JP2010208947A - Quinolone derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new compound which is a renin inhibitor and has excellent renin-inhibiting activity. <P>SOLUTION: There is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof. Therein, R<SP>1a</SP>is alkyl which may be substituted, or the like; R<SP>1b</SP>, R<SP>1c</SP>and R<SP>1d</SP>are each independently identically or differently H, halogen atom, OH, formyl, carboxy, cyano, alkyl which may be substituted, or the like; R<SP>2</SP>is alkyl which may be substituted, or the like; R<SP>3a</SP>, R<SP>3b</SP>, R<SP>3c</SP>and R<SP>3d</SP>are each independently identically or differently a group: -A-B (wherein, A is a single bond or the like; B is H, alkyl which may be substituted, or the like), or the like; (s) is 0 or the like. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a quinolone derivative useful as a medicine. More specifically, the present invention relates to a quinolone derivative that is effective as a renin inhibitor. Furthermore, the present invention relates to an antihypertensive agent comprising a quinolone derivative effective as a renin inhibitor as an active ingredient.

The renin-angiotensin (RA) system is an important hormonal system for maintaining blood pressure and electrolyte balance in the body, and plays an important role in the onset and progression of cardiovascular diseases such as hypertension, congestive heart failure, and kidney damage. Yes.
Renin, an important component of the RA system, is an aspartic protease that is secreted mainly into the blood from the kidney, specifically decomposing angiotensinogen produced in the liver and producing angiotensin I. Angiotensin I is converted to angiotensin II by an angiotensin converting enzyme (ACE) present in lungs and vascular endothelial cells. Angiotensin II contracts blood vessels and stimulates the adrenal glands to stimulate aldosterone secretion. Aldosterone acts on the kidneys to retain sodium and excrete potassium. These cascades lead to an increase in blood pressure (Non-Patent Document 1).

  In recent years, RA-related components are also provided in peripheral tissues such as the heart, blood vessels, kidneys, adrenal glands, and fats, and central tissues, and (pro) renin receptors are activated as a new component. (Non-patent Document 2), the importance of the local (tissue) RA system is being recognized. In contrast to the circulatory RA system related to short-term circulatory regulation, the tissue RA system induces long-term remodeling of various organs such as the heart, kidney, and blood vessels, thereby causing organs such as cardiac hypertrophy, arteriosclerosis, and kidney damage. The possibility of causing a failure has been pointed out (Non-patent Document 3).

Drugs that suppress the RA system include ACE inhibitors and angiotensin II receptor antagonists (ARBs), but these drugs (especially the former) are not only high blood pressure but also cardiovascular systems such as heart failure and diabetic nephropathy It has proven useful as a therapeutic agent for diseases and kidney diseases, and is widely applied clinically (Non-patent Documents 4 and 5).
There are multiple steps to suppress the RA system. Among them, renin is located in the uppermost stream of the RA system and controls the cascade, so inhibiting this is a theoretically very attractive approach. (Non-Patent Document 6, Non-Patent Document 7). In fact, aliskiren, a renin inhibitor developed in recent years, significantly suppresses plasma renin activity in clinical trials targeting hypertensive patients, and exhibits an excellent antihypertensive effect comparable to other RA inhibitors. It has been confirmed (Non-patent document 8, Non-patent document 9, Non-patent document 10).

  Various renin inhibitors have been reported. For example, Patent Document 1 and Patent Document 2 report that derivatives having a piperidine ring are effective as renin inhibitors. In Patent Document 3, it is reported that a derivative having a pyrrolidine ring is effective as a renin inhibitor. The compounds disclosed in these documents are structurally characterized by a partial structure in which the 3-position of the piperidine ring and pyrrolidine ring is bonded to an amino group via a carbonyl group or a methylene chain. However, it has not been known so far that a group of compounds having 3- (quinolonecarbonylamino) piperidine as a basic skeleton is useful as a renin inhibitor.

Nat Rev Drug Discov. 1 (8): p.621-36 (2002) Curr Hypertens Rep. 6 (2): p.129-32 (2004) Physiol. Rev. 86: p.747-803, (2006) Curr Diab Rep. 6 (1): p.8-16, (2006) J Hypertens Suppl. 23 (1): S9-17, (2005) J Exp Med. 106 (3): p.439-53, (1957) J Am Soc Nephrol 16: p.592-599, (2005) Hypertension 42 (6): p.1137-43, (2003) Circulation 111 (8): p.1012-8, (2005) J Hypertens. 24 (Suppl 4): S82.Abstract P4.269, (2006)

International Publication No. 06/069788 Pamphlet International Publication No. 06/094763 Pamphlet International Publication No. 06/066896 Pamphlet

  An object of the present invention is to provide a novel compound having an excellent renin inhibitory activity.

  As a result of intensive studies to achieve the above-mentioned problems, the present inventors have shown that the following compound or a pharmaceutically acceptable salt thereof (hereinafter sometimes abbreviated as the present compound if necessary) has an excellent renin inhibitory action. As a result, the present invention has been completed.

That is, the present invention is as follows.
Item 1: A compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

[Wherein, R ^1a represents an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, or an optionally substituted cycloalkenyl group. Is;
R ^1b , R ^1c and R ^1d are each independently the same or different and are each a hydrogen atom, a halogen atom, a hydroxyl group, a formyl group, a carboxy group, a cyano group, an optionally substituted alkyl group or an optionally substituted group. Alkenyl group, optionally substituted alkynyl group, optionally substituted cycloalkyl group, optionally substituted cycloalkenyl group, optionally substituted aryl group, optionally substituted aralkyl group, optionally substituted Heteroaryl group, optionally substituted heteroarylalkyl group, optionally substituted saturated heterocyclic group, optionally substituted alkylthio group, optionally substituted alkylsulfinyl group, optionally substituted alkylsulfonyl group Optionally substituted arylthio group, optionally substituted arylsulfinyl group, optionally substituted aryls A sulfonyl group, an optionally substituted alkoxy group, an optionally substituted alkynyloxy group, an optionally substituted cycloalkyloxy group, an optionally substituted aryloxy group, an optionally substituted aralkyloxy group, a substituted An optionally substituted heteroaryloxy group, an optionally substituted heteroarylalkyloxy group, an optionally substituted amino group, an optionally substituted aminocarbonyl group, an optionally substituted aminosulfonyl group, an optionally substituted An alkoxycarbonyl group, an optionally substituted cycloalkyloxycarbonyl group, an optionally substituted alkylcarbonyl group, an optionally substituted cycloalkylcarbonyl group, an optionally substituted arylcarbonyl group, or an optionally substituted A teloarylcarbonyl group;
R ² represents an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, or an optionally substituted A good aryl group, an optionally substituted aralkyl group, or an optionally substituted heteroaryl group;
R ^3a , R ^3b , R ^3c and R ^3d are each independently the same or different and are each a halogen atom, a cyano group, or a group: -AB
(Wherein, A represents a single _{bond, - (CH 2) s O} -, - (CH 2) s N (R 4) -, - (CH 2) s SO 2 -, - (CH 2) s CO- _{, - (CH 2) s COO} -, - (CH 2) s N (R 4) CO -, - (CH 2) s N (R 4) SO 2 -, - (CH 2) s N (R 4) ^{_{COO -, - (CH 2)}} s OCON (R 4) -, - (CH 2) s O-CO -, - (CH 2) s CON (R 4) -, - (CH 2) s N (R 4 ) CON (R ⁴ ) —, or — (CH ₂ ) _s SO ₂ N (R ⁴ ) —,
B is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, a substituted An optionally substituted aryl group, an optionally substituted aralkyl group, an optionally substituted heteroaryl group, an optionally substituted heteroarylalkyl group, or an optionally substituted saturated heterocyclic group (A is — _{^{(CH 2) s N (R}} 4) -, - (CH 2) s OCON (R 4) -, - (CH 2) s CON (R 4) -, - (CH 2) s N (R 4) CON In the case of (R ⁴ ) — and — (CH ₂ ) _s SO ₂ N (R ⁴ ) —, R ⁴ and B may be bonded together to form a ring. Or any two of R ^3a , R ^3b , R ^3c and R ^3d are hydrogen atoms and the remaining two together form a bridged ring with the piperidine ring;
R ⁴ represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, a substituted aryl group which may or substituted also to good heteroaryl group;
s is 0, 1 or 2. ]

Item 2: R ^1a is an optionally substituted C _1-6 alkyl group, an optionally substituted C _2-6 alkenyl group, an optionally substituted C _3-6 alkynyl group, an optionally substituted C _{3 A -10} cycloalkyl group, or an optionally substituted _C5-6 cycloalkenyl group;
R ^1b , R ^1c and R ^1d are each independently the same or different and are each a hydrogen atom, a halogen atom, a hydroxyl group, a formyl group, a carboxy group, a cyano group, an optionally substituted C _1-6 alkyl group or a substituted group. An optionally substituted C _2-6 alkenyl group, an optionally substituted C _3-6 alkynyl group, an optionally substituted C _3-10 cycloalkyl group, an _optionally substituted C _5-6 cycloalkenyl group, a substituted An _optionally substituted C _6-10 aryl group, an _optionally substituted C _7-14 aralkyl group, an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group, optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl C _1-4 alkyl group, optionally substituted 5- or 6-membered saturated heterocyclic group, optionally substituted C _1-6 alkylthio group Replaced Is a _{C 1-6} alkylsulfinyl group optionally, optionally substituted _{C 1-6} alkylsulfonyl group, optionally substituted _{C 6-10} arylthio group, optionally substituted _{C 6-10} arylsulfinyl group, C _6-10 arylsulfonyl group which may be substituted, C _1-6 alkoxy group which may be substituted, C _3-6 alkynyloxy group which may be substituted, C _3-10 cycloalkyloxy which may be substituted Group, optionally substituted C _6-10 aryloxy group, _optionally substituted C _7-14 aralkyloxy group, optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryloxy group An optionally substituted mono- or polycyclic heteroarylalkyloxy group, an optionally substituted amino group, an optionally substituted aminocarbo Nyl group, optionally substituted aminosulfonyl group, optionally substituted C _1-4 alkoxycarbonyl group, optionally substituted C _3-10 cycloalkyloxycarbonyl group, optionally substituted C _1-4 alkyl To a carbonyl group, an optionally substituted C _3-10 cycloalkylcarbonyl group, an optionally substituted C _6-10 arylcarbonyl group, or an optionally substituted 5- to 10-membered monocyclic or polycyclic Item 2. The compound according to Item 1, which is a teloarylcarbonyl group, or a pharmaceutically acceptable salt thereof.

Item 3: The compound according to Item 1 or 2, wherein R ^1a is an optionally substituted C _1-6 alkyl group, or an optionally substituted C _3-6 alkynyl group, or a pharmaceutically acceptable salt thereof. .

Item 4: The compound according to Item 3, or a pharmaceutically acceptable salt thereof, wherein R ^1a is an optionally substituted C _1-6 alkyl group.

Item 5: The compound according to Item 4, or a pharmaceutically acceptable salt thereof, wherein R ^1a is a C _1-6 alkyl group which may be substituted with C _1-4 alkoxy.

Item 6: The compound according to Item 5, or a pharmaceutically acceptable salt thereof, wherein R ^1a is 4-methoxybutyl.

Item 7: R ^1b , R ^1c and R ^1d are a hydrogen atom, a halogen atom, a carboxy group, a cyano group, an optionally substituted C _1-6 alkyl group, or an _optionally substituted 5- to 10-membered monocycle Formula or polycyclic heteroaryl group, C _1-6 alkylsulfonyl group which may be substituted, C _6-10 arylsulfonyl group which may be substituted, C _1-6 alkoxy group which may be substituted, substituted _May be a C _3-10 cycloalkyloxy group, an optionally substituted C _6-10 aryloxy group, an _optionally substituted C _7-14 aralkyloxy group, an optionally substituted amino group, an optionally substituted aminocarbonyl group, an optionally substituted aminosulfonyl group, a compound according to any one of claims 1 to claim 6 is optionally substituted C _1-4 alkoxycarbonyl be group, or its Pharmaceutically acceptable salts.

Item 8: R ^1b , R ^1c and R ^1d are each independently the same or different and are each a hydrogen atom, a halogen atom, an optionally substituted C _1-6 alkyl group, or an optionally substituted C _{1 1-} Item 8. The compound according to Item 7, which is a ₆ alkoxy group, or a pharmaceutically acceptable salt thereof.

Item 9: The compound according to Item 8, or a pharmaceutically acceptable salt thereof, wherein R ^1b , R ^1c and R ^1d are each independently the same and a hydrogen atom.

Item 10: R ² is an optionally substituted C _1-6 alkyl group, an optionally substituted C _2-6 alkenyl group, an optionally substituted C _3-6 alkynyl group, an optionally substituted C _{3 A -10} cycloalkyl group, an optionally substituted C _5-6 cycloalkenyl group, an optionally substituted C _6-10 aryl group, an optionally substituted C _7-14 aralkyl group, or an optionally substituted 5 Item 10. The compound according to any one of Items 1 to 9, or a pharmaceutically acceptable salt thereof, which is a 10-membered monocyclic or polycyclic heteroaryl group.

Item 11: The compound according to Item 10, or a pharmaceutically acceptable salt thereof, wherein R ² is an optionally substituted C _1-6 alkyl group, or an optionally substituted C _3-10 cycloalkyl group.

Item 12: The compound according to Item 11, or a pharmaceutically acceptable salt thereof, wherein R ² is an optionally substituted C _1-6 alkyl group.

Item 13: The compound according to Item 12, or a pharmaceutically acceptable salt thereof, wherein R ² is an isopropyl group.

Item 14: R ⁴ is a hydrogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C _3-10 cycloalkyl group, an optionally substituted C _6-10 aryl group, or a substituted atom Item 14. The compound according to any one of Items 1 to 13, which is a 5- to 10-membered monocyclic or polycyclic heteroaryl group, or a pharmaceutically acceptable salt thereof.

Item 15: R ^3a , R ^3b , R ^3c and R ^3d are each independently the same or different and are each a halogen atom, a cyano group, or a group: -AB
(Wherein, A represents a single _{bond, - (CH 2) s O} -, - (CH 2) s N (R 4) -, - (CH 2) s SO 2 -, - (CH 2) s CO- _{, - (CH 2) s COO} -, - (CH 2) s N (R 4) CO -, - (CH 2) s N (R 4) SO 2 -, - (CH 2) s N (R 4) ^{_{COO -, - (CH 2)}} s OCON (R 4) -, - (CH 2) s O-CO -, - (CH 2) s CON (R 4) -, - (CH 2) s N (R 4 ) CON (R ⁴ ) —, or — (CH ₂ ) _s SO ₂ N (R ⁴ ) —,
B represents a hydrogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C _2-6 alkenyl group, an optionally substituted C _3-6 alkynyl group, an optionally substituted C _{3-3- 10} cycloalkyl group, optionally substituted C _5-6 cycloalkenyl group, _optionally substituted C _6-10 aryl group, _optionally substituted C _7-14 aralkyl group, optionally substituted 5 membered to A 10-membered monocyclic or polycyclic heteroaryl group, an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl C _1-4 alkyl group, or an optionally substituted 5-membered or A 6-membered saturated heterocyclic group (A is — (CH ₂ ) _s N (R ⁴ ) —, — (CH ₂ ) _s OCON (R ⁴ ) —, — (CH ₂ ) _s CON (R ⁴ ) ^{_{-, - (CH 2) s}} N (R 4) CON (R 4) -, and _{- (CH 2) s SO 2} N (R 4) - in the case of may be bonded ^{R 4} and B together form a ring).. Or any two of R ^3a , R ^3b , R ^3c and R ^3d are hydrogen atoms and the remaining two together form a bridged ring with the piperidine ring, and s and R ⁴ are the term Item 15. The compound according to any one of Items 1 to 14, which is the same as 1, or a pharmaceutically acceptable salt thereof.

Item 16: R ^3a , R ^3b , R ^3c and R ^3d are each independently the same, and the group: -AB
(Here, A is a single bond, B is a hydrogen atom, The compound or its pharmaceutically acceptable salt as described in any one of claim | item 1 -14 which is a hydrogen atom.)

Item 17: A compound represented by formula (II) or a pharmaceutically acceptable salt thereof.

