JP2012107001A - Drug containing indole amide compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a therapeutic agent for diseases induced by the production, secretion or deposition of amyloid β protein.SOLUTION: An amyloid β production inhibition drug composition contains a compound of formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof.

Description

  The present invention relates to a compound having an inhibitory effect on amyloid β (hereinafter, Aβ) production and useful as a therapeutic agent for diseases induced by Aβ production, secretion and / or deposition.

  As for Alzheimer's disease, the number of patients as of 2008 is said to be about 6.6 million or more worldwide, and it is considered that the number of patients will surely continue to increase with aging. The current treatment of Alzheimer's disease is mainly symptomatic treatment, and has not led to radical treatment, and the development of more effective drugs is expected.

  Aβ, which is a major pathological determinant of Alzheimer's disease, is a metabolite of amyloid precursor protein (APP), and several types of fragments such as Aβ40 and Aβ42 are produced depending on the cleavage position of APP. In normal individuals, two major Aβs, Aβ40 and Aβ42, are found, but the dominant one is Aβ40. However, in patients with familial Alzheimer's disease, Aβ42 is significantly increased compared to normal, and in the neuritic plaques observed in the lesion area of Alzheimer's disease, Aβ42 is present at a very high rate compared to Aβ40. . It has also been reported that Aβ42 accumulates early and preferentially in soft tissue plaques, whereas Aβ40 is unrelated to early deposition of amyloid plaques. For this reason, Aβ42 is believed to play a major role in amyloid plaque deposition in familial Alzheimer's disease patients.

  Thus, Aβ, particularly Aβ42, is deeply involved in the onset and development of Alzheimer's disease, and it is considered that compounds that suppress the production of Aβ42 can be effective preventive or therapeutic agents for Alzheimer's disease.

  Several mechanisms of drugs have been studied with the aim of reducing Aβ production, but β-secretase inhibitors reduce the total amount of Aβ fragments. In addition to reducing the total amount of Aβ, the γ-secretase inhibitor also inhibits the enzyme activity itself of γ-secretase, so there is a concern about side effects. On the other hand, a γ-secretase-modifying agent does not inhibit the enzyme activity itself, selectively inhibits the production of Aβ42, and has little influence on the total amount of Aβ, so it may be a safe pharmaceutical with fewer side effects.

  The compounds structurally similar to the compounds according to the present invention are described in Patent Documents 1 to 12 and Non-Patent Documents 1 and 2, all of which are different from the compounds according to the present invention.

  In addition, as compounds having a γ-secretase inhibitory or modifying action or an Aβ production-inhibiting action, for example, compounds described in Patent Documents 13 to 35 below are known, and these compounds have a structure different from that of the compound according to the present invention. Is different.

International Publication No. 2004/072025 International Publication No. 2003/057212 International Publication No. 2002/000650 JP 2002-193923 A International Publication No. 2000/026197 European Patent Application No. 0624575 International Publication No. 2006/038680 International Publication No. 2008/092831 International Publication No. 2010/045188 International Publication No. 2004/076412 US Patent Application Publication No. 2004/0077646 US Patent Application Publication No. 2010/0009982 International Publication No. 2008/133273 International Publication No. 2008/133274 International Publication No. 2007/049532 International Publication No. 2009/075874 International Publication No. 2005/115990 International Publication No. 2007/120096 International Publication No. 2006/099379 International Publication No. 2009/009768 International Publication No. 2007/061930 International Publication No. 2005/092062 International Publication No. 2002/053594 International Publication No. 2003/039454 JP 2004-149429 A International Publication No. 2004/022523 International Publication No. 2003/043618 International Publication No. 2003/006423 US Pat. No. 6,528,505 International Publication No. 2000/024392 European Patent Application No. 0652009 International Publication No. 96/40982 US Patent Application Publication No. 2010/0137320 International Publication No. 2010/126002 International Publication No. 2011/007819

Soobshcheniya Akademii Nauk Gruzii (1991), 141 (3), 545-8. Journal of Medicinal Chemistry (1997), 40 (8), 1201-1210.

  Disclosed is a compound having a amyloid β production inhibitory effect, particularly a γ-secretase modifying effect, and useful as a therapeutic agent for diseases induced by Aβ production, secretion or deposition, such as Alzheimer's dementia.

  The present invention provides the following items.

1)
Formula (I):

[Wherein, -X ¹ = X ² -X ³ = X ⁴ -represents -C (R ¹ ) = C (R ² ) -C (R ³ ) = C (R ⁴ )-, -C (R ^{1 ) = N-C (R 3} ) = C (R 4) -, - C (R 1) = C (R 2) -N = C (R 4) -, - N = C (R 2) -C ( R ³ ) = C (R ⁴ ) —, or —C (R ¹ ) = C (R ² ) —C (R ³ ) = N—;
R ¹ , R ² , R ³ and R ⁴ are each independently hydrogen, halogen, hydroxy, carboxy, sulfo, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted Or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted carbocyclic oxy, substituted or unsubstituted heterocyclic oxy, mercapto, substituted or unsubstituted alkylthio, substituted Or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted carbocyclic thio, substituted or unsubstituted heterocyclic thio, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted acyl, substituted or Unsubstituted amino, substituted sulfonyl, Conversion sulfinyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, nitro, cyano, a substituted or unsubstituted carbocyclic group or a substituted or unsubstituted heterocyclic group;
R ⁵ is hydrogen, carboxy, sulfo, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted acyl, substituted sulfonyl, substituted sulfinyl, substituted or unsubstituted carbamoyl, or substituted or unsubstituted Of sulfamoyl;
R ⁶ is hydrogen, halogen, hydroxy, carboxy, sulfo, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxycarbonyl, Substituted or unsubstituted acyl, substituted sulfonyl, substituted sulfinyl, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, or substituted or unsubstituted carbocyclic group;
Ak ¹ or Ak ² each independently represents a single bond or a substituted or unsubstituted alkylene having 1 or 2 carbon atoms;
-L ¹ - ^{is, -C (= O) N (} R 8) -, - N (R 8) -C (= O) -, - SO 2 N (R 8) -, - N (R 8) SO _{2 -, - C (= O} ) -, - C (= O) -C (= O) -, - C (= O) -C (= O) -N (R 8) -, or -C (= O) O-;
Each R ⁸ is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted acyl;
Ring A is a benzene ring, pyridine ring, pyridazine ring, pyrimidine ring, cyclohexane ring, cyclohexene ring, tetrahydropyran ring, dihydropyridine ring, tetrahydropyridine ring, piperidine ring, piperazine ring, morpholine ring, octahydrocyclopentapyrrole ring, aza A bicyclooctane ring, a pyrrolidine ring, a thiazole ring, an imidazole ring, a pyrazole ring, an isoxazole ring, an oxazole ring or a thiazole ring;
Each R ⁷ independently represents halogen, hydroxy, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy; Substituted or unsubstituted alkynyloxy, substituted or unsubstituted acyloxy, substituted or unsubstituted carbocyclic oxy, substituted or unsubstituted heterocyclic oxy, mercapto, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio Substituted or unsubstituted alkynylthio, substituted or unsubstituted carbocyclic thio, substituted or unsubstituted heterocyclic thio, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted acyl, substituted or unsubstituted amino, substituted Sulfonyl, substituted Rufinyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, nitro, cyano, azide, substituted or unsubstituted carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group (provided that substituted or unsubstituted Except for substituted dihydrothiazine cyclic groups);
n is an integer of 0 to 5]
Or a pharmaceutically acceptable salt thereof or a solvate thereof, a pharmaceutical composition for inhibiting amyloid β production.
1 ')
Formula (I):

[Wherein, -X ¹ = X ² -X ³ = X ⁴ -represents -C (R ¹ ) = C (R ² ) -C (R ³ ) = C (R ⁴ )-, -C (R ^{1 ) = N-C (R 3} ) = C (R 4) -, - C (R 1) = C (R 2) -N = C (R 4) -, - N = C (R 2) -C ( R ³ ) = C (R ⁴ ) —, or —C (R ¹ ) = C (R ² ) —C (R ³ ) = N—;
R ¹ , R ² , R ³ and R ⁴ are each independently hydrogen, halogen, hydroxy, carboxy, sulfo, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted Or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted carbocyclic oxy, substituted or unsubstituted heterocyclic oxy, mercapto, substituted or unsubstituted alkylthio, substituted Or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted carbocyclic thio, substituted or unsubstituted heterocyclic thio, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted acyl, substituted or Unsubstituted amino, substituted sulfonyl, Conversion sulfinyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, nitro, cyano, a substituted or unsubstituted carbocyclic group or a substituted or unsubstituted heterocyclic group;
R ⁵ is hydrogen, carboxy, sulfo, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted acyl, substituted sulfonyl, substituted sulfinyl, substituted or unsubstituted carbamoyl, or substituted or unsubstituted Of sulfamoyl;
R ⁶ is hydrogen, halogen, hydroxy, carboxy, sulfo, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxycarbonyl, Substituted or unsubstituted acyl, substituted sulfonyl, substituted sulfinyl, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, or substituted or unsubstituted carbocyclic group;
Ak ¹ or Ak ² each independently represents a single bond or a substituted or unsubstituted alkylene having 1 or 2 carbon atoms;
-L ¹ - ^{is, -C (= O) N (} R 8) -, - N (R 8) -C (= O) -, - SO 2 N (R 8) -, - N (R 8) SO _{2 -, - C (= O} ) -, - C (= O) -C (= O) -, - C (= O) -C (= O) -N (R 8) -, or -C (= O) O-;
Each R ⁸ is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted acyl;
A ring is a benzene ring, pyridine ring, pyridazine ring, pyrimidine ring, cyclohexane ring, cyclohexene ring, tetrahydropyran ring, dihydropyridine ring, tetrahydropyridine ring, piperidine ring, piperazine ring, or morpholine ring;
Each R ⁷ independently represents halogen, hydroxy, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy; Substituted or unsubstituted alkynyloxy, substituted or unsubstituted acyloxy, substituted or unsubstituted carbocyclic oxy, substituted or unsubstituted heterocyclic oxy, mercapto, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio Substituted or unsubstituted alkynylthio, substituted or unsubstituted carbocyclic thio, substituted or unsubstituted heterocyclic thio, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted acyl, substituted or unsubstituted amino, substituted Sulfonyl, substituted Rufinyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, nitro, cyano, azide, substituted or unsubstituted carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group (provided that substituted or unsubstituted Except for substituted dihydrothiazine cyclic groups);
n is an integer of 0 to 5]
Or a pharmaceutically acceptable salt thereof or a solvate thereof, a pharmaceutical composition for inhibiting amyloid β production.

1 '')
A non-aromatic heterocyclic group in R ⁷ (excluding a substituted or unsubstituted dihydrothiazine cyclic group) is a non-aromatic heterocyclic group containing only a nitrogen atom as a hetero atom constituting the ring. The pharmaceutical composition for inhibiting amyloid β production according to 1) or 1 ′) above, which contains a certain compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

1 ''')
The non-aromatic heterocyclic group in R ⁷ (excluding a substituted or unsubstituted dihydrothiazine cyclic group) contains only a nitrogen atom as a hetero atom constituting the ring, and all the bonds in the ring are single. Amyloid β production according to 1), 1 ′) or 1 ″) above, which contains a compound that is a non-aromatic heterocyclic group that is a bond, or a pharmaceutically acceptable salt thereof, or a solvate thereof. Pharmaceutical composition for suppression.

2)
^{-X 1 = X 2 -X 3 =} X 4 - ^{is, -C (R 1) = C} (R 2) -C (R 3) = C (R 4) -, - C (R 1) = N- C (R ³ ) = C (R ⁴ ) —, or —C (R ¹ ) = C (R ² ) —N═C (R ⁴ ) —,
—L ¹ — is —C (═O) N (R ⁸ ) — or —N (R ⁸ ) —C (═O) — (wherein R ¹ , R ² , R ³ , R ⁴ , and R ⁸ is the same as 1) above, or a pharmaceutically acceptable salt or solvate thereof, 1), 1 ′), 1 ″) and 1 ′ ″. ) The pharmaceutical composition for inhibiting amyloid β production according to any one of the above.

3)
^{-X 1 = X 2 -X 3 =} X 4 - ^{is, -C (R 1) = C} (R 2) -C (R 3) = C (R 4) -, - C (R 1) = N- C (R ³ ) = C (R ⁴ ) —, or —C (R ¹ ) = C (R ² ) —N═C (R ⁴ ) — (wherein R ¹ , R ³ and R ⁴ are the above 1)).
R ² is OR ¹² , SR ¹³ , or N (R ¹⁴ ) (R ¹⁵ ) wherein R ¹² and R ¹³ are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted Alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic group, or substituted or unsubstituted heterocyclic group; R ¹⁴ and R ¹⁵ are each independently hydrogen, substituted or unsubstituted An alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted carbocyclic group, or substituted or unsubstituted heterocyclic group, or R ¹⁴ and R ¹⁵ together with the nitrogen atom to which they are attached. 1), 1 ′), 1 ″), 1 ′ ″) and the like, or a pharmaceutically acceptable salt thereof or a solvate thereof. Amyloid β production inhibitory pharmaceutical composition according to any one of beauty 2).

4)
^{-X 1 = X 2 -X 3 =} X 4 - ^{is, -C (R 1) = C} (R 2) -C (R 3) = C (R 4) -, - C (R 1) = N- C (R ³ ) = C (R ⁴ ) —, or —C (R ¹ ) = C (R ² ) —N═C (R ⁴ ) — (wherein R ¹ and R ⁴ are the above-mentioned 1 )),
R ² and R ³ are each independently OR ¹² , SR ¹³ , N (R ¹⁴ ) (R ¹⁵ ), substituted or unsubstituted pyridyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, substituted Or a compound that is unsubstituted oxazolyl, or substituted or unsubstituted thiazolyl (wherein R ¹² , R ¹³ , R ^14, and R ¹⁵ are as defined in 3) above, or a pharmaceutically acceptable salt thereof Or a pharmaceutical composition for inhibiting amyloid β production according to any one of 1), 1 ′), 1 ″), 1 ′ ″), 2) and 3), which contains a solvate thereof.

5)
1), 1 ′), 1 ″), 1 ′ ″) and 2 containing a compound in which R ⁵ and R ⁶ are both hydrogen, or a pharmaceutically acceptable salt thereof or a solvate thereof. A pharmaceutical composition for inhibiting amyloid β production according to any one of) to 4).

6)
1), 1 ′, wherein Ak ¹ is a single bond, and Ak ² is a single bond or a substituted or unsubstituted methylene, or a pharmaceutically acceptable salt thereof, or a solvate thereof. ), 1 ″), 1 ′ ″) and 2) to 5), the pharmaceutical composition for inhibiting amyloid β production.

7)
¹ ), wherein the compound, wherein -L ¹ -is -C (= O) NH- or -NH-C (= O)-, or a pharmaceutically acceptable salt thereof or a solvate thereof, The pharmaceutical composition for inhibiting amyloid β production according to any one of 1 ′), 1 ″), 1 ″ ′) and 2) to 6).

8)
1), 1 ′), 1 ″), 1 ′ ″) and the above compounds containing a compound in which the A ring is a benzene ring or a pyridine ring, or a pharmaceutically acceptable salt or solvate thereof. The pharmaceutical composition for inhibiting amyloid β production according to any one of 2) to 7).

9)
n is an integer from 1 to 5;
Wherein at least one R ⁷ is OR ¹⁶ , SR ¹⁷ , or N (R ¹⁸ ) (R ¹⁹ ), wherein R ¹⁶ and R ¹⁷ are each independently substituted or unsubstituted alkyl, substituted or unsubstituted A substituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted carbocyclic group, or a substituted or unsubstituted heterocyclic group; R ¹⁸ and R ¹⁹ are each independently hydrogen, substituted or Unsubstituted alkyl, or substituted or unsubstituted alkenyl, or R ¹⁸ and R ¹⁹ together with the nitrogen atom to which they are attached may form a non-aromatic heterocycle) and other R ⁷ is synonymous with 1) above;
The compound, or a pharmaceutically acceptable salt thereof or a solvate thereof, according to any one of 1), 1 ′), 1 ″), 1 ′ ″) and 2) to 8) above A pharmaceutical composition for inhibiting amyloid β production.

10)
^{-X 1 = X 2 -X 3 =} X 4 - ^{is, -C (R 1) = C} (R 2) -C (R 3) = C (R 4) -, - C (R 1) = N- ^{C (R 3) = C (} R 4) -, or ^{-C (R 1) = C (} R 2) -N = C (R 4) - a and;
R ¹ and R ⁴ are both hydrogen;
R ² and R ³ are each independently OR ¹² , SR ¹³ , N (R ¹⁴ ) (R ¹⁵ ), substituted or unsubstituted pyridyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, substituted Or unsubstituted oxazolyl, or substituted or unsubstituted thiazolyl;
R ¹² and R ¹³ are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted cyclo Is alkenyl;
R ¹⁴ and R ¹⁵ are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted cycloalkenyl, or R ¹⁴ and R ¹⁵ may form a heterocycle together with the nitrogen atom to which they are attached;
R ⁵ and R ⁶ are both hydrogen;
Ak ¹ is a single bond;
Ak ² is a single bond or substituted or unsubstituted methylene;
-L ¹ - is, -C (= O) NH- or -NH-C (= O) - and is,
The A ring is a benzene ring or a pyridine ring;
n is an integer from 1 to 5;
At least one R ⁷ is OR ¹⁶ , SR ¹⁷ , or N (R ¹⁸ ) (R ¹⁹ ), and the substitution positions of R ⁷ and Ak ² are in a para-position in the A ring; R ⁷ has the same meaning as in 1) above;
R ¹⁶ and R ¹⁷ are each independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic group, or substituted or unsubstituted hetero A cyclic group;
R ¹⁸ and R ¹⁹ are each independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkenyl, or R ¹⁸ and R ¹⁹ together with the nitrogen atom to which they are attached are non-aromatic 1), 1 ′), 1 ″), 1 ′ ″) and 2) containing a compound that may form a heterocyclic group, or a pharmaceutically acceptable salt thereof or a solvate thereof ~ 9) The pharmaceutical composition for inhibiting amyloid β production according to any one of the above.

11)
The pharmaceutical composition for inhibiting amyloid β production according to any one of 1), 1 ′), 1 ″), 1 ′ ″) and 2) to 10), which is a pharmaceutical composition for selectively inhibiting amyloid β42 production. object.

12)
Administering the compound according to any one of 1), 1 ′), 1 ″), 1 ′ ″) and 2) to 10), or a pharmaceutically acceptable salt thereof, or a solvate thereof. A method of suppressing amyloid β production, characterized by

13)
The compound according to any one of 1), 1 ′), 1 ″), 1 ′ ″) and 2) to 10), or a pharmaceutically acceptable salt thereof, which is used for inhibiting amyloid β production. Or a solvate thereof.

14)
Formula (II):

[Wherein, = X ² -X ³ = is = C (R ² ) -C (R ³ ) =, = NC (R ³ ) =, or = C (R ² ) -N =;
R ² is hydroxy, carboxy, sulfo, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted Alkynyloxy, substituted or unsubstituted carbocyclic oxy, substituted or unsubstituted heterocyclic oxy, mercapto, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted Substituted carbocyclic thio, substituted or unsubstituted heterocyclic thio, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted acyl, substituted or unsubstituted amino, substituted sulfonyl, substituted sulfinyl, substituted or unsubstituted carbamoyl, Replace Or an unsubstituted sulfamoyl, nitro, cyano, substituted or unsubstituted carbocyclic group, or substituted or unsubstituted heterocyclic group;
R ¹ , R ³ , and R ⁴ are each independently hydrogen, halogen, hydroxy, carboxy, sulfo, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted Substituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted carbocyclic oxy, substituted or unsubstituted heterocyclic oxy, mercapto, substituted or unsubstituted alkylthio, substituted or unsubstituted Substituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted carbocyclic thio, substituted or unsubstituted heterocyclic thio, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted acyl, substituted or unsubstituted Amino, substituted sulfonyl, substituted Rufiniru, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, nitro, cyano, a substituted or unsubstituted carbocyclic group or a substituted or unsubstituted heterocyclic group;
R ⁵ represents hydrogen, carboxy, sulfo, substituted or unsubstituted alkyl (excluding alkyl substituted with substituted or unsubstituted aryl), substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted acyl, substituted Sulfonyl, substituted sulfinyl, substituted or unsubstituted carbamoyl, or substituted or unsubstituted sulfamoyl;
R ⁶ is hydrogen, halogen, hydroxy, carboxy, sulfo, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted acyl, substituted sulfonyl, substituted sulfinyl, substituted or unsubstituted amino, substituted Or an unsubstituted carbamoyl, a substituted or unsubstituted sulfamoyl, or a substituted or unsubstituted carbocyclic group;
Ak ¹ is a single bond or a substituted or unsubstituted alkylene having 1 or 2 carbon atoms;
R ⁸ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted acyl;
= ^Y 1 -Y ² = ^{is, = C (R 9A) -C} (R 10A) =, = N-C (R 10A) =, or ^{= C (R} 9A) is -N =;
R ^9A and R ^9B are each independently hydrogen, halogen, hydroxy, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or Unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted carbocyclic oxy, substituted or unsubstituted heterocyclic oxy, mercapto, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted Or unsubstituted alkynylthio, substituted or unsubstituted carbocyclic thio, substituted or unsubstituted heterocyclic thio, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted acyl, substituted or unsubstituted amino, substituted sulfonyl, Substituted sulfinyl, Substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, nitro, cyano, azido, substituted or unsubstituted carbocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group;
One of R ^10A and R ^10B is hydrogen, halogen, hydroxy, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted Alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted carbocyclic oxy, substituted or unsubstituted heterocyclic oxy, mercapto, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted Alkynylthio, substituted or unsubstituted carbocyclic thio, substituted or unsubstituted heterocyclic thio, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted acyl, substituted or unsubstituted amino, substituted sulfonyl, substituted sulfinyl, Replace Or an unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, nitro, cyano, azide, substituted or unsubstituted carbocyclic group or substituted or unsubstituted non-aromatic heterocyclic group, the other being halogen, Hydroxy, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or Unsubstituted carbocyclic oxy, substituted or unsubstituted heterocyclic oxy, mercapto, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted carbocyclic thio, Substituted or unsubstituted heterocyclic ring O, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted acyl, substituted or unsubstituted amino, substituted sulfonyl, substituted sulfinyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, nitro, cyano, azide, A substituted or unsubstituted carbocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group, provided that when = Y ¹ -Y ² = is = C (R ^9A ) -N =, R ^10B is , Halogen, hydroxy, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy Substituted or unsubstituted carbocyclic oxy, substituted or non-substituted Substituted heterocyclic oxy, mercapto, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted carbocyclic thio, substituted or unsubstituted heterocyclic thio, substituted Or unsubstituted alkoxycarbonyl, substituted or unsubstituted acyl, substituted or unsubstituted amino, substituted sulfonyl, substituted sulfinyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, nitro, cyano, azide, substituted or unsubstituted A substituted carbocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group;
R ¹¹ is hydrogen, halogen, hydroxy, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or Unsubstituted alkynyloxy, substituted or unsubstituted acyloxy, substituted or unsubstituted carbocyclic oxy, substituted or unsubstituted heterocyclic oxy, mercapto, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or Unsubstituted alkynylthio, substituted or unsubstituted carbocyclic thio, substituted or unsubstituted heterocyclic thio, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted acyl, substituted or unsubstituted amino, substituted sulfonyl, substituted Sulfi Nyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, nitro, cyano, azide, substituted or unsubstituted carbocyclic group or substituted or unsubstituted non-aromatic heterocyclic group (provided that R ^{When 11} is hydrogen, hydroxy, methoxy, methylthio, methyl, trifluoromethyl, or halogen, neither R ^10A nor R ^10B is hydrogen;
When R ^10A or R ^10B is fluorine, R ¹¹ is

Rather than the group indicated by
R ^9A , R ^9B , R ^10A , R ^10B , and R ¹¹ are not simultaneously fluorine;
When R ^10A or R ^10B is —COOH or —COOMe, R ¹¹ is

Rather than the group indicated by
R ^10A , R ^10B , and R ¹¹ are not simultaneously methoxy;
When R ^10A or R ^10B is —OMe, R ¹¹ is

Rather than the group indicated by
When one of R ^10A or R ^10B is —SO ₂ Me, the other is

It is not a group indicated by
(Wherein the following compounds:

except for. Or a pharmaceutically acceptable salt thereof or a solvate thereof.

15)
= X ² -X ³ = is = C (R ² ) -C (R ³ ) = or = C (R ² ) -N = (wherein R ³ is as defined above 14)). ,
R ² is OR ¹² , SR ¹³ , or N (R ¹⁴ ) (R ¹⁵ ) (wherein R ¹² and R ¹³ are each independently hydrogen or substituted or unsubstituted alkyl, substituted or unsubstituted Alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic group, or substituted or unsubstituted heterocyclic group; R ¹⁴ and R ¹⁵ are each independently hydrogen, substituted or unsubstituted An alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted carbocyclic group, or substituted or unsubstituted heterocyclic group, or R ¹⁴ and R ¹⁵ together with the nitrogen atom to which they are attached. The compound according to 14) above, which may form a heterocycle, or a pharmaceutically acceptable salt thereof or a solvate thereof.

16)
The compound according to the above 14) or 15), wherein Ak ¹ is a single bond, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

17)
One of R ^10A and R ^10B is halogen or substituted or unsubstituted alkyl, and the other is hydrogen, halogen, hydroxy, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted Alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted carbocyclic oxy, substituted or unsubstituted heterocyclic oxy, mercapto, substituted or unsubstituted Alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted carbocyclic thio, substituted or unsubstituted heterocyclic thio, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted acyl , If replacement Is unsubstituted amino, substituted sulfonyl, substituted sulfinyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, nitro, cyano, azide, substituted or unsubstituted carbocyclic group or substituted or unsubstituted non-aromatic A heterocyclic group,
R ¹¹ is OR ¹⁶ , SR ¹⁷ , N (R ¹⁸ ) (R ¹⁹ ) (wherein R ¹⁶ and R ¹⁷ are each independently hydrogen, substituted or unsubstituted alkyl (provided that unsubstituted methyl Substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic group, or substituted or unsubstituted heterocyclic group; R ¹⁸ and R ¹⁹ are each independently Hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkenyl, or R ¹⁸ and R ¹⁹ together with the nitrogen atom to which they are attached may form a heterocycle) Or a compound according to any one of 14) to 16) above, which is an unsubstituted carbocyclic oxyalkyl or a substituted or unsubstituted heterocyclic oxyalkyl. Salt or solvate thereof is its pharmaceutically acceptable.

18)
The compound according to any one of 14) to 17) above, wherein R ^10A and R ^10B are each independently halogen or substituted or unsubstituted alkyl, or a pharmaceutically acceptable salt thereof, or a solvate thereof. object.

19)
R ¹¹ is OR ¹⁶ , SR ¹⁷ , N (R ¹⁸ ) (R ¹⁹ ) (wherein R ¹⁶ , R ¹⁷ and R ¹⁹ are each independently alkyl substituted with a substituted or unsubstituted carbocycle. A substituted or unsubstituted heterocycle substituted alkyl, a substituted or unsubstituted carbocyclic group, or a substituted or unsubstituted heterocyclic group, R ¹⁸ is hydrogen, substituted or unsubstituted alkyl, 14) to 18) above, which is substituted or unsubstituted cycloalkyl, or substituted or unsubstituted acyl, substituted or unsubstituted carbocyclic oxyalkyl, or substituted or unsubstituted heterocyclic oxyalkyl) Or a pharmaceutically acceptable salt or solvate thereof.

20)
Formula (III):

[Wherein, = X ² -X ³ = is = C (R ² ) -C (R ³ ) =, = NC (R ³ ) =, or = C (R ² ) -N =;
When = X ² -X ³ = is = C (R ² ) -C (R ³ ) =, either R ² or R ³ is substituted or unsubstituted pyridyl, substituted or unsubstituted imidazolyl, substituted Or unsubstituted pyrazolyl, substituted or unsubstituted oxazolyl, or substituted or unsubstituted thiazolyl, the other being hydrogen, halogen, hydroxy, carboxy, sulfo, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, Substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted carbocyclic oxy, substituted or unsubstituted heterocyclic oxy, mercapto, Substituted or unsubstituted alkylthio, substituted or unsubstituted alkenyl Thio, substituted or unsubstituted alkynylthio, substituted or unsubstituted carbocyclic thio, substituted or unsubstituted heterocyclic thio, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted acyl, substituted or unsubstituted amino, Substituted sulfonyl, substituted sulfinyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, nitro, cyano, substituted or unsubstituted carbocyclic group, or substituted or unsubstituted heterocyclic group;
When = X ² -X ³ === N—C (R ³ ) =, or = C (R ² ) —N =, R ² or R ³ is substituted or unsubstituted pyridyl, substituted or unsubstituted Imidazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted oxazolyl, or substituted or unsubstituted thiazolyl,
R ¹ and R ⁴ are each independently hydrogen, halogen, hydroxy, carboxy, sulfo, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, Substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted carbocyclic oxy, substituted or unsubstituted heterocyclic oxy, mercapto, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio Substituted or unsubstituted alkynylthio, substituted or unsubstituted carbocyclic thio, substituted or unsubstituted heterocyclic thio, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted acyl, substituted or unsubstituted amino, substituted Sulfonyl, substituted sulfini , Substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, nitro, cyano, a substituted or unsubstituted carbocyclic group or a substituted or unsubstituted heterocyclic group;
R ⁵ is hydrogen, carboxy, sulfo, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted acyl, substituted sulfonyl, substituted sulfinyl, substituted or unsubstituted carbamoyl, or substituted or unsubstituted Of sulfamoyl;
R ⁶ is hydrogen, halogen, hydroxy, carboxy, sulfo, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted acyl, substituted sulfonyl, substituted sulfinyl, substituted or unsubstituted amino, substituted Or an unsubstituted carbamoyl, a substituted or unsubstituted sulfamoyl, or a substituted or unsubstituted carbocyclic group;
Ak ¹ and Ak ² are each independently a single bond or a substituted or unsubstituted alkylene having 1 or 2 carbon atoms;
R ⁸ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted acyl;
A ring is a benzene ring, pyridine ring, pyridazine ring, pyrimidine ring, cyclohexane ring, cyclohexene ring, tetrahydropyran ring, dihydropyridine ring, tetrahydropyridine ring, piperidine ring, piperazine ring, or morpholine ring;
Each R ⁷ independently represents halogen, hydroxy, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy; Substituted or unsubstituted alkynyloxy, substituted or unsubstituted acyloxy, substituted or unsubstituted carbocyclic oxy, substituted or unsubstituted heterocyclic oxy, mercapto, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio Substituted or unsubstituted alkynylthio, substituted or unsubstituted carbocyclic thio, substituted or unsubstituted heterocyclic thio, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted acyl, substituted or unsubstituted amino, substituted Sulfonyl, substituted Rufinyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, nitro, cyano, azide, substituted or unsubstituted carbocyclic group, or substituted or unsubstituted non-aromatic heterocyclic group;
n is an integer of 0 to 5,
(However, ring A is not an unsubstituted pyridine ring;
When Ak ² is —CH ₂ —CH ₂ —, the A ring is not an unsubstituted morpholine ring;
Ring A is

is not. )] Or a pharmaceutically acceptable salt thereof or a solvate thereof.

