polycyclic derivatives of substituted pyridone

专利摘要:
The present invention relates to the following compounds which have antiviral activity. A1 is CR1AR1B, S or O; A2 is CR2AR2B, S or O; A3 is CR3AR3B, S or O; A4 is CR4AR4B, S or O; the number of hetero atoms between the constituent atoms of the ring, formed by A1, A2, A3, A4, the nitrogen atom adjacent to A1 and the carbon atom adjacent to A1, is 1 or 2; R1A and R1B are each independently hydrogen, halogen, alkyl or the like; R2A and R2B are each independently hydrogen, halogen, alkyl or the like; R3A and R3B are each independently hydrogen, halogen, alkyl or the like; R4A and R4B are each independently hydrogen, halogen, alkyl or the like; R3A and R3B can be considered together to form non-aromatic carbocycle or non-aromatic heterocycle; X is CH2, S or O; R1 is each independently halogen, hydroxy or similar; m is any integer from 0 to 2; and n is any integer from 1 to 2.
公开号:BR112017022550B1
申请号:R112017022550-6
申请日:2016-04-27
公开日:2021-02-23
发明作者:Makoto Kawai；Kenji Tomita；Toshiyuki Akiyama；Azusa OKANO；Masayoshi Miyagawa
申请人:Shionogi & Co., Ltd；
IPC主号:

专利说明:

Technical Field
[001] This invention relates to substituted polycyclic pyridone derivatives that have cap-dependent endonuclease inhibitory activity, their prodrugs and pharmaceutical compositions including them. Background Technique
[002] Influenza is an acute infectious respiratory disease caused by infection with an Influenza virus. In Japan, millions of patients are reported to have flu syndrome every winter, and the flu is accompanied by high morbidity and mortality. Influenza is a particularly important disease in high-risk populations such as infants and the elderly, a high rate of complications with pneumonia in the elderly, and death from influenza occurs in the elderly in many cases.
[003] They are known as anti-flu drugs Symmetrel (in the commercial name: Amantadine) and Flumadine (commercial name: Rimantadine), which inhibit the process of denucleation of a virus, and Oseltami- vir (commercial name: Tamiflu) and Zanamivir (commercial name : Relenza) which are neuraminidase inhibitors and suppress the budding and viral release of a cell. However, in view of the problems of the emergence of resistant strains and side effects and the fear of an epidemic worldwide by a new type of Influenza virus that has high pathogenicity and mortality, the development of an anti-flu drug has been desired. with an innovative mechanism.
[004] Considering that, for viral proliferation, a cap-dependent endonuclease is essential, which is an enzyme derived from the Influenza virus, whose enzymatic activity is specific to the virus and that a host does not have it, it is believed that the endonuclease is suitable as a target for an anti-influenza drug. The cap-dependent endonuclease of an Influenza virus has a host mRNA precursor as a substrate, and the endonuclease activity to produce a 9 to 13 base fragment including a cap structure (not including the number of bases of the cap structure). This fragment acts as a primer for a viral RNA polymerase and is used in the synthesis of an mRNA encoding a viral protein. That is, it is believed that a substance that inhibits cap-dependent endonuclease inhibits the synthesis of a viral protein by inhibiting the synthesis of the virus mRNA and, as a result, inhibits the proliferation of the virus.
[005] As the substance that inhibits cap-dependent endonuclease, flutimide (Patent Document 1 and Non-Patent Documents 1 and 2), 4-substituted 2,4-dioxobutanoic acid (Patent Document 2 and Non-Patent Documents) have been reported Patent 3 and 4), the compounds described in Patent Documents 3 to 12 and the like, however, these have not yet led to clinical use as anti-flu drugs. Patent Documents 9 and 12 describe compounds with a structure similar to that of this invention, but do not describe compounds related to the present invention. Furthermore, Patent Documents 13 to 15 describe compounds with a structure similar to that of this invention as a compound exhibiting integrase inhibitory activity, however, the documents do not describe cap-dependent endonuclease. In addition, Patent Documents 16 and 17 describe an invention, which relates to compounds with a structure similar to that of this invention, as a compound having the cap-dependent endonuclease inhibitory activity, which was deposited by the applicants, but which does not describe the compounds related to the present invention. DOCUMENTS FROM THE PREVIOUS TECHNIQUE PATENT DOCUMENTS
[006] Patent Document 1: GB2280435 Patent Document 2: US5475109 Patent Document 3: US20130090300 Patent Document 4: WO2013 / 057251 Patent Document 5: WO2013 / 174930 Patent Document 6: WO2014 / 023691 Patent Document 7: WO2014 / 043252 Patent Document 8: WO2014 / 074926 Patent Document 9: WO2014 / 108406 Patent Document 10: WO2014 / 108407 Patent Document 11: WO2014 / 108408 Patent Document 12: WO2015 / 038655 Patent Document 13: WO2005 / 016927 Patent Document 14: WO2006 / 066414 Patent Document 15: WO2007 / 049675 Patent Document 16: WO2010 / 147068 Patent Document 17: WO2012 / 039414 NON-PATENT DOCUMENTS
[007] Non-Patent Document 1: Tetrahedron Lett 1995, 36 (12), 2005 Non-Patent Document 2: Tetrahedron Lett 1995, 36 (12), 2009 Non-Patent Document 3: Antimicrobial Agents And Chemotherapy, Dec. 1994, p.2827-2837 Non-Patent Document 4: Antimicrobial Agents And Chemotherapy, May 1996, p.1304-1307 Summary of the Invention Problems to be solved by the invention
[008] The present invention aims to provide compounds with antiviral activities, especially activity to inhibit the growth of the Influenza virus. Another objective of the present invention is to provide a prodrug prepared from compounds used for in vivo administration (for example, oral administration), which is efficiently absorbed by the body after administration and shows a high pharmacological effect. Means to Solve Problems
[009] The present invention provides the inventions shown below. (1) A compound represented by Formula (I):
where: P is hydrogen or a PR group to form a prodrug; A1 is CR1AR1B, S or O; A2 is CR2AR2B, S or O; A3 is CR3AR3B, S or O; A4 is each independently CR4AR4B, S or O; the number of hetero atoms between the constituent atoms of the ring, formed by A1, A2, A3, A4, the nitrogen atom adjacent to A1 and the carbon atom adjacent to A4, is 1 or 2; R1A and R1B are each independently hydrogen, halogen, alkyl, haloalkyl, alkyloxy or phenyl; R2A and R2B are each independently hydrogen, halogen, alkyl, haloalkyl, alkyloxy or phenyl; R3A and R3B are each independently hydrogen, halogen, alkyl, haloalkyl, alkyloxy or phenyl; R4A and R4B are each independently hydrogen, halogen, alkyl, haloalkyl, alkyloxy or phenyl; R3A and R3B can be considered together with an adjacent carbon atom to form non-aromatic carbocycle or non-aromatic heterocycle; X is CH2, S or O; R1 is each independently halogen, hydroxy, alkyl, haloalkyl or alkyloxy; m is any integer from 0 to 2; and n is any integer from 1 to 2; provided that the following compounds are excluded:
where each definition has the same meaning as described above. (2) The compound according to (1), in which the group represented by the formula:
where each definition has the same meaning as described (1), it is a group represented by the formula:
wherein R2, R3, R4 and R5 are each independently hydrogen or fluorine; the number of fluorine atoms of R2, R3, R4 and R5 is 1 or 2, or their pharmaceutically acceptable salt. (3) The compound according to (1), in which the group represented by the formula:
where each definition has the same meaning as described (1), it is a group represented by the formula:
(4) The compound according to any one of (1) to (3), in which the group represented by the formula:
where each definition has the same meaning as described (1), is represented by the formula:
where each definition has the same meaning as described (1), or its pharmaceutically acceptable salt.


wherein each definition has the same meaning as described (1), or its pharmaceutically acceptable salt. (6) The compound according to (1) represented by the formula is as follows:
wherein each definition has the same meaning as described (1), or its pharmaceutically acceptable salt. (7) The compound according to (1), represented by the following formula:
wherein each definition has the same meaning as described (1), or its pharmaceutically acceptable salt. (8) The compound according to (1), represented by the following formula:
wherein each definition has the same meaning as described (1), or its pharmaceutically acceptable salt. (9) The compound according to (1), represented by the following formula:
wherein each definition has the same meaning as described (1), or its pharmaceutically acceptable salt. (10) The compound according to (1), represented by the following formula:
wherein each definition has the same meaning as described in claim 1, or its pharmaceutically acceptable salt. (11) The compound represented by the following formula:
where P is hydrogen or a PR group to form a prodrug, or its pharmaceutically acceptable salt. (12) The compound according to any one of (1) to (11), or its pharmaceutically acceptable salt, where PR is a group selected from the following formulas a) to ac): a) -C (= O ) -PR0, b) -C (= O) -PR1, c) -C (= O) -L-PR1, d) -C (= O) -LO-PR1, e) -C (= O) - LOLO-PR1, f) -C (= O) -LOC (= O) -PR1, g) -C (= O) -O-PR2, h) -C (= O) -N (-K) (PR2 ), i) -C (= O) -OLO-PR2, j) -C (PR3) 2-O-PR4, k) -C (PR3) 2-OLO-PR4, l) -C (PR3) 2- OC (= O) -PR4, m) -C (PR3) 2-OC (= O) -O-PR4, n) -C (PR3) 2-OC (= O) -N (-K) -PR4, o) -C (PR3) 2-OC (= O) -OLO-PR4, p) -C (PR3) 2-OC (= O) -OLN (PR4) 2, q) -C (PR3) 2-OC (= O) -N (-K) -LO-PR4, r) -C (PR3) 2-OC (= O) -N (-K) -LN (PR4) 2, s) -C (PR3) 2 -OC (= O) -OLOLO-PR4, t) -C (PR3) 2-OC (= O) -OLN (-K) -C (= O) -PR4, u) -C (PR3) 2-OP (= O) (- PR5) 2, v) -C (PR3) 2-PR6, w) -C (= N + (PR7) 2) (- N (PR7) 2), x) -C (PR3) 2 -C (PR3) 2-C (= O) -O-PR2, y) -C (PR3) 2-N (-K) -C (= O) -O-PR2, z) -P (= O) (-PR8) (- PR9), aa) -S (= O) 2-PR10, ab) -PR11 and ac) -C (PR3) 2-C (PR3) 2-O-PR2, where L is a linear or branched alkylene or linear or branched alkenylen; K is hydrogen or alkyl optionally substituted with a substituent group A; PR0 is alkyl optionally substituted with a group A substituent or alkenyl optionally substituted with a group A substituent; PR1 is carbocyclyl group optionally substituted with a substituent group A, heterocyclyl group optionally substituted with a group A substituting, alkylamino optionally substituted with a group A substituting or alkylsulfanyl optionally substituted with a group A substituting; PR2 is alkyl optionally substituted with a substituting group A, carbocyclyl group optionally substituted with a substituting group A, heterocyclyl group optionally substituted with a substituting group A, carbocyclylalkyl optionally substituted with a substituting group A, heterocyclylalkyl optionally substituted with a substituting group A or trialkylsilyl; PR3 is each independently hydrogen or alkyl; PR4 is each independently alkyl optionally substituted with a substituting group A, carbocyclyl group optionally substituted with a substituting group A, heterocyclyl group optionally substituted with a substituting group A, alkylamino optionally substituted with a substituting group A, carbocyclylalkyl optionally substituted with a group A substituent, heterocyclylalkyl optionally substituted with a substituent group A or trialkylsilyl; PR5 is each independently hydroxy or OBn; PR6 is a carbocyclyl group optionally substituted with a substituting group A or heterocyclyl group optionally substituted with a substituting group A; PR7 is each independently alkyl optionally substituted with a substituent group A; PR8 is alkyloxy optionally substituted with a substituent group A; PR9 is alkyloxy optionally substituted with a substituting group A, alkylamino optionally substituted with a substituting group A, carbocyclyloxy optionally substituted with a substituting group A, heterocyclyloxy optionally substituted with a substituting group A, carbocyclylamino optionally substituted with a substituting or heterocyclylamino group optionally substituted with a substituent group A; PR8 and PR9 can be considered together with a phosphorus atom adjacent to form heterocycle optionally substituted with a substituent group A; PR10 is alkyl optionally substituted with a substituting group A, carbocyclyl group optionally substituted with a substituting group A, heterocyclyl group optionally substituted with a substituting group A, carbocyclylalkyl optionally substituted with a substituting group A or heterocyclylalkyl optionally substituted with a substituting group A ; PR11 is alkyl optionally substituted with a substituent group A, alkenyl optionally substituted with a group A substituting, carbocyclyl group optionally substituted with a group A substituting or heterocyclyl group optionally substituted with a group A; Substitute Group A; oxo, alkyl, hydroxyalkyl, amino, alkylamino, carbocyclyl group, heterocyclyl group, carbocyclylalkyl, alkylcarbonyl, halogen, hydroxy, carboxy, alkylcarbonylamino, alkylcarbonylaminoalkyl, alkylcarbonyloxy, alkyloxycarbonyl, alkyloxycarbonyl, alkyloxycarbonyl, alkyloxycarbonyl, alkyloxycarbonyl, alkyloxycarbonyl cyano, nitro, azido, alkylsulfonyl, trialkylsilyl and phospho. (13) The compound according to (12), or its pharmaceutically acceptable salt, where PR is a group selected from the following formulas: a) -C (= O) -PR0, b) -C (= O) -PR1, g) -C (= O) -O-PR2, h) -C (= O) -N (-K) (PR2), i) -C (= O) -OLO-PR2, l) - C (PR3) 2-OC (= O) -PR4, m) -C (PR3) 2-OC (= O) -O-PR4, o) -C (PR3) 2-OC (= O) -OLO- PR4, v) -C (PR3) 2-PR6, x) -C (PR3) 2-C (PR3) 2-C (= O) -O-PR2, y) -C (PR3) 2-N (- K) -C (= O) -O-PR2 and z) -P (= O) (- PR8) (- PR9), where L is a linear or branched alkylene; K is hydrogen or alkyl optionally substituted with a substituent group A; PR0 is alkyl optionally substituted with a substituent group A; PR1 is a carbocyclyl group optionally substituted with a substituting group A or heterocyclyl group optionally substituted with a substituting group A; PR2 is alkyl optionally substituted with a substituting group A, carbocyclyl group optionally substituted with a substituting group A, heterocyclyl group optionally substituted with a substituting group A, carbocyclylalkyl optionally substituted with a substituting group A or heterocyclylalkyl optionally substituted with a substituting group A ; PR3 is each independently hydrogen or alkyl; PR4 is alkyl optionally substituted with a substituting group A, carbocyclyl group optionally substituted with a substituting group A or heterocyclyl group optionally substituted with a substituting group A; PR6 is a carbocyclyl group optionally substituted with a substituent group A, or heterocyclyl group optionally substituted with a group A substituent; PR8 is alkyloxy optionally substituted with a substituent group A; PR9 is alkyloxy optionally substituted with a substituting group A, alkylamino optionally substituted with a substituting group A, carbocyclyloxy optionally substituted with a substituting group A, heterocyclyloxy optionally substituted with a substituting group A, carbocyclylamino optionally substituted with a substituting or heterocyclylamino group optionally substituted with a substituent group A; and PR8 and PR9 can be considered together with a phosphorus atom adjacent to form heterocycle optionally substituted with a substituting group A, substituting Group A; oxo, alkyl, alkylamino, carbocyclyl group, heterocyclyl group, alkylcarbonyl, halogen, hydroxy, alkylcarbonylamino, alkylcarbonyloxy, alkyloxycarbonyl, alkyloxycarbonylalkyl, alkylaminocarbonyloxy, alkyloxy, cyano, nitro, azyl and alkylsulfonyl. (14) A compound represented by the following formula:
maceutically acceptable. (15) A compound represented by the following formula:
(16) A pharmaceutical composition comprising the compound of any one of (1) to (15), or its pharmaceutically acceptable salt. (17) The pharmaceutical composition according to (16), which exhibits anti-flu activity. (18) The pharmaceutical composition according to (16), which exhibits cap-dependent endonuclease inhibitory activity. (19) A method for treating and / or preventing a disease caused by a virus with a cap-dependent endonuclease, which is characterized by comprising administering the compound of any one of (1) to (15), or its pharmaceutically acceptable salt. (20) A compound according to any one of (1) to (15), or its pharmaceutically acceptable salt, to treat or prevent a disease caused by a virus having a cap-dependent endonuclease. (21) Use of the compound according to any one of (1) to (15), or its pharmaceutically acceptable salt, in the production of a therapeutic or prophylactic agent for a disease caused by a virus having a cap-dependent endonuclease. (22) A pharmaceutical composition comprising the compound of any one of (1) to (15), or its pharmaceutically acceptable salt, for oral administration. (23) The pharmaceutical composition according to (22), which is a tablet, powder, granule, capsule, pill, film, suspension, emulsion, elixir, syrup, lemonade, drink, flavored water, extract, decoction or dye. (24) The pharmaceutical composition according to (16), which is a sugar-coated tablet, film-coated tablet, enteric-coated tablet, long-release tablet, lozenge, sublingual tablet, oral tablet, chewable tablet, oral disintegrating tablet, dry syrup, soft capsule, microcapsule or prolonged-release capsule. (25) A pharmaceutical composition comprising the compound according to any one of (1) to (15), or its pharmaceutically acceptable salt, for parenteral administration. (26) The pharmaceutical composition according to (25), for dermal, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, transnasal, ophthalmic, in the inner or vaginal ear. (27) The pharmaceutical composition according to (25) or (26), which is an injection, infusion, eye drops, nasal drops, aerosol, for inhalation, lotion, impregnation, liniment, mouthwash, enema, ointment, plaster , gelatin, cream, adhesive, poultice, powder for external use or suppository. (28) A pharmaceutical composition comprising the compound according to any one of (1) to (15), or its pharmaceutically acceptable salt, for a pediatric or geriatric patient. (29) A pharmaceutical composition consisting of a combination of the compound according to any one of (1) to (15), or its pharmaceutically acceptable salt, and a neuraminidase inhibitor, RNA-dependent RNA polymerase inhibitor, inhibitor of M2 protein, inhibitor of binding of PB2 to cap, an anti-HA antibody or immunological agent. (30) A pharmaceutical composition comprising the compound according to any one of (1) to (15), or its pharmaceutically acceptable salt, for a combination therapy with a neuramini-dase inhibitor, RNA-dependent RNA polymerase inhibitor, inhibitor of the M2 protein, inhibitor of the binding of PB2 to the cap, an anti-HA antibody or immunological agent.
[0010] The present invention further provides a method for treating or preventing an infectious disease by the Influenza virus using the prodrug compound and the compound that exhibits influenza activity. The present invention further provides a parent compound of the prodrug compound. The parent compound is effective as an anti-flu agent or an intermediate to the prodrug compound. Effect of the Invention
[0011] The compound according to the present invention has an inhibitory activity on the cap-dependent endonuclease. The most preferred compound is a prodrug, and the prodrug becomes a parent compound having an inhibitory activity on cap-dependent en-donuclease in vivo after administration, thus being effective as a therapeutic agent and / or preventive agent for infectious disease by the Influenza virus. Brief Description of Drawings
[0012] Figure 1 shows the measured plasma concentration of compound III-2, after oral administration of the prophylactic Compound II-6, the original compound of which is Compound III-2, to rats under off-fast conditions.
[0013] Figure 2 shows the measured plasma concentration of compound II-6, after oral administration of the prophylactic Compound II-6, the original compound of which is Compound III-2, to rats under non-fasting conditions. Best way to carry out the invention
[0014] The meaning of each term used in the present description is explained below. Each term is used in a unified sense, and in the same sense when used alone, or when used in combination with another term.
[0015] The term "consist of" means having only the components.
[0016] The term "understand" means not restricted with components and not excluding factors not described.
[0017] "Optionally substituted with the substituting Group A" means that an arbitrated position can be substituted with one, two or more equal or different substituents, selected from the substituting Group A.
[0018] "Profármaco", in this description, refers to a position represented by Formula (II) in the formula of the following reaction:
where each symbol is the same as the above, or its pharmaceutically acceptable salt, and means a compound showing cap-dependent endonuclease inhibitory activity (CEN) and / or CPE inhibitory effect, when converted to a compound represented by Formula ( III) by a decomposition reaction caused by enzymes that metabolize drugs, hydrolyses, gastric acids, enterobacteria, etc. under physiological conditions in vivo.
[0019] The prodrug most preferably means a compound in which bioavailability and / or AUC (area under the blood concentration curve) in in vivo administration are more improved than those of the compound represented by Formula (III).
Therefore, the prodrug is efficiently absorbed by the body in the stomach and / or intestines after in vivo administration (for example, oral administration), then converted into the compound represented by Formula (III). Thus, the prodrug preferably shows a greater effect of treating and / or preventing influenza than the compound represented by Formula (III).
[0021] A modality of the "group represented by
", where each definition has the same meaning as described (1), is a group represented by the formula: Rt / rí R <-Q3D R5 S where R2, R3, R4 and R5 are each independently hydrogen or fluorine; the number of fluorine atoms in R2, R3, R4 and R5 is 1 or 2.