[Wherein, R ^12a is an optionally substituted C _1-6 alkyl group, an optionally substituted C _2-6 alkenyl group, an optionally substituted C _3-6 alkynyl group, an optionally substituted C _{A 3-10} cycloalkyl group, or an optionally substituted C _5-6 cycloalkenyl group;
R ^12b , R ^12c and R ^12d are a hydrogen atom, a halogen atom, a carboxy group, a cyano group, an optionally substituted C _1-6 alkyl group, an optionally substituted 5 to 10 membered monocyclic or polyvalent heteroaryl group, optionally substituted C _1-6 alkylsulfonyl group, optionally substituted C _6-10 arylsulfonyl group, optionally substituted C _1-6 alkoxy group, an optionally substituted C _3-6 cycloalkyloxy group, C _6-10 aryloxy group which may be substituted, C _7-14 aralkyloxy group which may be substituted, amino group which may be substituted, aminocarbonyl group which may be substituted , Optionally substituted aminosulfonyl group, optionally substituted C _1-4 alkoxycarbonyl group;
R ²² is an optionally substituted C _1-6 alkyl group, or an optionally substituted C _3-6 cycloalkyl group;
R ^32a , R ^32b , R ^32c and R ^32d are each independently the same or different and are each a halogen atom, a cyano group or a group: —A ² —B ²
(Wherein, ^{A 2} is a single _{bond, - (CH 2) s2 O} -, - (CH 2) s N (R 42) -, - (CH 2) s2 SO 2 -, - (CH 2) s2 CO _{-, - (CH 2) s2} COO -, - (CH 2) s2 N (R 42) CO -, - (CH 2) s2 N (R 42) SO 2 -, - (CH 2) s2 N (R 42 _{^{) COO -, - (CH 2}} ) s2 OCON (R 42) -, - (CH 2) s2 O-CO -, - (CH 2) s2 CON (R 42) -, - (CH 2) s2 N (R ^{42) CON (R 42) -} , or _{- (CH 2) s2 SO 2} N (R 42) - and is,
B ² represents a hydrogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C _2-6 alkenyl group, an optionally substituted C _3-6 alkynyl group, or an optionally substituted C _{3. A -6} cycloalkyl group, an _optionally substituted C _5-6 cycloalkenyl group, an _optionally substituted C _6-10 aryl group, an _optionally substituted C _7-14 aralkyl group, an optionally substituted 5 member A 10-membered monocyclic or polycyclic heteroaryl group, an optionally substituted 5-membered monocyclic or polycyclic heteroaryl C _1-4 alkyl group, or an optionally substituted 5-membered or a 6-membered to saturation is heterocyclic group (a is _{^{- (CH 2) s2 N (}} R 42) -, - (CH 2) s2 OCON (R 42) -, - (CH 2) s2 CON (R 42 _{) -, - (CH 2)} s2 N (R 42 CON ^{(R 42)} -, and _{- (CH 2) s2 SO 2} N (R 42) - in the case of ^may be attached ^{R 42} and B together form a ring).. Or any two of R ^32a , R ^32b , R ^32c and R ^32d are hydrogen atoms and the remaining two together form a bridged ring with the piperidine ring;
R ⁴² is a hydrogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C _3-6 cycloalkyl group, an optionally substituted C _6-10 aryl group, or an optionally substituted R ^42. A 5- to 10-membered monocyclic or polycyclic heteroaryl group;
s ₂ is 0, 1 or 2. ]

Item 18: R ^12a is optionally substituted with a fluorine atom or C _1-4 alkoxy, C _3-6 cycloalkyl, C _3-6 cycloalkyl, or C _1-4 alkoxy optionally substituted with C _1-4 1 selected from the group consisting of alkoxy, hydroxyl group, trifluoromethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, C _1-4 alkylcarbonylamino, C _1-4 alkoxycarbonylamino, and C _3-6 cycloalkoxy Item 18. The compound according to Item 17, or a pharmaceutically acceptable salt thereof, which is an optionally substituted C _1-6 alkyl group substituted with a group, or a C _3-6 alkynyl group.

Item 19: The compound according to Item 18 or a pharmaceutically acceptable salt thereof, wherein R ^12a is an optionally substituted C _1-6 alkyl group substituted with C _1-4 alkoxy.

Item 20: The compound according to Item 19, or a pharmaceutically acceptable salt thereof, wherein R ^12a is 4-methoxybutyl.

Item 21: R ^12b , R ^12c and R ^12d are each independently the same or different and are each a hydrogen atom, a halogen atom, an optionally substituted C _1-6 alkyl group, or an optionally substituted C _{1 1-} Item 21. The compound or a pharmaceutically acceptable salt thereof according to any one of Items 17 to 20, which is a ₆ alkoxy group.

Item 22: The compound according to Item 21, or a pharmaceutically acceptable salt thereof, wherein R ^12b , R ^12c and R ^12d are each independently the same and a hydrogen atom.

Item 23: The compound according to any one of Items 17 to 22, wherein R ²² is an optionally substituted C _1-6 alkyl group, or an optionally substituted C _3-6 cycloalkyl group, or Its pharmaceutically acceptable salt.

Item 24: The compound according to Item 23 or a pharmaceutically acceptable salt thereof, wherein R ²² is an optionally substituted C _1-6 alkyl group.

Item 25: The compound according to Item 24, or a pharmaceutically acceptable salt thereof, wherein R ²² is an isopropyl group.

Item 26: R ^32a , R ^32b and R ^32d are each independently the same and are the group: —A ² —B ² (where A ² is a single bond, and B ² is a hydrogen atom) .);
R ^32c is a group: -A ² -B ² (wherein A ² is a single bond, B ² is a hydrogen atom, an _optionally substituted C _6-10 aryl group, an _optionally substituted C The compound according to any one of items 17 to 25, which is a _7-14 aralkyl group, or a 5- to 10-membered monocyclic or polycyclic heteroaryl group which may be substituted; or Its pharmaceutically acceptable salt.

Item 27: R ^32c is a group: -A ² -B ² (wherein A ² is a single bond and B ² is an optionally substituted C _6-10 aryl group). 26, or a pharmaceutically acceptable salt thereof.

Item 28: R ^32a , R ^32c and R ^32d are each independently the same and are the group: —A ² —B ² (where A ² is a single bond, and B ² is a hydrogen atom) .);
R ^{32 b} is a group: ^{-A 2} -B 2 (wherein, ^{A 2} is a single _{bond, - (CH 2) s2 O} -, - (CH 2) s2 N (R 42) -, - (CH 2) ^{_{s2 COO -, - (CH 2}} ) s2 N (R 42) CO -, - (CH 2) s2 N (R 42) SO 2 -, - (CH 2) s2 N (R 42) COO -, - (CH _{^{2) s2 OCON (R 42)}} -, - (CH 2) s2 CON (R 42) -, - (CH 2) s2 N (R 42) CON (R 42) -, or _{- (CH 2)} s2 SO ₂ N (R ⁴² )-
B ² represents a hydrogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C _3-6 cycloalkyl group, an _optionally substituted C _6-10 aryl group _, or an _optionally substituted C _{A 7-14} aralkyl group, an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group, or an optionally substituted 5-membered or 6-membered saturated heterocyclic group (A ² There _{^{- (CH 2) s2 N (}} R 42) -, - (CH 2) s2 OCON (R 42) -, - (CH 2) s2 CON (R 42) -, - (CH 2) s2 N (R 42 ) CON ^{(R 42)} -, or _{- (CH 2) s2 SO 2} N (R 42) - in the case of ^{combines R 42} and ^{B 2} together may form a ring). . The compound according to any one of Items 17 to 25, or a pharmaceutically acceptable salt thereof.

Claim ^{29: A 2} in the ^{R 32 b} is a single _{bond, - (CH 2) s2 O} -, - (CH 2) s2 N (R 42) -, - (CH 2) s2 N (R 42) CO -, - _{^{(CH 2) s2 N (R}} 42) SO 2 -, - (CH 2) s2 N (R 42) COO -, - (CH 2) s2 OCON (R 42) -, or _{- (CH 2)} s2 N ( The compound according to Item 28, which is R ⁴² ) CON (R ⁴² ) —, or a pharmaceutically acceptable salt thereof.

Item 30: R ^32a , R ^32b and R ^32c are each independently the same and are the group: —A ² —B ² (where A ² is a single bond, and B ² is a hydrogen atom) .);
R ^32d is a group: ^{-A 2} -B 2 (wherein, ^{A 2} is a single _{bond, - (CH 2) s2 O} -, - (CH 2) s2 N (R 42) -, - (CH 2) ^{_{s2 COO -, - (CH 2}} ) s2 N (R 42) CO -, - (CH 2) s2 N (R 42) SO 2 -, - (CH 2) s2 N (R 42) COO -, - (CH _{^{2) s2 OCON (R 42)}} -, - (CH 2) s2 CON (R 42) -, - (CH 2) s2 N (R 42) CON (R 42) -, or _{- (CH 2)} s2 SO ₂ N (R ⁴² )-
B ² represents a hydrogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C _3-6 cycloalkyl group, an _optionally substituted C _6-10 aryl group _, or an _optionally substituted C _{A 7-14} aralkyl group, an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group, or an optionally substituted 5- or 6-membered saturated heterocyclic group (A ^d2 There _{^{- (CH 2) s2 N (}} R 42) -, - (CH 2) s2 OCON (R 42) -, - (CH 2) s2 CON (R 42) -, - (CH 2) s2 N (R 42 ) CON ^{(R 42)} -, or _{- (CH 2) s2 SO 2} N (R 42) - in the case of ^{combines R 42} and ^{B 2} together may form a ring). . The compound according to any one of Items 17 to 25, or a pharmaceutically acceptable salt thereof.

Claim ^{31: A 2} in the ^{R 32d} is a single _{bond, - (CH 2) s2 O} -, - (CH 2) s2 N (R 42) -, - (CH 2) s2 N (R 42) CO -, - _{^{(CH 2) s2 N (R}} 42) SO 2 -, - (CH 2) s2 N (R 42) COO -, - (CH 2) s2 OCON (R 42) -, or _{- (CH 2)} s2 N ( Item 30. The compound according to Item 30, which is R ⁴² ) CON (R ⁴² ) —, or a pharmaceutically acceptable salt thereof.

Item 32: R ^32a , R ^32b , R ^32c and R ^32d are each independently the same and are the group: —A ² —B ² (wherein A ² is a single bond, and B ² is hydrogen The compound according to any one of Items 17 to 25, or a pharmaceutically acceptable salt thereof.

Item 33: A pharmaceutical comprising the compound according to any one of Items 1 to 32 or a pharmaceutically acceptable salt thereof as an active ingredient.

Item 34: A renin inhibitor comprising the compound according to any one of Items 1 to 32 or a pharmaceutically acceptable salt thereof as an active ingredient.

Item 35: A therapeutic agent for hypertension comprising the compound according to any one of Items 1 to 32 or a pharmaceutically acceptable salt thereof as an active ingredient.

Item 36: Use of the compound according to any one of Items 1 to 32 or a pharmaceutically acceptable salt thereof for the manufacture of a renin inhibitor.

Item 37: Use of the compound according to any one of Items 1 to 32 or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic agent for hypertension.

Item 38: A method for treating hypertension, comprising administering an effective amount of the compound according to any one of Items 1 to 32 or a pharmaceutically acceptable salt thereof to a patient in need of treatment.

  Hereinafter, the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof is collectively referred to as “the compound of the present invention” as necessary.

  The compound of the present invention has excellent renin inhibitory activity and is useful as a therapeutic agent for hypertension.

The present invention is described in further detail below. In the present specification, the number of carbons in the definition of “substituent” may be expressed as “C _1-6 ”, for example. Specifically, the notation “C _1-6 alkyl” is synonymous with an alkyl group having 1 to 6 carbon atoms.
In this specification, the term “group” means a monovalent group. For example, “alkyl group” means a monovalent saturated hydrocarbon group. In addition, in the description of substituents in this specification, the term “group” may be omitted.
The number of substituents in the group defined as “optionally substituted” or “substituted” is not particularly limited as long as substitution is possible, and is 1 or more. In addition, unless otherwise specified, the description of each group also applies when the group is a part of another group or a substituent.

  Examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

“Alkyl group” means a straight-chain or branched saturated hydrocarbon group. For example, “C _1-6 alkyl group” and the like are preferable, and “C _1-4 alkyl group” and the like are preferable. Specific examples of the “alkyl group” include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1 -Dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl and the like.

“Alkenyl group” means a linear or branched unsaturated hydrocarbon group containing one double bond. For example, “C _3-6 alkynyl group” and the like can be mentioned. Specific examples include vinyl, propenyl, methylpropenyl, butenyl and methylbutenyl.

“Alkynyl group” means a linear or branched unsaturated hydrocarbon group containing one triple bond. For example, “C _2-6 alkynyl group” and the like can be mentioned. Specific examples include 1-propynyl, 2-propynyl, 2-butynyl, pentynyl, hexynyl and the like.

“Cycloalkyl group” means a cyclic saturated hydrocarbon group. For example, “C _3-10 cycloalkyl group” and the like are preferable, and “C _3-6 cycloalkyl group” and the like are preferable. Specific examples of the “cycloalkyl group” include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, norbornyl and the like.

“Cycloalkenyl group” means a cyclic unsaturated hydrocarbon group containing one double bond. For example, “C _5-6 cycloalkenyl group” and the like can be mentioned. Specific examples include 1-cyclopentenyl, 1-cyclohexenyl and the like.

“Aryl group” means an aromatic hydrocarbon group. For example, “C _6-10 aryl” and the like are preferable, and “C ₆ aryl group” (phenyl) and the like are preferable. Specific examples of the “aryl group” include phenyl, 1-naphthyl, 2-naphthyl and the like.

The “aralkyl group” means a group in which the “aryl group” is substituted on the “alkyl group”. For example, “C _7-14 aralkyl group” (C _6-10 aryl C _1-4 alkyl group), preferably “C _7-10 aralkyl group” (C ₆ aryl C _1-4 alkyl group) and the like. . Specific examples of the “aralkyl group” include benzyl, 2-phenylethyl, 1-phenylpropyl, 1-naphthylmethyl and the like.

  Examples of the “heteroaryl group” include a 5-membered to 10-membered monocyclic or polycyclic group, and the group includes the same or different heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom. It is different and includes one or more (for example, 1 to 4). Preferable examples include a 5-membered or 6-membered monocyclic group, and the like includes one heteroatom selected from a nitrogen atom, a sulfur atom, and an oxygen atom. Specific examples of the “heteroaryl group” include, for example, pyrrolyl, thienyl, benzothienyl, benzofuranyl, benzoxazolyl, benzthiazolyl, furyl, oxazolyl, thiazolyl, isoxazolyl, imidazolyl, pyrazolyl, pyridyl, pyrazyl, pyrimidyl, pyridadyl, quinolyl , Isoquinolyl, triazolyl, triazinyl, tetrazolyl, indolyl, imidazo [1,2-a] pyridyl, dibenzofuranyl, benzimidazolyl, quinoxalyl, cinnolyl, quinazolyl, indazolyl, naphthyridyl, quinolinolyl or isoquinolinolyl.

The “heteroarylalkyl group” means a group in which the “heteroaryl group” is substituted on the “alkyl group”. Examples of the heteroaryl moiety are the same as the specific examples exemplified as the heteroaryl group. An example is “heteroaryl C _1-4 alkyl”. Specifically, 2-pyridylmethyl etc. are mentioned, for example.

Examples of the “alkoxy group” include “C _1-6 alkoxy group”, preferably “C _1-4 alkoxy group” and the like. Specific examples of the “alkoxy group” include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.

Examples of the “alkylthio group” include “C _1-6 alkylthio group”, preferably “C _1-4 alkylthio group” and the like. Specific examples of the “alkylthio group” include, for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio, hexylthio and the like.

Examples of the “alkylsulfinyl group” include “C _1-6 alkylsulfinyl group”, preferably “C _1-4 alkylsulfinyl group” and the like. Specific examples of the “alkylsulfinyl group” include, for example, methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl, pentylsulfinyl, hexylsulfinyl and the like.