21)
= X ² -X ³ = is = C (R ² ) -C (R ³ ) =, and either R ² or R ³ is substituted or unsubstituted pyridyl, substituted or unsubstituted imidazolyl, or Substituted or unsubstituted pyrazolyl, the other being OR ¹² , SR ¹³ , or N (R ¹⁴ ) (R ¹⁵ ), wherein R ¹² and R ¹³ are each independently hydrogen, substituted or unsubstituted Alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic group, or substituted or unsubstituted heterocyclic group; R ¹⁴ and R ¹⁵ are each independently Hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted carbocyclic group, or substituted or unsubstituted heterocyclic group, or R ¹⁴ and R ¹⁵ may form a heterocycle together with the nitrogen atom to which they are bonded)), or a pharmaceutically acceptable salt thereof or a solvate thereof. object.

22)
The compound according to 20) or 21) above, wherein Ak ¹ is a single bond, and Ak ² is substituted or unsubstituted methylene, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

23)
The compound according to any one of 20) to 22) above, wherein the A ring is a benzene ring or a pyridine ring, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

24)
The compound according to any one of 14) to 23) above, wherein R ⁵ and R ⁶ are both hydrogen, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

25)
The compound according to any one of 14) to 24) above, wherein R ⁸ is hydrogen, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

26)
Formula (II):

[Wherein, = X ² -X ³ = is = C (H) -C (R ³ ) = or = C (H) -N =,
R ¹ , R ³ , and R ⁴ are each independently hydrogen, halogen, hydroxy, carboxy, sulfo, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted Substituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted carbocyclic oxy, substituted or unsubstituted heterocyclic oxy, mercapto, substituted or unsubstituted alkylthio, substituted or unsubstituted Substituted alkenylthio, substituted or unsubstituted alkynylthio,
Substituted or unsubstituted carbocyclic thio, substituted or unsubstituted heterocyclic thio, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted acyl, substituted or unsubstituted amino, substituted sulfonyl, substituted sulfinyl, substituted or unsubstituted A carbamoyl, substituted or unsubstituted sulfamoyl, nitro, cyano, substituted or unsubstituted carbocyclic group, or substituted or unsubstituted heterocyclic group;
R ⁵ represents hydrogen, carboxy, sulfo, substituted or unsubstituted alkyl (excluding alkyl substituted with substituted or unsubstituted aryl), substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted acyl, substituted Sulfonyl, substituted sulfinyl, substituted or unsubstituted carbamoyl, or substituted or unsubstituted sulfamoyl;
R ⁶ is hydrogen, halogen, hydroxy, carboxy, sulfo, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted acyl, substituted sulfonyl, substituted sulfinyl, substituted or unsubstituted amino, substituted Or unsubstituted carbamoyl, or substituted or unsubstituted sulfamoyl;
Ak ¹ is a single bond;
R ⁸ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted acyl;
= ^Y 1 -Y ² = ^{is, = C (R 9A) -C} (R 10A) =, = N-C (R 10A) =, or ^{= C (R} 9A) is -N =;
R ^9A and R ^9B are each independently hydrogen, halogen, hydroxy, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or Unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted carbocyclic oxy, substituted or unsubstituted heterocyclic oxy, mercapto, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted Or unsubstituted alkynylthio, substituted or unsubstituted carbocyclic thio, substituted or unsubstituted heterocyclic thio, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted acyl, substituted or unsubstituted amino, substituted sulfonyl, Substituted sulfinyl, Substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, nitro, cyano, azido, substituted or unsubstituted carbocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group;
R ^10A and R ^10B are each independently halogen or substituted or unsubstituted alkyl;
R ¹¹ is OR ¹⁶ , SR ¹⁷ , N (R ¹⁸ ) (R ¹⁹ ) (wherein R ¹⁶ , R ¹⁷ and R ¹⁹ are each independently alkyl substituted with a substituted or unsubstituted carbocycle. A substituted or unsubstituted heterocycle substituted alkyl, a substituted or unsubstituted carbocyclic group, or a substituted or unsubstituted heterocyclic group, R ¹⁸ is hydrogen, substituted or unsubstituted alkyl, Substituted or unsubstituted cycloalkyl, substituted or unsubstituted acyl, substituted or unsubstituted carbocyclic oxyalkyl, or substituted or unsubstituted heterocyclic oxyalkyl)]
Or a pharmaceutically acceptable salt or solvate thereof.

27)
Formula (I):

(In the formula, Ak ¹ and Ak ² are each independently a single bond; —L ¹ — is —C (═O) —; the A ring is a piperidine ring or a piperazine ring (provided that , atom on a ring bonded to Ak ² is always nitrogen ^{atom), - X 1 = X 2} -X 3 = X 4 -, R 1, R 2, R 3, R 4, R 5, R 6 , R ⁷ and n have the same meanings as in 1) above)
Or a pharmaceutically acceptable salt or solvate thereof.

28)
Pharmaceutical composition containing the compound in any one of said 14) -27), its pharmaceutically acceptable salt, or those solvates.

29)
A pharmaceutical composition for inhibiting amyloid β production, comprising the compound according to any one of 14) to 27) above, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

30)
The pharmaceutical composition for inhibiting amyloid β production according to any one of 1), 1 ′), 1 ″), 1 ′ ″) and 2) to 10), which is a pharmaceutical composition for γ-secretase modification.

31)
Administering the compound according to any one of 1), 1 ′), 1 ″), 1 ′ ″) and 2) to 10), or a pharmaceutically acceptable salt thereof, or a solvate thereof. A method for selectively suppressing the production of amyloid β42.

32)
Administering the compound according to any one of 1), 1 ′), 1 ″), 1 ′ ″) and 2) to 10), or a pharmaceutically acceptable salt thereof, or a solvate thereof. A method for modifying γ-secretase, characterized in that

33)
The compound according to any one of 1), 1 ′), 1 ″), 1 ′ ″) and 2) to 10), which is used for selectively suppressing the production of amyloid β42, or a pharmaceutical product thereof Top acceptable salts or solvates thereof.

34)
The compound according to any one of 1), 1 ′), 1 ″), 1 ′ ″) and 2) to 10), or a pharmaceutically acceptable salt thereof, which is used for modifying γ-secretase. Or a solvate thereof.

35)
A pharmaceutical composition for selective inhibition of amyloid β42 production comprising the compound according to any one of 14) to 27) above, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

36)
Pharmaceutical composition for gamma secretase modification containing the compound in any one of said 14) -27), its pharmaceutically acceptable salt, or those solvates.

  37) Any one of 1), 1 ′), 1 ″), 1 ′ ″), 2) to 10) and 14) to 27) for producing a pharmaceutical composition for inhibiting amyloid β production Use of the described compounds, or pharmaceutically acceptable salts or solvates thereof.

  38) Any one of 1), 1 ′), 1 ″), 1 ′ ″), 2) to 10), and 14) to 27) for producing a pharmaceutical composition for selectively inhibiting amyloid β42 production Or a pharmaceutically acceptable salt thereof, or a solvate thereof.

  39) Any one of 1), 1 ′), 1 ″), 1 ′ ″), 2) to 10) and 14) to 27) for producing a pharmaceutical composition for modifying γ-secretase Or a pharmaceutically acceptable salt or solvate thereof.

  40) Any one of the above 1), 1 ′), 1 ″), 1 ′ ″), 2) to 10) and 14) to 27) for use as a pharmaceutical composition for inhibiting amyloid β production Or a pharmaceutically acceptable salt or solvate thereof.

  41) Any one of the above 1), 1 ′), 1 ″), 1 ″ ′), 2) -10) and 14) -27) for use as a pharmaceutical composition for selective inhibition of amyloid β42 production Or a pharmaceutically acceptable salt or solvate thereof.

  42) Any one of 1), 1 ′), 1 ″), 1 ′ ″), 2) to 10), and 14) to 27) for use as a pharmaceutical composition for modifying γ-secretase Or a pharmaceutically acceptable salt or solvate thereof.

  The compound according to the present invention is useful as a therapeutic agent for diseases (such as Alzheimer's disease) induced by Aβ production, secretion or deposition.

The change in the amount of C-terminal fragment β (CTFβ) produced by the addition of the compound of the present invention is shown. The vertical axis represents CTFβ (%) of the compound addition group of the present invention relative to CTFβ of the group administered with DMSO alone. The change in the amount of C-terminal fragment β (CTFβ) produced by addition of the compound of the present invention is shown. The vertical axis represents CTFβ (%) of the compound addition group of the present invention relative to CTFβ of the group administered with DMSO alone.

  The meaning of each term used in this specification will be described below. In the present specification, each term is used in a unified meaning, and is used in the same meaning when used alone or in combination with other terms.

  In the present specification, “halogen” means fluorine, chlorine, bromine and iodine. Examples include fluorine, chlorine, and bromine.

  In the present specification, the halogen part of “halogenoalkyl” and “halogenoalkoxy” means the above “halogen”.

  In the present specification, “alkyl” includes a straight-chain or branched monovalent hydrocarbon group having 1 to 8 carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, n-octyl and the like. It is done. For example, C1-C6 alkyl is mentioned. For example, C1-C4 alkyl is mentioned. In particular, when a carbon number is specified, it means “alkyl” having a carbon number within the range.

  In the present specification, “alkenyl” includes a straight or branched monovalent hydrocarbon group having 2 to 8 carbon atoms and having one or more double bonds. . For example, vinyl, allyl, 1-propenyl, 2-butenyl, 2-pentenyl, 2-hexenyl, 2-heptenyl, 2-octenyl and the like can be mentioned. An example is C2-C6 alkenyl. An example is C2-C4 alkenyl. In particular, when a carbon number is specified, it means “alkenyl” having a carbon number within the range of the number.

  In the present specification, “alkynyl” includes straight or branched monovalent hydrocarbon groups having 2 to 8 carbon atoms and having one or more triple bonds. For example, ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, 2-pentynyl, 2-hexynyl, 2-heptynyl, 2-octynyl and the like can be mentioned. An example is C2-C6 alkynyl. An example is C2-C4 alkynyl. In particular, when a carbon number is specified, it means “alkynyl” having a carbon number within the range.

  In the present specification, “cycloalkyl” includes cycloalkyl having 3 to 8 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. An example is C3-C6 cycloalkyl. When the number of carbons is specified, it means “cycloalkyl” having the number of carbons within the range.

  In the present specification, “cycloalkenyl” includes cycloalkenyl having 3 to 8 carbon atoms. Examples thereof include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and examples thereof include C3-C6 cycloalkenyl. In particular, when a carbon number is specified, it means “cycloalkenyl” having a carbon number within the range.

  In the present specification, “alkoxy” includes methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, 2-pentyloxy, Examples include 3-pentyloxy, n-hexyloxy, isohexyloxy, 2-hexyloxy, 3-hexyloxy, n-heptyloxy, n-octyloxy, n-nonyloxy and the like. For example, C1-C9 alkoxy is mentioned. For example, C1-C6 alkoxy is mentioned. For example, C1-C5 alkoxy is mentioned. For example, C1-C4 alkoxy is mentioned. In particular, when a carbon number is specified, it means “alkoxy” having a carbon number within the range.

  In the present specification, as "alkylsulfonyl", methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, n-pentylsulfonyl, isopentyl Examples include sulfonyl, 2-pentylsulfonyl, 3-pentylsulfonyl, n-hexylsulfonyl, isohexylsulfonyl, 2-hexylsulfonyl, 3-hexylsulfonyl, n-heptylsulfonyl, n-octylsulfonyl and the like. For example, C1-C6 alkylsulfonyl is mentioned. For example, C1-C4 alkylsulfonyl is mentioned.

  In the present specification, “alkoxycarbonyl” includes methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, tert-butoxycarbonyl, n-pentyloxycarbonyl and the like. An example is C1-C4 alkoxycarbonyl. An example is C1-C2 alkoxycarbonyl.

  In the present specification, “acyl” includes formyl, alkylcarbonyl, alkenylcarbonyl, cycloalkylcarbonyl, cycloalkenylcarbonyl, arylcarbonyl, heteroarylcarbonyl, heterocyclylcarbonyl. For example, acetyl, propionyl, butyroyl, benzoyl and the like can be mentioned.

  In the present specification, “aryl” includes a monovalent group derived from a monocyclic or condensed aromatic carbocyclic ring. Whether aryl is a single ring or a fused ring, it can be attached at all possible positions. For example, phenyl, 1-naphthyl, 2-naphthyl, anthryl and the like can be mentioned. Examples include phenyl, 1-naphthyl and 2-naphthyl. An example is phenyl.

  In the present specification, the “carbocycle” includes cycloalkane, cycloalkene, aromatic carbocycle, non-aromatic carbocycle and the like.

  In the present specification, “cycloalkane” includes a carbocyclic ring having 3 to 10 carbon atoms. Examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, and the like. An example is C3-C8 cycloalkane. An example is C4-C8 cycloalkane.

  In the present specification, the “cycloalkene” includes those having one or more double bonds at any position in the ring of the “cycloalkane”. Examples include cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclononene, cyclodecene, and bicyclohexadiene.

  In the present specification, the “aromatic carbocycle” includes an aromatic 5- to 8-membered ring (preferably a 6-membered ring) containing only carbon atoms in the ring or a ring in which two or more of them are condensed. The monocyclic aromatic carbocycle includes a ring derived from a 5- to 8-membered (preferably 6-membered) aromatic carbocycle and optionally having a bond at any substitutable position. The condensed aromatic carbocyclic ring is a 5- to 8-membered (preferably 6-membered) monocyclic aromatic carbocyclic ring, and 1 to 4 5- to 8-membered (preferably 6-membered) monocyclic aromatic carbocyclic rings And a ring optionally having a bond at any substitutable position which is condensed with. An example is a 6-membered aromatic carbocycle. Examples of the aromatic carbocycle include a benzene ring, a naphthalene ring, and an anthracene ring. For example, a benzene ring and a naphthalene ring are mentioned.

  In the present specification, the “non-aromatic carbocycle” includes a non-aromatic 3- to 8-membered ring containing only a carbon atom in the ring or a ring in which two or more thereof are condensed and / or bridged. . The monocyclic non-aromatic carbocycle includes a ring derived from a 3- to 8-membered non-aromatic carbocycle and optionally having a bond at any substitutable position. The fused non-aromatic carbocycle is a 5- to 8-membered monocyclic non-aromatic carbocycle, wherein 1 to 4 5- to 8-membered monocyclic non-aromatic carbocycle and / or the above “aromatic carbocycle” And a ring optionally having a bond at any substitutable position. If it is non-aromatic, it may be saturated or unsaturated. For example, a 5-6 membered non-aromatic carbocycle is mentioned. Non-aromatic carbocycle includes, for example, cyclopropane ring, cyclobutane ring, cyclopentane ring, cyclohexane ring, cycloheptane ring, cyclooctane ring, cyclopropene ring, cyclobutene ring, cyclopentene ring, cyclohexene ring, cycloheptene ring, adamantyl A ring is mentioned. Examples thereof include a cyclopentane ring, a cyclohexane ring, a cyclopentene ring, a cyclohexene ring, and a tetrahydronaphthalene ring.

  In the present specification, the “carbocyclic group” includes a monovalent group derived from the above “carbocycle”, and includes cycloalkyl, cycloalkenyl, aryl and the like.

  In the present specification, the “heterocycle” includes a heterocycle having one or more heteroatoms arbitrarily selected from O, S and N in the ring, and includes heteroaryl, heterocyclyl, aromatic heterocycle and Includes non-aromatic heterocycles. For example, 5- or 6-membered heterocycles such as pyrrole, imidazole, pyrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazole, triazinyl, tetrazole, isoxazole, oxazole, oxadiazole, isothiazole, thiazole, thiadiazole, furan, thiophene, etc. Ring: indole, isoindole, indazole, indolizine, indoline, isoindoline, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, naphthyridine, quinoxaline, purine, pteridine, benzopyran, benzimidazole (benzimidazole), benzotriazole, benzisoxazole (Benzoisoxazole), benzoxazole (benzoxazole), benzodioxole (1,3-benzene) Zodioxole), benzoxadiazole (benzoxadiazole), benzoisothiazole, benzothiazole, benzothiadiazole, benzofuran, isobenzofuran, benzothiophene, benzotriazole, imidazopyridine, pyrazolopyridine, triazolopyridine, imidazothiazole, pyra Bicyclic condensed heterocycles such as dinopyridazine, quinazoline, quinoline, isoquinoline, naphthyridine, dihydrobenzofuran, tetrahydroquinoline, tetrahydroisoquinoline, dihydrobenzoxazine, tetrahydrobenzothiophene; carbazole, acridine, xanthene, phenothiazine, phenoxathiirane, phenoxazine , Dibenzofuran, imidazoquinoline and other three condensed heterocycles; dioxane, thiirane Oxirane, oxetane, oxathiolane, azetidine, aziridine, thiane, thiazolidine, pyrrolidine, pyrroline, imidazolidine, imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine, morpholine, thiomorpholine, dihydropyridine, dihydrobenzimidazole, tetrahydropyridine, tetrahydrofuran, tetrahydropyran, Non-aromatic heterocycles such as dihydropyran, tetrahydrothiazole, tetrahydroisothiazole, dihydrooxazine, hexahydroazepine (azepane), and tetrahydrodiazepine.

  In the present specification, “heteroaryl” is a monovalent group derived from a 5 to 6-membered aromatic heterocycle containing at least one oxygen atom, sulfur atom, and / or nitrogen atom in the ring. The group of is included. This may be fused with the above “aryl” and / or other heteroaryl at all possible positions. Whether the heteroaryl is a single ring or a fused ring, it can be attached at all possible positions. For example, pyrrolyl (eg, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), furyl (eg, 2-furyl, 3-furyl), thienyl (eg, 2-thienyl, 3-thienyl), imidazolyl (eg, 2 -Imidazolyl, 4-imidazolyl), pyrazolyl (eg 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), isothiazolyl (eg 3-isothiazolyl), isoxazolyl (eg 3-isoxazolyl), oxazolyl (eg 2-oxazolyl) , 4-oxazolyl, 5-oxazolyl), thiazolyl (eg 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), pyridyl (eg 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrazinyl (eg 2- Pyrazinyl), pyrimidinyl (eg 2-pyrimidinyl) , 4-pyrimidinyl), pyridazinyl (eg, 3-pyridazinyl), tetrazolyl (eg, 1H-tetrazolyl), oxadiazolyl (eg, 1,3,4-oxadiazolyl), thiadiazolyl (eg, 1,3,4-thiadiazolyl), Indolizinyl (eg, 2-indolidinyl, 6-indolidinyl), isoindolyl (eg, 2-isoindolyl), indolyl (eg, 1-indolyl, 2-indolyl, 3-indolyl), indazolyl (eg, 3-indazolyl), purinyl ( For example, 8-purinyl), quinolidinyl (eg, 2-quinolidinyl), isoquinolyl (eg, 3-isoquinolyl), quinolyl (eg, 2-quinolyl, 5-quinolyl), phthalazinyl (eg, 1-phthalazinyl), naphthyridinyl (Eg, 2-naphthyridinyl), quinazolinyl (eg, 2-quinazolinyl), cinnolinyl (eg, 3-cinnolinyl), pteridinyl (eg, 2-pteridinyl), carbazolyl (eg, 2-carbazolyl, 4-carbazolyl), phenant Lydinyl (eg 2-phenanthridinyl, 3-phenanthridinyl), acridinyl (eg 1-acrinidyl, 2-acrinidyl), dibenzofuranyl (eg 1-dibenzofuranyl, 2-dibenzofuranyl) ), Benzimidazolyl (eg, 2-benzimidazolyl), benzoisoxazolyl (eg, 3-benzoisoxazolyl), benzoxazolyl (eg, 2-benzoxazolyl), benzooxadiazolyl (eg, 4-Benzoxadiazolyl), benzoiso Thiazolyl (eg 3-benzoisothiazolyl), benzothiazolyl (eg 2-benzothiazolyl), benzofuryl (eg 3-benzofuryl), benzothienyl (eg 2-benzothienyl), dibenzothienyl (eg 2-dibenzothienyl) ) And the like.

  In the present specification, the “heterocyclyl” is derived from a 3-8 membered non-aromatic heterocycle containing at least one oxygen atom, sulfur atom and / or nitrogen atom in the ring. Includes monovalent groups. The non-aromatic heterocycle described above may have a bond at any substitutable position. Further, such a non-aromatic heterocycle may be further bridged with an alkyl chain having 1 to 4 carbon atoms. Further, such a non-aromatic heterocycle includes the above “cycloalkyl” (for example, 3 to 6 membered ring), the above “cycloalkenyl” (for example, 3 to 6 membered ring), the above “aryl”, It may be condensed with the above “heteroaryl” and / or other heterocyclyl. As long as the condensed ring is a non-aromatic ring, it may have unsaturation in any ring. For example, pyrrolinyl (eg, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl), pyrrolidinyl (eg, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl), pyrrolidinone, imidazolinyl (eg, 1-imidazolinyl, 2-imidazolinyl, 4-imidazolinyl), imidazolidinyl (eg 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl), imidazolidinone, pyrazolinyl (eg 1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl), pyrazolidinyl (eg 1-pyrazolidinyl) 3-pyrazolidinyl, 4-pyrazolidinyl), piperidinone, piperidino, piperidinyl (eg 2-piperidinyl, 3-piperidinyl, 4-piperidinyl), piperazinyl (eg 1-pipe Dinyl, 2-piperazinyl), morpholinyl (eg, 2-morpholinyl, 3-morpholinyl), morpholino, tetrahydropyranyl (eg, 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl), tetrahydrofuranyl ( Examples thereof include 2-tetrahydrofuranyl and 3-tetrahydrofuranyl).

  In the present specification, the “aromatic heterocycle” is an arbitrarily selected aromatic 5- to 8-membered ring containing at least one oxygen atom, sulfur atom, and / or nitrogen atom in the ring, or 2 Includes rings fused at least. Monocyclic aromatic heterocycles include rings derived from 5- to 8-membered aromatic heterocycles which may contain from 1 to 4 oxygen, sulfur and / or nitrogen atoms in the ring. . The monocyclic aromatic heterocycle may have a bond at any substitutable position. The fused aromatic heterocycle is a 5- to 8-membered monocyclic aromatic heterocycle which may contain 1 to 4 oxygen, sulfur and / or nitrogen atoms in the ring. Includes a ring fused to a 5- to 8-membered monocyclic aromatic carbocycle or other 5- to 8-membered monocyclic aromatic heterocycle. The fused aromatic heterocycle may have a bond at any substitutable position. For example, a 5-6 membered aromatic heterocycle is mentioned. Examples of the aromatic heterocycle include pyrrole ring, furan ring, thiophene ring, imidazole ring, pyrazole ring, isothiazole ring, isoxazole ring, oxazole ring, thiazole ring, pyridine ring, pyrazine ring, pyrimidine ring, pyridazine ring, tetrazole Ring, oxadiazole ring, thiadiazole ring, indolizine ring, isoindole ring, indole ring, indazole ring, azaindole ring, purine ring, quinolidine ring, isoquinoline ring, quinoline ring, phthalazine ring, naphthyridine ring, quinazoline Ring, cinnoline ring, pteridine ring, carbazole ring, phenanthridine ring, acridine ring, dibenzofuran ring, benzimidazole ring, benzisoxazole ring, benzoxazole ring, benzoxazole ring, benzoisothiazole ring, benzoti Tetrazole ring, benzofuran ring, benzothiophene ring, such as dibenzothiophene ring. Examples thereof include a thiophene ring, a pyridine ring, a furan ring, a thiazole ring, an oxazole ring, and a pyrimidine ring.

  In the present specification, the “non-aromatic heterocycle” is a non-aromatic 3- to 8-membered ring containing at least one oxygen atom, sulfur atom, and / or nitrogen atom in the ring, or any of them. Includes a ring in which two or more are fused. Moreover, such a non-aromatic heterocycle may be bridge | crosslinked with a C1-C4 alkyl chain. Further, such a non-aromatic heterocycle includes the above “aromatic carbocycle” (for example, a 6-membered ring), the above “non-aromatic carbocycle” (for example, a 3- to 6-membered ring), the above “ It may be fused with an “aromatic heterocycle” and / or other “non-aromatic heterocycle”. As long as the condensed ring is a non-aromatic ring, it may have unsaturation in any ring. For example, pyrroline ring, pyrrolidine ring, pyrrolidinone ring, imidazoline ring, imidazolidine ring, pyrazoline ring, pyrazolidine ring, piperidinone ring, piperidine ring, piperazine ring, diazepan ring, morpholine ring, tetrahydropyran ring, tetrahydrofuran ring, dihydropyran ring, Examples include a dihydrofuran ring, a benzodioxole ring, an octahydrocyclopentapyrrole ring, an octahydropyrrolopyrazine ring, an azabicyclooctane ring, a diazabicyclooctane ring, and an azabicyclohexane ring. Examples thereof include a dihydropyran ring, a tetrahydropyran ring, a dihydrofuran ring, and a tetrahydrofuran ring.

  In the present specification, the “heterocyclic group” includes a monovalent group derived from the above “heterocycle”, and includes heteroaryl, heterocyclyl and the like.

  In the present specification, the “non-aromatic heterocyclic group” includes a monovalent group derived from the “non-aromatic heterocyclic ring”.

  In the present specification, “azaindole” includes 4-azaindole, 5-azaindole, 6-azaindole, and 7-azaindole.

  In the present specification, the alkyl moiety of “halogenoalkyl”, “alkylcarbonyl”, “alkylsulfinyl”, “alkylamino”, “alkylcarbamoyl”, “alkylsulfamoyl”, and “alkylthio” is the above “alkyl”. Means.

  In the present specification, the alkoxy moiety of “halogenoalkoxy”, “alkoxysulfonyl” and “alkoxysulfinyl” means the above “alkoxy”.

  In the present specification, the alkenyl moiety of “alkenyloxy”, “alkenylcarbonyl”, “alkenylsulfonyl”, “alkenyloxysulfonyl”, “alkenylsulfinyl”, “alkenyloxysulfinyl” and “alkenylthio” is the above “alkenyl”. Means.

  In the present specification, the alkynyl moiety of “alkynyloxy”, “alkynylsulfonyl”, “alkynyloxysulfonyl”, “alkynylsulfinyl”, “alkynyloxysulfinyl” and “alkynylthio” means the above “alkynyl”.

  In the present specification, the cycloalkyl part of “cycloalkylcarbonyl”, “cycloalkylsulfonyl”, “cycloalkylsulfinyl”, “cycloalkoxysulfonyl” and “cycloalkoxysulfinyl” means the above “cycloalkyl”.

In the present specification, the cycloalkenyl moiety of “cycloalkenylcarbonyl”, “cycloalkenylsulfonyl”, “cycloalkenyloxysulfonyl”, “cycloalkenylsulfinyl” and “cycloalkenyloxysulfinyl” means the above “cycloalkenyl”. .

  In the present specification, the aryl part of “aryloxy”, “arylcarbonyl”, “aryloxycarbonyl”, “arylsulfonyl”, “aryloxysulfonyl” and “aryloxysulfinyl” means the above “aryl”.

  In the present specification, the heteroaryl moiety of “heteroarylcarbonyl”, “heteroaryloxycarbonyl”, “heteroarylsulfonyl”, “heteroarylsulfinyl”, “heteroaryloxysulfonyl” and “heteroaryloxysulfinyl” Means “heteroaryl”.

  In the present specification, "heterocyclylcarbonyl", "heterocyclylsulfonyl", "heterocyclylsulfinyl", "heterocyclyloxysulfonyl", "heterocyclyloxysulfinyl" and "heterocyclyloxycarbonyl" The heterocyclyl moiety means the above “heterocyclyl”.

  In the present specification, the carbocyclic moiety of “carbocyclic oxy”, “carbocyclic oxyalkyl” and “carbocyclic thio” means the above “carbocycle”.

