: 40℃

[0454] Wavelength: 280 nm.

[0455] Reference Example 1

[0456] tert-Butyl 4-(hydroxymethyl)-4-(3-methylbut-2-en-1-yl)piperidine-1-carboxylate

[0457]

[0458] a) Preparation of 1-tert-butyl 4-methyl 4-(3-methylbut-2-en-1-yl)piperidine-1,4-dicarboxylate

[0459] To a solution of 1-tert-butyl 4-methyl piperidine-1,4-dicarboxylate (69.0 g) in tetrahydrofuran (700 ml) was added dropwise 1 mol / L sodium bis(trimethylsilyl)amide (326 ml), and the reaction mixture was stirred at that temperature for 1 hour. The reaction mixture was warmed to -20 °C and stirred at that temperature for 1 hour. 1-Bromo-3-methyl-2-butene (42.6 ml) was added dropwise to the reaction mixture at -78 °C. The reaction mixture was warmed to -20 °C and stirred at that temperature for 3 hours. The reaction mixture was warmed to room temperature and stirred overnight. After the reaction was completed, an aqueous ammonium chloride solution was added to the reaction mixture. Subsequently, water and ethyl acetate were added thereto. The mixture was separated into an ethyl acetate layer and an aqueous layer in a separatory funnel. The obtained organic layer was washed with brine and dried over sodium sulfate. The solvent was removed in vacuo, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (69.0 g).

[0460] 1 H-NMR (400 MHz, CDCl3): 5.01 (1H, t, J = 7.5 Hz), 3.87-3.72 (2H, m), 3.68 (3H, s), 2.86 (2H, dd, J = 2.7, 11.4 Hz), 2.21 (2H, d, J = 7.3 Hz), 2.06(2H, d, J = 14.2 Hz), 1.69 (3H, s), 1.58 (3H, s), 1.44 (9H, s), 1.43-1.34(2H, m).

[0461] LC-MS (Condition 1); [M+H] + 312.3 / Rt (min.) 1.24.

[0462] b) Preparation of tert-butyl 4-(hydroxymethyl)-4-(3-methylbut-2-en-1-yl)piperidine-1-carboxylate (Reference Example 1)

[0463] To a solution of lithium aluminum hydride (9.25 g) in tetrahydrofuran (700 ml) was added dropwise a solution of 4-(3-methylbut-2-ene-1-yl)piperidine-1,4-dicarboxylic acid 1-tert-butyl 4-methyl ester (69.0 g) obtained in step a) in tetrahydrofuran (300 ml) at -78°C. The reaction mixture was stirred at this temperature for 1 hour. The reaction mixture was stirred at -20°C for 5 hours under a nitrogen atmosphere. After the reaction was completed, a saturated aqueous sodium sulfate solution was added to the reaction mixture at 0°C. The mixture was stirred at room temperature for 1 hour and dried over magnesium sulfate. The reaction mixture was filtered with celite, and the solvent of the filtrate was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain Reference Example 1 (58.0 g).

[0464] 1 H-NMR (400 MHz, CDCl3): 5.17 (1H, t, J = 7.8 Hz), 3.48-3.41 (2H, m), 3.46 (2H, s), 3.38-3.31 (2H, m), 2.09 (2H, d, J = 7.8 Hz), 1.73 (3H, s), 1.65(3H, s), 1.51-1.37 (4H, m), 1.46 (9H, s).

[0465] LC-MS (Condition 1); [M+H] + 284.3 / Rt (min.) 1.08.

[0466] Reference Example 2

[0467] The racemate of (4'aR,10'bR)-9'-chloro-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzofuran] and (4'aS,10'bS)-9'-chloro-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzofuran]

[0468]

[0469] To a solution of Reference Example 1 (69.0 g) in dichloromethane (1000 ml) were added 5-chloro-2-hydroxybenzaldehyde (48.0 g), trimethyl orthoformate (100 ml), and then p-toluenesulfonic acid monohydrate (1.90 g) at 0°C, and the reaction mixture was stirred at 0°C for 5 hours under a nitrogen atmosphere. The solvent was removed in vacuo, and 4 mol / L hydrochloric acid in ethyl acetate (300 ml) was added to the obtained residue at 0°C. The mixture was stirred at 0°C for 1 hour. The solvent was removed in vacuo, and the obtained residue was purified by amine silica gel column chromatography (chloroform / methanol) to obtain the racemate of Reference Example 2 (61.5 g).

[0470] 1 H-NMR (400 MHz, CDCl3): 7.38 (1H, s), 7.11 (1H, d, J = 8.6 Hz), 6.70 (1H, d, J = 8.6 Hz), 4.12 (1H, d, J = 11.4 Hz), 4.08 (1H, d, J = 10.9 Hz),3.31 (1H, d, J = 10.9 Hz), 2.90-2.86 (3H, m), 2.81-2.77 (1H, m), 1.91-1.80(3H, m), 1.57-1.53 ​​(1H, m), 1.39-1.37 (2H, m), 1.38 (3H, s), 1.17 (3H, s), 1.11-1.05 (1H, m).

[0471] LC-MS (Condition 1); [M+H] + 322.2 / Rt (min.) 0.77.

[0472] The obtained Reference Example 2 was optically resolved to obtain Reference Example 3 and Reference Example 4, which are optically active compounds of Reference Example 2.

[0473] Reference Example 3:

[0474] Condition A; Rt (min.) = 10.35

[0475] LC-MS (Condition 1); [M+H] + 322.2 / Rt (min.) 0.77.

[0476] Reference Example 4:

[0477] Condition A; Rt (min.) = 12.07

[0478] LC-MS (Condition 1); [M+H] + 322.2 / Rt (min.) 0.77.

[0479] Reference Examples 5-15

[0480] Reference Examples 5 to 15 shown in the following table were prepared in the same manner as Reference Example 2 from the respective corresponding starting compounds.

[0481]

[0482]

[0483] Shown below are the NMR data of Reference Examples 5, 6, 7, 10, 11 and 14 shown in the above table.

[0484] Reference Example 5

[0485] 1 H-NMR (400 MHz, DMSO-d6): 7.28 (1H, d, J = 7.3 Hz), 7.27 (1H, d, J =6.7 Hz), 6.84 (1H, dd, J = 7.3, 7.9 Hz), 4.17 (1H, d, J = 11.0 Hz), 3.94 (1H,d, J = 11.0 Hz), 3.34-3.27 (1H, m), 2.69-2.58 (4H, m), 1.82-1.74 (2H, m), 1.55-1.51 (1H, m), 1.41-1.37 (1H, m), 1.37 (3H, s), 1.24-1.22 (2H, m), 1.15(3H, s), 1.10-1.06 (1H, m).

