| Title of Invention | AMINODIHYDROTHIAZINE OR AMINODIHYDROOXAZINE COMPOUNDS |
|---|---|
| Abstract | A composition having BACE 1 inhibitory activity containing a compound represented by the general formula (I)- wherein ring A is an optionally substituted carbocyclic group or an optionally substituted heterocyclic group; E is lower alkylene! X is S, O. or NR1; R1 is a hydrogen atom or lower alkyl; R2a, R2b, R3a, R3b, R4a and R4b is each independently a hydrogen atom, halogen, or hydroxy etc.; n and m are each independently an integer of 0 to 3; n+m is an integer of 0 to 3; R5 is a hydrogen atom or substituted lower alkyl; its pharmaceutically acceptable salt, or a solvate thereof. |
| Full Text | DESCRIPTION AMINODIHYDROTHIAZINE DERIVATIVES [Technical field] [0001] The present invention relates to a compound which has reducing effect to produce amyloid β protein and is useful as an agent for treating disease induced by production, secretion and/or deposition of amyloid β protein. [Background Art] [0002] In the brain of Alzheimer's patient, the peptide composed of about 40 amino acids residue as is called amyloid β protein, that accumulates to form insoluble specks (senile specks) outside nerve cells is widely observed. It is concerned that this senile specks kill nerve cells to cause Alzheimer's disease. The therapeutic agents for Alzheimer's disease, such as decomposition agents of amyloid β protein and amyloid β vaccine, are under investigation. Secretase is an enzyme which cleaves amyloid β precursor protein (APP) in cell and produce amyloid β protein. The enzyme which controls the production of N terminus of amyloid β protein is called as BACE 1 (beta-site APP-cleaving enzyme 1, p-secretase). It is thought that inhibition of this enzyme leads to reduction of producing amyloid β protein and that the therapeutic agent for Alzheimer's disease will be created by the inhibition. Patent Literature 1 describes the compounds which are similar to those of the present invention, and the compounds have NO synthase enzyme inhibitory activity and are useful for dementia. Patent Literatures 2 to 4 and Non-patent Literatures 1 and 2 describe the compounds which are similar to those of the present invention, and are useful for hypertensive agent, analgesic like morphine, or tranquilizers, intermediate for medicine, analgesic respectively. Patent Literature 5 to 13 are known as BACE 1 inhibitor, however, all compounds in these literatures have different structures from the present invention. [Patent Literature l] International Patent Application Publication WO96/014842 [Patent Literature 2] US Patent 3235551 [Patent Literature 3] US Patent 3227713 [Patent Literature 4] JP AppUcation Publication H09-067355 [Patent Literature 5] International Patent AppUcation PubUcation WOOl/187293 [Patent Literature 6] International Patent AppUcation PubUcation WO04/014843 [Patent Literature 7] JP AppUcation PubUcation 2004-149429 [Patent Literature 8] International Patent Application Publication WO02/96897 [Patent Literature 9] International Patent Application Publication WO04/043916 [Patent Literature 10] International Patent Application Publication WO2005/058311 [Patent Literature 11] International Patent Application Publication WO2005/097767 [Patent Literature 12] International Patent Application Publication WO2006/041404 [Patent Literature 13] International Patent Application Publication WO2006/041405 [Non-Patent Literature l] Journal of Heterocyclic Chemistry, 14, 717-723 (1977) [Non-Patent Literature 2] Journal of Organic Chemistry, 33, 8, 3126-3132 (1968) [Disclosure of Invention] [Problems to be solved by the Invention] [0003] The present invention provides compounds which have reducing effects to produce amyloid β protein, especially BACE 1 inhibitory activity, and are useful as an agent for treating disease induced by production, secretion and/or deposition of amyloid β protein. [Means to Solve the Problems] [0004] The present invention provides-(a) a composition having BACE 1 inhibitory activity containing a compound represented by the general formula (I)-[Chemical formula l] wherein ring A is an optionally substituted carbocyclic group or an optionally substituted heterocyclic group.* [Chemical formula 2] Alk1 is lower alkylene or lower alkenylene; BP is a hydrogen atom, lower alkyl or acyl; X is S. O, or NRi; R1 is a hydrogen atom or lower alkyl; R2a and R2b are each independently a hydrogen atom, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted amino, optionally substituted amidino, optionally substituted acyl, optionally substituted carbamoyl, optionally substituted carbamoylcarbonyl, optionally substituted lower alkylsulfonyl, optionally substituted arylsulfonyl, an optionally substituted carbocyclic group or an optionally substituted heterocyclic group! R3a, R3b, R4a and R4b' are each independently a hydrogen atom, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted acyl, carboxy, optionally substituted lower alkoxycarbonyl, optionally substituted amino, optionally substituted carbamoyl, an optionally substituted carbocyclic group or an optionally substituted heterocycUc group; n and m are each independently an integer of 0 to 3; n+m is an integer of 1 to 3; each R3a, each R3b, each R4a, and each Rrb may be independently different; R5 is a hydrogen atom, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, an optionally substituted carbocycUc group or an optionaUy substituted heterocycUc group; [Chemical formula 3] when wherein R5a and R5b are each independently a hydrogen atom or lower alkyl; s is an integer of 1 to 4; each R5a and each R5b may be different; with the proviso that the compound wherein n+m is 2; R5 is a hydrogen atom; and ring A is non-substituted phenyl is excluded, its pharmaceutically acceptable salt, or a solvate thereof, (al) a composition having BACE 1 inhibitory activity containing a compound represented by the general formula (I)- [Chemical formula 4] wherein ring A is an optionally substituted carbocyclic group or an optionally substituted heterocyclic group; [Chemical formula 5] Alk1 is lower altylene; R° is a hydrogen atom, lower alkyl or acylJ X is S, O, or NRM R1 is a hydrogen atom or lower alkyl; R2a and R2b are each independently a hydrogen atom, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted amino, optionally substituted amidino, optionally substituted acyl, optionally substituted carbamoyl, optionally substituted lower alkylsulfonyl, optionally substituted arylsuKonyl, an optionally substituted carbocychc group or an optionally substituted heterocyclic group; R3a, R3b, R4a, and R4b are each independently a hydrogen atom, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted acyl carboxy optionally substituted lower alkoxycarbonyl optionally substituted amino, optionally substituted carbamoyl, an optionally substituted carbocyclic group or an optionally substituted heterocyclic group; n and m are each independently an integer of 0 to 3; n+m is an integer of 1 to 3;' each R3a, each R3b, each R4a and each R4b may be independently different! R5 is a hydrogen atom, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, an optionally substituted carbocyclic group or an optionally substituted heterocyclic group; [Chemical formula 6] when wherein R5a and R5b are each independently a hydrogen atom or lower alkyl; s is an integer of 1 to 4; each R5a and each R5b may be different; with the proviso that the compound wherein n+m is 2; R5 is a hydrogen atom; and ring A is non-substituted phenyl is excluded, its pharmaceutically acceptable salt, or a solvate thereof, [0005] (b) a composition having BACE 1 inhibitory activity according to (a), wherein X is S, (c) a composition having BACE 1 inhibitory activity according to (a), wherein n is 2, and m is 0, (d) a composition having BACE 1 inhibitory activity according to (a), wherein E is a bond, (e) a compound represented by the general formula (I): [Chemical formula 7] wherein each symbols are the same as described in (a), with the proviso that the compounds as shown below; i) wherein n+m is 2, R5 is a hydrogen atom, and ring A is non-substituted phenyl; ii) wherein n is 2, m is 0, R2a is a hydrogen atom, R2b is a hydrogen atom or acetyl, R5 is methyl, and ring A is phenyl or 4-methoxyphenyl; iii) wherein n is 2, m is 0, R2a is a hydrogen atom, R2b is a hydrogen atom or acetyl, R5 is ethyl, and ring A is 3,4-dimethoxyhenyl; iv) wherein n is 2, m is 0, R2a is a hydrogen atom, R2b is a hydrogen atom or acetyl, and R5 and ring A is phenyl; v) wherein n is 2, m is 0, R2a and R2b is a hydrogen atom, R5 and ring A are taken together to form [Chemical formula 8] wherein Me is methyl, and each symbols are the same as described above; and vi) wherein n+m is 2, R5 is a hydrogen atom, ring A is phenyl substituted with one or two substituent(s) selected from the group of hydroxy, halogen, lower alkyl, lower alkoxy, nitro, amino, lower alkylcarbonylamino, mercapto, lower alkylthio, and carbamoyl, non-substituted phenyl, or non-substituted naphthyl; are excluded, its pharmaceutically acceptable salt, or a solvate thereof, (£) the compound according to (e), wherein X is S, its pharmaceutically acceptable salt, or a solvate thereof, (g) the compound according to (e) or (f), wherein n is 2, and m is 0, its pharmaceutically acceptable salt, or a solvate thereof, [0006] (h) the compound according to any one of (e) to (g), wherein R5 is optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, an optionally substituted carbocyclic group or an optionally substituted heterocyclic group, its pharmaceutically acceptable salt, or a solvate thereof, (i) the compound according to any one of (e) to (h), wherein R2a is a hydrogen atom! R2b is a hydrogen atom, optionally substituted lower alkyl, optionally substituted acyl, optionally substituted