EA041753B1 - DIHYDROCHROMENE DERIVATIVES - Google Patents

Description

Technical field

The present invention relates to a dihydrochromene derivative and a pharmaceutically acceptable salt thereof, which can be used as a medicine, as well as an antitumor agent containing this derivative as an active ingredient.

Background of the invention

Conventional cancer therapies are sometimes not expected to have a significant survival effect, even if they can cause tumor regression, in part because it is currently assumed that cancer cells are directly involved in the ongoing spread of malignant tumors, metastasis or recurrence of cancer and resistance to anticancer agents. stem cells (hereinafter referred to, if necessary, CSC). 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 literature 1). In addition, CSCs may differ greatly in biological characteristics from normal cancer cells derived from CSC differentiation, and thus the development of an antitumor agent targeting CSCs is expected to lead to a new cancer treatment strategy (Non-Patent Literature 2).

One of the features of CSC is the ability to self-renewal (non-patent literature 3). Reliable methods established for determining the ability of cells to self-renewal include, for example, a method for measuring the sphere-forming ability of cancer cells in a non-adherent state in the absence of serum (non-patent literature 4).

Until now, there has been no literature data indicating that the present compounds of formula (1) shown below can exhibit an antitumor effect or an inhibitory effect on the sphere-forming ability of cancer cells.

Prior Art

non-patent reference.

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

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

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

[Non-Patent Literature 4] Ponti et al., Cancer Res 65(13): 5506-11. 2005.

The essence of the invention

Technical task.

It is an object of the present invention to provide useful compounds as a novel antitumor agent targeting CSCs, which are believed to be intimately involved in persistent cancer proliferation, cancer metastasis or recurrence, and resistance to antitumor agents.

Solution to the problem.

The inventors of the present invention have made rigorous studies to achieve the above object, and finally found that the compound of the following formula (1) or a pharmaceutically acceptable salt thereof (hereinafter referred to as the compound of the present invention, if necessary) has a strong inhibitory effect on the sphere-forming ability of cancer cells and is highly useful as a novel antitumor agent. Based on the data obtained, the present invention was created.

The present invention is described below.

Item 1 Compound of Formula (I)

or a pharmaceutically acceptable salt thereof, wherein

R ^1A , R ^1b , R ^1c and R ^1d each independently represent a hydrogen atom, a halogen atom or an azide, provided that all R ^1A , R ^1B , R ^1C and R ^1D do not represent a hydrogen atom,

R ^2A and R ^2B each independently represent a hydrogen atom or C _1-3 alkyl, r ³ a, r ^3b , r ^3c and r ^3d each independently represent a hydrogen atom, a halogen atom or C _1-6 alkyl,

L represents a bond or -C(O)-,

V is C _1-3 alkylene,

Q has formula (Q-1) or (Q-2):

- 1 041753

(CM) (Q-2) where R ^11a , R ^11b , R ^11c , R ^11d and R ^11e are each independently hydrogen, halogen, cyano, C1-6 alkyl (which may be substituted from 1 to 3 substituents independently selected from the group consisting of halogen, cyano, hydroxy, C1-6 alkoxy, -NR ^5a R ^6a and -NR ^7a COR ^8a ), C2. ₆ alkenyl (which may be substituted with 1 to 3 hydroxy groups), -CO ₂ R ^4a or -CONR9R ¹⁰ ,

R ^5a , R ^6a , R ^7a , R ⁹ and R ¹⁰ are each independently hydrogen or C1-3 alkyl, or when R ^5a and R ^6a are both C1-3 alkyl, they may be combined with an atom nitrogen to which they are attached to form a 3-6 membered nitrogen-containing saturated heterocyclyl, and when R ⁹ and R ¹⁰ are both C _1-3 alkyl, they can be combined with the nitrogen atom to which they are attached, with the formation of a 3-6-membered nitrogen-containing saturated heterocyclyl,

R ^4a and R ^8a are independently C _1-3 alkyl,

R ¹² represents a hydrogen atom or C _1-6 alkyl, and the asterisk (*) denotes the point of attachment to V, provided that the following compounds of formulas (Z-1) and (Z-2) are excluded:

oh oh

Item 2. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R ^3A , R ^3B , R ^3C and R ^3D represent a hydrogen atom.

Item 3. A compound according to any one of claims 1-2, or a pharmaceutically acceptable salt thereof, wherein R ^2A and R ^2B are each independently C _1-3 alkyl.

Item 4. A compound according to any one of claims 1 to 2, or a pharmaceutically acceptable salt thereof, wherein R ^2A and R ^2B are methyl.

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

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

Item 7. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein V is ethylene.

Item 8. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein V is methylene.

Item 9. A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, 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 all R ^1a , R ^1b , R ^1c and R ^1d do not represent a hydrogen atom.

Item 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R ^11a , R ^11b , R ^11c , R ^11d and R ^11e are each independently hydrogen, cyano, C1-6 alkyl (which may be substituted from 1 to 3 substituents independently selected from the group consisting of a fluorine atom, hydroxy and -NR ^7a COR ^8a ), C2-6alkenyl (which may be substituted with one hydroxy group) or -CO ₂ R ^4a .

Item 11. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R ^11a , R ^11b , R ^11c , R ^11d and R ^11e are each independently hydrogen, cyano, C _1-3 alkyl, or C _{2 -6} alkenyl, where alkyl and alkenyl can each be independently substituted with one hydroxy group.

Item 12. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R ^11a , R ^11b , R ^11c , R ^11d and R ^11e are each independently hydrogen or C _1-3 alkyl.

Item 13. The compound according to any one of claims 1, 10-12, or a pharmaceutically acceptable salt thereof, where R ¹² represents a hydrogen atom.

Item 14. A compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein formula (I) is a compound of formula (1-A)

Item 15. A compound according to any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein formula (I) is a compound of formula (1-B)

- 2 041753

Item 16. The compound according to any one of claims 1 to 13. Mula (I) is a compound of formula (1-C)

or a pharmaceutically acceptable salt thereof, wherein the formula

Item 17. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the following compounds:

(4'a8,10 ^, b8)-8'-chloro-5',5'-dimethyl-1-[(4-methyl-1H-imidazol-5-yl)methyl]-4'a,10'bdihydro- 2 Ή,4 'H,5 'H-spiro[piperidine-4,3'-pyrano[3,2-c] [ 1 ]benzopyran], (4' aR, 10'bR)-8'-chloro-5',5' -dimethyl-1 -[(4-methyl-1 H-imide azol-5 -yl)methyl]-4' a, 10' bdihydro-2 Ή,4 Ή, 5' H-spiro[piperidine- 4,3'-pyrano[3,2-c] [1]benzopyran], (4'aR, 10'bR)-9'-chloro-5', 5'-dimethyl-1-[(4-methyl- 1 H-imide azol-5-yl)methyl]-4'a,10'bdihydro-2 Ή,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c] [ 1 ]benzopyran], (4'a8,10 ^, b8)-9'-chloro-5',5'-dimethyl-1-[(4-methyl-1H-imidazol-5-yl)methyl]-4'a ,10'bdihydro-2 Ή,4 Ή, 5'H-spiro[piperidine-4,3'-pyrano[3,2-c] [1]benzopyran], (4'a8,10 ^, b8)-9'-chloro-5',5'-dimethyl-1-[(1-methyl-1H-imidazol-5-yl)methyl]-4'a,10'bdihydro-2 Ή,4 Ή, 5'H-spiro[ piperidine-4,3'-pyrano[3,2-c] [1]benzopyran], (4'aR, 10'bR)-9'-chloro-5', 5'-dimethyl-1-[(1- methyl-1 H-imide azol-5-yl)methyl]-4'a,10'bdihydro-2 Ή,4'H,5'H-spiro[piperidine-4,3'-pyrano[3,2-c ] [ 1 ]benzopyran], (4 'aR, 10 'b R)-8'-chloro-5', 5'-dimethyl-1-[(1-methyl-1 H-imide azol-5-yl)methyl]-4'a, 10'bdihydro-2 Ή,4 Ή , 5'H-spiro[piperidine-4,3'-pyrano[3,2-c] [1]benzopyran], (4'a8,10 ^, b8)-8'-chloro-5 ^, ,5'-dimethyl -1-[(1-methyl-1H-imidazol-5-yl)methyl]-4'a,10'bdihydro-2 Ή,4'H,5'H-spiro[piperidin-4,3'-pyrano[ 3,2-c] [ 1 ]benzopyran], (4'a8,10 ^, b8)-7 ^, -chloro-5',5'-dimethyl-1-[(1-methyl-1H-imidazol-5-yl )methyl]-4'a,10'bdihydro-2 Ή,4'H,5'H-spiro[piperidine-4,3'-pyrano[3,2-c][1]benzopyran], (4'aR , 10'bR)-7'-chloro-5',5'-dimethyl-1-[(1-methyl-1 H-imide azol-5-yl)methyl]-4'a, 10'bdihydro-2 Ή ,4 Ή, 5'H-spiro[piperidine-4,3'-pyrano[3,2-c] [1]benzopyran], (4'aR, 10'bR)-8'-chloro-1-[2 -( 1 H-imide azol-1 -yl)ethyl] -5', 5'-dimethyl-4'a, 10'b-dihydro2 Ή,4 Ή, 5'H-spiro[piper idine-4,3' -pyrano[3,2-c][1]benzopyran], (4'a8,10 ^, b8)-8'-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5', 5 ^, -dimethyl-4'a,10'b-dihydro2 Ή,4 Ή, 5'H-spiro[piperidine-4,3'-pyrano[3,2-c] [1] benzopyran], (4' a8,10 ^, b8)-9'-ft op-1-[2-(1H-imidazol-1-yl)ethyl]-5',5'-dimethyl-4'a,10'b-dihydro2 Ή,4 Ή, 5'H-spiro[piper idin- 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'bdihydro-2 Ή,4'H,5'H-spiro[piperidine-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 -dihydro2 Ή,4 Ή, 5'H-spiro[piperidine-4,3'-pyrano[3,2-c] [1] benzopyran], (4'a8,10 ^, b8)-9'-chloro- 1-[2-(1H-imidazol-1-yl)ethyl]-5',5 ^, -dimethyl-4'a,10'b-dihydro-

Ή,4 Ή, 5'H-spiro[piperidine-4,3'-pyrano[3,2-c] [1] benzopyran], (4'a8,10 ^, b8)-9'-fluoro-5' ,5 ^, -dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4'a,10'bdihydro-2 Ή,4'H,5'H-spiro[piperidine- 4,3 '-pyrano[3,2-c] [ 1 ]benzopyran],

- 3 041753 (4'aR, 10'bR)-9'-fluoro-5', 5'-dimethyl-1-[2-(2-methyl-1 H-imide azol-1-yl)ethyl]-4 'a, 10'bdihydro-2 Ή,4 Ή,5'H-spiro[piperidine-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'bdihydro-2 Ή.4 Ή.5' H-spiro[piperidine-4,3'-pyrano[3,2-c] [ 1 ]benzopyran], (4' aS, 10' b S)-9'-chloro-5', 5'-dimethyl-1 -[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4'a, 10'bdihydro-2 Ή.4 Ή.5'H-spiro[piperidine-4,3'-pyrano[3 ,2-c] [ 1 ]benzopyran], (4 'aS, 10 'b S)-8'-chloro-5', 5'-dimethyl-1 -[2-(2-methyl-1H-imidazole-1 -yl)ethyl]-4'a, 10'bdihydro-2 Ή,4 Ή.5'H-spiro[piperidine-4,3'-pyrano[3,2-c] [1]benzopyran], (4' aR,l O'bR)-8'-chloro-5',5'-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4'a,10'bdihydro- 2 Ή,4 Ή, 5'H-spiro[piperidine-4,3'-pyrano[3,2-c] [ 1 ]benzopyran], (l-{2-[(4'aR,10'bR)- 9'-φτop-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'Hspiro[piperidine-4,3'-pyrano[3,2-с] [1]benzopyran]-1-yl]ethyl}-1H-imidase ol-2-yl)methanol, (1-{2-[(4'a8,10'b8)-9'-fluoro-5',5'-dimethyl-4'a,10'b-dihydro-2' H,4'H,5'Hspiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran]-1-yl]ethyl}-1H-imidazol-2-yl)methanol, (1 - {2-[(4'aS, 10'b S)-9'-chloro-5', 5'-dimethyl-4'a, 10'b-dihydro-2 Ή,4 Ή, 5Ήspiro[piperidine- 4,3'-pyrano[3,2-c][1]benzopyran]-1-yl]ethyl}-1H-imidazol-2-yl)methanol, (1-!2-[(4'aK,10' bK)-9'-chloro-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'Hspiro[piperidine-4,3'-pyrano[3,2 -c][1]benzopyran]-1-yl]ethyl}-1H-imidazol-2-yl)methanol, (l-{2-[(4'aR,10'bR)-8'-chloro-5' ,5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'Hspiro[piperidine-4,3'-pyrano[3,2-c][1]benzopyran]-1 -yl]ethyl}-1H-imidazol-2-yl)methanol, (1-{2-[(4'aS, 10'b S)-8'-chloro-5',5'-dimethyl-4'a , 10' L-dihydro-2 Ή, 4 Ή, 5 Ήspiro[piperidine-4,3'-pyrano[3,2-c][1]benzopyran]-1-yl]ethyl}-1H-imidazol-2- yl)methanol, (1-{2-[(4'aS, 10'b S)-9'-chloro-5', 5'-dimethyl-4'a, 10'b-dihydro-2Ή, 4Ή , 5 Ήspiro[piper idin-4,3 '-pyrano[3,2-c] [ 1 ] benzopyran] -1 -yl]ethyl } -5 -methyl-1 H -imidazol-4yl)methanol, (l-{2-[(4'aR,10'bR)-9'-xlor-5',5'-dimethyl-4'a,10'b-dihydro-2'H ,4'H,5'Hspiro[piper idin-4,3'-pyrano[3,2-c] [1]benzopyran]-1-yl]ethyl }-5-methyl-1H-imidazol-4yl)methanol , (4'aS,10'bR)-8'-xflop-l-[(4-MeTnn-lH-HMHfla3Ofl-5-nn)MeTnn]-4'a,10'b-aHrHflpo2Ή,4Ή,5 'H -spiro[piperidine-4,3'-pyrano[3,2-c][ 1 ]benzopyran] and (4'aR,10'bS)-8'-xlor-l-[(4-methyl-lH-imidazole -5-yl)methyl]-4'a,10'b-dihydro2 Ή,4 Ή, 5'H-spiro[piperidine-4,3'-pyrano[3,2-c][1]benzopyran].