[0486] Reference Example 6

[0487] 1 H-NMR (400 MHz, DMSO-d6): 7.42 (1H, d, J = 7.6 Hz), 7.31 (1H, d, J =8.0 Hz), 6.79 (1H, dd, J = 7.6, 7.9 Hz), 4.18 (1H, d, J = 11.2 Hz), 3.94 (1H,d, J = 10.8 Hz), 3.29 (2H, d, J = 11.2 Hz), 2.65-2.60 (4H, m), 1.81-1.76 (2H,m), 1.54-1.51 (1H, m), 1.43-1.38 (1H, m), 1.37 (3H, s), 1.24-1.21 (2H, m),1.15 (3H, s), 1.15-1.10 (1H, m)。

[0488] Reference Example 7

[0489] 1 H-NMR (400 MHz, CDCl3): 7.33 (1H, d, J = 9.2 Hz), 6.88 (1H, d, J =8.4 Hz), 6.80 (1H, s), 4.14-4.07 (2H, m), 3.32 (1H, d, J = 11.6 Hz), 2.90-2.80 (4H, m), 1.93-1.82 (2H, m), 1.58-1.51 (1H, m), 1.38-1.34 (1H, m), 1.36(3H, s), 1.27-1.19 (2H, m), 1.24 (3H, s), 1.12-1.06 (1H, m)。

[0490] Reference Example 10

[0491] 1 H-NMR (400 MHz, DMSO-d6): 7.23 (1H, d, J = 8.8 Hz), 7.01 (1H, d, J =8.4 Hz), 6.91 (1H, s), 4.09 (1H, d, J = 10.4 Hz), 3.94 (1H, d, J = 11.6 Hz),3.28 (1H, d, J = 11.6 Hz), 2.64-2.57 (4H, m), 1.80-1.69 (2H, m), 1.54-1.50(1H, m), 1.40-1.35 (1H, m), 1.32 (3H, s), 1.22-1.21 (2H, m), 1.13 (3H, s),1.11-1.04 (1H, m)。

[0492] Reference Example 11

[0493] 1 H-NMR (400 MHz, DMSO-d6): 7.03-6.94 (2H, m), 6.74-6.70 (1H, m), 4.12(1H, d, J = 11.2 Hz), 3.95 (1H, d, J = 12.8 Hz), 3.27 (1H, d, J = 11.6 Hz),2.64-2.57 (4H, m), 1.80-1.69 (2H, m), 1.54-1.51 (1H, m), 1.41-1.37 (1H, m),1.31 (3H, s), 1.22-1.21 (2H, m), 1.13 (3H, s), 1.07-1.04 (1H, m)。

[0494] Reference Example 14

[0495] 1 H-NMR (400 MHz, DMSO-d6): 7.37 (1H, d, J = 2.4 Hz), 7.27 (1H, d, J =9.2 Hz), 6.69 (1H, d, J = 9.2 Hz), 4.14 (1H, d, J = 10.8 Hz), 3.95 (1H, d, J= 10.8 Hz), 3.28 (1H, d, J = 11.2 Hz), 2.64-2.57 (4H, m), 1.80-1.68 (2H, m), 1.54-1.50 (1H, m), 1.40-1.35 (1H, m), 1.32 (3H, s), 1.22-1.21 (2H, m), 1.12(3H, s), 1.11-1.04 (1H, m).

[0496] Reference Example 16

[0497] 1-[(4'aS,10'bS)-9'-chloro-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran]-1-yl]-2-chloroethan-1-one and 1-[(4'aR,10'bR)-9'-chloro-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran]-1-yl]-2-chloroethan-1-one racemate

[0498]

[0499] To a solution of Reference Example 2 (2.00 g) in tetrahydrofuran (150 ml) was added potassium carbonate (4.30 g) at 0°C, and then chloroacetyl chloride (0.7 ml) was added, and the reaction mixture was stirred at 0°C for 2 hours under a nitrogen atmosphere. The reaction mixture was filtered through celite, and the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain Reference Example 16 (2.05 g).

[0500] 1 H-NMR (400 MHz, CDCl3): 7.37 (1H, s), 7.11 (1H, d, J = 8.7 Hz), 6.70 (1H, d, J = 8.7 Hz), 4.12-4.05 (4H, m), 3.85-3.76 (1H, m), 3.60-3.36 (4H, m),1.90-1.84 (2H, m), 1.79-1.74 (1H, m), 1.66-1.57 (1H, m), 1.49-1.40 (2H, m),1.36 (3H, s), 1.17 (3H, s), 1.15-1.10 (1H, m).

[0501] LC-MS (Condition 1); [M+H] + 398.2 / Rt (min.) 1.17.

[0502] Reference Example 17

[0503] tert-Butyl 4-(hydroxymethyl)-4-(prop-2-yn-1-yl)piperidine-1-carboxylate

[0504]

[0505] a) Preparation of 1-tert-butyl 4-methyl 4-(prop-2-yn-1-yl)piperidine-1,4-dicarboxylate

[0506] A solution of 1-tert-butyl 4-methyl piperidine-1,4-dicarboxylate (1.00 g) in THF (24.0 ml) was cooled to -78°C. 1.0 mol / L sodium hexamethyldisilazide in THF (8.22 ml) was added to the cooled solution, and the reaction mixture was stirred at -78°C for 30 minutes and then at -18°C for 45 minutes. The reaction mixture was cooled to -78°C, and propargyl bromide (0.62 ml) was then added dropwise thereto. The reaction mixture was gradually warmed from -78°C to -20°C, and then a saturated aqueous ammonium chloride solution was added thereto. The mixture was extracted twice with ethyl acetate, and the obtained organic layer was dried over anhydrous sodium sulfate. The mixture was filtered, and the solvent of the filtrate was removed in vacuo. The obtained residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (982 mg).

[0507] LC-MS (Condition 1); [M+H] + 282.3 / Rt (min.) 1.02.

[0508] b) Preparation of tert-butyl 4-(hydroxymethyl)-4-(prop-2-yn-1-yl)piperidine-1-carboxylate (Reference Example 17)

[0509] A solution of the compound obtained in step a) (928 mg) in a mixture of methanol (8.2 ml) and THF (8.2 ml) was heated to 55° C. Sodium borohydride (449 mg) was added to the heated solution, and the reaction mixture was stirred for 1 hour. Additional sodium borohydride (449 mg) was added thereto, and the reaction mixture was stirred for 3 hours. The reaction solution was diluted with water. The mixture was extracted three times with ethyl acetate, and the obtained organic layer was dried over anhydrous sodium sulfate. The mixture was filtered, and the solvent of the filtrate was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain Reference Example 17 (515 mg).

[0510] LC-MS (Condition 1); [M+H] + 254.3 / Rt (min.) 0.84.