lower alkylsulfonyl, or optionally substituted amidino, its pharmaceutically acceptable salt, or a solvate thereof, (j) the compound according to any one of (e) to (h), wherein NR^^RSb jg represented by the formula ^ [Chemical formula 9] R6, R7, and R8 are each independently a hydrogen atom, lower alkyl or acyl, Y is optionally substituted lower alkylene, optionally substituted lower alkenylene or optionally substituted lower alkynylenel. Z is O or S; its pharmaceutically acceptable salt, or a solvate thereof, [0007] (k) the compound according to any one of (e) to (j), wherein ring A is substituted phenyl, its pharmaceutically acceptable salt, or a solvate thereof, (1) the compound according to any one of (e) to (j), wherein ring A is represented by the formula: [Chemical formula 10] wherein R9, R10 and R11 are hydrogen atom or G; G is halogen, hydroxy, cyano, nitro, mercapto, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted acyl, optionally substituted acyloxy, carboxy, optionally substituted lower alkoxycarbonyl, optionally substituted lower alkoxycarbonyloxy, optionally substituted aryloxycarbonyloxy, optionally substituted amino, optionally substituted carbamoyl, optionally substituted carbamoyloxy, optionally substituted lower alkylthio, optionally substituted arylthio, optionally substituted lower alkylsulfonyl, optionally substituted arylsulfonyl, optionally substituted lower alkylsulfinyl, optionally substituted arylsulfinyl, optionally substituted lower alkylsulfonyloxy, optionally substituted arylsulfonyloxy, an optionally substituted carbocyclic group, optionally substituted carbocyclicoxy, an optionally substituted heterocyclic group or optionally substituted heterocyclicoxy; each G may be independently different; its pharmaceutically acceptable salt, or a solvate thereof, (m) the compound according to (1), wherein G is represented by the formula: [Chemical formula 11] Q1, Q2, and Q3 are each independently a bond, optionally substituted lower alkylene, or optionally substituted lower alkenylenel, Q4 is optionally substituted lower alkylene or optionally substituted lower alkenylene; W1 and W2 are each independently O or S; W3 is O, S or NR12; R12 is a hydrogen atom, lower alkyl, hydroxy lower alkyl, lower alkoxy lower alkyl, lower alkoxycarbonyl lower alkyl, carbocyclic lower alkyl or acyl; R14 is a hydrogen atom or lower alkyl; ring B is an optionally substituted carbocycUc group or an optionally substituted heterocyclic group; Alk2 is optionally substituted lower alkyl; p is lor 2; if there are multiple W1, multiple W2, and multiple R12, each may be independently different; in (xii), the position of an oxygen atom may be cis or trans to a substituent R14, its pharmaceutically acceptable salt, or a solvate thereof. (n) the compound according to (m), wherein ring B is aryl optionally substituted with one or more substituents selected from the group of halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted acyl, optionally substituted amino, cyano, optionally substituted carbamoyl, an optionally substituted carbocyclic group, optionally substituted carbocyclicoxy or an optionally substituted heterocyclic group, or heteroaryl optionally substituted with one or more substituents selected from the group of halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted acyl, optionally substituted amino, cyano, optionally substituted carbamoyl, an optionally substituted carbocyclic group, optionally substituted carbocyclicoxy or an optionally substituted heterocyclic group, its pharmaceutically acceptable salt, or a solvate thereof, (o) the compound according to (m), wherein G is represented by the formula: [Chemical formula 12] wherein, each symbols are the same as described above, its pharmaceutically acceptable salt, or a solvate thereof, (p) the compound according to any one of (e) to (o), wherein R5 is C1 to C3 alkyl, its pharmaceutically acceptable salt, or a solvate thereof, (q) the compound according to any one of (e) to (o), wherein R5 is methyl, its pharmaceutically acceptable salt, or a solvate thereof, (r) the compound according to any one of (e) to (q), wherein R3a and R3b are each independently a hydrogen atom, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkoxy or optionally substituted aryl, its pharmaceutically acceptable salt, or a solvate thereof, (s) the compound according to any one of (e) to (q), wherein R3a and R3b are both hydrogen atoms, its pharmaceutically acceptable salt, or a solvate thereof, (t) a pharmaceutical composition containing the compound according to any one of (e) to (s), its pharmaceutically acceptable salt, or a solvate thereof as an active ingredient, (u) a composition having BACE 1 inhibitory activity containing the compound according to any one of (e) to (s), its pharmaceutically acceptable salt, or a solvate thereof, (v) a composition having BACE 1 inhibitory activity containing the compound according to any one of (a) to (d) or (u) as amyloid β reducing agent, (w) a composition having BACE 1 inhibitory activity according to any one of (a) to (d), (u) or (v) as therapeutic agent for disease induced by production, secretion and/or deposition of amyloid β protein, (x) a composition having BACE 1 inhibitory activity according to any one of (a) to (d), (u) or (v) as therapeutic agent for Alzheimer's disease. in addition, the present invention provides- (y) a method for treating disease induced by production, secretion and/or deposition of amyloid β protein comprising administering the compound as defined in any one of formula (I) in above (a), its pharmaceutically acceptable salt, or a solvate thereof, (z) use of compound as defined in any one of formula (1) in above (a), its pharmaceutically acceptable salt, or a solvate thereof, in the manufacture of a medicament for the treatment of disease induced by production, secretion and/or deposition of amyloid β protein, (aa) a method for treating Alzheimer's disease characterizing in administering the compound as defined in any one of formula (I) in above (a), its pharmaceutically acceptable salt, or a solvate thereof, (ab) use of compound as defined in any one of formula (I) in above (a), its pharmaceutically acceptable salt, or a solvate thereof, in the manufacture of a medicament for the treatment of Alzheimer's disease. [Effect of the Invention] [0009] The compounds in this invention are useful as an agent for treating disease such as Alzheimer's disease induced by production, secretion and/or deposition of amyloid β protein. [Best Mode for Carrying Out the Invention] [0010] As used herein, the "halogen" includes fluorine, chlorine, bromine, and iodine. A halogen part of the "halogeno lower alliyl", the "halogeno lower alkoxy", the "halogeno acyl", the "halogeno lower alkylthio" and the "halogeno lower alkoxycarbonyl" is the same. The "lower alkyl" includes a straight or branched alkyl of a carbon number of 1 to 15, preferably a carbon number of 1 to 10, further preferably a carbon number of 1 to 6, and more further preferably a carbon number of 1 to 3, and examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl, n-nonyl, and n-decyl. A lower alkyl part of the "carbocyclic lower alkyl", the "lower alkoxy", the "halogeno lower alkyl", the "halogeno lower alkoxy", the "halogeno lower alkylthio", the "hydroxy lower alkyl", the "lower alkoxycarbonyl", the "halogeno lower alkoxycarbonyl", the "lower alkoxycarbonyl lower alkyl", the "lower alkoxycarbonyloxy", the "lower alkylamino", the "lower alkylcarbonylamino", the "lower alkoxycarbonylamino", the "lower alkoxy lower alkyl", the "lower alkylcarbamoyl", the "hydroxy lower alkylcarbamoyl", the "amino lower alkyl", the "hydroxy imino lower alkyl", the "lower alkoxy imino lower alkyl", the "lower alkylthio", the "lower alkylsulfonyl", the "lower alkyl sulfamoyl", the "lower alkylsulfinyl", the "lower alkylsulfonyloxy", the "lower alkoxycarbonyl lower alkynyl", the "lower alkylthio lower alkyl", the "aryl lower alkyl", the "aryl lower alkylamino", the "aryl lower alkoxycarbonyl", the "aryl lower alkylcarbamoyl", the "heterocyclic group lower alkylamino" and the "heterocyclic group lower alkylcarbamoyl" is the same as that of the aforementioned "lower alkyl". The example of the "optionally substituted lower alkyl" as a substituent of ring A is lower alkyl optionally substituted with one or more substituents selected from the "substituent group a", "hydroxyimino" and "lower alkoxyimino"; the group defined as above (i), (ii), (iv), (vi), (viii), (x) (wherein each Q1 is optionally substituted lower alkylene); the group defined as (iii), (v), (vii), (ix) (wherein Q2 is optionally substituted lower alkylene); and the group (xii). In other "optionally substituted lower alkyl" is optionally substituted with one or more substituents selected from the "substituent group α" [0011] The "substituent group a" is selected from the group of halogen, hydroxy, lower alkoxy, hydroxy lower alkoxy, lower alkoxy lower alkoxy, acyl, acyloxy, carboxy, lower alkoxycarbonyl, amino, acylamino, lower alkylamino, lower alkylthio, carbamoyl, lower alkylcarbamoyl, hydroxy lower alkylcarbamoyl, sulfamoyl, lower alkylsulfamoyl, lower alkylsulfinyl, cyano, nitro, aryl, and heterocyclic group. Especially as a substituent of the "optionally substituted lower alkyl" in Alk2, halogen, hydroxy, lower alkoxy, lower alkoxy lower alkoxy, lower alkoxycarbonyl, amino, acylamino, lower alkylamino and/or lower alkylthio are preferable. The example of the "optionally substituted lower alkoxy" as a substituent of ring A is lower alkoxy optionally substituted with one or more substituents selected from the above "substituent group a"; above (iii) wherein Q1 is optionally substituted lower alkylene, Q2 is a bond, W2 is O; above (v) wherein Q1 is optionally substituted lower