[0022] Another modality is a group represented by the formula:


and a group represented by the formula: or is preferable, and a group represented by the formula: ^ / vx / vvn is especially preferable.
[0023] "PR group to form a prodrug" in the present description refers to a "PR" group in Formula (II), in the formula for the following reaction:
where each symbol is the same as the above, and the -OPR group is converted to the -OH group in Formula (III) by a decomposition reaction caused by metabolized enzymes from drugs, hydrolases, gastric acids, enterobacteria, etc. under physiological conditions in vivo.
[0024] The "PR group to form a prodrug" more preferably means a group that improves the bioavailability and / or AUC (area under the blood concentration curve) of the compound represented by Formula (III), when added to the compound represented by Formula (III).
[0025] Examples of the PR group for forming a prodrug include the groups described in Prog. Med. 5: 2157-2161 (1985) and provided by The British Library - "The world's Knowledge".
[0026] The "PR" group in the -OPR group in Formula (I) or (II) can be a group converted to a -OH group in vivo, and the examples preferably include a group selected from the following formulas a) to ac). a) -C (= O) -PR0, b) -C (= O) -PR1, c) -C (= O) -L-PR1, d) -C (= O) -LO-PR1, e) -C (= O) -LOLO-PR1, f) -C (= O) -LOC (= O) -PR1, g) -C (= O) -O-PR2, h) -C (= O) - N (-K) (PR2), i) -C (= O) -OLO-PR2, j) -C (PR3) 2-O-PR4, k) -C (PR3) 2-OLO-PR4, l) -C (PR3) 2-OC (= O) -PR4, m) -C (PR3) 2-OC (= O) -O-PR4, n) -C (PR3) 2-OC (= O) -N (-K) -PR4, o) -C (PR3) 2-OC (= O) -OLO-PR4, p) -C (PR3) 2-OC (= O) -OLN (PR4) 2, q) - C (PR3) 2-OC (= O) -N (-K) -LO-PR4, r) -C (PR3) 2-OC (= O) -N (-K) -LN (PR4) 2, s ) -C (PR3) 2-OC (= O) -OLOLO-PR4, t) -C (PR3) 2-OC (= O) -OLN (-K) -C (= O) -PR4, u) - C (PR3) 2-OP (= O) (- PR5) 2, v) -C (PR3) 2-PR6 (except for a benzyl group), w) -C (= N + (PR7) 2) (- N (PR7) 2), x) -C (PR3) 2-C (PR3) 2-C (= O) -O-PR2, y) -C (PR3) 2-N (-K) -C (= O ) -O-PR2, z) -P (= O) (- PR8) (- PR9), aa) -S (= O) 2-PR10, ab) -PR11 and ac) -C (PR3) 2-C (PR3) 2-O-PR2, where L is linear or branched alkylene or linear or branched alkenylen; K is hydrogen or alkyl optionally substituted with a substituent group A; PR0 is alkyl optionally substituted with a group A substituent or alkenyl optionally substituted with a group A substituent; PR1 is carbocyclyl group optionally substituted with a substituent group A, heterocyclyl group optionally substituted with a group A substituting, alkylamino optionally substituted with a group A substituting or alkylsulfanyl optionally substituted with a group A substituting; PR2 is alkyl optionally substituted with a substituting group A, carbocyclyl group optionally substituted with a substituting group A, heterocyclyl group optionally substituted with a substituting group A, carbocyclylalkyl optionally substituted with a substituting group A, heterocyclylalkyl optionally substituted with a substituting group A or trialkylsilyl; PR3 is each independently hydrogen or alkyl; PR4 is each independently alkyl optionally substituted with a substituting group A, carbocyclyl group optionally substituted with a substituting group A, heterocyclyl group optionally substituted with a substituting group A, alkylamino optionally substituted with a substituting group A, carbocyclylalkyl optionally substituted with a group A substituent, heterocyclylalkyl optionally substituted with a substituent group A or trialkylsilyl; PR5 is each independently hydroxy or OBn; PR6 is a carbocyclyl group optionally substituted with a substituting group A or heterocyclyl group optionally substituted with a substituting group A; PR7 is each independently alkyl optionally substituted with a substituent group A; PR8 is alkyloxy optionally substituted with a substituent group A; PR9 is alkyloxy optionally substituted with a substituting group A, alkylamino optionally substituted with a substituting group A, carbocyclyloxy optionally substituted with a substituting group A, heterocyclyloxy optionally substituted with a substituting group A, carbocyclylamino optionally substituted with a substituting or heterocyclylamino group optionally substituted with a substituent group A; PR8 and PR9 can be considered together with a phosphorus atom adjacent to form heterocycle optionally substituted with a substituent group A; PR10 is alkyl optionally substituted with a substituting group A, carbocyclyl group optionally substituted with a substituting group A, heterocyclyl group optionally substituted with a substituting group A, carbocyclylalkyl optionally substituted with a substituting group A or heterocyclylalkyl optionally substituted with a substituting group A ; PR11 is alkyl optionally substituted with a substituent group A, alkenyl optionally substituted with a group A substituting, carbocyclyl group optionally substituted with a group A substituting or heterocyclyl group optionally substituted with a group A substituting.
[0027] Substitute Group A; oxo, alkyl, hydroxyalkyl, amino, alkylamino al, carbociclila, heterocyclyl, carbociclilalquila, alkylcarbonyl, halogen, hydroxy, carboxy, alkylcarbonylamino, quila alquilcarbonilaminoal-, alkylcarbonyloxy, alquiloxicarbonila, alquiloxicarbonilalquila, alkylating loxicarbonilóxi, alkylaminocarbonyloxy, alkylaminoalkyl, alkyloxy, C year, nitro, azido, alkylsulfonyl, trialkylsilyl and phospho.
[0028] The PR group to form a prodrug is preferably a group selected from the following: a) -C (= O) -PR0, b) -C (= O) -PR1, g) -C (= O ) -O-PR2, h) -C (= O) -N (-K) (PR2), i) -C (= O) -OLO-PR2, l) -C (PR3) 2-OC (= O ) -PR4, m) -C (PR3) 2-OC (= O) -O-PR4, o) -C (PR3) 2-OC (= O) -OLO-PR4, v) -C (PR3) 2 -PR6 (except for a benzyl group), x) -C (PR3) 2-C (PR3) 2-C (= O) -O-PR2, y) -C (PR3) 2-N (-K) - C (= O) -O-PR2 and z) -P (= O) (- PR8) (- PR9), where L is a linear or branched alkylene; K is hydrogen or alkyl optionally substituted with a substituent group A; PR0 is alkyl optionally substituted with a substituent group A; PR1 is a carbocyclyl group optionally substituted with a substituting group A or heterocyclyl group optionally substituted with a substituting group A; PR2 is each independently alkyl optionally substituted with a substituting group A, carbocyclyl group optionally substituted with a substituting group A, heterocyclyl group optionally substituted with a substituting group A, carbocyclylalkyl optionally substituted with a substituting group A or optionally substituted heterocyclylalkyl with group A substituent; PR3 is each independently hydrogen or alkyl; PR4 is each independently alkyl optionally substituted with a substituting group A, carbocyclyl group optionally substituted with a substituting group A or heterocyclyl group optionally substituted with a substituting group A; PR6 is a carbocyclyl group optionally substituted with a substituting group A or heterocyclyl group optionally substituted with a substituting group A; PR8 is alkyloxy optionally substituted with a substituent group A; PR9 is alkyloxy optionally substituted with a substituting group A, alkylamino optionally substituted with a substituting group A, carbocyclyloxy optionally substituted with a substituting group A, heterocyclyloxy optionally substituted with a substituting group A, carbocyclylamino optionally substituted with a substituting or heterocyclylamino group optionally substituted with a substituent group A; and PR8 and PR9 can be considered together with a phosphorus atom adjacent to form heterocycle optionally substituted with a substituent group A.
[0029] Substitute Group A; oxo, alkyl, alkylamino, carbocyclyl, heterocyclyl, alkylcarbonyl, halogen, hydroxy, alkylcarbonylamino, alkylcarbonyloxy, alkyloxycarbonyl, alkyloxycarbonylalkyl, alkylaminocarbonyloxy, alkyloxy, nitro, azido, alkylsulfonyl and trialkyl.
[0030] "Converted to a prodrug" in the present description means that, as shown in the following reaction formula:
wherein each symbol is the same as the above, a hydroxy group in Formula (III), or its pharmaceutically acceptable salt, is converted to an -OPR group.
[0031] "Original compound" in the present description means a compound to serve as a source before synthesizing the "prodrug" and / or a compound released from the "prodrug" by reaction by enzymes, a gastric acid and the like, under physiological conditions in vivo, and specifically means a compound shown by Formula (III), or its pharmaceutically acceptable salt or a solvate thereof.
[0032] The term "halogen" includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. A fluorine atom and a chlorine atom are especially preferable.
The term "alkyl" includes a straight or branched C1 to C15 hydrocarbon group, preferably C1 to C10, more preferably C1 to C6 and most preferably C1 to C4. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl , n-octyl, iso-octyl, n-nonyl, n-decyl and the like.
[0034] A preferred embodiment of "alkyl" is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl or n-pentyl. A more preferred embodiment is methyl, ethyl, n-propyl, isopropyl or tert-butyl.
The term "alkenyl" includes a straight or branched C2 to C15 hydrocarbon group, preferably C2 to C10, more preferably C2 to C6 and still preferably C2 to C4 having one or more double bonds at any position. Examples include vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, propenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, dodecenyl, dodecenyl, dodecenyl, dodecenyl, dodecenyl , tetradecenyl, pentadecenyl and the like.
[0036] A preferred modality of "alkenyl" is vinyl, ally, propyl, isopropenyl or butenyl.
The term "alkylene" includes a linear or branched C1 to C15 bivalent hydrocarbon group, preferably C1 to C10, more preferably C1 to C6 and most preferably C1 to C4. Examples include methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene, hexamethylene and the like.
The term "alkenylene" includes a linear or branched C2 to C15 divalent hydrocarbon group, preferably C2 to C10, more preferably C2 to C6 and still preferably C2 to C4 having one or more double bonds at any position. Examples include vinylene, prenylene, butenylene, pentenylene and the like.
[0039] The term "hydroxyalkyl" means a group in which one or more hydroxyl groups replace the hydrogen atom (s) bonded to the above "alkyl" carbon atom (s). Examples include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 1,2-hydroxyethyl and the like.
[0040] A preferred embodiment of "hydroxyalkyl" is hydroxymethyl.
[0041] The term "alkyloxy" means a group in which the "alkyl" above is attached to an oxygen atom. Examples include methyloxy, ethyloxy, n-propyloxy, isopropyloxy, n-butyloxy, tert-butyloxy, isobutyloxy, sec-butyloxy, pentyloxy, isopentyloxy, hexyloxy and the like.
[0042] A preferred embodiment of "alkyloxy" is methyloxy, ethyloxy, n-propyloxy, isopropyloxy or tert-butyloxy.
[0043] The term "haloalkyl" means a group in which one or more "halogen" atoms described above are attached to the "alkyl" above. Examples include monofluoromethyl, monofluoroethyl, monofluoropropyl, 2,2,3,3,3-pentafluoropropyl, monochloromethyl, trifluoro-methyl, trichloromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichlorethyl, 1,2 -dibromo-ethyl, 1,1,1-trifluoropropan-2-yl and the like.
[0044] A preferred embodiment of "haloalkyl" is trifluoromethyl or trichloromethyl.
[0045] The term "alkylcarbonyl" means a group in which the above "alkyl" is attached to a carbonyl group. Examples include methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, tert-butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, pentylcarbonyl, iso-pentylcarbonyl, hexylcarbonyl and the like.
[0046] A preferred embodiment of "alkylcarbonyl" is methylcarbonyl, ethylcarbonyl or n-propylcarbonyl.
[0047] The term "alkylamino" means a group in which one or two hydrogen atoms attached to a nitrogen atom of an amino group is replaced by the "alkyl" above. The two alkyl groups can be the same or different. Examples include methylamino, ethylamino, isopropylamino, dimethylamino, diethylamino, N, N-diisopropylamino, N-methyl-N-ethylamino, N-isopropyl-N-ethylamino and the like.
[0048] A preferred embodiment of "alkylamino" is methylamino, ethylamino, dimethylamino or diethylamino.
[0049] The term "alkylaminoalkyl" means a group in which the above "alkylamino" is linked to the "alkyl" above.
[0050] The term "alkylaminocarbonyl" means a group in which the above "alkylamino" is attached to a carbonyl group.
[0051] The term "alkylaminocarbonyloxy" means a group in which the above "alkylaminocarbonyl" is attached to an oxygen atom.
[0052] The term "alkylcarbonylamino" means a group in which the "alkylcarbonyl" above replaces a hydrogen atom attached to a nitrogen atom of an amino group. Examples include methylcarbonylamino, ethylcarbonylamino, propylcarbonylamino, isopropylcarbonylamino, tert-butylcarbonylamino, isobutylcarbonylamino, sec-butylcarbonylamino and the like.
[0053] A preferred embodiment of "alkylcarbonylamino" is methylcarbonylamino or ethylcarbonylamino.
[0054] The term "alkylcarbonyloxy" means a group in which the "alkylcarbonyl" above is attached to an oxygen atom. Examples include methylcarbonyloxy, ethylcarbonyloxy, propylcarbonyloxy, isopropylcarbonyloxy, tert-butylcarbonyloxy, isobutylcarbonyloxy, sec-butylcarbonyloxy and the like.
[0055] A preferred embodiment of "alkylcarbonyloxy" is methylcarbonyloxy or ethylcarbonyloxy.
[0056] The term "alkylcarbonylaminoalkyl" means a group in which the above "alkylcarbonylamino" is linked to the "alkyl" above.
[0057] The term "alkyloxycarbonyl" means a group in which the above "alkyloxy" is attached to a carbonyl group. Examples include methyloxycarbonyl, ethyloxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl, tert-butyloxycarbonyl, isobutyloxycarbonyl, sec-butyloxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, hexyloxycarbonyl and the like.
[0058] A preferred embodiment of "alkyloxycarbonyl" is methyloxycarbonyl, ethyloxycarbonyl or propyloxycarbonyl.
[0059] The term "alkyloxycarbonylalkyl" means a group in which the "alkyloxycarbonyl" above is linked to the "alkyl" above.
[0060] The term "alkyloxycarbonyloxy" means a group in which the "alkyloxycarbonyl" above is attached to an oxygen atom.
[0061] The term "alkylsulfanyl" means a group in which the "alkyl" above replaces a hydrogen atom attached to a sulfur atom of a sulfanyl group. Examples include methylsulfanyl, ethylsulfanyl, n-propylsulfanyl, isopropylsulfanyl and the like.
[0062] The term "alkylsulfonyl" means a group in which the above "alkyl" is attached to a sulfonyl group. Examples include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, tert-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl and the like.
[0063] A preferred embodiment of "alkylsulfonyl" is methylsulfonyl or ethylsulfonyl.
[0064] The term "trialkylsilyl" means a group in which three of the "alkyl" above are attached to a silicon atom. The three alkyl groups can be the same or different. Examples include trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl and the like.
[0065] The term "carbocyclyl group" means a cyclic C3 to C20 hydrocarbon group, preferably C3 to C16, more preferably C4 to C12 and includes aromatic carbocyclyl and non-aromatic carbocyclyl.
[0066] The term "aromatic carbocyclyl" means an aromatic cyclic hydrocarbon group that is monocyclic or polycyclic having two or more rings. Examples include phenyl, naphthyl, anthryl, phenanthryl and the like.
[0067] A preferred embodiment of "aromatic carbocyclyl" is phenyl, 1-naphthyl or 2-naphthyl. Another modality of "aromatic carbocyclyl" is phenyl.
[0068] The term "non-aromatic carbocyclyl" means a saturated non-aromatic cyclic hydrocarbon group, which is monocyclic or polycyclic having two or more rings. Examples of "non-aromatic carbocyclyl", which is polycyclic with two or more rings, include a group of fused rings, in which a non-aromatic carbocyclyl, which is monocyclic or polycyclic with two or more rings, is fused with a " aromatic carbocyclyl "above.
[0069] In addition, examples of "non-aromatic carbocyclyl" also include a group with a bridge or a group that forms a spiro ring as follows:

[0070] The non-aromatic carbocyclyl which is monocyclic is preferably a C3 to C16 carbocyclyl, more preferably C3 to C12 and still preferably C3 to C8. Examples include cyclopropyl, cyclo-butyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclohexadienyl and the like.
[0071] Examples of non-aromatic carbocyclyl, which is polycyclic with two or more rings, include indanila, indenila, acenaftila, tetrahydronaftila, fluorenila and the like.
The term "carbocycle" means a cyclic C3 to C20 hydrocarbon, preferably C3 to C16, more preferably C4 to C12 and includes aromatic carbocycle and non-aromatic carbocycle.
[0073] The term "aromatic carbocycle" means a cyclic aromatic hydrocarbon that is monocyclic or polycyclic with two or more rings. Examples include benzene ring, naphthalene ring, anthra- cene ring, phenanthrene ring and the like.
[0074] A preferred modality of "aromatic carbocycle" is benzene ring and naphthalene ring. Another modality of "aromatic carbocycle" is benzene ring.
[0075] The term "non-aromatic carbocycle" means a saturated or unsaturated non-aromatic carbocycle that is monocyclic or polycyclic with two or more rings. Examples of the "non-aromatic carbocycle", which is polycyclic with two or more rings, include a fused ring in which a non-aromatic carbocycle, which is monocyclic or polycyclic with two or more rings, is fused with a ring of "aromatic carbocycle" above.
[0076] In addition, examples of the "non-aromatic carbocycle" also include a cycle with a bridge or a cycle that forms a spiro ring as follows:

The non-aromatic carbocycle which is monocyclic is preferably a C3 to C16 carbocycle, more preferably C3 to C12 and still preferably C3 to C8. Examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cycloane, cyclodecane, cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclohexadiene and the like.
[0078] Examples of non-aromatic carbocycle, which is polycyclic with two or more rings, include indane, indene, acenaphthalene, tetrahydronaphthalene, fluorine and the like.
[0079] The term "heterocyclyl group" includes an aromatic cyclyl and a non-aromatic heterocyclyl, which contains one or more heteroatoms selected independently from O, S and N.
[0080] The term "aromatic heterocyclyl" means an aromatic cyclyl, which is monocyclic or polycyclic with two or more rings, containing one or more heteroatoms independently selected from O, S and N. Examples of "aromatic heterocycly", which is polycyclic with two or more rings, includes a fused ring group, wherein an aromatic heterocyclyl, which is monocyclic or polycyclic with two or more rings, is fused with a "aromatic carbocyclyl" ring above.
[0081] Aromatic heterocyclyl, which is monocyclic, is preferably a 5- to 8-membered ring and more preferably 5 to 6-membered. Examples include pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiazolyl and thiazolyl and thiazolyl and thiazolyl and thiazolyl and thiazolyl and thiazolyl.
[0082] Examples of aromatic heterocyclyl, which is bicyclic, include indolyl, isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, cinolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purine-benzine, benzimidol, benzimidol , benzazoxadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzo-furyl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, tazolol, oxazolyl, oxazolyl, tazolol, oxazolyl, tyrolazole, oxazolyl, tyrolazole, oxazolyl, tyrolazole.
[0083] Examples of aromatic heterocyclyl, which is polycyclic with three or more rings, include carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxatinyl, phenoxazinyl, dibenzofuryl and the like.
[0084] The term "non-aromatic heterocyclyl" means a non-aromatic cyclyl, which is monocyclic or polycyclic with two or more rings, containing one or more heteroatoms independently selected from O, S and N. Examples of "non-aromatic heterocyclyl" ", which is polycyclic with two or more rings, includes a fused ring group, in which a non-aromatic heterocycle, which is monocyclic or polycyclic with two or more rings, is fused with an" aromatic carbocyclyl "ring, "non-aromatic carbocyclyl" and / or "aromatic heterocyclyl" above.
[0085] In addition, examples of "non-aromatic heterocyclyl" also include a group with a bridge or a group that forms a spiro ring as follows:

[0086] Non-aromatic heterocyclyl, which is monocyclic, is preferably a 3 to 8 membered ring and more preferably 5 to 6 membered. Examples include dioxanyl, tyranyl, oxiranyl, oxetanil, oxathiolanyl, azetidinyl, thianyl, thiazolidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, pipera-zinyl, morpholinyl, morpholinyl, morpholinyl, morpholine, morphine, morphine, morphine, morphine, morphine, morphine, morphine, chloride , tetrahydropyridinyl, tetrahydrofuryl, tetrahydropyranyl, dihydrothiazolinyl, tetrahydrothiazolinyl, tetrahydroisothiazolinyl, dihydroxoxinin, hexahydroazepinyl, tetrahydrodiazepinyl, tetrahydro-dioxin, dioxin, hydroxylidine, hydroxylidine, hydroxylidine , aziridinyl, dioxolinyl, oxepanyl, thiolanil, tinyl, thiazinyl and the like.
[0087] Examples of non-aromatic heterocyclyl, which is polycyclic with two or more rings, include indolinyl, isoindolinyl, chromanyl, isochromanyl and the like.
[0088] The term "heterocycle" includes an aromatic cycle and a non-aromatic heterocycle, which contains one or more heteroatoms selected independently from O, S and N.
[0089] The term "aromatic heterocycle" means an aromatic cycle, which is monocyclic or polycyclic with two or more rings, containing one or more heteroatoms independently selected from O, S and N. Examples of "aromatic heterocycle", which is polycyclic with two or more rings, includes a fused ring, wherein an aromatic heterocycle, which is monocyclic or polycyclic with two or more rings, is fused with a ring from the "aromatic carbocycle" above.
[0090] The aromatic heterocycle, which is monocyclic, is preferably a 5 to 8 membered ring and more preferably 5 to 6 membered. Examples include pyrrole, imidazole, pyrazole, pyridine, pyridazine, pyridine, pyrazine, triazole, triazine, tetrazole, furan, thiophene, isoxazole, oxazole, oxadiazole, isothiazole, thiazole, thiadiazole and the like.
[0091] Examples of aromatic heterocycle, which is bicyclic, include indoline, isoindoline, indazorin, indolizine, quinoline, isoquinoline, cinoline, phthalazine, quinazoline, naphthyridine, quinoxaline, purine, pertidine, benzimidazole, benzoxoxazole, benzoxoxazole, benzisoxazole, benzisoxazole, benzisoxazole. , benzoxadiazole, benzisothiazole, benzothiazole, benzothiadiazole, benzofuran, isobenzofuran, benzothiophene, benzotriazole, imidazopyridine, triazolopyridine, imidazothazole, pyrazinopyridazine, oxazolopyridine and similar thiazolopyridine and thiazolopyridine and thiazolopyridine.
[0092] Examples of aromatic heterocycle, which is polycyclic with three or more rings, include carbazole, acridine, xanthene, phenothiazine, phenoxatin, phenoxazine, dibenzofuran and the like.
[0093] The term "non-aromatic heterocycle" means a non-aromatic cycle, which is monocyclic or polycyclic with two or more rings, containing one or more heteroatoms selected independently from O, S and N. Examples of "non-aromatic heterocycle ", which is polycyclic with two or more rings, includes a fused ring, in which a non-aromatic heterocycle, which is monocyclic or polycyclic with two or more rings, is fused with a" aromatic carbocycle "," non-aromatic carbocycle "ring "and / or the" aromatic heterocycle "above.
[0094] In addition, examples of "non-aromatic heterocycle" also include a cycle with a bridge or a cycle that forms a spiro ring as follows:

[0095] The non-aromatic heterocycle, which is monocyclic, is preferably a 3 to 8 membered ring and more preferably 5 to 6 membered. Examples include dioxane, tyrane, oxirane, oxetane, oxatholone, azetidine, thio, thiazolidine, pyrrolidine, pyrroline, imidazolidine, imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine, morpholine, thio-morpholine, dihydropyridine, tetrahydrate -hydropyridine, tetrahydrofuran, tetrahydropyran, dihydrothiazoline, tetrahydrothiazoline, tetrahydroisothiazoline, dihydro-oxazine, hexahydroazepine, tetrahydrodiazepine, tetrahydropyridazine, hexahydroxine, dioxin, dioxin , dioxoline, oxepan, thiolane, thiazine and the like.
[0096] Examples of non-aromatic heterocycle, which is polycyclic with two or more rings, include indoline, isoindoline, chroman, isochroman and the like.
[0097] The "carbocycle" part of "carbocyclylalkyl", "carbocyclyloxy" or "carbocyclylamino" is the same as the "carbocycle" above.
[0098] The "heterocycle" part of "heterocyclylalkyl", "heterocyclyloxy" or "heterocyclylamino" is the same as the "heterocycle" above.
[0099] The present invention is characterized by the fact that the compound isolated by optical resolution of tricyclic compounds replaced by the other tricyclic group improves the cap-dependent en-donuclease inhibitory activity.
[00100] The present invention is also characterized by the fact that the present compound is efficiently absorbed by the body after administration (for example, oral administration), and that it shows high efficiency when introducing a PR group to form a propar- maco.
[00101] One or more atoms of hydrogen, carbon and / or others in the compounds of the present invention can be replaced by isotopes of hydrogen, carbon and / or other atoms respectively. Examples of isotopes include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine, such as 2H, 3H, 11C, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, 123I and 36Cl respectively. The compounds of the present invention include compounds substituted with such isotopes. Compounds substituted with the above isotopes are useful as medicaments and include all radiolabeled compounds of the compound of the present invention. A "radiolabeling method" in the production of "radiolabeled compounds" is encompassed by the present invention, and "radiolabeled compounds" are useful for studies on the pharmacokinetics of metabolized drugs, studies on binding assay and / or as diagnostic tools.
[00102] A radiolabeled compound of the present invention can be prepared using methods well known in the field of the invention. For example, a tritium-labeled compound of the present invention can be prepared by introducing tritium into a given compound of the present invention, through a catalytic halogenation reaction using tritium. This method comprises reacting a suitably halogenated precursor of the compound of the present invention with tritium gas in the presence of a suitable catalyst, such as Pd / C, and in the presence or absence of a base. The other suitable method for preparing a tritium-labeled compound that can be cited is "Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987)". A 14C-labeled compound can be prepared using a raw material containing 14C.
[00103] Pharmaceutically acceptable salts of the compounds of the present invention include, for example, alkali metal salts (for example, lithium, sodium, potassium and the like), alkaline earth metal (for example, calcium, barium or the like), magnesium, transition metal (for example, zinc, iron or the like), ammonia, organic bases (for example, trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, ethylenediamine, pyridine, picoline, quinoline or or amino acids, or salts with inorganic acids (for example, hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid or the like) or organic acids (for example, formic acid, acetic acid, propionic acid, trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid, mandelic acid, glutaric acid, malic acid, benzoic acid, f thalic acid, ascorbic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid or the like). Especially, salts with hydrochloric acid, sulfuric acid, phosphoric acid, tartaric acid, methanesulfonic acid and the like are included. These salts can be formed by the usual methods.
[00104] The compounds of the present invention or their pharmaceutically acceptable salts can form solvates (for example, hydrates or the like) and / or crystalline polymorphs. The present invention encompasses these various solvates and crystalline polymorphs. "Solvates" can be those in which any number of solvent molecules (e.g., water molecules or the like) are coordinated with the compounds of the present invention. When the compounds of the present invention or their pharmaceutically acceptable salts are left to stand in the atmosphere, the compounds can absorb water, resulting in the attachment of the adsorbed water or the formation of hydrates. Recrystallization of the compounds of the present invention or their pharmaceutically acceptable salts can produce crystalline polymorphs.
[00105] The PR group is preferably a group that is converted to an OH group by the action of metabolizing enzymes of drugs, hydrolases, gastric acids and / or enterobacteria, after in vivo administration (for example, oral administration).
[00106] Examples of the most preferred PR modalities include a group selected from the following formulas a) to ac). a) -C (= O) -PR0, b) -C (= O) -PR1, c) -C (= O) -L-PR1, d) -C (= O) -LO-PR1, e) -C (= O) -LOLO-PR1, f) -C (= O) -LOC (= O) -PR1, g) -C (= O) -O-PR2, h) -C (= O) - N (-K) (PR2), i) -C (= O) -OLO-PR2, j) -C (PR3) 2-O-PR4, k) -C (PR3) 2-OLO-PR4, l) -C (PR3) 2-OC (= O) -PR4, m) -C (PR3) 2-OC (= O) -O-PR4, n) -C (PR3) 2-OC (= O) -N (-K) -PR4, o) -C (PR3) 2-OC (= O) -OLO-PR4, p) -C (PR3) 2-OC (= O) -OLN (PR4) 2, q) - C (PR3) 2-OC (= O) -N (-K) -LO-PR4, r) -C (PR3) 2-OC (= O) -N (-K) -LN (PR4) 2, s ) -C (PR3) 2-OC (= O) -OLOLO-PR4, t) -C (PR3) 2-OC (= O) -OLN (-K) -C (= O) -PR4, u) - C (PR3) 2-OP (= O) (- PR5) 2, v) -C (PR3) 2-PR6 (except for a benzyl group), w) -C (= N + (PR7) 2) (- N (PR7) 2), x) -C (PR3) 2-C (PR3) 2-C (= O) -O-PR2, y) -C (PR3) 2-N (-K) -C (= O ) -O-PR2, z) -P (= O) (- PR8) (- PR9), aa) -S (= O) 2-PR10, ab) -PR11 and ac) -C (PR3) 2-C (PR3) 2-O-PR2, where L is linear or branched alkylene or linear or branched alkenylen; K is hydrogen or alkyl optionally substituted with a substituent group A; PR0 is alkyl optionally substituted with a group A substituent or alkenyl optionally substituted with a group A substituent; PR1 is carbocyclyl group optionally substituted with a substituent group A, heterocyclyl group optionally substituted with a group A substituting, alkylamino optionally substituted with a group A substituting or alkylsulfanyl optionally substituted with a group A substituting; PR2 is alkyl optionally substituted with a substituting group A, carbocyclyl group optionally substituted with a substituting group A, heterocyclyl group optionally substituted with a substituting group A, carbocyclylalkyl optionally substituted with a substituting group A, heterocyclylalkyl optionally substituted with a substituting group A or trialkylsilyl optionally substituted with the substituting Group A; PR3 is each independently hydrogen or alkyl; PR4 is each independently alkyl optionally substituted with a substituting group A, carbocyclyl group optionally substituted with a substituting group A, heterocyclyl group optionally substituted with a substituting group A, amino alkyl optionally substituted with a substituting group A, carbocyclylalkyl optionally substituted with a group The substituent, heterocyclylalkyl optionally substituted with a substituent group A or trialkylsilyl; PR5 is each independently hydroxy or OBn; PR6 is a carbocyclyl group optionally substituted with a substituent group A, or heterocyclyl group optionally substituted with a group A substituent; PR7 is each independently alkyl optionally substituted with a substituent group A; PR8 is alkyloxy optionally substituted with a substituent group A; PR9 is alkyloxy optionally substituted with a substituting group A, alkylamino optionally substituted with a substituting group A, carbocyclyloxy optionally substituted with a substituting group A, heterocyclyloxy optionally substituted with a substituting group A, carbocyclylamino optionally substituted with a substituting or heterocyclylamino group optionally substituted with a substituent group A; PR8 and PR9 can be considered together with a phosphorus atom adjacent to form heterocycle optionally substituted with a substituent group A; PR10 is alkyl optionally substituted with a substituting group A, carbocyclyl group optionally substituted with a substituting group A, heterocyclyl group optionally substituted with a substituting group A, carbocyclylalkyl optionally substituted with a substituting group A or heterocyclylalkyl optionally substituted with a substituting group A ; PR11 is alkyl optionally substituted with a substituent group A, alkenyl optionally substituted with a group A substituting, carbocyclyl group optionally substituted with a group A substituting or heterocyclyl group optionally substituted with a group A substituting.
[00107] Substitute Group A; oxo, alkyl, hydroxyalkyl, amino, alkylamino al, carbociclila, heterocyclyl, carbociclilalquila, alkylcarbonyl, halogen, hydroxy, carboxy, alkylcarbonylamino, quila alquilcarbonilaminoal-, alkylcarbonyloxy, alquiloxicarbonila, alquiloxicarbonilalquila, alkylating loxicarbonilóxi, alkylaminocarbonyloxy, alkylaminoalkyl, alkyloxy, C year, nitro, azido, alkylsulfonyl, trialkylsilyl and phospho.
[00108] Examples of the most preferred PR modalities include the following groups: a) -C (= O) -PR0, b) -C (= O) -PR1, g) -C (= O) -O-PR2 , H) -C (= O) -N (-K) (PR2), i) -C (= O) -OLO-PR2, l) -C (PR3) 2-OC (= O) -PR4, m ) -C (PR3) 2-OC (= O) -O-PR4, o) -C (PR3) 2-OC (= O) -OLO-PR4, v) -C (PR3) 2-PR6 (except for a benzyl group), x) -C (PR3) 2-C (PR3) 2-C (= O) -O-PR2, y) -C (PR3) 2-N (-K) -C (= O) -O-PR2 and z) -P (= O) (- PR8) (- PR9), where L is a linear or branched alkylene; K is hydrogen or alkyl optionally substituted with a substituent group A; PR0 is alkyl optionally substituted with a substituent group A; PR1 is a carbocyclyl group optionally substituted with a substituting group A or heterocyclyl group optionally substituted with a substituting group A; PR2 is alkyl optionally substituted with a substituting group A, carbocyclyl group optionally substituted with a substituting group A, heterocyclyl group optionally substituted with a substituting group A, carbocyclylalkyl optionally substituted with a substituting group A or heterocyclylalkyl optionally substituted with a substituting group A ; PR3 is each independently hydrogen or alkyl; PR4 is alkyl optionally substituted with a substituting group A, carbocyclyl group optionally substituted with a substituting group A or heterocyclyl group optionally substituted with a substituting group A; PR6 is a carbocyclyl group optionally substituted with a substituting group A or heterocyclyl group optionally substituted with a substituting group A; PR8 is alkyloxy optionally substituted with a substituent group A; PR9 is alkyloxy optionally substituted with a substituting group A, alkylamino optionally substituted with a substituting group A, carbocyclyloxy optionally substituted with a substituting group A, heterocyclyloxy optionally substituted with a substituting group A, carbocyclylamino optionally substituted with a substituting or heterocyclylamino group optionally substituted with a substituent group A; and PR8 and PR9 can be considered together with a phosphorus atom adjacent to form heterocycle optionally substituted with a substituent group A.
[00109] Substitute Group A; oxo, alkyl, alkylamino, carbocyclyl, heterocyclyl, alkylcarbonyl, halogen, hydroxy, alkylcarbonylamino, alkylcarbonyloxy, alkyloxycarbonyl, alkyloxycarbonylalkyl, alkylaminocarbonyloxy, alkyloxy, nitro, azido, alkylsulfonyl and trialkyl.
[00110] Examples of another embodiment of a preferred PR substituent include the following groups:
Method for Producing the Compound of the Present Invention
[00111] A general method for producing the compound of the present invention will be exemplified below. As for extraction and purification, the treatment that is carried out in a normal organic chemistry experiment can be conducted.
[00112] The synthesis of the compound of the present invention can be carried out with reference to procedures known in the field.
[00113] As a raw material compound, commercially available compounds, compounds described in the present description, compounds described in the references cited in this description and other known compounds can be used.
[00114] When it is desired to obtain a salt of the compound of the present invention, in the case where the compound of the present invention is obtained in the form of a salt, it can be purified in the state it is in and, in the case where the compound of the present invention is obtained in free form, a salt can be formed by a normal method, by dissolving or suspending the compound in a suitable organic solvent and adding an acid or a base.
[00115] Furthermore, the compound of the present invention and its pharmaceutically acceptable salts are present in the form of adducts with water or various solvents (hydrate or solvate) in some cases, and these adducts are included in the present invention.
[00116] In a synthesis method, as well as in Reference examples, Examples and Examples of Synthesis of Intermediates, the meaning of each abbreviation is as follows: Boc: tert-butoxycarbonyl DBU: diazabicycloundecene DMA: N, N -dimethylacetamide DMF: N, N-dimethylformamide HATU: O- (7-azabenzotriazol-1-yl) hexafluorophosphate -N, N, N ', N'- tetramethyluronium NMP: N-methylpyrrolidone OBn: benzyloxy THF: tetra-hydrofuran : propyl phosphonic anhydride WSC- HCl: N-ethyl-N 'hydrochloride - (3-dimethylaminopropyl) carbodiimide
[00117] The up and down part of the "wedge" and the "dotted line wedge" indicate the absolute configuration. (Preparation 1)
where P1 is a hydroxyl protecting group; RP is an acetal protecting group; L is a starting group; the other symbols are the same as the ones above. First step
[00118] Compound A3 can be obtained by adding Compound A2 to Compound A1 in the presence of a dehydrating-condensing agent such as dicyclohexylcarbodiimide, carbonyldiimidazole, dicyclohexylcarbodiimido-N-hydroxybenzotriazole, 4- (4,6,6 -dimethoxy- 1,3,5-triazin-2-yl) -4-methylmorpholine, hexafluorophosphoric acid-2- (7-aza- 1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium, WSC 'HCl, HATU, etc. in a solvent such as DMF, THF, dichloromethane, acetonitrile, etc., or in a mixed solvent of these, and carrying out a reaction of -20 ° C to 60 ° C, preferably -10 ° C to 40 ° C for 0.1 hour to 24 hours, preferably one hour to 12 hours.
Alternatively, Compound A3 can be obtained by adding an acylating reagent such as diphenylchlorophosphate, thionyl chloride, oxalyl chloride, etc. to Compound A1 in the presence or absence of a base such as pyridine, triethylamine, diisopropylethylamine, 1-methylimidazole, etc. in the presence of a solvent such as THF, dioxane, dichloromethane, DMF, etc., thus generating acid chloride and adding Compound A2 containing a substituent corresponding to an objective compound and carrying out a reaction of -20 ° C to 60 ° C, preferably -10 ° C to 40 ° C for 0.1 hour to 24 hours, preferably 0.5 hour to 12 hours. Second stage
[00120] Compound A4 can be obtained by adding potassium carbonate, sodium carbonate and O- (2,4-dinitrophenyl) hydroxylamine to Compound A3 in the presence of a solvent such as DMF, DMA, NMP, THF, etc., and performing a reaction of 10 ° C to 60 ° C, preferably 20 ° C to 40 ° C for 0.1 hour to 48 hours, preferably one hour to 24 hours. Third Stage
[00121] A deprotection reaction of a compound acetal protecting group of Compound A4 can be carried out by the general method described in Protective Groups in Organic Synthesis, Theodora W Green (John Wiley & Sons), etc. After that, a generated aldehyde group is subjected to an intramolecular reaction, thus obtaining Compound A5.
[00122] For example, the racemate of Compound A5 can be obtained by adding acetic acid and / or para-toluenesulfonic acid, methanesulfonic acid, etc., to Compound A4 in the presence of a solvent such as DMF, toluene, THF, etc., and carrying out a reaction of 10 ° C to 80 ° C, preferably 30 ° C to 60 ° C for 0.5 hour to 12 hours, preferably one hour to 6 hours. Compound A5 can be obtained by optical resolution of Compound A5 racemate by SFC or HPLC (chiral column). Fourth Stage
[00123]
[00124] Compound A7 can be obtained by adding Compound A6 and a base, such as sodium carbonate, potassium carbonate, cesium carbonate, etc., to Compound A5 in the presence of a solvent, such as DMF, DMA, NMP, THF , etc. or in a mixed solvent of these, and carrying out a reaction of 0 ° C to 60 ° C, preferably 10 ° C to 40 ° C for 0.1 hour to 48 hours, preferably one hour to 24 hours.
[00125] Alternatively, Compound A7 can be obtained by adding Compound A6 and T3P, methanesulfonic acid or para-toluene sulfonic acid to Compound A5 in the presence of a solvent, such as DMF, ethyl acetate, butyl acetate, 1,4- dioxane, etc. or in a mixed solvent of these, and carrying out a reaction of 40 ° C to 150 ° C, preferably 60 ° C to 120 ° C for 0.1 hour to 48 hours, preferably one hour to 24 hours Fifth Stage
[00126] A deprotection reaction of the hydroxyl protecting group of Compound A7 can be carried out by the general method described in Protective Groups in Organic Synthesis, Theodora W Green (John Wiley & Sons), etc. Sixth Stage
[00127] Compound (III) can be obtained by the general method including converting a hydroxyl group of Compound (II) to an ester group or ether group.
[00128] For example, one can use the method described in Protective Groups in Organic Synthesis, Theodora W Green (John Wiley & Sons), Prog. Med. 5: 2157-2161 (1985), and provided by The British Library - "The world's Knowledge", etc. (Preparation 2)
where P2 is an NH protecting group; L1 and L2 are a starting group; each other symbol is the same as the above. First step
[00129] Compound B2 can be obtained by adding Compound A2 and halogenated alkyl, such as methyl iodide, to Compound B1 in the presence of a base, such as diazabicycloundecene, in a solvent such as DMF, THF, dichloromethane, acetonitrile, etc., or in a mixed solvent of these, and carrying out a reaction of -20 ° C to 60 ° C, preferably -10 ° C to 40 ° C for 0.1 hour to 24 hours, preferably one hour to 24 hours.
Alternatively, Compound B2 can be obtained by adding an acylating reagent, such as diphenylchlorophosphate, thionyl chloride, oxalyl chloride, etc., to Compound B1 in a solvent, such as THF, dioxane, dichloromethane, DMF, etc. or in a mixed solvent of these, and adding alcohol in the presence of a base, such as pyridine, triethylamine, diisopropylethylamine, 1-methylimidazole, etc., and carrying out a reaction of -20 ° C to 60 ° C, preferably -10 ° C at 40 ° C for 0.1 hour to 24 hours, preferably 0.5 hour to 12 hours. Second stage
[00131] Compound B3 can be obtained by adding para-toluenesulfonic acid, pyridinium and hydrazine protected by Boc, etc., to Compound B2 in a solvent, such as THF, dioxane, dichloromethane, DMF, etc., or in a mixed solvent of these , and carrying out a reaction of 10 ° C to 150 ° C, preferably 40 ° C to 100 ° C for one hour to 48 hours, preferably one hour to 24 hours. Third Stage
[00132] A deprotection reaction of the amino protecting group of Compound B3 can be carried out by the general method described in Pro-tective Groups in Organic Synthesis, Theodora W Green (John Wiley & Sons), etc. Fourth Stage
[00133] Compound B6 can be obtained by adding a base, such as n-butyl lithium, etc. to Compound B5 in a solvent, such as THF, dioxane, dichloromethane, DMF, etc., or in a mixed solvent of these, and then adding alkyl haloformic acid and carrying out a reaction for 0.1 hour to 48 hours, preferably one hour to 24 hours. Fifth Stage
[00134] Compound B7 can be obtained by adding a reducing agent, such as diisobutylaluminum hydride and lithium, etc. to Compound B6 in a solvent such as THF, dioxane, dichloromethane, DMF, etc., or in a mixed solvent of these, and carrying out a reaction for 0.1 hour to 48 hours, preferably one hour to 24 hours. Sixth Stage
[00135] Compound B8 can be obtained by adding para-toluene sulfonic acid or methanesulfonic acid to Compound B7 in alcohol and carrying out a reaction from 0 ° C to 100 ° C for 0.1 hour to 48 hours, preferably one hour to 24 hours hours. Seventh Stage
[00136] Compound B10 can be obtained by adding alkyl haloformic acid to Compound B9 in the presence or absence of a base such as pyridine, triethylamine, diisopropylethylamine, 1-methylimidazole, etc., in a solvent such as THF, dioxane, dichloromethane, DMF, etc. ., or in a mixed solvent of these, and carrying out a reaction of -40 ° C to 40 ° C for 0.1 hour to 48 hours, preferably one hour to 24 hours. Eighth Stage
[00137] Compound B8 can be obtained by immersing a carbon electrode (anode) and a platinum electrode (cathode) in Compound B10 in a solvent such as alcohol in the presence of a base such as potassium carbonate and tetraethylamine perchlorate, and passing a constant current of 0.1 ~ 1.0 A with agitation for 0.1 hour to 48 hours, preferably one hour to 24 hours. Ninth to Tenth Stage
[00138] Compound (I) can be obtained from Compound B4 and B8 in the same way as in the third to sixth stage of preparation 1
[00139] The compound of the present invention exhibits cap-dependent endonuclease inhibitory activity and is useful as a therapeutic or preventive agent for influenza.
[00140] The compound of the present invention not only exhibits cap-dependent endonuclease inhibitory activity, but is also useful as a medicine, in addition to having all or any of the following excellent characteristics: a) The compound is a weak inhibitor of CYP enzymes ( for example, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4 and the like). b) The compound shows good pharmacokinetics, such as high bioavailability, moderate clearance and the like. c) The compound has high metabolic stability. d) The compound has no irreversible inhibitory action against CYP enzymes (for example, CYP3A4) when the concentration is within the range described in the present description as the measurement conditions. e) The compound does not exhibit mutagenicity. f) The compound is associated with low cardio-vascular risk. g) The compound has high solubility. h) The compound has no phototoxicity.
[00141] For the purpose of treating the diseases mentioned above in humans, the compounds of the present invention can be administered orally as a powder, granule, tablets, capsules, pills, a liquid and the like, or parenterally as an injectable , suppositories, a percutaneous drug, an inhalant and the like. Effective doses of the present compounds can be mixed with excipients suitable for the pharmaceutical form, such as fillers, binders, humectants, disintegrants and lubricants, as appropriate, to form pharmaceutical preparations. To prepare an injectable, sterilization is performed with a suitable vehicle.
[00142] The pharmaceutical compositions according to the present invention can be administered orally or parenterally. For oral administration, commonly used dosage forms, such as tablets, granules, powders and capsules, can be prepared according to conventional methods. For parenteral administration, any commonly used dosage form, such as an injectable, can be used appropriately. The compounds according to the present invention can be suitably used as oral preparations because they exhibit a high oral absorption capacity.
[00143] Effective doses of the compounds of the present invention can be mixed with various pharmaceutical excipients suitable for the pharmaceutical form, such as fillers, binders, disintegrants and lubricants, as appropriate, to form pharmaceutical compositions.
[00144] The dose depends on the condition of the disease, the route of administration or the age or weight of the patient. The usual oral dose for adults is 0.1 to 100 mg / kg per day, preferably 1 to 20 mg / kg per day.
[00145] The dose of the pharmaceutical composition of the present invention is preferably determined based on the age and weight of the patient, the type and severity of the disease, the route of administration and similar factors. The usual oral dose for adults is in the range of 0.05 to 100 mg / kg per day, preferably 0.1 to 10 mg / kg per day. The parenteral dose for adults varies significantly depending on the route of administration, but is usually in the range of 0.005 to 10 mg / kg per day, preferably 0.01 to 1 mg / kg per day. The dose can be administered once a day or can be divided into multiple daily doses.
[00146] The compound of the present invention can be used in combination with other drugs or the like (hereinafter referred to as combined drugs) to increase the activity of the compound, reduce the dose of the compound, or the like. In the case of treating influenza, the compound can be used in combination or in a formulation coupled with a neuraminidase inhibitor (for example, Oseltamivir, Zanamivir, Peramivir, Inabiru and the like); RNA-dependent RNA polymerase inhibitor (for example, Favipiravir); M2 protein inhibitor (for example, Amantadine); inhibitor of PB2 binding to Cap (for example, VX-787); anti-HA antibody (for example, MHAA4549A); immune agonists (eg, Nitazoxanide) are also possible. In that case, the timing of administration of a compound of the present invention and the combined drug is not limited. They can be administered to individuals to be treated at a time or at different times. In addition, a compound of the present invention and the combined drug can be administered as two or more formulations, which independently comprise each active ingredient, or a single formulation comprising each active ingredient.
[00147] The dose of the combined drugs can be selected appropriately in reference to the clinical dose. The composition ratio between the compounds of the present invention and the drugs administered can be appropriately selected, depending on the individual to be treated, the route of administration, the disease to be treated, the symptoms, the combination of drugs and similar factors . For administration to humans, for example, 1 mass part of the compounds of the present invention can be used in combination with 0.01 to 100 mass parts of the coadministered drugs.
[00148] The present invention will be explained in more detail below by way of Examples, Reference examples, Examples of Synthesis of Intermediates, as well as Test Examples of the present invention, however, the present invention is not limited by them.
[00149] The analysis by nuclear magnetic resonance (NMR) obtained in each reference example and example was performed at 300 MHz, and measured using DMSO-d6, CDCl3.
[00150] The term RT represents a retention time in LC / MS: liquid chromatography / mass spectrometry, and was measured under the following conditions. Measurement Conditions (1) Column: ACQUITY UPLC (Trademark) BEH C18 (1.7 μm, internal diameter 2.1 x 50 mm) (Waters) Flow rate: 0.8 mL / minute UV wavelength for detection: 254 nm Mobile phase: [A]: aqueous solution containing 0.1% formic acid, [B]: acetonitrile solution containing 0.1% formic acid Gradient: linear solvent gradient from 5% to 100% [B] in 3.5 minutes, and 100% solvent [B] was maintained for 0.5 minutes. (2) Column: Shim-pack XR-ODS (2.2 μm, internal diameter 50 x 3.0 mm) (Shimadzu) Flow rate: 1.6 mL / minute UV wavelength for detection: 254 nm Mobile phase: [A]: aqueous solution containing 0.1% formic acid, [B]: acetonitrile solution containing 0.1% formic acid Gradient: linear gradient of the solvent from 10% to 100% [B] carried out in 3 minutes, and solvent 100% [B] was maintained for 0.5 minutes.
First step
[00151] To a solution of Compound 1 (5.0 g, 49.5 mmols) in THF (100 ml), n-butyllithium 1.62 mol / L in hexane (30.5 ml, 49.5 mmols) dropwise at -78 ° C under nitrogen atmosphere, and the mixture was stirred at -78 ° C for two hours. A solution of allyl chloroformate (5.96 g, 49.5 mmols) in THF (20 ml) was added dropwise, and the mixture was stirred at -78 ° C for two hours. The mixture was cooled quickly with a saturated aqueous solution of ammonium chloride, warmed to room temperature and extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain Compound 2 (5.66 g, 62%). 1H NMR (CDCl3) δ: 3.83 (t, J = 8.0 Hz, 2H), 3.92 (t, J = 8.0 Hz, 2H), 4.26 (s, 2H), 4, 78 (d, J = 8.0 Hz, 2H), 5.30 (d, J = 12.0 Hz, 1H), 5.44 (d, J = 16 Hz, 1H), 5.93- 6.03 (m, 1H). Second stage
[00152] To a solution of Compound 2 (6.6 g, 35.6 mmols) in THF (66 mL), DIBAL-H 1.03 mol / L in hexane (45.0 mL, 46.3 mmols) dropwise, and the mixture was stirred at -78 ° C for one hour. The mixture was quenched with acetone and an aqueous solution of the Rochelle salt was added. The mixture was stirred and extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain Compound 3 (6.21 g, 93%). 1H NMR (CDCl3) δ: 3.44 (br, 1H), 3.50-3.64 (m, 2H), 3.71 (br, 1H), 3.95 (d, J = 8.0 Hz , 2H), 4.64 (d, J = 8.0 Hz, 2H), 5.24 (d, J = 12.0 Hz, 1H), 5.40 (d, J = 16.0 Hz, 1H ), 5.47 (d, J = 4 Hz, 1H), 5.87-6.00 (m, 1H). Third Stage
[00153] To a solution of Compound 3 (6.2 g, 33.1 mmol) in methanol (65 mL), p-toluenesulfonic acid monohydrate (0.63 g, 3.31 mmol) was added, and the mixture was stirred at room temperature overnight. The mixture was cooled quickly with an aqueous solution of sodium hydrogen carbonate, concentrated and extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain Compound 4 (5.77 g, 87%). 1H NMR (CDCl3) δ: 3.34 (s, 3H), 3.55 (br, 2H), 3.73-3.99 (m, 3H), 4.64 (d, J = 8.0 Hz , 2H), 5.10-5.20 (m, 1H), 5.25 (d, J = 8.0 Hz, 1H), 5.33 (d, J = 16 Hz, 1H), 5.88 -6.05 (m, 1H). Fourth Stage
[00154] To a solution of Compound 5 (20.0 g, 81 mmols) in DMF (100 ml), ethyl iodide (22.8 g, 146 mmols) and diazabicycloundecene (18.4 ml, 122 mmols), and the mixture was stirred at room temperature overnight. The mixture was poured into 10% aqueous ammonium chloride solution and extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain Compound 6 (22.3 g, 100%). 1H NMR (CDCl3) δ: 1.23 (t, J = 8.0 Hz, 3H), 4.28 (q, J = 8.0 Hz, 2H), 5.16 (s, 2H), 6, 57 (d, J = 4.0 Hz, 1H), 7.28-7.48 (m, 5H), 8.21 (d, J = 4.0 Hz, 1H). Fifth Stage
[00155] To a solution of Compound 6 (500 mg, 1.82 mmol) in DMA (5.0 mL), pyridinium p-toluenesulfonate (1.37 g, 5.47 mmol) and Boc-hydrazine were added (361 mg, 2.74 mmols), and the mixture was stirred at 60 ° C for 14 hours. To the mixture, water was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with a saturated aqueous solution of ammonium chloride and brine, dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound 7 (519 mg, 73%). 1H NMR (CDCl3) δ: 1.24 (t, J = 8.0 Hz, 3H), 1.46 (s, 9H), 4.26 (q, J = 8.0 Hz, 2H), 5, 28 (s, 2H), 6.40 (d, J = 8.0 Hz, 1H), 7.27-7.38 (m, 4H), 7.40-7.45 (m, 2H). Sixth Stage
[00156] Compound 7 (500 mg, 1.29 mmol) was dissolved in 4 mol / L hydrogen chloride in ethyl acetate (5 mL), and the mixture was stirred at room temperature for one hour. The mixture was concentrated under reduced pressure. To the residue obtained, a saturated aqueous solution of sodium hydrogen carbonate was added, and the mixture was extracted with dichloromethane. The obtained organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain Compound 8 (369 mg, 99%). 1H NMR (CDCl3) δ: 1.26 (t, J = 8.0 Hz, 3H), 4.31 (q, J = 8.0 Hz, 2H), 5.24 (s, 2H), 6, 47 (d, J = 8.0, 1H), 7.28-7.44 (m, 5H), 7.64 (d, J = 8.0, 1H). Seventh Stage
[00157] To a solution of Compound 8 (365 mg, 1.27 mmol) and Compound 4 (306 mg, 1.52 mmol) in acetonitrile (8 mL) was added tin chloride (0.223 mL, 1.90 mmol) dropwise at -25 ° C under nitrogen atmosphere, and the mixture was stirred at -25 ° C for 45 minutes. The mixture was quenched with a saturated aqueous solution of sodium hydrogen carbonate and dichloromethane was added. The mixture was stirred at room temperature and filtered through Celite, and the filtrate was extracted with dichloromethane. The obtained organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain crude Compound 9. The obtained Compound 9 was dissolved in THF (8 ml), morpholine (1.10 ml, 12.7 mmols), tetrakis (triphenylphosphine) palladium (146 mg, 0.127 mmol) was added thereto, and the mixture was stirred at room temperature for two hours. To the mixture, diethyl ether (16 ml) was added, and the precipitated solid was filtered and dried to obtain Compound 10 (418 mg, 100%). 1H NMR (CDCl3) δ: 2.90-2.99 (m, 1H), 3.13 (t, J = 12.0 Hz, 1H), 3.403.46 (m, 1H), 4.00-4 , 08 (m, 1H), 4.14 (d, J = 12.0 Hz, 1H), 5.07 (s, 2H), 6.22 (d, J = 8.0 Hz, 1H), 7 , 29-7.40 (m, 3H), 7.56 (d, J = 8.0 Hz, 2H), 7.71 (d, J = 8.0 Hz, 1H). Eighth Stage
[00158] To a suspension of (R) -2-tetrahydrofuric acid (855 mg, 7.36 mmol) and Compound 10 (2.00 g, 6.11 mmol) in ethyl acetate (9 mL), pyridine (4.00 ml, 49.6 mmols) and T3P (50% in ethyl acetate, 11.0 ml, 18.5 mmols) were added at room temperature, and the mixture was stirred overnight. The precipitated solid was filtered and washed with ethyl acetate (4 ml) and ethanol (4 ml). The obtained solid was suspended in ethanol (6 ml) and the suspension was stirred at room temperature for 6.5 hours. The suspension was filtered and the obtained solid was washed with ethanol (2 ml) twice to obtain Compound 11 (1.18 g, 45.4%). 1H NMR (DMSO) δ: 1.80-1.94 (m, 2H), 1.95-2.14 (m, 2H), 3.21-3.35 (m, 2H), 3.50- 3.60 (m, 1H), 3.70-3.82 (m, 3H), 4.00-4.05 (m, 1H), 4,324.38 (m, 1H), 5.14 (dd, J = 10.8 Hz, 21.6 Hz, 2H), 5.76-5.81 (m, 1H), 6.29 (d; J = 4.8 Hz, 1H), 7.28-7, 39 (m, 3H), 7.48-7.54 (m, 2H), 7.64-7.75 (m, 1H). Ninth Stage
[00159] To a suspension of Compound 11 (500 mg, 1.18 mmol) in ethanol (3.5 mL), DBU (0.0035 mL, 0.023 mmol) was added at room temperature, and the mixture was stirred for 30 minutes. To the suspension obtained, diisopropyl ether (6.5 ml) was added, and the mixture was stirred at room temperature for 30 minutes. The precipitated solid was filtered and washed with ethyl acetate (1.5 ml) twice to obtain Compound i1 (346 mg, 89.9%). 1H NMR (DMSO) δ: 2.80-3.00 (m, 1H), 3.10-3.18 (m, 1H), 3.38-3.50 (m, 1H), 3.98- 4.08 (m, 2H), 4.10-4.20 (m, 1H), 4.76-4.84 (m, 1H), 5.045.14 (m, 2H), 6.22 (m, J = 7.6 Hz, 1H), 7.27-7.40 (m, 4H), 7.56-7.60 (m, 2H), 7.70 (d, J = 7.6 Hz, 1H ).
First step
[00160] To a suspension of Compound 13 (8.0 g, 50.8 mmol) in dichloromethane (120 mL), triethylamine (17.6 mL, 127 mmol) was added in an ice-water bath, allyl chloroformate ( 6.44 ml, 60.9 mmols) was added dropwise and the mixture was stirred at 0 ° C for one hour. To the mixture, water was added, and the mixture was extracted with dichloromethane. The obtained organic layer was washed with a 5% aqueous solution of citric acid and a saturated aqueous solution of sodium hydrogencarbonate, dried with anhydrous magnesium sulfate and was concentrated under reduced pressure to obtain Compound 14 (10.1 g, 97 %). 1H NMR (CDCl3) δ: 1.96 (br, 4H), 3.62 (s, 4H), 4.60 (s, 2H), 5.22 (d, J = 12.0 Hz, 1H), 5.30 (d, J = 16.0 Hz, 1H), 5.86-5.99 (m, 1H). Second stage
[00161] To a solution of Compound 14 (0.9 g, 4.39 mmol), potassium carbonate (60 mg, 0.44 mmol) and tetraethylammonium perchlorate (50 mg, 0.22 mmol) in methanol (30 mL), a carbon electrode (anode) and a platinum electrode (cathode) were immersed, and a constant current of 0.1 A was passed into the mixture with stirring at room temperature for 6 hours. To the mixture, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The obtained organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain Compound 15 (992 mg, 96%). 1H NMR (CDCl3) δ: 1.81 - 2.15 (m, 3H), 2.39 (t, J = 12.0 Hz, 1H), 3.27 (s, 3H), 3.61 (s , 1H), 4.11 (br, 1H), 4.61 (br, 2H), 5.20-5.36 (m, 2H), 5.57 (br, 1H), 5.88-5, 99 (m, 1H). Third Stage
[00162] Compound 16 was obtained in the same way as in the seventh and eighth stages in Reference Example 1. Fourth Stage
[00163] The optical resolution of Compound 16 (870 mg, 2.41 mmols) by the Waters SFC30 System (Daicel CHIRALPAK IB, liquefied carbon dioxide-methanol) provided Compound i2 (270 mg, 31%). Analytical Conditions Waters System SFC30 (SPRC4-5N406) Column: CHIRALPAK IB / SFC (5 μm, internal diameter 250 x 4.6 mm) (DAICEL) Flow rate: 8.0 mL / minute; UV wavelength for de-protection: 254 nm Back pressure: 100 bar (10 MPa) Mobile phase: [A]: liquefied carbon dioxide, [B]: methanol Gradient: 5% solvent [B] was maintained for 1 minute , a linear gradient of the solvent 5% to 40% [B] was performed in 6 minutes, solvent 40% [B] was maintained for 2 minutes and solvent 5% [B] was maintained for 1 minute. Elution time: 7.3 minutes.
Reference Example 3 OMe OBn O Boc H 24 First Stage
[00164] To a solution of Compound 17 (4.00 g, 16.3 mmols) in dichloromethane (40 ml), oxalyl dichloride (1.56 ml, 17.9 mmols) and DMF (0.013 ml, 0.162 mmol) in an ice bath, and the mixture was warmed to room temperature and stirred for 5 hours. The mixture was concentrated under reduced pressure, and the residue obtained was dissolved in dichloromethane (40 ml), 2,2,2-trifluoroethanol (2.44 g, 24.4 mmols), triethylamine (4.50 ml, 32.5 mmols) and 4- (dimethylamino) pyridine (99.0 mg, 0.812 mmol) were added in an ice bath, and the mixture was warmed to room temperature and stirred for one hour. The mixture was concentrated under reduced pressure, and to the residue obtained, a 1 mol / L aqueous solution of hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with 1 mol / L aqueous solution of hydrochloric acid and brine, dried with anhydrous magnesium sulfate to obtain Compound 18 (5.33 g, 100%). 1H NMR (CDCl3) δ: 4.64 (q, J = 8.2 Hz, 2H), 5.38 (s, 2H), 6.49 (d, J = 5.6 Hz, 1H), 7, 30-7.38 (m, 3H), 7.43-7.49 (m, 2H), 7.75 (d, J = 5.6 Hz, 1H). Second and Third Steps
[00165] Compound 20 was obtained in the same way as in the fifth and sixth steps of Reference Example 1. 1H NMR (CDCl3) δ: 4.55 (q, J = 8.3 Hz, 2H), 5.18 ( s, 2H), 5.29 (s, 2H), 6.37 (d, J = 7.8 Hz, 1H), 7.30-7.42 (m, 6H). Fourth and Fifth Steps
[00166] Compound 23 was obtained in the same way as in the seventh stage of Reference Example 1. LC / MS (ESI): m / z = 342.1 [M + H] +, RT = 1.00; 1.09 minutes, method (1) Sixth Stage
[00167] To a solution of Compound 23 (820 mg, 2.40 mmols) in dichloromethane (16.5 ml), Boc2O (0.837 ml, 3.60 mmols), triethylamine (0.499 ml, 3.60 mmols) was added ) and 4- (dimethylamino) pyridine (44.0 mg, 0.360 mmol), and the mixture was stirred at room temperature for 3.5 hours. To the mixture, a 1 mol / L aqueous solution of hydrochloric acid was added and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with 1 mol / L aqueous solution of hydrochloric acid and brine, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound 24 (593 mg, 56%) and Compound i3 (170 mg, 16%). Compound 24: LC / MS (ESI): m / z = 441.9 [M + H] +, RT = 1.67 minutes, method (1) Seventh Step
[00168] Compound 24 (547 mg, 1.24 mmol) was dissolved in acetic acid (5.5 ml) and the mixture was stirred at 80 ° C for 5 hours. The mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound i3 (454 mg, 100%). 1H NMR (CDCl3) δ: 1.46 (d, J = 6.4 Hz, 3H), 3.45 (dd, J = 10.5; 10.5 Hz, 1H), 3.55 (dd, J = 11.7; 4.3 Hz, 1H), 3.92 (dd, J = 11.7; 3.6 Hz, 1H), 3.95-4.01 (m, 2H), 4.76 ( dq, J = 13.9; 4.3 Hz, 1H), 5.19 (d, J = 10.2 Hz, 1H), 5.22 (d, J = 10.2 Hz, 1H), 5, 36 (d, J = 12.9 Hz, 1H), 6.28 (d, J = 7.8 Hz, 1H), 7.25 (d, J = 7.8 Hz, 1H), 7.28- 7.36 (m, 3H), 7,567.61 (m, 2H). Example 1 OBn O OH O
First step
[00169] Compound i1 (1100 g, 3360 mmols) and 7,8-difluoro-6,11-dihydrodibenzothiepine-11-ol (977 g, 3697 mmols) were suspended in T3P 50% by weight in ethyl acetate (3208 g, 5041 mmols) and ethyl acetate (1.1 L). To the mixture, methanesulfonic acid (436 ml, 6721 mmols) was added at room temperature and the mixture was stirred at 70 ° C for 5.5 hours. To the mixture, water was added in an ice water bath and the mixture was stirred at room temperature for one hour. THF was added and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with water and 8% aqueous sodium hydrogen carbonate solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was dissolved in THF (5.5 L) and potassium carbonate (790 g, 5713 mmols) was added to it. The mixture was heated to 50 ° C, benzyl bromide (240 mL, 2016 mmols) was added dropwise and the mixture was stirred at 60 ° C for 8.5 hours. To the mixture, 2 mol / L aqueous hydrochloric acid was added dropwise in an ice-water bath, and the mixture was stirred at room temperature for 10 minutes and extracted with ethyl acetate. The obtained organic layer was washed with water and 8% aqueous sodium hydrogen carbonate solution and dried with anhydrous magnesium sulfate. Activated carbon (Norit SX-2, 240 g) was added, the mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. To the obtained residue, ethyl acetate and hexane were added and the precipitated solid was filtered to obtain Compound 25 (1019 g, 1776 mmols, 53%). 1H NMR (CDCl3) δ: 2.88 (1H, t, J = 11.2 Hz), 3.28-3.39 (2H, m), 3.72 (1H, d, J = 12.6 Hz ), 3.86 (1H, d, J = 9.6 Hz), 4.03 (1H, d, J = 13.9 Hz), 4.45 (1H, d, J = 8.6 Hz), 4.67 (1H, d, J = 13.1 Hz), 5.19-5.26 (2H, m), 5.45 (1H, d, J = 10.9 Hz), 5.63 (1H , d, J = 10.9 Hz), 5.77 (1H, d, J = 7.6 Hz), 6.40 (1H, d, J = 7.8 Hz), 6.68 (1H, t , J = 6.9 Hz), 6.94-7.01 (2H, m), 7.03-7.12 (3H, m), 7.29-7.38 (3H, m), 7, 61 (2H, d, J = 7.1 Hz). Second stage
[00170] To a solution of Compound 25 (1200 g, 2092 mmols) in DMA (3.6 L), lithium chloride (443 g, 10.5 moles) was added at room temperature, and the mixture was stirred at 80 ° C for 3 hours. To the mixture, acetone (1.2 L), 0.5 mol / L aqueous solution of hydrochloric acid (6.0 L) and water (2.4 L) were added in an ice water bath, and the mixture it was stirred for an hour. The precipitated solid was filtered. The obtained solid was dissolved in chloroform, isopropyl ether was added and the precipitated solid was filtered to obtain Compound III-2 (950 g, 1965 mmols, 94%). 1H NMR (CDCl3) δ: 2.99 (1H, dt, J = 17.5; 6.8 Hz), 3.47 (1H, td, J = 11.9; 2.5 Hz), 3.60 (1H, t, J = 10.6 Hz), 3.81 (1H, dd, J = 11.9; 3.3 Hz), 3.96 (1H, dd, J = 11.0; 2.9 Hz), 4.07 (1H, d, J = 13.8 Hz), 4.58 (1H, dd, J = 10.0; 2.9 Hz), 4.67 (1H, dd, J = 13 , 5; 1.9 Hz), 5.26-5.30 (2H, m), 5.75 (1H, d, J = 7.8 Hz), 6.69 (1H, d, J = 7, 7 Hz), 6.83-6.87 (1H, m), 6.99-7.04 (2H, m), 7.07-7.15 (3H, m).
Example 2 First Step
[00171] Compound i1 (400 mg, 1.22 mmol) and 6.11-dihydrodibenzothiepine-11-ol (418 mg, 1.83 mmol) were dissolved in T3P 50% in ethyl acetate (7.27 mL, 12.2 mmols) and the mixture was stirred in a tightly closed tube at 110 ° C for 1.5 hours. To the mixture, water was added and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol and ethyl acetate-methanol) to obtain Compound 26 (316 mg, 47%). 1H NMR (CDCl3) δ: 2.86 (dd, J = 11.4; 11.4 Hz, 1H), 3.26-3.40 (m, 2H), 3.55 (d, J = 13, 4 Hz, 1H), 3.70 (d, J = 10.4 Hz, 1H), 3.86 (d, J = 10.4 Hz, 1H), 4.48 (d, J = 9.5 Hz , 1H), 4.66 (d, J = 13.4 Hz, 1H), 5.20 (s, 1H), 5.43-5.50 (m, 2H), 5.63 (d, J = 10.9 Hz, 1H), 5.79 (d, J = 7.8 Hz, 1H), 6.40 (d, J = 7.7 Hz, 1H), 6.62-6.69 (m, 1H), 7.02-7.07 (m, 3H), 7.18 (d, J = 7.4 Hz, 1H), 7.27-7.44 (m, 6H), 7.60-7 , 66 (m, 2H). Second stage
[00172] Compound III-1 was obtained in the same way as in the Second Step of Example 1. 1H NMR (CDCl3) δ: 2.98 (dd, J = 13.0; 12.3 Hz, 1H), 3, 46 (dd, J = 13.1; 10.0 Hz, 1H), 3.55-3.63 (m, 2H), 3.79 (d, J = 11.4 Hz, 1H), 3.96 (d, J = 11.0 Hz, 1H), 4.62-4.66 (m, 2H), 5.26 (s, 1H), 5.52 (d, J = 13.4 Hz, 1H) , 5.75 (d, J = 7.7 Hz, 1H), 6.70 (d, J = 7.7 Hz, 1H), 6.79-6.85 (m, 1H), 7.05- 7.12 (m, 3H), 7.23 (d, J = 7.4 Hz, 1H), 7.30 (t, J = 7.3 Hz, 1H), 7.36 (d, J = 7 , 4 Hz, 1H), 7.44 (t, J = 7.4 Hz, 1H). Example 3
First step
[00173] Compound 27 (290 mg, 0.880 mmol) and Compound i1 (240 mg, 0.733 mmol) were dissolved in T3P 50% in ethyl acetate (2.4 mL), and the mixture was stirred in an airtight tube closed at 100 ° C for 1.5 hours. To the mixture, water was added and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-ethyl acetate-methanol) to obtain Compound 28 (106 mg, 24%). 1H NMR (CDCl3) δ: 2.37 (s, 3H), 2.94-3.03 (m, 1H), 3.15-3.23 (m, 1H), 3.28 (t, J = 10.4 Hz, 1H), 3.58 (d, J = 13.2 Hz, 1H), 3.66 (dd, J = 3.2 Hz, 11.6 Hz, 1H), 3.84 (dd , J = 2.8 Hz, 10.8 Hz, 1H), 4.40-4.52 (m, 2H), 5.49 (t, J = 13.6 Hz, 2H), 5.60 (d , J = 10.4 Hz, 2H), 5.78 (d, J = 7.6 Hz, 1H), 6.41 (d, J = 7.2 Hz, 1H), 6.66-6.71 (m, 1H), 6.98-7.12 (m, 4H), 7.21 (d, J = 7.6 Hz, 1H), 7.30-7.42 (m, 4H), 7, 56-7.61 (m, 2H). Second stage
[00174] To a solution of Compound 28 (100 mg, 0.168 mmol) in methanol (1 mL), 2 mol / L aqueous sodium hydroxide solution (252 μL, 0.50 mmol) was added and the mixture was stirred at room temperature. environment for an hour. To the mixture, 2 mol / L aqueous hydrochloric acid solution (0.3mL) was added and the mixture was extracted with chloroform. The obtained organic layer was concentrated under reduced pressure. The residue obtained was dissolved in DMA (1.0 ml), lithium chloride (35.6 mg, 0.839 mmol) was added and the mixture was stirred at 100 ° C for 15 hours. The mixture was purified by reverse phase chromatography on a silica gel column (acetonitrile-water) to obtain Compound III-24 (20 mg, 26%). 1H NMR (CDCl3) δ: 3.09 (t, J = 11.2 Hz, 1H), 3.40-3.58 (m, 3H), 3.76 (d, J = 10.8 Hz, 1H ), 3.91 (d, J = 10.8 Hz, 1H), 4.66 (d, J = 13.2 Hz, 1H), 4.73 (d, J = 9.6 Hz, 1H), 5.50 (d, J = 13.6 Hz, 1H), 5.79 (d, J = 6.8 Hz, 1H), 6.25 (s, 1H), 6.61-6.70 (m , 2H), 6.79 (d, J = 6.8 Hz, 1H), 6,937.08 (m, 3H), 7.10-7.19 (m, 2H).
[00175] The compounds of the following examples were synthesized from commercially available compounds or intermediates described in the Reference Example according to the examples above.