[0511] Reference Example 18

[0512] A mixture of tert-butyl 4-(hydroxymethyl)-4-[(2E)-3-(phenylthio)prop-2-en-1-yl]piperidine-1-carboxylate and tert-butyl 4-(hydroxymethyl)-4-[(2Z)-3-(phenylthio)prop-2-en-1-yl]piperidine-1-carboxylate

[0513]

[0514] A solution of Reference Example 17 (515 mg), azobisisobutyronitrile (100 mg) and thiophenol (207 μl) in toluene (10 ml) was stirred at 80° C. for 1 hour under a nitrogen atmosphere. The reaction solution was concentrated in vacuo, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain Reference Example 18 (498 mg).

[0515] LC-MS (Condition 1); [M+H] + 364.3 / Rt (min.) 1.17.

[0516] Reference Example 19

[0517] The racemate of (4'aS,10'bS)-8'-chloro-5'-(phenylthio)-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran]-1-carboxylic acid tert-butyl ester and (4'aR,10'bR)-8'-chloro-5'-(phenylthio)-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran]-1-carboxylic acid tert-butyl ester

[0518]

[0519] A solution of Reference Example 18 (479 mg), trimethyl orthoformate (288 μl) and p-toluenesulfonic acid monohydrate (12.5 mg) in dichloromethane (6.6 ml) was stirred at 0° C., 4-chloro-2-hydroxybenzaldehyde (411 mg) was added thereto, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated in vacuo, and the obtained residue was purified by amino column chromatography (chloroform) to obtain Reference Example 19 (691 mg).

[0520] LC-MS (Condition 1); [M+H] + 446.3 / Rt (min.) 1.45.

[0521] Reference Example 20

[0522] The racemate of (4'aS,10'bR)-8'-chloro-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran]-1-carboxylic acid tert-butyl ester and (4'aR,10'bS)-8'-chloro-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran]-1-carboxylic acid tert-butyl ester

[0523]

[0524] A solution of Reference Example 19 (309 mg), azobisisobutyronitrile (10 mg) and tributyltin hydride (489 μl) in toluene (6.2 ml) was stirred at 100° C. for 1 hour under a nitrogen atmosphere. The reaction solution was concentrated in vacuo, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain Reference Example 20 (167 mg).

[0525] LC-MS (Condition 1); [M+H] + 338.3 / Rt (min.) 1.35.

[0526] Reference Example 21

[0527] The racemate of (4'aR,10'bS)-8'-chloro-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran] and (4'aS,10'bR)-8'-chloro-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran]

[0528]

[0529] A solution of Reference Example 20 (167 mg) in 4 mol / L hydrochloric acid / dioxane (1.7 ml) was stirred at 70° C. for 30 minutes. The reaction solution was concentrated in vacuo, and the obtained residue was purified by amino column chromatography (chloroform / methanol) to obtain Reference Example 21 (105 mg).

[0530] LC-MS (Condition 1); [M+H] + 294.3 / Rt (min.) 0.70.

[0531] Example 1

[0532] 1-[(4'aS,10'bS)-9'-chloro-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran]-1-yl]-2-(2-methyl-1H-imidazol-1-yl)ethan-1-one and 1-[(4'aR,10'bR)-9'-chloro-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran]-1-yl]-2-(2-methyl-1H-imidazol-1-yl)ethan-1-one racemate

[0533]

[0534] To a solution of Reference Example 16 (2.0 g) in tetrahydrofuran (50 ml) were added potassium carbonate (4.0 g) and 2-methyl-1H-imidazole (1.53 g), and the reaction mixture was stirred at 60° C. for 2 hours. The reaction solution was filtered through celite, and the solvent was removed in vacuo, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain Example 1 (2.05 g).

[0535] 1 H-NMR (400 MHz, CDCl3): 7.36 (1H, s), 7.10 (1H, d, J = 8.8 Hz), 6.97-6.90 (1H, m), 6.83-6.75 (1H, m), 6.70 (1H, d, J = 8.7 Hz), 4.65 (2H, s),4.11-4.06 (2H, m), 3.85-3.76 (1H, m), 3.47-3.36 (4H, m), 2.34 (3H, s), 1.90-1.70 (4H, m), 1.60-1.50 (1H, m), 1.43-1.37 (2H, m), 1.35 (3H,s), 1.16 (3H,s), 1.15-1.10 (1H, m).

[0536] LC-MS (Condition 1); [M+H] + 443.9 / Rt (min.) 0.79.

[0537] Example 2-17

[0538] Examples 2 to 17 shown in the following table were prepared in the same manner as Reference Example 16 and Example 1 from the respective corresponding starting compounds.

[0539]

[0540]

[0541]

[0542] Shown below are the NMR data for Examples 2 and 7 shown in the table above.

[0543] Example 2

[0544] 1 H-NMR (400 MHz, DMSO-d6): 7.08-6.95 (2H, m), 6.90-6.86 (1H, m),6.79-6.69 (1H, m), 6.66 (1H, m), 4.89 (2H, m), 4.18 (1H, d, J = 10.8 Hz),4.00 (1H, d, J = 12.0 Hz), 3.50-3.30 (5H, m), 2.12 (3H, s), 1.86-1.83 (1H,m), 1.74-1.66 (2H, m), 1.64-1.50 (1H, m), 1.40-1.33 (2H, m), 1.35-1.30 (1H,m), 1.33 (3H, s), 1.17-1.13 (1H, m), 1.13 (3H, s)。

[0545] Example 7

[0546] 1 H-NMR (400 MHz, DMSO-d6): 7.39 (1H, s), 7.30 (1H, d, J = 8.4 Hz),6.88 (1H, s), 6.72-6.66 (2H, m), 4.90-4.88 (2H, m), 4.19 (1H, d, J = 10.8Hz), 4.01 (1H, d, J = 11.6 Hz), 3.50-3.36 (5H, m), 2.12 (3H, s), 1.86-1.83(1H, m), 1.76-1.66 (2H, m), 1.64-1.53 (1H, m), 1.40-1.33 (2H, m), 1.36-1.31(1H, m), 1.34 (3H, s), 1.18-1.13 (1H, m), 1.14 (3H, s)。

[0547] Embodiment 18

[0548] The racemate of (4'aR,10'bR)-8'-chloro-5',5'-dimethyl-1-[(4-methyl-1H-imidazol-5-yl)methyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran] and (4'aS,10'bS)-8'-chloro-5',5'-dimethyl-1-[(4-methyl-1H-imidazol-5-yl)methyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran]

[0549]

[0550] To a solution of Reference Example 7 (200 mg) in tetrahydrofuran (10 ml) was added 4-methyl-1H-imidazole-5-carboxaldehyde (137 mg) at 0°C, and then sodium triacetoxyborohydride (397 mg) was added, and the reaction mixture was stirred at 0°C for 2 hours under a nitrogen atmosphere. Water and saturated sodium carbonate were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium carbonate aqueous solution and brine, dried over magnesium sulfate, filtered and then concentrated in vacuo. The obtained residue was purified by silica gel column chromatography (chloroform / methanol) to obtain Example 18 (49 mg).