alkylene, Q2 is a bond, W2 is O; above (vi) wherein Q1 is a bond, Q2 is optionally substituted lower alkylene, W2 is O; or above (xi) wherein Q4 is optionally substituted lower alkylene, W2 is O. In other case, the substituents of the "optionally substituted lower alkoxy", the "optionally substituted lower alkoxycarbonyl", the "optionally substituted lower alkoxycarbonyloxy", the "optionally substituted lower alkylsulfonyl", the "optionally substituted lower alkylsulfinyl", the "optionally substituted lower alkylsulfonyloxy" and the "optionally substituted lower alkylthio" are one or more substituents selected from the "substituent group a", [0012] The "lower alkenyl" includes a straight or branched alkenyl of a carbon number of 2 to 15, preferably a carbon number of 2 to 10, further preferably a carbon number of 2 to 6 and more further preferably a carbon number of 2 to 4 having one or more double bonds at an arbitrary position. Specifically examples include vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodenyl, tridecenyl, tetradecenyl, and pentadecenyl. The "lower alkynyl" includes a straight or branched alkynyl of a carbon number of 2 to 10, preferably a carbon number of 2 to 8, further preferably a carbon number of 3 to 6, having one or more triple bonds at an arbitrary position. Specifically, examples include ethynyl, propenyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, and decynyl. These may further have a double bond at an arbitrary position, A lower alkynyl part of the "lower alkoxycarbonyl lower alkynyl" is the same as that of above "lower alkynyl". The example of the "optionally substituted lower alkenyl" as a substituent of ring A is lower alkenyl optionally substituted with one or more substituents selected from the above "substituent group a"J above (0, (ii), (iv), (vi), (viii) or (x), wherein Q1 is optionally substituted lower alkenylene; (iii), (v), (vii) or (ix), wherein Q2 is optionally substituted lower alkenylene. In other case, the substituents of the "optionally substituted lower alkenyl" and the "optionally substituted lower alkynyl" are one or more substituents selected from the "substituent group a". [0013] The example of the "optionally substituted lower amino" as a substituent of ring A is amino optionally substituted with one or more substituents selected from the group of lower alkyl, acyl, hydroxy, lower alkoxy, lower alkoxycarbonyl, a carbocyclic group and a heterocyclic group; (ii), wherein Q1 is a bond; (iv), wherein Q1 is a bond; (v), wherein Q2 is a bond, W3 is NR12; (ix), wherein Q2 is a bond; (xiii); or (xiv). The example of the "optionally substituted carbamoyl" as a substituent of ring A is carbamoyl optionally substituted with one or more substituents selected from the group of lower alkyl, acyl, hydroxy, lower alkoxy, lower alkoxycarbonyl, a carbocyclic group and a heterocyclic group; (i), (viii), wherein each Q1 is bond; or (xv). In other case, the substituents of the "optionally substituted amino", the "optionally substituted amidino", the "optionally substituted carbamoyl", the "optionally substituted carbamoylcarbonyl", and the "optionally substituted carbamoyloxy" are one or two substituents selected from the group of lower alkyl, acyl, hydroxy, lower alkoxy, lower alkoxycarbonyl, a carbocyclic group and a heterocyclic group, and the like. The "acyl" includes acyl of a carbon number of 1 to 10, carbocyclic carbonyl and heterocyclic carbonyl. Specifically, formyl, acetyl, propyonyl, butylyl, isobutylyl, valeryl, pivaloyl, hexanoyl, acryloyl, propioloyl, methacryloyl, crotonoyl, benzoyl, cyclohexanecarbonyl, pyridinecarbonyl, furancarbonyl, thiophenecarbonyl, benzothiazolcarbonyl, pyradinecarbonyl, piperidinecarbonyl, thiomorpholinocarbonyl, and the like. The part of the acyl of the "halogenoacyl", the "acylamino" and the "acyloxy" is the same as the aforementioned "acyl". The substituent of the "optionally substituted acyl" and "optionally substituted acyloxy" is one or more substituents selected from the group of the "substituent group a". The ring part of the "carbocyclic carbonyl" and the "heterocyclic carbonyl" is optionally substituted with one or more substituents selected from the group of "lower alkyl"; the "substituent group a"; and "lower alkyl substituted with one or more substituents selected from the group of the substituent a". [0014] The "carbocyclic group" includes cycloalkyl, cycloalkenyl, aryl and non-aromatic fused carbocyclic group. The "cycloalkyl" includes a carbocyclic group of a carbon number of 3 to 10, preferably a carbon number of 3 to 8, further preferably a carbon number of 4 to 8, and examples include, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl, and the like. The "cycloalkenyl" includes cycloalkenyl having one or more double bonds at an arbitrary position in a ring of the aforementioned cycloalkyl, and examples include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptynyl, cyclooctynyl, and cyclohexadienyl, and the like. The "aryl" includes phenyl, naphthyl, anthryl, and phenanthryl, and the like, and phenyl is particularly preferable. The "non-aromatic fused a carbocyclic group" includes group fused with two or more ring groups selected from the group of the above "cycloalkyl", the "cycloalkenyl" and the "aryl". Specifically, examples include indanyl, indenyl, tetrahydronaphthyl, and fluorenyl, and the like. The carbocyclic part of the "carbocyclicoxy", and the "carbocyclic lower alkyl" is the same as the aforementioned "carbocyclic group". The aryl part of the "aryl lower alkyl", the "aryloxy", the "aryloxycarbonyl", the "aryloxycarbonyloxy", the "aryl lower alkoxycarbonyl", the "arylthio", the "arylamino", the "aryl lower alkylamino", the "arylsulfonyl", the "arylsulfonyloxy", the "arylsulfinyl", the "arylsulfamoyl", the "arylcarbamoyl" and the "aryl lower alkylcarbamoyl" is the same as the aforementioned "aryl". [0015] The "heterocyclic group" includes a heterocyclic group having one or more heteroatoms arbitrary selected from O, S, and N in a ring, specifically includes a 5-to 6-membered heteroaryl such as pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furyl and thienyl; a bicyclic fused heterocyclic group such as indolyl, isoindolyl, indazolyl, indolidinyl, indolinyl, isoindolinyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthridinyl, quinoxalinyl, purinyl, pteridinyl, benzopyranyl, benzimidazolyl, benzioxazolyl, benzoxazolyl, benzoxadiazolyl, benzoisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, pyrazolopyridyl, triazolopyxidyl, imidazothiazolyl, pyrazinopyridazinyl, quinazolinyl, quinolyl, isoquinolyl, naphthyridinyl, dihydrobenzofuryl, tetrahydroquinolyl, tetrahydroisoquinolyl, dihydrobenzoxazine, tetrahydrobenzothienyl; a tricyclic fused heterocyclic group such as carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, dibenzofuryl, and imidazoquinolyl; a non-aromatic heterocyclic group such as dioxanyl, thiiranyl, oxyranyl, oxathioranyl, azethidinyl, thianyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, dihydropyridyl, dihydrobenzoimidazolyl, tetrahydropyridyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiazolyl, tetrahydroisothiazolyl, dihydroxadinyl, hexahydroazepinyl, tetrahydroazepyinyl. Preferable is a 5- to 6-membered heteroaryl, or a non-aromatic heterocyclic group. The heterocyclic part of the "heterocyclicoxy", the "heterocyclic thio", the "heterocyclic carbonyl", the "heterocyclic amino", the "heterocyclic carbonylamino", the "heterocyclic sulfamoyl", the "heterocyclic sulfonyl", the "heterocyclic carbamoyl", the "heterocyclicoxycarbonyl", the "heterocyclic lower alkylamino" and the "heterocyclic lower alkyl carbamoyl" is the same as the aforementioned "heterocyclic group". [0016] The example of the substituent of the "optionaUy substituted carbocyclic group" and the "optionally substituted heterocyclic group" in ring A isi the substituent a, wherein preferable is for example, halogen, hydroxy, acyl, acyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, amino, lower alkylamino, lower alkylthio; lower alkyl substituted with one or more substituents selected from the group of substituent a, wherein preferable is halogen, hydroxy, lower alkoxy, lower alkoxycarbonyl, and the like; amino lower alkyl substituted with one or more substituents selected from the group of substituent a, wherein preferable is acyl, lower alkyl and /or lower alkoxy, and the like; hydroxyimino lower alkyl; lower alkoxyimino lower alkyl; lower alkenyl substituted with one or more substituents selected from the group of substituent a, wherein preferable is lower alkoxycarbonyl, halogen and /or halogeno lower alkoxycarbonyl, and the like; lower alkynyl substituted with one or more substituents selected from the group of substituent a, wherein preferable is for example, lower alkoxycarbonyl, lower alkoxy substituted with one or more substituents selected from the group of substituent a, wherein preferable is for example, lower alkyl carbamoyl and /or hydroxy lower alkyl carbamoyl, lower alkylthio substituted with one or more substituents selected from the group of substituent a, lower alkylamino substituted with one or more substituents selected from the group of substituent a, lower alkylsidfonyl substituted with one or more substituents selected from the group of substituent a, aryl lower alkoxycarbonyl substituted with one or more substituents selected from the group of substituent a, azido, and lower alkyl, acyl substituted with one or more substituents selected from the group of substituent a, cycloalkyl substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl, lower alkylsulfinyl substituted with one or more substituents selected from the group of substituent a, sulfamoyl, aryl substituted with one or more substituents selected from the group of