  In the present specification, the heterocyclic moiety of “heterocyclic oxy”, “heterocyclic oxyalkyl” and “heterocyclic thio” means the above “heterocycle”.

  In the present specification, the acyl part of “acylamino” and “acyloxy” means the above “acyl”.

  In the present specification, “substituted or unsubstituted alkyl”, “substituted or unsubstituted alkenyl”, “substituted or unsubstituted alkynyl”, “substituted or unsubstituted alkoxycarbonyl”, “substituted or unsubstituted alkoxy” , “Substituted or unsubstituted alkenyloxy”, “substituted or unsubstituted alkynyloxy”, “substituted or unsubstituted alkylthio”, “substituted or unsubstituted alkenylthio”, “substituted or unsubstituted alkynylthio”, Examples of the substituent in “substituted or unsubstituted methylene” include one or more groups selected from the following substituent group α.

In the present specification, “substituted or unsubstituted aryl”, “substituted or unsubstituted cycloalkyl”, “substituted or unsubstituted cycloalkenyl”, “substituted or unsubstituted carbocyclic oxy”, “substituted or unsubstituted” "Heterocyclic oxy", "substituted or unsubstituted carbocyclic thio", "substituted or unsubstituted heterocyclic thio", "substituted or unsubstituted carbocyclic group", "substituted or unsubstituted heterocyclic group" , "Substituted or unsubstituted pyridyl", "substituted or unsubstituted imidazolyl", "substituted or unsubstituted pyrazolyl", "substituted or unsubstituted oxazolyl", "substituted or unsubstituted thiazolyl", "substituted or unsubstituted Substituted non-aromatic heterocyclic group "," substituted or unsubstituted carbocyclic oxyalkyl "," substituted or unsubstituted heterocyclic oxyal Le ", as a substituent group in the" substituted or unsubstituted carbocyclic "and" substituted or unsubstituted heterocyclic ring ",
One or more groups selected from the following substituent group α,
Alkyl optionally substituted with one or more groups selected from substituent group α,
Alkenyl optionally substituted with one or more groups selected from substituent group α,
Alkynyl optionally substituted with one or more groups selected from substituent group α,
Alkoxy substituted with one or more groups selected from substituent group α,
Alkylthio substituted with one or more groups selected from substituent group α,
Amino substituted with one or more groups selected from substituent group α,
Alkylamino substituted with one or more groups selected from substituent group α,
Alkylsulfonyl optionally substituted with one or more groups selected from substituent group α,
Alkoxycarbonyl substituted with one or more groups selected from the substituent group α,
Acyl substituted with one or more groups selected from the substituent group α,
And oxo and the like, and may be substituted with one or more groups selected from these.

  In the present specification, “optionally substituted with” means that it may or may not be substituted with, that is, both “substituted or unsubstituted”. Is meant to be included. Specifically, the “alkyl optionally substituted with one or more groups selected from substituent group α” means alkyl substituted with one or more groups selected from substituent group α, or non-substituted It is meant to include both substituted alkyls.

  In the present specification, examples of the substituent of “substituted or unsubstituted acyl” and “substituted or unsubstituted acyloxy” include one or more groups selected from the substituent group α. The ring portion of carbocyclic carbonyl and heterocyclic carbonyl is represented by one or more groups selected from alkyl, the following substituent group α, and alkyl substituted by one or more groups selected from substituent group α. May be substituted.

  Here, the substituent group α is halogen, hydroxy, acyl, acyloxy, carboxy, alkoxycarbonyl, amino, acylamino, alkylamino, alkoxycarbonylamino, carbamoylamino, alkylcarbamoylamino, mercapto, alkylthio, carbamoyl, alkylcarbamoyl, sulfamoyl. , Alkylsulfamoyl, cyano, nitro, alkylene, alkoxy optionally substituted with one or more groups selected from the following substituent group β, carbocycle optionally substituted with the following substituent group β A carbon group optionally substituted with one or more groups selected from the formula group, one or more groups selected from the following substituent group β, and one or more groups selected from the following substituent group β Ring thio, substituted with one or more groups selected from the following substituent group β Carbocyclic amino, which may be substituted with one or more groups selected from the following substituent group β, which may be substituted with one or more groups selected from carbocyclic carbonyl, substituent group β A heterocyclic group, a heterocyclic oxy optionally substituted with one or more groups selected from the following substituent group β, and substituted with one or more groups selected from the following substituent group β A heterocyclic thio, which may be substituted with one or more groups selected from the following substituent group β, which is substituted with one or more groups selected from the following heterocyclic amino and substituent group β Or a group consisting of heterocyclic carbonyls.

  Here, the substituent group β is alkyl, halogenoalkyl, halogen, hydroxy, alkoxy, halogenoalkoxy, acyl, acyloxy, carboxy, alkoxycarbonyl, amino, acylamino, alkylamino, alkoxycarbonylamino, mercapto, alkylthio, carbamoyl, alkyl It is a group consisting of carbamoyl, sulfamoyl, alkylsulfamoyl, cyano, nitro, cycloalkyl, phenyl, pyrrole.

  In the present specification, “substituted or unsubstituted amino” means the above “substituted or unsubstituted alkyl”, the above “substituted or unsubstituted cycloalkyl”, the above “substituted or unsubstituted aryl”, and the above “substituted”. Or “unsubstituted carbocyclic group”, the above “substituted or unsubstituted heterocyclic group”, the above “substituted or unsubstituted acyl”, the above “substituted or unsubstituted alkoxycarbonyl”, and the following “substituted sulfonyl”. Includes aminos optionally substituted at one or two positions. “Substituted or unsubstituted amino” includes amino, acylamino, alkylamino, alkoxycarbonylamino, carbamoylamino, alkylcarbamoylamino. The alkylamino includes both monoalkylamino and dialkylamino. Examples of the “substituted or unsubstituted amino” include amino, methylamino, dimethylamino, ethylamino, diethylamino, ethylmethylamino, cyclohexylamino, benzylamino, acetylamino, benzoylamino, methoxycarbonylamino, methylsulfonylamino, Examples include tetrahydropyranylamino, tetrahydrofuranylamino, morpholinoamino, morpholinylamino, piperidinylamino, piperazinylamino and the like. Examples thereof include amino, methylamino, dimethylamino, ethylmethylamino, diethylamino, acetylamino, methylsulfonylamino, tetrahydropyranylamino, tetrahydrofuranylamino, morpholinoamino, piperidinylamino and the like.

  In the present specification, “substituted or unsubstituted carbamoyl” includes substituted or unsubstituted aminocarbonyl in which the substituted or unsubstituted amino moiety is the above “substituted or unsubstituted amino”. Examples of the “substituted or unsubstituted carbamoyl” include carbamoyl, N-methylcarbamoyl, N, N-dimethylcarbamoyl, N-ethyl-N-methylcarbamoyl, N, N-diethylcarbamoyl, Nn-propylaminocarbamoyl. N-isopropylcarbamoyl, N-morpholinocarbamoyl, N-tetrahydrofuranylcarbamoyl, N-piperidylcarbamoyl, N-tetrahydropyranylcarbamoyl, N-benzylcarbamoyl, N-acetylcarbamoyl, N-methylsulfonylcarbamoyl, N- (2,2 , 2-trifluoroethyl) carbamoyl, N- (2-hydroxy-1-methylethyl) carbamoyl, and the like. For example, carbamoyl, N-methylcarbamoyl, N, N-dimethylcarbamoyl, Nn-propylaminocarbamoyl, N-isopropylcarbamoyl, N-morpholinocarbamoyl, N-tetrahydrofuranylcarbamoyl, N-piperidylcarbamoyl, N-tetrahydropyranylcarbamoyl N-methylsulfonylcarbamoyl, N- (2,2,2-trifluoroethyl) carbamoyl, N- (2-hydroxy-1-methylethyl) carbamoyl and the like.

  In the present specification, the “substituted or unsubstituted sulfamoyl” includes a substituted or unsubstituted aminosulfonyl in which the substituted or unsubstituted amino moiety is the above “substituted or unsubstituted amino”. Examples of “substituted or unsubstituted sulfamoyl” include sulfamoyl, N-methylsulfamoyl, N, N-dimethylsulfamoyl, N-ethyl-N-methylsulfamoyl, N, N-diethylsulfamoyl. N-propylaminosulfamoyl, N-isopropylsulfamoyl, N-morpholinosulfamoyl, N-tetrahydrofuranylsulfamoyl, N-piperidylsulfamoyl, N-tetrahydropyranylsulfamoyl, N-benzyl Examples thereof include sulfamoyl, N-acetylsulfamoyl, N-methylsulfonylsulfamoyl and the like. For example, sulfamoyl, N-methylsulfamoyl, N, N-dimethylsulfamoyl, Nn-propylaminosulfamoyl, N-isopropylsulfamoyl, N-morpholinosulfamoyl, N-tetrahydrofuranylsulfamoyl N-piperidylsulfamoyl, N-tetrahydropyranylsulfamoyl, N-methylsulfonylsulfamoyl and the like.

  In the present specification, “substituted sulfonyl” means alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, alkoxysulfonyl, alkenyloxysulfonyl, alkynyloxysulfonyl, cycloalkylsulfonyl, cycloalkenylsulfonyl, cycloalkoxysulfonyl, cycloalkenyloxysulfonyl, aryl Including sulfonyl, aryloxysulfonyl, heteroarylsulfonyl, heteroaryloxysulfonyl, heterocyclylsulfonyl, heterocyclyloxysulfonyl and the like.

  In the present specification, “substituted sulfinyl” refers to alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, alkoxysulfinyl, alkenyloxysulfinyl, alkynyloxysulfinyl, cycloalkylsulfinyl, cycloalkenylsulfinyl, cycloalkoxysulfinyl, cycloalkenyloxysulfinyl, aryl Includes sulfinyl, aryloxysulfinyl, heteroarylsulfinyl, heteroaryloxysulfinyl, heterocyclylsulfinyl, heterocyclyloxysulfinyl and the like.

  In the present specification, “alkylene” includes a linear or branched carbon chain. In the present specification, “alkylene having 1 or 2 carbon atoms” includes a divalent carbon chain having 1 or 2 carbon atoms. Specifically, methylene and dimethylene. In the present specification, “alkylene having 1 to 3 carbon atoms” includes a divalent carbon chain having 1 to 3 carbon atoms. Specifically, methylene, dimethylene, and propylene.

  Examples of the substituent in “substituted or unsubstituted alkylene having 1 or 2 carbon atoms” include alkyl and one or more groups selected from the above substituent group α. For example, C2-5 alkylene etc. are mentioned as a substituent.

In the present specification, examples of the substituent of the “substituted or unsubstituted dihydrothiazine cyclic group” include methyl and amino. For example, as a substituent of “substituted or unsubstituted dihydrothiazine cyclic group”,
One or more groups selected from the above substituent group α,
Alkyl optionally substituted with one or more groups selected from substituent group α,
Alkenyl optionally substituted with one or more groups selected from substituent group α,
Alkynyl optionally substituted with one or more groups selected from substituent group α,
Alkoxy substituted with one or more groups selected from substituent group α,
Alkylthio substituted with one or more groups selected from substituent group α,
Alkylamino substituted with one or more groups selected from substituent group α,
Alkylsulfonyl optionally substituted with one or more groups selected from substituent group α,
Alkoxycarbonyl substituted with one or more groups selected from the substituent group α,
Acyl substituted with one or more groups selected from the substituent group α,
And oxo and the like, and may be substituted with one or more groups selected from the group.

  In the present specification, the “non-aromatic heterocycle containing only a nitrogen atom as a hetero atom constituting the ring” includes a non-aromatic heterocycle having one or more nitrogen atoms in the ring, for example, pyrrolidine , Pyrroline, imidazolidine, imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine, dihydropyridine, dihydrobenzimidazole, tetrahydropyridine, hexahydroazepine (azepane), tetrahydrodiazepine and the like.

  In the present specification, “a non-aromatic heterocycle containing only a nitrogen atom as a hetero atom constituting the ring, and all the bonds in the ring are single bonds” means a saturated non-aromatic ring having one or more nitrogen atoms in the ring. An aromatic heterocycle is included, and examples thereof include pyrrolidine, imidazolidine, pyrazolidine, piperidine, piperazine, hexahydroazepine (azepane) and the like.

In the general formula (I) or (III), “n is an integer of 0 to 5”
When the A ring is a benzene ring, cyclohexane ring, cyclohexene ring, tetrahydropyran ring, tetrahydropyridine ring, dihydropyridine ring, piperidine ring, piperazine ring, or morpholine ring, n is an integer of 0 to 5,
When A ring is a pyridine ring, n is an integer of 0 to 4,
When A ring is a pyridazine ring or a pyrimidine ring, n is an integer of 0 to 3.

In the general formula (I), “n is an integer of 1 to 5”
When the A ring is a benzene ring, cyclohexane ring, cyclohexene ring, tetrahydropyran ring, tetrahydropyridine ring, dihydropyridine ring, piperidine ring, piperazine ring, or morpholine ring, n is an integer of 1 to 5,
When A ring is a pyridine ring, n is an integer of 1 to 4,
When A ring is a pyridazine ring or a pyrimidine ring, n is an integer of 1 to 3.

In the general formula (I), (II) or (III), when R ² is N (R ¹⁴ ) (R ¹⁵ ), “R ¹⁴ and R ¹⁵ are taken together with the nitrogen atom to which they are bonded. To form a heterocycle "means -C (R < ¹ >) = C (R < ² >)-C (R < ³ >) = C (R < ⁴ >)-or -C (R < ¹ >) = C (R < ² >)-N = This includes the case where the atom of R ² directly bonded to the carbon atom substituted with R ² in C (R ⁴ ) — is a nitrogen atom and forms a heterocycle containing the nitrogen atom. For example, pyrrole, imidazole, pyrazole, triazole, triazine, tetrazole, azetidine, thiazolidine, pyrrolidine, pyrroline, imidazolidine, imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine, morpholine, thiomorpholine, dihydropyridine, dihydrobenzimidazole, tetrahydropyridine, tetrahydro Thiazole, tetrahydroisothiazole, hexahydroazepine (azepane), tetrahydrodiazepine and the like (where -C (R < ¹ >) = C (R < ² >)-C (R < ³ >) = C (R < ⁴ >)-or -C (R ¹ ) = C (R ² ) —N═C (R ⁴ ) —, wherein each R ² atom directly bonded to a carbon atom substituted with R ² is a nitrogen atom.

When at least one R ⁷ in general formula (I) or R ¹¹ in general formula (II) is N (R ¹⁸ ) (R ¹⁹ ), “R ¹⁸ and R ¹⁹ are the nitrogen to which they are attached. “To form a non-aromatic heterocycle together with an atom” includes a case where the atom directly bonded to the A ring is a nitrogen atom and forms a non-aromatic heterocycle containing the nitrogen atom. For example, pyrrolidine, pyrroline, imidazolidine, imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine, dihydropyridine, dihydrobenzimidazole, tetrahydropyridine, hexahydroazepine (azepane), tetrahydrodiazepine, octahydropyrrolopyrazine, azabicyclohexane, etc. , The atom directly bonded to the A ring is a nitrogen atom).

In the general formula (I), “the A ring is a piperidine ring or a piperazine ring (wherein the atom on the A ring bonded to Ak ² is necessarily a nitrogen atom)”

[Wherein R ⁷ and n are as defined above in 1)]
It means that.

In -Ak ¹ -L ¹ -Ak ^2- of the general formula (I), -L ¹ -is -C (= O) N (R ⁸ )-, -C (= O) -C (= O)- When N (R ⁸ ) — or —C (═O) O— and Ak ¹ is a single bond, the indole ring or azaindole ring is bonded to “—C (═O)” of L ¹ above. It means to do. Similarly, the general formula ^{(I) -Ak 1 -L 1 -Ak} 2 of - in, -L ¹ - ^{is, -N (R 8) -C (} = O) -, or -N ^(R 8) SO ₂ When Ak ¹ is a single bond, the indole ring or azaindole ring is bonded to the “N” atom of L ¹ . Further, in the case where -L ¹ -is -SO ₂ N (R ⁸ )-in -Ak ¹ -L ¹ -Ak ^2- of the general formula (I) and Ak ¹ is a single bond, then indole The ring or azaindole ring is bound to the “S” atom of L ¹ above.

  In the present specification, the “solvate” includes, for example, solvates with organic solvents, hydrates and the like. When forming a hydrate, it may be coordinated with any number of water molecules.

  The compounds according to the present invention include pharmaceutically acceptable salts. For example, alkali metals (lithium, sodium, potassium, etc.), alkaline earth metals (calcium, etc.), magnesium, transition metals (iron, zinc, etc.), ammonium, salts with organic bases and amino acids, or inorganic acids (hydrochloric acid, sulfuric acid) , Nitric acid, hydrobromic acid, phosphoric acid or hydroiodic acid), and organic acids (acetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid, mandelic acid, glutaric acid, malic acid, Benzoic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid and the like). In particular, hydrochloric acid, phosphoric acid, tartaric acid, methanesulfonic acid and the like are preferable. These salts can be formed by a commonly performed method.

  Further, the compound of the general formula (I), the compound of the general formula (II) or the compound of the general formula (III) according to the present invention is not limited to a specific isomer, but all possible isomers (keto- Enol isomers, imine-enamine isomers, diastereoisomers, optical isomers and rotational isomers) and racemates.

Furthermore, one or more hydrogen, carbon or other atoms of the compound of general formula (I), the compound of general formula (II) or the compound of general formula (III) is hydrogen, carbon or an isotope of another atom. Can be replaced. Compounds of general formula (I), compounds of general formula (II) or compounds of general formula (III) are all compounds of general formula (I), compounds of general formula (II) or compounds of general formula (III) Of radiolabels. Such “radiolabeled”, “radiolabeled” and the like of the compound of general formula (I), the compound of general formula (II) or the compound of general formula (III) are each included in the present invention, It is useful as a research and / or diagnostic tool in pharmacokinetic studies and binding assays. Examples of isotopes that can be incorporated into the compounds of formula I of the present invention are ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ^{18 respectively.} F
, And as ³⁶ Cl, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine are included. The radiolabeled compound of the present invention can be prepared by methods well known in the art. For example, the tritium-labeled compound of the general formula (I), the general formula (II) or the general formula (III) is converted into the general formula (I) or the general formula (II) by, for example, catalytic dehalogenation reaction using tritium. Alternatively, it can be prepared by introducing tritium into a specific compound of the general formula (III). This method is suitable for compounds of general formula (I), compounds of general formula (II) or compounds of general formula (III) in the presence of a suitable catalyst, for example Pd / C, in the presence or absence of a base. And reacting a halogen-substituted precursor with tritium gas. For suitable methods for preparing other tritium labeled compounds, reference may be made to the document Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987). ^{A 14} C-labeled compound can be prepared by using a raw material having ¹⁴ C carbon.

  A general synthesis method of the compound (I) according to the present invention is shown below. Any of the starting materials and reaction reagents used in these syntheses are commercially available or can be prepared according to methods well known in the art using commercially available compounds.

The compounds described in the examples were synthesized generally according to these, but are not particularly limited to these methods. Reaction solvents, bases, palladium catalysts, and phosphine ligands that can be used in the production of the compounds are described below. In the general synthesis method, preferable ones are shown, but the present invention is not particularly limited to them.
(1) Reaction solvent: DMF, NMP, DMA, dimethyl sulfoxide, aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.), saturated hydrocarbons (eg, cyclohexane, hexane, etc.), halogenated hydrocarbons ( Examples, dichloromethane, chloroform, 1,2-dichloroethane, etc.), ethers (eg, tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane, etc.), esters (eg, methyl acetate, ethyl acetate, etc.), ketones (Eg, acetone, methyl ethyl ketone, etc.), nitriles (eg, acetonitrile, etc.), alcohols (eg, methanol, ethanol, t-butanol, etc.), water, and mixed solvents thereof.
(2) Base: metal hydride (eg, sodium hydride), metal hydroxide (eg, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide), metal carbonate (eg, sodium carbonate) Potassium carbonate, calcium carbonate, cesium carbonate, etc.), metal alkoxides (eg, sodium methoxide, sodium ethoxide, sodium t-butoxide, sodium 2-methylbutane-2-olate, potassium t-butoxide, etc.), sodium bicarbonate, Metal sodium, organic amine (eg, triethylamine, diisopropylethylamine, DBU, pyridine, 4-dimethylaminopyridine, 2,6-lutidine, etc.), alkyl lithium (n-BuLi, sec-BuLi, tert-BuLi) and the like.
(3) Pd catalyst used for Pd coupling: Pd (PPh ₃ ) ₄ , PdCl ₂ (dppf), PdCl ₂ (PPh ₃ ) ₂ , Pd (OAc) ₂ , Pd ₂ (dba) ₃ , PdCl _{2 and the} like.
(4) Phosphine ligands: PPh ₃ , BINAP, Xantphos, S-Phos, X-Phos, DPPF, t-Bu ₃ P, tris o-tolylphosphine, Ru-Phos and the like.

The compound represented by the formula (I) of the present invention can be produced, for example, by the synthetic route shown below.
(Manufacturing method A)

(Wherein B is COOH, CO—Hal, SO ₂ —Hal, or CO—CO—Hal and C is NHR ⁸ or OH, or C is COOH, CO—Hal, SO ₂ —Hal, or CO-CO-Hal, B is NHR ⁸ , Hal is halogen, and other symbols are as defined in 1) above.
Compound (I) can be produced by reacting compound a and compound b, which are known compounds or compounds obtained from known compounds by conventional methods. For example, compound a is a carboxylic acid compound, halogenocarbonyl compound, halogenosulfonyl compound, or halogenodicarbonyl compound, and compound b is an amine compound. Compound a may be a salt such as hydrochloride or bromate. As the reaction solvent, the reaction solvent described in 1) above can be used, preferably a solvent such as tetrahydrofuran, dichloromethane, chloroform, acetate ester, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide and the like. However, there is no particular limitation as long as it is a solvent other than the solvent that hinders the reaction under the present conditions. What is necessary is just to perform at room temperature-200 degreeC in presence of bases, such as DBU, a triethylamine, and a pyridine, and when reactivity is low, it can prepare by heating suitably. When one of B and C is COOH, in the presence of a condensing agent (N, N′dicyclohexylcarbodiimide, N-dimethylaminopropyl-N′-ethylcarbodiimide, diethyl phosphate cyanide diphenyl phosphate azide, etc.) You may make it react.

Instead of compound b in which C is NHR ⁸ ,

(Wherein, ring A is a piperidine ring, piperazine ring or morpholine ring, and the other symbols have the same meanings as in 1) above),
In Formula (I), Ak ² is a single bond; -L ¹ -is -C (= O)-; and the A ring is a piperidine ring, piperazine ring or morpholine ring (provided that Ak ² bonded to atoms on the ring a is always a nitrogen ^{atom), Ak 1, -X 1 =} X 2 -X 3 = X 4 -, R 1, R 2, R 3, R 4, R 5, R 6 , R ⁷ , and n can also produce a compound having the same meaning as in 1) above.

In all the steps described above, when there are substituents that interfere with the reaction (for example, hydroxy, mercapto, amino, formyl, carbonyl, carboxyl, etc.), Protective Group in Organic Groups (Protective Groups)
in Organic Synthesis) and the like, and the protecting group may be removed at a desired stage.

  Among the compounds of the general formula (I) according to the present invention, the following compounds are particularly preferable.

  In general formula (I):

[Wherein R ² , R ³ and R ⁶ are each independently halogen (preferably fluorine or chlorine), hydroxy, carboxy, sulfo, amino, hydroxyalkyl (preferably hydroxymethyl), carboxyalkyl (preferably Carboxymethyl), alkoxy (preferably methoxy or ethoxy), halogenoalkoxy (preferably trifluoromethoxy), piperidinyl or pyrrolidinyl]

And

[Wherein R ^A , R ^B1 and R ^B2 are each independently halogen (preferably fluorine or chlorine), alkyl (preferably methyl, ethyl), or alkoxy (preferably methoxy or ethoxy), or halogenoalkyl. (Preferably trifluoromethyl), halogenoalkoxy (preferably trifluoromethoxy);
Ring B is a benzene ring, pyridine ring, pyridazine ring, pyrimidine ring, cyclohexane ring, cyclohexene ring, tetrahydropyran ring, dihydropyridine ring, tetrahydropyridine ring, piperidine ring, piperazine ring, or morpholine ring (preferably benzene or pyridine ring). Is;
n is an integer of 0 to 5 (preferably an integer of 0 to 3), provided that the A ring is a benzene ring, cyclohexane ring, cyclohexene ring, tetrahydropyran ring, tetrahydropyridine ring, dihydropyridine ring, piperidine ring, piperazine ring. , Or morpholine ring, n is an integer of 0-5, when A ring is a pyridine ring, n is an integer of 0-4, and when A ring is a pyridazine ring or pyrimidine ring, n Is an integer from 0 to 3;
Ak ³ is a single bond or an alkylene having 1 to 3 carbon atoms (preferably a single bond or methylene)].

  Specific embodiments include the following. In general formula (I):