[0551] 1 H-NMR (400 MHz, DMSO-d6): 11.61 (1H, d, J = 17.7 Hz), 7.35 (1H, d, J= 7.9 Hz), 7.28 (1H, d, J = 7.9 Hz), 6.87 (1H, d, J = 7.9 Hz), 6.77 (1H, s),4.11 (1H, d, J = 10.4 Hz), 3.87 (1H, d, J = 10.4 Hz), 3.34-3.26 (3H, m), 2.49(3H, s), 2.31-2.22 (4H, m), 2.11-2.03 (1H, m), 1.71-1.67 (2H, m), 1.60-1.56 (1H, m), 1.49-1.44 (1H, m), 1.31 (3H, s), 1.13 (3H, s), 1.13-1.08 (2H, m).

[0552] LC-MS (Condition 1); [M+H] + 416.7 / Rt (min.) 0.59.

[0553] Examples 19-37

[0554] Examples 19-37 shown in the following table were prepared in the manner of Example 18 from the respective corresponding starting compounds.

[0555]

[0556]

[0557] Shown below are the NMR data for Examples 20 and 33 shown in the table above.

[0558] Embodiment 20

[0559] 1 H-NMR (400 MHz, DMSO-d6): 11.61 (1H, d, J = 17.7 Hz), 7.35 (1H, d,J = 7.9 Hz), 7.28 (1H, d, J = 7.9 Hz), 6.87 (1H, d, J = 7.9 Hz), 6.77 (1H,s), 4.11 (1H, d, J = 10.4 Hz), 3.87 (1H, d, J = 10.4 Hz), 3.34-3.26 (3H, m), 2.49 (3H, s), 2.31-2.22 (4H, m), 2.11-2.03 (1H, m), 1.71-1.67 (2H, m), 1.60-1.56 (1H, m), 1.49-1.44 (1H, m), 1.31 (3H, s), 1.13 (3H, s), 1.13-1.08 (2H,m).

[0560] Embodiment 33

[0561] 1 H-NMR (400 MHz, DMSO-d6): 7.50 (1H, s), 7.29 (1H, d, J = 7.6 Hz), 6.89 (1H, d, J = 8.4 Hz), 6.77 (1H, s), 6.71 (1H, s), 4.12 (1H, d, J = 10.8Hz), 3.88 (1H, d, J = 10.4 Hz), 3.58 (3H, m), 3.44-3.30 (2H, m), 2.39-2.20(4H, m), 1.74-1.70 (2H, m), 1.60-1.51 (2H, m), 1.50-1.30 (2H,m), 1.32 (3H,s), 1.14 (3H, s), 1.13-1.10 (1H, m).

[0562] Embodiment 38

[0563] The racemate of (4'aR,10'bR)-8'-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran] and (4'aS,10'bS)-8'-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran]

[0564]

[0565] To a solution of Reference Example 7 (200 mg) in acetonitrile (10.0 ml) was added 2-bromoethanol (137 mg) and triethylamine (0.70 ml) at 0°C, and the reaction mixture was stirred at 70°C for 1 hour under a nitrogen atmosphere. The reaction mixture was cooled to 0°C and concentrated. Dichloromethane (10.0 ml), triethylamine (0.57 ml) and methanesulfonyl chloride (0.09 ml) were added thereto, and the reaction mixture was stirred for 30 minutes. Imidazole (0.50 g) was added thereto at room temperature, and the reaction mixture was stirred at 50°C for 1 hour under a nitrogen atmosphere. A saturated aqueous sodium carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium carbonate solution, and then with brine, dried over magnesium sulfate, filtered and then concentrated in vacuo. The obtained residue was purified by silica gel column chromatography (chloroform / methanol) to obtain Example 38 (49 mg).

[0566] 1 H-NMR (400 MHz, DMSO-d6): 7.59 (1H, s), 7.29 (1H, d, J = 7.9 Hz), 7.15 (1H, s), 6.88 (1H, d, J = 8.5 Hz), 6.83 (1H, s), 6.78 (1H, s), 4.12 (1H,d, J = 11.2 Hz), 4.04-4.01 (2H, m), 3.90 (1H, d, J = 10.8 Hz), 3.32-3.26 (3H,m), 2.59 (2H, t, J = 6.0 Hz), 2.52-2.46 (4H, m), 2.43-2.25 (4H, m), 1.73 (2H,d, J = 7.9 Hz), 1.60-1.56 (1H, m), 1.49-1.44 (1H, m), 1.32 (3H, s), 1.13 (3H,s), 1.13-1.08 (2H, m).

[0567] LC-MS (Condition 1); [M+H] + 416.7 / Rt (min.) 0.59.

[0568] Examples 39-63

[0569] Examples 39-63 shown in the following table were prepared in the manner of Example 38 from the respective corresponding starting compounds.

[0570]

[0571]

[0572]

[0573] Shown below are the NMR data for Examples 42, 60, 61 and 63 shown in the table above.

[0574] Embodiment 42

[0575] 1 H-NMR (400 MHz, DMSO-d6): 7.59 (1H, s), 7.29 (1H, d, J = 7.9 Hz),7.15 (1H, s), 6.88 (1H, d, J = 8.5 Hz), 6.83 (1H, s), 6.78 (1H, s), 4.12 (1H,d, J = 11.2 Hz), 4.04-4.01 (2H, m), 3.90 (1H, d, J = 10.8 Hz), 3.32-3.26 (3H,m), 2.59 (2H, t, J = 6.0 Hz), 2.52-2.46 (4H, m), 2.43-2.25 (4H, m), 1.73 (2H,d, J = 7.9 Hz), 1.60-1.56 (1H, m), 1.49-1.44 (1H, m), 1.32 (3H, s), 1.13 (3H,s), 1.13-1.08 (2H, m)。

[0576] Embodiment 60

[0577] 1 H-NMR (400 MHz, CDCl3): 7.34 (1H, d, J = 8.0 Hz), 7.31 (1H, s), 6.99-6.90 (2H, m), 6.99 (1H, d, J = 8.4 Hz), 6.82 (1H, s), 4.11-4.07 (2H, m),4.00-3.96 (2H, m), 3.76-3.72 (2H, m), 3.33 (1H, d, J = 11.2 Hz), 2.93-2.90(2H, m), 2.67-2.66 (2H, m), 2.55-2.45 (3H, m), 2.39-2.32 (1H, m), 1.99 (3H,s), 1.91-1.87 (2H, m), 1.80-1.77 (1H, m), 1.65-1.55 (1H, m), 1.44-1.41 (2H,m), 1.41 (3H, s), 1.29 (3H, s), 1.21-1.12 (1H, m)。