substituent a, azido, and lower alkyl, heterocyclic group substituted with one or more substituents selected from the group of substituent a, azido, and lower alkyl, aryloxy substituted with one or more substituents selected from the group of substituent a, azido, and lower alkyl, heterocyclicoxy substituted with one or more substituents selected from the group of substituent a, azido, and lower alkyl, arylthio substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl, heteroarylthio substituted with one or more substituents selected trom the group ot substituent α, azido, and lower alkyl, arylamino substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl, heterocyclicamino substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl, aryl lower alkylamino substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl, heterocyclic lower alkylamino substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl, lower alkyl sulfamoyl substituted with one or more substituents selected from the group of substituent α, aryl sulfamoyl substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl, heterocyclic sulfamoyl substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl, arylsulfonyl substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl, heterocyclic sulfonyl substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl, aryl carbamoyl substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl, heterocyclic carbamoyl substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl, aryl lower alkylcarbamoyl substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl, heterocyclic lower alkylcarbamoyl substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl, aryloxycarbonyl substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl, heterocyclicoxycarbonyl substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl, lower alkylenedioxy optionally substituted with halogen; oxo; azido; [Chemical formula 13] wherein Q1, Q2 and Q3 are each independently a bond, optionally substituted lower alkylene or optionally substituted lower alkenylene; Q4 is optionally substituted lower alkylene or optionally substituted lower alkenylene; W1 and W2 are each independently 0 or S; W3 is O, S or NR12; R12 is a hydrogen atom, lower alkyl, hydroxy lower alkyl, lower alkoxy lower alkyl, lower alkoxycarbonyl lower alkyl, carbocyclic group lower alkyl or acyl; R14 is a hydrogen atom or lower alkyl; ring B is an optionally substituted carbocyclic group or an optionally substituted heterocyclic group J Alk2 is optionally substituted lower alkyl; and the ring A is optionally substituted with one or more substituents selected from these groups. If there are multiple W1 multiple W3, and multiple R12 each may be independently different. In addition, an oxygen atom in (xii) may be cis or trans position to the substituent R14, The substituent of the "substituted phenyl" is, in the same way, phenyl substituted with one or two substituents selected preferably from the group of the substituent α, or (i) to (xv). [0017] The substituent of the "optionally substituted carbocyclic group" or the "optionally substituted heterocyclic group" in ring B is optionally substituted with one or more substituents selected from the following group of, for example; the substituent α, wherein preferable is halogen, hydroxy, lower alkoxy, carboxy, lower alkoxycarbonyl, acyl, amino, lower alkylamino, acylamino, carbamoyl, lower alkylcarbamoyl, cyano, and nitro, and the like; lower alkyl substituted with one or more substituents selected from the group of the substituent α, wherein preferable is halogen, hydroxy, and lower alkoxy, and the like; amino lower alkyl, hydroxyimino lower alkyl, or lower alkoximino lower alkyl, substituted with one or more substituents selected from the group of substituent α; lower alkenyl substituted with one or more substituents selected from the group of substituent α, lower alkynyl substituted with one or more substituents selected from the group of substituent α; lower alkoxy substituted with one or more substituents selected from the group of substituent α, wherein preferable is halogen, hydroxy, and the like; lower alkylthio substituted with one or more substituents selected from the group of substituent α, wherein preferable is halogen; lower alkylamino substituted with one or more substituents selected from the group of substituent α, wherein preferable is amino; lower alkylsulfonyl substituted with one or more substituents selected from the group of substituent α,; aryl lower alkoxycarbonyl substituted with one or more substituents selected from the group of substituent α, and lower alkyl; acyl substituted with one or more substituents selected from the group of substituent α, wherein preferable is halogen; lower alkylsulfonyl substituted with one or more substituents selected from the group of substituent α,; sulfamoyl; lower alkyl sulfamoyl substituted with one or more substituents selected from the group of substituent α,; cycloalkyl substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl; aryl substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl; heterocyclic group substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl, wherein preferable is halogen, lower alkyl, and the like; aryloxy substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl; heterocyclicoxy substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl; arylthio substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl, wherein preferable is halogen, hydroxy, lower alkoxy, acyl, and the like! heterocyclic thio substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl; arylamino substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl, wherein preferable is halogen, hydroxy, lower alkoxy, acyl; heterocyclic amino substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl; aryl lower alkylamino substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl, wherein preferable is halogen, hydroxy, lower alkoxy, acyl; heterocyclic lower alkylamino substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl; arylsulfamoyl substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl; heterocyclic sulfamoyl substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl; arylsulfonyl substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl; heterocyclic sulfonyl substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl; arylcarbamoyl substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl; heterocyclic carbamoyl substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl; aryl lower alkylcarbamoyl substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl; heterocyclic lower alkylcarbamoyl substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl; aryloxy carbonyl substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl; heterocyclicoxycarbonyl substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl; lower alkylenedioxy optionally substituted with halogen; oxoJ and the like. [0018] In other case, the substituent of the "optionally substituted carbocyclic group", the "optionally substituted heterocyclic group", the "optionally substituted carbocyclicoxy", the "optionally substituted arylsulfonyl", the "optionally substituted aryloxycarbonyloxy", the "optionally substituted heterocyclicoxy", the "optionally substituted arylsulfinyl", the "optionally substituted arylsulfonyloxy", the "optionally substituted arylthio" is one or more substituents selected from the group of "lower alkyl" and the "substituent α,". "heteroaryl" include aromatic ring group in the aforementioned "heterocyclic group". The substituent of the "optionally substituted 5' to 6-membered heteroaryl" is the same as the substituent of the "optionally substituted heterocyclic group" in the aforementioned "ring B". Preferable is one or more substituent selected from lower alkyl and a substituent α, [0019] The "lower alkylene" includes a straight or branched bivalent carbon chain of a carbon number of 1 to 10, preferably a carbon number of 1 to 6, further preferably a carbon number of 1 to 3. Specifically, examples include methylene, dimethylene, trimethylene, teteramethylene, and methyltrimethylene, and the like. The part of lower alkylene of the "lower alkylenedioxy" is the same as the aforementioned "lower alkylene". The "lower alkenylene" includes a straight or branched bivalent carbon chain of a carbon number of 2 to 10, preferably a carbon number of 2 to 6, further preferably a carbon number of 2 to 4 having double bond at an arbitrary position. Specifically, examples include vinylene, propenylene, butenylene, butadienylene, methylpropenylene, pentenylene, and hexenylene, and the like. The "lower alkynylene" includes a straight or branched bivalent carbon chain of a carbon number of 2 to 10, preferably a carbon number of 2 to 6, further preferably a carbon number of 2 to 4 having triple bond at an arbitrary position. Specifically, examples include ethynylene, propynylene, butynylene, pentynylene, and hexynylene, and the like. The substituent of the "optionally substituted lower alkylene", the "optionally substituted lower alkenylene", the "optionally substituted lower alkynylene" is the substituent α, preferable is halogen, hydroxy and the like. [0020] The "each R3a, each R3b, each R4a, and each R4b may be independently different" means when n is 2 or 3, two or three R3a may be independently different, and two or three R3b may be independently different. In the same way, when m is 2 or 3, two or three R4a may be independently different, and two or three R4b may be independently different. [0021] [Chemical formula 14] wherein each symbols are the same as described above; preferably, R5a and R5b are all hydrogen atoms. [0022] In this description, "solvate" includes, for example, a solvate with an organic solvent and a hydrate, and the like. When