A compound wherein the combination (a, b, c) is:
combination
(a, b, c) = (a1, b1, c1), (a1, b1, c2), (a1, b1, c3), (a1, b1, c4), (a1, b1, c5), (a1 , b1, c6), (a1, b1, c7), (a1, b1, c8), (a1, b1, c9), (a1, b1, c10), (a1, b1, c11), (a1, b1 , c12), (a1, b1, c13), (a1, b2, c1), (a1, b2, c2), (a1, b2, c3), (a1, b2, c4), (a1, b2, c5 ), (a1, b2, c6), (a1, b2, c7), (a1, b2, c8), (a1, b2, c9), (a1, b2, c10), (a1, b2, c11), (a1, b2, c12), (a1, b2, c13), (a1, b3, c1), (a1, b3, c2), (a1, b3, c3), (a1, b3, c4), (a1 , b3, c5), (a1, b3, c6), (a1, b3, c7), (a1, b3, c8), (a1, b3, c9), (a1, b3, c10), (a1, b3 , c11), (a1, b3, c12), (a1, b3, c13), (a1, b4, c1), (a1, b4, c2), (a1, b4, c3), (a1, b4, c4 ), (a1, b4, c5), (a1, b4, c6), (a1, b4, c7), (a1, b4, c8), (a1, b4, c9), (a1, b4, c10), (a1, b4, c11), (a1, b4, c12), (a1, b4, c13), (a1, b5, c1), (a1, b5, c2), (a1, b5, c3), (a1 , b5, c4), (a1, b5, c5), (a1, b5, c6), (a1, b5, c7), (a1, b5, c8), (a1, b5, c9), (a1, b5 , c10), (a1, b5, c11), (a1, b5, c12), (a1, b5, c13), (a1, b6, c1), (a1, b6, c2), (a1, b6, c3 ), (a1, b6, c4), (a1, b6, c5), (a1, b6, c6), (a1, b6, c7), (a1, b6, c8), (a1, b6, c9), (a1, b6, c10), (a1, b6, c11), (a1, b6, c12), (a1, b6, c13), (a1, b7, c1), (a1, b7, c2), (a1 , b7, c3), (a1, b7, c4), (a1, b7, c5), (a1, b7, c6), (a1, b7, c7), (a1, b7, c8), (a1, b7 , c9), (a1, b7, c10) , (a1, b7, c11), (a1, b7, c12), (a1, b7, c13), (a1, b8, c1), (a1, b8, c2), (a1, b8, c3), ( a1, b8, c4), (a1, b8, c5), (a1, b8, c6), (a1, b8, c7), (a1, b8, c8), (a1, b8, c9), (a1, b8, c10), (a1, b8, c11), (a1, b8, c12), (a1, b8, c13), (a1, b9, c1), (a1, b9, c2), (a1, b9, c3), (a1, b9, c4), (a1, b9, c5), (a1, b9, c6), (a1, b9, c7), (a1, b9, c8), (a1, b9, c9) , (a1, b9, c10), (a1, b9, c11), (a1, b9, c12), (a1, b9, c13), (a1, b10, c1), (a1, b10, c2), ( a1, b10, c3), (a1, b10, c4), (a1, b10, c5), (a1, b10, c6), (a1, b10, c7), (a1, b10, c8), (a1, b10, c9), (a1, b10, c10), (a1, b10, c11), (a1, b10, c12), (a1, b10, c13), (a1, b11, c1), (a1, b11, c2), (a1, b11, c3), (a1, b11, c4), (a1, b11, c5), (a1, b11, c6), (a1, b11, c7), (a1, b11, c8) , (a1, b11, c9), (a1, b11, c10), (a1, b11, c11), (a1, b11, c12), (a1, b11, c13), (a2, b1, c1), ( a2, b1, c2), (a2, b1, c3), (a2, b1, c4), (a2, b1, c5), (a2, b1, c6), (a2, b1, c7), (a2, b1, c8), (a2, b1, c9), (a2, b1, c10), (a2, b1, c11), (a2, b1, c12), (a2, b1, c13), (a2, b2, c1), (a2, b2, c2), (a2, b2, c3), (a2, b2, c4), (a2, b2, c5), (a2, b2, c6), (a2, b2, c7) , (a2, b2, c8), (a2, b2, c9), (a2, b2, c10), (a2, b2, c11), (a2, b2, c12), (a2, b2, c13), ( a2, b3, c1), (a2, b3, c2), (a2, b3, c3), (a2, b3, c4), (a2, b3, c5), (a2, b3, c6), (a2, b3, c7), (a2, b3, c8), (a2, b3, c9), (a2, b3, c10), (a2, b3, c11), (a2 , b3, c12), (a2, b3, c13), (a2, b4, c1), (a2, b4, c2), (a2, b4, c3), (a2, b4, c4), (a2, b4 , c5), (a2, b4, c6), (a2, b4, c7), (a2, b4, c8), (a2, b4, c9), (a2, b4, c10), (a2, b4, c11 ), (a2, b4, c12), (a2, b4, c13), (
a2, b5, c1), (a2, b5, c2), (a2, b5, c3), (a2, b5, c4), (a2, b5, c5), (a2, b5, c6), (a2, b5, c7), (a2, b5, c8), (a2, b5, c9), (a2, b5, c10), (a2, b5, c11), (a2, b5, c12), (a2, b5, c13), (a2, b6, c1), (a2, b6, c2), (a2, b6, c3), (a2, b6, c4), (a2, b6, c5), (a2, b6, c6) , (a2, b6, c7), (a2, b6, c8), (a2, b6, c9), (a2, b6, c10), (a2, b6, c11), (a2, b6, c12), ( a2, b6, c13), (a2, b7, c1), (a2, b7, c2), (a2, b7, c3), (a2, b7, c4), (a2, b7, c5), (a2, b7, c6),
(a2, b7, c7), (a2, b7, c8), (a2, b7, c9), (a2, b7, c10), (a2, b7, c11), (a2, b7, c12), (a2 , b7, c13), (a2, b8, c1), (a2, b8, c2), (a2, b8, c3), (a2, b8, c4), (a2, b8, c5), (a2, b8 , c6), (a2, b8, c7), (a2, b8, c8), (a2, b8, c9), (a2, b8, c10), (a2, b8, c11), (a2, b8, c12 ), (a2, b8, c13), (a2, b9, c1), (a2, b9, c2), (a2, b9, c3), (a2, b9, c4), (a2, b9, c5), (a2, b9, c6), (a2, b9, c7), (a2, b9, c8), (a2, b9, c9), (a2, b9, c10), (a2, b9, c11), (a2 , b9, c12), (a2, b9, c13), (a2, b10, c1), (a2, b10, c2), (a2, b10, c3), (a2, b10, c4), (a2, b10 , c5), (a2, b10, c6), (a2, b10, c7), (a2, b10, c8), (a2, b10, c9), (a2, b10, c10), (a2, b10, c11 ), (a2, b10, c12), (a2, b10, c13), (a2, b11, c1), (a2, b11, c2), (a2, b11, c3), (a2, b11, c4), (a2, b11, c5), (a2, b11, c6), (a2, b11, c7), (a2, b11, c8), (a2, b11, c9), (a2, b11, c10), (a2 , b11, c11), (a2, b11, c12), (a2, b11, c13), (a3, b1, c1), (a3, b1, c2), (a3, b1, c3), (a3, b1 , c4), (a3, b1, c5), (a3, b1, c6), (a3, b1, c7), (a3, b1, c8), (a3, b1, c9), (a3, b1, c10 ), (a3, b1, c11), (a3, b1, c12), (a3, b1, c13), (a3, b2, c1), (a3, b2, c2), (a3, b2, c3), (a3, b2, c4), (a3, b2, c5), (a3, b2, c6), (a3, b2, c7), (a3, b2, c8), (a3, b2, c9), (a3 , b2, c10), (a3, b2, c11), (a3, b2, c12), (a3, b2, c13), (a3, b3, c1), (a3, b3, c2), (a3, b3, c3), (a3, b3, c4), (a3, b3, c5), (a3, b3, c6), (a3, b3, c7), (a3 , b3, c8), (a3, b3, c9), (a3, b3, c10), (a3, b3, c11), (a3, b3, c12), (a3, b3, c13), (a3, b4 , c1), (a3, b4, c2), (a3, b4, c3), (a3, b4, c4), (a3, b4, c5), (a3, b4, c6), (a3, b4, c7 ), (a3, b4, c8), (a3, b4, c9), (a3, b4, c10), (a3, b4, c11), (a3, b4, c12), (a3, b4, c13), (a3, b5, c1), (a3, b5, c2), (a3, b5, c3), (a3, b5, c4), (a3, b5, c5), (a3, b5, c6), (a3 , b5, c7), (a3, b5, c8), (a3, b5, c9), (a3, b5, c10), (a3, b5, c11), (a3, b5, c12), (a3, b5 , c13), (a3, b6, c1), (a3, b6, c2), (a3, b6, c3), (a3, b6, c4), (a3, b6, c5), (a3, b6, c6 ), (a3, b6, c7), (a3, b6, c8), (a3, b6, c9), (a3, b6, c10), (a3, b6, c11), (a3, b6, c12), (a3, b6, c13), (a3, b7, c1), (a3, b7, c2), (a3, b7, c3), (a3, b7, c4), (a3, b7, c5), (a3 , b7, c6), (a3, b7, c7), (a3, b7, c8), (a3, b7, c9), (a3, b7, c10), (a3, b7, c11), (a3, b7 , c12), (a3, b7, c13), (a3, b8, c1), (a3, b8, c2), (a3, b8, c3), (a3, b8, c4), (a3, b8, c5 ), (a3, b8, c6),
(a3, b8, c7), (a3, b8, c8), (a3, b8, c9), (a3, b8, c10), (a3, b8, c11), (a3, b8, c12), (a3 , b8, c13), (a3, b9, c1), (a3, b9, c2), (a3, b9, c3), (a3, b9, c4), (a3, b9, c5), (a3, b9 , c6), (a3, b9, c7), (a3, b9, c8), (a3, b9, c9), (a3, b9, c10), (a3, b9, c11), (a3, b9, c12 ), (a3, b9, c13), (a3, b10, c1), (a3, b10, c2), (a3, b10, c3), (a3, b10, c4), (a3, b10, c5), (a3, b10, c6), (a3, b10, c7), (a3, b10, c8), (a3, b10, c9), (a3, b10, c10), (a3, b10, c11), (a3 , b10, c12), (a3, b10, c13), (a3, b11, c1), (a3, b11, c2), (a3, b11, c3), (a3, b11, c4), (a3, b11 , c5), (a3, b11, c6), (a3, b11, c7), (a3, b11, c8), (a3, b11, c9), (a3, b11, c10), (a3, b11, c11 ), (a3, b11, c12), (a3, b11, c13), (a4, b1, c1), (a4, b1, c2), (a4, b1, c3), (a4, b1, c4), (a4, b1, c5), (a4, b1, c6), (a4, b1, c7), (a4, b1, c8), (a4, b1, c9), (a4, b1, c10), (a4 , b1, c11), (a4, b1, c12), (a4, b1, c13), (a4, b2, c1), (a4, b2, c2), (a4, b2, c3), (a4, b2 , c4), (a4, b2, c5), (a4, b2, c6), (a4, b2, c7), (a4, b2, c8), (a4, b2, c9), (a4, b2, c10 ), (a4, b2, c11), (a4, b2, c12), (a4, b2, c13), (a4, b3, c1), (a4, b3, c2), (a4, b3, c3), (a4, b3, c4), (a4, b3, c5), (a4, b3, c6), (a4, b3, c7), (a4, b3, c8), (a4, b3, c9), (a4 , b3, c10), (a4, b3, c11), (a4, b3, c12), (a4, b3, c13), (a4, b4, c1), (a4, b4, c2), (a4, b4, c3), (a4, b4, c4), (a4, b4, c5), (a4, b4, c6), (a4, b4, c7), (a4 , b4, c8), (a4, b4, c9), (a4, b4, c10), (a4, b4, c11), (a4, b4, c12), (a4, b4, c13), (a4, b5 , c1), (a4, b5, c2), (a4, b5, c3), (a4, b5, c4), (a4, b5, c5), (a4, b5, c6), (a4, b5, c7 ), (a4, b5, c8), (a4, b5, c9), (a4, b5, c10), (a4, b5, c11), (a4, b5, c12), (a4, b5, c13), (a4, b6, c1), (a4, b6, c2), (a4, b6, c3), (a4, b6, c4), (a4, b6, c5), (a4, b6, c6), (a4 , b6, c7), (a4, b6, c8), (a4, b6, c9), (a4, b6, c10), (a4, b6, c11), (a4, b6, c12), (a4, b6 , c13), (a4, b7, c1), (a4, b7, c2), (a4, b7, c3), (a4, b7, c4), (a4, b7, c5), (a4, b7, c6 ), (a4, b7, c7), (a4, b7, c8), (a4, b7, c9), (a4, b7, c10), (a4, b7, c11), (a4, b7, c12), (a4, b7, c13), (a4, b8, c1), (a4, b8, c2), (a4, b8, c3), (a4, b8, c4), (a4, b8, c5), (a4 , b8, c6), (a4, b8, c7), (a4, b8, c8), (a4, b8, c9), (a4, b8, c10), (a4, b8, c11), (a4, b8 , c12), (a4, b8, c13), (a4, b9, c1), (a4, b9, c2), (a4, b9, c3), (a4
, b9, c4), (a4, b9, c5), (a4, b9, c6), (a4, b9, c7), (a4, b9, c8), (a4, b9, c9), (a4, b9 , c10), (a4, b9, c11), (a4, b9, c12), (a4, b9, c13), (a4, b10, c1), (a4, b10, c2), (a4, b10, c3 ), (a4, b10, c4), (a4, b10, c5), (a4, b10, c6), (a4, b10, c7), (a4, b10, c8), (a4, b10, c9), (a4, b10, c10), (a4, b10, c11), (a4, b10, c12), (a4, b10, c13), (a4, b11, c1), (a4, b11, c2), (a4 , b11, c3), (a4, b11, c4), (a4, b11, c5), (a4, b11, c6), (a4, b11, c7), (a4, b11, c8), (a4, b11 , c9), (a4, b11, c10), (a4, b11, c11), (a4, b11, c12), (a4, b11, c13), (a5, b1, c1), (a5, b1, c2 ), (a5, b1, c3), (a5, b1, c4), (a5, b1, c5), (a5, b1, c6), (a5, b1, c7), (a5, b1, c8), (a5, b1, c9), (a5, b1, c10), (a5, b1, c11), (a5, b1, c12), (a5, b1, c13), (a5, b2, c1), (a5 , b2, c2), (a5, b2, c3), (a5, b2, c4), (a5, b2, c5), (a5, b2, c6), (a5, b2, c7), (a5, b2 , c8), (a5, b2, c9), (a5, b2, c10), (a5, b2, c11), (a5, b2, c12), (a5, b2, c13), (a5, b3, c1 ), (a5, b3, c2), (a5, b3, c3), (a5, b3, c4), (a5, b3, c5), (a5, b3, c6), (a5, b3, c7), (a5, b3, c8), (a5, b3, c9), (a5, b3, c10), (a5, b3, c11), (a5, b3, c12), (a5, b3, c13), (a5 , b4, c1), (a5, b4, c2), (a5, b4, c3), (a5, b4, c4), (a5, b4, c5), (a5, b4, c6), (a5, b4 , c7), (a5, b4, c8), (a5, b4, c9), (a5, b4, c10), (a5, b4, c11), (a5, b 4, c12), (a5, b4, c13), (a5, b5, c1), (a5, b5, c2), (a5, b5, c3), (a5, b5, c4), (a5, b5, c5), (a5, b5, c6), (a5, b5, c7), (a5, b5, c8), (a5, b5, c9), (a5, b5, c10), (a5, b5, c11) , (a5, b5, c12), (a5, b5, c13), (a5, b6, c1), (a5, b6, c2), (a5, b6, c3), (a5, b6, c4), ( a5, b6, c5), (a5, b6, c6), (a5, b6, c7), (a5, b6, c8), (a5, b6, c9), (a5, b6, c10), (a5, b6, c11), (a5, b6, c12), (a5, b6, c13), (a5, b7, c1), (a5, b7, c2), (a5, b7, c3), (a5, b7, c4), (a5, b7, c5), (a5, b7, c6), (a5, b7, c7), (a5, b7, c8), (a5, b7, c9), (a5, b7, c10) , (a5, b7, c11), (a5, b7, c12), (a5, b7, c13), (a5, b8, c1), (a5, b8, c2), (a5, b8, c3), ( a5, b8, c4), (a5, b8, c5), (a5, b8, c6), (a5, b8, c7), (a5, b8, c8), (a5, b8, c9), (a5, b8, c10), (a5, b8, c11), (a5, b8, c12), (a5, b8, c13), (a5, b9, c1), (a5, b9, c2), (a5, b9, c3), (a5, b9, c4), (a5, b9, c5), (a5, b9, c6), (a5, b9, c7), (a5, b9, c8), (a5, b9, c9) , (a5, b9, c10), (a5, b9, c11), (a5, b9, c12), (a5, b9, c13), (a5, b10, c1), (a5, b10, c2), ( a5, b10, c3), (a5, b10, c4), (a5, b10, c5), (a5, b10, c6), (a5, b10, c7), (a5, b10, c8), (a5, b10, c9), (a5, b10, c10), (a5, b10, c11), (a5, b10, c12), (a5, b10, c13), (a5, b11, c1), (a5, b11, c2), (a5, b11, c3), (a5, b11, c4), (a5, b11, c5), (a5, b11, c6), (a5, b11, c7), (a 5, b11, c8), (a5, b11, c9), (a5, b11, c10), (a5, b11, c11), (a5, b11, c12), (a5, b11, c13), (a6, b1, c1), (a6, b1, c2), (a6, b1, c3), (a6, b1, c4), (a6, b1, c5), (a6, b1, c6), (a6, b1, c7), (a6, b1, c8), (a6, b1, c9), (a6, b1, c10), (a6, b1, c11), (a6, b1, c12), (a6, b1, c13) , (a6, b2, c1), (a6, b2, c2), (a6, b2, c3), (a6, b2, c4), (a6, b2, c5), (a6, b2, c6), ( a6, b2, c7), (a6, b2, c8), (a6, b2, c9), (a6, b2, c10), (a6, b2, c11), (a6, b2, c12), (a6, b2, c13), (a6, b3, c1), (a6, b3, c2), (a6, b3, c3), (a6, b3, c4), (a6, b3, c5), (a6, b3, c6), (a6, b3, c7), (a6, b3, c8), (a6, b3, c9), (a6, b3, c10), (a6, b3, c11), (a6, b3, c12) , (a6, b3, c13), (a6, b4, c1), (a6, b4, c2), (a6, b4, c3), (a6, b4, c4), (a6, b4, c5), ( a6, b4, c6),
(a6, b4, c7), (a6, b4, c8), (a6, b4, c9), (a6, b4, c10), (a6, b4, c11), (a6, b4, c12), (a6 , b4, c13), (a6, b5, c1), (a6, b5, c2), (a6, b5, c3), (a6, b5, c4), (a6, b5, c5), (a6, b5 , c6), (a6, b5, c7), (a6, b5, c8), (a6, b5, c9), (a6, b5, c10), (a6, b5, c11), (a6, b5, c12 ), (a6, b5, c13), (a6, b6, c1), (a6, b6, c2), (a6, b6, c3), (a6, b6, c4), (a6, b6, c5), (a6, b6, c6), (a6, b6, c7), (a6, b6, c8), (a6, b6, c9), (a6, b6, c10), (a6, b6, c11), (a6 , b6, c12), (a6, b6, c13), (a6, b7, c1), (a6, b7, c2), (a6, b7, c3), (a6, b7, c4), (a6, b7 , c5), (a6, b7, c6), (a6, b7, c7), (a6, b7, c8), (a6, b7, c9), (a6, b7, c10), (a6, b7, c11 ), (a6, b7, c12), (a6, b7, c13), (a6, b8, c1), (a6, b8, c2), (a6, b8, c3), (a6, b8, c4), (a6, b8, c5), (a6, b8, c6), (a6, b8, c7), (a6, b8, c8), (a6, b8, c9), (a6, b8, c10), (a6 , b8, c11), (a6, b8, c12), (a6, b8, c13), (a6, b9, c1), (a6, b9, c2), (a6, b9, c3), (a6, b9 , c4), (a6, b9, c5), (a6, b9, c6), (a6, b9, c7), (a6, b9, c8), (a6, b9, c9), (a6, b9, c10 ), (a6, b9, c11), (a6, b9, c12), (a6, b9, c13), (a6, b10, c1), (a6, b10, c2), (a6, b10, c3), (a6, b10, c4), (a6, b10, c5), (a6, b10, c6), (a6, b10, c7), (a6, b10, c8), (a6, b10, c9), (a6 , b10, c10), (a6, b10, c11), (a6, b10, c12), (a6, b10, c13), (a6, b11, c1), (a6, b11, c2), (a6, b11, c3), (a6, b11, c4), (a6, b11, c5), (a6, b11, c6), (a6, b11, c7), (a6, b11, c8), (a6 , b11, c9), (a6, b11, c10), (a6, b11, c11), (a6, b11, c12), (a6, b11, c13).

  Moreover, the following compounds are preferable as another embodiment. In general formula (I):

Wherein R ² and R ³ are each independently
(D1) OR ¹² , SR ¹³ , N (R ¹⁴ ) (R ¹⁵ ), substituted or unsubstituted pyridyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted oxazolyl, or substituted or Unsubstituted thiazolyl;
(D2) OR ¹² , SR ¹³ or N (R ¹⁴ ) (R ¹⁵ ); or (d3) substituted or unsubstituted pyridyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted oxazolyl Or substituted or unsubstituted thiazolyl;
R ¹² and R ¹³ are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted cyclo Is alkenyl;
R ¹⁴ and R ¹⁵ are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted carbocyclic group, or substituted or unsubstituted heterocyclic group, or R ¹⁴ and R ¹⁵ together with the nitrogen atom to which they are attached may form a heterocycle;
],

And

[N is an integer of 1 to 5;
R ^{7 ′} is one R ⁷ that is para to the substitution position of Ak ^{2 in} the A ring, and (e1) OR ¹⁶ , SR ¹⁷ , or N (R ¹⁸ ) (R ¹⁹ );
(E2) OR ¹⁶ or SR ¹⁷ ; or (e3) N (R ¹⁸ ) (R ¹⁹ );
And the other R ⁷ has the same meaning as 1) above;
(F1) R ¹⁶ and R ¹⁷ are each independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic group, or substituted or unsubstituted A substituted heterocyclic group,
R ¹⁸ and R ¹⁹ are each independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkenyl, or R ¹⁸ and R ¹⁹ together with the nitrogen atom to which they are attached are non-aromatic Or (f2) R ¹⁶ , R ¹⁷ and R ¹⁹ are each independently an alkyl, substituted or unsubstituted heterocycle substituted with a substituted or unsubstituted carbocycle. A substituted alkyl, a substituted or unsubstituted carbocyclic group, or a substituted or unsubstituted heterocyclic group, R ¹⁸ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or Substituted or unsubstituted acyl, substituted or unsubstituted carbocyclic oxyalkyl, or substituted or unsubstituted heterocyclic oxyalkyl ;
] The compound which is.

  Specific embodiments include the following. In general formula (I)

(D) is the above (d1) to (d3), (e) is the above (e1) to (e3), and (f) is the above (f1) or (f2).