[0578] Embodiment 61

[0579] 1 H-NMR (400 MHz, CDCl3): 7.42 (1H, s), 7.21 (1H, d, J = 8.4 Hz), 7.18(1H, s), 6.77 (1H, d, J = 8.4 Hz), 6.69-6.67 (2H, m), 6.54 (1H, s), 3.99-3.96(2H, m), 3.91-3.88 (2H, m), 3.43-3.42 (2H, m), 3.21 (1H, d, J = 11.2 Hz),2.67-2.64 (2H, m), 2.61-2.58 (2H, m), 2.45-2.35 (3H, m), 2.30-2.24 (1H, m),1.87 (3H, s), 1.76-1.67 (2H, m), 1.53-1.49 (1H, m), 1.42-1.38 (1H, m), 1.35-1.30 (1H, m), 1.28 (3H, s), 1.08 (3H, s), 1.04-0.97 (1H, m)。

[0580] Embodiment 63

[0581] 1 H-NMR (400 MHz, DMSO-d6): 8.18 (1H, d, J = 4.4 Hz), 7.72 (1H, s),7.45 (1H, s), 7.29 (1H, d, J = 7.6 Hz), 6.88 (1H, d, J = 7.6 Hz), 6.77 (1H,s), 4.37-4.33 (2H, m), 4.10 (1H, d, J = 11.6 Hz), 3.88 (1H, d, J = 11.6 Hz),3.31-3.26 (2H, m), 2.70 (3H, s), 2.57-2.53 (2H, m), 2.37-2.29 (4H, m), 1.72-1.67 (2H, m), 1.60-1.55 (1H, m), 1.50-1.40 (1H, m), 1.32-1.23 (2H, m), 1.29(3H, s), 1.13 (3H, s), 1.13-1.06 (1H, m)。

[0582] Embodiment 64

[0583] The racemate of (4'aS,10'bR)-8'-chloro-1-[(4-methyl-1H-imidazol-5-yl)methyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran] and (4'aR,10'bS)-8'-chloro-1-[(4-methyl-1H-imidazol-5-yl)methyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran]

[0584]

[0585] To a solution of Reference Example 21 (103 mg) and 4-methyl-1H-imidazole-5-carbaldehyde (77 mg) in THF (3.5 ml) and methanol (1.0 ml) was added sodium triacetoxyborohydride (223 mg), and the reaction mixture was stirred at room temperature for 2 hours. Additional sodium triacetoxyborohydride (77 mg) was added thereto, and the reaction mixture was stirred for another 30 minutes. The reaction solution was concentrated, and the obtained residue was purified by silica gel column chromatography (ethyl acetate / methanol) to obtain Example 64 (97 mg).

[0586] 1 H-NMR (400 MHz, DMSO-d6): 11.65 (0.5H, s), 11.60 (0.5H, s), 7.35(1H, s), 7.25 (1H, d, J = 8.3 Hz), 6.89 (1H, dd, J = 8.3, 1.8 Hz), 6.81 (1H,d, J = 1.8 Hz), 4.17 (1H, dd, J = 11.0, 3.7 Hz), 4.12 (1H, d, J = 10.4 Hz), 3.86-3.92 (2H, m), 3.26-3.38 (3H, m), 2.21-2.37 (4H, m), 2.11 (1.5H, s), 2.03(1.5H, s), 1.86-1.95 (1H, m), 1.75 (1H, d, J = 12.2 Hz), 1.55 (2H, br), 1.27(2H, br), 0.95 (1H, t, J = 12.5 Hz).

[0587] LC-MS (Condition 1); [M+H] + 388.7 / Rt (min.) 0.57.

[0588] Examples 64a and 64b

[0589] The obtained Example 64 was optically resolved to obtain Example 64a and Example 64b, which are optically active compounds of Example 64.

[0590] Example 64a:

[0591] Condition D; Rt (min.) = 10.26

[0592] LC-MS (Condition 1); [M+H] + 388.1 / Rt (min.) 0.60.

[0593] Embodiment 64b:

[0594] Condition D; Rt (min.) = 14.02

[0595] LC-MS (Condition 1); [M+H] + 388.0 / Rt (min.) 0.61.

[0596] Embodiment 65

[0597]

[0598] To a solution of Example 51 (15 mg) in methanol (0.2 ml) was added fumaric acid (8.1 mg), and the reaction mixture was stirred at 60°C for 1 hour. The reaction mixture was allowed to stand overnight at room temperature and dried by evaporation. Ethyl acetate (0.3 ml) was added to the residue, and the mixture was stirred at 40°C for 4 hours. The precipitated solid was collected on a Kiriyama filter, washed with ethyl acetate, and dried in vacuo at 50°C to afford Example 65 (15 mg) as a white solid.

[0599] 1 H-NMR (400 MHz, DMSO-d6) δ: 7.29 (1H, d, J = 8.5 Hz), 7.11 (1H, d, J = 1.2 Hz), 6.88 (1H, dd, J = 8.2, 2.1 Hz), 6.81 (1H, d, J = 1.2 Hz), 6.78 (1H,d,J = 2.4 Hz), 6.59 (4H, s), 4.12 (1H, d, J = 11.0 Hz), 3.97 (2H, t, J = 6.7Hz), 3.90 (1H, d, J = 11.6 Hz), 3.30 (1H, d, J = 11.6 Hz), 2.59 (2H, t, J =6.4 Hz), 2.46-2.39 (2H, m), 2.38-2.25 (2H, m), 2.32 (3H, s), 1.81-1.65 (2H,m), 1.65-1.55 (1H, m), 1.37-1.23 (1H, m), 1.32 (3H, s), 1.15-1.05 (1H, m),1.13 (3H, s).

[0600] LC-MS (Condition 2); [M+H] + 430 / Rt (min.) 1.519.

[0601] Examples 66-78

[0602] Examples 66-78 shown in the following table were prepared in a similar manner to Example 65 from the respective corresponding starting compounds by respective salification.

[0603]

[0604]

[0605]

[0606]

[0607] test

[0608] Hereinafter, the results of evaluating the compounds of the present invention using pharmacological tests are shown, which also illustrate the pharmacological activities of the compounds, however, the technical scope of the present invention should not be limited thereto.

[0609] Test 1: Inhibition test of cancer cell sphere formation assay

[0610] Reliable methods established to measure the cell self-renewal ability, which is one of the properties of CSCs, include a method for measuring the sphere-forming ability of cancer cells under non-adherent conditions in the absence of serum (Cancer Res 65, 5506-5511 (2005)). HT-29 cells can be obtained from the American Type Culture Collection (ATCC). HT-29 cells were cultured at 37°C in 5% CO2 using McCoy's 5a medium containing 10% fetal bovine serum (FBS) and 1% penicillin / streptomycin. HT-29 cells were seeded at 350-800 cells / well in a 384-well black clear bottom ultra-low attachment microplate (Corning Cat. No. 3827) using DMEM / F12 medium containing 2% B27 supplement (GIBCO), 20 ng / mL epidermal growth factor (EGF) (peprotech), 10 ng / mL basic fibroblast growth factor (bFGF) (peprotech), 5 μg / mL insulin (Sigma), and 1% penicillin / streptomycin. Each test compound was added to each well so that the final concentration of DMSO was adjusted to 0.1%, and the cells were cultured for 4 days. CellTiter-Glo was then used to TM The number of viable cells in each well was measured using a luminescent cell viability assay kit (Luminescent Cell Viability Assay, Promega) to calculate the concentration of each test compound that inhibited cell proliferation by 50% (Sphere IC 50 value; μmol / L).