Examples of the “alkylsulfonyl group” include “C _1-6 alkylsulfonyl group” and the like, and preferably “C _1-4 alkylsulfonyl group” and the like. Specific examples of the “alkylsulfonyl group” include, for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, pentylsulfonyl, hexylsulfonyl and the like.

Examples of the “arylthio group” include “C _6-10 arylthio group” and the like. Specific examples include phenylthio, 1-naphthylthio, 2-naphthylthio and the like.

Examples of the “arylsulfinyl group” include “C _6-10 arylsulfinyl group” and the like. Specific examples include phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl and the like.

Examples of the “arylsulfonyl group” include “C _6-10 arylsulfonyl group” and the like. Specific examples include phenylsulfonyl, tosyl, 1-naphthylsulfonyl and 2-naphthylsulfonyl.

Examples of the “alkynyloxy group” include those exemplified by the above “C _3-6 alkynyl group” for the “alkynyl” moiety. Specific examples include 2-butynyloxy and 3-pentynyloxy.

Examples of the “cycloalkyloxy group” include “C _3-10 cycloalkyloxy group”, and preferably “C _3-6 cycloalkyloxy group”. Specific examples of the “cycloalkyloxy group” include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, adamantyloxy, norbornyloxy and the like.

Examples of the “aryloxy group” include “C _6-10 aryloxy group” and the like. Specific examples include phenoxy, 1-naphthyloxy, 2-naphthyloxy and the like.

Examples of the “aralkyloxy group” include “C _7-14 aralkyloxy group” (C _6-10 aryl C _1-4 alkyloxy group) and the like, preferably “C _7-10 aralkyloxy group” ( "phenyl _{C 1-4} alkyl group"), and the like. Specific examples of the “aralkyloxy group” include benzyloxy, phenethyloxy, naphthylmethyloxy and the like.

  The “heteroaryloxy group” means a group in which the “aralkyl” part of the “aralkyloxy group” is replaced with “heteroaryl”. For example, “5- to 10-membered monocyclic or polycyclic heteroaryloxy group” and the like can be mentioned.

The “alkoxycarbonyl group” means a group in which the “alkoxy group” is bonded to a carbonyl group. For example, “C _1-4 alkoxycarbonyl group” and the like can be mentioned. Specific examples include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 2-propoxycarbonyl, tert-butoxycarbonyl, and the like.

  The “cycloalkyloxycarbonyl group” means a group in which the “cycloalkyloxy group” is bonded to a carbonyl group. Specifically, examples of the cycloalkyloxy moiety include those exemplified as the aforementioned cycloalkyloxy group.

“Alkylcarbonyl group” means a group in which the “alkyl group” is bonded to a carbonyl group. An example is “C _1-4 alkylcarbonyl”. Specific examples include acetyl, propionyl, butyryl and the like.

The “cycloalkylcarbonyl group” means a group in which the “cycloalkyl group” is bonded to a carbonyl group. Examples include “C _3-10 cycloalkylcarbonyl group”, preferably “C _3-6 cycloalkylcarbonyl group” and the like. Specific examples of “cycloalkylcarbonyl group” include cyclopropylcarbonyl , Cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, adamantylcarbonyl, norbornylcarbonyl and the like.

The “arylcarbonyl group” means a group in which the “aryl group” is bonded to a carbonyl group. Examples of the “aryl” moiety include “C _6-10 aryl group” and the like, preferably “C ₆ aryl group” (phenyl) and the like. For example, “C _6-10 arylcarbonyl group” is preferable, and “phenylcarbonyl group” is preferable.

  Specific examples of the “arylcarbonyl group” include benzoyl, 1-naphthoyl, 2-naphthoyl and the like.

  The “heteroarylcarbonyl group” means a group in which the “heteroaryl” is bonded to a carbonyl group. Examples thereof include those in which the “heteroaryl” moiety is exemplified as the aforementioned heteroaryl group. Specific examples include 2-pyridylcarbonyl and the like.

  Examples of the “saturated heterocyclic group” include a 5-membered or 6-membered saturated heterocyclic group having 1 to 3 of the same or different atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. The nitrogen atom, oxygen atom and sulfur atom are all atoms constituting a ring. Specifically, pyranyl, tetrahydrofuryl, pyrrolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, hexamethyleneiminyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, oxoimidazolidinyl, dioxoimidazolidinyl, oxo Examples include oxazolidinyl, dioxooxazolidinyl, dioxothiazolidinyl, tetrahydrofuranyl, tetrahydropyridinyl and the like. In the group, the nitrogen atom constituting the ring is not a bond of the “group”. That is, the group does not include concepts such as a pyrrolidino group.

  The “saturated heterocyclic group” may form a condensed ring with a 6-membered aromatic hydrocarbon or a 6-membered unsaturated heterocycle. For example, a bicyclic 11- or 12-membered “saturated heterocycle” in which the 5-membered or 6-membered “saturated heterocyclic group” described above and a 6-membered aromatic hydrocarbon or 6-membered unsaturated heterocycle are fused. Is mentioned. Examples of the 6-membered aromatic hydrocarbon include benzene. Examples of the 6-membered unsaturated heterocycle include pyridine, pyrimidine, pyridazine and the like. Specifically, dihydroindolyl, dihydroisoindolyl, dihydropurinyl, dihydrothiazolopyrimidinyl, dihydrobenzodioxanyl, isoindolinyl, indazolyl, pyrrololidinyl, tetrahydroquinolinyl, decahydroquinolinyl, tetrahydroisoquinolinyl , Decahydroisoquinolinyl, tetrahydronaphthyridinyl, tetrahydropyridazepinyl and the like.

Examples of the substituent in the “optionally substituted alkyl group” and the “optionally substituted alkoxy group” include, for example,
(A) a halogen atom,
(B) a cyano group,
(C) a C _3-6 cycloalkyl group (which may be substituted with a fluorine atom or a hydroxyl group),
(D) ^groups: -OR ^{50 (R} 50 is a hydrogen atom, a fluorine _{atom, C 3-6} cycloalkyl or _{C 1-4} alkoxy which may be substituted with _{C 1-4 alkyl, C 3-6} cycloalkyl, Or phenyl or benzyl which may be substituted with 1 to 3 groups of the same or different types selected from the group consisting of a halogen atom, cyano, C _1-4 alkyl and C _1-4 alkoxy.
(E) Group: —COR ⁵⁰ (R ⁵⁰ is as defined above),
(F) Group: —OCOR ⁵¹ (R ⁵¹ is a hydrogen atom, C _1-4 alkyl or C _3-6 cycloalkyl),
(G) Group: —COOR ⁵¹ (R ⁵¹ is as defined above),
(H) Group: —NR ⁵³ COR ⁵² (R ⁵² is C _1-4 alkyl, C _1-4 alkoxy or C _3-6 cycloalkyl, R ⁵³ is a hydrogen atom, C _1-6 alkyl or C _3-6 cycloalkyl).
(I) Group: —NR ⁵³ R ⁵⁴ (R ⁵³ is the same as defined above, and R ⁵⁴ is a hydrogen atom, C _1-6 alkyl, C _3-6 cycloalkyl or benzyl, or R ⁵³ and R ⁵⁴ together form a ring).
(J) Group: —CONR ⁵³ R ⁵⁴ (R ⁵³ and R ⁵⁴ are as defined above), or (k) Group: —OCONR ⁵³ R ⁵⁴ (wherein R ⁵³ and R ⁵⁴ are as defined above). .).

In the above, “R ⁵³ and R ⁵⁴ together form a ring” means in the group: —NR ⁵³ R ⁵⁴ , the group: —CONR ⁵³ R ⁵⁴ and the group: —OCONR ⁵³ R ⁵⁴ , NR ⁵³ R ^It means that ⁵⁴ nitrogen atoms together with R ⁵³ and R ⁵⁴ form a nitrogen atom such as a pyrrolidine ring, a piperidine ring, or a morpholine ring.

In the definitions represented by the above (d) to (k), for example,
Group: —OR ⁵⁰ (hydroxy, trifluoromethoxy, phenoxy, etc.),
Group: —COR ⁵⁰ (formyl, methylcarbonyl, etc.),
Group: -OCOR ⁵¹ (methylcarbonyloxy, n-butylcarbonyloxy, cyclohexyloxy, etc.),
Group: —COOR ⁵¹ (carboxy, methoxycarbonyl, etc.),
Groups: —NR ⁵³ COR ⁵² (such as methoxycarbonylamino),
Groups: —NR ⁵³ R ⁵⁴ (amino, mono- or dimethylamino, N-methyl-N-ethylamino, etc.),
Groups: -CONR ⁵³ R ⁵⁴ (aminocarbonyl, cyclopropylaminocarbonyl, benzylamino, etc.),
The group: —OCONR ⁵³ R ⁵⁴ (aminocarbonyloxy and the like) is specifically exemplified (R ⁵⁰ , R ⁵¹ , R ⁵² , R ⁵³ and R ⁵⁴ have the same meaning as described above).

  Preferably, it is selected from the group consisting of (a), (c), (d), (e), (f), (g), (h), (i), (j) and (k). Groups and the like.

  Specific examples of the “substituted alkyl group” include 3- (trifluoromethyl) propyl, 3- (trifluoromethoxy) propyl; 2-aminocarbonylethyl; 2- (methylcarbonylamino) ethyl; 2- (methoxycarbonylamino) ) Ethyl; mono-cyclopropylaminocarbonylmethyl, benzylaminomethyl, 2- (aminocarbonyl) -2′-methyl-propyl and the like.

  Specific examples of the “substituted alkyl” moiety in the “substituted alkoxy group” include the specific examples of the “substituted alkyl group”.

Examples of the substituent in the “substituted alkenyl group” and the “substituted alkynyl group” include, for example,
(A2) a halogen atom,
(B2) a nitro group,
(C2) a cyano group,
(D2) C _1-4 alkyl group (this group may be substituted with a hydroxyl group),
(E2) a C _3-6 cycloalkyl group,
(F2) based on: ^{-OR 50,}
(G2) Group: —COR ⁵⁰ ,
(H2) group: —OCOR ⁵¹ , or (i2) group: —COOR ^{51 and the} like (R ⁵⁰ and R ⁵¹ are the same as described above).

Examples of the substituent in the “optionally substituted cycloalkyl group” and the “optionally substituted cycloalkyloxy group” include, for example,
(A3) a halogen atom,
(B3) a cyano group,
(C3) a hydroxyl group,
(D3) C _1-4 alkoxy,
(E3) a C _1-4 alkyl group,
(F3) C _6-10 aryl group (the group is, for example,
(F31) a halogen atom,
(F32) C _1-4 alkyl,
(F33) a hydroxyl group,
(F34) It may be substituted with C _1-4 alkoxy. ), Or (g3) group: —CONR ⁵³ R ^{54 and the} like (R ⁵³ and R ⁵⁴ are the same as described above).

  Specific examples of the “substituted cycloalkyloxy group” include groups in which the specific examples of the “substituted cycloalkyl group” are directly bonded to an oxygen atom.

Examples of the substituent in the “optionally substituted cycloalkenyl group” include:
(A4) a halogen atom,
(B4) a nitro group,
(C4) a cyano group,
(D4) a C _3-6 cycloalkyl group,
(E4) based on: ^{-OR 50,}
(F4) group: —COR ⁵⁰ ,
(G4) group: —OCOR ⁵¹ , or (h4) group: —COOR ^{51 and the} like (R ⁵⁰ and R ⁵¹ are the same as described above).

Examples of the substituent in the “optionally substituted alkylcarbonyl group” and the “substituted cycloalkylcarbonyl group” include, for example,
(A5) a halogen atom,
(B5) a nitro group,
(C5) a cyano group,
(D5) C _3-6 cycloalkyl group, or (e5) group: —OR ^{50 and the} like can be mentioned (R ⁵⁰ is the same as described above).

Examples of the substituent in the “optionally substituted alkylthio group”, “optionally substituted alkylsulfinyl group”, “optionally substituted alkylsulfonyl group” and “optionally substituted alkyloxycarbonyl group” include: , A halogen atom, a hydroxyl group, nitro, cyano, or —OR ⁵⁰ (R ⁵⁰ is the same as described above).

As the substituent in the “optionally substituted amino group”,
(A6) a methyl group (the group may be substituted with a C _3-6 cycloalkyl group which may be substituted with 1 to 2 fluorine atoms),
(B6) C _2-6 alkyl group [the group is, for example,
(B61) a halogen atom,
(B62) C _1-4 alkoxy (this group may be substituted with 1 to 3 fluorine atoms), or (b63) may be substituted with a hydroxyl group. ] Etc. are mentioned.

  In addition, two substituents of the amino are bonded to each other, for example, pyrrolidine (the pyrrolidine may be further substituted with a hydroxyl group), piperidine, morpholine, thiomorpholine, thiomorpholine oxide, thiomorpholine dioxide, or A piperazine (the nitrogen atom of the piperazine may be substituted with methyl, ethyl) or the like, and forms a saturated heterocycle which may contain at least one nitrogen atom and oxygen atom, which may be the same or different. Also good.

  Specific examples include monomethylamino; dimethylamino; N-methyl-N-ethylamino; (3-methoxypropyl) amino; 3-trifluorobenzylamino; cyclopropylamino; 4-fluorophenylamino; morpholino; -1-yl and the like can be mentioned.

  The substituents in the “optionally substituted aminosulfonyl group” and the “optionally substituted aminocarbonyl group” are the same as the examples of the substituents in the above “substituted amino group”. Examples of the “substituted aminosulfonyl group” include dimethylaminosulfonyl, morpholinosulfonyl and the like. Examples of the “substituted aminocarbonyl group” include dimethylaminocarbonyl, morpholinocarbonyl, (2-pyrrolidone-1-yl) -carbonyl, cyclopropylmethylaminocarbonyl, (2,2-difluorocyclopropyl) methylaminocarbonyl. , (3,3,3-trifluoropropyl) aminocarbonyl, (2-hydroxy-2-methyl-propyl) aminocarbonyl, and the like.

Examples of the substituent in the “optionally substituted aryl group” and the “optionally substituted heteroaryl group” include, for example,
(A7) a halogen atom,
(B7) a nitro group,
(C7) a cyano group,
(D7) C _1-4 alkyl group (the group may be substituted with, for example, a halogen atom, a hydroxyl group, or amino),
(E7) C _6-10 aryl group (the group is, for example,
(E71) a halogen atom,
(E72) carboxy,
(E73) cyano,
(E74) C _1-4 alkyl optionally substituted with carboxy, or (e75) optionally substituted with a fluorine atom, a hydroxyl group, or C _1-4 alkoxy optionally substituted with carboxy. ),
(F7) based on: ^{-OR 50,}
(G7) based on: -COR ^50,
(H7) group: -OCOR ⁵¹ ,
(I7) group: —COOR ⁵¹ ,
(J7) group: —NR ⁵³ COR ⁵² ,
(K7) ^{group: -NR} 53 ^{R 54,}
(L7) group: —CONR ⁵³ R ⁵⁴ , or (m7) group: —SO ₂ R ^{50 and the} like can be mentioned (R ⁵⁰ , R ⁵¹ , R ⁵² , R ⁵³ and R ⁵⁴ are the same as above). .

As the substituent of the aryl moiety in the “optionally substituted aralkyl group”,
(A8) a halogen atom,
(B8) a nitro group,
(C8) a cyano group,
(D8) C _1-4 alkyl group (the group may be substituted with, for example, a halogen atom, a hydroxyl group, or amino),
(E8) Phenyl group (this group may be substituted with a halogen atom, cyano or C _1-4 alkoxy)
(F8) based on: ^{-OR 50,}
(G8) based on: -COR ^50,
(H8) group: -OCOR ⁵¹ ,
(I8) group: —COOR ⁵¹ ,
(J8) ^group: -NR 53 ^{COR 52,}
(K8) ^{group: -NR} 53 ^{R 54,}
(L8) group: —CONR ⁵³ R ⁵⁴ , or (m8) group: —SO ₂ R ^{50 and the} like are mentioned (R ⁵⁰ , R ⁵¹ , R ⁵² , R ⁵³ and R ⁵⁴ are the same as described above). .

  Examples of the substituent of the heteroaryl moiety of the “optionally substituted heteroarylalkyl group” include those exemplified as the substituent in the “optionally substituted heteroaryl group”.