Specific embodiments include the following. In the general formula (I), the above (A),
(B) A compound in which the combination (a, b, c, d, e, f) of (C), (d), (e) and (f) is as follows:
Combination (a, b, c, d, e, f) = (a1, b1, c14, d1, e1, f1), (a1, b1, c14, d1, e1, f2), (a1, b1, c14, d1, e2, f1), (a1, b1, c14, d1, e2, f2), (a1, b1, c14, d1, e3, f1), (a1, b1, c14, d1, e3, f2), ( a1, b1, c14, d2, e1, f1), (a1, b1, c14, d2, e1, f2), (a1, b1, c14, d2, e2, f1), (a1, b1, c14, d2, e2, f2), (a1, b1, c14, d2, e3, f1), (a1, b1, c14, d2, e3, f2), (a1, b1, c14, d3, e1, f1), (a1, b1, c14, d3, e1, f2), (a1, b1, c14, d3, e2, f1), (a1, b1, c14, d3, e2, f2), (a1, b1, c14, d3, e3, f1), (a1, b1, c14, d3, e3, f2), (a1, b1, c15, d1, e1, f1), (a1, b1, c15, d1, e1, f2), (a1, b1, c15, d1, e2, f1), (a1, b1, c15, d1, e2, f2), (a1, b1, c15, d1, e3, f1), (a1, b1, c15, d1, e3, f2) , (a1, b1, c15, d2, e1, f1), (a1, b1, c15, d2, e1, f2), (a1, b1, c15, d2, e2, f1), (a1, b1, c15, d2, e2, f2), (a1, b1, c15, d2, e3, f1), (a1, b1, c15, d2, e3, f2), (a1, b1, c15, d3, e1, f1), ( a1, b1, c15, d3, e1, f2), (a1, b1, c15, d3, e2, f1), (a1, b1, c15, d3, e2, f2), (a1, b1, c15, d3, e3, f1), (a1, b1, c15, d3, e3, f2), (a1, b1, c16, d1, e1, f1), (a1, b1, c16, d1, e1, f2), (a1, b1, c16, d1, e2, f1), (a1, b1, c16, d1, e2, f2), (a1, b1, c16, d1, e3, f1), (a1, b1, c16, d1, e3, f2), (a1, b1, c16, d2, e1, f1), (a1, b1, c16, d2, e1, f2), (a1, b1, c16, d2, e2, f1), (a1, b1, c16, d2, e2, f2), (a1, b 1, c16, d2, e3, f1), (a1, b1, c16, d2, e3, f2), (a1, b1, c16, d3, e1, f1), (a1, b1, c16, d3, e1, f2), (a1, b1, c16, d3, e2, f1), (a1, b1, c16, d3, e2, f2), (a1, b1, c16, d3, e3, f1), (a1, b1, c16, d3, e3, f2), (a1, b2, c14, d1, e1, f1), (a1, b2, c14, d1, e1, f2), (a1, b2, c14, d1, e2, f1) , (a1, b2, c14, d1, e2, f2), (a1, b2, c14, d1, e3, f1), (a1, b2, c14, d1, e3, f2), (a1, b2, c14, d2, e1, f1), (a1, b2, c14, d2, e1, f2), (a1, b2, c14, d2, e2, f1), (a1, b2, c14, d2, e2, f2), ( a1, b2, c14, d2, e3, f1), (a1, b2, c14, d2, e3, f2), (a1, b2, c14, d3, e1, f1), (a1, b2, c14, d3, e1, f2), (a1, b2, c14, d3, e2, f1), (a1, b2, c14, d3, e2, f2), (a1, b2, c14, d3, e3, f1), (a1, b2, c14, d3, e3, f2), (a1, b2, c15, d1, e1, f1), (a1, b2, c15, d1, e1, f2), (a1, b2, c15, d1, e2, f1), (a1, b2, c15, d1, e2, f2), (a1, b2, c15, d1, e3, f1), (a1, b2, c15, d1, e3, f2), (a1, b2, c15, d2, e1, f1), (a1, b2, c15, d2, e1, f2), (a1, b2, c15, d2, e2, f1), (a1, b2, c15, d2, e2, f2) , (a1, b2, c15, d2, e3, f1), (a1, b2, c15, d2, e3, f2), (a1, b2, c15, d3, e1, f1), (a1, b2, c15, d3, e1, f2), (a1, b2, c15, d3, e2, f1), (a1, b2, c15, d3, e2, f2), (a1, b2, c15, d3, e3, f1), ( a1, b2, c15, d3, e3, f2), (a1, b2, c16, d1, e1, f1), (a1, b2, c16, d1, e1, f2), (a1, b2, c16, d1, e2, f1), (a1, b2, c16, d1, e2, f 2), (a1, b2, c16, d1, e3, f1), (a1, b2, c16, d1, e3, f2), (a1, b2, c16, d2, e1, f1), (a1, b2, c16, d2, e1, f2), (a1, b2, c16, d2, e2, f1), (a1, b2, c16, d2, e2, f2), (a1, b2, c16, d2, e3, f1) , (a1, b2, c16, d2, e3, f2), (a1, b2, c16, d3, e1, f1), (a1, b2, c16, d3, e1, f2), (a1, b2, c16, d3, e2, f1), (a1, b2, c16, d3, e2, f2), (a1, b2, c16, d3, e3, f1), (a1, b2, c16, d3, e3, f2), ( a1, b12, c14, d1, e1, f1), (a1, b12, c14, d1, e1, f2), (a1, b12, c14, d1, e2, f1), (a1, b12, c14, d1, e2, f2), (a1, b12, c14, d1, e3, f1), (a1, b12, c14, d1, e3, f2), (a1, b12, c14, d2, e1, f1), (a1, b12, c14, d2, e1, f2), (a1, b12, c14, d2, e2, f1), (a1, b12, c14, d2, e2, f2), (a1, b12, c14, d2, e3, f1), (a1, b12, c14, d2, e3, f2), (a1, b12, c14, d3, e1, f1), (a1, b12, c14, d3, e1, f2), (a1, b12, c14, d3, e2, f1), (a1, b12, c14, d3, e2, f2), (a1, b12, c14, d3, e3, f1), (a1, b12, c14, d3, e3, f2) , (a1, b12, c15, d1, e1, f1), (a1, b12, c15, d1, e1, f2), (a1, b12, c15, d1, e2, f1), (a1, b12, c15, d1, e2, f2), (a1, b12, c15, d1, e3, f1), (a1, b12, c15, d1, e3, f2), (a1, b12, c15, d2, e1, f1), ( a1, b12, c15, d2, e1, f2), (a1, b12, c15, d2, e2, f1), (a1, b12, c15, d2, e2, f2), (a1, b12, c15, d2, e3, f1), (a1, b12, c15, d2, e3, f2), (a1, b12, c15, d3, e1, f1), (a1, b12, c15, d3, e1, f2) , (a1, b12, c15, d3, e2, f1), (a1, b12, c15, d3, e2, f2), (a1, b12, c15, d3, e3, f1), (a1, b12, c15, d3, e3, f2), (a1, b12, c16, d1, e1, f1), (a1, b12, c16, d1, e1, f2), (a1, b12, c16, d1, e2, f1), ( a1, b12, c16, d1, e2, f2), (a1, b12, c16, d1, e3, f1), (a1, b12, c16, d1, e3, f2), (a1, b12, c16, d2, e1, f1), (a1, b12, c16, d2, e1, f2), (a1, b12, c16, d2, e2, f1), (a1, b12, c16, d2, e2, f2), (a1, b12, c16, d2, e3, f1), (a1, b12, c16, d2, e3, f2), (a1, b12, c16, d3, e1, f1), (a1, b12, c16, d3, e1, f2), (a1, b12, c16, d3, e2, f1), (a1, b12, c16, d3, e2, f2), (a1, b12, c16, d3, e3, f1), (a1, b12, c16, d3, e3, f2), (a1, b13, c14, d1, e1, f1), (a1, b13, c14, d1, e1, f2), (a1, b13, c14, d1, e2, f1) , (a1, b13, c14, d1, e2, f2), (a1, b13, c14, d1, e3, f1), (a1, b13, c14, d1, e3, f2), (a1, b13, c14, d2, e1, f1), (a1, b13, c14, d2, e1, f2), (a1, b13, c14, d2, e2, f1), (a1, b13, c14, d2, e2, f2), ( a1, b13, c14, d2, e3, f1), (a1, b13, c14, d2, e3, f2), (a1, b13, c14, d3, e1, f1), (a1, b13, c14, d3, e1, f2), (a1, b13, c14, d3, e2, f1), (a1, b13, c14, d3, e2, f2), (a1, b13, c14, d3, e3, f1), (a1, b13, c14, d3, e3, f2), (a1, b13, c15, d1, e1, f1), (a1, b13, c15, d1, e1, f2), (a1, b13, c15, d1, e2, f1), (a1, b13, c15, d1, e2, f2), (a1, b13, c15, d1, e3, f1), (a1, b13, c 15, d1, e3, f2), (a1, b13, c15, d2, e1, f1), (a1, b13, c15, d2, e1, f2), (a1, b13, c15, d2, e2, f1) , (a1, b13, c15, d2, e2, f2), (a1, b13, c15, d2, e3, f1), (a1, b13, c15, d2, e3, f2), (a1, b13, c15, d3, e1, f1), (a1, b13, c15, d3, e1, f2), (a1, b13, c15, d3, e2, f1), (a1, b13, c15, d3, e2, f2), ( a1, b13, c15, d3, e3, f1), (a1, b13, c15, d3, e3, f2), (a1, b13, c16, d1, e1, f1), (a1, b13, c16, d1, e1, f2), (a1, b13, c16, d1, e2, f1), (a1, b13, c16, d1, e2, f2), (a1, b13, c16, d1, e3, f1), (a1, b13, c16, d1, e3, f2), (a1, b13, c16, d2, e1, f1), (a1, b13, c16, d2, e1, f2), (a1, b13, c16, d2, e2, f1), (a1, b13, c16, d2, e2, f2), (a1, b13, c16, d2, e3, f1), (a1, b13, c16, d2, e3, f2), (a1, b13, c16, d3, e1, f1), (a1, b13, c16, d3, e1, f2), (a1, b13, c16, d3, e2, f1), (a1, b13, c16, d3, e2, f2) , (a1, b13, c16, d3, e3, f1), (a1, b13, c16, d3, e3, f2), (a2, b1, c14, d1, e1, f1), (a2, b1, c14, d1, e1, f2), (a2, b1, c14, d1, e2, f1), (a2, b1, c14, d1, e2, f2), (a2, b1, c14, d1, e3, f1), ( a2, b1, c14, d1, e3, f2), (a2, b1, c14, d2, e1, f1), (a2, b1, c14, d2, e1, f2), (a2, b1, c14, d2, e2, f1), (a2, b1, c14, d2, e2, f2), (a2, b1, c14, d2, e3, f1), (a2, b1, c14, d2, e3, f2), (a2, b1, c14, d3, e1, f1), (a2, b1, c14, d3, e1, f2), (a2, b1, c14, d3, e2, f1), (a2, b1, c14, d 3, e2, f2), (a2, b1, c14, d3, e3, f1), (a2, b1, c14, d3, e3, f2), (a2, b1, c15, d1, e1, f1), ( a2, b1, c15, d1, e1, f2), (a2, b1, c15, d1, e2, f1), (a2, b1, c15, d1, e2, f2), (a2, b1, c15, d1, e3, f1), (a2, b1, c15, d1, e3, f2), (a2, b1, c15, d2, e1, f1), (a2, b1, c15, d2, e1, f2), (a2, b1, c15, d2, e2, f1), (a2, b1, c15, d2, e2, f2), (a2, b1, c15, d2, e3, f1), (a2, b1, c15, d2, e3, f2), (a2, b1, c15, d3, e1, f1), (a2, b1, c15, d3, e1, f2), (a2, b1, c15, d3, e2, f1), (a2, b1, c15, d3, e2, f2), (a2, b1, c15, d3, e3, f1), (a2, b1, c15, d3, e3, f2), (a2, b1, c16, d1, e1, f1) , (a2, b1, c16, d1, e1, f2), (a2, b1, c16, d1, e2, f1), (a2, b1, c16, d1, e2, f2), (a2, b1, c16, d1, e3, f1), (a2, b1, c16, d1, e3, f2), (a2, b1, c16, d2, e1, f1), (a2, b1, c16, d2, e1, f2), ( a2, b1, c16, d2, e2, f1), (a2, b1, c16, d2, e2, f2), (a2, b1, c16, d2, e3, f1), (a2, b1, c16, d2, e3, f2), (a2, b1, c16, d3, e1, f1), (a2, b1, c16, d3, e1, f2), (a2, b1, c16, d3, e2, f1), (a2, b1, c16, d3, e2, f2), (a2, b1, c16, d3, e3, f1), (a2, b1, c16, d3, e3, f2), (a2, b2, c14, d1, e1, f1), (a2, b2, c14, d1, e1, f2), (a2, b2, c14, d1, e2, f1), (a2, b2, c14, d1, e2, f2), (a2, b2, c14, d1, e3, f1), (a2, b2, c14, d1, e3, f2), (a2, b2, c14, d2, e1, f1), (a2, b2, c14, d2, e1, f2) , (a2, b2, c14, d2, e2, f1), (a2, b2, c14, d2, e2, f2), (a2, b2, c14, d2, e3, f1), (a2, b2, c14, d2, e3, f2), (a2, b2, c14, d3, e1, f1), (a2, b2, c14, d3, e1, f2), (a2, b2, c14, d3, e2, f1), (a2, b2, c14, d3, e2, f2), (a2, b2, c14, d3, e3, f1), (a2, b2, c14, d3, e3, f2), (a2, b2, c15, d1, e1, f1), (a2, b2, c15, d1, e1, f2) , (a2, b2, c15, d1, e2, f1), (a2, b2, c15, d1, e2, f2), (a2, b2, c15, d1, e3, f1), (a2, b2, c15, d1, e3, f2), (a2, b2, c15, d2, e1, f1), (a2, b2, c15, d2, e1, f2), (a2, b2, c15, d2, e2, f1), ( a2, b2, c15, d2, e2, f2), (a2, b2, c15, d2, e3, f1), (a2, b2, c15, d2, e3, f2), (a2, b2, c15, d3, e1, f1), (a2, b2, c15, d3, e1, f2), (a2, b2, c15, d3, e2, f1), (a2, b2, c15, d3, e2, f2), (a2, b2, c15, d3, e3, f1), (a2, b2, c15, d3, e3, f2), (a2, b2, c16, d1, e1, f1), (a2, b2, c16, d1, e1, f2), (a2, b2, c16, d1, e2, f1), (a2, b2, c16, d1, e2, f2), (a2, b2, c16, d1, e3, f1), (a2, b2, c16, d1, e3, f2), (a2, b2, c16, d2, e1, f1), (a2, b2, c16, d2, e1, f2), (a2, b2, c16, d2, e2, f1) , (a2, b2, c16, d2, e2, f2), (a2, b2, c16, d2, e3, f1), (a2, b2, c16, d2, e3, f2), (a2, b2, c16, d3, e1, f1), (a2, b2, c16, d3, e1, f2), (a2, b2, c16, d3, e2, f1), (a2, b2, c16, d3, e2, f2), ( a2, b2, c16, d3, e3, f1), (a2, b2, c16, d3, e3, f2), (a2, b12, c14, d1, e1, f1), (a2, b12, c14, d1, e1, f2), (a2, b12, c14, d1, e2, f1), (a2, b12, c14, d1, e2, f2), (a2, b12, c14, d1, e3, f1), (a2, b12, c14, d1, e3, f2), (a2, b12, c14, d2, e1, f1), (a2, b12, c14, d2, e1, f2), (a2, b12, c14, d2, e2, f1), (a2, b12, c14, d2, e2, f2), (a2, b12, c14, d2, e3, f1), (a2, b12, c14, d2, e3, f2), (a2, b12, c14, d3, e1, f1), (a2, b12, c14, d3, e1, f2), (a2, b12, c14, d3, e2, f1), (a2, b12, c14, d3, e2, f2), (a2, b12, c14, d3, e3, f1) , (a2, b12, c14, d3, e3, f2), (a2, b12, c15, d1, e1, f1), (a2, b12, c15, d1, e1, f2), (a2, b12, c15, d1, e2, f1), (a2, b12, c15, d1, e2, f2), (a2, b12, c15, d1, e3, f1), (a2, b12, c15, d1, e3, f2), ( a2, b12, c15, d2, e1, f1), (a2, b12, c15, d2, e1, f2), (a2, b12, c15, d2, e2, f1), (a2, b12, c15, d2, e2, f2), (a2, b12, c15, d2, e3, f1), (a2, b12, c15, d2, e3, f2), (a2, b12, c15, d3, e1, f1), (a2, b12, c15, d3, e1, f2), (a2, b12, c15, d3, e2, f1), (a2, b12, c15, d3, e2, f2), (a2, b12, c15, d3, e3, f1), (a2, b12, c15, d3, e3, f2), (a2, b12, c16, d1, e1, f1), (a2, b12, c16, d1, e1, f2), (a2, b12, c16, d1, e2, f1), (a2, b12, c16, d1, e2, f2), (a2, b12, c16, d1, e3, f1), (a2, b12, c16, d1, e3, f2) , (a2, b12, c16, d2, e1, f1), (a2, b12, c16, d2, e1, f2), (a2, b12, c16, d2, e2, f1), (a2, b12, c16, d2, e2, f2), (a2, b12, c16, d2, e3, f1), (a2, b12, c16, d2, e3, f2), (a2 , b12, c16, d3, e1, f1), (a2, b12, c16, d3, e1, f2), (a2, b12, c16, d3, e2, f1), (a2, b12, c16, d3, e2 , f2), (a2, b12, c16, d3, e3, f1), (a2, b12, c16, d3, e3, f2), (a2, b13, c14, d1, e1, f1), (a2, b13 , c14, d1, e1, f2), (a2, b13, c14, d1, e2, f1), (a2, b13, c14, d1, e2, f2), (a2, b13, c14, d1, e3, f1 ), (a2, b13, c14, d1, e3, f2), (a2, b13, c14, d2, e1, f1), (a2, b13, c14, d2, e1, f2), (a2, b13, c14 , d2, e2, f1), (a2, b13, c14, d2, e2, f2), (a2, b13, c14, d2, e3, f1), (a2, b13, c14, d2, e3, f2), (a2, b13, c14, d3, e1, f1), (a2, b13, c14, d3, e1, f2), (a2, b13, c14, d3, e2, f1), (a2, b13, c14, d3 , e2, f2), (a2, b13, c14, d3, e3, f1), (a2, b13, c14, d3, e3, f2), (a2, b13, c15, d1, e1, f1), (a2 , b13, c15, d1, e1, f2), (a2, b13, c15, d1, e2, f1), (a2, b13, c15, d1, e2, f2), (a2, b13, c15, d1, e3 , f1), (a2, b13, c15, d1, e3, f2), (a2, b13, c15, d2, e1, f1), (a2, b13, c15, d2, e1, f2), (a2, b13 , c15, d2, e2, f1), (a2, b13, c15, d2, e2, f2), (a2, b13, c15, d2, e3, f1), (a2, b13, c15, d2, e3, f2 ), (a2, b13, c15, d3, e1, f1), (a2, b13, c15, d3, e1, f2), (a2, b13, c15, d3, e2, f1), (a2, b13, c15 , d3, e2, f2), (a2, b13, c15, d3, e3, f1), (a2, b13, c15, d3, e3, f2), (a2, b13, c16, d1, e1, f1), (a2, b13, c16, d1, e1, f2), (a2, b13, c16, d1, e2, f1), (a2, b13, c16, d 1, e2, f2), (a2, b13, c16, d1, e3, f1), (a2, b13, c16, d1, e3, f2), (a2, b13, c16, d2, e1, f1), ( a2, b13, c16, d2, e1, f2), (a2, b13, c16, d2, e2, f1), (a2, b13, c16, d2, e2, f2), (a2, b13, c16, d2, e3, f1), (a2, b13, c16, d2, e3, f2), (a2, b13, c16, d3, e1, f1), (a2, b13, c16, d3, e1, f2), (a2, b13, c16, d3, e2, f1), (a2, b13, c16, d3, e2, f2), (a2, b13, c16, d3, e3, f1), (a2, b13, c16, d3, e3, f2), (a3, b1, c14, d1, e1, f1), (a3, b1, c14, d1, e1, f2), (a3, b1, c14, d1, e2, f1), (a3, b1, c14, d1, e2, f2), (a3, b1, c14, d1, e3, f1), (a3, b1, c14, d1, e3, f2), (a3, b1, c14, d2, e1, f1) , (a3, b1, c14, d2, e1, f2), (a3, b1, c14, d2, e2, f1), (a3, b1, c14, d2, e2, f2), (a3, b1, c14, d2, e3, f1), (a3, b1, c14, d2, e3, f2), (a3, b1, c14, d3, e1, f1), (a3, b1, c14, d3, e1, f2), ( a3, b1, c14, d3, e2, f1), (a3, b1, c14, d3, e2, f2), (a3, b1, c14, d3, e3, f1), (a3, b1, c14, d3, e3, f2), (a3, b1, c15, d1, e1, f1), (a3, b1, c15, d1, e1, f2), (a3, b1, c15, d1, e2, f1), (a3, b1, c15, d1, e2, f2), (a3, b1, c15, d1, e3, f1), (a3, b1, c15, d1, e3, f2), (a3, b1, c15, d2, e1, f1), (a3, b1, c15, d2, e1, f2), (a3, b1, c15, d2, e2, f1), (a3, b1, c15, d2, e2, f2), (a3, b1, c15, d2, e3, f1), (a3, b1, c15, d2, e3, f2), (a3, b1, c15, d3, e1, f1), (a3, b1, c15, d3, e1, f2) , (a3, b1, c15, d3, e2, f1), (a3, b1, c15, d3, e2, f2), (a3, b1, c15, d3, e3, f1), (a3, b1, c15, d3, e3, f2), ( a3, b1, c16, d1, e1, f1), (a3, b1, c16, d1, e1, f2), (a3, b1, c16, d1, e2, f1), (a3, b1, c16, d1, e2, f2), (a3, b1, c16, d1, e3, f1), (a3, b1, c16, d1, e3, f2), (a3, b1, c16, d2, e1, f1), (a3, b1, c16, d2, e1, f2), (a3, b
1, c16, d2, e2, f1), (a3, b1, c16, d2, e2, f2), (a3, b1, c16, d2, e3, f1), (a3, b1, c16, d2, e3, f2), (a3, b1, c16, d3, e1, f1), (a3, b1, c16, d3, e1, f2), (a3, b1, c16, d3, e2, f1), (a3, b1, c16, d3, e2, f2), (a3, b1, c16, d3, e3, f1), (a3, b1, c16, d3, e3, f2), (a3, b2, c14, d1, e1, f1) , (a3, b2, c14, d1, e1, f2), (a3, b2, c14, d1, e2, f1), (a3, b2, c14, d1, e2, f2), (a3, b2, c14, d1, e3, f1), (a3, b2, c14, d1, e3, f2), (a3, b2, c14, d2, e1, f1), (a3, b2, c14, d2, e1, f2), ( a3, b2, c14, d2, e2, f1), (a3, b2, c14, d2, e2, f2), (a3, b2, c14, d2, e3, f1), (a3, b2, c14, d2, e3, f2), (a3, b2, c14, d3, e1, f1), (a3, b2, c14, d3, e1, f2), (a3, b2, c14, d3, e2, f1), (a3, b2, c14, d3, e2, f2), (a3, b2, c14, d3, e3, f1), (a3, b2, c14, d3, e3, f2), (a3, b2, c15, d1, e1, f1), (a3, b2, c15, d1, e1, f2), (a3, b2, c15, d1, e2, f1), (a3, b2, c15, d1, e2, f2), (a3, b2, c15, d1, e3, f1), (a3, b2, c15, d1, e3, f2), (a3, b2, c15, d2, e1, f1), (a3, b2, c15, d2, e1, f2) , (a3, b2, c15, d2, e2, f1), (a3, b2, c15, d2, e2, f2), (a3, b2, c15, d2, e3, f1), (a3, b2, c15, d2, e3, f2), (a3, b2, c15, d3, e1, f1), (a3, b2, c15, d3, e1, f2), (a3, b2, c15, d3, e2, f1), ( a3, b2, c15, d3, e2, f2), (a3, b2, c15, d3, e3, f1), (a3, b2, c15, d3, e3, f2), (a3, b2, c16, d1, e1, f1), (a3, b2, c16, d1, e1, f 2), (a3, b2, c16, d1, e2, f1), (a3, b2, c16, d1, e2, f2), (a3, b2, c16, d1, e3, f1), (a3, b2, c16, d1, e3, f2), (a3, b2, c16, d2, e1, f1), (a3, b2, c16, d2, e1, f2), (a3, b2, c16, d2, e2, f1) , (a3, b2, c16, d2, e2, f2), (a3, b2, c16, d2, e3, f1), (a3, b2, c16, d2, e3, f2), (a3, b2, c16, d3, e1, f1), (a3, b2, c16, d3, e1, f2), (a3, b2, c16, d3, e2, f1), (a3, b2, c16, d3, e2, f2), ( a3, b2, c16, d3, e3, f1), (a3, b2, c16, d3, e3, f2), (a3, b12, c14, d1, e1, f1), (a3, b12, c14, d1, e1, f2), (a3, b12, c14, d1, e2, f1), (a3, b12, c14, d1, e2, f2), (a3, b12, c14, d1, e3, f1), (a3, b12, c14, d1, e3, f2), (a3, b12, c14, d2, e1, f1), (a3, b12, c14, d2, e1, f2), (a3, b12, c14, d2, e2, f1), (a3, b12, c14, d2, e2, f2), (a3, b12, c14, d2, e3, f1), (a3, b12, c14, d2, e3, f2), (a3, b12, c14, d3, e1, f1), (a3, b12, c14, d3, e1, f2), (a3, b12, c14, d3, e2, f1), (a3, b12, c14, d3, e2, f2) , (a3, b12, c14, d3, e3, f1), (a3, b12, c14, d3, e3, f2), (a3, b12, c15, d1, e1, f1), (a3, b12, c15, d1, e1, f2), (a3, b12, c15, d1, e2, f1), (a3, b12, c15, d1, e2, f2), (a3, b12, c15, d1, e3, f1), ( a3, b12, c15, d1, e3, f2), (a3, b12, c15, d2, e1, f1), (a3, b12, c15, d2, e1, f2), (a3, b12, c15, d2, e2, f1), (a3, b12, c15, d2, e2, f2), (a3, b12, c15, d2, e3, f1), (a3, b12, c15, d2, e3, f2), ( a3, b12, c15, d3, e1, f1), (a3, b12, c15, d3, e1, f2), (a3, b12, c15, d3, e2, f1), (a3, b12, c15, d3, e2, f2), (a3, b12, c15, d3, e3, f1), (a3, b12, c15, d3, e3, f2), (a3, b12, c16, d1, e1, f1), (a3, b12, c16, d1, e1, f2), (a3, b12, c16, d1, e2, f1), (a3, b12, c16, d1, e2, f2), (a3, b12, c16, d1, e3, f1), (a3, b12, c16, d1, e3, f2), (a3, b12, c16, d2, e1, f1), (a3, b12, c16, d2, e1, f2), (a3, b12, c16, d2, e2, f1), (a3, b12, c16, d2, e2, f2), (a3, b12, c16, d2, e3, f1), (a3, b12, c16, d2, e3, f2) , (a3, b12, c16, d3, e1, f1), (a3, b12, c16, d3, e1, f2), (a3, b12, c16, d3, e2, f1), (a3, b12, c16, d3, e2, f2), (a3, b12, c16, d3, e3, f1), (a3, b12, c16, d3, e3, f2), (a3, b13, c14, d1, e1, f1), ( a3, b13, c14, d1, e1, f2), (a3, b13, c14, d1, e2, f1), (a3, b13, c14, d1, e2, f2), (a3, b13, c14, d1, e3, f1), (a3, b13, c14, d1, e3, f2), (a3, b13, c14, d2, e1, f1), (a3, b13, c14, d2, e1, f2), (a3, b13, c14, d2, e2, f1), (a3, b13, c14, d2, e2, f2), (a3, b13, c14, d2, e3, f1), (a3, b13, c14, d2, e3, f2), (a3, b13, c14, d3, e1, f1), (a3, b13, c14, d3, e1, f2), (a3, b13, c14, d3, e2, f1), (a3, b13, c14, d3, e2, f2), (a3, b13, c14, d3, e3, f1), (a3, b13, c14, d3, e3, f2), (a3, b13, c15, d1, e1, f1) , (a3, b13, c15, d1, e1, f2), (a3, b13, c15, d1, e2, f1), (a3, b13, c15 , d1, e2, f2), (a3, b13, c15, d1, e3, f1), (a3, b13, c15, d1, e3, f2), (a3, b13, c15, d2, e1, f1), (a3, b13, c15, d2, e1, f2), (a3, b13, c15, d2, e2, f1), (a3, b13, c15, d2, e2, f2), (a3, b13, c15, d2 , e3, f1), (a3, b13, c15, d2, e3, f2), (a3, b13, c15, d3, e1, f1), (a3, b13, c15, d3, e1, f2), (a3 , b13, c15, d3, e2, f1), (a3, b13, c15, d3, e2, f2), (a3, b13, c15, d3, e3, f1), (a3, b13, c15, d3, e3 , f2), (a3, b13, c16, d1, e1, f1), (a3, b13, c16, d1, e1, f2), (a3, b13, c16, d1, e2, f1), (a3, b13 , c16, d1, e2, f2), (a3, b13, c16, d1, e3, f1), (a3, b13, c16, d1, e3, f2), (a3, b13, c16, d2, e1, f1 ), (a3, b13, c16, d2, e1, f2), (a3, b13, c16, d2, e2, f1), (a3, b13, c16, d2, e2, f2), (a3, b13, c16 , d2, e3, f1), (a3, b13, c16, d2, e3, f2), (a3, b13, c16, d3, e1, f1), (a3, b13, c16, d3, e1, f2), (a3, b13, c16, d3, e2, f1), (a3, b13, c16, d3, e2, f2), (a3, b13, c16, d3, e3, f1), (a3, b13, c16, d3 , e3, f2).

  Moreover, as another embodiment, the following compounds are preferable. In general formula (I):

Wherein each R ⁸ is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted acyl.

[N is an integer of 0 to 5;
Each R ⁷ independently represents halogen, hydroxy, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy; Substituted or unsubstituted alkynyloxy, substituted or unsubstituted acyloxy, substituted or unsubstituted carbocyclic oxy, substituted or unsubstituted heterocyclic oxy, mercapto, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio Substituted or unsubstituted alkynylthio, substituted or unsubstituted carbocyclic thio, substituted or unsubstituted heterocyclic thio, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted acyl, substituted or unsubstituted amino, substituted Sulfonyl, substituted Rufinyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, nitro, cyano, azide, substituted or unsubstituted carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group (provided that substituted or unsubstituted A substituted dihydrothiazine cyclic group).

  Specific embodiments include the following. In general formula (I):

A combination (L1, C) of:
Combination (L1, C) =
(L1-1, C1), (L1-1, C2), (L1-1, C3), (L1-1, C4), (L1-1, C5), (L1-1, C6), (L1 -1, C7), (L1-1, C8), (L1-1, C9), (L1-1, C10), (L1-1, C11), (L1-1, C12), (L1-1 , C13), (L1-1, C14), (L1-1, C15), (L1-1, C16), (L1-1, C17), (L1-2, C1), (L1-2, C2 ), (L1-2, C3), (L1-2, C4), (L1-2, C5), (L1-2, C6), (L1-2, C7), (L1-2, C8), (L1-2, C9), (L1-2, C10), (L1-2, C11), (L1-2, C12), (L1-2, C13), (L1-2, C14), (L1 -2, C15), (L1-2, C16), (L1-2, C17), (L1-3, C1), (L1-3, C2), (L1-3, C3), (L1-3 , C4), (L1-3, C5), (L1-3, C6), (L1-3, C7), (L1-3, C8), (L1-3, C9), (L1-3, C10 ), (L1-3, C11), (L1-3, C12), (L1-3, C13), (L1-3, C14), (L1-3, C15), (L1-3, C16), (L1-3, C17), (L1-4, C1), (L1-4, C2), (L1-4, C3), (L1-4, C4), (L1-4, C5), (L1 -4, C6), (L1-4, C7), (L1-4, C8), (L1-4, C9), (L1-4, C10), (L1-4, C11), (L1-4 , C12), (L1-4, C13), (L1-4, C14), (L1-4, C15), (L1-4, C16), (L1-4, C17), (L1-5, C1 ), (L1-5, C2), (L1-5, C3), (L1-5, C4), (L1-5, C5), (L1-5, C6), (L1-5, C7), (L1-5, C8), (L1-5, C9), (L1-5, C10), (L1-5, C11), (L1-5, C12), (L1-5, C13), (L1 -5, C14), (L1-5, C15), (L1-5, C16), (L1-5, C17), (L1-6, C1), (L1-6, C2), (L1-6 , C3), (L1-6, C4), (L1-6, C5), (L1-6, C6), (L1-6, C7), (L1-6, C8), (L1-6, C9 ), (L1-6, C10), (L1-6, C11 ), (L1-6, C12), (L1-6, C13), (L1-6, C14), (L1-6, C15), (L1-6, C16), (L1-6, C17), (L1-7, C1), (L1-7, C2), (L1-7, C3), (L1-7, C4), (L1-7, C5), (L1-7, C6), (L1 -7, C7), (L1-7, C8), (L1-7, C9), (L1-7, C10), (L1-7, C11), (L1-7, C12), (L1-7 , C13), (L1-7, C14), (L1-7, C15), (L1-7, C16), (L1-7, C17), (L1-8, C1), (L1-8, C2 ), (L1-8, C3), (L1-8, C4), (L1-8, C5), (L1-8, C6), (L1-8, C7), (L1-8, C8), (L1-8, C9), (L1-8, C10), (L1-8, C11), (L1-8, C12), (L1-8, C13), (L1-8, C14), (L1 -8, C15), (L1-8, C16), (L1-8, C17).

In the compound in which (L1) and (C) are described in the above combination, the variable groups X ¹ , X ² _, X ³ , X ⁴ _, R ⁵ , R ⁶ , Ak ¹ and Ak ² of the general formula (I) are: Independently, any combination of groups described in 1) above may be used. Preferably, X ¹ , X ² _, X ³ , X ⁴ _, R ⁵ , R ⁶ , Ak ¹ , and Ak ² are each independently in (A) and Ak ¹ and Ak ² in (B). It may be any combination of the groups described.

Furthermore, as another embodiment, the following compounds are preferable. Under the condition (L1, C), one of R ⁷ in the general formula (I) is present in the para position with respect to the bond of ring A, and R ⁷ is R ¹¹ (that is,

And)

[R ¹⁶ , R ¹⁷ and R ¹⁹ are each independently alkyl substituted with a substituted or unsubstituted carbocycle, alkyl substituted with a substituted or unsubstituted heterocycle, substituted or unsubstituted carbocyclic Or a substituted or unsubstituted heterocyclic group, R ¹⁸ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted acyl, substituted or unsubstituted carbocycle The compound is an oxyalkyl or a substituted or unsubstituted heterocyclic oxyalkyl].