Example 4
[00176] To a suspension of Compound III-2 (1.00 g, 2.07 mmols) in DMA (5 ml), chloromethyl methyl carbonate (0.483 g, 3.10 mmols), potassium carbonate (0.572) g, 4.14 mmols) and potassium iodide (0.343 g, 2.07 mmols), and the mixture was stirred at 50 ° C for 6 hours. To the mixture, DMA (1 ml) was added and the mixture was stirred for 6 hours. The mixture was cooled to room temperature, DMA (6 ml) was added, and the mixture was stirred at 50 ° C for 5 minutes. The mixture was filtered. To the filtrate obtained, 1 mol / L aqueous solution of hydrochloric acid (10 ml) and water (4 ml) was added and the mixture was stirred for one hour. The precipitated solid was filtered and dried under reduced pressure at 60 ° C for 3 hours to obtain Compound II-6 (1.10 g, 1.93 mmol, 93%). 1H NMR (DMSO-D6) δ: 2.91-2.98 (1H, m), 3.24-3.31 (1H, m), 3.44 (1H, t, J = 10.4 Hz) , 3.69 (1H, dd, J = 11.5; 2.8 Hz), 3.73 (3H, s), 4.00 (1H, dd, J = 10.8; 2.9 Hz), 4.06 (1H, d, J = 14.3 Hz), 4.40 (1H, d, J = 11.8 Hz), 4.45 (1H, dd, J = 9.9; 2.9 Hz ), 5.42 (1H, dd, J = 14.4; 1.8 Hz), 5.67 (1H, d, J = 6.5 Hz), 5.72-5.75 (3H, m) , 6.83-6.87 (1H, m), 7.01 (1H, d, J = 6.9 Hz), 7.09 (1H, dd, J = 8.0; 1.1 Hz), 7.14-7.18 (1H, m), 7.23 (1H, d, J = 7.8 Hz), 7.37-7.44 (2H, m) Example 5
First step
[00177] To a solution of chloromethyl chloroformate (300 mg, 2.33 mmoles) and Compound 30 (330 mg, 2.79 mmols) in dichloromethane (6.0 mL), was added pyridine (207 μL , 2.56 mmols) at 0 ° C under a nitrogen atmosphere, and the mixture was stirred at 0 ° C for 30 minutes, warmed to room temperature and stirred for one hour. To the mixture, 2 mol / L aqueous hydrochloric acid solution was added and the mixture was extracted with dichloromethane. The obtained organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain Compound 31 (440 mg, 90%). 1H NMR (CDCl3) δ: 1.65 (s, 6H), 3.77 (s, 3H), 5.71 (s, 2H). Second stage
[00178] Compound III-2 (300 mg, 0.62 mmol), potassium carbonate (172 mg, 1.24 mmol), potassium iodide (103 mg. 0.62 mmol) and Compound 31 (261 mg , 1.24 mmol) were dissolved in DMA (3.0 mL) and the mixture was stirred at 80 ° C for 3 hours. To the mixture, 2 mol / L aqueous hydrochloric acid solution was added and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound II-61 (350 mg, 86%). 1H NMR (CDCl3) δ: 1.63 (s, 3H), 1.67 (s, 3H), 2.86-2.93 (m, 1H), 3.38-3.61 (m, 2H) , 3.68-3.78 (m, 4H), 3.90-3.96 (m, 1H), 4.06 (d, J = 14.0 Hz, 1H), 4.51 (dd, J = 2.0 Hz, 9.6 Hz, 1H), 4.65 (d, J = 12.4 Hz, 1H), 5.21 (d, J = 14.4 Hz, 1H), 5.36 (s, 1H), 5.80-5.95 (m, 3H), 6.85-6.92 (m, 2H), 7.03-7.22 (m, 5H).
Example 6
[00179] To a solution of Compound III-2 (90 mg, 0.186 mmol) in dichloromethane (2 mL), acetic anhydride (0.053 mL, 0.558 mmol), triethylamine (0.077 mL, 0.558 mmol) and a catalytic amount were added of DMAP, and the mixture was stirred at room temperature for two hours. The mixture was concentrated under reduced pressure and the residue obtained was purified by silica gel column chromatography (chloroform-methanol). To the obtained solution, ether was added and the precipitated solid was filtered to obtain Compound II-4 (71 mg, 73%). 1H NMR (CDCl3) δ: 2.46 (s, 3H), 2.88-2.99 (m, 1H), 3.35-3.50 (m, 1H), 3.60-3.65 ( m, 1H), 3.75-3.83 (m, 1H), 3.90-4.00 (m, 1H), 4.05 (d, J = 14.0 Hz, 1H), 4.52 -4.57 (m, 1H), 4.60-4.70 (m, 1H), 5.24-5.34 (m, 1H), 5.35 (s, 1H), 5.88 (d , J = 7.6Hz, 1H), 6.85-6.82 (m, 1H), 6.90-7.05 (m, 2H), 7.06-7.20 (m, 4H) LC / MS (ESI): m / z = 526.2 [M + H] +, RT = 1.87 minutes, method (1).
Example 7 First Step
[00180] To a solution of triphosgene (300 mg, 2.54 mmols) in dichloromethane (6.0 mL), pyridine (257 μL, 3.17 mmols) was added at 0 ° C under a nitrogen atmosphere and the mixture was stirred for 15 minutes. To the mixture, a solution of Compound 30 (377 mg, 1.27 mmol) in dichloromethane (1.0 mL) was added, and the mixture was stirred at 0 ° C for 15 minutes, warmed to room temperature and stirred for 15 minutes. The mixture was concentrated under reduced pressure, ethyl acetate (4.0mL) was added and the mixture was filtered. The filtrate was concentrated under reduced pressure to obtain Compound 32 (380 mg). Second stage
[00181] To a solution of Compound III-2 (350 mg, 0.724 mmol) in dichloromethane (3.5 mL), Compound 32 (196 mg, 1.09 mmol) and triethylamine (301 μL, 2, 17 mmols) at 0 ° C and the mixture was stirred at 0 ° C for 30 minutes. To the mixture, 2 mol / L aqueous hydrochloric acid solution was added and the mixture was extracted with dichloromethane. The organic layer obtained was washed with brine, dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound II-65 (380 mg, 84%). 1H NMR (CDCl3) δ: 1.73 (s, 3H), 1.77 (s, 3H), 2.90-2.99 (m, 1H), 3.37-3.43 (m, 1H) , 3.57 (t, J = 8.8 Hz, 1H), 3.76 (dd, J = 2.8 Hz, 12.0 Hz, 1H), 3.81 (s, 3H), 3.94 ( dd, J = 2.8 Hz, 10.8 Hz, 1H), 4.05 (d, J = 14.0 Hz, 1H), 4.55 (dd, J = 2.8 Hz, 9.6 Hz , 1H), 4.65 (d, J = 12.0 Hz, 1H), 5.28 (d, J = 12.0 Hz, 1H), 5.34 (s, 1H), 5.89 (d , J = 8.0 Hz, 1H), 6,866.95 (m, 2H), 7.03-7.15 (m, 5H).
Example 8
[00182] To a solution of Compound 33 (276 mg, 0.402 mmol) in THF (1 mL), acetic acid (121 mg, 2.01 mmol) and TBAF 1 mol / L in THF (1.21 mL) were added , 1.21 mmol) in an ice water bath, and the mixture was stirred at room temperature for 4 hours. The mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-methanol) to obtain Compound II-129 (179 mg, 78%). LC / MS (ESI): m / z = 572.0 [M + H] +, RT = 1.74 minutes, method (2)
Example 9
[00183] To a solution of Compound III-2 (300 mg, 0.62 mmol) in DMF (4 mL), potassium carbonate (258 mg, 1.87 mmol), 4- (chloromethyl) acetate were added phenyl (344 mg, 1.87 mmol) and sodium iodide (139 mg, 1.87 mmol) at room temperature and the mixture was stirred at 65 ° C for one hour. To the mixture, water was added and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with water, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-methanol) to obtain Compound II-115 (120 mg, 31%). LC / MS (ESI): m / z = 631.95 [M + H] +, RT = 2.07 minutes, method (2) Example 10