Examples of the substituent of the “saturated heterocyclic group” and “saturated heterocycle” include a halogen atom, a hydroxyl group, a nitro group, a cyano group, a C _1-4 alkyl group (the alkyl group is substituted with, for example, a halogen atom) C _1-4 alkoxy group (the alkoxy group may be substituted with, for example, a halogen atom), group: —COOR ⁵⁰ , amino group, mono- or di-C _1-4. Examples thereof include an alkylamino group, a C ₆ aryl group, an aminocarbonyl group, an oxo group, and a thioxo group. Preferably, for example, a halogen atom, a hydroxyl group, a nitro group, a cyano group, a C _1-4 alkyl group, a C _1-4 alkoxy group, amino and the like can be mentioned. The group may be substituted with two of the same or different groups in the substituent.

Examples of the substituent in the definition ^{"R 1a",} for example,
(A9) C _3-6 alkynyl group, or (b9) C _1-6 alkyl group (the group is
(C90) C _3-6 cycloalkyl (which may be substituted with a fluorine atom or C _1-4 alkoxy),
(C91) C _1-4 alkoxy (which may be substituted with C _3-6 cycloalkyl or C _1-4 alkoxy),
(C92) a hydroxyl group,
(C93) trifluoromethyl,
(C94) trifluoromethoxy,
(C95) difluoromethoxy,
(C96) monofluoromethoxy,
(C97) _C1-4 alkylcarbonylamino,
(C98) C _1-4 alkoxycarbonylamino, or (c99) C _3-6 cycloalkoxy may be substituted. ) And the like.

The “C _1-6 alkyl group substituted with C _1-4 alkoxy” may be substituted with 1 to 3 fluorine atoms. Specific examples include 4-methoxy-3-fluoro-butyl (Q91), 4-methoxy-3,3-difluoro-butyl (Q85), and the like. That is, in this case, a group in which the “C _1-4 alkoxy group” is substituted with 1 to 3 fluorine atoms (for example, trifluoromethoxy, difluoromethoxy, monofluoromethoxy and the like) is excluded. The substituent of the definition “R ^12a ” is the same as described above.

Specific examples of the “substituted C _1-6 alkyl group” in the definition “R ^1a ” include, for example, 3-pentynyl (Q79), 4-hexynyl (Q84), 3-hexynyl (Q92); 3- (cyclo Propyl) propyl (Q75), 3- (2,2-difluorocyclopropyl) propyl (Q77), 3- (cyclopentyl) propyl (Q78), (3-isopropyloxycyclobutyl) methyl (Q83); 4- (methoxy ) Butyl (Q73), 3- (isopropyloxy) propyl (Q81), 4- (cyclopropylmethyloxy) butyl (Q86), 3- (ethoxy) propyl (Q89), (2-methoxyethoxy) methyl (Q90) 4- (hydroxy) butyl (Q69); 4- (trifluoromethyl) butyl (Q70); 4- (trifluoro 4- (difluoromethoxy) butyl (Q72); 4- (monofluoromethoxy) butyl (Q88); 3- (methylcarbonylamino) propyl (Q74); 2- (methoxycarbonylamino) ethyl (Q68); 4- (cyclopropyloxy) butyl (Q87) and the like.

As the substituents in the definitions “R ^1b ”, “R ^1c ” and “R ^1d ”, for example,
(A10) a hydrogen atom,
(B10) a halogen atom,
(C10) a carboxy group,
(D10) a cyano group,
(E10) C _1-6 alkyl group (this group may be substituted with 1 to 3 fluorine atoms),
(F10) a 5- to 10-membered monocyclic heteroaryl group,
(G10) a C _1-6 alkylsulfonyl group,
(H10) a C _6-10 arylsulfonyl group,
(I10) C _1-6 alkoxy group (the group is
(I101) 1 to 3 fluorine atoms,
(I102) C _1-4 alkoxy, or (i103) optionally substituted with 1-2 fluorine atoms and optionally substituted with a C _3-6 cycloalkyl group. ),
(J10) C _3-6 cycloalkyloxy group (the group may be substituted with 1 to 2 fluorine atoms),
(K10) C _6-10 aryloxy group (may be substituted with 1 to 3 halogen atoms),
(L10) C _7-14 aralkyloxy group,
(M10) an optionally substituted amino group,
(N10) an optionally substituted aminocarbonyl group,
(O10) An optionally substituted aminosulfonyl group, (p10) C _1-4 alkoxycarbonyl group and the like can be mentioned.

  Specific examples of the group include, for example, methyl (Q3), trifluoromethyl (Q4); 5-oxazolyl (Q25); methylsulfonyl (Q20); phenylsulfonyl (Q23); methyloxy (Q5), isopropyloxy ( Q6), difluoromethyloxy (Q8), trifluoromethoxy (Q9), 2,2,2-trifluoroethoxy (Q10), propyloxy (Q11), 3-methoxypropyloxy (Q12), cyclopropylmethyloxy ( Q13); cyclopropyloxy (Q7), 2-fluorocyclopropyloxy (Q38), 2,2-difluorocyclopropyloxy (Q59); 4-fluorophenyloxy (Q14); benzyloxy (Q15); 2-pyrrolidone -1-yl (Q21); dimethylaminocarbonyl ( 18), morpholinocarbonyl (Q19); dimethylamino sulfonyl (Q22), morpholinosulfonyl (Q24); ethoxycarbonyl (Q17), and the like.

As the substituent in the definition “R ² ”, for example,
(A11) a C _1-6 alkyl group (the group may be substituted with 1 to 3 fluorine atoms or a C _3-6 cycloalkyl group), or (b11) a C _3-6 cycloalkyl group. (The group may be substituted with 1 to 2 fluorine atoms).

  Specific examples of the group include cyclopropylmethyl (Q146), 2- (cyclobutyl) ethyl (Q147), 2,2′-difluoro-isopropyl (Q148); 2-fluorocyclopropyl (Q149), and the like. It is done.

"A is ^{_{- (CH 2) s N (}} R 4) -, - (CH 2) s OCON (R 4) -, - (CH 2) s CON (R 4) -, - (CH 2) s N ( In the case of R ⁴ ) CON (R ⁴ ) — and — (CH ₂ ) _s SO ₂ N (R ⁴ ) —, R ⁴ and B are bonded together to form a ring. Examples thereof include pyrrolidino, piperidino, morpholino and the like. The ring may be substituted with the same substituent as the above-mentioned “saturated heterocyclic group”. When A is “— (CH ₂ ) _s N (R ⁴ ) CON (R ⁴ ) —”, R ⁴ and B of “CON (R ⁴ )” are bonded together to form a ring. Form. Specific examples include 4-hydroxypiperidino; 2-methoxymorpholino; 4-formyl-piperidino; 4-methoxycarbonylpiperidino; 4-aminocarbonylpiperidino; 4-N-methylaminopiperidino; 3 -Phenylpyrrolidino; 4-dimethylaminopiperidino and the like.

In the compound of formula (I), when A is — (CH ₂ ) _s N (R ⁴ ) CON (R ⁴ ) —, each R ⁴ may be independently different. Specific examples of the above include A being “— (CH ₂ ) _s NHCON (CH ₃ ) —”.

"Any two of R ^3a , R ^3b , R ^3c and R ^3d are hydrogen atoms, and any two of them together form a piperidine ring and a bridged ring" means that the remaining two of the above definitions are This definition means forming a bridged ring with the substituted piperidine ring. Specific examples of the definition and “two of R ^32a , R ^32b , R ^32c and R ^32d are hydrogen atoms and the remaining two together form a piperidine ring and a bridged ring” include the following: And the group exemplified by the structural formula of

In the compound of the formula (I), the “ ^optionally substituted alkyl group” in the definitions “R ^3a ”, “R ^3b ”, “R ^3c ” and “R ^3d ” is substituted with 1 to 3 halogen atoms A C _1-6 alkyl group which may be substituted, a C _3-6 cycloalkyl group which may be substituted with a halogen atom or a hydroxyl group, a group: —OR ⁵⁰ , a group: —COR ⁵⁰ , a group: —OCOR ⁵¹ , a group: — COOR ⁵¹ , group: —NR ⁵³ COR ⁵⁵ , group: —NR ⁵³ R ⁵⁵ , group: —CONR ⁵³ R ⁵⁵ , group: —OCONR ⁵³ R ⁵⁵ and the same or different selected from the group consisting of substituent group α A C _1-6 alkyl group that may be substituted with 1 to 2 groups, and the like (R ⁵⁰ , R ⁵¹ , R ⁵² , and R ⁵³ are the same as the above, R ⁵⁵ is a hydrogen atom, C _3-6 Black alkyl, benzyl, or _{C 3-6} cycloalkyl or _{C 1-6} alkyl optionally substituted by ^{aminocarbonyl, R 53} and ^{R 55} may form a ring together. However, group : In the case where A is a single bond in -AB, it is limited to the case where the alkyl group has 3 or more carbon atoms.) The same applies to the case of formula (II).

  Examples of the “substituted alkyl group” with two different kinds of substituents selected from the groups exemplified above include compounds represented by the following formulae.

  Examples of the substituent group α include one group selected from a compound group represented by the following formula.

In the above “substituted alkyl group”, in the C _1-6 alkyl group substituted with the group: —COOR ⁵¹ , one carbon atom of the C _1-6 alkyl chain constitutes a C _3-6 cycloalkyl ring. Also included are groups that Specific examples include compounds represented by the following formula.

In the “substituted alkyl group”, the C _1-6 alkyl group substituted with the substituent group α or aminocarbonyl has one carbon atom of the C _1-6 alkyl chain as a C _3-6 cycloalkyl ring. The group which comprises is also included. Specific examples include compounds represented by the following formula.

In the “substituted alkyl group”, the C _1-6 alkyl group substituted by the substituent group α includes a group in which the ring of the substituent group α and the C _1-6 alkyl group form a spiro. It is. Specific examples include compounds represented by the following formula.

“R ⁵³ and R ⁵⁵ together form a ring” is synonymous with the above-mentioned “R ⁵³ and R ⁵⁴ together form a ring”.

Unless otherwise specified in the present specification, in the definitions “R ^3a ” to “R ^3d ”,
The “optionally substituted C _7-14 aralkyl group” is a halogen atom, cyano, C _1-4 alkyl (the group may be substituted with 1 to 3 halogen atoms, or one hydroxyl group or amino group). 1 to 3 groups selected from the group consisting of: —CONR ⁵³ R ⁵⁴ , group: —SO ₂ R ⁵⁰ and group: —OR ⁵⁰ , or one C _6-10 aryl group ( The group may be substituted with a halogen atom, C _1-4 alkyl optionally substituted with carboxy, carboxy, cyano, or C _1-4 alkoxy optionally substituted with a fluorine atom, hydroxyl group, or carboxy. ) is substituted with be a good _{C 7-14} aralkyl group optionally;
The “optionally substituted C _6-10 aryl group” is a halogen atom, cyano, C _1-4 alkyl (the group may be substituted with 1 to 3 halogen atoms, or one hydroxyl group or amino group). And 1 to 3 groups selected from the group consisting of —OR ⁵⁰ , or one C _6-10 aryl group (the group is a halogen atom, C ₁ which may be substituted with carboxy) _-4 alkyl, carboxy, cyano, or a C _6-10 aryl group that may be substituted with a fluorine atom, a hydroxyl group, or a C _1-4 alkoxy that may be substituted with carboxy;
The “optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group” is a halogen atom, cyano, C _1-4 alkyl (the group is represented by 1 to 3 halogen atoms, or 1 And 1 to 3 groups selected from the group consisting of —OR ⁵⁰ , or one C _6-10 aryl group (the group is a halogen atom) , C _1-4 alkyl optionally substituted with carboxy, carboxy, cyano, or C _1-4 alkoxy optionally substituted with fluorine atom, hydroxyl group, or carboxy. A good 5- to 10-membered monocyclic or polycyclic heteroaryl group;
The “optionally substituted 5- or 6-membered saturated heterocyclic group” is 1 selected from the group consisting of a halogen atom, a hydroxyl group, cyano, C _1-4 alkyl, C _1-4 alkoxy, oxo and amino. And a 5- or 6-membered saturated heterocyclic ring which may be substituted with one group (R ⁵⁰ , R ⁵³ and R ⁵⁴ are the same as described above).

In the compound of the formula (II), the “ ^optionally substituted C _6-10 aryl group” of “B ² ” in the definition “R ^32c ” is preferably a C ₆ aryl group (phenyl group). Examples of the substituent, group: 1 to 3 groups selected from the group consisting of ^{-OR 50} or one of _{C 6} aryl group (in which, is optionally substituted halogen atom, carboxy _{C 1- 4} alkyl, carboxy, cyano, or a C _1-4 alkoxy which may be substituted with a fluorine atom, a hydroxyl group, or carboxy is preferable. (R ⁵⁰ is the same as described above.)

The compounds of formula (I) and formula (II) are preferably compounds having the absolute configuration shown below (the symbols in the formula have the same meaning as described above).

  “Pharmaceutically acceptable salts” include, for example, inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate or nitrate, or acetate, propionate, oxalate, succinate, Organic salts such as lactate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate, benzenesulfonate, p-toluenesulfonate or ascorbate It is done.

  In addition, the present invention includes a compound represented by the formula (I) or a prodrug thereof, or a pharmaceutically acceptable salt thereof. Moreover, solvates, such as these hydrates or ethanol solvates, are also included. Further, all forms of crystal forms are also included.

  In the present specification, the term “prodrug of the compound of formula (I)” means a compound that is converted into a compound of formula (I) by a reaction with an enzyme, gastric acid or the like under physiological conditions in vivo, that is, enzymatically oxidized, It means a compound that undergoes reduction, hydrolysis or the like and changes to a compound of formula (I), or a compound that undergoes hydrolysis by gastric acid or the like and changes to a compound of compound (I).

  The compounds of formula (I) may exist as tautomers. Accordingly, the present invention also includes tautomers of the compounds of formula (I).

  The compound of the present invention may have at least one asymmetric carbon atom. Accordingly, the present invention includes not only racemic forms of the compounds of the present invention but also optically active forms of these compounds. When the compound of the present invention has two or more asymmetric carbon atoms, stereoisomerism may occur. Accordingly, the present invention also includes stereoisomers of these compounds and mixtures thereof.

  Preferred examples of the compound of the present invention include the following compounds. In the exemplified compounds in the following table, the following abbreviations may be used as partial structures for the purpose of simplifying the description.

Hereinafter, the method for producing the compound represented by the formula (I) in the present invention will be described with reference to examples, but the present invention is not limited thereto. In the present specification, the following abbreviations may be used for the sake of simplicity.
Boc: tert-butoxycarbonyl group Cbz: benzyloxycarbonyl group TMS: trimethylsilyl group TBS: tert-butyldimethylsilyl group SEM: 2-[(trimethylsilyl) ethoxy] methyl group Ac: acetyl group Me: methyl group Et: ethyl group Pr : Propyl group i-Pr: isopropyl group Bu: butyl group i-Bu: isobutyl group t-Bu: tert-butyl group Ph: phenyl group Bn: benzyl group Ms: methanesulfonyl group TFA: trifluoroacetic acid Alloc: allyloxycarbonyl Group Tf: trifluoromethanesulfonate

  The compound represented by the formula (I) can be synthesized from known compounds by combining known synthesis methods. For example, it can be synthesized by the following method. The compound represented by the formula (I) can be synthesized by appropriately selecting and combining the methods shown below according to the type of the starting material.

Manufacturing method 1
The compound represented by the formula (I) or a salt thereof is produced, for example, by the method shown below.