Specific embodiments include the following. A compound in which the combination (L1, C, R11) of the above (L1), (C) and (R11) is as follows:
Combination (L1, C, R11) = (L1-1, C1, R11-1), (L1-1, C1, R11-2), (L1-1, C1, R11-3), (L1-1, C2, R11-1), (L1-1, C2, R11-2), (L1-1, C2, R11-3), (L1-1, C3, R11-1), (L1-1, C3, R11-2), (L1-1, C3, R11-3), (L1-1, C4, R11-1), (L1-1, C4, R11-2), (L1-1, C4, R11- 3), (L1-1, C5, R11-1), (L1-1, C5, R11-2), (L1-1, C5, R11-3), (L1-1, C6, R11-1) , (L1-1, C6, R11-2), (L1-1, C6, R11-3), (L1-1, C7, R11-1), (L1-1, C7, R11-2), ( L1-1, C7, R11-3), (L1-1, C8, R11-1), (L1-1, C8, R11-2), (L1-1, C8, R11-3), (L1- 1, C9, R11-1), (L1-1, C9, R11-2), (L1-1, C9, R11-3), (L1-1, C10, R11-1), (L1-1, C10, R11-2), (L1-1, C10, R11-3), (L1-1, C11, R11-1), (L1-1, C11, R11-2), (L1-1, C11, R11-3), (L1-1, C12, R11-1), (L1-1, C12, R11-2), (L1-1, C12, R11-3), (L1-1, C13, R11- 1), (L1-1, C13, R11-2), (L1-1, C13, R11-3), (L1-1, C14, R11-1), (L1-1, C14, R11-2) , (L1-1, C14, R11-3), (L1-1, C15, R11-1), (L1-1, C15, R11-2), (L1-1, C15, R11-3), ( L1-1, C16, R11-1), (L1-1, C16, R11-2), (L1-1, C16, R11-3), (L1-1, C17, R11-1), (L1- 1, C17, R11-2), (L1-1, C17, R11-3), (L1-2, C1, R11-1), (L1-2, C1, R11-2), (L1-2, C1, R11-3), (L1-2, C2, R11-1), (L1-2, C2, R11-2), (L1-2, C2, R11-3), (L1-2, C3, R11-1), (L1-2, C3, R11-2), (L1-2, C3, R11-3), (L1-2, C4, R11-1), (L1-2, C4, R11-2), (L1-2, C4, R11-3), (L1-2, C5, R11-1), (L1-2, C5, R11-2), (L1-2, C5, R11-3), (L1-2, C6, R11-1), (L1-2, C6, R11- 2), (L1-2, C6, R11-3), (L1-2, C7, R11-1), (L1-2, C7, R11-2), (L1-2, C7, R11-3) , (L1-2, C8, R11-1), (L1-2, C8, R11-2), (L1-2, C8, R11-3), (L1-2, C9, R11-1), ( L1-2, C9, R11-2), (L1-2, C9, R11-3), (L1-2, C10, R11-1), (L1-2, C10, R11-2), (L1- 2, C10, R11-3), (L1-2, C11, R11-1), (L1-2, C11, R11-2), (L1-2, C11, R11-3), (L1-2, C12, R11-1), (L1-2, C12, R11-2), (L1-2, C12, R11-3), (L1-2, C13, R11-1), (L1-2, C13, R11-2), (L1-2, C13, R11-3), (L1-2, C14, R11-1), (L1-2, C14, R11-2), (L1-2, C14, R11- 3), (L1-2, C15, R11-1), (L1-2, C15, R11-2), (L1-2, C15, R11-3), (L1-2, C16, R11-1) , (L1-2, C16, R11-2), (L1-2, C16, R11-3), (L1-2, C17, R11-1), (L1-2, C17, R11-2), ( L1-2, C17, R11-3), (L1-3, C1, R11-1), (L1-3, C1, R11-2), (L1-3, C1, R11-3), (L1- 3, C2, R11-1), (L1-3, C2, R11-2), (L1-3, C2, R11-3), (L1-3, C3, R11-1), (L1-3, C3, R11-2), (L1-3, C3, R11-3), (L1-3, C4, R11-1), (L1-3, C4, R11-2), (L1-3, C4, R11-3), (L1-3, C5, R11-1), (L1-3, C5, R11-2), (L1-3, C5, R11-3), (L1-3, C6, R11- 1), (L1-3, C6, R11-2), (L1-3, C6, R11-3), (L1-3, C7, R11-1), (L1-3, C7, R11-2), (L1-3, C7, R11-3), (L1-3, C8, R11-1), (L1-3, C8, R11-2), (L1-3, C8, R11-3), (L1-3, C9, R11-1), (L1-3, C9, R11-2), (L1-3, C9, R11- 3), (L1-3, C10, R11-1), (L1-3, C10, R11-2), (L1-3, C10, R11-3), (L1-3, C11, R11-1) , (L1-3, C11, R11-2), (L1-3, C11, R11-3), (L1-3, C12, R11-1), (L1-3, C12, R11-2), ( L1-3, C12, R11-3), (L1-3, C13, R11-1), (L1-3, C13, R11-2), (L1-3, C13, R11-3), (L1- 3, C14, R11-1), (L1-3, C14, R11-2), (L1-3, C14, R11-3), (L1-3, C15, R11-1), (L1-3, C15, R11-2), (L1-3, C15, R11-3), (L1-3, C16, R11-1), (L1-3, C16, R11-2), (L1-3, C16, R11-3), (L1-3, C17, R11-1), (L1-3, C17, R11-2), (L1-3, C17, R11-3), (L1-4, C1, R11- 1), (L1-4, C1, R11-2), (L1-4, C1, R11-3), (L1-4, C2, R11-1), (L1-4, C2, R11-2) , (L1-4, C2, R11-3), (L1-4, C3, R11-1), (L1-4, C3, R11-2), (L1-4, C3, R11-3), ( L1-4, C4, R11-1), (L1-4, C4, R11-2), (L1-4, C4, R11-3), (L1-4, C5, R11-1), (L1- 4, C5, R11-2), (L1-4, C5, R11-3), (L1-4, C6, R11-1), (L1-4, C6, R11-2), (L1-4, C6, R11-3), (L1-4, C7, R11-1), (L1-4, C7, R11-2), (L1-4, C7, R11-3), (L1-4, C8, R11-1), (L1-4, C8, R11-2), (L1-4, C8, R11-3), (L1-4, C9, R11-1), (L1-4, C9, R11- 2), (L1-4, C9, R11-3), (L1-4, C10, R11-1), (L1-4 , C10, R11-2), (L1-4, C10, R11-3), (L1-4, C11, R11-1), (L1-4, C11, R11-2), (L1-4, C11 , R11-3), (L1-4, C12, R11-1), (L1-4, C12, R11-2), (L1-4, C12, R11-3), (L1-4, C13, R11 -1), (L1-4, C13, R11-2), (L1-4, C13, R11-3), (L1-4, C14, R11-1), (L1-4, C14, R11-2) ), (L1-4, C14, R11-3), (L1-4, C15, R11-1), (L1-4, C15, R11-2), (L1-4, C15, R11-3), (L1-4, C16, R11-1), (L1-4, C16, R11-2), (L1-4, C16, R11-3), (L1-4, C17, R11-1), (L1 -4, C17, R11-2), (L1-4, C17, R11-3), (L1-5, C1, R11-1), (L1-5, C1, R11-2), (L1-5 , C1, R11-3), (L1-5, C2, R11-1), (L1-5, C2, R11-2), (L1-5, C2, R11-3), (L1-5, C3 , R11-1), (L1-5, C3, R11-2), (L1-5, C3, R11-3), (L1-5, C4, R11-1), (L1-5, C4, R11 -2), (L1-5, C4, R11-3), (L1-5, C5, R11-1), (L1-5, C5, R11-2), (L1-5, C5, R11-3) ), (L1-5, C6, R11-1), (L1-5, C6, R11-2), (L1-5, C6, R11-3), (L1-5, C7, R11-1), (L1-5, C7, R11-2), (L1-5, C7, R11-3), (L1-5, C8, R11-1), (L1-5, C8, R11-2), (L1 -5, C8, R11-3), (L1-5, C9, R11-1), (L1-5, C9, R11-2), (L1-5, C9, R11-3), (L1-5 , C10, R11-1), (L1-5, C10, R11-2), (L1-5, C10, R11-3), (L1-5, C11, R11-1), (L1-5, C11 , R11-2), (L1-5, C11, R11-3), (L1-5, C12, R11-1), (L1-5, C12, R11-2), (L1-5, C12, R11 -3), (L1-5, C13, R11-1), (L1-5, C13, R1 1-2), (L1-5, C13, R11-3), (L1-5, C14, R11-1), (L1-5, C14, R11-2), (L1-5, C14, R11- 3), (L1-5, C15, R11-1), (L1-5, C15, R11-2), (L1-5, C15, R11-3), (L1-5, C16, R11-1) , (L1-5, C16, R11-2), (L1-5, C16, R11-3), (L1-5, C17, R11-1), (L1-5, C17, R11-2), ( L1-5, C17, R11-3), (L1-6, C1, R11-1), (L1-6, C1, R11-2), (L1-6, C1, R11-3), (L1- 6, C2, R11-1), (L1-6, C2, R11-2), (L1-6, C2, R11-3), (L1-6, C3, R11-1), (L1-6, C3, R11-2), (L1-6, C3, R11-3), (L1-6, C4, R11-1), (L1-6, C4, R11-2), (L1-6, C4, R11-3), (L1-6, C5, R11-1), (L1-6, C5, R11-2), (L1-6, C5, R11-3), (L1-6, C6, R11- 1), (L1-6, C6, R11-2), (L1-6, C6, R11-3), (L1-6, C7, R11-1), (L1-6, C7, R11-2) , (L1-6, C7, R11-3), (L1-6, C8, R11-1), (L1-6, C8, R11-2), (L1-6, C8, R11-3), ( L1-6, C9, R11-1), (L1-6, C9, R11-2), (L1-6, C9, R11-3), (L1-6, C10, R11-1), (L1- 6, C10, R11-2), (L1-6, C10, R11-3), (L1-6, C11, R11-1), (L1-6, C11, R11-2), (L1-6, C11, R11-3), (L1-6, C12, R11-1), (L1-6, C12, R11-2), (L1-6, C12, R11-3), (L1-6, C13, R11-1), (L1-6, C13, R11-2), (L1-6, C13, R11-3), (L1-6, C14, R11-1), (L1-6, C14, R11- 2), (L1-6, C14, R11-3), (L1-6, C15, R11-1), (L1-6, C15, R11-2), (L1-6, C15, R11-3) , (L1-6, C16, R11-1), (L1-6, C16, R11-2), (L 1-6, C16, R11-3), (L1-6, C17, R11-1), (L1-6, C17, R11-2), (L1-6, C17, R11-3), (L1- 7, C1, R11-1), (L1-7, C1, R11-2), (L1-7, C1, R11-3), (L1-7, C2, R11-1), (L1-7, C2, R11-2), (L1-7, C2, R11-3), (L1-7, C3, R11-1), (L1-7, C3, R11-2), (L1-7, C3, R11-3), (L1-7, C4, R11-1), (L1-7, C4, R11-2), (L1-7, C4, R11-3), (L1-7, C5, R11- 1), (L1-7, C5, R11-2), (L1-7, C5, R11-3), (L1-7, C6, R11-1), (L1-7, C6, R11-2) , (L1-7, C6, R11-3), (L1-7, C7, R11-1), (L1-7, C7, R11-2), (L1-7, C7, R11-3), ( L1-7, C8, R11-1), (L1-7, C8, R11-2), (L1-7, C8, R11-3), (L1-7, C9, R11-1), (L1- 7, C9, R11-2), (L1-7, C9, R11-3), (L1-7, C10, R11-1), (L1-7, C10, R11-2), (L1-7, C10, R11-3), (L1-7, C11, R11-1), (L1-7, C11, R11-2), (L1-7, C11, R11-3), (L1-7, C12, R11-1), (L1-7, C12, R11-2), (L1-7, C12, R11-3), (L1-7, C13, R11-1), (L1-7, C13, R11- 2), (L1-7, C13, R11-3), (L1-7, C14, R11-1), (L1-7, C14, R11-2), (L1-7, C14, R11-3) , (L1-7, C15, R11-1), (L1-7, C15, R11-2), (L1-7, C15, R11-3), (L1-7, C16, R11-1), ( L1-7, C16, R11-2), (L1-7, C16, R11-3), (L1-7, C17, R11-1), (L1-7, C17, R11-2), (L1- 7, C17, R11-3), (L1-8, C1, R11-1), (L1-8, C1, R11-2), (L1-8, C1, R11-3), (L1-8, C2, R11-1), (L1-8, C2, R11-2), (L1-8, C2, R11-3 ), (L1-8, C3, R11-1), (L1-8, C3, R11-2), (L1-8, C3, R11-3), (L1-8, C4, R11-1), (L1-8, C4, R11-2), (L1-8, C4, R11-3), (L1-8, C5, R11-1), (L1-8, C5, R11-2), (L1 -8, C5, R11-3), (L1-8, C6, R11-1), (L1-8, C6, R11-2), (L1-8, C6, R11-3), (L1-8 , C7, R11-1), (L1-8, C7, R11-2), (L1-8, C7, R11-3), (L1-8, C8, R11-1), (L1-8, C8 , R11-2), (L1-8, C8, R11-3), (L1-8, C9, R11-1), (L1-8, C9, R11-2), (L1-8, C9, R11 -3), (L1-8, C10, R11-1), (L1-8, C10, R11-2), (L1-8, C10, R11-3), (L1-8, C11, R11-1 ), (L1-8, C11, R11-2), (L1-8, C11, R11-3), (L1-8, C12, R11-1), (L1-8, C12, R11-2), (L1-8, C12, R11-3), (L1-8, C13, R11-1), (L1-8, C13, R11-2), (L1-8, C13, R11-3), (L1 -8, C14, R11-1), (L1-8, C14, R11-2), (L1-8, C14, R11-3), (L1-8, C15, R11-1), (L1-8 , C15, R11-2), (L1-8, C15, R11-3), (L1-8, C16, R11-1), (L1-8, C16, R11-2), (L1-8, C16 , R11-3), (L1-8, C17, R11-1), (L1-8, C17, R11-2), (L1-8, C17, R11-3).

In the compounds in which (L1), (C) and (R11) are described in the above combinations, the variable groups X ¹ , X ² _, X ³ , X ⁴ _, R ⁵ , R ⁶ , Ak ¹ of the general formula (I) And Ak ² may each independently be a combination of any groups described in 1) above. Preferably, X ¹ , X ² _, X ³ , X ⁴ _, R ⁵ , R ⁶ , Ak ¹ , and Ak ² are each independently in (A) and Ak ¹ and Ak ² in (B). It may be any combination of the groups described.

  The following compounds are mentioned as an embodiment of the present invention.

  Formula (I)

[In the formula, -X ¹ = X ² -X ³ = X ⁴ -is -C (R ¹ ) = C (R ² ) -C (R ³ ) = C (R ⁴ )-, -C (R ¹ ) = N-C (R ³ ) = C (R ⁴ )-, -C (R ¹ ) = C (R ² ) -N = C (R ⁴ )-, -N = C (R ² ) -C (R ³ ) = C (R ⁴ )-, or -C (R ¹ ) = C (R ² ) -C (R ³ ) = N-;
R ¹ , R ² , R ³ and R ⁴ are each independently hydrogen, halogen, substituted or unsubstituted alkenyl, substituted or unsubstituted alkoxy, substituted or unsubstituted acyl, substituted or unsubstituted amino, With a substituted sulfonyl, nitro, or substituted or unsubstituted heterocyclic group (specifically, imidazolyl, pyridyl, pyrazolyl, piperidinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrrolidinyl, piperazinyl, morpholinyl, or pyrrolidyl) Yes;
R ⁵ is hydrogen or substituted or unsubstituted alkyl;
R ⁶ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted amino, or a substituted or unsubstituted carbocyclic group (specifically, phenyl);
Ak ¹ or Ak ² each independently represents a single bond or a substituted or unsubstituted alkylene having 1 or 2 carbon atoms;
—L ¹ — represents —C (═O) N (R ⁸ ) —, —C (═O) —, —C (═O) —C (═O) —N (R ⁸ ) —, or —C (= O) O-;
Each R ⁸ is independently hydrogen, or substituted or unsubstituted alkyl;
Ring A is a benzene ring, pyridine ring, pyridazine ring, pyrimidine ring, cyclohexane ring, cyclohexene ring, tetrahydropyran ring, tetrahydropyridine ring, piperidine ring, piperazine ring;
R ⁷ each independently represents halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted acyloxy, substituted or Unsubstituted carbocyclic oxy, substituted or unsubstituted heterocyclic oxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted acyl, substituted or unsubstituted amino, substituted sulfonyl, substituted or unsubstituted carbamoyl, cyano, An azide, a substituted or unsubstituted carbocyclic group (specifically, phenyl), a substituted or unsubstituted non-aromatic heterocyclic group (specifically, morpholinyl, piperidinyl, azepanyl, pyrrolidinyl, or Piperazinyl) (but not substituted or Is an unsubstituted dihydrothiazine cyclic group);
n is an integer of 0 to 3]
A compound represented by

  As another embodiment of the present invention, the following compounds may be mentioned.

  Formula (II)

[Wherein, = X ² -X ³ = is = C (R ² ) -C (R ³ ) =, = NC (R ³ ) =, or = C (R ² ) -N =;
R ² represents hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted carbocyclic oxy, substituted or unsubstituted amino, or substituted or unsubstituted heterocyclic group (specifically Is pyrrolidinyl);
R ¹ , R ³ , and R ⁴ are each independently hydrogen, or substituted or unsubstituted alkoxy;
R ⁵ is hydrogen;
R ⁶ is hydrogen or substituted or unsubstituted alkyl;
Ak ¹ is a single bond;
R ⁸ is hydrogen or substituted or unsubstituted alkyl;
= ^Y 1 -Y ² = ^{is, = C (R 9A) -C} (R 10A) =, or ^{= C (R} 9A) is -N =;
R ^9A and R ^9B are hydrogen;
One of R ^10A and R ^10B is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted amino, and the other is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted amino; ^{However, =} when Y 1 -Y ² = is ^{= C (R} 9A) -N ^{= a, R 10B} is a halogen;
R ¹¹ is hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted acyloxy, substituted or unsubstituted carbocyclic oxy, substituted or unsubstituted heterocyclic oxy, substituted Or an unsubstituted alkoxycarbonyl, or a substituted or unsubstituted non-aromatic heterocyclic group (specifically, piperazinyl, morpholinyl, or piperazinyl) (wherein R ¹¹ is hydrogen, hydroxy, methoxy, When methylthio, methyl, trifluoromethyl, or halogen, both R ^10A and R ^10B are not hydrogen;
When R ^10A or R ^10B is fluorine, R ¹¹ is

Rather than the group indicated by
R ^9A , R ^9B , R ^10A , R ^10B , and R ¹¹ are not simultaneously fluorine;
When R ^10A or R ^10B is —COOH or —COOMe, R ¹¹ is

Rather than the group indicated by
R ^10A , R ^10B , and R ¹¹ are not simultaneously methoxy;
When R ^10A or R ^10B is methoxy, R ¹¹ is

Rather than the group indicated by
When one of R ^10A or R ^10B is —SO ₂ Me, the other is

It is not a group indicated by
(Wherein the following compounds:

except for. )
Still another embodiment of the present invention includes the following compounds:

  Formula (III)

[Wherein = X ² -X ³ = is = C (R ² ) -C (R ³ ) =;
Either R ² or R ³ is substituted or unsubstituted pyridyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, or substituted or unsubstituted thiazolyl, and the other is hydrogen, or substituted or unsubstituted Unsubstituted alkoxy;
R ¹ and R ⁴ are hydrogen;
R ⁵ is hydrogen;
R ⁶ is hydrogen;
Ak ¹ and Ak ² are each independently a single bond or a substituted or unsubstituted alkylene having 1 or 2 carbon atoms;
R ⁸ is hydrogen or substituted or unsubstituted alkyl;
A ring is a benzene ring, a pyridine ring, a cyclohexane ring, a tetrahydropyran ring, or a piperidine ring;
Each R ⁷ is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted carbocyclic oxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted acyl, or Substituted or unsubstituted amino;
n is an integer from 0 to 2,
(However, ring A is not an unsubstituted pyridine ring;
When Ak ² is —CH ₂ —CH ₂ —, the A ring is not an unsubstituted morpholine ring;
Ring A is

is not. )].

  The compound of the general formula (I), the compound of the general formula (II) or the compound of the general formula (III) according to the present invention is useful for diseases induced by production, secretion or deposition of amyloid β protein, for example, Alzheimer Type dementia (Alzheimer's disease, Alzheimer's type senile dementia, etc.), Down's syndrome, memory impairment, prion disease (Kreuzfeld-Jakob disease, etc.), mild cognitive impairment (MCI), Dutch hereditary amyloid cerebral hemorrhage, cerebral amyloid angiopathy , Other degenerative dementia, mixed vascular dementia, dementia associated with Parkinson's disease, dementia associated with progressive supranuclear paralysis, dementia associated with corticobasal degeneration, diffuse Lewy bodies For treatment and / or prevention of Alzheimer's disease, age-related macular degeneration, Parkinson's disease, amyloid angiopathy, etc. To be the case.

  Since the compound of the general formula (I), the compound of the general formula (II) or the compound of the general formula (III) according to the present invention selectively inhibits Aβ42 production, it can be a pharmaceutical with reduced side effects. In addition, the compound according to the present invention has high selectivity for other enzymes, high metabolic stability, high solubility, high oral absorption, good bioavailability, good clearance, brain migration It also has advantages such as high potency, long half-life, high non-protein binding rate, low hERG channel inhibition, low CYP inhibition, and / or negative Ames test.

  When administering the compound of general formula (I), the compound of general formula (II) or the compound of general formula (III) according to the present invention, other drugs (for example, other Alzheimer-type dementia therapeutic agents such as acetylcholinesterase, etc.) ). For example, it can be used in combination with drugs for treating dementia such as donepezil hydrochloride, tacrine, galantamine, rivastigmine, zanapezil, memantine, and vinpocetine.

  When administering the compound of general formula (I), the compound of general formula (II) or the compound of general formula (III) according to the present invention to humans, powders, granules, tablets, capsules, pills, liquids, etc. And can be administered parenterally as injections, suppositories, transdermal absorption agents, inhalants and the like. In addition, excipients, binders, wetting agents, disintegrants, lubricants and other pharmaceutical additives suitable for the dosage form may be mixed with an effective amount of the present compound as necessary to obtain a pharmaceutical preparation. it can.

  The dose varies depending on the disease state, administration route, patient age, or body weight, but is usually 0.1 μg to 1 g / day, preferably 0.01 to 200 mg / day when orally administered to an adult. In the case of parenteral administration, it is usually 1 μg to 10 g / day, preferably 0.1 to 2 g / day.

  Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples, but the present invention is not limited thereto.

In this specification, the meaning of each abbreviation is as follows.
Me: methyl Et: ethyl iPr: isopropyl t-Bu: t-butyl Ph: phenyl Bn: benzyl Boc: t-butoxycarbonyl SEM: 2- (trimethylsilyl) ethoxymethyl TBDPS: t-butyldiphenylsilyl DMA: dimethylacetamide DMF: Dimethylformamide DMSO: Dimethyl sulfoxide DBU: 1,8-diazabicyclo [5.4.0] undec-7-ene DIPEA: Diisopropylethylamine NBS: N-bromosuccinimide EDC: 1-ethyl-3- (3-dimethylaminopropyl) Carbodiimide hydrochloride HATU: 2- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium IPA: isopropyl alcohol NMP: N-methylpyrrolide hexafluorophosphate n-BuLi: n-butyl lithium sec-BuLi: sec-butyl lithium tert-BuLi: tert-butyl lithium Pd _{(PPh 3) 4:} tetrakis triphenylphosphine palladium PdCl ₂ (dppf): [1,1'- bis ( Diphenylphosphino) ferrocene] -dichloropalladium (II)
PdCl ₂ (PPh ₃ ) ₂ : bistriphenylphosphine-dichloropalladium (II)
Pd (OAc) ₂ : Palladium acetate Pd ₂ (dba) ₃ : Tris (dibenzylideneacetone) bispalladium PPh ₃ : Triphenylphosphine Xantphos: 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene BINAP: 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl S-Phos: 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl X-Phos: 2-dicyclohexylphosphino-2 ′, 4 ', 6'-Triisopropylbiphenyl DPPF: 1,1'-bis (diphenylphosphino) ferrocene t-Bu ₃ P: tri (t-butyl) phosphine RuPhos: 2-dicyclohexylphosphine O-2', 6'-di Isopropoxy-1,1′-biphenyl.

  LC / MS was measured under the following conditions.

Analytical LCMS
(Method A)
Column: Xbridge C18 (5 μm, id 4.6 × 50 mm) (Waters)
Flow rate: 3 mL / min UV detection wavelength: 254 nm
Mobile phase: [A] is a 0.1% formic acid-containing aqueous solution, [B] is a 0.1% formic acid-containing acetonitrile solution Gradient: linear gradient of 10% -100% solvent [B] in 3 minutes, 1 minute 100% solvent [B] was maintained.
(Method B)
Column: Shim-pack XR-ODS (2.2 μm, id 50 × 3.0 mm) (Shimadzu)
Flow rate: 1.6 mL / min UV detection wavelength: 254 nm
Mobile phase: [A] is a 0.1% formic acid-containing aqueous solution, [B] is a 0.1% formic acid-containing acetonitrile solution Gradient: linear gradient of 10% -100% solvent [B] in 3 minutes, 1 minute 100% solvent [B] was maintained.
(Method C)
Column: Luna C18 (2) (5 μm, id 4.6 × 50 mm) (Phenomenex)
Flow rate: 3 mL / min UV detection wavelength: 254 nm
Mobile phase: [A] is a 0.1% formic acid-containing aqueous solution, [B] is a 0.1% formic acid-containing acetonitrile solution Gradient: linear gradient of 10% -100% solvent [B] in 3 minutes, 1 minute 100% solvent [B] was maintained.
(Method D)
Column: Gemini-NX (5 μm, id 4.6 × 50 mm) (Phenomenex)
Flow rate: 3 mL / min UV detection wavelength: 254 nm
Mobile phase: [A] is a 0.1% formic acid-containing aqueous solution, [B] is a 0.1% formic acid-containing methanol solution gradient: A linear gradient of 5% -100% solvent [B] is performed in 3.5 minutes, 100% solvent [B] was maintained for 0.5 minutes.
(Method E)
Column: XBridge C18 (5 μm id 4.6 × 50 mm) (Waters)
Flow rate: 2 mL / min UV detection wavelength: 254 nm
Mobile phase: [A] is an aqueous solution containing 10 mM ammonium carbonate, [B] is an acetonitrile gradient: linear gradient of 10% -100% solvent [B] is performed for 3 minutes, and 100% solvent [B] is maintained for 1 minute. did.
(Method F)
Column: Gemini-NX (5 μm, id 4.6 × 50 mm) (Phenomenex)
Flow rate: 3 mL / min UV detection wavelength: 254 nm
Mobile phase: [A] is a 10 mM ammonium carbonate-containing aqueous solution, [B] is a methanol gradient: 5% -100% solvent [B] is linearly gradient over 3.5 minutes, and 100% solvent [B] is added for 0.5 minutes. B] was maintained.
(Method I)
Column: ACQUITY UPLC BEH C18 (1.7 μm id 2.1 × 50 mm) (Waters)
Flow rate: 0.8 mL / min UV detection wavelength: 254 nm
Mobile phase: [A] is a 0.1% formic acid-containing aqueous solution, [B] is a 0.1% formic acid-containing acetonitrile solution. Gradient: Perform a linear gradient of 10% -100% solvent [B] in 3.5 minutes. 100% solvent [B] was maintained for 0.5 minutes.

  Example 1 Synthesis of Compound 9

To a solution of 5-methoxyindole-2-carboxylic acid (1.00 g, 5.23 mmol), 4-phenoxyaniline (1.07 g, 5.75 mmol) and N-hydroxybenzotriazole (0.78 g, 5.75 mmol) in DMF (20.0 ml), EDC (1.20 g, 6.28 mmol) was added and stirred at room temperature for 2 hours. Ethyl acetate (50 ml) and saturated aqueous sodium hydrogen carbonate solution (50 ml) were added, and the mixture was partitioned into an organic layer and an aqueous layer. The organic layer was washed twice with brine (50 ml). The organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Hexane was added to the residue and collected by filtration to obtain the desired product as a colorless solid (1.27 g, 68%).
LC-MS (Method B): 2.44 min, [M + H] = 359.05
1H NMR (300 MHz, DMSO-d6) δ 3.78 (s, 3H), 6.88 (dd, J = 8.7 Hz, J = 2.4 Hz, 1H), 6.95-7.15 (m, 5H), 7.07 (s, 1H) , 7.32 (s, 1H), 7.30-7.45 (m, 3H), 7.82 (m, 2H), 10.20 (s, 1H), 11.59 (s, 1H).

  Example 2 Synthesis of Compound 25

5-Methoxy-1H-pyrrolo [2,3-c] pyridine-2-carboxylic acid (0.10 g, 0.52 mmol), 3-chloroaniline (0.073 g, 0.57 mmol) and N-hydroxybenzotriazole (0.077 g, 5.75 mmol) in DMF (3.0 ml) was added EDC (0.12 g, 0.62 mmol) and stirred at room temperature. Ethyl acetate (30 ml) and saturated aqueous sodium hydrogen carbonate solution (15 ml) were added, and the mixture was partitioned into an organic layer and an aqueous layer. The organic layer was washed twice with brine (15 ml). The organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Diethyl ether was added to the residue and collected by filtration to obtain the desired product as a yellow powder (0.076 g, 48%).
LC-MS (Method B): 1.57 min, [M + H] = 302.05
1H NMR (300 MHz, DMSO-d6) δ 3.85 (s, 3H), 7.02 (s, 1H), 7.19 (dd, J
= 1.2 Hz, J = 8.1 HZ, 1H), 7.30 (s, 1H), 7.41 (t, J = 8.1 Hz, 1H), 7.73 (dd, J = 1.2 Hz, J = 8.1 Hz, 1H), 7.97 ( s, 1H), 8.46 (s, 1H), 10.52 (s, 1H), 11.96 (s, 1H).

Example 3 Synthesis of Compound 181 (First Step)

DMF (60.0 ml) of 5-methoxyindole-2-carboxylic acid (3.78 g, 19.8 mmol), 4-amino-2-chlorophenol (3.12 g, 21.8 mmol) and N-hydroxybenzotriazole (2.94 g, 21.8 mmol) ) To the solution was added EDC (4.55 g, 23.7 mmol), and the mixture was stirred at room temperature for 3 hours. Ethyl acetate (150 ml) and saturated aqueous sodium hydrogen carbonate solution (100 ml) were added, and the mixture was partitioned into an organic layer and an aqueous layer. The organic layer was washed 3 times with water (100 ml). The organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Diethyl ether was added to the residue and collected by filtration to obtain the desired product as a brown powder (5.53 g, 88%).
LC-MS (Method B): 1.78 min, [M + H] = 317.05
1H NMR (300 MHz, DMSO-d6) δ 3.79 (s, 3H), 6.86 (dd, J = 9.0 Hz, J = 2.4 Hz, 1H), 6.95 (d, J = 8.7 Hz, 1H), 7.11 (d , J = 2.4 Hz, 1H), 7.25 (d, J = 1.5 Hz, 1H), 7.34 (d, J = 8.7 Hz, 1H), 7.50 (dd, J = 8.7 Hz, J = 2.4 Hz, 1H), 7.83 (d, J = 2.4 Hz, 1H), 9.96 (s, 1H), 10.05 (s, 1H), 11.52 (s, 1H).
(Second step)

To a solution of N- (3-chloro-4-hydroxyphenyl) -5-methoxy-1H-indole-2-carboxamide (0.0525 g, 0.166 mmol) in DMF (2.0 ml) was added 3-methoxybenzyl bromide (0.035 ml, 0.249 mmol) and potassium carbonate (0.0458 g, 0.332 mmol) were added, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate (20 ml) and water (10 ml) were added, and the organic layer and aqueous layer were partitioned. The organic layer was washed twice with water (10 ml). The organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane / ethyl acetate: 0% -20%) to obtain the desired product as a white powder (0.055 g, 76%).
LC-MS (Method B): 2.47 min, [M + H] = 437.25
1H NMR (300 MHz, DMSO-d6) δ 3.76 (s, 3H), 5.17 (s, 2H), 6.87 (m, 2H), 7.02 (m, 2H), 7.12 (d, J = 3.0 Hz, 1H) , 7.22-7.35 (m, 4H), 7.65 (dd, J = 9.0 Hz, J = 3.0 Hz, 1H), 7.94 (d, J = 3.0 Hz, 1H), 10.16 (s, 1H), 11.57 (s, 1H).

Example 4 Synthesis of Compound 186 (First Step)

DMF (5-methoxyindole-2-carboxylic acid (0.10 g, 0.52 mmol), 4-amino-2,6-dichlorophenol (0.10 g, 0.58 mmol) and N-hydroxybenzotriazole (0.078 g, 0.58 mmol) 2.0 ml) solution was added EDC (0.12 g, 0.63 mmol) and stirred at room temperature for 18 hours. Ethyl acetate (30 ml) and saturated aqueous sodium hydrogen carbonate solution (30 ml) were added, and the mixture was partitioned into an organic layer and an aqueous layer. The organic layer was washed 3 times with water (30 ml). The organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Diethyl ether was added to the residue and collected by filtration to obtain the desired product as a brown powder (0.10 g, 57%).
LC-MS (Method B): 1.95 min, [M + H] = 351.051H NMR (300 MHz, DMSO-d6) δ 3.77 (s, 3H), 6.88 (dd, J = 9.0 Hz, J = 2.4 Hz, 1H), 7.13 (s, 1H), 7.27 (s, 1H), 7.35 (d, J = 9.0 Hz, 1H), 7.84 (s, 2H), 10.19 (s, 1H), 11.60 (s, 1H).
(Second process)

To a solution of N- (3,5-dichloro-4-hydroxyphenyl) -5-methoxy-1H-indole-2-carboxamide (0.0502 g, 0.143 mmol) in DMF (2.0 ml) was added 3-fluorobenzyl bromide (0.026 ml, 0.214 mmol) and potassium carbonate (0.0395 g, 0.286 mmol) were added, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate (20 ml) and water (10 ml) were added, and the organic layer and aqueous layer were partitioned. The organic layer was washed twice with water (10 ml). The organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane / ethyl acetate: 0% -20%) to obtain the desired product as a white powder (0.036 g, 55%).
LC-MS (Method B): 2.72 min, [M + H] = 459.15
1H NMR (300 MHz, DMSO-d6) δ 3.77 (s, 3H), 5.03 (s, 2H), 6.88 (dd, J = 9.0 Hz, J = 3.0 Hz, 1H), 7.14 (d, J = 3.0 Hz , 1H), 7.21 (m, 1H), 7.25-7.40 (m, 4H), 7.46 (m, 1H), 7.98 (s, 2H), 10.36 (s, 1H),
11.65 (s, 1H).