[0611] Each compound of each example was subjected to the test of Test 1. The concentration of each test compound at which 50% cell proliferation was inhibited (Sphere IC 50 Values; μmol / L) are shown in the table below.

[0612]

[0613] As shown in the above table, Examples 20, 26, 32, 33, 34, 38, 39, 40, 41, 42, 44, 45, 46, 47, 48, 49, 51, 52, 53, 54, 56 and 64a exhibited potent activity in inhibiting cell proliferation under spheroid culture conditions.

[0614] Test 2: Test to evaluate hERG inhibition

[0615] Each test compound was added to a cultured CHO cell line stably expressing hERG so that the final concentration of DMSO was adjusted to 0.0135 to 0.5%. The hERG current was measured using QPatch HT (Sophion Inc.), and the concentration at which 50% of the hERG current was inhibited by each test compound (IC 50 value; μM).

[0616] The compounds of the examples were tested according to Test 2. And, hERG / HT-29 was calculated by dividing the compound concentration (50% inhibition of hERG current) obtained in Test 2 by the compound concentration (50% inhibition of HT-29 cell proliferation) obtained in Test 1. The results are shown in the following table.

[0617]

[0618] As shown in the above table, Examples 20, 26, 32, 33, 34, 38, 39, 40, 41, 42, 44, 46, 47, 48, 49, 51, 52, 53, 54, 56 and 64a showed a good deviation between the concentration that inhibited cell proliferation by 50% and the concentration that inhibited hERG current by 50%.

[0619] Industrial Applicability

[0620] The compounds of the present invention have a potent inhibitory effect on the spheroidizing ability of cancer cells and are thus useful as antitumor agents.< / v> < / v> < / v> < / v> < / v>

Claims

1. Compounds of formula (I): or a pharmaceutically acceptable salt thereof, wherein R 1A , R 1B , R 1C and R 1D are each independently a hydrogen atom, a halogen atom, an azido group or a cyano group, provided that R 1A , R 1B , R 1C and R 1D Not all of them are hydrogen atoms. R 2A and R 2B are independently a hydrogen atom or a C 1-3 alkyl, R 3A , R 3B , R 3C and R 3D are independently a hydrogen atom, a halogen atom, a hydroxyl group, a C 1-6 Alkyl, or C 1-6 Alkoxy, L is a bond or -C(O)-, V is 1 to 3 independently selected from fluorine atoms, hydroxyl groups, C 1-6 Alkoxy and cyano substituents substituted C 1-6 Alkylene, Q is an imidazolyl group which may be substituted by 1 to 3 groups independently selected from halogen atoms, cyano groups, C 1-6 Alkyl, C 2-6 Alkenyl, -CO2R 4a and-CONR 9 R 10 Substituents, wherein the C 1-6 The alkyl group may be 1 to 3 independently selected from halogen atoms, cyano groups, hydroxyl groups, C 1-6 Alkoxy, -NR 5a R 6a and-NR 7a COR 8a Substituents are substituted, the C 2-6 The alkenyl group may be substituted by 1 to 3 hydroxyl groups. R 5a , R 6a , R 7a , R 9 and R 10 are independently a hydrogen atom or a C 1-3 Alkyl, or When R 5a and R 6a Both C 1-3 alkyl, they may combine with the nitrogen atom to which they are attached to form a 3- to 6-membered nitrogen-containing saturated heterocyclic group, and When R 9 and R 10 Both C 1-3 alkyl, they may combine with the nitrogen atom to which they are attached to form a 3- to 6-membered nitrogen-containing saturated heterocyclic group, and R 4a and R 8a Independently for C 1-3 alkyl, Provided that the following compounds of formula (Z-1) and (Z-2) are not included:

2. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 3A , R 3B , R 3C and R 3D It's a hydrogen atom.

3. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein R 2A and R 2B are independently a hydrogen atom or a C 1-3 alkyl.

4. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein R 2A and R 2B It's methyl.

5. A compound of formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein L is a bond.

6. A compound of formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein L is -CO-.

7. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein V is C 1-6 Alkylene.

8. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein V is C 1-3 Alkylene.

9. A compound of formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein V is ethylene.

10. A compound of formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein V is a methylene group.

11. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein R 1A , R 1B , R 1C and R 1D are each independently a hydrogen atom, a fluorine atom or a chlorine atom, provided that R 1A , R 1B , R 1C and R 1D Not all are hydrogen atoms.

12. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein Q is formula (Q-1) or (Q-2): in R 11A , R 11B , R 11C , R 11D and R 11E are each independently a hydrogen atom, a halogen atom, a cyano group, a C 1-6 Alkyl, C 2-6 Alkenyl, -CO2R 4a or-CONR 9 R 10 , the C 1-6 The alkyl group may be 1 to 3 independently selected from halogen atoms, cyano groups, hydroxyl groups, C 1-6 Alkoxy, -NR 5a R 6a and-NR 7a COR 8a Substituents are substituted, the C 2-6 The alkenyl group may be substituted by 1 to 3 hydroxyl groups. R 5a , R 6a , R 7a , R 9 and R 10 are independently a hydrogen atom or a C 1-3 Alkyl, or When R 5a and R 6a Both C 1-3 alkyl, they may combine with the nitrogen atom to which they are attached to form a 3- to 6-membered nitrogen-containing saturated heterocyclic group, and When R 9 and R 10 Both C 1-3 When alkyl groups are present, they may combine with the nitrogen atom to which they are attached to form a 3- to 6-membered nitrogen-containing saturated heterocyclic group, R 4a and R 8a Independently for C 1-3 alkyl, R 12 is a hydrogen atom or C 1-6 Alkyl, and The asterisk (*) is the junction with V.

13. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 12, wherein R 11A , R 11B , R 11C , R 11D and R 11E are independently a hydrogen atom, a cyano group, a C 1-6 Alkyl, C 2-6 Alkenyl or -CO2R 4a , the C 1-6 The alkyl group may be substituted by 1 to 3 groups independently selected from fluorine atoms, hydroxyl groups and -NR 7a COR 8a Substituents are substituted, the C 2-6 The alkenyl group may be substituted with one hydroxy group.

14. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 12, wherein R 11A , R 11B , R 11C , R 11D and R 11E are independently a hydrogen atom, a cyano group, a C 1-3 Alkyl or C 2-6 Alkenyl, wherein the alkyl and the alkenyl may each independently be substituted with one hydroxyl group.

15. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 12, wherein R 11A , R 11B , R 11C , R 11D and R 11E are independently a hydrogen atom or a C 1-3 alkyl.

16. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 12 to 15, wherein R 12 It's a hydrogen atom.

17. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 16, wherein formula (I) is formula (1-A):

18. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 16, wherein formula (I) is formula (1-B):

19. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 16, wherein formula (I) is formula (1-C):

20. A compound or a pharmaceutically acceptable salt thereof selected from: (4'aS,10'bS)-8'-chloro-5',5'-dimethyl-1-[(4-methyl-1H-imidazol-5-yl)methyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran], (4'aR,10'bR)-8'-chloro-5',5'-dimethyl-1-[(4-methyl-1H-imidazol-5-yl)methyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran], (4'aR,10'bR)-9'-chloro-5',5'-dimethyl-1-[(4-methyl-1H-imidazol-5-yl)methyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran], (4'aS,10'bS)-9'-chloro-5',5'-dimethyl-1-[(4-methyl-1H-imidazol-5-yl)methyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran], (4'aS,10'bS)-9'-chloro-5',5'-dimethyl-1-[(1-methyl-1H-imidazol-5-yl)methyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran], (4'aR,10'bR)-9'-chloro-5',5'-dimethyl-1-[(1-methyl-1H-imidazol-5-yl)methyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran], (4'aR,10'bR)-8'-chloro-5',5'-dimethyl-1-[(1-methyl-1H-imidazol-5-yl)methyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran], (4'aS,10'bS)-8'-chloro-5',5'-dimethyl-1-[(1-methyl-1H-imidazol-5-yl)methyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran], (4'aS,10'bS)-7'-chloro-5',5'-dimethyl-1-[(1-methyl-1H-imidazol-5-yl)methyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran], (4'aR,10'bR)-7'-chloro-5',5'-dimethyl-1-[(1-methyl-1H-imidazol-5-yl)methyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran], (4'aR,10'bR)-8'-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran], (4'aS,10'bS)-8'-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran], (4'aS,10'bS)-9'-fluoro-1-[2-(1H-imidazol-1-yl)ethyl]-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran], (4'aR,10'bR)-9'-fluoro-1-[2-(1H-imidazol-1-yl)ethyl]-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran], (4'aR,10'bR)-9'-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran], (4'aS,10'bS)-9'-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran], (4'aS,10'bS)-9'-fluoro-5',5'-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran], (4'aR,10'bR)-9'-fluoro-5',5'-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran], (4'aR,10'bR)-9'-chloro-5',5'-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran], (4'aS,10'bS)-9'-chloro-5',5'-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran], (4'aS,10'bS)-8'-chloro-5',5'-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran], (4'aR,10'bR)-8'-chloro-5',5'-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran], (1-{2-[(4'aR,10'bR)-9'-fluoro-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran]-1-yl]ethyl}-1H-imidazol-2-yl)methanol, (1-{2-[(4'aS,10'bS)-9'-fluoro-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran]-1-yl]ethyl}-1H-imidazol-2-yl)methanol, (1-{2-[(4'aS,10'bS)-9'-chloro-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran]-1-yl]ethyl}-1H-imidazol-2-yl)methanol, (1-{2-[(4'aR,10'bR)-9'-chloro-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran]-1-yl]ethyl}-1H-imidazol-2-yl)methanol, (1-{2-[(4'aR,10'bR)-8'-chloro-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran]-1-yl]ethyl}-1H-imidazol-2-yl)methanol, (1-{2-[(4'aS,10'bS)-8'-chloro-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran]-1-yl]ethyl}-1H-imidazol-2-yl)methanol, (1-{2-[(4'aS,10'bS)-9'-chloro-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran]-1-yl]ethyl}-5-methyl-1H-imidazol-4-yl)methanol, (1-{2-[(4'aR,10'bR)-9'-chloro-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran]-1-yl]ethyl}-5-methyl-1H-imidazol-4-yl)methanol, (4'aS,10'bR)-8'-chloro-1-[(4-methyl-1H-imidazol-5-yl)methyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran], and (4'aR,10'bS)-8'-chloro-1-[(4-methyl-1H-imidazol-5-yl)methyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran].

21. A compound or a pharmaceutically acceptable salt thereof selected from: (4'aS,10'bS)-8'-chloro-5',5'-dimethyl-1-[(4-methyl-1H-imidazol-5-yl)methyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran], (4'aR,10'bR)-8'-chloro-5',5'-dimethyl-1-[(4-methyl-1H-imidazol-5-yl)methyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran], (4'aR,10'bR)-9'-chloro-5',5'-dimethyl-1-[(4-methyl-1H-imidazol-5-yl)methyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran], (4'aS,10'bS)-9'-chloro-5',5'-dimethyl-1-[(4-methyl-1H-imidazol-5-yl)methyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran], (4'aS,10'bS)-9'-chloro-5',5'-dimethyl-1-[(1-methyl-1H-imidazol-5-yl)methyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran], (4'aR,10'bR)-9'-chloro-5',5'-dimethyl-1-[(1-methyl-1H-imidazol-5-yl)methyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran], (4'aR,10'bR)-8'-chloro-5',5'-dimethyl-1-[(1-methyl-1H-imidazol-5-yl)methyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran], (4'aS,10'bS)-8'-chloro-5',5'-dimethyl-1-[(1-methyl-1H-imidazol-5-yl)methyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran], (4'aS,10'bS)-7'-chloro-5',5'-dimethyl-1-[(1-methyl-1H-imidazol-5-yl)methyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran], and (4'aR,10'bR)-7'-chloro-5',5'-dimethyl-1-[(1-methyl-1H-imidazol-5-yl)methyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran].

22. A compound or a pharmaceutically acceptable salt thereof selected from: (4'aR,10'bR)-8'-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran], (4'aS,10'bS)-8'-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran], (4'aS,10'bS)-9'-fluoro-1-[2-(1H-imidazol-1-yl)ethyl]-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran], (4'aR,10'bR)-9'-fluoro-1-[2-(1H-imidazol-1-yl)ethyl]-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran], (4'aR,10'bR)-9'-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran], (4'aS,10'bS)-9'-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran], (4'aS,10'bS)-9'-fluoro-5',5'-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran], (4'aR,10'bR)-9'-fluoro-5',5'-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran], (4'aR,10'bR)-9'-chloro-5',5'-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran], (4'aS,10'bS)-9'-chloro-5',5'-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran], (4'aS,10'bS)-8'-chloro-5',5'-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran], (4'aR,10'bR)-8'-chloro-5',5'-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran], (1-{2-[(4'aR,10'bR)-9'-fluoro-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran]-1-yl]ethyl}-1H-imidazol-2-yl)methanol, (1-{2-[(4'aS,10'bS)-9'-fluoro-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran]-1-yl]ethyl}-1H-imidazol-2-yl)methanol, (1-{2-[(4'aS,10'bS)-9'-chloro-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran]-1-yl]ethyl}-1H-imidazol-2-yl)methanol, (1-{2-[(4'aR,10'bR)-9'-chloro-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran]-1-yl]ethyl}-1H-imidazol-2-yl)methanol, (1-{2-[(4'aR,10'bR)-8'-chloro-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran]-1-yl]ethyl}-1H-imidazol-2-yl)methanol, (1-{2-[(4'aS,10'bS)-8'-chloro-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran]-1-yl]ethyl}-1H-imidazol-2-yl)methanol, (1-{2-[(4'aS,10'bS)-9'-chloro-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran]-1-yl]ethyl}-5-methyl-1H-imidazol-4-yl)methanol, and (1-{2-[(4'aR,10'bR)-9'-chloro-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran]-1-yl]ethyl}-5-methyl-1H-imidazol-4-yl)methanol.