Item 18. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the following compounds:

- 4 041753 (4'a8,10'b8)-8'-chloro-5',5'-dimethyl-1-[(4-methyl-1H-imidazol-5-yl)methyl]-4'a,10 'bdihydro-2 Ή,4 Ή,5'H-spiro[piperidine-4,3'-pyrano[3,2-c] [1]benzopyran], (4'aR,10'bR)-8'-χlor -5',5'-dimethyl-l-[(4-methyl-lH-imidazol-5-yl)methyl]-4'a,10'bdihydro-2 Ή,4 Ή,5'H-spiro[piperidine- 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'bdihydro-2 Ή,4 Ή,5'H-spiro[piperidin-4,3'-pyrano[3,2-c] [1]benzopyran ], (4'a8,10'b8)-9'-chloro-5',5'-dimethyl-1-[(4-methyl-1H-imidazol-5-yl)methyl]-4'a,10' bdihydro-2 Ή, 4 Ή, 5'H-spiro[piperidine-4,3'-pyrano[3,2-c] [1]benzopyran], (4'a8,10'b8)-9'-chloro- 5',5'-dimethyl-1-[(1-methyl-1H-imidazol-5-yl)methyl]-4'a,10'bdihydro-2 Ή, 4 Ή, 5'H-spiro[piperidine-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'bdihydro-2 Ή,4 Ή,5'H-spiro[piperidin-4,3'-pyrano[3,2-c] [1]benzopyran] , (4'aR,10'bR)-8'-χlor-5',5'-dim etyl-l-[(l-methyl-lH-imidazol-5-yl)methyl]-4'a,10'bdihydro-2 Ή, 4 Ή, 5'H-spiro[piperidine-4,3'-pyrano[ 3,2-c] [ 1 ]benzopyran], (4'a8,10'b8)-8'-chloro-5',5'-dimethyl-1-[(1-methyl-1H-imidazol-5-yl )methyl]-4'a,10'bdihydro-2 Ή, 4 Ή, 5'H-spiro[piperidine-4,3'-pyrano[3,2-c] [1]benzopyran], (4'a8, 10'b8)-7'-chloro-5',5'-dimethyl-1-[(1-methyl-1H-imidazol-5-yl)methyl]-4'a,10'bdihydro-2Ή,4Ή,5 'H-spiro[piperidine-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'bdihydro-2 Ή,4 Ή, 5'H-spiro[piperidin-4,3'-pyrano[3,2 -c] [ 1 ]benzopyran].

Item 19. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the following compounds:

(4'aR, 10'bR)-8'-chloro-1-[2-(1H-imide azol-1-yl)ethyl]-5',5'-dimethyl-4'a, 10'b- dihydro2Ή,4Ή,5' H-spiro[piper idine-4,3'-pyrano[3,2-c] [1] benzopyran], (4'a8,10'b8)-8'-chloro-1-[ 2-(1H-imidazol-1-yl)ethyl]-5',5'-dimethyl-4'a,10'b-dihydro2Ή,4Ή,5'H-spiro[piper idine-4,3'-pyrano[ 3,2-c] [ 1 ] benzopyran], (4' aS, 10' b S)-9'-fluoro-1-[2-(1H-imidazol-1-yl)ethyl]-5',5' -dimethyl-4'a, 1O'b-dihydro2Ή,4Ή,5'H-spiro[piperidine-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'bdihydro-2 Ή.4 Ή.5'H -spiro[piperidine-4,3 '-pyrano[3,2-c] [ 1 ]benzopyran], (4 'aR, 10 'bR)-9 '-chloro-1 - [2-( 1 H-imide azole -1 -yl)ethyl] -5',5'-dimethyl-4'a, 10'b-dihydro2Ή,4Ή,5'H-spiro[piperidine-4,3'-pyrano[3,2-c] [1] benzopyran], (4'a8,10'b8)-9'-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5',5'-dimethyl-4'a, 10'L-dihydro2Ή,4Ή,5'H-spiro[piperidine-4,3'-pyrano[3,2-c][1]benzopyran],

- 5 041753 (4' aS, 10' b S)-9'-fluoro-5',5'-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4' a, 10'bdihydro-2 Ή.4 Ή.5'H-spiro[piperidine-4,3'-pyrano[3,2-c] [1]benzopyran], (4'aR, 10'bR)-9 '-fluoro-5', 5'-dimethyl-1 - [2-(2-methyl-1 H-imide azol-1-yl)ethyl] -4' a, 10' bdihydro-2 Ή.4 Ή.5 'H-spiro[piperidine-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'bdihydro-2 Ή.4 Ή.5'H-spiro[piperidine-4,3'-pyrano[3 ,2-c] [ 1 ]benzopyran], (4 'aS, 10 'b S)-9 '-chloro-5 ', 5'-dimethyl-1 -[2-(2-methyl-1H-imidazole-1 -yl)ethyl]-4'a, 10'bdihydro-2 Ή,4 Ή.5'H-spiro[piperidine-4,3'-pyrano[3,2-c] [1]benzopyran], (4' aS,10'b S)-8'-chloro-5',5'-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4'a, 10'bdihydro- 2 Ή,4 Ή,5 'H-spiro[piperidine-4,3'-pyrano[3,2-c] [ 1 ]benzopyran], (4'aR,l O'bR)-8'-chloro-5 ',5'-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4'a,10'bdihydro-2 Ή, 4 Ή, 5'H-spiro[piperidine- 4.3'- pyrano[3,2-c] [ 1 ]benzopyran], (l-{2-[(4'aR,10'bR)-9'-φτop-5',5'-dimethyl-4'a,10' b-dihydro-2'H,4'H,5'Hspiro [piperidine-4,3'-pyrano[3,2-c][1]benzopyran] -1 -yl]ethyl } -1 H-imide azol- 2-yl)methanol, (1-{2-[(4'a8,10'b8)-9'-fluoro-5',5'-dimethyl-4'a,10'b-dihydro-2'H, 4'H,5'Hspiro [piperidin-4,3'-pyrano[3,2-c] [ 1 ] benzopyran] -1 -yl]ethyl } -1 H-imide azol-2-yl)methanol, (1 - {2-[(4'aS, 10'b S)-9'-chloro-5',5'-dimethyl-4'a,10'b-dihydro-2Ή,4Ή,5Ήspiro[piperidine- 4,3 '-pyrano[3,2-c] [ 1 ] benzopyran] -1 -yl] ethyl } -1 H-imide azol-2-yl) methanol, (l-{2-[(4'aR, 10'bR)-9'-xlor-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'Hspiro [piperidine-4,3'-pyrano[3 ,2-c] [ 1 ] benzopyran] -1 -yl]ethyl } -1 H-imide azol-2-yl)methanol, (1-[2-[(4'aK,O'bK)-8'- chloro-5',5'-dimethyl-4'a,N0'b-dihydro-2'H,4'H,5'Hspiro [piperidine-4,3'-pyrano[3,2-c] [1] benzopyran]-1-yl]ethyl }-1 H-imide azol-2-yl)methanol, (1-{2-[(4'aS, 10'b S)-8'-chloro-5',5' -dimethyl-4'a,10'b-dihydro-2Ή,4Ή,5Ήspiro[piperidine-4,3'-p irano[3,2-c] [ 1 ] benzopyran] -1 -yl] ethyl } -1 H-imide azol-2-yl) methanol, (1 - {2-[(4 'aS, 10 'b S) -9'-chloro-5',5'-dimethyl-4'a, 10'b-dihydro-2Ή,4Ή,5Ήspiro[piperidine-4,3'-pyrano[3,2-c][1 ]benzopyran] -1 -yl]ethyl } -5 -methyl-1 H-imidazol-4yl)methanol and (1-[2-[(4'aK,O'bK)-9'-chloro-5',5 '-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'Hspiro [piperidin-4,3'-pyrano[3,2-c] [1] benzopyran] -1 -yl ]ethyl } -5-methyl-1 H-imidazol-4yl)methanol.

Item 20. A compound according to item 1 or a pharmaceutically acceptable salt thereof, selected from the following compounds:

(4'a8,10'b8)-8'-chloro-5',5'-dimethyl-1-[(4-methyl-1H-imidazol-5-yl)methyl]-4'a,10'bdihydro- 2 Ή,4'H,5'H-spiro[piperidine-4,3'-pyrano[3,2-c] [1]benzopyran], (4'aR,l 0'N1)-8'-chloro- 5',5'-dimethyl-1-[(4-methyl-1 H-imidazol-5-yl)methyl]-4'a,10'bdihydro-2 Ή,4 Ή, 5'H-spiro[piperidine- 4,3'-pyrano[3,2-c] [1]benzopyran], (4'aR, 10'bR)-8'-chloro-1-[2-(1H-imide azol-1-yl) ethyl]-5',5'-dimethyl-4'a,10'b-dihydro2 Ή,4Ή,5'H-spiro[piperidine-4,3'-pyrano[3,2-c] [1] benzopyran], (4' aS, 10' b S)-8'-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5', 5'-dimethyl-4'a, 10' b-dihydro2 Ή,4 Ή, 5'H-spiro[piperidine-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'bdihydro-2'H,4'H,5'H -spiro[piperidine-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'bdihydro-2 Ή,4'H,5'H-spiro[piperidin-4,3'-pyrano[3, 2-c] [ 1 ]benzopyran].

Item 21. The compound of claim 1, or a pharmaceutically acceptable salt thereof, is (4'a8,10'b8)-8'-chloro-5',5'-dimethyl-1-[(4-methyl-1H-imidazole- 5-yl)methyl]-4'a,10'bdihydro-2 Ή, 4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran].

Item 22. The compound according to claim 1 or its pharmaceutically acceptable salt is (4'aR, 10'bR)-8'-chloro-5',5'-dimethyl-1-[(4-methyl-1H-imidazole- 5-yl)methyl]-4'a,10'bdihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran].

Item 23. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, is

- 6 041753 (4'aR, 10'bR)-8'-chloro-1-[2-(1H-imide azol-1-yl)ethyl]-5',5'-dimethyl-4'a, 10 'L-dihydro2 Ή,4 Ή, 5'H-spiro[piperidine-4,3'-pyrano[3,2-c] [1] benzopyran].

Item 24. The compound of claim 1, or a pharmaceutically acceptable salt thereof, is (4'a8,10'b8)-8'-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5', 5'-dimethyl-4'a,10'b-dihydro2 Ή,4 Ή, 5Ή-spiro [piperidine-4,3'-pyrano[3,2-c] [1] benzopyran].

Item 25. A compound according to claim 1 or a pharmaceutically acceptable salt thereof is: (4'a8,10'b8)-9'-fluoro-5',5'-dimethyl-1-[2-(2-methyl-1H -imidazol-1-yl)ethyl]-4'a,10'bdihydro-2 Ή,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c] [1]benzopyran ].

Item 26. The compound of claim 1, or a pharmaceutically acceptable salt thereof, is (4' aR, 10' bR)-9'-fluoro-5', 5'-dimethyl-1-[2-(2-methyl-1 H -imide azol-1-yl)ethyl]-4'a, 10'bdihydro-2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c][1 ]benzopyran].

Item 27. The compound according to claim 1 or its phosphate selected from the following compounds: (4'a8,10'b8)-8'-chloro-5',5'-dimethyl-1-[(4-methyl-1H- imidazol-5-yl)methyl]-4'a,10'bdihydro-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'а,10' bdihydro-2 Ή,4 Ή, 5'H-spiro[piperidine-4,3'-pyrano[3,2-c] [1]benzopyran], (4'aR, 10'bR)-8'-chloro- 1 - [2-( 1 H-imide azol-1 -yl)ethyl] -5', 5'-dimethyl-4'a, 10'b-dihydro2 Ή,4 Ή, 5'H-spiro[piper idin- 4,3'-pyrano[3,2-c] [1] benzopyran], (4'a8,10'b8)-8'-chloro-1-[2-(1H-imidazol-1-yl)ethyl] -5',5'-dimethyl-4'a, 10'b-dihydro2 Ή,4 Ή, 5'H-spiro[piperidine-4,3'-pyrano[3,2-c] [ 1 ] benzopyran] , (4'a8,10'b8)-9'-fluoro-5',5'-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4'a,10 'bdihydro-2'H,4'H,5'H-spiro[piperidine-4,3'-pyrano[3,2-c][1]benzopyran] and (4'aR, 10'bR)-9' -fluoro-5',5'-dimethyl-1-[2-(2-methyl-1H-imide azol-1-yl)ethyl]-4'a,10'bdihydro-2 Ή,4'H,5 'H-spiro[piperidine-4,3'-pyr but[3,2-c] [ 1 ]benzopyran].

Item 28. The compound according to claim 1 or its fumarate selected from the following compounds: (4'a8,10'b8)-8'-chloro-5',5'-dimethyl-1-[(4-methyl-1H- imidazol-5-yl)methyl]-4'a,10'bdihydro-2 Ή, 4'H,5'H-spiro[piperidin-4,3'-pyrano[3,2-c] [1]benzopyran] , (4'aR, 10'bR)-8'-xnop-5',5'-dimethyl-1-[(4-methyl-1H-imidazol-5-yl)methyl]-4'a,10'bdihydro -2 Ή, 4'H,5'H-spiro[piperidine-4,3'-pyrano[3,2-c] [1]benzopyran], (4'aR, 10'bR)-8'-chloro- 1 - [2 - (1 H-imide azol-1 -yl)ethyl] -5', 5'-dimethyl-4' a, 10' b -dihydro2 Ή,4 Ή, 5 Ή-spiro [piperidine-4, 3'-pyrano[3,2-c] [1]benzopyran], (4'a8,10'b8)-8'-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5 ',5'-dimethyl-4'a, 10'b-dihydro2 Ή,4 Ή, 5 Ή-spiro [piperidine-4,3'-pyrano[3,2-c] [ 1 ]benzopyran], (4' a8,10'b8)-9'-fluoro-5',5'-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4'a,10'bdihydro-2 Ή,4 'H,5' H-spiro[piperidine-4,3'-pyrano[3,2-c] [ 1 ]benzopyran] and (4' aR, 10' bR)-9'-fluoro-5' , 5' - dimethyl-1 - [2-(2-methyl-1 H-imide azol-1 -yl)ethyl] -4'a,10'bdihydro-2 Ή,4'H,5'H-spiro[ P iperidine-4,3'-pyrano[3,2-c] [ 1 ]benzopyran].