hydrate is formed, arbitrary number of water molecules may be coordinated. The compound (I) includes a pharmaceutically acceptable salt. Examples include salts with alkali metals (lithium, sodium or potassium, and the like), alkaline earth metals (magnesium or calcium, and the like), ammonium, organic bases or amino acids, and salts with inorganic acids (hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid or hydroiodic acid, and the like), and organic acid (acetic acid, trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid, manderic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, or ethanesulfonic acid, and the like). Particularly, hydrochloric acid, phosphoric acid, tartaric acid, or methanesulfonic acid is preferable. These salts can be formed by a conventional method. In addition, the compound (I) is not limited to a specific isomer, but includes all possible isomers (keto-enol isomer, imine-enamine isomer, diastereo isomer, optical isomer, and rotational isomer, and the like) and racemates. For example, the compound (I), wherein R2a is a hydrogen atom, includes following tautomer, [Chemical formula 16] [0023] The compound (I) in this invention can be prepared by the process described in, for example Non-patent Document 1 or following process. [0024] The synthesis of aminodihydrothiazine ring; Method A [Chemical formula 17] In formula, at least either R2b or R3c is a hydrogen atom, either R3c= or R3d is each independently a hydrogen atom, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted acyl, carboxy, optionally substituted lower alkoxycarbonyl, optionally substituted amino, optionally substituted carbamoyl, an optionally substituted carbocyclic group or an optionally substituted heterocyclic group. Other symbols are the same as described above. (Step 1) To a solution of compound (a), which is commercially avsiilable or prepared by known method, in appropriate solvent or mixture of solvents, such as ether, tetrahydrofuran, and the like is added the Grignard reagent having substituent corresponds to the target compound; for example vinylmagnesium chloride, vinylmagnesium bromide, or propenylmagnesium bromide, and the like! at -100°C to 50°C, preferably -80°C to 0°C. The mixture is reacted for 0.2 to 24 hours, preferably 0.5 to 5 hours, to obtain compound (b). (Step 2) The compound (b) in solvent, such as toluene or absence of solvent is treated with thiourea derivatives having substituent corresponds to the target compound, such as thiourea, N-methylthiourea, N,N'-dimethylthiourea, and the like in the presence of an acid or mixture of acids, such as acetic acid, trifluoroacetic acid, hydrochloric acid, or sulfuric acid, and the like. The mixture is reacted at -20°C to 100°C, preferably 0°C to 50°C for 0.5 to 120 hours, preferably 1 to 72 hours, to obtain the compound (c). (Step 3) The compound (c) in solvent, such as toluene or absence of solvent is treated with an acid or mixture of acids, such as trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, and the like. The mixture is reacted at ■20°C to 100°C, preferably 0°C to 50°C for 0.5 to 120 hours, preferably 1 to 72 hours, to obtain the compound (l"2), wherein R2b is a hydrogen atom, or the compound (I-l), wherein R2c is a hydrogen atom. [0025] The synthesis of aminodihydrothiazine ring; Method B In formula, L is leaving group such as halogen or sulfonyloxy, and the like. Other symbols are the same as described above. (Step 1) The compound (d) which is commercially available or prepared by known method is reacted with thiocyanic acid; for example, sodium thiocyanic acid, ammonium thiocyanic acid, and the like; in solvent; for example, toluene, chloroform, tetrahydrofuran, and the like; in the presence of acid; for example, water, hydrochloric acid, sulfuric acid, and the hke; at 0°C to 150°C, preferably 20°C to 100°C for 0.5 to 24 hours, preferably 1 to 12 hours, to obtain the compound (e), (Step 2) To the compound (e) in solvent or mixture of solvents; for example, tetrahydrofuran, methanol, ethanol, water, and the like; in the presence or the absence of buffer hke sodium dihydorgen phosphate, and the Hke; reducing agent; for example sodium borohydride, and the like; is added and the mixture is reacted at -80°C to 50°C, preferably -20°C to 20°C for 0.1 to 24 hours, preferably 0.5 to 12 hours, to obtain the compound (f). (Step 3) The compound (f) in the presence or the absence of solvent; for example, toluene, dichloromethane, and the like; is reacted with halogenating agent; for example thionyl chloride, phosphorus oxychloride, carbon tetrabromide-triphenylphosphine, and the like; at -80°C to 50°C, preferably -20°C to 20°C for 0.1 to 24 hours, preferably 0.5 to 12 hours, to obtain the compound (g). Alternatively, the compound (f) in the presence or the absence of solvent; for example, toluene, dichloromethane, and the like; under base; for example triethylamine, and the hke; is reacted with sulfonating agent; for example, methanesulfonyl chloride, p-toluenesulfonylchloride, and the like; at -80°C to 50°C, preferably -20°C to 20°C for 0.1 to 24 hours, preferably 0.5 to 12 hours, to obtain the compound (g), (Step 4) To the compound (g) in solvent or mixture of solvents, for example methanol, ethanol, water, and the Hke; is reacted with primary amine; for example, ammonia or methylamine, and the Hke; at -20°C to 80°C, preferably 0°C to 40°C for 0.5 to 48 hours, preferably 1 to 24 hours, to obtain the compound (1-3), [0026] The synthesis of aminodihydrothiazine ring; Method C [Chemical formula 19] In formula, R is a hydrogen atom or protective groups of carboxyl group. Other symbols are the same as described above. (Step 1) The compound (h) which is commercially available or prepared by known method is reacted with reducing agent; for example, lithium aluminium hydride, diisobutyl aluminium hydride, and the like; in solvent; for example tetrahydrofuran, ether, and the like; at -80°C to 150°C, preferably 25°Cto 100°C for 0.1 to 24 hours, preferably 0.5 to 12 hours, to obtain the compound (i). (Step 2) The compound (i) in solvent; for example, toluene, chloroform, tetrahydrofuran, and the like; in the presence or the absence of base; for example, diisopropylethylamine, triethylamine, pyridine, sodium hydroxide, and the like; is reacted with corresponding isothiocyanate; for example, 4-methoxybenzylisothiocyanate, t-butylisothiocyanate, and the like; or corresponding thiocarbamoylhalide; for example, N,N-dimethylthiocarbamoylchloride, N,N-diethylthiocarbamoylchloride, and the like; at 0°C to 150°C, preferably 20°C to 100°Cfor 0.5 to 120 hours, preferably 1 to 72 hours, to obtain the compound (j). (Step 3) The compound (j) in solvent; for example, acetonitrile, toluene, dichloromethane, and the like; is reacted with halogenating agent; for example thionyl chloride, phosphorus oxychloride, carbon tetrabromide-triphenylphosphine, and the like; at -80°C to 50°C, preferably -20°C to 20°C for 0.1 to 24 hours, preferably 0.5 to 12 hours, or alternatively, the compound (j) in solvent; for example, toluene, dichloromethane, and the like; in the presence of base; for example triethylamine, and the like; is reacted with sulfonating agent; for example, methanesulfonyl chloride, p-toluenesulfonylchloride, and the like; at -80°C to 50°C, preferably -20°C to 20°Cfor 0.1 to 24 hours, preferably 0.5 to 12 hours. The obtained halogenated compound or sulfonylated compound is reacted with base; for example, diisopropylamine, potassium carbonate, sodium hydrogencarbonate, sodium hydride, sodium hydroxide, and the like; at 0°C to 150°C, preferably 20°C to 100°C for 0,5 to 120 hours, preferably 1 to 72 hours, to obtain the compound (1-4). [0027] The synthesis of aminodihydrothiazine ring; Method D The synthesis of aminothiazoline ring; Method A The synthesis of tetrahydrothiazepine ring; Method A [Chemical formula 20] In formula, L is leaving group such as halogen or sulfonyloxy, and the like; m is an integer of 1 to 3; and the other symbols are the same as described above. (Step 1) The compound (k) which is commercially available or prepared by known method is reacted with azide reagent; for example, sodium azide, and the like! in solvent; for example N,N-dimethylformamide, tetrahydrofuran, and the like; at 0°C to 200°C, preferably 40°C to 150°C for 0.5 to 24 hours, preferably 1 to 12 hours, to obtain the compound (D. (Step 2) The compound (1) is reacted with reducing agent; for example, lithium aluminium hydride, diisobutyl aluminium hydride, and the like; in solvent; for example tetrahydrofuran, ether, and the like; at -80°C to 150°C, preferably 25**Cto 100°C for 0.1 to 24 hours, preferably 0.5 to 12 hours, to obtain the compound (m). (Step 3) The compound (m) in solvent; for example, toluene, chloroform, tetrahydrofuran, and the like; is reacted with corresponding isothiocyanate; for example, methylisothiocyanate, ethyHsothiocyanate, and the Hke; or corresponding thiocarbamoylhalide; for example, N,N-dimethylthiocarbamoylchloride, N,N"diethylthiocarbamoylchloride, and the like; at 0°C to 150°C, preferably 20°C to 100°C for 0.5 to 120 hours, preferably 1 to 72 hours, to obtain the compound (n), (Step 4) The compound (n) in solvent; for example, acetonitrile, toluene, dichloromethane and the like; is reacted with halogenating agent; for example thionyl chloride, phosphorus oxychloride, carbon tetrabromide-triphenylphosphine, and the like; at -80°C to 50°C, preferably -20°C to 20°C for 0.1 to 24 hours, preferably 0.5 to 12 hoiirs, or alternatively, the compound (n) in solvent; for example, toluene, dichloromethane, and the like; in the presence of base; for example diisopropylethylamine, triethylamine, and the like; is reacted with sulfonating agent; for example, methanesulfonyl chloride, p-toluenesulfonylchloride, and the like; at -80°C to 50°C, preferably ■20°C to 20°C for 0.1 to 24 hours, preferably 0.5 to 12 hours. The obtained halogenated compound or sulfonylated compound is reacted with base; for example, diisopropylamine, potassium carbonate, sodium hydrogencarbonate, sodium hydride, sodium hydroxide, and the like; at 0°C to 150°C, preferably 20°C to 100°C for 0.5 to 120 hours, preferably 1 to 72 hours, to obtain the compound (1-5). [0028] The synthesis of aminodihydrothiazine ring; Method E The synthesis of aminothiazohne ring; Method B The synthesis of tetrahydrothiazepine ring; Method B [Chemical formula 2l] In formula, at lease one of R3b and R3c is a hydrogen atom, n is an integer of 1 to 3, and the other symbols are the same as described above. (Step 1) The compound (o) which is commercially available or prepared by known method is reacted with substituted thiourea; for example, thiourea, N-methylthiourea, N,N,"dimethylthiourea, N,N'-dimethylthiourea, and the like; in solvent; for example, ethanol, methanol, tetrahydrofuran, toluene, and the like; at -20°C to 200°C, preferably 0°C to 150°C for 0.5 to 200 hours, preferably 1 to 120 hours, to obtain the compound (p). (Step 2) To the compound (p) in solvent or mixture of solvents! for example, ether, tetrahydrofuran, and the like; the Grignard reagent having substituent corresponding to target compound; for example methylmagnesium chloride, ethylmagnesium bromide, or benzylmagnesium bromide, and the like; is added at -100°C to 50°C, preferably -80°C to 30°C, and the mixture is reacted for 0,2 to 24 ho\irs, preferably 0.5 to 5 hours, to obtain the compound (q). (Step 3) To the compound (q) in the presence or the absence of solvent; for example, toluene, and the like; acid or mixture of acids, such as trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, and the like; is added and the mixture is reacted at -20°C to 100°C, preferably 0°C to 50°C for 0.5 to 200 hours, preferably 1 to 150 hours, to obtain the compound (I-6)(wherein R2c is H), or the compound (I-7) (wherein R2b ig jj). [0029] In formula, each symbols are the same as described above. (Step 1) The compound (r) which is commercially available or prepared by known method is reacted with ammonium chloride in solvent; for example, acetic acid, and the like; at 0°C to 200°C preferably 10°C to 100°C for 0.1 to 100 hours, preferably 0.5 to 24 hours, to obtain the compound (s). (Step 2) The compound (s) is reacted with reducing agent; for example, lithium aluminium hydride, diisobutyl aluminium hydride, and the like; in solvent; for example tetrahydrofuran, ether, and the hke; at -80°C to 150°C, preferably 0°C to 100°C for 0.1 to 24 hours, preferably 0.5 to 12 hours, to obtain the compound (t). . (Step 3) The compound (t) in solvent; for example, toluene, chloroform. tetrahydrofuran, and the like; in the presence or the absence of base; for example, diisopropylethylamine, triethylamine, pyridine, sodium hydroxide, and the like! is reacted with corresponding isothiocyanate; for example, 4-methoxybenzylisothiocyanate, t"butylisothiocyanate, and the like; or corresponding carbamoylhalide; for example, N,N-dimethylthiocarbamoylchloride, N,N-diethylthiocarbamoylchloride, and the like; at 0°C to 150°C, preferably 20°C to 100°C for 0.5 to 120 hours, preferably 1 to 72 hours, to obtain the compound (u). (Step 4) The compound (u) in solvent; for example, acetonitrile, toluene, dichloromethane, and the like; is reacted with halogenating agent; for example thionyl chloride, phosphorus oxychloride, carbon tetrabromide-triphenylphosphine, and the like; at -80°C to 50°C, preferably -20°C to 20°C for 0.1 to 24 hours, preferably 0.5 to 12 hours, or alternatively, the compound (u) in solvent; for example, toluene, dichloromethane, and the like; in the presence of base; for example triethylamine, and the like; is reacted with sulfonating agent; for example, methanesulfonyl chloride, p-toluenesulfonylchloride, and the like! at -80°C to 50°C, preferably "20°Co 20°C for 0.1 to 24 hours, preferably 0.5 to 12 hours. The obtained halogenated compound or sulfonylated compound is reacted with base; for example, diisopropylamine, potassium carbonate, sodium hydrogencarbonate, sodium hydride, sodium hydroxide, and the hke; at 0°Cto 150°C, preferably 20°C to 100°C for 0.5 to 120 hours, preferably 1 to 72 hours, to obtain the compound (1-8). [0030] The synthesis of aminodihydrooxazine ring; Method A The synthesis of aminotetrahydrooxazepine ring; Method A [Chemical formula 23] In formula, each symbols are the same as described above. (Step 1) The compound (n) which is obtained by Step 3(the compound (m) to the compound (n)) of "The synthesis of aminodihydrothiazine ring; Method D", in solvent; for example, methanol, ethanol, N,N-dimethylformamide, tetrahydrofuran, and the like; in the presence or the absence of base; for example, diisopropylethylamine, triethylamine, pyridine, sodium hydroxide, and the lite; is reacted with alkylating agent; for example, methyl iodide, dimethyl sulfate, benzyl bromide, and the like; at 0°C to 200°C, preferably 40°C to 150°C for 0.1 to 48 hours, preferably 0.5 to 24 hours, to obtain the compound (v). (Step 2) The compound (v) in solvent; for example, N, N-dimethylformamide, tetrahydrofuran, dichloromethane, and the like; in the presence or the absence of base; for example, diisopropylethylamine, triethylamine, pyridine, sodium hydroxide, and the like; is reacted with metallic oxide; for example, silver oxide, mercury oxide, manganese dioxide, and the like; at 0°C to 200°C, preferably ICC to 150°Cfor 1 to 120 hours, preferably 0.5 to 100 hours, to obtain the compound (1-9). [0031] The synthesis of aminodihydrooxazine ring; Method B The synthesis of aminoxazoline ring The synthesis of aminotetrahydrooxazepine ring; Method B [Chemical formula 24] In formula, R15 is optionally substituted lower alkyl; for example, t-butyl, benzyl, and the like; R16 is hydrogen atom or lower alkyl; n is an integer of 1 to 3, and the other symbols are the same as described above. (Step 1) The compound (w) which is commercially available or prepared by known method in solvent; for example, toluene, t-butylalcohol, tetrahydrofuran, and the like; in the presence of base; for example, diisopropylethylamine, triethylamine, pyridine, and the like; is reacted with azide reagent; for example, diphenyl phosphoryl azide, and the like; at 0°Cto 200°C, preferably 40°C to 150°C for 1 to 48 hours, preferably 0.5 to 24 hours, to obtain the compound (x). (Step 2) The compound (x) in solvent; for example, toluene, xylene, N,N-dimethylformamide, tetrahydrofuran, and the like; is reacted with alcohol; for example, t-butylalcohol, 3,4-dimethoxybenzylalcohol, 4-methoxybenzylalcohol, and the like; at 0°C to 300°C, preferably 50°C to 200°C for 1 to 800 hours, preferably 5 to 500 hours, to obtain the compound (y). (Step 3) The compound (y) in the presence or the absence of solvent; for example, water, toluene, dichloromethane, methanol, 1,4-dioxane, acetic acid, ethyl acetate, and the likeJ in the presence of acid; for example, hydrochloric acid, sulfuric acid, hydrobromic acid, trifluoroacetic acid, and the like; at 0°C to 200°C, preferably 25°C to 150°Cfor 0.1 to 48 hours, preferably 0.5 to 24 hours, to obtain the compound (z). (Step 4) The compound (z) in solvent; for example, toluene, chloroform, tetrahydrofuran, and the like; in the presence of base; for example, diisopropylethylamine, triethylamine, pyridine, and the like; is reacted with corresponding isothiocyanate, or thiocarbamoylhalide corresponding to target compound; for example, N,N"dimethylthiocarbamoylchloride, N,N-diethylthiocarbamoylchloride, and the like; at 0°C to 150°C, preferably 20°C to 100°C for 0.5 to 120 hours, preferably 1 to 72 hours, to obtain the compound (aa). (Step 5) The compound (aa) in solvent; for example, methanol, ethanol, N,N-dimethylformamide, tetrahydrofuran, and the like; in the presence or the absence of base; for example, diisopropylethylamine, triethylamine, pyridine, sodium hydroxide, and the like; is reacted with alkylating agent; for example, methyl iodide, dimethyl sulfate, benzyl bromide, and the like; at 0°C to 200°C preferably 40°C to 150°C for 1 to 48 hours, preferably 0.5 to 24 hours, to obtain the compound (ab). (Step 6) The compound (ab) in solvent; for example, N,N-dimethylformamide, tetrahydrofuran, dichloromethane, and the like; in the presence of base; for example, diisopropylethylamine, triethylamine, pyridine, sodium hydroxide, and the like; is reacted with metallic oxide; for example, silver oxide, mercury oxide, manganese dioxide, and the like; at 0°C to 200°C, preferably 10°C to 150°C for 1 to 120 hours, preferably 0.5 to 100 hours, to obtain the compound (I-10). [0032] The synthesis of aminotetrahydropyrimidine ring [Chemical formula 25] In formula, each symbols are the same as described above. (Step 1) To the compound (ac) prepared by known method in solvent; for example, N,N-dimethylformamide, methanol, and the like! is reacted with azide reagent; for example, sodium azide, lithium azide, and the like; at 20°C to 150°C, preferably 50°C to 100°C for 0.5 to 120 hours, preferably 1 to 72 hours, to obtain the compound (ad). (Step 2) To the suspension of lithium aluminium hydride in solvent; for example, tetrahydrofuran, or ether, and the Like; the compound (ad) dissolved in solvent; for example, tetrahydrofuran, or diethyl ether, and the like; is added under nitrogen atmosphere, at -30°C to 20°C, preferably -30°C to 0°C, and the mixture is reacted for 1 minute to 10 hours, preferably 10 minutes to 1 hour, or alternatively to the compound (ad) in solvent; for example, ethanol, isopropanol, or n-butanol, and the like; Raney-Nickel is added at 10 °C to 110°C, preferably 50°C to 80°C, and reacted for 1 minute to 10 hours, preferably 10 