23. A compound or a pharmaceutically acceptable salt thereof selected from: (4'aS,10'bS)-8'-chloro-5',5'-dimethyl-1-[(4-methyl-1H-imidazol-5-yl)methyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran], (4'aR,10'bR)-8'-chloro-5',5'-dimethyl-1-[(4-methyl-1H-imidazol-5-yl)methyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran], (4'aR,10'bR)-8'-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran], (4'aS,10'bS)-8'-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran], (4'aS,10'bS)-9'-fluoro-5',5'-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran], and (4'aR,10'bR)-9'-Fluoro-5',5'-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran].

24. A compound or a pharmaceutically acceptable salt thereof selected from: (4'aS,10'bS)-8'-chloro-5',5'-dimethyl-1-[(4-methyl-1H-imidazol-5-yl)methyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran].

25. A compound or a pharmaceutically acceptable salt thereof selected from: (4'aR,10'bR)-8'-chloro-5',5'-dimethyl-1-[(4-methyl-1H-imidazol-5-yl)methyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran].

26. A compound or a pharmaceutically acceptable salt thereof selected from: (4'aR,10'bR)-8'-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran].

27. A compound or a pharmaceutically acceptable salt thereof selected from: (4'aS,10'bS)-8'-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran].

28. A compound or a pharmaceutically acceptable salt thereof selected from: (4'aS,10'bS)-9'-Fluoro-5',5'-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran].

29. A compound or a pharmaceutically acceptable salt thereof selected from: (4'aR,10'bR)-9'-Fluoro-5',5'-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran].

30. A compound or a phosphate thereof selected from: (4'aS,10'bS)-8'-chloro-5',5'-dimethyl-1-[(4-methyl-1H-imidazol-5-yl)methyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran], (4'aR,10'bR)-8'-chloro-5',5'-dimethyl-1-[(4-methyl-1H-imidazol-5-yl)methyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran], (4'aR,10'bR)-8'-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran], (4'aS,10'bS)-8'-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran], (4'aS,10'bS)-9'-fluoro-5',5'-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran], and (4'aR,10'bR)-9'-Fluoro-5',5'-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran].

31. A compound or a fumarate thereof selected from: (4'aS,10'bS)-8'-chloro-5',5'-dimethyl-1-[(4-methyl-1H-imidazol-5-yl)methyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran], (4'aR,10'bR)-8'-chloro-5',5'-dimethyl-1-[(4-methyl-1H-imidazol-5-yl)methyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran], (4'aR,10'bR)-8'-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran], (4'aS,10'bS)-8'-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran], (4'aS,10'bS)-9'-fluoro-5',5'-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran], and (4'aR,10'bR)-9'-Fluoro-5',5'-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran].

32. A compound or its p-toluenesulfonate salt selected from: (4'aS,10'bS)-8'-chloro-5',5'-dimethyl-1-[(4-methyl-1H-imidazol-5-yl)methyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran], (4'aR,10'bR)-8'-chloro-5',5'-dimethyl-1-[(4-methyl-1H-imidazol-5-yl)methyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran], (4'aR,10'bR)-8'-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran], (4'aS,10'bS)-8'-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran], (4'aS,10'bS)-9'-fluoro-5',5'-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran], and (4'aR,10'bR)-9'-Fluoro-5',5'-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran].

33. A medicament comprising the compound according to any one of claims 1 to 32 or a pharmaceutically acceptable salt thereof as an active ingredient.

34. An antitumor drug comprising the compound according to any one of claims 1 to 32 or a pharmaceutically acceptable salt thereof as an effective ingredient.

35. The anti-tumor drug according to claim 34, wherein the tumor is acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, polycythemia vera, malignant lymphoma, myeloma, brain tumor, small cell lung cancer, non-small cell lung cancer, breast cancer, gastric cancer, colon cancer or rectal cancer.

36. A pharmaceutical composition comprising a compound according to any one of claims 1 to 32 or a pharmaceutically acceptable salt thereof, used in combination with another agent or a pharmaceutically acceptable salt thereof, wherein the other agent is at least one selected from the group consisting of anticancer alkylating agents, anticancer antimetabolites, anticancer antibiotics, anticancer drugs of plant origin, anticancer platinum complexes, anticancer camptothecin derivatives, anticancer tyrosine kinase inhibitors, anticancer serine / threonine kinase inhibitors, anticancer phospholipid kinase inhibitors, anticancer monoclonal antibodies, interferons, biological response modifiers, hormone preparations, angiogenesis inhibitors, immune checkpoint inhibitors, epigenetics-related molecule inhibitors, protein post-translational modification inhibitors, proteasome inhibitors, and other antitumor drugs.

37. A compound according to any one of claims 1 to 32 or a pharmaceutically acceptable salt thereof for use in treating cancer, used in combination with another agent or a pharmaceutically acceptable salt thereof, wherein the other agent is at least one agent selected from the group consisting of anticancer alkylating agents, anticancer antimetabolites, anticancer antibiotics, anticancer drugs of plant origin, anticancer platinum complexes, anticancer camptothecin derivatives, anticancer tyrosine kinase inhibitors, anticancer serine / threonine kinase inhibitors, anticancer phospholipid kinase inhibitors, anticancer monoclonal antibodies, interferons, biological response modifiers, hormone preparations, angiogenesis inhibitors, immune checkpoint inhibitors, epigenetics-related molecule inhibitors, protein post-translational modification inhibitors, proteasome inhibitors and other anti-tumor drugs.

38. Use of a compound according to any one of claims 1 to 32 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancer, wherein the cancer is acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, polycythemia vera, malignant lymphoma, myeloma, brain tumor, small cell lung cancer, non-small cell lung cancer, breast cancer, gastric cancer, colon cancer or rectal cancer.

39. A pharmaceutical composition for treating cancer, comprising a compound according to any one of claims 1 to 32 or a pharmaceutically acceptable salt thereof.

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