Item 29. The compound according to claim 1 or its p-toluenesulfonate selected from the following compounds: (4'a8,10'b8)-8'-chloro-5',5'-dimethyl-1-[(4-methyl- 1H-imidazol-5-yl)methyl]-4'a,10'bdihydro-2 Ή,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-1 H-imide azol-5-yl)methyl]-4'a ,1O'bdihydro-2 Ή,4'H,5'H-spiro[piperidine-4,3'-pyrano[3,2-c] [1]benzopyran], (4'aR, 10'bR)-8 '-chloro-1 - [2-( 1 H-imide azol-1 -yl)ethyl] -5', 5'-dimethyl-4'a, 10'b-dihydro2 Ή,4 Ή, 5'H-spiro [piperidine-4,3'-pyrano[3,2-c] [1]benzopyran], (4'a8,10'b8)-8'-chloro-1-[2-(1H-imidazol-1-yl )ethyl]-5',5'-dimethyl-4'a,10'b-dihydro2 Ή,4 Ή, 5'H-spiro[piperidine-4,3'-pyrano[3,2-c] [1] benzopyran], (4'a8,10'b8)-9'-fluoro-5',5'-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4'a ,10'bdihydro-2'H,4'H,5'H-spiro[piperidine-4,3'-pyrano[3,2-c][1]benzopyran] and (4'aR, 10'bR)- 9'-fluoro-5',5'-dimethyl-1-[2-(2-methyl-1H-imide azol-1-yl)ethyl]-4'a,10'bdihydro-2 Ή,4'H .5 'N- spiro[piperidine-4,3'-pyrano[3,2-c] [1]benzopyran].

- 7 041753

Item 30. A pharmaceutical composition for the treatment of cancer, comprising an effective amount of a compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable additives.

Invention effect.

The compound of the present invention can exhibit an inhibitory effect on the ability to generate CSC, and thus it can be used as an antitumor drug. In a further preferred embodiment, the compound of the present invention is expected to be extremely safe since it has a large difference between the cell proliferation inhibiting concentration and the hERG current inhibiting concentration.

Description of embodiments of the invention

Hereinafter, the terms used in this document are explained as follows.

In case the expression optionally substituted or substituted is used in the definition of substituent groups, the number of substituent groups is not limited as long as substitutions are available, i. it is equal to one or more. Unless otherwise indicated, the definition of each substituent group also extends to the case of partial inclusion of a substituent group or the case where a substituent group is present in another substituent group.

The term halogen atom includes, for example, fluorine atom, chlorine atom, bromine atom and iodine atom. Preferably, it represents a fluorine atom or a chlorine atom.

Term C ₁ . ₆ alkyl means alkyl having from 1 to 6 carbon atoms, and the same applies in the case of a different number of carbon atoms.

Term C ₁ . ₆ αkyl denotes a straight or branched saturated hydrocarbon group containing from 1 to 6 carbon atoms. _C1 . ₆ alkyl preferably includes C ₁ . ₄ αkyl, more preferably C ₁ . ₃ alkyl. Term C ₁ . ₃ alkyl includes, for example, methyl, ethyl, propyl, 1-methylethyl and the like. Term C ₁ . ₄ alkyl includes, for example, butyl, 1,1-dimethylethyl, 1-methylpropyl, 2methylpropyl, and the like, in addition to the examples listed for said C _1-3 αalkyl. The term C _1-6 alkyl includes, for example, pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylbutyl, 2methylbutyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, hexyl, and the like. , in addition to the examples listed for the specified C ₁ . ₄ alkyl.

Term C ₂ . _6αalkenyl is a straight or branched unsaturated hydrocarbon group containing 2 to 6 carbon atoms and 1 to 3 double bonds. Term C ₂ . ₆ alkenyl preferably includes C ₂ . ₄ alkenyl. Term C ₂ . ₄ alkenyl includes, for example, vinyl, propenyl, methylpropenyl, butenyl and the like. Term C ₂ . ₆ alkenyl includes, for example, pentenyl, hexenyl and the like, in addition to the examples listed for said C ₂ . ₄ alkenyls.

Term C ₁ . ₆ αlkoxy is C ₁ . ₆ alkyloxy, and fragment C ₁ . ₆ alkyl is defined for the indicated C ₁ . ₆ alkyl. Term C ₁ . ₆ alkoxy preferably includes C ₁ . ₄ αlkoxy, more preferably C ₁ . ₃ alkoxy. Term C ₁ . ₃ alkoxy includes, for example, methoxy, ethoxy, propoxy, 1-methylethoxy and the like. Term C ₁ . _4αlkoxy includes, for example, butoxy, 1,1-dimethylethoxy, 1methylpropoxy, 2-methylpropoxy, and the like, in addition to the examples listed for said C ₁ . ₃ alkoxy. Term C ₁ . _6αlkoxy includes, for example, pentyloxy, 1,1-dimethylpropoxy, 1,2dimethylpropoxy, 1-methylbutoxy, 2-methylbutoxy, 4-methylpentyloxy, 3-methylpentyloxy, 2methylpentyloxy, 1-methylpentyloxy, hexyloxy and the like, in addition to the examples listed for specified C ₁ . ₄ alkoxy.

Term C ₁ . ₆ alkylene denotes a straight or branched divalent saturated hydrocarbon group having from 1 to 6 carbon atoms. Term C ₁ . ₆ alkylene preferably includes C ₁ . ₃ alkylene. Term C ₁ . _3α- kylene includes, for example, methylene, ethylene, propylene, 1-methylethylene and the like.

Term C ₃ . ₇ cycloalkyl denotes a cyclic saturated hydrocarbon group containing from 3 to 7 carbon atoms, which may have a partially unsaturated bonded or bridged structure. Term C ₃ . ₇ cycloalkyl includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.

The term 3-7 membered saturated heterocyclyl means a saturated heterocycle consisting of 3-7 carbon atoms and 1-2 atoms independently selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, which may have partially unsaturated bonded or bridging structure. The term 3-7 membered saturated heterocyclyl generally includes 3-7 membered monocyclic saturated heterocyclyl, preferably 4-7 membered monocyclic saturated heterocyclyl, more preferably 5- or 6-membered saturated monocyclic heterocyclyl includes, for example, tetrahydrofuryl, pyrrolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, hexamethyleneiminyl, oxazolidinyl, thiazolidinyl, oxoimidazolidinyl, dioxoimidazolidinyl, oxooxazolidinyl, dioxooxazolidinyl, dioxothiazolidinyl, tetrahydrofuranyl, tetrahydropyranyl and the like. The term 3-7-membered monocyclic saturated heterocyclyl includes, for example, epoxy, aziridine, oxetanyl, azeti-dine, and the like, in addition to the examples listed for said 5- or 6-membered monocyclic saturated heterocyclyl.

The term imidazole group means an imidazole ring group, which may also be referred to as an imidazolyl group. The imidazole group is not limited so long as the direct bonding position is the carbon atom or nitrogen atom constituting the imidazole ring, and it includes the following formulas. In the following formulas, * indicates the point of attachment. In the following formulas, when the point of attachment is a carbon atom, examples of structures are shown in which the NH group of the imidazole ring is substituted with a methyl group.

The terms malignant neoplasm and tumor are used interchangeably, and both refer to a malignant tumor that includes cancer, sarcoma, and hemoblastosis. The terms malignancy 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, choriocarcinoma, uterine cancer, cancer cervix, urothelial carcinoma, renal cell carcinoma, prostate cancer, testicular cancer, Wilms' tumor, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's sarcoma, chondrosarcoma, soft tissue sarcoma, skin cancer, and the like.

The pharmaceutically acceptable salt of the compound of formula (1) when the compound has an acidic group includes, for example, alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; inorganic metal salts such as a zinc salt; and salts of organic bases such as triethylamine, triethanolamine, tri(hydroxymethyl)aminomethane, and a basic amino acid.

A pharmaceutically acceptable salt of a compound of formula (1) when the compound has a basic group includes, for example, inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate and nitrate; and organic acid salts such as acetate, propionate, succinate, lactate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate, p-toluenesulfonate, benzenesulfonate, ascorbate, and acidic amino acids.

Preferred salts of the starting materials and intermediates, as well as salts that are acceptable as pharmaceutical drugs, 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, formate, and toluenesulfonate) and inorganic acid salts (such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate and phosphate), amino acid salts (eg arginine, aspartate and glutamate), metal salts such as alkali metal salts (eg sodium salt and potassium salt) and alkaline earth metal salts (eg calcium salt and magnesium), ammonium salts, and organic base salts (e.g., trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, and N,N'-dibenzylethylenediamine salt), or they may be appropriately selected by one skilled in the art.

Ways.

Hereinafter, the methods for producing the compound of the present invention of formula (1) are illustrated by examples, but the methods for producing the compound of the present invention should not be limited to these examples. The compounds used in the following process may exist in their salt form, as long as the reactions are not affected.

The compound of the present invention can be obtained from known compounds as starting materials, for example, by the following methods or similar methods, or optionally in combination with synthetic methods well known to a person skilled in the art.

In each method illustrated below, any functional groups that need to be protected can optionally be protected, and then after completion of the reaction or series of reactions to obtain the desired compound, the protecting groups can be removed, even if the use of protecting groups is not specifically described. The introduction and removal of protecting groups can be carried out in a manner commonly used in organic synthetic chemistry (eg, see Protective Groups in Organic Synthesis, 3rd Ed., John Wiley and Sons, inc., New York (1999)) or a similar method.

Method 1.

The present compound of formula (1c) can be obtained, for example, by the following method

- 9 041753

where R ^1A , R ^1b , R ^1c , R ^1d , R ^2A , R ^2B , R ^3A , R ^3B , R ^3C , R ^3D , V and Q have the meanings defined in claim 1, and LG ¹ denotes a deletable group, which includes, for example, a halogen atom and hydroxy.

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

Stage 1-1.

The compound (1c) can be obtained by reacting the compound (1a) obtained by the method below with a compound (1b) such as a carboxylic acid derivative and an acid chloride derivative in the presence or absence of a suitable condensing agent and/or a suitable base in a suitable solvent .

As used herein, the base includes amines such as triethylamine, diisopropylethylamine, and pyridine; alkali metal carbonates such as potassium carbonate, sodium carbonate and sodium bicarbonate; etc. It preferably includes triethylamine, diisopropylethylamine and pyridine.

The condensing agent used herein may be suitably selected from condensing agents commonly used in organic synthesis chemistry, which preferably includes 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 1-hydroxybenzotriazole.

The solvent used herein should not be limited unless the solvent is reacted under the reaction conditions of this step, but it includes, for example, ethereal 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, Nmethyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone, acetonitrile and dimethyl sulfoxide; and their mixture. The solvent preferably includes tetrahydrofuran, toluene, N,N-dimethylformamide and acetonitrile.

The reaction time is usually 5 minutes to 72 hours, preferably 30 minutes to 24 hours.

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

Method 2.

The present compound of formula (1c) can also be obtained, for example, by the following method:

where R ^1A , R ^1b , R ^1c , R ^1d , R ^2A , R ^2B , R ^3A , R ^3B , R ^3C , R ^3D , V and Q have the meanings given in paragraph 1, LG ¹ has the meanings given in method 1, and LG ² denotes a leaving group that includes, for example, a halogen atom, methanesulfonyloxy, ethanesulfonyloxy, p-toluenesulfonyloxy and trifluoromethanesulfonyloxy.

Compound (2a) can be produced in a known manner, as described, for example, in ACS chemical biology, 12(8): 2124-2131 (2017), etc., or a similar method, or it is commercially available.

- 10 041753

Stage 2-1.

Compound (2b) can be obtained from compound (1a) obtained by the method below and compound (2a) by the method described for Step 1-1 in Method 1 or a similar method.

Stage 2-2.

Compound (1c) can be obtained by reacting compound (2b) and an imidazole derivative (QH) in the presence or absence of a suitable base in a suitable solvent.

The base used herein includes, for example, organic bases such as triethylamine, diisopropylethylamine, tributylamine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8diazabicyclo[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.

The solvent used herein should not be limited unless the solvent is reacted under the reaction conditions of this step, but it includes, for example, ethereal 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-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone, acetonitrile and dimethyl sulfoxide; and their mixture. The solvent preferably includes tetrahydrofuran, toluene, N,N-dimethylformamide and acetonitrile.

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

The reaction time is usually 30 minutes to 48 hours, preferably 6 to 12 hours.

Method 3.

The compound of formula (3b) can be obtained, for example, by the following method

(1a) (Za) (3b) where R ^1a , R ^1b , R ^1c , R ^1d , R ^2A , R ^2b , R ^3A , R ^3b , R ^3C , R ^3d and Q have the meanings defined in paragraph 1.

Compound (3 a) 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) and etc., or a similar method, or it is commercially available.

Stage 3-1.

Compound (3b) can be prepared from compound (1a) and compound (3a) in a known manner as described, for example, in 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), etc., or a similar method.

Method 4.

The compound of formula (4b) can be obtained, for example, by the following method

R ^1C (1a) (4a) (4b) 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 1, and LG ² has the meanings indicated in method 2.

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

Stage 4-1.

Compound (4b) can be obtained from compound (1a) obtained by the method below and compound (4a) by the method described for Step 2-2 in Method 2 or a similar method.

Method 5.

The compound of formula (5c) can be obtained, for example, by the following method

- 11 041753

where R ^1a , R ^1b , R ^1c , R ^1d , R ^2A , R ^2B , R ^3A , R ^3B , R ^3C , R ^3D , V and Q have the meanings defined in claim 1 and LG ² has the meanings regardless defined in method 2.

Compound (5a) can be produced in a known manner, such as described in Journal of Organic Chemistry, 25:24-26 (I960), etc., or a similar method, or it is commercially available.

Stage 5-1.

Compound (5b) can be obtained from compound (la) obtained by the method below and compound (5a) by the method described for Step 2-1 in Method 2 or a similar method.

Stage 5-2.

Compound (5c) can be obtained from compound (5b) and compound Q by the method described for Step 2-2 in Method 2 or a similar method.

Method 6.