minutes to 1 hour, to obtain the compound (ae). (Step 3) The compound (ae) in solvent; for example, tetrahydrofuran, dichloromethane, and the like; in the presence of acid; for example, acetic acid, or propionic acid, and the like; is reacted with reducing agent; for example, sodium cyanoborohydride, sodium triacetoxyborohydride, and the like; at -50 °C to 100°C, preferably 0°C to 50°C, for 0.1 to 48 hours, preferably 0.5 to 24 hours, or the compound (ae) in solvent; for example, tetrahydrofuran, N,N-dimethylformamide, and the like; in the presence of dehydrating agent; for example, l-ehthyl-3-(3-dimethylaminopropyl)carbodiimide-N-hydroxybenzotria2ole, carbonyldiimidazole, and the like; or in the presence of base; for example, triethylamine, potassium carbonate, and the Like; is reacted with carboxyUc acid; for example, formic acid, acetic acid, and the like! at ■50°C to 100°C, preferably O'°C to 50°C for 0.1 to 48 hours, preferably 0.5 to 16 hours, to obtain the compound (af). And next, to the suspension of lithium aluminium hydride in solvent; for example, tetrahydrofuran, or diethyl ether, and the like; the aforementioned amide compound dissolved in solvent; for example, tetrahydrofuran, or ether, and the Like; is added at -50°C to GO'°C, preferably 0°C to SO'°C, and the mixture is reacted for 1 minute to 48 hours, preferably 10 minutes to 10 hours, to obtain the compound (a£). (Step 4) The compound (ae) or the compound (a£) in solvent; for example, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, and the like; is reacted with 3,5-dimethylpyrazole-l-carboxyamidine or S-methylthiourea at 0°C to 150°C, preferably 20°C to 100°C, and the mixture is reacted for 0,5 to 120 hours, preferably 1 to 24 hours, to obtain the compound (ag). (Step 5) To the compound (ag) (wherein at least either R2b or R2c is a hydrogen atom) in the presence or the absence of solvent; for example, toluene, and the like; acid; for example, trifluoroacetic acid, methane sulfonic acid, trifluoromethanesulfonic acid, and the like, or the mixture thereof is added and the mixture is reacted at -20°C to 100°C, preferably 0°C to 50°C, and the mixture is reacted for 0.5 to 120 hours, preferably 1 to 72 hours, to obtain the compound (1-2) (wherein R2b is a hydrogen atom) or the compound (l-l) (wherein R2c is a hydrogen atom) respectively. Proviso, if R2a, R2b , and 3b have fragile structure under acidic condition; for example, t'butyloxycarbonyl, and the like; R2a, R2b, and R2c in the compound (J-l) or the compound (1-2) may be transformed into a hydrogen atom. [0033] The synthesis of aminothiazoline ring; Method C [Chemical formula 26] I In formula, Hal is halogen, and other symbols are the same as described above. (Step 1) The compound (ah) which is commercially available or prepared by known method in solvent; for example, toluene, chloroform, tetrahydrofuran, and the like; or in mixed-solvent; for example, chloroform-water, and the like; is reacted with halogen; for example, including iodine, bromine, chorine; phase transfer catalyst; for example, sodium thiocyanic acid, ammonium thiocyanic acid, and the like; at 0°C to 150°C, preferably 20°C to 100°C, for 0,5 to 48 hours, preferably 1 to 24 hours, to obtain the compound (ai). (Step 2) The compound (ai) in solvent; for example, toluene, chloroform, tetrahydrofuran, and the like; is reacted with amine having substituent corresponding to target compound; for example ammonia, methylamine, diethylamine, and the like; at 0°C to 150°C, preferably 20°C to 100°C, for 0.5 to 48 hours, preferably 1 to 24 hours, to obtain the compound (Ml). [0034] The aminoacyl derivative-1 In formula, R17 is optionally substituted lower alkyl, an optionally substituted carbocyclic group or an optionally substituted heterocyclic group, and the other symbols are the same as described above. The compound (1-12) wherein R2b is a hydrogen atom in the presence or the absence of solvent; for example, tetrahydrofuran, dichloromethane, and the like; in the presence of base; for example, pyridine, trie thy lamine, and the like; is reacted with acylating agent having substituent corresponding to target compound; for example, benzoyl chloride, 2-furoyl chloride, acetic anhydride, and the like; at -80°C to 100°C, preferably -20°C to 40°C, for 0.1 to 24 hours, preferably 1 to 12 hours, or alternatively, the compound (1-12) in solvent; for example, N,N-dimethylformamide, tetrahydrofuran, dichloromethane, and the like; in the presence of dehydrating agent; for example, dicyclohexylcarbodiimide, carbonyldiimidazole, and the Lite; is reacted with carboxylic acid having substituent corresponding to target compound; for example, amino acid, glycolic acid, and the Kke; at -80°C to 100°C, preferably -20°C to 40°C, for 0.1 to 24 hours, preferably 1 to 12 hours, to obtain the compound (1-13) and/or the compound (1-14) (wherein R2a is a hydrogen atom). [0035] The guanidino derivatives In formula, each symbols are the same as described above. The compound (I" 12) wherein R2b is a hydrogen atom in solvent; for example, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, and the like; in the presence or the absence of base; for example, triethylamine, sodium hydrogencarbonate, and the like; is reacted with 3,5-dimethylpyrazole-l-carboxyamidine, or S-methylisothiourea etc. at 0°C to 150°C preferably 20'°C to 100°C, for 0.5 to 120 hours, preferably 1 to 24 hours, to obtain the compound (1-15). [0036] The carbamoyl derivatives [Chemical formula 29] In formula, CONR18R19 is optionally substituted carbamoyl, and the other symbols are the same as described above. The compound (1-16) having a carboxyl group as substituent of ring A in solvent; for example, N,N-dimethylformamide, tetrahydrofuran, dichloromethane, and the like; in the presence of dehydrating agent; for example. dicyclohexylcarbodiimide, carbonyldiimidazole, dicyclohexylcarbodiimide-N-hydroxybenzotriazole, and the like; is reacted with primary amine or secondary amine (aniline, 2'aminopyridine, dimethylamine etc.) at -80°C to 100°C, preferably -20°C to 40°C, for 0.1 to 24 hours, preferably 1 to 12 hours, to obtain the compound (I-17). [0037] The acylamino derivative-2 [Chemical formula 30] In formula, NHR20 is optionally substituted amino; NR20COR21 is optionally substituted acyl amino, optionally substituted ureido, carboxy amino having substituent on oxygen atom, and the other symbols are the same as described above. The compound (1-18) having an optionally substituted amino group on ring A in the presence or the absence of solvent; for example, tetrahydrofuran, dichloromethane, and the like; in the presence or the absence of base; for example, pyridine, triethylamine, and the like; is reacted with reagent including acid chloride, acid anhydride, chloroformate ester derivatives, isocyanate derivatives (benzoyl chloride, 2-furoyl chloride, acetic anhydride, benzyl chloroformate, di-t-butyl dicarbonate, phenyl isocyanate etc.), at -80°C to 100°C, preferably ■20°C to 40°C, for 0.1 to 24 hours, preferably 1 to 12 hours. Or alternatively, the compound (1-18) having an optionally substituted amino group on ring A in solvent; for example, N,N-dimethylformamide, tetrahydrofuran, dichloromethane, and the like; in the presence of dehydrating agent; for example, dicyclohexylcarbodiimide, carbonyldiimidazole, dicyclohexylcarbodiimide-N-hydroxybenzotriazole, and the like; is reacted with carboxylic acid having substituent corresponding to target compound; for example, benzoic acid, 2-pyridinecarboxylic acid, and the like; at -80°C to 100°C, preferably -20°C to 40°C, for 0.1 to 24 hours, preferably 1 to 12 hours, to obtain the compound (1-19). [0038] The alkylamino derivatives [Chemical formula 31] In formula, NHR20 is optionally substituted amino, R22 is lower alkyl. The compound(I-18) having an amino group on ring A in solvent; for example, dichloromethane, tetrahydrofuran, and the like; in the presence or the absence of acid; for example, acetic acid, and the like; is reacted with aldehyde having substituent corresponding to target compound; for example, benzaldehyde, pyridine-2-carboaldehyde, and the like; and reducing agent; for example, sodium borohydride, sodium triacetoxyborohydride, and the like; at -80°C to 100°C, preferably 0°Cto 40°C, for 0.5 to 150 hours, preferably 1 to 24 hours, to obtain the compound (I-20). [0039] The substituted alkoxy derivatives [Chemical formula 32] In formula, R23 is optionally substituted lower alkyl, an optionally substituted carbocyclic group or an optionally substituted heterocyclic group, etc., and the other symbols are the same as described above. The compound (1-21) having a hydroxy group as substituent of A ring in solvent; for example, N,N"dimethylformamide, tetrahydrofuran, and the like; in the presence of base; for example potassium carbonate, sodium hydroxide, sodium hydride, and the like; is reacted with alkylating agent having substituent corresponding to target compound; for example, benzylchloride, methyl iodide, and the like; at -80°C to 100°C, preferably 0°C to 40°C, for 0.5 to 150 hours, preferably 1 to 24 hours, or alternatively, the compound (I" 18) in solvent; for example, N,N-dimethylformamide, tetrahydrofuran, and the like; under Mitsunobu reagent; for example triphenylphosphine-azodicarboxylic acid ethyl ester, and the like; is reacted with alcohol; for example, 2-aminoethanol, and the like; at -80°C to 100°C, preferably 0°C to 40°C, for 0.5 to 72 hours, preferably 1 to 24 hours, to obtain the CLAIMS [Claim 1] A composition having BACE 1 inhibitory activity containing a compound represented by the general formula (I)• [Chemical formula l] ( wherein ring A is an optionally substituted carbocyclic group or an optionally substituted heterocyclic group, [Chemical formula 2] Alk1 is lower alkylene or lower alkenylene; R 