[00184] To a solution of Compound III-2 (150 mg, 0.31 mmol) in dichloromethane (2 mL) was added 3 mmol / g triphenylphosphine supported on polymer (310 mg, 0.93 mmol), pyridin- 4-ylmethanol (68 mg, 0.62 mmol) and DEAD 40% in toluene (270 mg, 0.62 mmol) at room temperature, and the mixture was stirred at room temperature for 30 minutes. The mixture was purified by amino column chromatography (ethyl acetate-methanol) to obtain Compound II-143 (63 mg, 35%). LC / MS (ESI): m / z = 575.00 [M + H] +, RT = 1.43 minutes, method (2)
Example 11
[00185] To a solution of Compound III-2 (65 mg, 0.134 mmol) in pyridine (0.8 mL), dimethylcarbamoyl chloride (21.7 mg, 0.202 mmol) was added and the mixture was stirred at 80 ° C at night. To the mixture, 1 mol / L aqueous hydrochloric acid solution was added and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was solidified with ethyl acetate-hexane to obtain Compound II-27 (65 mg, 87%). 1H NMR (CDCl3) δ: 2.89 (t, J = 11.2 Hz, 1H), 2.99 (s, 1H), 3.01 (s, 3H), 3.18-3.26 (m , 4H), 3.45 (t, J = 10.8 Hz, 1H), 3.59 (t, J = 10.8 Hz, 1H), 3.70-3.80 (m, 1H), 3 , 90-3.98 (m, 1H), 4.03 (d, J = 13.6 Hz, 1H), 4.50-4.70 (m, 2H), 5.21-5.35 (m , 2H), 5.82 (d, J = 7.6 Hz, 1H), 6.91 (t, J = 7.6 Hz, 1H), 7.00-7.20 (m, 6H).
Example 12
[00186] To a solution of ethyl phosphorodichloridate (135 mg, 0.829 mmol) in dichloromethane (3 ml), L-valine methyl ester hydrochloride (139 mg, 0.829 mmol) was added and then added a solution of triethylamine (168 mg, 1.66 mmol) in dichloromethane (2 ml) dropwise at -78 ° C. The mixture was stirred at room temperature for one hour. Compound III-2 (200 mg, 0.414 mmol) and triethylamine (126 mg, 1.25 mmol) were added, and the mixture was stirred at the same temperature for 6 hours. The mixture was concentrated and the residue obtained was purified by silica gel column chromatography (ethyl acetate-methanol) to obtain Compound II-55 (112 mg, 38%). LC / MS (ESI): m / z = 705.05 [M + H] +, RT = 2.18 minutes, method (2).
Example 13
[00187] To a solution of ethyl phosphorodichloridate (202 mg, 1.24 mmol) in dichloromethane (3 mL), a mixture of triethylamine (126 mg, 1.24 mmol) and methyl glycolate (112) was added 1.24 mmol) in dichloromethane (2 mL) dropwise. The mixture was stirred at room temperature for two hours. Compound III-2 (200 mg, 0.414 mmol) and triethylamine (126 mg, 1.25 mmol) were added and the mixture was stirred at the same temperature for one hour. The mixture was concentrated and the residue obtained was purified by silica gel column chromatography (ethyl acetate-methanol) to obtain Compound II-57 (143 mg, 52%). LC / MS (ESI): m / z = 664.00 [M + H] +, RT = 1.93 minutes, method (2).
Example 14
[00188] To a solution of phosphoryl chloride (1.53 g, 10 mmols) in dichloromethane (10 ml), a mixture of triethylamine (2.12 g, 20.95 mmols) and methyl glycolate (1 , 89 mg, 21 mmol) in dichloromethane (5 mL) dropwise. The mixture was stirred at room temperature for two hours. To the mixture (2 ml), Compound III-2 (200 mg, 0.414 mmol) and triethylamine (126 mg, 1.25 mmol) were added and the mixture was stirred at the same temperature for one hour. The mixture was concentrated and the residue obtained was purified by silica gel column chromatography (ethyl acetate-methanol) to obtain Compound II-58 (166 mg, 57%). LC / MS (ESI): m / z = 707.90 [M + H] +, RT = 1.93 minutes, method (2).
The following example compounds were synthesized from commercially available compounds according to the examples above.






