[Wherein, R ^1a , R ^1b , R ^1c , R ^1d , R ^3a , R ^3b , R ^3c , R ^3d and R ² have the same ^meanings as described in item 1 above, and R ¹¹⁷ represents a fluorine atom or C _A C _1-3 alkyl group that may be substituted with _1-3 alkoxy, or a C _3-6 cycloalkyl group that may be substituted with a fluorine atom or C _1-3 alkoxy, and R ¹¹⁸ is C _1-2. an alkyl ^{group, R 119} is a fluorine atom or a _{C 1-3} optionally substituted alkoxy _{C 1-5} alkyl group or a fluorine atom or _{C 1-3} optionally _{C 3-6} cycloalkyl which may be substituted by alkoxy, Represents an alkyl group, R ¹²⁰ represents a fluorine atom or a C _1-3 alkoxy group, m ₁₀₄ represents an integer of 0, 1, 2, or 3, X ¹ represents a hydroxyl group or a chlorine atom, X ² Represents an iodine atom, a bromine atom, a chlorine atom, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, or a p-toluenesulfonyloxy group, and Y ¹ represents Cbz, Boc, or Alloc. ]

1) Step 1
When X ¹ represents a hydroxyl group, the compound of formula (1-3), the compound of formula (1-1), in an inert solvent, using a condensing agent, in the presence of a base, if necessary the formula It can be synthesized by reacting with the compound (1-2). In some cases, a phase transfer catalyst can also be used.
The base is not particularly limited as long as it is used as a base in a normal reaction. For example, N-methylmorpholine, triethylamine, diisopropylethylamine, tributylamine, 1,8-diazabicyclo [5.4.0] undeca- 7-ene, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [5.4.0] undec-7-ene, pyridine, dimethylaminopyridine, picoline, etc. Organic bases or inorganic bases such as sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, or sodium hydride can be used. Examples of the phase transfer catalyst include quaternary ammonium salts such as tetrabutylammonium bromide or benzyltriethylammonium bromide, or crown ethers such as 18-crown-6-ether. Examples of the condensing agent include those described in Experimental Chemistry Course (The Chemical Society of Japan, Maruzen) Vol. For example, phosphate esters such as diethyl cyanophosphate or diphenylphosphoryl azide, carbodiimides such as 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide / hydrochloride, dicyclohexylcarbodiimide, 2,2′-dipyridyl disulfide A combination of disulfides such as triphenyltriphosphine, phosphorus halides such as N, N′-bis (2-oxo-3-oxazolidinyl) phosphinic chloride, azo such as diethyl azodicarboxylate Examples include a combination of a dicarboxylic acid diester and a phosphine such as triphenylphosphine, or a 2-halo-1-lower alkylpyridinium halide such as 2-chloro-1-methylpyridinium iodide. Examples of the inert solvent include ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane, or 1,2-dimethoxyethane, hydrocarbon solvents such as hexane, heptane, toluene, benzene, and xylene, dichloromethane, Halogenated hydrocarbon solvents such as chloroform or 1,2-dichloroethane, ketone solvents such as acetone, or aprotic solvents such as acetonitrile, N, N′-dimethylformamide, dimethyl sulfoxide, or hexamethylenephosphoamide These may be mixed solvents. The reaction temperature is selected from the range of about -70 ° C to about 80 ° C.

When X ¹ represents a chlorine atom, the compound of the formula (1-3) is obtained by converting the compound of the formula (1-2) into the formula (1-1) in an inert solvent, if necessary, in the presence of a base. It can synthesize | combine by making it react with the compound of. Examples of the base include N-methylmorpholine, triethylamine, diisopropylethylamine, tributylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene, 1,5-diazabicyclo [4.3.0] non- And organic bases such as 5-ene, 1,4-diazabicyclo [5.4.0] undec-7-ene, pyridine, dimethylaminopyridine, and picoline. The base is usually used in an amount of 1 to 20 equivalents relative to the compound of formula (1-1) in which X ¹ is a chlorine atom. Examples of the inert solvent include halogenated hydrocarbon solvents such as dichloromethane, chloroform, or 1,2-dichloroethane. The reaction temperature is selected from the range of about −10 ° C. to about 50 ° C.

The compound of formula (1-1) in which X ¹ is a chlorine atom is obtained by converting the compound of formula (1-1) in which X ¹ is a hydroxyl group in an inert solvent in the presence or absence of an additive. Alternatively, it can be synthesized by reacting with thionyl chloride. Examples of the additive include dimethylformamide and diethylformamide. Examples of the inert solvent include halogenated hydrocarbon solvents such as dichloromethane, dichloroethane, and chloroform. The reaction temperature is selected from the range of about −10 ° C. to about 50 ° C. After completion of the reaction, the compound of the formula (1-1) in which X ¹ is a hydroxyl group can be obtained by concentrating the reaction solution under reduced pressure in the presence of a hydrocarbon solvent such as benzene or toluene.
R ^3a , R ^3b and R ^3c which are substituents of the compound (1-3) were shown in Production Method 2 to Production Method 18 using the production methods described in Production Method 2 to Production Method 18. It can also be converted to a substituent.

2) Step 2
Compound (I) can be produced from Compound (1-3) by a method similar to that described in the literature (for example, Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.)). it can.

3) Step 3
Compound (1-2) can be produced from compound (1-4) by the same method as in Step 7 described in Production Method 1. In addition, when R ^{2 of} the compound (1-5) is an optionally substituted aryl group or an optionally substituted heteroaryl group, the literature (J. Org. Chem. 71, 6522 (2006), etc.) Compound (1-2) can be produced from compound (1-4) by a method similar to the production method described.

4) Step 4
Literature (for example, J. Org. Chem. 61, 3849 (1996), J. Org. Chem. 68, 4120 (2003), J. Org. Chem. 63, 370 (1998), J. Org. Chem. 70, 2195 (2005), etc.) can be used to produce compound (1-2) from compound (1-4). Specifically, the following production examples are given.
Compound (1-2) is a compound selected from Compound (1-8), Compound (1-9) and Compound (1-10) in the presence or absence of acetic acid in an inert solvent And a reductive amination reaction with the compound (1-4) using a borohydride compound such as sodium triacetoxyborohydride or sodium cyanoborohydride. Examples of the inert solvent include halogenated hydrocarbon solvents such as dichloromethane or dichloroethane, alcohol solvents such as methanol or ethanol, ether solvents such as tetrahydrofuran, 1,4-dioxane, or 1,2-dimethoxyethane. Etc. The borohydride compound is generally used in an amount of 1 to 3 equivalents relative to compound (1-4). The reaction temperature is selected from the range of about −10 ° C. to about 40 ° C.

5) Step 5
Compound (1-2) can be produced from compound (1-6) by the same method as in Step 4 described in Production Method 1.

6) Step 6
Compound (1-7) can be produced from compound (1-1) by the same method as in Process 1 described in Production Method 1.

7) Step 7
Compound (1-3) can be produced by reacting compound (1-7) with compound (1-5) in the presence of a base in an inert solvent. Bases include alkali metal salts such as sodium bicarbonate, potassium carbonate, or sodium hydroxide, organic bases such as triethylamine or 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), hydrogenation Examples thereof include alkali metal hydrides such as sodium or potassium hydride, and alkoxy alkali metals such as t-butoxy potassium. Also, when X ² is a chlorine atom or a bromine atom, it may be used an additive such as sodium iodide or potassium iodide. Examples of the inert solvent include ether solvents such as tetrahydrofuran or 1,4-dioxane, aprotic solvents such as dimethylformamide or dimethyl sulfoxide, or halogenated hydrocarbon solvents such as dichloromethane or dichloroethane. These may be a mixed solvent. The reaction temperature is selected from the range of about 0 ° C to about 150 ° C.

Manufacturing method 2
Among the compounds represented by formula (1-4), the compound represented by formula (2-3) or a salt thereof is produced, for example, by the method shown below.

[Wherein Y ¹ has the same meaning as described above, Y ² represents Cbz, Boc or Alloc, and R ¹⁰⁰ represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, An optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, an optionally substituted aryl group, an optionally substituted aralkyl group, an optionally substituted heteroaryl group Represents a heteroarylalkyl group which may be substituted, or a saturated heterocyclic group which may be substituted. ]

1) Step 1
Compound (2-2) can be produced from compound (2-1) by a method similar to the production method described in the literature (for example, Comprehensive Organic transformation, RC Larro, VCH publisher Inc., 1989). . Compound (2-1) can be produced by a method similar to the production method described in the literature (for example, WO05 / 028467 and the like).
2) Step 2
The compound (2-3) is produced from the compound (2-2) by a method similar to the method described in the literature (for example, Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.)). be able to.

Production method 3
Among the compounds represented by the formula (1-4), the compound represented by the formula (3-6) or a salt thereof is produced, for example, by the method shown below.

[Wherein, Y ¹ and Y ² are as defined above, X ³ represents a chlorine atom or a bromine atom, R ¹⁰¹ represents a C _1-4 alkyl group, R ¹⁰² represents a hydrogen atom, A C _3-6 cycloalkyl group, a benzyl group, or a C _1-6 alkyl group optionally substituted with C _3-6 cycloalkyl or aminocarbonyl, and R ¹⁰³ represents a hydrogen atom, a C _1-6 alkyl group, Or a C _3-6 cycloalkyl group, or R ¹⁰² and R ¹⁰³ together form a ring. ]

1) Step 1
Compound (3-2) can be produced from compound (2-1) by a method similar to the production method described in the literature (for example, Comprehensive Organic transformation, RC Larro, VCH publisher Inc., 1989). . Compound (2-1) can be produced by a method similar to the production method described in the literature (for example, WO05 / 028467 and the like).
2) Step 2 to Step 3
Compound (3-5) can be produced from Compound (3-2) by a method similar to the method described in the literature (for example, Comprehensive Organic transformation, RC Larro, VCH publisher Inc., 1989). it can.
3) Step 4
Compound (3-6) is produced from compound (3-5) by a method similar to the method described in the literature (for example, Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.), etc.) be able to.

Manufacturing method 4
Among the compounds represented by formula (1-4), the compounds represented by formula (4-3) and formula (4-6) or salts thereof are produced, for example, by the method shown below.

Wherein, Y ¹ and Y ² are the same as defined above, R ¹⁰⁴ is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, a substituted Cycloalkyl group which may be substituted, cycloalkenyl group which may be substituted, aryl group which may be substituted, aralkyl group which may be substituted, heteroaryl group which may be substituted, heteroarylalkyl which may be substituted Or a saturated heterocyclic group which may be substituted, and R ¹⁰⁵ is an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, or an optionally substituted group. It is a heteroaryl group, or R ¹⁰⁴ and R ¹⁰⁵ are combined to form a ring, and X ⁴ is an iodine atom, bromine atom, chlorine atom, methanesulfo group. A nyloxy group, a trifluoromethanesulfonyloxy group, or a p-toluenesulfonyloxy group is represented. ]

1) Step 1
Compound (4-2) can be produced from compound (2-1) by a method similar to the production method described in the literature (for example, Comprehensive Organic transformation, RC Larro, VCH publisher Inc., 1989). . Compound (2-1) can be produced by a method similar to the production method described in the literature (for example, WO05 / 028467 and the like).
2) Step 2
The compound (4-3) is produced from the compound (4-2) by a method similar to that described in the literature (for example, Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.)). be able to.
3) Step 3
Compound (4-5) can be produced from compound (4-2) by a method similar to the production method described in the literature (for example, Comprehensive Organic transformation, RC Laroc, VCH publisher Inc., 1989). .
4) Step 4
Compound (4-6) is produced from compound (4-5) by a method similar to the method described in the literature (for example, Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.), etc.) be able to.

Manufacturing method 5
Among the compounds represented by formula (1-4), the compound represented by formula (5-4) or a salt thereof is produced, for example, by the method shown below.

[Wherein, Y ¹ and Y ² are as defined above, R ¹⁰⁶ represents a C _1-4 alkyl group, and R ¹⁰⁷ represents an ^optionally substituted alkyl group or an optionally substituted alkenyl group. , An optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, an optionally substituted aryl group, an optionally substituted aralkyl group, an optionally substituted heteroaryl A group, a heteroarylalkyl group which may be substituted, or a saturated heterocyclic group which may be substituted; ]

1) Step 1
Compound (5-2) can be produced from compound (5-1) by a method similar to the production method described in the literature (for example, Comprehensive Organic transformation, RC Larro, VCH publisher Inc., 1989). . Compound (5-1) can be produced by a method similar to the production method described in the literature (for example, WO 97/18813, WO 02/10172, Tetrahedron Letters 46, 7495 (2005), WO 02/02525, etc.). .
2) Step 2
Compound (5-3) can be produced from compound (5-2) by a method similar to the production method described in the literature (for example, Comprehensive Organic transformation, RC Larro, VCH publisher Inc., 1989). .
3) Step 3
Compound (5-4) is produced from Compound (5-3) by a method similar to that described in the literature (for example, Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.)). be able to.

Manufacturing method 6
Among the compounds represented by the formula (1-4), the compound represented by the formula (6-5) or a salt thereof is produced, for example, by the method shown below.

[Wherein Y ¹ , Y ² and R ¹⁰⁶ have the same meanings as described above, R ¹⁰⁸ represents a C _1-4 alkyl group, and R ¹⁰⁹ represents an ^optionally substituted alkyl group, which may be substituted. Good alkenyl group, optionally substituted alkynyl group, optionally substituted cycloalkyl group, optionally substituted cycloalkenyl group, optionally substituted aryl group, optionally substituted aralkyl group, optionally substituted Represents a heteroaryl group which may be substituted, a heteroarylalkyl group which may be substituted, or a saturated heterocyclic group which may be substituted; ]

1) Step 1
Compound (6-1) can be produced from compound (5-1) by a method similar to the production method described in the literature (for example, Comprehensive Organic transformation, RC Laroc, VCH publisher Inc., 1989). . The compound (5-1) was described in literature (for example, WO97 / 18813, WO02 / 10172, Tetrahedron Letters 46, 7495 (2005), WO02 / 02525, J. Org. Chem. 70, 6956 (2005), etc.) It can be manufactured by a method similar to the manufacturing method.
2) Step 2
Compound (6-1) by a method similar to that described in the literature (for example, Comprehensive Organic transformation, RC Larro, VCH publisher Inc., 1989, J. Org. Chem. 57, 7194 (1992)). ) To produce compound (6-2).
3) Step 3 to Step 4
Compound (6-4) can be produced from Compound (6-2) by a method similar to the method described in the literature (for example, Comprehensive Organic transformation, RC Larro, VCH publisher Inc., 1989). it can.
4) Step 5
The compound (6-5) is produced from the compound (6-4) by a method similar to the method described in the literature (for example, Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.)). be able to.

Manufacturing method 7
Among the compounds represented by formula (1-4), the compounds represented by formula (7-4), formula (7-6), and formula (7-8) or salts thereof are, for example, the methods shown below. Manufactured by.

[Wherein R ¹⁰⁵ , X ⁴ , Y ¹ and Y ² have the same meanings as described above, X ⁵ represents a hydroxyl group or a chlorine atom, and R ¹¹⁰ and R ¹¹¹ may be substituted with a hydrogen atom. An alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, an optionally substituted aryl group, and an optionally substituted It represents an aralkyl group, an optionally substituted heteroaryl group, an optionally substituted heteroarylalkyl group, or an optionally substituted saturated heterocyclic group. ]

1) Step 1
It is described in literature (for example, Comprehensive Organic transformation, RC Larroc, VCH publisher Inc., 1989, Chem. Pharm. Bull. 40, 102 (1992), J. Med. Chem. 26, 507 (1983), etc.) Compound (7-3) can be produced from compound (7-1) by a method similar to the method or the like. Compound (7-1) can be produced by a method similar to the production method described in the literature (for example, WO05 / 028467 and the like).
2) Step 2
The compound (7-4) is produced from the compound (7-3) by a method similar to the method described in the literature (for example, Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.)). be able to.
3) Step 3
Compound (7-5) can be produced from Compound (7-3) by a method similar to the method described in the literature (for example, Comprehensive Organic transformation, RC Larro, VCH publisher Inc., 1989). it can.
4) Step 4
Compound (7-6) is produced from Compound (7-5) by a method similar to that described in the literature (for example, Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.)). be able to.
5) Step 5
Literature (for example, Comprehensive Organic transformation, RC Larroc, VCH publisher Inc., 1989, J. Org. Chem. 61, 3849 (1996), J. Org. Chem. 68, 4120 (2003), J. Org. Chem. 63, 370 (1998), J. Org. Chem. 70, 2195 (2005), etc.) and the compound (7-1) is produced from the compound (7-1) by a method similar to the method described in the above. be able to.
6) Step 6
Compound (7-8) is produced from Compound (7-7) by a method similar to the method described in literature (for example, Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.)). be able to.

Manufacturing method 8
Among the compounds represented by formula (1-4), the compound represented by formula (8-4) or a salt thereof is produced, for example, by the method shown below.