Example 5 Synthesis of Compound 37 (First Step)

To a solution of ethyl 2-methyl-3-oxobutanoate (11.7 g, 81.0 mmol) in ethanol (375 ml) was added a solution of potassium hydroxide (5.36 g, 81.0 mmol) in water (37.5 ml), and the mixture was stirred under ice cooling. . To this solution, 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) aniline (7.50 g, 36.9 mmol) in water (262 ml) was added to a 2 mol / L hydrochloric acid aqueous solution (36.9 ml, 73.8 mmol) and sodium nitrite (2.80 g, 40.6 mmol) were added, and the solution prepared by stirring for 1 hour under ice cooling was added, followed by stirring for 1 hour under ice cooling. The reaction mixture was concentrated under reduced pressure, ethyl acetate (500 ml) was added to the residue, and the mixture was partitioned between an organic layer and an aqueous layer. The organic layer was washed twice with water (150 ml). The organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel chromatography (chloroform / methanol: 0% -1%) to obtain the desired product as an orange powder (5.15 g, 44%).
LC-MS (Method B): 1.51 min, [M + H] = 316.90
1H NMR (300 MHz, DMSO-d6) δ 1.25 (t, J = 7.2 Hz, 3H), 2.06 (s, 3H), 2.12 (s, 3H), 3.77 (s, 3H), 4.18 (q, J = 7.2 Hz, 2H), 6.90 (dd, J = 8.4 Hz, J = 2.1 Hz, 1H), 6.99 (s, 1H), 7.07 (d, J = 2.1 Hz, 1H), 7.22 (d, J = 8.4 Hz , 1H), 7.61 (s, 1H), 9.98 (s, 1H).
(Second step)

(E) -2- (2- (3-Methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl) hydrazono) ethyl propanoate (5.00 g, 15.8 mmol) in toluene (100 ml) Polyphosphoric acid (15.0 g) was added to the suspension and stirred at 100 ° C. for 30 minutes. Water (100 ml) was added and the organic layer and the aqueous layer were partitioned. To the aqueous layer was added 2 mol / L aqueous sodium carbonate solution (80 ml), and the mixture was extracted with chloroform (300 ml). The organic layer was washed once with water (100 ml). The organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Diethyl ether was added to the residue and collected by filtration to obtain the desired product as an orange powder (2.28 g, 48%).
LC-MS (Method B): 1.42 min, [M + H] = 299.90
1H NMR (300 MHz, DMSO-d6) δ 1.32 (t, J = 7.2 Hz, 3H), 2.14 (s, 3H), 3.80 (s, 3H), 4.31 (q, J = 7.2 Hz, 2H), 7.02 (s, 1H), 7.04 (s, 1H), 7.11 (s, 1H), 7.59 (s, 1H), 7.63 (s, 1H), 11.90 (s, 1H).
(Third step)

To a solution of ethyl 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -1H-indole-2-carboxylate (2.00 g, 6.68 mmol) in ethanol (20.0 ml) and THF (40.0 ml) 2 mol / L aqueous sodium hydroxide solution (5.00 ml, 10.0 mmol) was added and stirred at 50 ° C. for 2.5 hours. 2 mol / L hydrochloric acid aqueous solution (5.00 ml) was added, and the reaction mixture was concentrated under reduced pressure. The precipitated solid was collected by filtration and washed with water to obtain the desired product as a white powder (1.59 g, 88%).
LC-MS (Method B): 0.74 min, [M + H] = 272.95
1H NMR (300 MHz, DMSO-d6) δ 2.22 (s, 3H), 3.83 (s, 3H), 7.07 (s, 1H), 7.09 (s, 1H), 7.23 (s, 1H), 7.68 (s, 1H), 8.15 (s, 1H), 11.87 (s, 1H).
(4th process)

6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -1H-indole-2-carboxylic acid (0.050 g, 0.184 mmol), 2- (4-fluorophenyl) propan-2-amine ( EDC (0.042 g, 0.221 mmol) was added to a DMF (2.0 ml) solution of 0.034 g, 0.221 mmol) and N-hydroxybenzotriazole (0.027 g, 0.203 mmol), and the mixture was stirred at room temperature for 18 hours. Ethyl acetate (30 ml) and saturated aqueous sodium hydrogen carbonate solution (10 ml) were added, and the organic layer and aqueous layer were partitioned. The organic layer was washed twice with water (20 ml). The organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Diethyl ether was added to the residue and collected by filtration to obtain the desired product as a white powder (0.039 g, 52%).
LC-MS (Method B): 1.33 min, [M + H] = 406.90
1H NMR (300 MHz, DMSO-d6) δ 1.69 (s, 6H), 2.16 (s, 3H), 3.78 (s, 3H), 7.00-7.15 (m, 4H), 7.29 (s, 1H), 7.40 ( m, 2H), 7.59 (s, 1H), 7.68 (s, 1H), 8.41 (s, 1H), 11.45 (s, 1H).
Example 6 Synthesis of Compound 64

DMF (2.0 ml) of 5-methoxyindole-2-carboxylic acid (0.10 g, 0.525 mmol), 5-fluoropyridin-3-amine (0.065 g, 0.575 mmol) and N-hydroxybenzotriazole (0.078 g, 0.575 mmol) ) To the solution, EDC (0.120 g, 0.628 mmol) was added and stirred at 50 ° C. for 10 hours. Ethyl acetate (20 ml) and saturated aqueous sodium hydrogen carbonate solution (10 ml) were added, and the mixture was partitioned into an organic layer and an aqueous layer. The organic layer was washed 3 times with water (20 ml). The organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Diethyl ether was added to the residue and collected by filtration to obtain the desired product as a yellow powder (0.074 g, 50%).
LC-MS (Method B): 1.69 min, [M + H] = 286.05

Example 7 Synthesis of Compound 55 (First Step)

To a solution of ethyl 2-methyl-3-oxobutanoate (7.85 g, 54.4 mmol) in ethanol (200 ml) was added a solution of potassium hydroxide (3.59 g, 54.4 mmol) in water (20.0 ml), and the mixture was stirred under ice cooling. To this solution, 4-bromo-3-methoxyaniline (5.00 g, 24.8 mmol) in water (175 ml) was added to a 2 mol / L hydrochloric acid aqueous solution (24.8 ml, 49.5 mmol) and sodium nitrite (1.88 g, 27.2 mmol). The solution prepared by stirring for 1 hour under ice-cooling was added, and the mixture was stirred for 1 hour under ice-cooling. The reaction mixture was concentrated under reduced pressure, water (100 ml) was added to the residue, and the mixture was collected by filtration to obtain the desired product as a brown solid (7.23 g, 93%).
LC-MS (Method B): 2.12 min, [M + H] = 315.05
1H NMR (300 MHz, CDCl ₃ ) δ 1.38 (t, J = 7.2 Hz, 3H), 2.11 (s, 3H), 3.92 (s, 3H), 4.32 (q, J = 7.2 Hz, 2H), 6.60 ( dd, J = 8.7 Hz, J = 2.4 Hz, 1H), 6.91 (d, J = 2.4 Hz, 1H), 7.40 (d, J = 8.7 Hz,
1H), 7.67 (brs, 1H).
(Second step)

To a suspension of ethyl (E) -2- (2- (4-bromo-3-methoxyphenyl) hydrazono) propanoate (0.50 g, 1.59 mmol) in toluene (10 ml) was added polyphosphoric acid (1.50 g). And stirred at 100 ° C. for 1 hour. A 2 mol / L aqueous sodium carbonate solution (20 ml) was added, and the mixture was extracted with ethyl acetate (50 ml). The organic layer was washed twice with water (50 ml). The organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane / ethyl acetate: 0% -20%) to obtain the desired product as an orange powder (0.15 g, 31%).
LC-MS (Method B): 2.26 min, [M + H] = 297.75
1H NMR (300 MHz, CDCl ₃ ) δ 1.41 (t, J = 7.2 Hz, 3H), 3.94 (s, 3H), 4.40 (q, J = 7.2 Hz, 2H), 6.88 (s, 1H), 7.11 ( s, 1H), 7.26 (s, 1H), 7.85 (s, 1H), 8.87 (brs, 1H).
(Third step)

Ethyl 5-bromo-6-methoxy-1H-indole-2-carboxylate (0.14 g, 0.47 mmol), 1-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane 2-yl) -1H-pyrazole (0.11 g, 0.52 mmol) and tetrakis (triphenylphosphine) palladium (0.055 g, 0.048 mmol) in DMF (5.0 ml) in 2 mol / L sodium carbonate aqueous solution (0.48 ml) Was added to degas the reaction system. The mixture was stirred at 100 ° C. for 2 hours under a nitrogen stream. Ethyl acetate (30 ml) and water (30 ml) were added, and the organic layer and aqueous layer were partitioned. The organic layer was washed 3 times with water (30 ml). The organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane / ethyl acetate: 0% -50%) to obtain the desired product as a yellow solid (0.093 g, 65%).
LC-MS (Method B): 1.75 min, [M + H] = 300.15
1H NMR (300 MHz, CDCl ₃ ) δ 1.41 (t, J = 6.9 Hz, 3H), 3.93 (s, 3H), 3.95 (s, 3H), 4.39 (q, J = 6.9 Hz, 2H), 6.88 ( s, 1H), 7.15 (s, 1H), 7.23 (s, 1H), 7.77 (s, 1H), 7.85 (s, 1H), 8.83 (brs, 1H).
(4th process)

To a solution of ethyl 6-methoxy-5- (1-methyl-1H-pyrazol-4-yl) -1H-indole-2-carboxylate (0.083 g, 0.28 mmol) in ethanol (7.5 ml) was added 2 mol / L water. A sodium oxide aqueous solution (0.21 ml, 0.42 mmol) was added, and the mixture was stirred at 75 ° C. for 5 hours. 2 mol / L hydrochloric acid aqueous solution (0.21 ml) was added, and the reaction mixture was concentrated under reduced pressure. The precipitated solid was collected by filtration and washed with water to obtain the desired product as a brown powder (0.068 g, 90%).
LC-MS (Method B): 1.26 min, [M + H] = 272.10
1H NMR (300 MHz, DMSO-d6) δ 3.86 (s, 3H), 3.87 (s, 3H), 6.93 (s, 1H), 6.99 (s, 1H), 7.77 (s, 1H), 7.82 (s, 1H), 8.01 (s, 1H), 11.54 (s, 1H), 12.72 (brs, 1H).
(5th process)

6-methoxy-5- (1-methyl-1H-pyrazol-4-yl) -1H-indole-2-carboxylic acid (0.050 g, 0.184 mmol), 1- (4-chlorophenyl) ethanamine (0.032 g, 0.203 mmol) ) And N-hydroxybenzotriazole (0.027 g, 0.203 mmol) in DMF (2.0 ml) were added EDC (0.042 g, 0.221 mmol) and stirred at room temperature for 18 hours. Ethyl acetate (30 ml) and saturated aqueous sodium hydrogen carbonate solution (10 ml) were added, and the mixture was partitioned into an organic layer and an aqueous layer. The organic layer was washed twice with water (20 ml). The organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Diethyl ether was added to the residue and collected by filtration to obtain the desired product as a white powder (0.034 g, 45%).
LC-MS (Method B): 2.04 min, [M + H] = 408.95
1H NMR (300 MHz, DMSO-d6) δ 1.48 (d, J = 6.9 Hz, 3H), 3.85 (s, 3H), 3.86 (s, 3H), 5.17 (m, 1H), 6.93 (s, 1H) , 7.14 (s, 1H), 7.40 (m, 4H), 7.75 (s, 1H), 7.84 (s, 1H), 8.01 (s, 1H), 8.70 (d, J = 7.8 Hz, 1H), 11.32 ( s, 1H).

  The following compounds were synthesized in the same manner. The structural formula and physical property values (LC / MS retention time, mass spectrum and / or NMR spectrum, measurement conditions) are shown below.

However, when there is description of HCl, it means a hydrochloride, and when there is description of Chiral, it means that the compound is a chiral compound.

Test example 1
Measurement of Aβ42 production inhibitory effect using human-type APP ₆₉₅ gene-introduced neuroblasts Concentration-dependent effects of each test compound were tested using the Aβ42 production concentration and cell survival activity secreted by SH-SY5Y-APPwt cells as test items . Secreted Aβ42 production was evaluated by ELISA. Cell viability was evaluated using a reagent for measuring the number of living cells.

SH-SY5Y-APPwt cells were established as stable expression cells by introducing human APP ₆₉₅ into SH-SY5Y cells, which are human neuroblasts. The cells were cultured in DMEM containing 10% FCS.

SH-SY5Y-APPwt cells are seeded in a 96-well plate at 1.2 × 10 ⁵ cells / 150 uL DMEM per well. At the same time, the DMSO solution of the test compound was diluted with the DMEM solution to a final concentration of 4 times, and 50 uL of this diluted solution was added and mixed well with the cells to make the final DMEM solution 200 uL per well. The final DMSO concentration was adjusted to 1%. DAPT (Calbiochem), which is a γ-secretase inhibitor, was used as a control compound. After 24 hours, the culture supernatant was collected and subjected to ELISA after appropriate dilution as an ELISA sample for Aβ42 measurement. The cultured cells were used for live cell count measurement.

For ELISA, human / rat β amyloid (42) ELISA kit (Human / Rat β Amyloid (42) ELISA Kit) WAKO (Wako Pure Chemical Industries) was used. The method was the method described in the package insert recommended by the manufacturer. For each sample, the percentage (% of control) relative to the Aβ42 concentration in the culture supernatant of the control group was calculated, and then the IC ₅₀ value of each test compound was calculated. The cell viability activity was measured using the living cell count reagent SF (Nacalai Tesque). The method was the method described in the package insert recommended by the manufacturer. For each sample, the percentage (% of control) relative to the number of viable cells in the control group was calculated, and the cell viability was evaluated.

The results are shown below.
(result)

Test example 2
Measurement of γ-secretase activity inhibitory action of test compound Each test compound was evaluated for APP processing by γ-secretase in SHSY5Y-APPwt cells, that is, C-terminal fragment β (CTF-terminal fragment β: CTFβ serving as a substrate for γ-secretase ) The γ-secretase inhibitory effect was tested in a concentration-dependent manner using the amount as an evaluation item (10 times the test compound Aβ42 IC50 value and 2 times the 100-fold concentration). The amount of CTFβ produced by γ-secretase inhibition was evaluated by ELISA. SHSY5Y-APPwt cells were established as stable expression cells by introducing human APP695 into SHSY5Y cells. The cells were cultured in DMEM containing 10% FCS. SHSY5Y-APPwt cells are seeded in a 6-well plate at 1.0 × 10 ⁶ cells / well / mL DMEM. At the same time, the DMSO solution of the test compound was diluted with the DMEM solution so that the final concentration was doubled, and 1 mL of this diluted solution was added and mixed well with the cells to make the final DMEM solution 2 mL per well. The final DMSO concentration was adjusted to 1%. As control compounds, DAPT (Calbiochem), which is a γ-secretase inhibitor, and BACE inhibitor IV, which is a β-secretase inhibitor, were used. After 24 hours, the cultured cells were collected and dissolved in a 1% TritonX100-containing TBS buffer, and the cell extract, which was a centrifugal supernatant (14000 rpm, 4 ° C., 10 minutes), was quantified with a protein quantification kit (Pierce). A diluted cell extract was used as an evaluation sample, and the amount of CTFβ was quantified using a βCTF ELISA kit (IBL). For quantification, the percentage (% of Control) relative to CTFβ of the control group to which only DMSO was added was calculated, and the amount of increase or decrease in CTFβ of each test compound was calculated. At this time, the test compound having γ-secretase activity inhibition increases the amount of CTFβ, which is a γ-secretase substrate, in a concentration-dependent manner. On the other hand, a test compound having β-secretase activity inhibition decreases the amount of CTFβ, which is a γ-secretase substrate, in a concentration-dependent manner.

  Compound numbers 64, 175, 185, 463, 542, 549, 551 and 59 were evaluated. The results are shown in FIG. 1 and FIG. The control compound γ-secretase inhibitor DAPT increased the amount of CTFβ in a concentration-dependent manner, and the β-secretase inhibitor BACE inhibitor IV decreased the amount of CTFβ in a concentration-dependent manner. On the other hand, for Compound Nos. 64, 175, 185, 463, 542, 549, 551, and 59, no increase or decrease in the concentration-dependent amount of CTFβ was observed. That is, it was found that the above compound has no inhibitory action on γ-secretase activity but has an inhibitory action on Aβ42 production. This indicated that the compound is a γ-secretase modifying agent.

Test Example 3 CYP3A4 Fluorescence MBI Test The CYP3A4 fluorescence MBI test is a test for examining the enhancement of CYP3A4 inhibition of the compounds of the present invention by metabolic reaction. 7-Benzyloxytrifluoromethylcoumarin (BFC) is debenzylated by CYP3A4 enzyme (E. coli expression enzyme) to produce a fluorescent metabolite 7-hydroxytrifluoromethylcoumarin (7-HFC). 7-HFC production reaction is performed as an index.

  The reaction conditions are as follows: substrate, 5.6 μmol / L 7-BFC; pre-reaction time, 0 or 30 minutes; reaction time, 15 minutes; reaction temperature, 25 ° C. (room temperature); CYP3A4 content (E. coli expression enzyme), Pre-reaction 62.5 pmol / mL, reaction 6.25 pmol / mL (10-fold dilution); compound concentration of the present invention, 0.625, 1.25, 2.5, 5, 10, 20 μmol / L (6 points) ).

  The enzyme and the compound solution of the present invention are added to the 96-well plate as a pre-reaction solution in K-Pi buffer (pH 7.4) in the above-mentioned pre-reaction composition, and the substrate and K-Pi buffer are added to another 96-well plate. A part of the solution was transferred so that it was diluted to 1/10, and the reaction using NADPH as a coenzyme was started as an indicator (no pre-reaction). After reaction for a predetermined time, acetonitrile / 0.5 mol / L The reaction is stopped by adding Tris (trishydroxyaminomethane) = 4/1. In addition, NADPH is also added to the remaining pre-reaction solution to start the pre-reaction (pre-reaction is present), and after pre-reaction for a predetermined time, one plate is diluted to 1/10 with the substrate and K-Pi buffer. Start the reaction with the part as the indicator. After the reaction for a predetermined time, the reaction is stopped by adding acetonitrile / 0.5 mol / L Tris (trishydroxyaminomethane) = 4/1. The fluorescence value of 7-HFC, which is a metabolite, is measured on the plate on which each index reaction has been performed with a fluorescent plate reader (Ex = 420 nm, Em = 535 nm).

A control (100%) was obtained by adding only DMSO, which is a solvent in which the compound of the present invention was dissolved, to the reaction system, and the residual activity (%) at each concentration of the compound of the present invention was calculated. Using the rate, IC ₅₀ is calculated by inverse estimation using a logistic model. The case where the difference in IC ₅₀ values is 5 μM or more is (+), and the case where it is 3 μM or less is (−).

Test Example 4 CYP Inhibition Test Using commercially available pooled human liver microsomes, O-deethylation of 7-ethoxyresorufin as a typical substrate metabolic reaction of major human CYP5 molecular species (CYP1A2, 2C9, 2C19, 2D6, 3A4) ( CYP1A2), tolbutamide methyl-hydroxylation (CYP2C9), mephenytoin 4′-hydroxylation (CYP2C19), dextromethorphan O-demethylation (CYP2D6), and terfenadine hydroxylation (CYP3A4) The degree to which the metabolite production amount is inhibited by the compound of the present invention is evaluated.

  The reaction conditions are as follows: substrate, 0.5 μmol / L ethoxyresorufin (CYP1A2), 100 μmol / L tolbutamide (CYP2C9), 50 μmol / L S-mephenytoin (CYP2C19), 5 μmol / L dextromethorphan (CYP2D6), 1 μmol / L terfenadine (CYP3A4); reaction time, 15 minutes; reaction temperature, 37 ° C .; enzyme, pooled human liver microsome 0.2 mg protein / mL; compound concentration of the present invention 1, 5, 10, 20 μmol / L (4 points) .

  As a reaction solution in a 96-well plate, 5 kinds of each substrate, human liver microsome, and the compound of the present invention are added in 50 mM Hepes buffer with the above composition, and NADPH as a coenzyme is added to start a metabolic reaction as an index. To do. After reacting at 37 ° C. for 15 minutes, the reaction is stopped by adding a methanol / acetonitrile = 1/1 (v / v) solution. After centrifuging at 3000 rpm for 15 minutes, resorufin (CYP1A2 metabolite) in the supernatant of the centrifugation was analyzed with a fluorescent multi-label counter, tolbutamide hydroxide (CYP2C9 metabolite), mephenytoin 4 ′ hydroxide (CYP2C19 metabolite), Dextrorphan (CYP2D6 metabolite) and terfenadine alcohol (CYP3A4 metabolite) are quantified by LC / MS / MS.

The control (100%) was obtained by adding only DMSO, which is a solvent in which the drug was dissolved, to the reaction system, the residual activity (%) was calculated, and the IC ₅₀ was calculated by inverse estimation using a logistic model using the concentration and the inhibition rate. calculate.

Test Example 5 Fluctuation Ames Test
20 μL of Salmonella typhimurium TA98 strain, TA100 strain, which has been cryopreserved, is inoculated into 10 mL liquid nutrient medium (2.5% Oxoid nutritive broth No. 2) and cultured at 37 ° C. for 10 hours before shaking. For TA98 strain, 9 mL of the bacterial solution is centrifuged (2000 × g, 10 minutes) to remove the culture solution. 9 mL of Micro F buffer (K ₂ HPO ₄ : 3.5 g / L, KH ₂ PO ₄ : 1 g / L, (NH ₄ ) ₂ SO ₄ : 1 g / L, trisodium citrate dihydrate: 0. MicroF containing 110 mL Exposure medium (Biotin: 8 μg / mL, Histidine: 0.2 μg / mL, Glucose: 8 mg / mL) suspended in 25 g / L, MgSO ₄ · 7H ₂ 0: 0.1 g / L) The TA100 strain is added to 120 mL of Exposure medium with respect to the 3.16 mL bacterial solution to prepare a test bacterial solution. Compound DMSO solution of the present invention (maximum dose of 50 mg / mL to several-fold dilution at 2-3 times common ratio), DMSO as negative control, and non-metabolic activation condition as a positive control. Nitroquinoline-1-oxide DMSO solution, 0.25 μg / mL 2- (2-furyl) -3- (5-nitro-2-furyl) acrylamide DMSO solution for TA100 strain, TA98 under metabolic activation conditions 40 μg / mL 2-aminoanthracene DMSO solution for the strain and 20 μg / mL 2-aminoanthracene DMSO solution for the TA100 strain, respectively, and 588 μL of the test bacterial solution (498 μL and S9mix90 μL of the test bacterial solution under metabolic activation conditions) And the mixture is incubated at 37 ° C. for 90 minutes with shaking. 2300 μL of 460 μL of the bacterial solution exposed to the compound of the present invention was added to Indicator Medium (BioF: 8 μg / mL, histidine: 0.2 μg / mL, glucose: 8 mg / mL, bromocresol purple: 37.5 μg / mL). 50 μL each and dispense into 48 wells / dose of the microplate, followed by static culture at 37 ° C. for 3 days. Since wells containing bacteria that have acquired growth ability by mutation of the amino acid (histidine) synthase gene change from purple to yellow due to pH change, the number of bacteria growth wells that changed to yellow in 48 wells per dose was counted. Evaluation is made in comparison with the negative control group.

Test Example 6 Solubility test The solubility of the compound of the present invention is determined under the condition of addition of 1% DMSO. Prepare a 10 mM compound solution in DMSO, and add 6 μL of the compound solution to a pH 6.8 artificial intestinal solution (250 mL of 0.2 mol / L potassium dihydrogen phosphate test solution, 118 mL of 0.2 mol / L NaOH test solution, add 1000 mL to add water) Add to 594 μL. After allowing to stand at 25 ° C. for 16 hours, the mixed solution is subjected to suction filtration. The filtrate is diluted 2-fold with methanol / water = 1/1, and the concentration in the filtrate is measured by HPLC or LC / MS / MS by the absolute calibration method.

Test Example 7 Metabolic Stability Test A commercially available pooled human liver microsome and the compound of the present invention are reacted for a certain period of time, and the residual rate is calculated by comparing the reaction sample with the unreacted sample to evaluate the degree of metabolism of the compound of the present invention in the liver. .

  In 0.2 mL buffer (50 mmol / L Tris-HCl pH 7.4, 150 mmol / L potassium chloride, 10 mmol / L magnesium chloride) containing 0.5 mg protein / mL human liver microsomes in the presence of 1 mmol / LNADPH The reaction was carried out at 0 ° C. for 0 minutes or 30 minutes (oxidative reaction). After the reaction, 50 μL of the reaction solution was added to 100 μL of methanol / acetonitrile = 1/1 (v / v) solution, mixed, and centrifuged at 3000 rpm for 15 minutes. The compound of the present invention in the centrifugal supernatant is quantified by LC / MS / MS, and the residual amount of the compound of the present invention after the reaction is calculated with the compound amount at 0 minute reaction as 100%.

Test Example 8 hERG Test For the purpose of risk assessment of ECG QT interval prolongation, HEK293 cells expressing human ether-a-go-go related gene (hERG) channels are used to play an important role in the ventricular repolarization process The action of the compounds of the present invention on the delayed rectifier K ⁺ current (I _Kr ) will be examined.

Using a fully automatic patch clamp system (PatchXpress 7000A, Axon Instruments Inc.), the cells were held at a membrane potential of −80 mV by the whole cell patch clamp method, and after giving a leak potential of −50 mV, depolarization of +40 mV Record the I _Kr elicited when the stimulus is applied for 2 seconds, followed by a -50 mV repolarization stimulus for 2 seconds. After the generated current was stabilized, an extracellular solution (NaCl: 137 mmol / L, KCl: 4 mmol / L, CaCl ₂ .2H ₂ O: 1.8 mmol / L, MgCl ₂ ) in which the compound of the present invention was dissolved at a concentration of 5 μM. 6H ₂ O: 1 mmol / L, glucose: 10 mmol / L, HEPES (4- (2-hydroxyethyl) -1-piperazine etheric acid, 4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid): 10 mmol / L PH = 7.4) is applied to the cells for 10 minutes at room temperature. From the obtained I _Kr , the absolute value of the maximum tail current is measured based on the current value at the holding membrane potential using analysis software (DataXpress ver. 1, Molecular Devices Corporation). Furthermore, the inhibition rate with respect to the maximum tail current before application of the compound of the present invention is calculated, and compared with the vehicle application group (0.1% dimethyl sulfoxide solution), the effect of the compound of the present invention on I _Kr is evaluated.

Test Example 9 Powder Solubility Test An appropriate amount of the compound of the present invention is placed in an appropriate container, and JP-1 solution (2.0 g of sodium chloride, water is added to 7.0 mL of hydrochloric acid to 1000 mL), JP-2 solution ( Add 500 mL of water to 500 mL of phosphate buffer solution at pH 6.8), and add 200 μL of 20 mmol / L sodium taurocholate (TCA) / JP-2 solution (add water to 1.08 g of TCA to make 100 mL). When dissolved after adding the test solution, the compound of the present invention is added as appropriate. After sealing at 37 ° C. for 1 hour, the mixture is filtered, and 100 μL of methanol is added to 100 μL of each filtrate to perform 2-fold dilution. Change the dilution factor as necessary. Check for bubbles and deposits, seal and shake. The compound of the present invention is quantified using HPLC by the absolute calibration curve method.

Test Example 10 BA test Examination of oral absorbability Experimental materials and methods (1) Animals used: Mice or SD rats are used.
(2) Breeding conditions: Mice and SD rats are allowed to freely take solid feed and sterilized tap water.
(3) Setting of dosage and grouping: oral administration and intravenous administration are administered at a predetermined dosage. Set the group as follows. (Dose may vary for each compound)
Oral administration 1-30 mg / kg (n = 2-3)
Intravenous administration 0.5-10 mg / kg (n = 2-3)
(4) Preparation of administration solution: Oral administration is administered as a solution or suspension. Intravenous administration is administered after solubilization.
(5) Administration method: Oral administration is forcibly administered into the stomach with an oral sonde. Intravenous administration is performed from the tail vein using a syringe with an injection needle.
(6) Evaluation items: Blood is collected over time, and the concentration of the compound of the present invention in plasma is measured using LC / MS / MS.
(7) Statistical analysis: The plasma concentration-time curve area (AUC) is calculated using the non-linear least squares program WinNonlin (registered trademark) for the plasma compound concentration transition in plasma, and the oral administration group and intravenous administration The bioavailability (BA) of the compound of the present invention is calculated from the AUC of the group.

Formulation Example 1
A granule containing the following ingredients is produced.

Ingredient Compound represented by formula (I) 10 mg
Lactose 700 mg
Corn starch 274 mg
HPC-L 16 mg
The compound of formula (I) and lactose are passed through a 60 mesh sieve. Pass corn starch through a 120 mesh sieve. These are mixed in a V-type mixer. An HPC-L (low viscosity hydroxypropylcellulose) aqueous solution is added to the mixed powder, followed by kneading, granulation (extruded granulation, pore diameter: 0.5 to 1 mm), and drying step. The obtained dried granules are combed with a vibration sieve (12/60 mesh) to obtain granules.