The compounds linked with the present invention and / or the original compounds of the compounds linked with the present invention are useful for symptoms and / or diseases that are induced by the Influenza virus. For example, they are useful for treating and / or preventing or ameliorating symptoms, flu-like symptoms that accompany fever, burning, headache, muscle pain, general malaise etc., symptoms of airway inflammation such as pharyngalgia, nasal discharge, nasal congestion, cough , phlegm, etc., gastrointestinal symptoms such as abdominal pain, vomiting, diarrhea, etc. and, moreover, complications that accompany secondary infections such as acute encephalopathy and pneumonia.
[00191] As the compounds linked to the present invention are prodrug, they offer as advantages high oral absorption capacity, good bioavailability, good clearance and good pulmonary transit, and are, therefore, excellent drugs.
[00192] Because they have effects such as high inhibitory activity on the cap structure-dependent endonuclease and high selectivity due to a virus-specific enzyme, the original compounds of the compounds linked to the present invention can be drugs having reduced side effects.
[00193] Furthermore, as the compounds linked to the present invention and / or the original compounds of the compounds linked to the present invention also have the advantages of high metabolic stability, high solubility, good oral absorption capacity, good bioavailability, good clearance, high pulmonary transit, long half-life, high rate of non-protein binding, low inhibition of the hERG channel, low CYP inhibition, the CPE inhibitor effect (cytopathic effect) is recognized and / or the negativity is displayed in a phototoxicity test, Ames test and gene toxicity test or toxicity such as liver damage is not caused. Therefore, the compounds linked to the present invention can be excellent drugs.
The compounds linked to the present invention and / or the original compounds of the compounds linked to the present invention can be administered orally or parenterally. In the case of oral administration, the present compounds can also be used as a normal preparation, for example, as any pharmaceutical form of solid preparations such as tablets, powders, granules, capsules, etc .; solutions; oil suspensions; or liquid preparations such as syrups or elixirs etc. In the case of parenteral administration, the compounds linked to the present invention can be used as injectables in aqueous or oil-based suspensions, or nasal drops. When preparing them, conventional excipients, binders, lubricants, aqueous solvents, oil solvents, emulsifiers, suspending agents, preservatives, stabilizers, etc. can be arbitrarily used. The pharmaceutical composition of the present invention can be produced by combining (for example, mixing) a therapeutically effective amount of the present compound with pharmaceutically acceptable vehicles or diluents.
The dose of the compounds linked to the present invention is different depending on the method of administration, the age, weight and condition of the patient and the type of the disease and, normally, in the case of oral administration between approximately 0.05 mg and 3000 mg, preferably 0.1 mg to 1000 mg for adult daily, if necessary, per division. In addition, in the case of parenteral administration, between approximately 0.01 mg and 1000 mg, preferably from 0.05 mg to 500 mg for adult per day are administered. Test example 1: Measurement of cap-dependent endonuclease activity (CEN). 1) Substrate Preparation
[00196] 30 mer RNA (5'-pp- [m2'-O] GAA UAU (-Cy3) GCA UCA CUA GUA AGC UUU GCU CUA-BHQ2-3 ': manufactured by Japan Bio Services Co., LTD) , in which G at the 5 'end is modified by diphosphate, a hydroxy group at the 2' position is modified by methoxylation, the sixth U from the 5 'end is marked with Cy3, and the 3' end is marked with BHQ2, has been purchased, and the cap structure was added using the ScriptCap system manufactured by EPICENTRE (the product was m7G [5 '] - ppp- [5'] [m2'-O] GAA UAU (-Cy3) GCA UCA CUA GUA AGC UUU GCU CUA (-BHQ2) -3 '). This was separated and purified by denatured polyacrylamide gel electrophoresis and used as a substrate. 2) Enzyme Preparation
[00197] RNP was prepared from a viral particle using a standard method (Reference Document: VIROLOGY (1976) 73, p327-338 OLGA M. ROCHOVANSKY). Specifically, the A / WSN / 33 virus (1 x 103 PFU / mL, 200 μL) was inoculated into 10-day embryonated hen's eggs. After incubation at 37 ° C for 2 days, the allantoic liquid from the chicken egg was recovered. A viral particle was purified by ultracentrifugation using 20% sucrose, solubilized with TritonX-100 and lysolecithin, and a fraction of RNP (50-70% glycerol fraction) was collected by ultracentrifugation using 30-70% glycerol density gradient, and was used as an enzyme solution (containing approximately 1 nM PB1-PB2-PA complex). 3) Enzyme Reaction
[00198] An enzymatic reaction solution (2.5 μL) (composition: 53 mM Tris hydrochloride (pH 7.8), 1 mM MgCl2, 1.25 mM dithiothreitol, 80 mM NaCl, 12.5% glycerol, enzyme solution (0.15 μL) was dispensed into a 384-well polypropylene plate. Then, 0.5 μL of a test compound solution, which had been serially diluted with dimethylsulfoxide (DMSO), was added to the plate. As a positive control (PC) or negative control (NC), 0.5 μL of DMSO was added to the plate respectively. Each plate was mixed a lot. Then, 2 μL of a substrate solution (1.4 nM substrate RNA, 0.05% Tween20) was added to initiate a reaction. After incubation at room temperature for 60 minutes, 1 μL of the reaction solution was collected and added to 10 μL of a formed Hi-Di solution (containing the GeneScan 120 Liz Size size standard as a size marker: manufactured Applied Biosystems (ABI)) to stop the reaction. For NC, the reaction was stopped in advance by adding EDTA (4.5 mM) before the reaction started (all concentrations described above are final concentrations). 3) Measurement of the inhibition index (IC50 value)
[00199] The solution for which the reaction was stopped was heated to 85 ° C for 5 minutes, quickly cooled on ice for 2 minutes, and investigated with an ABI PRIZM 3730 genetic analyzer. A cap-dependent endonuclease product peak was quantified by the ABI Genemapper analysis software, an inhibition index of the CEN reaction (%) of a test compound was obtained by defining the fluorescence intensities of PC and NC as 0% inhibition and 100% inhibition, respectively. An IC50 value was obtained with the curve fitting software (XLfit 2.0: Model 205 (manufactured by IDBS) etc.). The IC50 values of test substances carrying an original compound are shown in Table 39. Example Test 2: Confirmation test of the CPE inhibitory effect Material FCS E-MEM 2% (prepared by adding kanamycin and FCS to MEM (Minimum Essential Medium) (Invitrogen )) 0.5% BSA E-MEM (prepared by adding kanamycin and BSA MEM (Minimum Essential Medium) (Invitrogen)) HBSS (Hanks Balanced Saline) MDBK cell
[00200] The cells were adjusted to an appropriate number of cells (3 x 105 / ml) with FCS E-MEM 2%. MDCK cell
[00201] After washing with HBSS twice, the number of cells was adjusted (5 x 105 / ml) with 0.5% BSA E-MEM. Trypsin Solution
[00202] Swine pancreas trypsin (SIGMA) was dissolved in PBS (-) and passed through a 0.45 μm filter. EnVision (PerkinElmer) WST-8 Kit (Kishida Chemical Co., Ltd.) 10% SDS Solution <Operating Procedure> Sample Dilution and Dispensing Test
[00203] As a culture medium, FCS E-MEM 2% was used in the case of MDBK cells, and BSA E-MEM 0.5% in the case of MDCK cells. After that, for the dilution of viruses, cells and test sample, the same culture medium was used.
[00204] A test sample was diluted with culture medium to an appropriate concentration in advance and then a two to five fold serial dilution in a 96 well plate (50 μL / well) was prepared. Two plates, one to measure anti-flu activity and the other to measure cytotoxicity, were prepared. Each trial was performed in triplicate for each drug.
[00205] In the case of MDCK cells, Trypsin was added to the cells to a final concentration of 3 μg / mL just to measure anti-flu activity. Dilution and Dispensing of Influenza Viruses
[00206] An Influenza virus was diluted with culture medium to an appropriate concentration in advance, and 50 μL / well was dispensed in a 96-well plate containing a test substance. 50 μL / well of a culture medium was dispensed on a plate containing a test substance to measure cytotoxicity. Cell Dilution and Dispensing
[00207] 100 μL / well of cells that were adjusted to the appropriate number of cells were dispensed on a 96-well plate containing a test sample.
[00208] The plate was mixed with a mixer and kept in a CO2 incubator for 3 days to measure anti-flu activity and measure cytotoxicity. Dispensing of WST-8
[00209] The cells in the 96-well plate that had been incubated for 3 days were observed visually under a microscope, and the appearance of the cells, the presence or absence of a crystal of the test substance were checked. The supernatant was removed so that the cells were not absorbed from the plate.
[00210] The WST-8 Kit was diluted 10 times with the culture medium, and 100 μL was dispensed in each well. After mixing, the cells were kept in a CO2 incubator for 1 to 3 hours.
[00211] After incubation, in relation to the plate to measure anti-flu activity, 10 μL / well of a 10% SDS solution was dispensed to inactivate the virus. Absorbance measurement
[00212] After the 96-well plate was mixed, absorbance was measured with EnVision at two wavelengths 450 nm / 620 nm. Calculation of the value of each item measured
[00213] The value was calculated using Microsoft Excel or a program with calculation and equivalent processing capacity based on the following calculation equation:
[00214] Calculation of effective inhibition concentration to achieve 50% death of cells infected by the Influenza virus (EC50) EC50 = 10Z Z = (50% - High%) / (High% - Low%) x {log (High concentration ) - log (Low concentration)} + log (High concentration)
[00215] For test substances (compounds of Reference Examples) carrying an original compound, the measurement results of Example Test 1 and Test Example 2 are shown in Table 39.