0 is a hydrogen atom, lower alkyl, or acyl; X is S, O, or NR1; R1 is a hydrogen atom or lower alkyl; R2a and R2b are each independently a hydrogen atom, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted amino, optionally substituted amidino, optionally substituted acyl, optionally substituted carbamoyl, optionally substituted carbamoylcarbonyl, optionally substituted lower alkylsulfonyl, optionally substituted arylsulfonyl, an optionally substituted carbocyclic group, or an optionally substituted heterocyclic group; R3 a , R3 b R4 a, and R4b are each independently a hydrogen atom, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted acyl, carboxy, optionally substituted lower alkoxycarbonyl, optionally substituted amino, optionally substituted carbamoyl, an optionally substituted carbocyclic group, or an optionally substituted heterocyclic group; n and m are each independently an integer of 0 to 3; n+m is an integer of 1 to 3; each R3a, each R3b, each R4a, and each R4b may be independently different; R5 is a hydrogen atom, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, an optionally substituted carbocyclic group, an optionally substituted heterocyclic group; [Chemical formula 3] When wherein R5a and R5b are each independently a hydrogen atom or lower alkyl; s is an integer of 1 to 4; each R5a and each R5b may be different; with the proviso that the compound wherein n+m is 2; Ra is a hydrogen atom; and ring A is non-substituted phenyl is excluded, its pharmaceutically acceptable salt, or a solvate thereof, [Claim 2] A composition having BACE 1 inhibitory activity according to claim 1, wherein X is S. [Claim 3] A composition having BACE 1 inhibitory activity according to claim 1, wherein n is 2 and m is 0. [Claim 4] A composition having BACE 1 inhibitory activity according to claim 1, wherein E is a bond. [Claim 5] A compound represented by the general formula (I); [Chemical formula 4] wherein each symbols are the same as described in claim 1, with the proviso that the compounds; i) wherein n+m is 2, R5 is a hydrogen atom, and ring A is non-substituted phenyl; ii) wherein n is 2, m is 0, R2a is a hydrogen atom, R2b is a hydrogen atom or acetyl, R5 is methyl, and ring A is phenyl or 4-methoxyphenyl; ui) wherein n is 2, m is 0, R2a is a hydrogen atom, R2b is a hydrogen atom or acetyl, R5 is ethyl, and ring A is 3,4-dimethoxyphenyl; iv) wherein n is 2, m is 0, R^^ is a hydrogen atom, R^^ is a hydrogen atom or acetyl, R5 and ring A is phenyl; v) wherein n is 2, m is 0, R2a and R2b are a hydrogen atom, R5 and ring A are taken together to form [Chemical formula 5] wherein Me is methyl and each symbols are the same as described above; and vi) wherein n+m is 2, R5 is a hydrogen atom, ring A is phenyl substituted with one or two substituent(s) selected from the group consisting of hydroxy, halogen, lower alkyl, lower alkoxy, nitro, amino, lower alkylcarbonylamino, mercapto, lower alkylthio, and carbamoyl, non-substituted phenyl, or non-substituted naphthyL* are excluded, its pharmaceutically acceptable salt, or a solvate thereof. [Claim 6] The compound according to claim 5, wherein X is S, its pharmaceutically acceptable salt, or a solvate thereof. [Claim 7] The compound according to claim 5 or 6, wherein n is 2 and m is 0, its pharmaceutically acceptable salt, or a solvate thereof. [Claim 8] The compound according to any one of the claims 5 to 7, wherein R5 is optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, an optionally substituted carbocyclic group, or an optionally substituted heterocyclic group, its pharmaceutically acceptable salt, or a solvate thereof. [Claim 9] The compound according to any one of the claims 5 to 8, wherein R2a is a hydrogen atom; R2b is a hydrogen atom, optionally substituted lower alkyl, optionally substituted acyl, optionally substituted lower alkylsulfonyl, or optionally substituted amidino, its pharmaceutically acceptable salt, or a solvate thereof. [Claim 10] The compound according to any one of the claims 5 to 8, wherein NR2aR2b is represented by the formula; [Chemical formula 6] in; R6, R7, and R8 are each independently a hydrogen atom, lower alkyl, or acyl; Y is optionally substituted lower alkylene, optionally substituted lower alkenylene, or optionally substituted lower alkynylene; Z is O or S; its pharmaceutically acceptable salt, or a solvate thereof, [Claim 11] The compound according to any one of the claims 5 to 10, wherein ring A is optionally substituted phenyl, its pharmaceutically acceptable salt, or a solvate thereof. [Claim 12] The compound according to any one of the claims 5 to 10, wherein ring A is represented by the formula-[Chemical formula 7] wherein R9, R10, and R11 are a hydrogen atom or G; G is halogen, hydroxy, cyano, nitro, mercapto, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted acyl, optionally substituted acyloxy, carboxy, optionally substituted lower alkoxycarbonyl, optionally substituted lower alkoxycarbonyloxy, optionally substituted lower aryloxycarbonyloxy, optionally substituted amino, optionally substituted carbamoyl, optionally substituted carbamoyloxy, optionally substituted lower alkylthio, optionally substituted lower arylthio, optionally substituted lower alkylsulfonyl, optionally substituted arylsvdfonyl, optionally substituted lower alkyl sulfinyl, optionally substituted arylsulfinyl, optionally substituted lower alkylsulfonyloxy, optionally substituted arylsulfonyloxy, optionally substituted sulfamoyl, an optionally substituted carbocyclic group, optionally substituted carbocychcoxy, an optionally substituted heterocyclic group, or optionally substituted heterocyclicoxy; each G may be independently differenti its pharmaceutically acceptable salt, or a solvate thereof. [Claim 13] The compound according to claim 12, wherein G is represented by the formula* [Chemical formula 8] Q1, Q2, and Q3 are each independently a bond, optionally substituted lower alkylene, or optionally substituted lower alkenylenei Q4 is optionally substituted lower alkylene or optionally substituted lower alkenylene; W1 and W2 are each independently O or S; W3 is O, S, or NR12; R12 is a hydrogen atom, lower alkyl, hydroxy lower alkyl, lower alkoxy lower alkyl, lower alkoxycarbonyl lower alkyl, carbocyclic lower alkyl, or acyl; R14 is a hydrogen atom or lower alkyl; ring B is an optionally substituted carbocyclic group or an optionally substituted heterocyclic group; Alk2 is optionally substituted lower alkyl; p is 1 or 2; if there are multiple W\1,multiple W2 and multiple R12, each are independently different, its pharmaceutically acceptable salt, or a solvate thereof. [Claim 14] The compound according to claim 13, wherein ring B is aryl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted acyl, optionally substituted amino, cyano, optionally substituted carbamoyl, an optionally substituted carbocyclic group, optionally substituted carbocyclicoxy, and an optionally substituted heterocyclic group or heteroaryl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted acyl, optionally substituted amino, cyano, optionally substituted carbamoyl, an optionally substituted carbocyclic group, optionally substituted carbocyclicoxy, and an optionally substituted heterocyclic group, its pharmaceutically acceptable salt, or a solvate thereof. [Claim 15} The compound according to claim 13, wherein G is represented by the formula- [Chemical formula 9] its pharmaceutically acceptable salt, or a solvate thereof. [Claim 16] The compound according to any one of the claims 5 to 15, wherein R5 is Cl to C3 alkyl, its pharmaceutically acceptable salt, or a solvate thereof. [Claim 17] The compound according to any one of the claims 5 to 15, wherein R5 is methyl, its pharmaceutically acceptable salt, or a solvate thereof. [Claim 18] The compound according to any one of the claims 5 to 17, wherein R3a and R3b are each independently a hydrogen atom, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkoxy, or optionally substituted aryl, its pharmaceutically acceptable salt, or a solvate thereof, [Claim 19] The compound according to any one of the claims 5 to 17, wherein all of R3a and all of R3b are hydrogen atoms, its pharmaceutically acceptable salt, or a solvate thereof. [Claim 20] A pharmaceutical composition containing the compound as defined in any one of the claims 5 to 19, its pharmaceutically acceptable salt, or a solvate thereof as an active ingredient. [Claim 21] A composition having BACE 1 inhibitory activity containing the compound as defined in any one of the claims 5 to 19, its pharmaceutically acceptable salt, or a solvate thereof. |
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| Patent Number | 269593 | ||||||||||||||||||||||||||||||||||||||||||
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| Indian Patent Application Number | 2017/CHENP/2008 | ||||||||||||||||||||||||||||||||||||||||||
| PG Journal Number | 44/2015 | ||||||||||||||||||||||||||||||||||||||||||
| Publication Date | 30-Oct-2015 | ||||||||||||||||||||||||||||||||||||||||||
| Grant Date | 28-Oct-2015 | ||||||||||||||||||||||||||||||||||||||||||
| Date of Filing | 24-Apr-2008 | ||||||||||||||||||||||||||||||||||||||||||
| Name of Patentee | Shionogi & Co., Ltd. | ||||||||||||||||||||||||||||||||||||||||||
| Applicant Address | 1-8, DOSHOMACHI 3-CHOMECHUO-KU, OSAKA-SHIOSAKA 541-0045 | ||||||||||||||||||||||||||||||||||||||||||
Inventors:
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| PCT International Classification Number | C07D 239/14 | ||||||||||||||||||||||||||||||||||||||||||
| PCT International Application Number | PCT/JP06/321015 | ||||||||||||||||||||||||||||||||||||||||||
| PCT International Filing date | 2006-10-23 | ||||||||||||||||||||||||||||||||||||||||||
PCT Conventions:
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