[Wherein, R ¹⁰¹ , R ¹⁰² , R ¹⁰³ , X ³ , Y ¹ and Y ² have the same meanings as described above. ]

1) Step 1
From compound (7-1) to compound (8) by a method similar to the production method described in the literature (for example, Comprehensive Organic transformation, RC Larro, VCH publisher Inc., 1989, Synthetic Communications 34, 219 (2004)). -1) can be produced. Compound (7-1) can be produced by a method similar to the production method described in the literature (for example, WO05 / 028467 and the like).
2) Step 2 to Step 3
Compound (8-3) can be produced from Compound (8-1) by a method similar to the method described in the literature (for example, Comprehensive Organic transformation, RC Larro, VCH publisher Inc., 1989). it can.
3) Step 4
Compound (8-4) is produced from Compound (8-3) by a method similar to that described in the literature (for example, Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.)). be able to.

Manufacturing method 9
Among the compounds represented by formula (1-4), the compound represented by formula (9-4) or a salt thereof is produced, for example, by the method shown below.

[Wherein, R ¹⁰¹ , R ¹⁰² , R ¹⁰³ , R ¹⁰⁵ , X ⁴ , Y ¹ and Y ² are as defined above. ]

1) Step 1 to Step 3
Compound (9-3) can be produced from compound (8-1) by a method similar to the production method described in the literature (for example, Comprehensive Organic transformation, RC Laroc, VCH publisher Inc., 1989). .
2) Step 4
The compound (9-4) is produced from the compound (9-3) by a method similar to the method described in the literature (for example, Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.)). be able to.

Manufacturing method 10
Among the compounds represented by formula (1-4), the compounds represented by formula (10-4) and formula (10-6) or salts thereof are produced, for example, by the method shown below.

[Wherein, R ¹⁰² , R ¹⁰³ , R ¹⁰⁵ , X ⁴ , Y ¹ and Y ² have the same meanings as described above. ]

1) Step 1
Compound (10-2) can be produced from compound (7-1) by a method similar to the production method described in the literature (for example, Tetrahedron: Asymmetry 16, 2599 (2005)). Compound (7-1) can be produced by a method similar to the production method described in the literature (for example, WO05 / 028467 and the like).
2) Step 2
Compound (10-3) can be produced from compound (10-2) by a method similar to the method described in the literature (eg, Tetrahedron: Asymmetry 16, 2599 (2005)).
3) Step 3
The compound (10-4) is produced from the compound (10-3) by a method similar to the method described in the literature (for example, Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.)). be able to.
4) Step 4
Compound (10-5) can be produced from compound (10-3) by a method similar to the production method described in the literature (for example, Comprehensive Organic transformation, RC Larro, VCH publisher Inc., 1989). .
5) Step 5
The compound (10-6) is produced from the compound (10-5) by a method similar to the method described in the literature (for example, Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.)). be able to.

Manufacturing method 11
Among the compounds represented by formula (1-4), the compounds represented by formula (11-3) and formula (11-5) or salts thereof are produced by, for example, the method shown below.

[Wherein, R ¹⁰⁴ , R ¹⁰⁵ , X ⁴ , Y ¹ and Y ² have the same meanings as described above. ]

1) Step 1
Compound (11-2) can be produced by reacting compound (7-1) with compound (11-1) by a method similar to the production method described in the literature (for example, WO01 / 057044 etc.). .
2) Step 2
The compound (11-3) is produced from the compound (11-2) by a method similar to the method described in the literature (for example, Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.)). be able to.
3) Step 3
Compound (11-4) can be produced from compound (11-2) by a method similar to the production method described in the literature (for example, Comprehensive Organic transformation, RC Larro, VCH publisher Inc., 1989). .
4) Step 4
The compound (11-5) is produced from the compound (11-4) by a method similar to the method described in the literature (for example, Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.)). be able to.

Production method 12
Among the compounds represented by the formula (1-4), the compound represented by the formula (12-3) or a salt thereof is produced, for example, by the method shown below.

[Wherein R ¹⁰⁴ , Y ¹ and Y ² have the same meanings as described above, and R ¹¹² represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, or optionally substituted. an aryl group or a substituted by heteroaryl group, ^{wherein, R 104} and ^{R 112} may form a ring _{together, m 100a} is 0 or _{1, m 100b} is 1 or 2. ]

1) Step 1
Compound (12-2) can be produced from compound (12-1) by a method similar to the production method described in the literature (for example, Comprehensive Organic transformation, RC Larro, VCH publisher Inc., 1989). .
2) Step 2
The compound (12-3) is produced from the compound (12-2) by a method similar to the method described in the literature (for example, Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.)). be able to.

Production method 13
Of the compounds represented by formula (1-4), the compounds represented by formula (13-4) and formula (13-6) or salts thereof are produced, for example, by the method shown below.

[Wherein R ¹⁰⁵ , X ⁴ , Y ¹ and Y ² have the same meanings as described above, A ¹⁰⁰ is —SO ₂ — or —CO—, and B ¹⁰⁰ is a hydrogen atom, substituted. An optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, an optionally substituted aryl group, a substituted Represents an aralkyl group that may be substituted, a heteroaryl group that may be substituted, a heteroarylalkyl group that may be substituted, or a saturated heterocyclic group that may be substituted; m ₁₀₁ represents an integer of 0 or 1; ]

1) Step 1 to Step 2
Compound (13-3) can be produced from compound (13-1) by a method similar to the production method described in the literature (for example, Comprehensive Organic transformation, RC Larro, VCH publisher Inc., 1989). .
2) Step 3
The compound (13-4) is produced from the compound (13-3) by a method similar to that described in the literature (for example, Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.)). be able to.
3) Step 4
Compound (13-5) can be produced from compound (13-3) by a method similar to the production method described in the literature (for example, Comprehensive Organic transformation, RC Larro, VCH publisher Inc., 1989). .
4) Step 5
The compound (13-6) is produced from the compound (13-5) by a method similar to the method described in the literature (for example, Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.)). be able to.

Manufacturing method 14
Among the compounds represented by formula (1-4), the compound represented by formula (14-2) or a salt thereof is produced, for example, by the method shown below.

[Wherein, R ¹⁰⁴ , R ¹¹² , Y ¹ and Y ² have the same meanings as described above. ]
1) Step 1
Compound (14-1) can be produced from compound (6-1) by a method similar to the production method described in the literature (for example, Comprehensive Organic transformation, RC Larro, VCH publisher Inc., 1989). .
2) Step 2
The compound (14-2) is produced from the compound (14-1) by a method similar to the method described in the literature (for example, Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.)). be able to.

Production method 15
Among the compounds represented by formula (1-4), the compound represented by formula (15-3) or a salt thereof is produced, for example, by the method shown below.

[Wherein, R ¹⁰⁴ , R ¹¹² , R ¹⁰⁸ , Y ¹ and Y ² have the same meanings as described above. ]

1) Step 1 to Step 2
Compound (15-2) can be produced from compound (6-2) by a method similar to the production method described in the literature (for example, Comprehensive Organic transformation, RC Larro, VCH publisher Inc., 1989). .
2) Step 3
Compound (15-3) is produced from Compound (15-2) by a method similar to the method described in the literature (for example, Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.)) be able to.

Production method 16
Among the compounds represented by formula (1-4), the compounds represented by formula (16-4) and formula (16-6) or salts thereof are produced, for example, by the method shown below.

Wherein Y ¹ and Y ² are as defined above, m _100c is an integer of 0 to 4, R ¹¹³ is a halogen atom, an optionally substituted C _3-6 cycloalkyl group, group: ^{-OR 50,} group: -COR ^50, group: -OCOR ^51, group: -COOR ^{51, group:} -NR 53 ^{COR 55, group: -NR} 53 ^{R 55,} group: ^-CONR 53 ^{R 55,} group: —OCONR ⁵³ R ⁵⁵ , or substituent group α (R ⁵⁰ , R ⁵¹ , R ⁵² , R ⁵³ , R ⁵⁵ and substituent group α are the same as described above). ]

1) Step 1
From the compound (16-1) to the compound (16) by a method similar to the production method described in the literature (for example, Tetrahedron: Asymmetry 17, 993 (2006), Comprehensive Organic transformation, RC Laroc, VCH publisher Inc., 1989). 16-2) can be manufactured.
2) Step 2
Documents (for example, Tetrahedron: Asymmetry 8, 3685 (1997), J. Org. Chem. 61, 6033 (1996), JP-A-8-12605, Comprehensive Organic transformation, RC Rallock, VCH publisher Inc., 1989, etc.) The compound (16-3) can be produced from the compound (16-2) by the same production method as described above.
3) Step 3
Compound (16-4) is produced from Compound (16-3) by a method similar to that described in the literature (for example, Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.)). be able to.
4) Step 4
Compound (16-5) can be produced from compound (16-3) by a method similar to the production method described in the literature (for example, Comprehensive Organic transformation, RC Larro, VCH publisher Inc., 1989). .
5) Step 5
Compound (16-6) is produced from Compound (16-5) by a method similar to the method described in literature (for example, Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.)). be able to.

Manufacturing method 17
Of the compounds represented by formula (1-4), the compounds represented by formula (17-3) and formula (17-5) or salts thereof are produced, for example, by the method shown below.

[Wherein, R ¹⁰⁴ , R ¹⁰⁵ , X ⁴ , Y ¹ and Y ² have the same meanings as described above, and m ₁₀₂ represents 0 or an integer of 1. ]

1) Step 1
Compound (17-2) can be produced by reacting compound (17-1) and compound (11-1) by a method similar to the production method described in the literature (for example, WO01 / 057044). .

2) Step 2
The compound (17-3) is produced from the compound (17-2) by a method similar to the method described in the literature (for example, Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.)). be able to.
3) Step 3
Compound (17-4) can be produced from compound (17-2) by a method similar to the production method described in the literature (for example, Comprehensive Organic transformation, RC Laroc, VCH publisher Inc., 1989). .
4) Step 4
The compound (17-5) is produced from the compound (17-4) by a method similar to the method described in the literature (for example, Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.)). be able to.

Production method 18
Among the compounds represented by formula (1-4), the compounds represented by formula (18-5) and formula (18-7) or salts thereof are produced, for example, by the method shown below.

[Wherein R ¹⁰⁵ , X ⁴ , Y ¹ and Y ² have the same meanings as described above, m ₁₀₃ represents 0 or an integer of 1, and R ¹¹⁴ represents a hydrogen atom or an optionally substituted alkyl. Group, alkenyl group which may be substituted, alkynyl group which may be substituted, cycloalkyl group which may be substituted, cycloalkenyl group which may be substituted, aryl group which may be substituted, aralkyl which may be substituted A group, a heteroaryl group which may be substituted, a heteroarylalkyl group which may be substituted, or a saturated heterocyclic group which may be substituted; ]

1) Step 1
Compound (18-2) can be produced from compound (18-1) by a method similar to the production method described in the literature (for example, Tetrahedron Letters 43, 4275 (2002)).
2) Step 2
Compound (18-4) can be produced from compound (18-2) by a method similar to the production method described in the literature (for example, Comprehensive Organic transformation, RC Laroc, VCH publisher Inc., 1989). .
3) Step 3
Compound (18-5) is produced from Compound (18-4) by a method similar to that described in the literature (for example, Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.)). be able to.
4) Step 4
Compound (18-6) can be produced from compound (18-4) by a method similar to the production method described in the literature (for example, Comprehensive Organic transformation, RC Laroc, VCH publisher Inc., 1989). .
5) Step 5
The compound (18-7) is produced from the compound (18-6) by a method similar to that described in the literature (for example, Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.)). be able to.

Manufacturing method 19
Of the compounds represented by formula (1-4), the compound represented by formula (19-13) or a salt thereof is produced, for example, by the method shown below.

[Wherein, R ¹¹⁵ represents an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, An aryl group that may be substituted, an aralkyl group that may be substituted, a heteroaryl group that may be substituted, a heteroarylalkyl group that may be substituted, or a saturated heterocyclic group that may be substituted. ]

1) Step 1 to Step 8
Compound (19-11) can be produced from compound (19-1) by a method similar to the production method described in the literature (for example, WO06 / 039325).
2) Step 9 to Step 10
The compound (19-13) is produced from the compound (19-11) by a method similar to the production method described in the literature (for example, Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.)). Can do.

Manufacturing method 20
Among the compounds represented by formula (1-4), the compound represented by formula (20-8) or a salt thereof is produced, for example, by the method shown below.

[Wherein, R ² is the same as defined in the above item 1, and R ¹¹⁶ represents an optionally substituted aryl group or an optionally substituted heteroaryl group. ]

1) Step 1 to Step 5
Compound (20-7) can be produced from compound (20-1) by a method similar to the production method described in the literature (for example, Bioorganic & Medicinal Chemistry 13, 59 (2005)).
2) Step 6
Production of compound (20-8) from compound (20-7) by a method similar to the production method described in the literature (for example, Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.)) Can do.

Production method 21
Among the compounds represented by the formula (1-4), the compound represented by the formula (22-3) or a salt thereof is produced, for example, by the method shown below.

[Wherein, m _100a , R ¹¹² , A ¹⁰⁰ , B ¹⁰⁰ , Y ¹ and Y ² are as defined above. ]
1) Step 1
Compound (21-2) can be produced from compound (21-1) by the same method as in Step 2 described in Production Method 13. Compound (21-1) can be produced by a method similar to the production method described in production method 12.
2) Step 2
The compound (21-3) is produced from the compound (21-2) by a method similar to the production method described in the literature (for example, Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.)). Can do.

Production method 22
Among the compounds represented by the formula (1-1) in which X ¹ is a hydroxyl group, the compound represented by the formula (22-6) or a salt thereof is produced, for example, by the method shown below.

[Wherein, R ^1a , R ^1b , R ^1c and R ^1d are the same as described above, R ⁵⁰¹ represents methyl or ethyl, R ⁵⁰⁰ represents a C _1-4 alkyl group, and X ⁶ represents , An iodine atom, a bromine atom, a chlorine atom, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, or a p-toluenesulfonyloxy group. ]

1) Step 1
Compound (22-3a) can be produced by reacting compound (22-1) and compound (22-2) in an inert solvent. Examples of the inert solvent include hydrocarbon solvents such as toluene, benzene, and xylene. The reaction temperature is selected from the range of about 50 ° C to about 150 ° C. From the compound (22-1) to the compound (22) by a method similar to the production method described in the literature (for example, Chem. Rev. 105, 559 (2005), J. Med. Chem. 49, 2526 (2006)). -3a) can also be produced. In addition, the compound (22-3a) may be a compound (22-3b) which is a tautomer.
2) Step 2
Compound (22-5) can be produced by reacting compound (22-3a) with compound (22-4) in the presence of a base in an inert solvent. Examples of the base include potassium carbonate or an inorganic base such as sodium hydride. Examples of the inert solvent include aprotic solvents such as N, N′-dimethylformamide, dimethyl sulfoxide, or hexamethylenephosphoamide. The reaction temperature is selected from the range of about 20 ° C to about 100 ° C.
3) Step 3
Compound (22-7) can be produced by treating compound (22-6) with a base in an inert solvent. Examples of the base include potassium hydroxide or an inorganic base such as sodium hydride. Examples of the inert solvent include water, methanol, ethanol, tetrahydrofuran, or 1,4-dioxane, and a mixed solvent thereof may be used. The reaction temperature is selected from the range of about 50 ° C to about 120 ° C.

Manufacturing method 23
The compound represented by the formula (22-6) or a salt thereof can also be produced, for example, by the method shown below.

[Wherein, R ^1a , R ^1b , R ^1c and R ^1d are the same as described above. ]

1) Step 1 to Step 4
Compound (23-6) can be produced from compound (23-1) by a method similar to the production method described in the literature (for example, J Chem. Rev. 105, 559 (2005)).
2) Step 5
Compound (22-6) can be produced from compound (23-6) by the same method as in Step 3 described in Production Method 22.

Production method 24
Among the compounds represented by formula (1-4), the compound represented by formula (24-3) or a salt thereof is produced, for example, by the method shown below.