[00216] Based on the above results, the original compounds exhibit high cap-dependent endonuclease inhibitory activity (CEN) and / or high CPE inhibitory effect and thus can be a useful agent for the treatment and / or prevention of symptoms and / or illness induced by Influenza virus infection.
[00217] Examples of biological tests for compounds of the present invention have been described below. Example Test 3: CYP inhibition test
[00218] Using commercially available clustered human liver microsomes and employing, as markers, O-deethylation of 7-ethoxytyresorphine (CYP1A2), tolbutamide methylhydroxylation (CYP2C9), mefenytoin 4'-hydroxylation (CYP2C19) , O-demethylation of dextromethorphan (CYP2D6) and hydroxylation of terphenene (CYP3A4) as typical reactions of the metabolism of substrates of 5 main forms of CYP enzymes (CYP1A2, 2C9, 2C19, 2D6, 3A4), a inhibition of each quantity of metabolite produced by a compound of the present invention.
[00219] The reaction conditions were as follows: substrate, ethoxiresorufin 0.5 μmol / L (CYP1A2), tolbutamide 100 μmol / L (CYP2C9), S-mefenitoinamefenitoina 50 μmol / L (CYP2C19), dextrometorfano 5 L (CYP2D6), terfenedin 1 μmol / L (CYP3A4); reaction time, 15 minutes; reaction temperature, 37 ° C; enzyme, human hepatic microsome clustered 0.2 mg protein / mL; concentration of a compound of the present invention, 1, 5, 10, 20 μmol / L (four points).
[00220] Each of the five types of substrates, human liver microsome, or a compound of the present invention in 50 mmol / L Hepes buffer as reaction solution was added to a 96-well plate with the composition described above, NADPH, as cofactor was added to start the metabolism reactions as markers and, after incubation at 37 ° C for 15 minutes, a solution of methanol / acetonitrile = 1/1 (v / v) was added to stop the reaction. After centrifugation at 3000 rpm for 15 minutes, resorufin (CYP1A2 metabolite) in the supernatant was quantified by a fluorescent multibrand counter, and toltributamide hydroxide (CYP2C9P metabolite), 4 'mefenitoin hydroxide (CYP2C19 metabolite) dextromethorphan (CYP2D6 metabolite) and terfenadine alcohol (CYP3A4 metabolite) were quantified by LC / MS / MS.
[00221] The addition of only DMSO, as the solvent that dissolves a compound of the present invention, to the reaction system was adopted as a control (100%), the remaining activity (%) was calculated at each concentration of a compound of the present invention , added as the solution, and the IC50 was calculated by inverse presumption with a logistic model using a concentration and inhibition rate. Result Compound III-2: five types> 20 μmol / L Example Test 4: BA test Experimental materials and methods to assess oral absorption (1) Experimental animals: SD mice or rats. (2) Breeding condition: SD mice or rats had free access to solid feed and sterile running water. (3) Dose definition and grouping: Oral and intravenous administration performed at the predetermined dose. The groups were established as below. (The dose was changed according to the compound) Oral administration: 1 to 30 mg / kg (n = 2 to 3) Intravenous administration: 0.5 to 10 mg / kg (n = 2 to 3) (4) administered solutions: Oral administration was performed as a solution or suspension. Intravenous administration was performed after solubilization. (5) Routes of administration: Oral administration was mandatorily performed in the stomach by an oral tube. Intravenous administration was made from the caudal vein using needle syringes. (6) Items evaluated: Blood was collected in series, and the concentration of a compound of the present invention in plasma was measured by LC / MS / MS. (7) Statistical analysis: Near the transition of the concentration of a compound of the present invention in plasma, the area under the plasma concentration versus time curve (AUC) was calculated by the program using the nonlinear least squares method, WinNonlin (a mark registered), and the bioavailability (BA) of a compound of the present invention was calculated from the AUCs of the oral administration group and the intravenous administration group. Result Compound II-6: 14.9% Compound III-2: 4.2%
[00222] Based on the above results, the prodrug improved bioavailability in addition to the original compound.
[00223] Therefore, the compound of the present invention has excellent oral absorption capacity and can be a useful agent for the treatment and / or prevention of symptom and / or disease induced by the Influenza virus infection. Test Example 5: Metabolic stability test
[00224] With commercially available clustered human liver microsomes, a compound of the present invention was reacted for a constant time, and the remaining rate was calculated by comparing a reacted sample and an unreacted sample, thereby evaluating a degree of metabolism in the liver.
[00225] A reaction was carried out (oxidative reaction) at 37 ° C for 0 minutes or 30 minutes in the presence of 1 mmol / L NADPH in 0.2 ml of a buffer (Tris-HCl 50 mmol / L, pH 7.4 , potassium chloride 150 mmol / L, magnesium chloride 10 mmol / L) containing 0.5 mg of protein / mL of human liver microsomes. After the reaction, 50 μL of the reaction solution was added to 100 μL of methanol / acetonitrile = 1/1 (v / v), mixed and centrifuged at 3000 rpm for 15 minutes. The compound of the present invention in the supernatant was quantified by LC / MS / MS or solid phase extraction (SPE) / MS, and the remaining amount of the compound of the present invention was calculated after the reaction was calculated, leaving an amount of the compound in the reaction time 0 minute was 100%. The hydrolysis reaction was carried out in the absence of NADPH, and the glucuronidation reaction occurred in the presence of 5 mM UDP-glucuronic acid in place of NADPH, followed by similar operations. Result The% inhibition was shown at 2 μmol / L of test compound. Compound III-2: 90.1% Test Example 6: CYP3A4 fluorescent MBI test
[00226] The CYP3A4 fluorescent MBI test is a test that investigates whether the inhibition of CYP3A4 by a compound of the present invention is enhanced by a reaction of the metabolism, and the test was carried out using, as CYP3A4 an enzyme expressed in Escherichia coli and using, as an index, a reaction in which 7-benzyloxytrifluoromethylcoumarin (7-BFC) is de-benzylated by the enzyme CYP3A4 to produce a 7-hydroxytrifluoromethylcoumarin (HFC) metabolite that emits fluorescent light.
[00227] The reaction conditions were as follows: substrate, 7- BFC 5.6 μmol / L; pre-reaction time, 0 or 30 minutes; reaction time, 15 minutes; reaction temperature, 25 ° C (room temperature); CYP3A4 content (expressed in Escherichia coli), in the pre-reaction 62.5 pmol / mL, in the reaction 6.25 pmol / mL (diluted 10 times); concentration of the test drug of a compound of the present invention, 0.625; 1.25; 2.5; 5; 10; 20 μmol / L (six points).
[00228] An enzyme in a K-Pi buffer (pH 7.4) and a solution of a compound of the present invention, as a pre-reaction solution, were added to a 96-well plate in the composition above the pre-reaction, a part of this was transferred to another 96-well plate so that it was 1/10 diluted with the substrate and buffer K-Pi, NADPH, as cofactor, was added to start a reaction as an index (without pre-incubation) and after a predetermined reaction time, acetonitrile / 0.5 mol / L Tris (trishidroxiaminometano) = 4/1 (V / V) was added to stop the reaction. In addition, NADPH was added to a remaining pre-incubation solution to initiate a pre-incubation (with pre-incubation) and, after a predetermined pre-incubation time, a portion was transferred to another plate so that 1 / 10 diluted with substrate and a KPi buffer and start a reaction as an index. After a predetermined reaction time, acetonitrile / 0.5 mol / L Tris (trishidroxiaminometano) = 4/1 (V / V) was added to stop the reaction. For the plate on which each index reaction had been performed, a fluorescent value of 7-HFC, which is a metabolite, was measured with a fluorescent plate reader (Ex = 420 nm, Em = 535 nm).
[00229] The addition of only DMSO, a solvent that dissolves a compound of the present invention, to a reaction system was adopted as a control (100%), the remaining activity (%) was calculated at each concentration of a compound of the present invention, added as the solution, and IC50 was calculated by inverse assumption with a logistic model using a concentration and an inhibition rate. A difference between IC50 values equal to or greater than 5 μmol / L was defined as (+) and the difference equal to or less than 3 μmol / L was defined as (-). Result Compound III-2: (-) Test Example 7: Ames fluctuation test Mutagenicity of compounds of the present invention was evaluated. 20 μL of frozen stored rat typhoid bacillus (Salmonella typhimurium cepa TA98, strain TA100) were inoculated into 10 mL of a liquid nutrient medium (2.5% No 2 oxy nutrient broth), and cultured before shaking at 37 ° C for 10 hours. 9 mL of a bacterial solution of the TA98 strain was centrifuged (2000 x g, 10 minutes) to remove the culture solution. The bacteria were suspended in 9 mL of a Micro F buffer (K2HPO4: 3.5 g / L, KH2PO4: 1 g / L, (NH4) 2SO4: 1 g / L, dehydrated trisodium citrate: 0.25 g / L, MgSO4 • 7H2O: 0.1 g / L), the suspension was added to 110 mL of Exposure medium (Micro F buffer containing Biotin: 8 μg / mL, histidine: 0.2 μg / mL, glucose: 8 mg / mL) . The strain TA100 was added to 120 mL of the Exposure medium in relation to 3.16 mL of the bacterial solution. to prepare a test bacterial solution. 12 μL of DMSO solution of a compound of the present invention (several stages of dilution from the maximum dose of 50 mg / mL 2 to 3 times), DMSO as a negative control, and 50 μg / mL of 4-nitroquinoline solution -1-DMSO oxide for the TA98 strain, 0.25 μg / mL of 2- (2-furyl) -3- (5-nitro-2-furyl) acrylamide solution for the TA100 strain under the non-activating condition of metabolism, 40 μg / mL of 2-aminoanthracene DMSO solution for strain TA98, 20 μg / mL of 2-aminoanthracene solution DMSO for strain TA100 under metabolism-activating condition as positive control, and 588 μL of the test bacterial solution (one mixed solution with 498 μL of the test bacterial solution and 90 μL of S9 mixture under the metabolism-activating condition) were mixed and cultured stirred at 37 ° C for 90 minutes. 460 μL of bacterial solution exposed to a compound of the present invention were mixed with 2300 μL of Indicator medium (Micro F buffer containing biotin: 8 μg / mL, histidine: 0.2 μg / mL, glucose: 8 mg / mL, Bromo Cresol Purple: 37.5 μg / mL), 50 μL were dispensed in a microplate, 48 wells / dose, and subjected to stationary culture at 37 ° C for 3 days. Like a cavity containing a bacterium that has obtained the ability to proliferate by mutating an enzyme gene that synthesizes an amino acid (histidine) turns from purple to yellow due to a change in pH, the proliferating bacterial cavity that has become yellow in 48 wells per dose is counted and evaluated by comparing it to the negative control group. (-) means that mutagenicity is negative and (+) is positive. Compound Result III-2: (-) Test Example 8: hERG Test
[00230] For the purpose of assessing the risk of QT prolongation on the electrocardiogram of the compound of the present invention, the effects of the compound of the present invention on the delayed rectifier current of K + (IKr), which plays an important role in the process of ventricular repolarization, were studied using HEK293 cells expressing the human ether-a-go-go related gene (hERG) channel.
[00231] After a cell was retained at a membrane potential of -80 mV by the whole cell patch clamp method using an automatic patch clamp system (PatchXpress 7000A, Axon Instruments Inc.), pulse-induced IKr was recorded depolarization at +40 mV for 2 seconds and, in addition, stimulation of the repolarization pulse at -50 mV for 2 seconds. After the current generated was stabilized, an extracellular solution was applied (NaCl: 135 mmol / L, KCl: 5.4 mmol / L, NaH2PO4: 0.3 mmol / L, CaCl2 • 2H2O: 1.8 mmol / L , MgCl2 • 6H2O: 1 mmol / L, glucose: 10 mmol / L, HEPES (4- (2-hydroxyethyl) -1-piperazine-ethanesulfonic acid): 10 mmol / L, pH = 7.4), in which the compound of the present invention had been dissolved at an objective concentration, in the cell at room temperature for 10 minutes. From the IKr record, an absolute value of the peak flow current was measured based on the value of the current at the resting membrane potential using analytical software (DataXpress ver.1, Molecular Devices Corporation). In addition, the% inhibition in relation to the peak flow current before the application of the compound of the present invention was calculated and compared to the group in which the vehicle was applied (0.1% dimethyl sulfoxide solution) to evaluate the influence of the compound of the present invention. invention on IKr. Result% inhibition was shown from 0.3 to 10 μM of the test compound. Compound III-2: 7.9% Test Example 9: Solubility Test
[00232] The solubility of the compound of the present invention was terminated under conditions of addition of 1% DMSO. A solution of compound 10 mmol / L was prepared with DMSO, and 2 μL of the solution of the compound of the present invention were added, respectively, to 198 μL of JP-1 solution (water was added to 2.0 g of sodium chloride and 7.0 mL of hydrochloric acid to reach 1000 mL) and JP-2 solution (1 volume of water was added to 1 volume of the solution with 3.40 g of potassium dihydrogen phosphate and 3.55 g of anhydrous disodium hydrogen phosphate to reach 1000 mL). The mixture was stirred for one hour at room temperature, and was filtered. The filtrate was diluted ten times with methanol / water = 1/1 (v / v), and the concentration of the compound in the filtrate was measured with LC / MS or SPE / MS by the absolute calibration method. Compound III-2 Result: 42.2 μmol / L Test Example 10: Powder solubility test
[00233] Adequate amounts of the compound of the present invention were filled into flasks, and 200 μL of JP-1st liquid was added water to 2.0 g of sodium chloride in 7.0 mL hydrochloric acid to reach 1000 mL), Liquid JP-2nd (water was added to 500 ml of phosphate buffer solution with pH 6.8) and sodium taurochlorate 20 mmols / L (TCA) / JP-2nd liquid (JP-2nd liquid was added to 1.08 g of TCA in JP-2nd Liquid to reach 100mL) were added to each vial. When the compound had completely dissolved, a suitable amount of the compound was added. After stirring for one hour at 37 ° C, the mixture was filtered and 100 μL of methanol was added to 100 μL of each filtrate (double dilution). The amplitude of the dilution was changed, if necessary. After the presence of air bubbles and precipitates was confirmed, the vials were shaken hermetically closed with a stopper. The concentration of the compound was determined with HPLC by the absolute calibration method. Compound Result III-2: JP-1 Solution; 7.1 μg / mL, JP-2 Solution; 4.4 μg / mL, 20 mmol / L TCA / JP-2 Solution; 16.1 μg / mL Test Example 11: Ames Test
[00234] The Ames test was performed with salmonella (Salmonella typhimurium) TA 98, TA100, TA1535 and TA1537 and Escherichia coli WP2uvrA as the test strains with or without metabolic activation in the pre-incubation method to verify the presence or absence of gene mutagenicity of compounds of the present invention. Compound Result III-2: (-) Example Test 12: Hemolysis test by light
[00235] The compound of the present invention was dissolved in target concentrations and was mixed with a suspension of red blood cells 2.5% v / v, prepared from defibrinized sheep blood in a microplate at concentrations from 0.0008 to 0.1 % m / v. The mixtures were exposed to 10 J / cm2 of UV irradiation within a wavelength range of 290 to 400 nm, UVA and UVB using ultraviolet, GL20SE and FL20S-BLB fluorescent lamps manufactured by Sankyo Denki Co., Ltd. and Panasonic Corporation, respectively. After irradiation was completed, the mixtures were centrifuged, and the mixture supernatant was collected and placed on a microplate. Phototoxicity was assessed by measuring absorbance at a wavelength of 540 nm and 630 nm in the supernatant. The absorbance data at the wavelength of 540 nm and 630 nm were used as indicators of damage to the biomembrane (% of photo-hemolysis) and hyperoxidation of the lipid membrane (methemoglobin formation), respectively. The phototoxicity criteria were as follows; it was considered non-phototoxic (-) when the% of photo-haemolysis <10 and the maximum change in absorbance at 630 nm (ΔOD) <0.05. It was considered non-phototoxic (+) when the photo-hemolysis was above 10% and the maximum change in absorbance at 630 nm (ΔOD) was above 0.05. Composite Result III-2: (-)
[00236] Figures 1 and 2 show the result of the measurement of the plasma concentration of Compound III-2 and Compound II-6 after oral administration of the compound Compound II-6, whose original compound is Compound III-2, the rats in non-fasting conditions.
[00237] In addition, the concentration of Compound II-6 in all plasma samples was at the limit of determination or less. Therefore, the prodrug Compound II-6, the parent compound of which is Compound III-2, has been shown to change rapidly to Compound III-2 in vivo after administration (see Figure 2).
[00238] Based on the results of the above test, it was revealed that the compound converted to a prodrug was absorbed by the body after oral administration, and quickly converted to an original compound in the blood. Therefore, the compound of the present invention can be a useful agent for the treatment and / or prevention of symptom and / or disease induced by infection with the Influenza virus. Test Example 13: Test for intravenous administration
[00239] Experimental materials and test method for intravenous administration (1) Animals used: SD rats. (2) Breeding conditions: SD rats were fed pellets and sterile running water ad libitum. (3) Dose and pool: A predetermined dose was administered intravenously. The groups were defined as follows (The dose varied for each compound)
[00240] Intravenous administration: 0.5-1 mg / kg (n = 2-3) (4) Preparation of the administered solution: Intravenous administration was performed after solubilization. (5) Method of administration: Intravenous administration was performed by a syringe equipped with a needle in the caudal vein. (6) Outcome: blood was collected over time, and the plasma concentration of the compound of the present invention was measured using LC / MS / MS. (7) Statistical analysis: In relation to the plasma concentration transition of the compound of the present invention, the total body clearance (CLtot) and the elimination half-life (t1 / 2, z) were calculated using the minimum program WinNonlin (R) nonlinear squares. Results Compound No. III-2: CLtot: 16.4 mL / min / kg t1 / 2, z: 3.4 hours
[00241] From the above results, it was found that Compound III-2 is a compound with low total body clearance and long half-life.
[00242] Therefore, the compound of the present invention has excellent persistence and can be a useful agent for the treatment and / or prevention of symptom and / or disease induced by infection by the Influenza virus. Formulation Example
[00243] The following formulation Examples only exemplify and are not intended to limit the scope of the invention. Formulation example 1: Tablets
[00244] The compounds of the present invention, lactose and calcium stearate are mixed. The mixture is crushed, granulated and dried to provide an adequate size of granules. Then, calcium stearate is added to the granules, and the mixture is pressed and shaped to provide tablets. Formulation example 2: Capsules
[00245] The compounds of the present invention, lactose and calcium stearate are mixed uniformly to obtain powdered drugs in the form of powders or fine granules. Powdered medicines are filled into containers to provide capsules. Formulation example 3: Granules
[00246] The compounds of the present invention, lactose and calcium stearate are mixed uniformly, and the mixture is pressed and molded. It is then crushed, granulated and sieved to provide suitable granule sizes. Formulation example 4: Tablets for oral disintegration
[00247] The compounds of the present invention and crystalline cellulose are mixed, granulated and pressed to provide oral disintegrating tablets. Formulation example 5: Dry syrups
[00248] The compounds of the present invention and lactose are mixed, crushed, granulated and sieved to provide suitable sizes of dry syrups. Formulation example 6: Injectables
[00249] The compounds of the present invention and phosphate buffer are mixed to provide injectables. Formulation example 7: Infusions
[00250] The compounds of the present invention and phosphate buffer are mixed to provide injectables. Formulation example 8: Inhalables
[00251] The compound of the present invention and lactose are mixed and crushed into fine powder to provide inhalables. Formulation example 9: Polishes
[00252] The compounds of the present invention and petrolatum are mixed to provide ointments. Formulation example 10: Adhesives
[00253] The compounds of the present invention and base as an adhesive plaster or the like are mixed to provide adhesives. Industrial Applicability
[00254] The compound of the present invention has cap-dependent endonuclease (CEN) inhibitory activity after absorption by the body. The compound of the present invention can be a useful agent for the treatment and / or prevention of symptom and / or disease induced by infection with the Influenza virus.

权利要求:
Claims (2)
[0001]
1. Compound, characterized by the fact that it is represented by the Formula:
[0002]
2. Compound, characterized by the fact that it is represented by the Formula: , or its pharmaceutically acceptable salt.

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法律状态:
2019-10-01| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|Free format text: DE ACORDO COM O ARTIGO 229-C DA LEI NO 10196/2001, QUE MODIFICOU A LEI NO 9279/96, A CONCESSAO DA PATENTE ESTA CONDICIONADA A ANUENCIA PREVIA DA ANVISA. CONSIDERANDO A APROVACAO DOS TERMOS DO PARECER NO 337/PGF/EA/2010, BEM COMO A PORTARIA INTERMINISTERIAL NO 1065 DE 24/05/2012, ENCAMINHA-SE O PRESENTE PEDIDO PARA AS PROVIDENCIAS CABIVEIS. |

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2020-02-11| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|

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2020-05-26| B07A| Application suspended after technical examination (opinion) [chapter 7.1 patent gazette]|

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2021-01-05| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2021-02-23| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 27/04/2016, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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申请号 | 申请日 | 专利标题

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JP2015090909|2015-04-28|

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JP2015-090909|2015-04-28|

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