The preparation of an intermediate compound of formula (la) can be carried out, for example, in the following way

(1a) where R ^1A , R ^1B , R ^1C , R ^1D , R ^2A , R ^2B , R ^3A , R ^3B , R ^3C and R ^3D are as defined in claim 1, and P is an amino protecting group which includes amino protecting groups as described in Protective Groups in Organic Synthesis (edited by Theodora W. Greene, Peter GM Wuts, issued by John Wiley & Sons, Inc. (1999).

Stage 6-1.

The compound (6c) can be obtained from the commercially available compound (6a) and compound (6b) obtained by the following method in a known manner, described, for example, in Journal of the Chemical Society, Perkin Transactions l, (ll): 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), etc., or a similar method .

- 12 041753

Stage 6-2.

Compound (1a) can be obtained by removing the protecting group P in compound (6c). This step can be carried out, for example, in accordance with Protective Groups in Organic Synthesis (edited by Theodora W. Greene, Peter G. M. Wuts, issued by John Wiley & Sons, Inc., 1999).

Method 7.

The preparation of an intermediate compound of formula (6b) can be carried out, for example, in the following way

(7a) (7b) (7c)

(6b) where R ^2A , R ^2b , R ^3A , R ^3b , R ^3C and R ^3D are as defined in claim 1, P is as defined in method 6, and LG ² is as defined in method 2.

Stage 7-1.

Compound (7c) can be prepared from a commercially available compound (7a) and a commercially available compound (7b) in a known manner as described, for example, in 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 a similar method.

Stage 7-2.

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 Method Research &. Development, 17(2): 257-264 (2013), etc., or a similar method.

The compound of the present invention, which has the desired substituents at the desired positions, can be obtained by a suitable combination of the above methods. Intermediates and desired compounds in the above processes can be isolated/purified using purification methods commonly used in organic chemistry, such as filtration, extraction, washing, drying, concentration, crystallization, various chromatography, etc. or their combinations. Some intermediates can be used in the next step without any purification.

The starting compounds or intermediates in the above methods may be in the form of a salt such as the hydrochloride, or directly in the free form, depending on the reaction conditions, etc. If the free form of the parent compound or intermediate presented as a salt is to be used, the salt form can be dissolved or suspended in a suitable solvent and neutralized with a base such as aqueous sodium bicarbonate or an acid to convert it to the free form.

The compound of formula (1), or a pharmaceutically acceptable salt thereof, may sometimes exist as a tautomer such as the keto-enol form, a regioisomer, a geometric isomer, or an optical isomer. All of these possible isomers and mixtures thereof in any ratio of components are also included in the present invention.

The optical isomers at the appropriate stage of the above processes can be separated by known separation methods such as the optically active column method and the fractional crystallization method. In addition, an optically active starting material can be used.

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

- 13 041753

The term "treatment" as used herein means administering to a person (ie, a patient) who has been diagnosed by a physician as having developed a disease, an active ingredient of the present invention.

The compound of the present invention can be administered orally or parenterally directly or as a suitable drug. The dosage form includes, for example, tablet, capsule, powder, granules, liquid, suspension, injection, patch, poultice, and the like, but is not limited to. The drug preparation is prepared in the usual way using pharmaceutically acceptable additives.

As an additive, a neutral adjuvant, a leavening agent, a binder, a fluidizing agent, a lubricant, a coating agent, a solubilizer, a solubilizing adjuvant, a thickener, a dispersant, a stabilizing agent, a sweetening agent, a flavoring agent, and the like can be used, depending on the purpose. The additive used herein includes, for example, lactose, mannitol, crystalline cellulose, low-substituted hydroxypropyl cellulose, corn starch, partially pregelatinized starch, calcium carmellose, croscarmellose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, magnesium stearate, sodium stearyl fumarate, polyethylene glycol, propylene glycol , titanium oxide, talc and the like.

The route of administration should be chosen to be the most effective route of treatment, which includes oral and parenteral administration such as intravenous injection, smear, inhalation and eye drops. Oral administration is preferred. The dosage form includes, for example, a tablet and an injection, and preferably a tablet. The dose of the pharmaceutical composition and the frequency of its administration may depend on the route of administration and on the patient's disease, symptom, age, body weight, etc., so they cannot be uniquely determined. Typically, the present compound may be administered to an adult human at a dose of about 0.0001 to about 5000 mg/day, preferably about 0.001 to about 1000 mg/day, more preferably about 0.1 to about 500 mg, particularly preferably from about 1 to about 300 mg, and these doses can be administered once a day or several times a day, preferably one to three times a day.

The protecting groups, condensing agents, etc. used herein are sometimes referred to as IUPAC-IUB abbreviations that are commonly used in this technical field. However, the compound names used in this document need not always be based on the IUPAC nomenclature system.

Examples

The present invention is explained in more detail below with reference to reference examples, examples and tests; however, the technical scope of the present invention should not be limited to this. The names of the compounds used in the Reference Examples and Examples need not always be based on the IUPAC nomenclature system.

In the present description, the following abbreviations are sometimes used.

Hex: hexane,

IPA: isopropyl alcohol,

THF: tetrahydrofuran,

TFA: trifluoroacetic acid,

MeCN: acetonitrile,

Me: methyl,

Et: ethyl,

Pr: propyl,

Ph: phenyl,

Boc: tert-butoxycarbonyl.

The NMR data used to identify the compounds were obtained on a JEOL JNM-AL AL400 series.

The symbols used for NMR data have the following meanings: s denotes a singlet, d denotes a doublet, dd denotes a doublet of doublets, t denotes a triplet, t denotes a triplet of doublets, q denotes a quartet, m denotes a multiplet, br. means wide, wide. c denotes wide singlet, br. m denotes wide multiplet, J denotes binding constant.

The LC/MS analytical conditions used to identify compounds are shown below. [MS(m/z)] mass spectrometry data is shown as [M+H]+ or [M+2H] ²⁺ , and retention time is shown as Rt (minutes).

Analytical method LC/MS (condition 1).

Detection equipment: ACQUITY™ SQ detector (Waters Corporation).

HPLC: UPLC ACQUITY™ system.

Column: Waters ACQUITY™ UPLC VEN C18 (1.7 µM, 2.1x30 mm).

- 14 041753

Solvent: A: 0.06% formic acid/H2O, B: 0.06% formic acid/MeCN.

Gradient Conditions: Linear Gradient 0.0 to 1.3 min 2 to 96% B.

Flow rate: 0.8 ml/min.

UV: 220 and 254 nm.

Analytical method LC/MS (condition 2).

LCMS-2020 system (Shimadzu Corporation).

Column: Kinetex™ 1.7 µM Minibore column, C18 (30x2.1 mm).

Solvent: A: 0.05% TFA/H2O, B: MeCN.

Gradient conditions: linear gradient 0.0 to 1.7 min 10 to 99% B, 1.9 min B 99%.

Flow rate: 0.50 ml/min.

UV: 220 nm and 254 nm.

The optical activity of the compounds of the present invention and their synthetic intermediates were analyzed under the following conditions.

HPLC system for optical resolution.

Pump: LC-20AD (Shimadzu Corporation).

Detector: SPD-20A (Shimadzu Corporation).

Pump: SIL-20A (Shimadzu Corporation).

Condition a.

Column: CHIRALPAK IE.

Size: 0.46 cm int. dia.x25 cm length.

Mobile phase: H-Hex/EtOH/iso-PrNH ₂ =90/10/0.1<v/v>.

Flow rate: 1.0 ml/min.

Temperature: 40°C.

Wavelength: 287 nm.

Condition B.

Column: CHIRALPAK IE.

Size: 0.46 cm int. dia.x25 cm length.

Mobile phase: n-Hex/1PA/iso-PrNH ₂ =80/20/0.1 <v/v>.

Flow rate: 1.0 ml/min.

Temperature: 40°C.

Wavelength: 285 nm.

Condition C.

Column: CHIRALPAK IE.

Size: 0.46 cm int. dia.x25 cm length.

Mobile phase: MeOH/iso-PrNH ₂ =l00/0.1<v/v>.

Flow rate: 1.0 ml/min.

Temperature: 40°C.

Wavelength: 280 nm.

Condition D.

Column: CHIRALPAK AD-H.

Size: 0.46 cm int. dia.x25 cm length.

Mobile phase: n-Hex/IPA/EtOH/iso-PrNH ₂ =85/5/10/0.1<v/v>.

Flow rate: 1.0 ml/min.

Temperature: 40°C.

Wavelength: 280 nm.

Condition E.

Column: CHIRALPAK AD-H.

Size: 0.46 cm int. dia.x25 cm length.

Mobile phase: MeOH/Et ₂ NH=100/0.1 <v/v>.

Flow rate: 1.0 ml/min.

Temperature: 40°C.

Wavelength: 280 nm.

Reference example 1.

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

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

To a solution of 1-tert-butyl 4-methylpiperidine-1,4-dicarboxylate (69.0 g) in tetrahydrofuran (700 ml) at -78°C was added dropwise 1 mol/l sodium bis(trimethylsilyl)amide (326 ml) and

- 15 041753 the reaction mixture was stirred at this temperature for one hour. The reaction mixture was heated to -20°C and stirred at this temperature for one hour. 1-Bromo-3-methyl-2-butene (42.6 ml) was added dropwise to the reaction mixture at -78°C. The reaction mixture was heated to -20° C. and stirred at this temperature for 3 hours. The reaction mixture was warmed to room temperature and stirred overnight. After completion of the reaction, an aqueous solution of ammonium chloride was added to the reaction mixture. Then water and ethyl acetate were added. The mixture was separated in a separatory funnel into an ethyl acetate layer and an aqueous layer. The resulting organic layer was washed with brine, dried over sodium sulfate. The solvent was removed in vacuo and the resulting residue was purified by column chromatography (hexane/ethyl acetate) to give the title compound (69.0 g).

1 H NMR (400 MHz, CDCl ₃ ): 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).

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

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

To a solution of lithium aluminum hydride (9.25 g) in tetrahydrofuran (700 ml) at a temperature of -78°C was added dropwise a solution in tetrahydrofuran (300 ml) of 1-tert-butyl 4-methyl 4-(3-methylbut-2-en- 1yl)piperidine-1,4-dicarboxylate (69.0 g) obtained in step a). The reaction mixture was stirred at this temperature for one hour. The reaction mixture was stirred at −20° C. under nitrogen atmosphere for 5 hours. After completion of the reaction, a saturated aqueous sodium sulfate solution was added to the reaction mixture at 0° C. The mixture was stirred at room temperature for one hour and dried over magnesium sulfate. The reaction mixture was filtered through Celite and the filtered solvent was removed in vacuo. The resulting residue was purified by column chromatography (hexane/ethyl acetate) to obtain the compound of Reference Example 1 (58.0 g).

¹ H NMR (400 MHz, CDCl ₃ ): 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).

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

Reference example 2.

Racemate (4'aR, 10'bR)-9'-chloro-5',5'-dimethyl-4'a, 10'b-dihydro-2Ή,4Ή,5Ή-spiro[piperidine-4,3'pyrano[ 3,2-c] [ 1]benzofuran] and (4'aS, 10'bS)-9'-chloro-5',5'-dimethyl-4'a, 10b-dihydro-2'H,4'H ,5'Hspiro[piperidine-4,3'-pyrano[3,2-c][1]benzofuran].

Reference Example 1 Reference Example 2

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

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).

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

The resulting compound of Reference Example 2 was subjected to optical separation to obtain the compound of Reference Example 3 and the compound of Reference Example 4, which are optically active derivatives of the compound of Reference Example 2.

Connection of Reference Example 3.

Condition A; Rt (min.)=10.35.

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

Connection of Reference Example 4.

Condition A; Rt (min.)=12.07.

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

Examples 5-15.

The compounds of Reference Examples 5-15 shown in the following table were prepared from each respective starting compound by the method of Reference Example 2.

- 16 041753

Reference Example R ¹ A ω R ¹ s ^R1D Racemic or chiral Rt (min) (Condition) LC-MS (condition 1) [M+H] ⁺ / Rt(MHH) 5 C1 n n n Racemic - 322.5/0.72 6 Vg n n n Racemic - 366.2/0.74 7 H C1 n n Racemic - 322.5/0.75 8 n C1 n n chiral 8.09 (Condition C) 322.5/0.74 9 n C1 n n chiral 11.27 (Condition C) 322.5/0.76 10 n Vg n n Racemic - 366.2/0.77 eleven n n F n Racemic - 306.5/0.65 12 n n F n chiral 6.07 (Condition B) 306.5/0.63 13 n n F n chiral 7.35 (Condition B) 306.5/0.65 14 n n Vg n Racemic - 366.2/0.75 15 n n N ₃ n Racemic - 329.3/0.78

NMR data for the compounds of reference examples 5, 6, 7, 10, 11 and 14 presented in the table above are shown below.

Connection of Reference Example 5.

Ή NMR (400 MHz, DMSO-a ₆ ): 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 (1Н, d, J=11.0 Hz), 3.94 (1Н, 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 (1N, m), 1.37 (ZN, s), 1.24-1.22 (2N, m), 1.15 (ZN, s), 1.10-1.06 ( 1H, m).

Compound of Reference Example 6.

Ή NMR (400 MHz, DMSO-a ₆ ): 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 ( 2Н, d, J=11.2 Hz), 2.65-2.60 (4Н, m), 1.81-1.76 (2Н, m), 1.54-1.51 (1Н, m) , 1.43-1.38 (W, m), 1.37 (W, s), 1.24-1.21 (2H, m), 1.15 (W, s), 1.15-1 .10 (1H, m).

Compound of Reference Example 7.

Ή NMR (400 MHz, CDC1 ₃ ): 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 (2Н, m), 1.58-1.51 (1Н, m), 1.38-1.34 (1Н, m), 1.36 (ЗН, s), 1.27-1.19 (2Н , m), 1.24 (ZN, s), 1.12-1.06 (W, m).

Compound of Reference Example 10.

Ή NMR (400 MHz, DMSO-b ₆ ): 7.23 (1H, d, J=8.8 Hz), 7.01 (1H, d, J=8.4 Hz), 6.91 (1H, s), 4.09 (1H, d, 1=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 (ZN, s), 1.22-1.21 (2H, m), 1.13 (ZN, s), 1.11-1.04 (1H, m).

Compound of Reference Example 11.

Ή NMR (400 MHz, DMSO-a ₆ ): 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 (ZN, s), 1.22 -1.21 (2H, m), 1.13 (ZH, s), 1.07-1.04 (1H, m).

Compound of Reference Example 14.