[Wherein, R ¹¹² , s and Y ² are the same as described above, and R ⁵⁰² represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group or an optionally substituted alkynyl group. , An optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, an optionally substituted aryl group, an optionally substituted aralkyl group, an optionally substituted heteroaryl group, an optionally substituted hetero Represents an arylalkyl group or an optionally substituted saturated heterocyclic group, and R ⁵⁰³ represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, Alternatively, it represents a heteroaryl group which may be substituted. ]
1) Step 1
Compound (24-2) can be produced from Compound (21-1) by a method similar to the production method described in the literature (for example, Bioorganic & Medicinal Chemistry Letters 1621, 16 (2006), WO99 / 054321 etc.). it can.
2) Step 2
The compound (24-3) is produced from the compound (24-2) by a method similar to that described in the literature (for example, Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.)). be able to.

  In each of the above production steps, when the starting compound of each reaction has a group active in the reaction such as a hydroxyl group, an amino group or a carboxy group, these groups other than the site to be reacted are preliminarily added as necessary. The compound of interest can be obtained by protecting with an appropriate protecting group and removing the protecting group after each reaction or several reactions. As a protecting group for protecting a hydroxyl group, an amino group, a carboxy group, etc., a usual protecting group used in the field of organic synthetic chemistry may be used. (For example, the method described in Protective Groups in Organic Synthesis, TW Greene, PGM Wuts, 2nd edition, John Wiley & Sons, Inc. (1991)).

  For example, examples of the hydroxyl-protecting group include a tert-butyldimethylsilyl group, a methoxymethyl group, and a tetrahydropyranyl group. Examples of the amino-protecting group include a tert-butyloxycarbonyl group and a benzyloxycarbonyl group. It is done. Such a hydroxyl-protecting group can be removed by reacting in a solvent such as hydrous methanol, hydrous ethanol, hydrous tetrahydrofuran or the like in the presence of an acid such as a base, sulfuric acid or acetic acid. In the case of a tert-butyldimethylsilyl group, for example, the reaction can be carried out in a solvent such as tetrahydrofuran in the presence of tetrabutylammonium fluoride. In the case of a tert-butyloxycarbonyl group, the amino protecting group is removed in the presence of an acid such as hydrochloric acid or trifluoroacetic acid in a solvent such as hydrous tetrahydrofuran, methylene chloride, chloroform or hydrous methanol. In the case of a benzyloxycarbonyl group, for example, it can be carried out by reacting in a solvent such as acetic acid in the presence of an acid such as hydrobromic acid.

  Examples of the form of protection when protecting the carboxy group include tert-butyl ester, ortho ester, acid amide and the like. In the case of tert-butyl ester, such removal of the protecting group is carried out by reaction in a water-containing solvent, for example, in the presence of hydrochloric acid, and in the case of ortho ester, for example, water-containing methanol, water-containing tetrahydrofuran, water-containing 1 In the case of acid amide, for example, in the presence of an acid such as hydrochloric acid or sulfuric acid, water is treated with an acid in a solvent such as 1,2-dimethoxyethane and subsequently with an alkali such as sodium hydroxide. The reaction can be carried out in a solvent such as hydrous methanol or hydrous tetrahydrofuran.

  The compounds of formula (I) also include those having an optically active center, so that they can be obtained as racemates or in optically active form when optically active starting materials are used. it can. If necessary, the racemates obtained can be physically or chemically resolved into their optical enantiomers by known methods. Preferably, diastereomers are formed from the racemate by a reaction using an optically active resolving agent. Different forms of diastereomers can be resolved by known methods such as fractional crystallization.

  The compound of the present invention can be converted to a salt by mixing with a pharmaceutically acceptable acid in a solvent such as water, methanol, ethanol, acetone or the like. Examples of the pharmaceutically acceptable acid are the same as those of the inorganic acid salt or organic acid acid salt exemplified above.

  The compound of the present invention can be applied to the treatment of various diseases because of its inhibitory action on renin. The compounds described herein are useful as therapeutic agents for hypertension. These compounds are also useful for the management of acute and chronic congestive heart failure. These compounds may be used in primary and secondary pulmonary hypertension, secondary hyperaldosteronemia, primary and secondary pulmonary hyperaldosteronemia, renal failure such as glomerulonephritis, diabetic nephropathy, glomerulosclerosis, primary It is also useful for the treatment of renal disease, end-stage renal disease, renovascular hypertension, left ventricular failure, diabetic retinopathy, and minimizing vascular disorders such as migraine, Raynaud's disease, and atherosclerosis processes Expected to be. It is also useful for treating diseases associated with high intraocular pressure, such as glaucoma.

  The compounds of the present invention, when used therapeutically, are used as pharmaceutical compositions as oral or parenteral (eg, intravenous, subcutaneous, or intramuscular injection, topical, rectal, transdermal, or nasal Administration). Examples of compositions for oral administration include tablets, capsules, pills, granules, powders, solutions, suspensions, etc. Examples of compositions for parenteral administration include, for example, injections. Aqueous agents or oily agents, ointments, creams, lotions, aerosols, suppositories, patches and the like can be mentioned. These preparations can be prepared using conventionally known techniques, and can contain non-toxic and inert carriers or excipients usually used in the pharmaceutical field.

  The dose varies depending on the individual compound and the patient's disease, age, weight, sex, symptom, route of administration, etc., but the compound of the present invention or a pharmaceutically acceptable salt thereof is usually used for adults (body weight 50 kg). The salt to be administered is administered in an amount of 0.1 to 1000 mg / day, preferably 1 to 300 mg / day once a day or divided into 2 to 3 times a day. It can also be administered once every few days to several weeks.

  The compound of the present invention is for the purpose of enhancing its effect, and is a drug such as a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, an antihyperlipidemic agent, an antihypertensive agent, an antiobesity agent, a diuretic agent, etc. Can be used in combination. The administration timing of the compound of the present invention and the concomitant drug is not limited, and these may be administered to the administration subject at the same time or may be administered with a time difference. Moreover, it is good also as a mixture of this invention compound and a concomitant drug. The dose of the concomitant drug can be appropriately selected based on the clinically used dose. The compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like. For example, when the administration subject is a human, the concomitant drug may be used in an amount of 0.01 to 100 parts by weight per 1 part by weight of the compound of the present invention.

  Examples of diabetes therapeutic agents include insulin preparations (eg, animal insulin preparations extracted from bovine and porcine pancreas; human insulin preparations synthesized by genetic engineering using Escherichia coli and yeast), insulin resistance improving agents ( Examples, pioglitazone or its hydrochloride, troglitazone, rosiglitazone or its maleate, GI-262570, JTT-501, MCC-555, YM-440, KRP-297, CS-011, etc.), α-glucosidase inhibitor ( Examples, voglibose, acarbose, miglitol, emiglitate, etc.), biguanides (eg, metformin, etc.), insulin secretagogues (eg, tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride, etc. Sulfonyl urea agents; repaglinide, senagrinide, nateglinide, mitiglinide, etc.), GLP-1, GLP-1 analogues (exenatide, liraglutide, SUN-E7001, AVE010, BIM-51077, CJC1131, etc.), protein tyrosine phosphatase inhibitors (eg, vanadic acid) Etc.), β3 agonists (eg, GW-427353B, N-5984, etc.), DPPIV inhibitors (eg, sitagliptin, vildagliptin, saxagliptin, SYR-322, etc.).

  Examples of the therapeutic agent for diabetic complications include aldose reductase inhibitors (eg, torrestat, epalrestat, zenarestat, zopolestat, minarestat, fidarestat, SK-860, CT-112, etc.), neurotrophic factors (eg, NGF, NT -3, BDNF, etc.), PKC inhibitors (eg, LY-333531, etc.), AGE inhibitors (eg, ALT946, pimagedin, pyratoxatin, N-phenacylthiazolium bromide (ALT766), etc.), active oxygen scavengers (eg, ALT766) Examples, thioctic acid, etc.) and cerebral vasodilators (eg, thioprid, mexiletine, etc.). Antihyperlipidemic agents include HMG-CoA reductase inhibitors (eg, pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, itavastatin, or their sodium salts), squalene synthase inhibitors, ACAT inhibitors, etc. Can be mentioned. As an antihypertensive agent, an angiotensin converting enzyme inhibitor (eg, captopril, enalapril, alacepril, delapril, lizinopril, imidapril, benazepril, cilazapril, temocapril, trandolapril, etc.), angiotensin II antagonist (eg, olmesartan, medoxomil, candesalmil, candesalmil) Cilexetil, losartan, eprosartan, valsantan, telmisartan, irbesartan, tasosartan, etc.), calcium antagonists (eg, nicardipine hydrochloride, manidipine hydrochloride, nisoldipine, nitrendipine, nilvadipine, amlodipine, etc.), ACE / NEP inhibitors (eg, omapatrilate) , Fasiditol, etc.), beta blockers (eg, atenolol, bisoprolol, betaxolol, metoprolol, etc.), alpha blockers (eg, urapidil, Lazocine, doxazosin, bunazosin, etc.), αβ blockers (eg, amosulalol, arotinolol, labetalol, carvedilol, etc.).

  Examples of anti-obesity agents include central anti-obesity agents (eg, phentermine, sibutramine, ampepramon, dexamphetamine, mazindol, SR-141716A, etc.), pancreatic lipase inhibitors (eg, orlistat, etc.), peptide anorectic agents (Eg, leptin, CNTF (ciliary neurotrophic factor), etc.), cholecystokinin agonists (eg, lynchtrypto, FPL-15849, etc.) and the like. Examples of diuretics include xanthine derivatives (eg, sodium salicylate theobromine, calcium salicylate theobromine, etc.), thiazide preparations (eg, etiazide, cyclopenthiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benchylhydrochlorothiazide, pentfurizide, polythiazide. , Methiclotiazide, etc.), anti-aldosterone preparations (eg, spironolactone, triamterene, etc.), carbonic anhydrase inhibitors (eg, acetazolamide, etc.), chlorobenzenesulfonamide preparations (eg, chlorthalidone, mefluside, indapamide, etc.), azosemide, isosorbide , Ethacrynic acid, piretanide, bumetanide, furosemide and the like.

  Two or more of the above concomitant drugs may be used in combination at an appropriate ratio.

  When the compound of the present invention is used in combination with a concomitant drug, the amount of these drugs used can be reduced within a safe range considering the side effects of the drug. Therefore, side effects that may be caused by these drugs can be safely prevented.

  Hereinafter, the present invention will be described more specifically with reference examples, examples, and test examples, but the present invention is not limited thereto. In addition, the compound names shown in the following Reference Examples and Examples do not necessarily follow the IUPAC nomenclature. Note that abbreviations may be used to simplify the description, but these abbreviations have the same meanings as described above.

Reference example 1
tert-butyl (3R) -3- (isopropylamino) piperidine-1-carboxylate

Dissolve tert-butyl (3R) -3-aminopiperidine-1-carboxylate (63.0 g) in methanol (300 ml) and acetone (93 ml), and slowly add sodium triacetoxyborohydride (100 g). In addition, the mixture was heated and stirred at 50 ° C. for 8 hours. Water (500 ml) was added to the reaction mixture, and methanol was distilled off under reduced pressure. An aqueous potassium carbonate solution was added to adjust the pH to 11, and the mixture was extracted twice with chloroform. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (83.75 g) as a colorless liquid.

MS (ESI +) 243 (M ⁺ +1, 100%).

Reference example 2
Ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate

Aniline (3.72 g) was dissolved in toluene (40 ml), diethyl ethoxymethylenemalonate (9.51 g) was added, and the mixture was stirred with heating at 100 ° C. for 10 hr. The reaction mixture was allowed to cool and toluene was distilled off under reduced pressure. The reaction mixture was dissolved in diphenyl ether (40 ml), heated to 240 ° C., and heated and stirred for 1 hour. The reaction mixture was allowed to cool to 60 ° C., hexane (40 ml) was added, and the mixture was heated with stirring at 60 ° C. for 1 hr. The precipitated solid was collected by filtration, washed with hexane, and dried under reduced pressure to give the title compound (1.60 g) as a white solid.

MS (ESI +) 218 (M ⁺ +1, 55%).

Reference example 3
Ethyl 8-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate

  2-Fluoroaniline (5.00 g) and diethyl ethoxymethylenemalonate (9.73 g) were mixed and stirred with heating at 120 ° C. for 1 hour. After allowing to cool, the solidified reaction mixture was dissolved in warm diphenyl ether (50 ml), heated to 240 ° C. and stirred for 1 hour. After allowing to cool, the precipitated solid was collected by filtration, washed with hexane, and dried under reduced pressure to give the title compound (2.01 g) as a white solid.

MS (ESI +) 236 (M ⁺ +1, 68%).

Reference example 4
Ethyl 7-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate

  The title compound (2.60 g) was synthesized in the same manner as in Reference Example 3.

MS (ESI +) 236 (M ⁺ +1, 45%).

Reference Example 5
Ethyl 6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate

  The title compound (1.30 g) was synthesized in the same manner as in Reference Example 3.

MS (ESI +) 236 (M ⁺ +1, 50%).

Reference Example 6
Ethyl 7-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate

  The title compound (0.86 g) was synthesized in the same manner as in Reference Example 3.

MS (ESI +) 232 (M ⁺ +1, 100%).

Reference Example 7
Ethyl 7-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylate

  The title compound (4.33 g) was synthesized in the same manner as in Reference Example 3.

MS (ESI +) 252 (M ⁺ +1, 100%).

Reference Example 8
Ethyl 1- (4-methoxybutyl) -4-oxo-1,4-dihydroquinoline-3-carboxylate

  The compound of Reference Example 2 (0.87 g) was dissolved in N, N-dimethylformamide (20 ml), 55% sodium hydride (209 mg) was added, and the temperature was raised to 60 ° C. After 20 minutes, potassium iodide (797 mg) was added, 1-chloro-4-methoxybutane (740 mg) was added dropwise, the temperature was raised to 80 ° C., and the mixture was heated and stirred for 8 hours. The reaction mixture was allowed to cool, toluene was added, and the reaction solvent was distilled off under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate (100 ml). The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the title crude product compound (1.15 g).

MS (ESI +) 304 (M ⁺ +1, 53%).

Reference Example 9
Ethyl 8-fluoro-1- (4-methoxybutyl) -4-oxo-1,4-dihydroquinoline-3-carboxylate

  To a solution of the compound of Reference Example 3 (2.00 g) in N, N-dimethylformamide (50 ml) was added cesium carbonate (8.30 g), 1-chloro-4-methoxybutane (1.15 g), and sodium iodide (1.30 g). ) Was added and stirred at 80 ° C. for 6 hours. 1-Chloro-4-methoxybutane (1.04 g) was added to the reaction mixture, and the mixture was further stirred with heating at 80 ° C. for 6 hr. After allowing to cool, saturated brine (200 ml) was poured into the reaction mixture, and the mixture was extracted twice with ethyl acetate (100 ml). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 4/1 to 0/1) to give the title compound (1.49 g).

MS (ESI +) 322 (M ⁺ +1, 100%).

Reference Example 10
Ethyl 7-fluoro-1- (4-methoxybutyl) -4-oxo-1,4-dihydroquinoline-3-carboxylate

  The title compound (1.10 g) was synthesized in the same manner as in Reference Example 9 using the compound of Reference Example 4.

MS (ESI +) 322 (M ⁺ +1, 100%).

Reference Example 11
Ethyl 6-fluoro-1- (4-methoxybutyl) -4-oxo-1,4-dihydroquinoline-3-carboxylate

  The title compound (1.45 g) was synthesized in the same manner as in Reference Example 9 using the compound of Reference Example 5.

MS (ESI +) 322 (M ⁺ +1, 60%).

Reference Example 12
Ethyl 7-methyl-1- (4-methoxybutyl) -4-oxo-1,4-dihydroquinoline-3-carboxylate

  The title compound (0.48 g) was synthesized in the same manner as in Reference Example 9 using the compound of Reference Example 6.

MS (ESI +) 318 (M ⁺ +1, 100%).

Reference Example 13
Ethyl 7-chloro-1- (4-methoxybutyl) -4-oxo-1,4-dihydroquinoline-3-carboxylate

  The title compound (1.24 g) was synthesized in the same manner as in Reference Example 9 using the compound of Reference Example 7.