Formulation Example 2
A capsule filling granule containing the following ingredients is produced.

Ingredient Compound represented by formula (I) 15 mg
Lactose 90 mg
Corn starch 42 mg
HPC-L 3 mg
The compound of formula (I), lactose, is passed through a 60 mesh sieve. Pass corn starch through a 120 mesh sieve. These are mixed, the HPC-L solution is added to the mixed powder, kneaded, granulated and dried. After the resulting dried granules are sized, 150 mg thereof is filled into a No. 4 hard gelatin capsule.

Formulation Example 3
A tablet containing the following ingredients is produced.

Ingredient Compound represented by formula (I) 10 mg
Lactose 90 mg
Microcrystalline cellulose 30 mg
CMC-Na 15 mg
Magnesium stearate 5 mg
The compound of formula (I), lactose, microcrystalline cellulose, CMC-Na (carboxymethylcellulose sodium salt) are passed through a 60 mesh sieve and mixed. The mixed powder is mixed with magnesium stearate to obtain a mixed powder for tableting. The mixed powder is directly hit to obtain a 150 mg tablet.

Formulation Example 4
The following ingredients are heated and mixed and then sterilized to give an injection.

Ingredient Compound represented by formula (I) 3 mg
Nonionic surfactant 15 mg
Purified water for injection 1 ml

Formulation Example 5
A haptic agent containing the following components is produced.

Ingredient Compound represented by formula (I) 50 mg
Aqueous base (5% ethanol / 5% butylene glycol / 90% purified water) 950 mg
Glycerin Kaolin Polyvinyl alcohol aqueous solution The compound represented by the formula (I) is added to the aqueous base, and after ultrasonic irradiation for about 15 minutes, the mixture is sufficiently stirred to obtain a solution. 5 parts of glycerin, 1 part of kaolin and 5 parts of an aqueous polyvinyl alcohol solution are uniformly mixed, and 1 part of the prepared solution is added. This is further mixed to obtain a paste, which is coated on a non-woven fabric and covered with a polyester film to obtain a happing agent.

  The compound according to the present invention is useful as a therapeutic agent for diseases induced by production, secretion or deposition of amyloid β protein.

Claims (29)

Formula (I):

[Wherein, -X ¹ = X ² -X ³ = X ⁴ -represents -C (R ¹ ) = C (R ² ) -C (R ³ ) = C (R ⁴ )-, -C (R ^{1 ) = N-C (R 3} ) = C (R 4) -, - C (R 1) = C (R 2) -N = C (R 4) -, - N = C (R 2) -C ( R ³ ) = C (R ⁴ ) —, or —C (R ¹ ) = C (R ² ) —C (R ³ ) = N—;
R ¹ , R ² , R ³ and R ⁴ are each independently hydrogen, halogen, hydroxy, carboxy, sulfo, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted Or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted carbocyclic oxy, substituted or unsubstituted heterocyclic oxy, mercapto, substituted or unsubstituted alkylthio, substituted Or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted carbocyclic thio, substituted or unsubstituted heterocyclic thio, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted acyl, substituted or Unsubstituted amino, substituted sulfonyl, Conversion sulfinyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, nitro, cyano, a substituted or unsubstituted carbocyclic group or a substituted or unsubstituted heterocyclic group;
R ⁵ is hydrogen, carboxy, sulfo, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted acyl, substituted sulfonyl, substituted sulfinyl, substituted or unsubstituted carbamoyl, or substituted or unsubstituted Of sulfamoyl;
R ⁶ is hydrogen, halogen, hydroxy, carboxy, sulfo, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxycarbonyl, Substituted or unsubstituted acyl, substituted sulfonyl, substituted sulfinyl, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, or substituted or unsubstituted carbocyclic group;
Ak ¹ or Ak ² each independently represents a single bond or a substituted or unsubstituted alkylene having 1 or 2 carbon atoms;
-L ¹ - ^{is, -C (= O) N (} R 8) -, - N (R 8) -C (= O) -, - SO 2 N (R 8) -, - N (R 8) SO _{2 -, - C (= O} ) -, - C (= O) -C (= O) -, - C (= O) -C (= O) -N (R 8) -, or -C (= O) O-;
Each R ⁸ is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted acyl;
Ring A is a benzene ring, pyridine ring, pyridazine ring, pyrimidine ring, cyclohexane ring, cyclohexene ring, tetrahydropyran ring, dihydropyridine ring, tetrahydropyridine ring, piperidine ring, piperazine ring, morpholine ring, octahydrocyclopentapyrrole ring, aza A bicyclooctane ring, a pyrrolidine ring, a thiazole ring, an imidazole ring, a pyrazole ring, an isoxazole ring, an oxazole ring or a thiazole ring;
Each R ⁷ independently represents halogen, hydroxy, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy; Substituted or unsubstituted alkynyloxy, substituted or unsubstituted acyloxy, substituted or unsubstituted carbocyclic oxy, substituted or unsubstituted heterocyclic oxy, mercapto, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio Substituted or unsubstituted alkynylthio, substituted or unsubstituted carbocyclic thio, substituted or unsubstituted heterocyclic thio, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted acyl, substituted or unsubstituted amino, substituted Sulfonyl, substituted Rufinyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, nitro, cyano, azide, substituted or unsubstituted carbocyclic group, or substituted or unsubstituted non-aromatic heterocyclic group (provided that Excluding unsubstituted dihydrothiazine cyclic groups);
n is an integer of 0 to 5]
Or a pharmaceutically acceptable salt thereof or a solvate thereof, a pharmaceutical composition for inhibiting amyloid β production. ^{-X 1 = X 2 -X 3 =} X 4 - ^{is, -C (R 1) = C} (R 2) -C (R 3) = C (R 4) -, - C (R 1) = N- C (R ³ ) = C (R ⁴ ) —, or —C (R ¹ ) = C (R ² ) —N═C (R ⁴ ) —,
—L ¹ — is —C (═O) N (R ⁸ ) — or —N (R ⁸ ) —C (═O) — (wherein R ¹ , R ² , R ³ , R ⁴ , and R ^The pharmaceutical composition for inhibiting amyloid β production according to claim 1, comprising a compound as defined in claim 1 or a pharmaceutically acceptable salt thereof or a solvate thereof. ^{-X 1 = X 2 -X 3 =} X 4 - ^{is, -C (R 1) = C} (R 2) -C (R 3) = C (R 4) -, - C (R 1) = N- C (R ³ ) = C (R ⁴ ) —, or —C (R ¹ ) = C (R ² ) —N═C (R ⁴ ) —, wherein R ¹ , R ³ and R ⁴ are claimed And is synonymous with item 1),
R ² is OR ¹² , SR ¹³ , or N (R ¹⁴ ) (R ¹⁵ ) wherein R ¹² and R ¹³ are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted Alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic group, or substituted or unsubstituted heterocyclic group; R ¹⁴ and R ¹⁵ are each independently hydrogen, substituted or unsubstituted An alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted carbocyclic group, or substituted or unsubstituted heterocyclic group, or R ¹⁴ and R ¹⁵ together with the nitrogen atom to which they are attached. The amyloid according to claim 1 or 2, which comprises a compound which may form a heterocycle, or a pharmaceutically acceptable salt thereof or a solvate thereof. β production inhibitory pharmaceutical composition. ^{-X 1 = X 2 -X 3 =} X 4 - ^{is, -C (R 1) = C} (R 2) -C (R 3) = C (R 4) -, - C (R 1) = N- C (R ³ ) = C (R ⁴ ) —, or —C (R ¹ ) = C (R ² ) —N═C (R ⁴ ) —, wherein R ¹ and R ⁴ are claims 1),
R ² and R ³ are each independently OR ¹² , SR ¹³ , N (R ¹⁴ ) (R ¹⁵ ), substituted or unsubstituted pyridyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, substituted Or a compound which is unsubstituted oxazolyl, or substituted or unsubstituted thiazolyl (wherein R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ are as defined in claim 3), or a pharmaceutically acceptable salt thereof Or the pharmaceutical composition for amyloid beta production suppression of Claim 1 or 2 containing those solvates. The pharmaceutical composition for inhibiting amyloid β production according to any one of claims 1 to 4, comprising a compound in which R ⁵ and R ⁶ are both hydrogen, or a pharmaceutically acceptable salt thereof, or a solvate thereof. The compound according to claim 1, wherein Ak ¹ is a single bond and Ak ² is a single bond or a compound that is substituted or unsubstituted methylene, or a pharmaceutically acceptable salt thereof, or a solvate thereof. A pharmaceutical composition for inhibiting amyloid β production according to any one of the above. -L < ¹ >-contains a compound which is -C (= O) NH- or -NH-C (= O)-, or a pharmaceutically acceptable salt thereof or a solvate thereof. 6. The pharmaceutical composition for inhibiting amyloid β production according to any one of 6.   The pharmaceutical composition for inhibiting amyloid β production according to any one of claims 1 to 7, comprising a compound wherein the A ring is a benzene ring or a pyridine ring, or a pharmaceutically acceptable salt thereof, or a solvate thereof. . n is an integer from 1 to 5;
Wherein at least one R ⁷ is OR ¹⁶ , SR ¹⁷ , or N (R ¹⁸ ) (R ¹⁹ ), wherein R ¹⁶ and R ¹⁷ are each independently substituted or unsubstituted alkyl, substituted or unsubstituted A substituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted carbocyclic group, or a substituted or unsubstituted heterocyclic group; R ¹⁸ and R ¹⁹ are each independently hydrogen, substituted or Unsubstituted alkyl, or substituted or unsubstituted alkenyl, or R ¹⁸ and R ¹⁹ together with the nitrogen atom to which they are attached may form a non-aromatic heterocycle) and other R ⁷ is synonymous with claim 1;
The pharmaceutical composition for inhibiting amyloid β production according to any one of claims 1 to 8, comprising a compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof. ^{-X 1 = X 2 -X 3 =} X 4 - ^{is, -C (R 1) = C} (R 2) -C (R 3) = C (R 4) -, - C (R 1) = N- ^{C (R 3) = C (} R 4) -, or ^{-C (R 1) = C (} R 2) -N = C (R 4) - a and;
R ¹ and R ⁴ are both hydrogen;
R ² and R ³ are each independently OR ¹² , SR ¹³ , N (R ¹⁴ ) (R ¹⁵ ), substituted or unsubstituted pyridyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, substituted Or unsubstituted oxazolyl, or substituted or unsubstituted thiazolyl;
R ¹² and R ¹³ are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted cyclo Is alkenyl;
R ¹⁴ and R ¹⁵ are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted cycloalkenyl, or R ¹⁴ and R ¹⁵ may form a heterocycle together with the nitrogen atom to which they are attached;
R ⁵ and R ⁶ are both hydrogen;
Ak ¹ is a single bond;
Ak ² is a single bond or substituted or unsubstituted methylene;
-L ¹ - is, -C (= O) NH- or -NH-C (= O) - and is,
The A ring is a benzene ring or a pyridine ring;
n is an integer from 1 to 5;
At least one R ⁷ is OR ¹⁶ , SR ¹⁷ , or N (R ¹⁸ ) (R ¹⁹ ), and the substitution positions of R ⁷ and Ak ² are in a para-position in the A ring; R ⁷ is as defined in claim 1;
R ¹⁶ and R ¹⁷ are each independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic group, or substituted or unsubstituted hetero A cyclic group;
R ¹⁸ and R ¹⁹ are each independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkenyl, or R ¹⁸ and R ¹⁹ together with the nitrogen atom to which they are attached are non-aromatic The pharmaceutical composition for amyloid beta production suppression in any one of Claims 1-9 containing the compound which may form a heterocyclic group, or its pharmaceutically acceptable salt, or those solvates.   The pharmaceutical composition for inhibiting amyloid β production according to any one of claims 1 to 10, which is a pharmaceutical composition for inhibiting selective production of amyloid β42.   A method for inhibiting amyloid β production, comprising administering the compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, or a solvate thereof.   The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, or a solvate thereof, which is used for inhibiting amyloid β production. Formula (II):

[Wherein, = X ² -X ³ = is = C (R ² ) -C (R ³ ) =, = NC (R ³ ) =, or = C (R ² ) -N =;
R ² is hydroxy, carboxy, sulfo, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted Alkynyloxy, substituted or unsubstituted carbocyclic oxy, substituted or unsubstituted heterocyclic oxy, mercapto, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted Substituted carbocyclic thio, substituted or unsubstituted heterocyclic thio, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted acyl, substituted or unsubstituted amino, substituted sulfonyl, substituted sulfinyl, substituted or unsubstituted carbamoyl, Replace Or an unsubstituted sulfamoyl, nitro, cyano, substituted or unsubstituted carbocyclic group, or substituted or unsubstituted heterocyclic group;
R ¹ , R ³ , and R ⁴ are each independently hydrogen, halogen, hydroxy, carboxy, sulfo, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted Substituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted carbocyclic oxy, substituted or unsubstituted heterocyclic oxy, mercapto, substituted or unsubstituted alkylthio, substituted or unsubstituted Substituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted carbocyclic thio, substituted or unsubstituted heterocyclic thio, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted acyl, substituted or unsubstituted Amino, substituted sulfonyl, substituted Rufiniru, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, nitro, cyano, a substituted or unsubstituted carbocyclic group or a substituted or unsubstituted heterocyclic group;
R ⁵ represents hydrogen, carboxy, sulfo, substituted or unsubstituted alkyl (excluding alkyl substituted with substituted or unsubstituted aryl), substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted acyl, substituted Sulfonyl, substituted sulfinyl, substituted or unsubstituted carbamoyl, or substituted or unsubstituted sulfamoyl;
R ⁶ is hydrogen, halogen, hydroxy, carboxy, sulfo, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted acyl, substituted sulfonyl, substituted sulfinyl, substituted or unsubstituted amino, substituted Or an unsubstituted carbamoyl, a substituted or unsubstituted sulfamoyl, or a substituted or unsubstituted carbocyclic group;
Ak ¹ is a single bond or a substituted or unsubstituted alkylene having 1 or 2 carbon atoms;
R ⁸ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted acyl;
= ^Y 1 -Y ² = ^{is, = C (R 9A) -C} (R 10A) =, = N-C (R 10A) =, or ^{= C (R} 9A) is -N =;
R ^9A and R ^9B are each independently hydrogen, halogen, hydroxy, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or Unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted carbocyclic oxy, substituted or unsubstituted heterocyclic oxy, mercapto, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted Or unsubstituted alkynylthio, substituted or unsubstituted carbocyclic thio, substituted or unsubstituted heterocyclic thio, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted acyl, substituted or unsubstituted amino, substituted sulfonyl, Substituted sulfinyl, Substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, nitro, cyano, azido, substituted or unsubstituted carbocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group;
One of R ^10A and R ^10B is hydrogen, halogen, hydroxy, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted Alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted carbocyclic oxy, substituted or unsubstituted heterocyclic oxy, mercapto, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted Alkynylthio, substituted or unsubstituted carbocyclic thio, substituted or unsubstituted heterocyclic thio, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted acyl, substituted or unsubstituted amino, substituted sulfonyl, substituted sulfinyl, Replace Or an unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, nitro, cyano, azide, substituted or unsubstituted carbocyclic group or substituted or unsubstituted non-aromatic heterocyclic group, the other being halogen, Hydroxy, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or Unsubstituted carbocyclic oxy, substituted or unsubstituted heterocyclic oxy, mercapto, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted carbocyclic thio, Substituted or unsubstituted heterocyclic ring O, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted acyl, substituted or unsubstituted amino, substituted sulfonyl, substituted sulfinyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, nitro, cyano, azide, A substituted or unsubstituted carbocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group, provided that when = Y ¹ -Y ² = is = C (R ^9A ) -N =, R ^10B is , Halogen, hydroxy, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy Substituted or unsubstituted carbocyclic oxy, substituted or non-substituted Substituted heterocyclic oxy, mercapto, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted carbocyclic thio, substituted or unsubstituted heterocyclic thio, substituted Or unsubstituted alkoxycarbonyl, substituted or unsubstituted acyl, substituted or unsubstituted amino, substituted sulfonyl, substituted sulfinyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, nitro, cyano, azide, substituted or unsubstituted A substituted carbocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group;
R ¹¹ is hydrogen, halogen, hydroxy, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or Unsubstituted alkynyloxy, substituted or unsubstituted acyloxy, substituted or unsubstituted carbocyclic oxy, substituted or unsubstituted heterocyclic oxy, mercapto, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or Unsubstituted alkynylthio, substituted or unsubstituted carbocyclic thio, substituted or unsubstituted heterocyclic thio, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted acyl, substituted or unsubstituted amino, substituted sulfonyl, substituted Sulfi Nyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, nitro, cyano, azide, substituted or unsubstituted carbocyclic group or substituted or unsubstituted non-aromatic heterocyclic group (provided that R ^{When 11} is hydrogen, hydroxy, methoxy, methylthio, methyl, trifluoromethyl, or halogen, neither R ^10A nor R ^10B is hydrogen;
When R ^10A or R ^10B is fluorine, R ¹¹ is

Rather than the group indicated by
R ^9A , R ^9B , R ^10A , R ^10B , and R ¹¹ are not simultaneously fluorine;
When R ^10A or R ^10B is —COOH or —COOMe, R ¹¹ is

Rather than the group indicated by
R ^10A , R ^10B , and R ¹¹ are not simultaneously methoxy;
When R ^10A or R ^10B is methoxy, R ¹¹ is

Rather than the group indicated by
When one of R ^10A or R ^10B is —SO ₂ Me, the other is

Is not a group indicated by
(Wherein the following compounds:

except for. Or a pharmaceutically acceptable salt thereof or a solvate thereof. = ^X 2 -X ³ = ^{is, = C (R 2) -C} (R 3) = or ^{= C (R 2) -N =} ( wherein, ^{R 3} are as defined in claim 14) be ,
R ² is OR ¹² , SR ¹³ , or N (R ¹⁴ ) (R ¹⁵ ) (wherein R ¹² and R ¹³ are each independently hydrogen or substituted or unsubstituted alkyl, substituted or unsubstituted Alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic group, or substituted or unsubstituted heterocyclic group; R ¹⁴ and R ¹⁵ are each independently hydrogen, substituted or unsubstituted An alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted carbocyclic group, or substituted or unsubstituted heterocyclic group, or R ¹⁴ and R ¹⁵ together with the nitrogen atom to which they are attached. 15. The compound according to claim 14, or a pharmaceutically acceptable salt thereof or a solvate thereof, which may form a heterocycle. The compound according to claim 14 or 15, wherein Ak ¹ is a single bond, or a pharmaceutically acceptable salt thereof, or a solvate thereof. One of R ^10A and R ^10B is halogen or substituted or unsubstituted alkyl, and the other is hydrogen, halogen, hydroxy, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted Alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted carbocyclic oxy, substituted or unsubstituted heterocyclic oxy, mercapto, substituted or unsubstituted Alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted carbocyclic thio, substituted or unsubstituted heterocyclic thio, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted acyl , If replacement Is unsubstituted amino, substituted sulfonyl, substituted sulfinyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, nitro, cyano, azide, substituted or unsubstituted carbocyclic group or substituted or unsubstituted non-aromatic A heterocyclic group,
R ¹¹ is OR ¹⁶ , SR ¹⁷ , N (R ¹⁸ ) (R ¹⁹ ) (wherein R ¹⁶ and R ¹⁷ are each independently hydrogen, substituted or unsubstituted alkyl (provided that unsubstituted methyl Substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic group, or substituted or unsubstituted heterocyclic group; R ¹⁸ and R ¹⁹ are each independently Hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkenyl, or R ¹⁸ and R ¹⁹ together with the nitrogen atom to which they are attached may form a heterocycle) Or a compound according to any one of claims 14 to 16, which is an unsubstituted carbocyclic oxyalkyl, or a substituted or unsubstituted heterocyclic oxyalkyl. A pharmaceutically acceptable salt or solvate thereof. The compound according to any one of claims 14 to 17, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R ^10A and R ^10B are each independently halogen or substituted or unsubstituted alkyl. . R ¹¹ is OR ¹⁶ , SR ¹⁷ , N (R ¹⁸ ) (R ¹⁹ ) (wherein R ¹⁶ , R ¹⁷ and R ¹⁹ are each independently alkyl substituted with a substituted or unsubstituted carbocycle. A substituted or unsubstituted heterocycle substituted alkyl, a substituted or unsubstituted carbocyclic group, or a substituted or unsubstituted heterocyclic group, R ¹⁸ is hydrogen, substituted or unsubstituted alkyl, Substituted or unsubstituted cycloalkyl, or substituted or unsubstituted acyl, substituted or unsubstituted carbocyclic oxyalkyl, or substituted or unsubstituted heterocyclic oxyalkyl). The compound according to any one of the above, or a pharmaceutically acceptable salt thereof, or a solvate thereof. Formula (III):

[Wherein, = X ² -X ³ = is = C (R ² ) -C (R ³ ) =, = NC (R ³ ) =, or = C (R ² ) -N =;
When = X ² -X ³ = is = C (R ² ) -C (R ³ ) =, either R ² or R ³ is substituted or unsubstituted pyridyl, substituted or unsubstituted imidazolyl, substituted Or unsubstituted pyrazolyl, substituted or unsubstituted oxazolyl, or substituted or unsubstituted thiazolyl, the other being hydrogen, halogen, hydroxy, carboxy, sulfo, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, Substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted carbocyclic oxy, substituted or unsubstituted heterocyclic oxy, mercapto, Substituted or unsubstituted alkylthio, substituted or unsubstituted alkenyl Thio, substituted or unsubstituted alkynylthio, substituted or unsubstituted carbocyclic thio, substituted or unsubstituted heterocyclic thio, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted acyl, substituted or unsubstituted amino, Substituted sulfonyl, substituted sulfinyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, nitro, cyano, substituted or unsubstituted carbocyclic group, or substituted or unsubstituted heterocyclic group;
When = X ² -X ³ === N—C (R ³ ) =, or = C (R ² ) —N =, R ² or R ³ is substituted or unsubstituted pyridyl, substituted or unsubstituted Imidazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted oxazolyl, or substituted or unsubstituted thiazolyl,
R ¹ and R ⁴ are each independently hydrogen, halogen, hydroxy, carboxy, sulfo, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, Substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted carbocyclic oxy, substituted or unsubstituted heterocyclic oxy, mercapto, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio Substituted or unsubstituted alkynylthio, substituted or unsubstituted carbocyclic thio, substituted or unsubstituted heterocyclic thio, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted acyl, substituted or unsubstituted amino, substituted Sulfonyl, substituted sulfini , Substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, nitro, cyano, a substituted or unsubstituted carbocyclic group or a substituted or unsubstituted heterocyclic group;
R ⁵ is hydrogen, carboxy, sulfo, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted acyl, substituted sulfonyl, substituted sulfinyl, substituted or unsubstituted carbamoyl, or substituted or unsubstituted Of sulfamoyl;
R ⁶ is hydrogen, halogen, hydroxy, carboxy, sulfo, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted acyl, substituted sulfonyl, substituted sulfinyl, substituted or unsubstituted amino, substituted Or an unsubstituted carbamoyl, a substituted or unsubstituted sulfamoyl, or a substituted or unsubstituted carbocyclic group;
Ak ¹ and Ak ² are each independently a single bond or a substituted or unsubstituted alkylene having 1 or 2 carbon atoms;
R ⁸ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted acyl;
A ring is a benzene ring, pyridine ring, pyridazine ring, pyrimidine ring, cyclohexane ring, cyclohexene ring, tetrahydropyran ring, dihydropyridine ring, tetrahydropyridine ring, piperidine ring, piperazine ring, or morpholine ring;
Each R ⁷ independently represents halogen, hydroxy, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy; Substituted or unsubstituted alkynyloxy, substituted or unsubstituted acyloxy, substituted or unsubstituted carbocyclic oxy, substituted or unsubstituted heterocyclic oxy, mercapto, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio Substituted or unsubstituted alkynylthio, substituted or unsubstituted carbocyclic thio, substituted or unsubstituted heterocyclic thio, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted acyl, substituted or unsubstituted amino, substituted Sulfonyl, substituted Rufinyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, nitro, cyano, azide, substituted or unsubstituted carbocyclic group, or substituted or unsubstituted non-aromatic heterocyclic group;
n is an integer from 0 to 5 (where A ring is not an unsubstituted pyridine ring;
When Ak ² is —CH ₂ —CH ₂ —, the A ring is not an unsubstituted morpholine ring;
Ring A is

is not. )] Or a pharmaceutically acceptable salt thereof or a solvate thereof. = X ² -X ³ = is = C (R ² ) -C (R ³ ) =, and either R ² or R ³ is substituted or unsubstituted pyridyl, substituted or unsubstituted imidazolyl, or Substituted or unsubstituted pyrazolyl, the other being OR ¹² , SR ¹³ , or N (R ¹⁴ ) (R ¹⁵ ), wherein R ¹² and R ¹³ are each independently hydrogen, substituted or unsubstituted Alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic group, or substituted or unsubstituted heterocyclic group; R ¹⁴ and R ¹⁵ are each independently Hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted carbocyclic group, or substituted or unsubstituted heterocyclic group, or R The compound according to claim 20, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein ¹⁴ and R ¹⁵ may form a heterocycle together with the nitrogen atom to which they are bonded. . The compound according to claim 20 or 21, or a pharmaceutically acceptable salt or solvate thereof, wherein Ak ¹ is a single bond and Ak ² is substituted or unsubstituted methylene.   The compound according to any one of claims 20 to 22, or a pharmaceutically acceptable salt or solvate thereof, wherein the A ring is a benzene ring or a pyridine ring. R ⁵ and R ⁶ are both hydrogen, the compound, or a pharmaceutically acceptable salt or solvate thereof according to any one of claims 14 to 23. The compound according to any one of claims 14 to 24, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R ⁸ is hydrogen. Formula (II):

[Wherein, = X ² -X ³ = is = C (H) -C (R ³ ) = or = C (H) -N =,
R ¹ , R ³ , and R ⁴ are each independently hydrogen, halogen, hydroxy, carboxy, sulfo, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted Substituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted carbocyclic oxy, substituted or unsubstituted heterocyclic oxy, mercapto, substituted or unsubstituted alkylthio, substituted or unsubstituted Substituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted carbocyclic thio, substituted or unsubstituted heterocyclic thio, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted acyl, substituted or unsubstituted Amino, substituted sulfonyl, substituted Rufiniru, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, nitro, cyano, a substituted or unsubstituted carbocyclic group or a substituted or unsubstituted heterocyclic group;
R ⁵ represents hydrogen, carboxy, sulfo, substituted or unsubstituted alkyl (excluding alkyl substituted with substituted or unsubstituted aryl), substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted acyl, substituted Sulfonyl, substituted sulfinyl, substituted or unsubstituted carbamoyl, or substituted or unsubstituted sulfamoyl;
R ⁶ is hydrogen, halogen, hydroxy, carboxy, sulfo, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted acyl, substituted sulfonyl, substituted sulfinyl, substituted or unsubstituted amino, substituted Or unsubstituted carbamoyl, or substituted or unsubstituted sulfamoyl;
Ak ¹ is a single bond;
R ⁸ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted acyl;
= ^Y 1 -Y ² = ^{is, = C (R 9A) -C} (R 10A) =, = N-C (R 10A) =, or ^{= C (R} 9A) is -N =;
R ^9A and R ^9B are each independently hydrogen, halogen, hydroxy, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or Unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted carbocyclic oxy, substituted or unsubstituted heterocyclic oxy, mercapto, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted Or unsubstituted alkynylthio, substituted or unsubstituted carbocyclic thio, substituted or unsubstituted heterocyclic thio, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted acyl, substituted or unsubstituted amino, substituted sulfonyl, Substituted sulfinyl, Substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, nitro, cyano, azido, substituted or unsubstituted carbocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group;
R ^10A and R ^10B are each independently halogen or substituted or unsubstituted alkyl;
R ¹¹ is OR ¹⁶ , SR ¹⁷ , N (R ¹⁸ ) (R ¹⁹ ) (wherein R ¹⁶ , R ¹⁷ and R ¹⁹ are each independently alkyl substituted with a substituted or unsubstituted carbocycle. A substituted or unsubstituted heterocycle substituted alkyl, a substituted or unsubstituted carbocyclic group, or a substituted or unsubstituted heterocyclic group, R ¹⁸ is hydrogen, substituted or unsubstituted alkyl, Substituted or unsubstituted cycloalkyl, substituted or unsubstituted acyl, substituted or unsubstituted carbocyclic oxyalkyl, or substituted or unsubstituted heterocyclic oxyalkyl)]
Or a pharmaceutically acceptable salt or solvate thereof. Formula (I):

(In the formula, Ak ¹ and Ak ² are each independently a single bond; —L ¹ — is —C (═O) —; the A ring is a piperidine ring or a piperazine ring (provided that , atom on a ring bonded to Ak ² is always nitrogen ^{atom), - X 1 = X 2} -X 3 = X 4 -, R 1, R 2, R 3, R 4, R 5, R 6 , R ⁷ , and n are as defined in claim 1)
Or a pharmaceutically acceptable salt or solvate thereof.   A pharmaceutical composition comprising the compound according to any one of claims 14 to 27, or a pharmaceutically acceptable salt thereof, or a solvate thereof.   A pharmaceutical composition for inhibiting amyloid β production, comprising the compound according to any one of claims 14 to 27, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

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