Ή NMR (400 MHz, DMSO-b ₆ ): 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 (1N, m), 1.32 (ZN, s), 1.22-1.21 (2N, m), 1.12 (ZN, s), 1.11-1.04 (1N , m).

Reference example 16.

Racemate 1-[(4'a8,10'b8)-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-chloroethane-1 -one and 1 - [(4'aR, 10'bK) -9'- chloro-5', 5'-dimethyl-4'a, 10bdihydro-2 Ή,4Ή,5 Ή-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran]-1-yl ]-2-chloroethane-1-one.

- 17041753

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

¹ H NMR (400 MHz, CDCl ₃ ): 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).

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

Reference example 17.

tert-Butyl 4-(hydroxymethyl)-4-(prop-2-yn-1-yl)piperidine-1-carboxylate.

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

A solution of 1-tert-butyl 4-methylpiperidine-1,4-dicarboxylate (1.00 g) in THF (24.0 ml) was cooled to -78°C. To the cooled solution was added 1.0 mol/L sodium hexamethyldisilazide in THF (8.22 ml) 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 then propargyl bromide (0.62 ml) was added dropwise. The reaction mixture was gradually heated from 78°C to -20°C, and then a saturated aqueous ammonium chloride solution was added. The mixture was extracted twice with ethyl acetate, and the resulting organic layer was dried over anhydrous sodium sulfate. The mixture was filtered and the filtered solvent was removed in vacuo. The resulting residue was purified by column chromatography (chloroform/methanol) to give the title compound (982 mg).

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

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

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 a temperature of 55°C. Sodium borohydride (449 mg) was added to the heated solution, and the reaction mixture was stirred for one hour. Additional sodium borohydride (449 mg) was added 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 resulting organic layer was dried over anhydrous sodium sulfate. The mixture was filtered and the filtered solvent was removed in vacuo. The resulting residue was purified by column chromatography (hexane/ethyl acetate) to obtain the compound of Reference Example 17 (515 mg).

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

Reference example 18.

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

i^Nlioc

NSG NSG

Reference Example 17 Reference Example 18

A solution of the compound of Reference Example 17 (515 mg), azobisisobutyronitrile (100 mg) and benzenethiol (207 μl) in toluene (10 ml) was stirred at 80° C. under nitrogen for one hour. The reaction solution was concentrated in vacuo, and the resulting residue was purified by column chromatography (hexane/ethyl acetate) to obtain Reference Example 18 (498 mg).

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

- 18 041753

Reference example 19.

Racemate tert-butyl (4'aS, 10'bS)-8'-chloro-5'-(phenylsulfanyl)-4'a, 10b-dihydro-2H,4'H,5'Hspiro[piperidine-4,3' -pyrano[3,2-c][1]benzopyran]-1-carboxylate and tert-butyl (4'aR,10'bR)-8'-chloro-5'(phenylsulfanyl)-4'a,10'b -dihydro-2Ή,4Ή,5Ή-spiro[piperidine-4,3'-pyrano[3,2-c][1]benzopyran]-1carboxylate.

Reference Example 10 Reference Example 13

A solution of the compound 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 and the mixture was stirred at room temperature overnight. The reaction solution was concentrated in vacuo, and the resulting residue was purified by amino silica gel column chromatography (chloroform) to obtain Reference Example 19 (691 mg).

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

Reference example 20.

Racemate tert-butyl (4'aS, 10'bS)-8'-chloro-4'a, 10'b-dihydro-2Ή,4Ή,5Ή-spiro[piperidine-4,3'pyrano[3,2-c ][1]benzopyran]-1-carboxylate and tert-butyl (4'aR,10'bS)-8'-chloro-4'a,10'b-dihydro2'H,4'H,5'H-spiro [piperidine-4,3'-pyrano[3,2-c] [ 1]benzopyran]-1-carboxylate.

Reference Example 19 Reference Example 20

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

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

Reference example 21.

Racemate (4'aR,10'bS)-8'-chloro-4'a,10'b-dihydro-2Ή,4Ή,5Ή-spiro[piperidine-4,3'-pyrano[3,2c][1] benzopyran] and (4'aS,10'bR)-8'-chloro-4'a,10'b-dihydro-2Ή,4H,5Ή-spiro[piperidine-4,3'-pyrano[3,2c][ 1] benzopyran].

W'NBoc <^NH fA| ⁰ Ιι^Ί ⁰

Reference Example 20 Reference Example 21

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 resulting residue was purified by amino silica gel column chromatography (chloroform/methanol) to obtain Reference Example 21 (105 mg).

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

Example 1

Racemate 1 -[(4'aS, 10'bS)-9'-chloro-5',5'-dimethyl-4'a, 10'b-dihydro-2Ή,4Ή,5Ή-spiro[piperidine-4,3 'pyrano[3,2-c] [ 1]benzopyran]-1 -yl]-2-(2-methyl-1 H-imidazol-1 -yl)ethan-1-one and 1-[(4'aR, 10'bR)-9'-chloro5',5'-dimethyl-4'a,10'b-dihydro-2Ή,4Ή,5Ή-spiro[piperidine-4,3'-pyrano[3,2-c][ 1]benzopyran]-1-yl]-2-(2methyl-1H-imidazol-1-yl)ethan-1-one.

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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 resulting residue was purified by column chromatography (hexane/ethyl acetate) to give the compound of Example 1 (2.05 g).

*H NMR (400 MHz, CDC1 ₃ ): 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 (ZN, s), 1.901.70 (4H, m), 1.60-1, 50 (1N, m), 1.43-1.37 (2N, m), 1.35 (ZN, s), 1.16 (ZN, s), 1.15-1.10 (1N, m) .

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

Example 2-17.

The compounds of Examples 2-17 shown in the following table were prepared from each respective starting compound by the method of Reference Example 16 and Example 1.

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3 H n C1 H Me''-iAn Chiral e Reference Example 3 443.9/0.79 4 n n C1 H Me''-iAn Chiral e Reference Example 4 443.9/0.79 5 n C1 n H Me''-iAn Racemic skoe Reference Example 7 444.0/0.83 6 C1 n n H Me Racemic Reference Example 5 444.0/0.78 7 n n Vg H Me''ίΑν Racemic skoe Reference Example 14 488.0/0.82 8 n Vg n H Me Racemic skoe Reference Example 10 488.0/0.83 9 Vg n n H Me^N^N Racemic skoe Reference Example 6 488.0/0.81 10 n n N ₃ H Me Racemic skoe Reference Example 15 451.0/0.75 AND n n N ₃ H CN Racemic skoe Reference Example 15 462.4/1.09 12 n n Cl H CN Racemic skoe Reference Example 2 455.3/1.12 13 n n Cl H ^-n^n Racemic skoe Reference Example 2 460.6/0.75 14 n n Cl H Me^ ^- ^OH Racemic skoe Reference Example 2 474.0/0.76 15 n n Cl H r ^N^N Racemic skoe Reference Example 2 460.0/0.78 16 n n Cl H Racemic skoe Reference Example 2 462.0/0.85 17 n n Cl H )^F F F Racemic skoe Reference Example 2 498.4/1.15

NMR data for the compounds of examples 2 and 7 presented in the table above are shown below.

Compound example 2.

Ή NMR (400 MHz, DMSO-b ₆ ): 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).

Compound of example 7.

1H NMR (400 MHz, DMSO-a ₆ ): 7.39 (1H, s), 7.30 (1H, d, J=8.4 Hz), 6.88 (1H, s), 6.72- 6.66 (2H, m), 4.904.88 (2H, m), 4.19 (1H, d, J=10.8 Hz), 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).

Example 18.

Racemate (4'aR,10'bR)-8'-chloro-5',5'-dimethyl-1-[(4-methyl-III-imidazol-5-yl)methyl]-4'a,10'b -dihydro2'H,4'H,5'H-spiro[piperidine-4,3'-pyrano[3,2-c][1]benzopyran] and (4'aS, 10'bS)-8'-chloro -5',5'-dimethyl-1-[(4methyl-III-imidazol-5-yl)methyl]-4'a,10'b-dihydro-2Ή,4Ή,5Ή-spiro[niperudin-4,3' -nurano[3,2c] [ 1 ]benzopyran].

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Reference Example 7 Example 18

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

¹ H NMR (400 MHz, DMSO-d ₆ ): 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).

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

Examples 19-37.

The compounds of examples 19-37 shown in the following table were prepared from each respective starting compound following the procedure of example 18.

B2£

Example R ¹ A ^R1B R1C ^R1D Q Racemic or chiral Source connection LC-MS (Condition 1): [M+H] ⁺ / Rt (min) 19 n Cl Η Η Η Me^ ^N Chiral Reference Example 8 416.3/0.60 20 n Cl Η Η Ξ y φ < ζ^ζχ chiral oh Reference Example 9 416.3/0.59 21 n Η F Η χζ^ζ ir Φ Racemich eskoe Reference Example 11 400.4/0.61 22 n Η F Η χζ^ζ > φ chiral oh Reference Example 12 400.3/0.60 23 n Η F Η χζ^ζ > φ Chiral Reference Example 13 400.3/0.61

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24 H n C1 n n me ⁿ Racemich eskoe Reference example 2 416.0/0.60 25 n n C1 n n X> Me^N chiral oe Reference example 3 416.0/0.61 26 n n C1 n n Me^N chiral oe Reference example 4 416.1/0.60 27 C1 n n n ιζ^ζ Racemich eskoe Reference example 5 416.4/0.66 28 n n C1 n |_| ><,N Me jTz)^ Racemich eskoe Reference example 2 444.3/0.66 29 n n C1 n V H Racemich eskoe Reference example 2 402.3/0.75 thirty n n C1 n Tl$-Me H Racemich eskoe Reference example 2 416.3/0.70 31 n n F n ^z <^s (D Racemich eskoe Reference Example 11 400.4/0.55 32 n n C1 n F Racemich eskoe Reference example 2 416.6/0.57 33 n C1 n n Me Racemich eskoe Reference example 7 416.6/0.93 34 C1 n n n F Racemich eskoe Reference example 5 416.3/0.62 35 n n C1 n Χ,Ν nA Racemich eskoe Reference example 2 402.0/0.70 36 n n C1 n >4^N ,nA Me Racemich eskoe Reference example 2 416.0/0.77 37 n C1 n n ><,NHO chiral oh Reference example 9 486.4/0.65

NMR data for the compounds of examples 20 and 33, presented in the table above, are shown below.

Compound of example 20.

1H NMR (400 MHz, DMSO-66): 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).

Compound of example 33.

1 H NMR (400 MHz, DMSO-06): 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=10.8 Hz), 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).

Example 38.

Racemate (4'aR,10bR)-8'-chloro-1-[2-(III-imidazol-1-yl)ethyl]-5',5'-dimethyl-4'a,10'b-dihydro-2H ,4H,5Hspiro[piperidine-4,3'-pyrano[3,2-c][1]benzopyran] and (4'aS,10'bS)-8'-chloro-1-[2-(1H-imidazole -1-yl)ethyl]5',5'-dimethyl-4'a,10'b-dihydro-2Ή,4Ή,5Ή-spiro[piperidine-4,3'-pyrano[3,2-c][1 ]benzopyran].

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Reference Example 7 Example Sv

To a solution of the compound of Reference Example 7 (200 mg) in acetonitrile (10.0 ml) at 0° C. were added 2-bromoethanol (137 mg) and triethylamine (0.70 ml), and the reaction mixture was stirred at 70° C. under atmosphere nitrogen for an hour. 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 and the reaction mixture was stirred for 30 minutes. At room temperature, imidazole (0.50 g) was added and the reaction mixture was stirred at 50° C. under nitrogen for one hour. A saturated sodium carbonate aqueous solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium carbonate and then with brine, dried over magnesium sulfate, filtered and then concentrated in vacuo. The resulting residue was purified by column chromatography (chloroform/methanol) to give the compound of Example 38 (49 mg).

¹ H NMR (400 MHz, DMSO^): 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), 1.491.44 (1H, m), 1.32 (3H, s), 1.13 (3H, s), 1.13-1.08 (2H, m).

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

Examples 39-63.

The compounds of examples 39-63 shown in the following table were prepared from each respective starting compound by the method of example 38.

^R1C

Example R ¹ A ^R1B R1C ^R1D Q Racemic or chiral Source connection LC-MS (condition): [M+H] ⁺ /Rt (min) 39 n H F n Racemich eskoe Reference Example 11 400.4/0.52 40 n n C1 n Racemich eskoe Reference Example 2 416.3/0.57 41 n C1 n n Chiral Reference Example 8 416.3/0.57 42 n C1 n n ^•N^N Chiral Reference Example 9 416.3/0.58

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43 Η Η F Η Me ^-Ν^Ν Racemich eskoe Reference Example AND 414.4/0.53 44 Η Η F Η Me chiral oh Reference Example 12 414.4/0.54 45 Η Η F Η Me chiral oh Reference Example 13 414.4/0.54 46 Η Η C1 Η Me ^-Ν^Ν Racemich eskoe Reference Example 2 430.3/0.57 47 Η Η C1 Η Me chiral oh Reference Example 3 430.3/0.57 48 Η Η C1 Η Me chiral oh Reference Example 4 430.4/0.58 49 Η C1 Η Η Me ^-Ν^Ν Racemich eskoe Reference Example 7 430.3/0.60 50 Η C1 Η Η Me chiral oh Reference Example 8 430.3/0.63 51 Η C1 Η Η Me chiral oh Reference Example 9 430.3/0.61 52 Η Η F Η ^ζ Π and ο τ Racemich eskoe Reference Example 11 430.4/0.55 53 Η Η C1 Η I ο and Z^ t Racemich eskoe Reference Example 2 446.3/0.61 54 Η C1 Η Η Γ Racemich eskoe Reference Example 7 446.3/0.61

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55 H n C1 n ^-N^N ^<he Racemich eskoe Reference Example 2 446.3/0.61 56 n n C1 n Me^^OH Racemich eskoe Reference Example 2 460.3/0.63 57 n C1 n n Me ^N^N ^OH Racemich eskoe Reference Example 7 460.3/0.62 58 n n C1 n CN Racemich eskoe Reference Example 2 441.0/0.84 59 n n C1 n ^oh oh Racemich eskoe Reference Example 2 474.3/1.15 60 n C1 n n About Me^NH Chiral Reference Example 9 501.2/0.76 61 n C1 n n ^-v^v ΗΝMe—^ Chiral Reference Example 9 501.3/0.66 62 n C1 n n νη ₂ chiral oh Reference Example 9 459.2/0.89 63 n C1 n n ^•Ν^Ν ΗΝ Me Chiral Reference Example 9 473.3/0.74

NMR data for the compounds of examples 42, 60, 61, and 63 presented in the table above, are shown below.

Compound of example 42.

1H NMR (400 MHz, DMSO^): 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), 1.491.44 (1H, m), 1.32 (3H, s), 1.13 (3H, s), 1.13-1.08 (2H, m).

Compound of example 60.

Ή NMR (400 MHz, CDC^): 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).

Compound of example 61.

¹ H NMR (400 MHz, CDCb): 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).

Compound of example 63.

1 H NMR (400 MHz, DMSO-d ₆ ): 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), 3.313.26 (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).

Example 64.

Racemate (4'aS,10'bR)-8'-chloro-1-[(4-methyl-1H-imidazol-5-yl)methyl]-4'a,10'b-dihydro-2Ή,4Ή,5Ήspiro [piperidine-4,3'-pyrano[3,2-c][1]benzopyran] and (4'aR,10'bS)-8'-chloro-1-[(4-methyl-1H-imidazol-5yl )methyl]-4'a,10'b-dihydro-2H,4Ή,5H-spiro[piperidine-4,3'-pyrano[3,2-c][1]benzopyran].

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Reference Example 21 Example 64

To a solution of the compound 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. More sodium triacetoxyborohydride (77 mg) was added and the reaction mixture was stirred for an additional 30 minutes. The reaction solution was concentrated, and the resulting residue was purified by column chromatography (ethyl acetate/methanol) to give the compound of Example 64 (97 mg).

¹ H NMR (400 MHz, DMSO-I6): 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=12.2Hz), 1.55(2H, br), 1.27(2H, br), 0.95(1H, t, J =12.5 Hz), LC-MS (condition 1); [M+H]+ 388.7/Rt (min.) 0.57.

Examples 64a and 64b.

The resulting compound of Example 64 was subjected to optical resolution to obtain the compound of Example 64a and the compound of Example 64b, which are optically active derivatives of the compound of Example 64.

Example 64a.

Condition D; Rt (min.)=10.26.

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

Example 64b.

Condition D; Rt (min.)=14.02.

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

Example 65.

Example 51 Example 65

To a solution of the compound 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 one hour. The reaction mixture was left to stand at room temperature overnight 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 at 50° C. in vacuo to give the compound of Example 65 (15 mg ) as a white solid.

¹ H NMR (400 MHz, DMSOL) 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=6.7 Hz), 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).

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

Examples 66-78.

The compounds of Examples 66-78 shown in the following table were prepared from each respective starting compound by converting each to a salt as in Example 65.

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Example Salt valenti awn Source connection Ή-NMR (400 MHz, DMSO-ab) δ: 66 phosphate 2 Example 20 7.66 (1H, s), 7.29 (1H, d, J=8.2 Hz), 6.89 (1H, dd, >8.2, 2.3 Hz), 6.79 (1H, d, J=2.3 Hz), 5.70 (9H, br s), 4.15 (1H, d, >11.0 Hz), 3.94 (ZN, s), 3.36 (1H , d, >11.4 Hz), 3.01-2.77 (4Н, m), 2.19 (ЗН, s), 1.84-1.62 (4Н, m), 1.54-1 .47 (2H, m), 1.34 (3H, s), 1.14 (3H, s). 67 phosphate 2 Example 32 7.73 (1H, s), 7.24 (1H, dd, >2.7, 0.9 Hz), 7.16 (1H, dd, >8.7.2.7 Hz), 6.92 (1H, s), 6.74 (1H, d, >8.7 Hz), 5.58 (YH, br s), 4.15 (1H, d, >11.0 Hz), 3.91 (1Н, d, >11.0 Hz), 3.67 (2Н, s), 3.63 (ЗН, s), 3.33 (1Н, d, >11.4 Hz), 2.59-2 .52 (2N, m), 1.83-1.52 (5N, m), 1.41-1.35 (2N, m), 1.33 (ZN, s), 1.13 (ZN, s ), 1.14-1.10 (1H, m). 68 fumarate 2 Example 34 7.56 (1H, s), 7.29 (1H, d, >4.6 Hz), 6.88 (1H, dd, >8.2, 2.3 Hz), 6.78 (1H, d , >1.8 Hz), 6.76 (1H, s), 6.60 (4H, s), 4.12 (1H, d, >10.5 Hz), 3.88 (1H, d, > 11.4 Hz), 3.59 (ZN, s), 3.47 (2N, s), 3.31 (1N, d, >11.4 Hz), 2.44-2.34 (ZN, m ), 2.33-2.24 (1H, m), 1.80-1.66 (2H, m), 1.65-1.45 (2H, m), 1.35-1.28 (2H , m), 1.32 (ZN, s), 1.15-

- 28 041753

1.06 (1H, m), 1.13 (ZN, s). 69 phosphate 2 Example 34 7.71 (1H, s), 7.29 (1H, d, J=8.2 Hz), 6.90 (1H, s), 6.89 (1H, dd, J=8.5, 2, 1 Hz), 6.78 (1H, d, J=l.8 Hz), 5.23 (13H, br s), 4.13 (d, 1H, J=10.5 Hz), 3.90 (1Н, d, J=ll.0 Hz), 3.65 (2Н, s), 3.63 (ЗН, s), 3.33 (1Н, d, J=ll.4 Hz), 2.60 -2.48 (ZN, m), 1.841.50 (4N, m), 1.40-1.35 (2N, m), 1.33 (ZN, s), 1.15-10.8 (2N , m), 1.13 (ZN, s). 70 p-toluenesulfonate 2 Example 34 9.62-9.14 (0.5H, br. m), 9.05 (1H, s), 7.79 (1H, s), 7.47 (4H, dt, J=7.9, 2 .1 Hz), 7.29 (1H, d, J=8.5 Hz), 7.11 (4H, d, J=7.9 Hz), 6.91 (1H, dd, J=8.2 , 2.1 Hz), 6.80 (1H, d, J=l.8 Hz), 4.49 (1.5H, br. s), 4.34 (0.5H, br. s), 4 .17 (1Н, d, 1=10.4 Hz), 3.87 (ЗН, s), 3.63-2.94 (2Н, m), 2.28 (6Н, s), 1.79- 1.69 (1H, m), 1.67-1.22 (6H, m), 1.15 (3H, s). 71 fumarate 2 Example 42 7.66 (1H, s), 7.29 (1H, d, J=8.7 Hz), 7.18 (1H, s), 6.91-6.82 (2H, m), 6.78 (1Н, d, J=l.8 Hz), 6.61 (4Н, s), 4.15-3.99 (ЗН, m), 3.90 (1Н, d, J=ll.0 Hz) , 3.30 (1H, d, J=11.4 Hz), 2.65 (2H, t, J=6.4 Hz), 2.472.29 (2H, m), 1.80-1.56( ZN, m), 1.56-1.44 (1H, m), 1.35-1.29 (2H, m), 1.32 (ZN, s), 1.19-1.05 (1H, m), 1.13 (ZN, s). 72 phosphate 2 Example 42 7.74 (1H, s), 7.29 (1H, d, J=7.9 Hz), 7.21 (1H, s), 6.92 (1H, s), 6.89 (1H, dd , J=8.2, 1.8 Hz), 6.78 (1Н, d, J=l.8 Hz), 4.15-4.07 (ЗН, m), 3.90 (1Н, d, J=11.0 Hz), 3.31 (1H, d, J=ll.0 Hz), 2.72 (2H, t, J=6.0 Hz), 2.45-2.36 (2H, m), 1.81-1.58 (ZN, m), 1.58-1.47 (1N, m), 1.38-1.27 (2N, m), 1.33 (ZN, s) , 1.17-1.06 (1H, m), 1.13 (ZN, s).

- 29 041753

73 p-toluenesulfonate 2 Example 42 9.11 (1H, s), 7.78 (1H, t, J=l.6), 7.72 (1H, t, J=l.6 Hz), 7.47 (4H, dt, J= 8.2, 1.8 Hz), 7.30 (1H, d, J=8.2 Hz), 7.11 (4H, d, J=8.2 Hz), 6.91 (1H, dd, J=8.2, 2.3 Hz), 6.80(1H, d, J=2.3 Hz), 4.62(2H, t, J=6.2 Hz), 4.17(1H, d, J=11.0 Hz), 3.65 (2Н, br. s), 3.28-2.89 (ЗН, m), 2.28 (6Н, s), 2.232.00 (1Н, m ), 1.80-1.68 (1N, m), 1.68-1.43 (ZN, m), 1.42-1.26 (4N, m), 1.15 (ZN, s). 74 fumarate 2 Example 44 7.10 (1H, d, J=l.4 Hz), 7.01 (1H, dd, >9.1, 3.2 Hz), 6.97 (1H, td, >8.5, 3, 2 Hz), 6.80 (1H, d, >1.4 Hz), 6.72 (1H, dd, J - 8.9, 4.8 Hz), 6.59 (4H, s), 4, 13 (1H, d, >10.5 Hz), 3.97 (2H, t, J=6.4 Hz), 3.91 (1H, d, >11.4 Hz), 3.30 (1H, d, >11.4 Hz), 2.59 (2Н, t, J=6.6 Hz), 2.46-2.38 (ЗН, m), 2.38-2.31 (2Н, m) , 2.31 (ZN, s), 1.791.56 (ZN, m), 1.55-1.44 (1N, m), 1.36-1.26 (2N, m), 1.31 (ZN , s), 1.14-1.05 (1H, m), 1.11 (ZN, s). 75 phosphate 2 Example 44 7.27 (1H, d, >1.8 Hz), 7.04-6.98 (2H, m), 6.96 (1H, dd, >8.7, 3.2 Hz), 6.72 (1Н, dd, >8.7, 4.6 Hz), 6.09 (YuN, br s), 4.13 (1Н, d, >11.0 Hz), 4.07 (2Н, t, J=6.4 Hz), 3.91 (1H, d, >11.4 Hz), 3.31 (1H, d, >11.4 Hz), 2.68 (2H, t, J=6, 4 Hz), 2.452.39 (2Н, m), 2.40 (ЗН, s), 1.80-1.58 (ЗН, m), 1.57-1.46 (1Н, m), 1, 37-1.30 (2N, m), 1.31 (ZN, s), 1.14-1.07 (1N, m), 1.11 (ZN, s) 76 p-toluenesulfonate 2 Example 44 9.41-9.16 (1H, wt), 7.66 (1H, d, >1.8 Hz), 7.61 (1H, d, >2.3 Hz), 7.47 (4H , dt, >8.2, 1.8 Hz), 7.11 (4H, d, J=7.8 Hz), 7.06-6.96 (2H, m), 6.74 (1H, dd , >8.9, 4.8

- 30 041753

Hz), 4.50 (2Н, t, J=6.9 Hz), 4.38-4.12 (2Н, m), 3.69-3.51 (ЗН, m), 3.28-2 .98 (ZN, m), 2.61 (ZN, s), 2.28 (6N, s), 1.90 (1.5N, s), 1.80-1.59 (2N, m), 1.69-1.46(2H, m), 1.40-1.27(5H, m), 1.18-1.08(4H, m). 77 phosphate 2 Example 51 7.29 (1H, d, J=8.5 Hz), 7.22 (1H, d, J=1.2 Hz), 6.95 (1H, d, J=1.2 Hz), 6, 88 (1Н, dd, J=8.2.2.1 Hz), 6.78 (1Н, d, J=l.8 Hz), 5.47 (YuN, br s), 4.12 (1Н , d, J=11.0 Hz), 4.01 (2H, t, J=6.4 Hz), 3.90 (1H, d, J=11.0 Hz), 3.31 (1H, d , J=11.0 Hz), 2.64 (2H, t, J=6.4 Hz), 2.48-2.42 (2H, m), 2.42-2.33 (2H, m) , 2.37 (ZN, s), 1.80-1.67 (2H, m), 1.66-1.56 (1H, m), 1.56-1.45 (1H, m), 1 .38-1.27 (2N, m), 1.33 (ZN, s), 1.15-1.07 (1N, m), 1.13 (ZN, s). 78 p-toluenesulfonate 2 Example 51 9.39-9.16 (1H, wt. m), 7.65 (1H, d, J=l.8 Hz), 7.61 (1H, d, J=l.8 Hz), 7.47 (4Н, dt, J=8.2, 1.8 Hz), 7.33-7.27 (1Н, m), 7.11 (4Н, dt, J=7.8 Hz), 6.91 ( 1H, dd, J=8.2, 2.3 Hz), 6.80 (1H, d, J=2.3 Hz), 4.50 (2H, t, J=6.9 Hz), 4, 37-4.12 (2N, m), 3.68-3.51 (ZN, m), 3.28-2.98 (ZN, m), 2.61 (ZN, s), 2.28 ( 6H, s), 2.25-2.07 (2H, m), 1.90 (1.5H, s), 1.80-1.47 (5H, m), 1.45-1.27 ( 5H, m), 1.21-1.08 (4H, m).

Tests.

The following shows the results of tests in which the compounds of the present invention were evaluated using pharmacological experiments, which also explain the pharmacological activity of the compounds, however, the technical scope of the present invention should not be limited to this.

Test 1. Inhibition test to analyze the sphere-forming ability of cancer cells.

Reliable methods developed to determine the ability of cells to self-renew, which is one of the properties of CSC, include a method for determining the sphere-forming ability of cancer cells in a non-adherent state in the absence of serum (Cancer Res 65, 5506-5511 (2005)). T29 cells were 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 in a 384-well ultra-low binding black bottom microplate (Corning Cat. No. 3827) at 350-800 cells/well 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 to bring the final concentration of DMSO to 0.1%, and the cells were cultured for 4 days. The number of viable cells in each well was then measured using a CellTiter-GloTM fluorescent cell viability assay (Promega) to calculate the concentration of each test compound that caused 50% inhibition of cell proliferation (Sphere IC ₅₀ value; µmol/L).

Test 1 experiment was performed for each compound of each example. The concentration of each test compound that causes 50% inhibition of cell proliferation (sphere substance value; µmol/l) is shown in the following table.

- 31 041753

Example IC50 (µmol/l) Example IC50 (µmol/l) Example IC50 (µmol/l) 1 0.08 31 0.06 61 1.30 2 0.24 32 <0.01 62 N.D. 3 0.08 33 <0.01 63 6.8 4 0.31 34 <0.01 64 0.07 5 0.41 35 0.21 64a <0.01 6 0.61 36 0.04 64b 0.05 7 0.09 37 0.25 8 0.31 38 <0.01 9 0.77 39 <0.01 10 0.24 40 <0.01 AND 4.09 41 <0.01 12 0.55 42 <0.01 13 1.20 43 0.05 14 15 16 17 18 19 20 21 22 23 24 25 0.40 0.30 4.40 8.30 0.02 0.04 <0.01 0.21 0.24 0.06 0.09 0.07 44 45 46 47 48 49 50 51 52 53 54 55 <0.01 <0.01 <0.01 <0.01 <0.01 <0.01 0.03 <0.01 <0.01 <0.01 <0.01 0.06 26 <0.01 56 <0.01 27 0.35 57 0.07 28 0.09 58 0.07 29 0.81 59 0.98 thirty 2.28 60 0.16

As shown in the table above, the compounds of examples 20, 26, 32, 33, 34, 38, 39, 40, 41, 42, 44, 45, 46, 47, 48, 49, 51, 52, 53, 54, 56 and 64a showed strong activity in inhibiting cell proliferation under spheral culture conditions.

Test 2 hERG inhibition test.

To a cultured CHO cell strain that stably expresses hERG, each test compound was added to adjust the final concentration of DMSO to 0.0135-0.5%. 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 was calculated (IC ₅₀ value; μM).

Example compounds were tested according to Test 2. And hERG/HT-29 was calculated by dividing the compound concentration obtained in Test 2 (50% hERG current inhibited) by the compound concentration obtained in Test 1 (50% HT-29 cell proliferation inhibited) . The results are shown in the following table._________________________________________________

Example Binding inhibition (1C ₅₀ , μM) hERG/ NT-29 Example Binding inhibition (1C ₅₀ , μM) hERG/ NT-29

- 32 041753

1 <0.3 - 36 1.0 25.0 2 <0.3 - 37 N.D. - 3 0.2 2.50 38 0.8 >80 4 <0.3 - 39 1.0 >100 5 <0.3 - 40 1.4 >140 6 <0.3 - 41 0.7 >70 7 <0.3 - 42 1.4 >140 8 0.3 0.97 43 1.0 20 9 <0.3 - 44 3.6 >360 10 <0.3 - 45 0.4 >40 eleven 4.9 1.20 46 1.2 >120 12 2.9 5.27 47 1.9 >190 13 1.3 1.08 48 0.8 >80 14 oh, s 0.75 49 1.4 >140 15 1.6 5.33 50 1.5 50 16 1.9 0.43 51 0.9 >90 17 3.0 0.36 52 1.5 >150 18 0.6 thirty 53 0.8 >80 19 0.4 10 54 1.4 >140 20 1.4 >140 55 1.6 26.7 21 1.5 7.14 56 0.8 >80 22 1.6 6.67 57 1.1 15.7 23 1.4 23.3 58 1.9 27.1 24 3.8 42.2 59 0.4 0.41 25 0.4 5.7 60 1.1 6.88 26 0.6 >60 61 N.D. - 27 0.4 1.14 62 6.3 - 28 0.7 7.78 63 N.D. - 29 2.6 3.21 64 0.4 5.71 thirty 17 7.46 64a 0.6 >60 31 1.4 23.3 64b <0.3 - 32 0.8 >80 33 1.4 >140 34 1.4 >140 35 3.5 16.7

As shown in the table above, the compounds of 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 difference between the concentration inhibiting 50% of cell proliferation and the concentration inhibiting 50% hERG current.

Industrial applicability.

The compounds of the present invention have a strong inhibitory effect on the sphere-forming ability of cancer cells and thus can be used as an antitumor agent.

Claims (30)

1. Compound of formula (I) -33 041753 or a pharmaceutically acceptable salt thereof, where R ^1a , R ^1b , R ^1c and R ^1d each independently represent a hydrogen atom, a halogen atom or an azide, provided that all R ^1a , R ^1b , R ^1c and R ^1d do not represent a hydrogen atom, R ^2A and R ^2b are each independently hydrogen or C _1-3 alkyl, R ^3A , R ^3b , R ^3C and R ^3d are each independently hydrogen, halogen or C _1-6 alkyl, L represents a bond or -C(O)-, V is C _1-3 alkylene, Q has formula (Q-1) or (Q-2): (Q-1) (Q-2) where R ^11a , R ^11b , R ^11c , R ^11d and R ^11e are each independently hydrogen, halogen, cyano, C1-6 alkyl (which may be substituted from 1 up to 3 substituents independently selected from the group consisting of halogen, cyano, hydroxy, C1-6alkoxy, -NR ^5a R ^6a and -NR ^7a COR ^8a ), C2-6alkenyl (which may be substituted by 1 to 3 hydroxy groups), -CO ₂ R ^4a or -CONR ⁹ R ¹⁰ , R ^5a , R ^6a , R ^7a , R ⁹ and R ¹⁰ are each independently hydrogen or C _1-3 alkyl, or when R ^5a and R ^6a are both C _1-3 alkyl, they may be combined with the nitrogen atom to which they are attached to form a 3-6 membered nitrogen-containing saturated heterocyclyl, and when R ⁹ and R ¹⁰ are both C _1-3 alkyl, they can be combined with a nitrogen atom to which they are attached, with the formation of a 3-6-membered nitrogen-containing saturated heterocyclyl, R ^4a and R ^8a are independently C _1-3 alkyl, R ¹² represents a hydrogen atom or C _1-6 alkyl, and the asterisk (*) denotes the point of attachment to V, provided that the following compounds of formulas (Z-1) and (Z-2) are excluded: 2. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R ^3A , R ^3b , R ^3C and R ^3d represent a hydrogen atom. 3. A compound according to any one of claims 1-2, or a pharmaceutically acceptable salt thereof, wherein R ^2A and R ^2b are each independently C _1-3 alkyl. 4. A compound according to any one of claims 1 to 2, or a pharmaceutically acceptable salt thereof, wherein R ^2A and R ^2b are methyl. 5. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein L is a bond. 6. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein L is -CO-. 7. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein V is ethylene. 8. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein V is methylene. 9. A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, 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 all R ^1a , R ^1b , R ^1c and R ^1d do not represent a hydrogen atom. 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R ^11a , R ^11b , R ^11c , R ^11d and R ^11e are each independently hydrogen, cyano, C1-6 alkyl (which may be substituted from 1 up to 3 substituents independently selected from the group consisting of a fluorine atom, hydroxy and -NR ^7a COR ^8a ), C2-6alkenyl (which may be substituted with one hydroxy group) or -CO ₂ R ^4a . 11. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R ^11a , R ^11b , R ^11c , R ^11d and R ^11e are each independently hydrogen, cyano, C _1-3 alkyl, or C _{2- 6} alkenyl, where alkyl and alkenyl can each be independently substituted with one hydroxy group. 12. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R ^11a , R ^11b , R ^11c , R ^11d and R ^11e are each independently hydrogen or C _1-3 alkyl. - 34 041753 13. The compound according to any one of claims 1, 10-12 or a pharmaceutically acceptable salt thereof, where R ¹² represents a hydrogen atom. 14. A compound according to any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (1-A) ^R2 ^ r ^N ' ^L “ ^{v Q} ( ¹ ' ^a ) JL JLh _R ib^T^ _R id _R 1C 15. A compound according to any one of claims ^1-13 , or ^a pharmaceutically acceptable salt thereof, ^wherein the compound of formula (I) is a compound of formula (1-B) JL JL J (1-B) w^° _R ib Y^ _R id _R ^1C 16. A compound according to any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (1-C) ^R ^ <Ν ^{Λ V} ° ^r1 ? X 1 J (1-c) D' Dn _R ib y^ _R iD _R 1C 17. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the following compounds: (4'aS,10'bS)-8'-chloro-5',5'-dimethyl-1-[(4-methyl-1H-imidazol-5-yl)methyl]-4'a,10'b- dihydro2Ή,4Ή,5Ή-spiro[piperidine-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, 10b-dihydro2Ή,4Ή,5Ή-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, 10b-dihydro2Ή,4Ή,5Ή-spiro[piperidine-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-dihydro2Ή,4Ή,5Ή-cniro[piperidin-4,3'-pyrano[ 3,2-c][1]benzopyran], (4'aS, 10'bS)-9'-chloro-5',5'-dimethyl-1-[(1 -methyl-1 H-imidazole-5- yl)methyl]-4'a, 10b-dihydro2Ή,4Ή,5Ή-spiro[piperidine-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-dihydro2Ή,4Ή,5Ή-spiro[piperidine- 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, 10b-dihydro2Ή,4Ή,5Ή-spiro[piperidin-4,3'-p irano[3,2-c][1]benzopyran], (4'aS,10'bS)-8'-chloro-5',5'-dimethyl-1-[(1-methyl-1H-imidazole-5 -yl)methyl]-4'a,10'b-dihydro2Ή,4Ή,5Ή-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran], (4'aS, 10' bS)-1'-chloro-5',5'-dimethyl-1-[(1-methyl-1 H-imidazol-5-yl)methyl]-4'a, 10b-dihydro2'H,4'H, 5'H-spiro [piperidine-4,3'-pyrano[3,2-c] [ 1 ] benzopyran], (4'aR,10'bR)-7'-chloro-5',5'-dimethyl- 1-[(1-methyl-III-imidazol-5-yl)methyl]-4'a,10'b-dihydro2H,4Ή,5Ή-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-2Ή,4Ή,5Ήspiro[piperidine-4,3'-pyrano[3,2-c] [1] benzopyran], (4'aS, 10'bS)-8'-chloro-1- [2-( 1 H-imidazol-1 -yl)ethyl]-5',5'-dimethyl-4'a, 10'b-dihydro-2'H,4'H,5'Hspiro [piperidine-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-2Ή,4Ή,5Ήspiro [piperidine-4,3'-pyrano[3,2-c] [ 1 ] benzopyran], (4'aR, 10'bR)-9'-fluoro-1-[2-(1 H-imidazol-1-yl)ethyl]-5',5'-dimethyl-4'a, 10b-digid ro-2'Н,4'Н,5'Нspiro[piperidine-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-2Ή,4Ή,5Ήspiro[piperidine-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-2Ή,4Ή,5Ήspiro [piperidine-4,3'-pyrano[3,2-c] [1] benzopyran], (4'aS, 10'bS)-9 '-fluoro-5',5'-dimethyl- 1-[2-(2-methyl-1 H-imidazol-1 -yl)ethyl]-4'a, 10b-dihydro2'H,4'H,5' H-spiro [piperidine-4,3'-pyrano[3,2-c] [ 1 ] benzopyran], - 35 041753 (4'aR, 10'bR)-9'-fluoro-5',5'-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4'a , 10'b-dihydro2H,4H,5H-spiro[piperidine-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-dihydro2H,4H,5H-spiro[piperidine-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-dihydro2H,4H,5H-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- dihydro2Н,4Н,5Н-spiro[piperidine-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-dihydro2H,4H,5H-spiro[piperidine-4,3'-pyrano[3, 2-c][1]benzopyran], (1-{2-[(4'aR,10'bR)-9'-fluoro-5',5'-dimethyl-4'a,10'b-dihydro- 2Ή,4Ή,5Ή-cniro[nineridin-4,3'pyrano[3,2-c] [ 1 ]benzopyran] -1 -yl]ethyl} -1 H-imidazol-2-yl)methanol, (1-{ 2-[(4'aS,10'bS)-9'-fluoro-5',5'-dimethyl-4'a,10'b-dihydro-2Ή,4Ή,5Ή-spiro[pip eridin-4,3'pyrano[3,2-c] [ 1 ]benzopyran] -1 -yl]ethyl} -1 H-imidazol-2-yl)methanol, (1-{2-[(4'aS, 10'bS)-9'-chloro-5',5'-dimethyl-4'a,10'b-dihydro-2Ή,4Ή,5Ή-сniro[nineridine-4,3'pyrano[3,2-c] [ 1 ] benzopyran] -1 -yl] ethyl} -1 H-imidazol-2-yl) methanol, (1-{2-[(4'aR,10'bR)-9'-chloro-5',5 '-dimethyl-4'a,10'b-dihydro-2Ή,4Ή,5Ή-cniro[nineridin-4,3'pyrano[3,2-c] [1] benzopyran] -1 -yl]ethyl} -1 N-imidazol-2-yl)methanol, (1-{2-[(4'aR,10'bR)-8'-chloro-5',5'-dimethyl-4'a,10'b-dihydro- 2Ή,4Ή,5Ή-cniro[nineridin-4,3'pyrano[3,2-c] [ 1 ]benzopyran] -1 -yl]ethyl} -1 H-imidazol-2-yl)methanol, (1-{ 2-[(4'aS,10'bS)-8'-chloro-5',5'-dimethyl-4'a,10'b-dihydro-2Ή,4Ή,5Ή-cniro[nineridine-4,3' pyrano[3,2-c] [ 1 ] benzopyran] -1 -yl]ethyl} -1 H-imidazol-2-yl)methanol, (1-{2-[(4'aS,10'bS)-9 '-chloro-5',5'-dimethyl-4'a,10'b-dihydro-2Ή,4Ή,5Ή-cniro[nineridine-4,3'pyrano[3,2-c] [ 1 ] benzopyran] - 1 -yl]ethyl} -5-methyl-1 H-imidazol-4-yl)methanol, (1-{2-[(4'aR,10'bR)-9'-chloro-5',5'- dimethyl-4'a,10'b-dihydro-2H,4H,5H-cniro[nineridine-4,3'pyrano[3,2-c] [ 1 ]benzopyran] -1 -yl]ethyl} -5-methyl-1 H-imidazol-4-yl)methanol, (4'aS, 10'bR)-8'-chloro-1 -[(4-methyl- 1 H-imidazol-5-yl)methyl]-4'a, 10b-dihydro-2H,4H,5Hspiro[piperidine-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, 10b-dihydro-2H,4H,5Hspiro[piperidine-4, 3'-pyrano[3,2-c] [1] benzopyran]. 18. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the following compounds: (4'aS,10'bS)-8'-chloro-5',5'-dimethyl-1-[(4-methyl-III-imidazol-5-yl)methyl]-4'a,10'b- dihydro2Н,4Н,5Н-spiro[piperidine-4,3'-pyrano[3,2-c][1]benzopyran], (4'aR,10'bR)-8'-chloro-5',5'- dimethyl-1-[(4-methyl-III-imidazol-5-yl)methyl]-4'a,10'b-dihydro2H,4H,5H-spiro[piperidine-4,3'-pyrano[3,2- c][1]benzopyran], (4'aR,10'bR)-9'-chloro-5',5'-dimethyl-1-[(4-methyl-III-imidazol-5-yl)methyl]- 4'a,10'b-dihydro2Н,4Н,5Н-spiro[piperidine-4,3'-pyrano[3,2-c][1]benzopyran], (4'aS,10'bS)-9'- chloro-5',5'-dimethyl-1-[(4-methyl-III-imidazol-5-yl)methyl]-4'a,10'b-dihydro2H,4H,5H-spiro[piperidine-4,3 '-pyrano[3,2-c][1]benzopyran], (4'aS,10'bS)-9'-chloro-5',5'-dimethyl-1-[(1-methyl-III-imidazole -5-yl)methyl]-4'a,10'b-dihydro2H,4H,5H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran], (4'aR, 10'bR)-9'-chloro-5',5'-dimethyl-1-[(1-methyl-1 H-imidazol-5-yl)methyl]-4'a, 10b-dihydro2H,4H,5H- spiro[piperidine-4,3'-pyrano[3,2-c][1]benzopyran], (4'aR,10'bR)-8'-chloro-5',5'-dimethyl-1-[( 1-methyl-III-imidazol-5-yl)methyl]-4'a,10'b-dihydro2H,4H,5H-spiro[piperidine-4,3'-pyrano[3, 2-c][1]benzopyran], (4'aS,10'bS)-8'-chloro-5',5'-dimethyl-1-[(1-methyl-III-imidazol-5-yl)methyl ]-4'a,10'b-dihydro2Н,4Н,5Н-spiro[piperidine-4,3'-pyrano[3,2-c][1]benzopyran], (4'aS,10'bS)-1 '-chloro-5',5'-dimethyl-1-[(1-methyl-III-imidazol-5-yl)methyl]-4'a,10'b-dihydro2H,4H,5H-spiro[piperidine-4 ,3'-pyrano[3,2-c][1]benzopyran] and (4'aR, 10'bR)-1'-chloro-5',5'-dimethyl-1-[(1 -methyl-1 N-imidazol-5-yl)methyl]-4'a,10b-dihydro2H,4H,5H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran]. 19. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the following compounds: (4'aR,10'bR)-8'-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5',5'-dimethyl-4'a,10'b-dihydro- 2Ή,4Ή,5Ήspiro[piperidine-4,3'-pyrano[3,2-c] [ 1 ] benzopyran], (4'aS,10'bS)-8'-chloro-1-[2-(1Н- imidazol-1-yl)ethyl]-5',5'-dimethyl-4'a,10'b-dihydro-2Ή,4Ή,5Ήspiro[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-2Ή,4Ή,5Ήspiro[piperidine-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-2Ή,4Ή,5Ήspiro[piperidin-4,3'-pyrano[3,2- c] [ 1 ] benzopyran], - 36 041753 (4'aR, 10'bR)-9'-chloro-1-[2-( 1 H-imidazol-1 -yl)ethyl] -5',5'-dimethyl-4'a, 10b- dihydro-2H,4H,5'Hspiro[piperidine-4,3'-pyrano[3,2-c] [1] benzopyran], (4'aS,10'bS)-9'-chloro-1-[2 -(1H-umidazol-1-yl)ethyl]-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'Hspiro[piperidine-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,10b-dihydro2H,4H,5H-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, 10b-dihydro2H,4H,5H- spiro[piperidine-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-dihydro2H,4H,5H-spiro[piperidine-4,3'-pyrano[3,2-c][1 ]benzopyran], (4'aS,10'bS)-9'-chloro-5',5'-dimethyl-1-[2-(2-methyl-III-imidazol-1-yl)ethyl]-4' a,10'b-dihydro2Н,4Н,5Н-spiro[piperidine-4,3'-pyrano[3,2-c][1]benzopyran], (4'aS,10'bS)-8'-chloro- 5',5'-dimethyl-1-[2-(2-methyl-III-imidazol-1-yl)ethyl]-4'a,10'b-dihydro2Н,4Н ,5H-spiro[piperidine-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-dihydro2H,4H,5H-spiro[piperidine-4,3'-pyrano[3,2-c ][1]benzopyran], (1-{2-[(4'aR,10'bR)-9'-fluoro-5',5'-dimethyl-4'a,10'b-dihydro-2Ή,4Ή ,5Ή-spiro[piperudin-4,3'pyrano[3,2-c] [ 1 ]benzopyran] -1 -yl]ethyl} -1 H-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-cniro[nunerudin-4 ,3'pyrano[3,2-c] [ 1 ]benzopyran] -1 -yl]ethyl} -1 H-imidazol-2-yl)methanol, (1-{2-[(4'aS,10'bS )-9'-chloro-5',5'-dimethyl-4'a,10'b-dihydro-2Ή,4Ή,5Ή-sniro[nunerudin-4,3'pyrano[3,2-c] [1] benzopyran] -1 -yl]ethyl} -1 H-imidazol-2-yl)methanol, (1-{2-[(4'aR,10'bR)-9'-chloro-5',5'-dumetul -4'a,10'b-dihydro-2Ή,4Ή,5Ή-sniro[nunerudin-4,3'pyrano[3,2-c] [1]benzopyran]-1-yl]ethyl}-1H-imidazole -2-yl)methanol, (1-{2-[(4'aR,10'bR)-8'-chloro-5',5'-dimethyl-4'a,10'b-dihydro-2Ή,4Ή ,5Ή-cniro[nunerudin-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-2Ή,4Ή,5Ή-cniro [nunerudin-4,3'pyrano[3,2-c] [ 1 ]benzopyran] -1 -yl]ethyl} -1 H-imidazol-2-yl)methanol, (1-{2-[(4'aS ,10'bS)-9'-chloro-5',5'-dimethyl-4'a,10'b-dihydro-2Ή,4Ή,5Ή-sniro[nunerudin-4,3'pyrano[3,2-c ] [ 1 ] benzopyran] -1 -yl] ethyl} -5-methyl-1 H-imidazol-4-yl) methanol and (1-{2-[(4'aR,10'bR)-9'-chloro -5',5'-dimethyl-4'a,10'b-dihydro-2Ή,4Ή,5Ή-sniro[nunerudin-4,3'pyrano[3,2-c] [1] benzopyran]-1-yl ]ethyl} -5-methyl-1H-imidazol-4-yl)methanol. 20. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the following compounds: (4'aS,10'bS)-8'-chloro-5',5'-dimethyl-1-[(4-methyl-III-imidazol-5-yl)methyl]-4'a,10'b- dihydro2Н,4Н,5Н-spiro[piperidine-4,3'-pyrano[3,2-c][1]benzopyran], (4'aR,10'bR)-8'-chloro-5',5'- dimethyl-1-[(4-methyl-III-imidazol-5-yl)methyl]-4'a,10'b-dihydro2H,4H,5H-spiro[piperidine-4,3'-pyrano[3,2- c][1]benzopyran], (4'aR,10'bR)-8'-chloro-1-[2-(III-imidazol-1-yl)ethyl]-5',5'-dimethyl-4' a,10'b-dihydro-2Н,4Н,5Ήspiro[piperidine-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-2Ή,4Ή,5Ήspiro[piperidin-4,3'-pyrano[ 3,2-c] [1] benzopyran], (4'aS, 10'bS)-9'-fluoro-5',5'-dimethyl-1-[2-(2-methyl-1H-imidazole- 1-yl)ethyl]-4'a, 10b-dihydro2Ή,4H,5H-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, 10b-dihydro2H,4H,5H-spiro[ piperidine-4,3'-pyrano[3,2-c][1]benzopyran]. 21. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is (4'aS,10'bS)-8'-chloro-5',5'-dimethyl-1-[(4-methyl-1H-imidazole -5-yl)methyl]-4'a,10'b-dihydro- 2H,4H,5H-spiro[piperidine-4,3'-pyrano[3,2-c][1]benzopyran]. 22. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is (4'aR,10'bR)-8'-chloro-5',5'-dimethyl-1-[(4-methyl-1H-imidazole -5-yl)methyl]-4'a,10'b-dihydro2H,4H,5H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran]. 23. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is (4'aR,10'bR)-8'-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5' ,5'-dimethyl-4'a,10'b-dihydro-2Ή,4Ή,5Ήspiro[piperidine-4,3'-pyrano[3,2-c] [1] benzopyran]. 24. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is (4'aS,10'bS)-8'-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5' ,5'-dimethyl-4'a,10'b-dihydro-2Ή,4Ή,5Ήspiro[piperidine-4,3'-pyrano[3,2-c] [1] benzopyran]. 25. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is (4'aS, 10'bS)-9'-fluoro-5',5'-dimethyl-1-[2-(2-methyl-1 N-imidazol-1-yl)ethyl]-4'a,10b-dihydro2H,4H,5H-spiro[piperidin-4,3'-pyrano[3,2-c][1]benzopyran]. 26. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is - 37 041753 (4'aR, 10'bR)-9'-φτop-5',5'-dimethyl-1 -[2-(2-methyl-1 H-imidazol-1 -yl)ethyl] -4' a, 10'L-dihydro2'H,4'H,5'H-spiro[piperidine-4,3'-pyrano[3,2-c][1]benzopyran]. 27. The compound according to claim 1 or its phosphate, selected from the following compounds: (4'a8,10'b8)-8'-chloro-5',5'-dimethyl-1-[(4-methyl-1H-imidazol-5-yl)methyl]-4'a,10'b- dihydro2'H,4'H,5'H-spiro[piperidine-4,3'-pyrano[3,2-c][1]benzopyran], (4'aR,10'bR)-8'-xnop- 5',5'-flHMeTHn-l-[(4-MeTHn-lH-HMHfla3on-5-Hn)MeTmi]-4'a,10'b-flHrHflpo2'H,4'H,5'H-spiro[piperidine -4,3'-pyrano[3,2-c][1]benzopyran], (4'aR,10'bR)-8'-xnop-l-[2-(lH-HMHfla3on-l-Hn)3THn ]-5',5'-flHMeTHn-4'a,10'b-flHrHflpo-2'H,4'H,5'Hspiro [piperidine-4,3'-pyrano[3,2-с] [ 1 ] benzopyran], (4'a8,10'b8)-8'-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5',5'-dimethyl-4'a,10'b -dihydro-2'H,4'H,5'Hspiro[piperidine-4,3'-pyrano[3,2-c] [1] benzopyran], (4'aS, 10'L8)-9'-fluoro -5',5'-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4'a, 10'b-dihydro2'H,4'H,5'H -spiro[piperidine-4,3'-pyrano[3,2-c][1]benzopyran] and (4'aR, 10'bR)-9'-φτop-5',5'-dimethyl-1 -[ 2-(2-methyl-1H-imidazol-1-yl)ethyl]-4'a, 10'b-dihydro2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[ 3,2-c][1]benzopyran]. 28. The compound according to claim 1 or its fumarate selected from the following compounds: (4'a8,10'b8)-8'-chloro-5',5'-dimethyl-1-[(4-methyl-1H-imidazol-5-yl)methyl]-4'a,10'b- dihydro2'H,4'H,5'H-spiro[piperidine-4,3'-pyrano[3,2-c][1]benzopyran], (4'aR,10'bR)-8'-xnop- 5',5'-flHMeTHn-l-[(4-MeTHn-lH-HMHfla3on-5-Hn)MeTmi]-4'a,10'b-flHrHflpo2'H,4'H,5'H-spiro[piperidine -4,3'-pyrano[3,2-c][1]benzopyran], (4'aR,10'bR)-8'-xnop-l-[2-(lH-HMHfla3on-l-Hn)3THn ]-5',5'-flHMeTHn-4'a,10'b-flHrHflpo-2'H,4'H,5'Hspiro [piperidine-4,3'-pyrano[3,2-с] [ 1 ] benzopyran], (4'a8,10'b8)-8'-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5',5'-dimethyl-4'a,10'b -dihydro-2'H,4'H,5'Hspiro[piperidine-4,3'-pyrano[3,2-c] [1] benzopyran], (4'aS, 10'L8)-9'-fluoro -5',5'-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4'a, 10'b-dihydro2'H,4'H,5'H -spiro[piperidine-4,3'-pyrano[3,2-c][1]benzopyran] and (4'aR, 10'bR)-9'-φτop-5',5'-dimethyl-1 -[ 2-(2-methyl-1H-imidazol-1-yl)ethyl]-4'a, 10'b-dihydro2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[ 3,2-c][1]benzopyran]. 29. The compound according to claim 1 or its p-toluenesulfonate selected from the following compounds: (4'a8,10'b8)-8'-chloro-5',5'-dimethyl-1-[(4-methyl-1H-imidazol-5-yl)methyl]-4'a,10'b- dihydro2'H,4'H,5'H-spiro[piperidine-4,3'-pyrano[3,2-c][1]benzopyran], (4'aR,10'bR)-8'-xnop- 5',5'-flHMeTHn-l-[(4-MeTHn-lH-HMHfla3on-5-Hn)MeTmi]-4'a,10'b-flHrHflpo2'H,4'H,5'H-spiro[piperidine -4,3'-pyrano[3,2-c][1]benzopyran], (4'aR,10'bR)-8'-xnop-l-[2-(lH-HMHfla3on-l-Hn)3THn ]-5',5'-flHMeTHn-4'a,10'b-flHrHflpo-2'H,4'H,5'Hspiro [piperidine-4,3'-pyrano[3,2-с] [ 1 ] benzopyran], (4'a8,10'b8)-8'-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5',5'-dimethyl-4'a,10'b -dihydro-2'H,4'H,5'Hspiro[piperidine-4,3'-pyrano[3,2-c] [1] benzopyran], (4'aS, 10'b8)-9'-fluoro -5',5'-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4'a, 10'b-dihydro2'H,4'H,5'H -spiro[piperidine-4,3'-pyrano[3,2-c][1]benzopyran] and (4'aR, 10'bR)-9'-φτop-5',5'-dimethyl-1 -[ 2-(2-methyl-1H-imidazol-1-yl)ethyl]-4'a, 10'b-dihydro2'H,4'H,5'H-spiro[piperidin-4,3'-pyrano[ 3,2-c][1]benzopyran]. 30. A pharmaceutical composition for the treatment of cancer, comprising an effective amount of a compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable additives.