MS (ESI +) 338 (M ⁺ +1, 100%).
Reference Example 14
Ethyl 7-fluoro-1- (3-methoxypropyl) -4-oxo-1,4-dihydroquinoline-3-carboxylate

  To a solution of Reference Example 4 (2.50 g) in N, N-dimethylformamide (100 ml), cesium carbonate (6.90 g) and 1-bromo-3-methoxypropane (2.44 g) were added and stirred at 80 ° C. for 8 hours. did. After allowing to cool, saturated brine (200 ml) was poured into the reaction mixture, and the mixture was extracted twice with ethyl acetate (100 ml). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 4/1 to 0/1) to give the title compound (1.20 g).

MS (ESI +) 308 (M ⁺ +1, 100%).

Reference Example 15
1- (4-Methoxybutyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid

  Reference Example 8 (1.15 g) was dissolved in ethanol (20 ml) and tetrahydrofuran (20 ml), 10% aqueous sodium hydroxide solution (4.8 ml) was added, and the mixture was stirred with heating at 50 ° C. for 6 hr. The reaction mixture was allowed to cool, ethanol was distilled off under reduced pressure, and 5% aqueous potassium hydrogen sulfate solution was added to adjust to pH2. Extracted with ethyl acetate (200 ml). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (0.84 g).

MS (ESI +) 276 (M ⁺ +1, 66%).

Reference Example 16
8-Fluoro-1- (4-methoxybutyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid

  The title compound (1.01 g) was synthesized in the same manner as in Reference Example 15 using the compound of Reference Example 9.

MS (ESI +) 294 (M ⁺ +1, 100%).

Reference Example 17
7-Fluoro-1- (4-methoxybutyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid

  The title compound (723 mg) was synthesized in the same manner as in Reference Example 15 using the compound of Reference Example 10.

MS (ESI +) 294 (M ⁺ +1, 100%).

Reference Example 18
6-Fluoro-1- (4-methoxybutyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid

  The title compound (1.41 g) was synthesized in the same manner as in Reference Example 15 using the compound of Reference Example 11.

MS (ESI +) 294 (M ⁺ +1, 58%).

Reference Example 19
7-Methyl-1- (4-methoxybutyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid

  The title compound (0.37 mg) was synthesized in the same manner as in Reference Example 15 using the compound of Reference Example 12.

MS (ESI +) 290 (M ⁺ +1, 100%).

Reference Example 20
7-Chloro-1- (4-methoxybutyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid

  The title compound (0.88 g) was synthesized in the same manner as in Reference Example 15 using the compound of Reference Example 13.

MS (ESI +) 310 (M ⁺ +1, 100%).

Reference Example 21
7-Fluoro-1- (3-methoxypropyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid

  The title compound (960 mg) was synthesized in the same manner as in Reference Example 15 using the compound of Reference Example 14.

MS (ESI +) 280 (M ⁺ +1, 65%).

Reference Example 22
tert-butyl (3R) -3- (isopropyl {[1- (4-methoxybutyl) -4-oxo-1,4-dihydroquinolin-3-yl] carbonyl} amino) piperidine-1-carboxylate

  Reference Example 15 (325 mg) was dissolved in dichloromethane (10 ml), oxalyl chloride (97 μl) and DMF (2 drops) were added, and the mixture was stirred at room temperature for 1 hour. Toluene (10 ml) was added to the reaction solution and concentrated under reduced pressure. The crude product was dissolved in dichloromethane (10 ml), a dichloromethane solution (5 ml) in which Reference Example 1 (121 mg) and triethylamine (139 μl) were mixed was added dropwise, and the mixture was stirred at 25 ° C. for 24 hours. Water was added to the reaction mixture, and the mixture was extracted twice with chloroform (50 ml). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform / methanol = 30/1) to give the title compound (152 mg) as a white amorphous product.

MS (ESI +) 500 (M ⁺ +1, 100%).

Reference Example 23
tert-butyl (3R) -3-[{[8-fluoro-1- (4-methoxybutyl) -4-oxo-1,4-dihydroquinolin-3-yl] carbonyl} (isopropyl) amino] piperidine-1 -Carboxylate

  The title compound (480 mg) was synthesized in the same manner as in Reference Example 22 using the compound of Reference Example 16.

MS (ESI +) 518 (M ⁺ +1, 95%).

Reference Example 24
tert-butyl (3R) -3-[{[7-fluoro-1- (4-methoxybutyl) -4-oxo-1,4-dihydroquinolin-3-yl] carbonyl} (isopropyl) amino] piperidine-1 -Carboxylate

  The title compound (680 mg) was synthesized in the same manner as in Reference Example 22 using the compound of Reference Example 17.

MS (ESI +) 518 (M ⁺ +1, 95%).

Reference Example 25
tert-Butyl (3R) -3-[{[7-ethoxy-1- (4-methoxybutyl) -4-oxo-1,4-dihydroquinolin-3-yl] carbonyl} (isopropyl) amino] piperidine-1 -Carboxylate

  The title compound (8 mg) was synthesized in the same manner as in Reference Example 22.

MS (ESI +) 544 (M ⁺ +1, 100%).

Reference Example 26
tert-Butyl (3R) -3-[{[6-Fluoro-1- (4-methoxybutyl) -4-oxo-1,4-dihydroquinolin-3-yl] carbonyl} (isopropyl) amino] piperidine-1 -Carboxylate

  The title compound (341 mg) was synthesized in the same manner as in Reference Example 22 using the compound of Reference Example 18.

MS (ESI +) 518 (M ⁺ +1, 95%).

Reference Example 27
tert-butyl (3R) -3-[{[7-methyl-1- (4-methoxybutyl) -4-oxo-1,4-dihydroquinolin-3-yl] carbonyl} (isopropyl) amino] piperidine-1 -Carboxylate

  The title compound (0.11 g) was synthesized in the same manner as in Reference Example 22 using the compound of Reference Example 19.

MS (ESI +) 514 (M ⁺ +1, 100%).

Reference Example 28
tert-Butyl (3R) -3-[{[7-Chloro-1- (4-methoxybutyl) -4-oxo-1,4-dihydroquinolin-3-yl] carbonyl} (isopropyl) amino] piperidine-1 -Carboxylate

  The title compound (0.43 g) was synthesized in the same manner as in Reference Example 22 using the compound of Reference Example 20.

MS (ESI +) 534 (M ⁺ +1, 100%).

Reference Example 29
tert-butyl (3R) -3-[{[7-fluoro-1- (3-methoxypropyl) -4-oxo-1,4-dihydroquinolin-3-yl] carbonyl} (isopropyl) amino] piperidine-1 -Carboxylate

  The title compound (310 mg) was synthesized in the same manner as in Reference Example 22 using the compound of Reference Example 21.

MS (ESI +) 504 (M ⁺ +1, 95%).

Example 1
N-isopropyl-1- (4-methoxybutyl) -4-oxo-N-[(3R) -piperidin-3-yl] -1,4-dihydroquinoline-3-carboxamide hydrochloride

  Reference Example 22 (152 mg) was dissolved in dioxane (3 ml), 4N hydrochloric acid / dioxane solution (3 mL) was added, and the mixture was stirred at 25 ° C. for 3 hr. The reaction solution was concentrated under reduced pressure and solidified with chloroform / hexane (1/4) to give the title compound (95 mg) as a white amorphous.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 8.22-8.19 (d, 1H, J = 7.8 Hz), 8.16 (s, 1H), 7.80-7.2 (m, 2H), 7.45-7.39 (m, 1H ), 4.33-4.30 (m, 2H), 3.77-3.67 (m, 2H), 3.55-3.24 (m, 3H), 3.18 (s, 3H), 3.06-3.00 (m, 1H), 2.76-2.66 (m , 2H), 1.86-1.66 (m, 5H), 1.54-1.40 (m, 3H), 1.23-1.09 (m, 6H).

MS (ESI +) 400 (M ⁺ +1, 100%).

Example 2
8-Fluoro-N-isopropyl-1- (4-methoxybutyl) -4-oxo-N-[(3R) -piperidin-3-yl] -1,4-dihydroquinoline-3-carboxamide hydrochloride

  The title compound (181 mg) was synthesized in the same manner as in Example 1 using the compound of Reference Example 23.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ8.20-8.00 (m, 2H), 7.65 (dd, 1H, J = 14.7 and 7.5 Hz), 7.45-7.35 (m, 1H), 4.50-4.20 ( m, 2H), 3.90-3.55 (m, 3H), 3.44-2.95 (m, 6H), 2.85-2.50 (m, 2H), 1.95-1.62 (m, 5H), 1.60-1.05 (m, 9H).

MS (ESI +) 418 (M ⁺ +1, 100%).

Example 3
7-Fluoro-N-isopropyl-1- (4-methoxybutyl) -4-oxo-N-[(3R) -piperidin-3-yl] -1,4-dihydroquinoline-3-carboxamide hydrochloride

  The title compound (120 mg) was synthesized in the same manner as in Example 1 using the compound of Reference Example 24.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 8.35-8.10 (m, 2H), 7.65 (d, 1H, J = 11.1 Hz), 7.26 (t, 1H, J = 8.1 Hz), 4.45-4.10 (m, 2H), 3.95-3.50 (m, 3H), 3.40-2.90 (m, 6H), 2.85-2.50 (m, 2H), 2.00-1.60 (m, 5H), 1.60-0.95 (m, 9H) .

MS (ESI +) 418 (M ⁺ +1, 100%).

Example 4
6-Fluoro-N-isopropyl-1- (4-methoxybutyl) -4-oxo-N-[(3R) -piperidin-3-yl] -1,4-dihydroquinoline-3-carboxamide hydrochloride

  The title compound (120 mg) was synthesized in the same manner as in Example 1 using the compound of Reference Example 26.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ8.20 (s, 1H), 7.95-7.80 (m, 2H), 7.75-7.60 (m, 1H), 4.45-4.25 (m, 2H), 3.90- 3.50 (m, 3H), 3.40-2.90 (m, 6H), 2.85-2.50 (m, 2H), 2.00-1.60 (m, 5H), 1.60-1.00 (m, 9H).

MS (ESI +) 418 (M ⁺ +1, 95%).

Example 5
7-Methyl-N-isopropyl-1- (4-methoxybutyl) -4-oxo-N-[(3R) -piperidin-3-yl] -1,4-dihydroquinoline-3-carboxamide trifluoroacetate

  Reference Example 27 (0.11 g) was dissolved in methylene chloride (1 ml), trifluoroacetic acid (0.3 mL) was added, and the mixture was stirred at 25 ° C. for 1 hr. The reaction solution was concentrated under reduced pressure to give the title compound (116 mg) as a yellow amorphous.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.32 (d, 1H, J = 8.4 Hz), 7.91 (s, 1H,), 7.30 (s, 1H,), 7.29 (d, 1H, J = 8.4 Hz ), 4.23 (t, 2H, J = 7.6 Hz), 3.99-3.94 (m, 2H), 3.74-3.72 (m, 1H), 3.31-3.46 (m, 7H), 3.03 (m, 1H), 2.54- 2.61 (m, 4H), 2.01-1.94 (m, 5H), 1.67 (m, 2H), 1.28-1.16 (m, 6H).

MS (ESI +) 414 (M ⁺ +1, 85%).

Example 6
7-Chloro-N-isopropyl-1- (4-methoxybutyl) -4-oxo-N-[(3R) -piperidin-3-yl] -1,4-dihydroquinoline-3-carboxamide hydrochloride

  The title compound (380 mg) was synthesized in the same manner as in Example 1 using the compound of Reference Example 28.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.36 (d, 1H, J = 8.4 Hz), 7.92 (s, 1H,), 7.48 (s, 1H,), 7.35 (d, 1H, J = 8.4 Hz ), 4.17-4.13 (m, 3H), 3.93-3.86 (m, 2H), 3.46-3.39 (m, 4H), 3.36 (s, 3H), 2.94-2.91 (m, 1H), 2.78-2.76 (m , 1H), 2.09-1.93 (m, 5H), 1.69 (m, 2H), 1.32-1.29 (m, 6H).

MS (ESI +) 434 (M ⁺ +1, 100%).

Example 7
7-Ethoxy-N-isopropyl-1- (4-methoxybutyl) -4-oxo-N-[(3R) -piperidin-3-yl] -1,4-dihydroquinoline-3-carboxamide hydrochloride

  Using the compound of Reference Example 25, the title compound (4 mg) was synthesized in the same manner as in Example 1.

MS (ESI +) 444 (M ⁺ +1, 100%).

Example 8
7-Fluoro-N-isopropyl-1- (3-methoxypropyl) -4-oxo-N-[(3R) -piperidin-3-yl] -1,4-dihydroquinoline-3-carboxamide hydrochloride

  The title compound (310 mg) was synthesized in the same manner as in Example 1 using the compound of Reference Example 29.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ8.24 (t, 1H, J = 7.5 Hz), 8.09 (s, 1H), 7.62 (d, 1H, J = 10.8 Hz), 7.26 (t, 1H , J = 7.5 Hz), 4.45-4.20 (m, 2H), 3.95-3.60 (m, 3H), 3.40-3.15 (m, 5H), 3.15-2.90 (m, 1H), 2.85-2.50 (m, 2H ), 2.00-1.60 (m, 5H), 1.50-1.00 (m, 7H).

MS (ESI +) 404 (M ⁺ +1, 100%).

In vitro renin inhibition test
50 μg of recombinant human renin was reacted with a substrate and a test compound for 1 hour at 37 ° C. in 0.1 M HEPES buffer pH 7.4 containing 0.1 M NaCl, 1 mM EDTA and 0.1 mg / mL BSA. Arg-Glu (EDANS) -Ile-His-Pro-Phe-His-Leu-Val-Ile-His-Thr-Lys (DABCYL) -Arg or DABCYL-γ-Abu-Ile-His-Pro- Phe-His-Leu-Val-Ile-His-Thr-EDANS was added to a final concentration of 4 μM. An increase in fluorescence intensity at an excitation wavelength of 340 nm and a fluorescence wavelength of 500 nm was detected using a fluorescence plate reader, and the concentration of the compound that inhibited by 50% was calculated as an IC ₅₀ value from the enzyme inhibitory activity when multiple concentrations of the test compound were added.

  The compounds of the present invention are useful as therapeutic agents for hypertension. These compounds are also useful for the management of acute and chronic congestive heart failure. These compounds may be used in primary and secondary pulmonary hypertension, secondary hyperaldosteronemia, primary and secondary pulmonary hyperaldosteronemia, renal failure such as glomerulonephritis, diabetic nephropathy, glomerulosclerosis, primary It is also useful for the treatment of renal disease, end-stage renal disease, renovascular hypertension, left ventricular failure, diabetic retinopathy, and minimizing vascular disorders such as migraine, Raynaud's disease, and atherosclerosis processes Expected to be. It is also useful for treating diseases associated with high intraocular pressure, such as glaucoma.

The amino acid sequence described in SEQ ID NO: 1 is an amino acid sequence used in the renin inhibitory action measurement test.

The amino acid sequence described in SEQ ID NO: 2 is an amino acid sequence used in the renin inhibitory action measurement test.

Claims (11)

A compound represented by formula (I) or a pharmaceutically acceptable salt thereof.
[Wherein, R ^1a represents an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, or an optionally substituted cycloalkenyl group. Is;
R ^1b , R ^1c and R ^1d are each independently the same or different and are each a hydrogen atom, a halogen atom, a hydroxyl group, a formyl group, a carboxy group, a cyano group, an optionally substituted alkyl group or an optionally substituted group. Alkenyl group, optionally substituted alkynyl group, optionally substituted cycloalkyl group, optionally substituted cycloalkenyl group, optionally substituted aryl group, optionally substituted aralkyl group, optionally substituted Heteroaryl group, optionally substituted heteroarylalkyl group, optionally substituted saturated heterocyclic group, optionally substituted alkylthio group, optionally substituted alkylsulfinyl group, optionally substituted alkylsulfonyl group Optionally substituted arylthio group, optionally substituted arylsulfinyl group, optionally substituted aryls A sulfonyl group, an optionally substituted alkoxy group, an optionally substituted alkynyloxy group, an optionally substituted cycloalkyloxy group, an optionally substituted aryloxy group, an optionally substituted aralkyloxy group, a substituted An optionally substituted heteroaryloxy group, an optionally substituted heteroarylalkyloxy group, an optionally substituted amino group, an optionally substituted aminocarbonyl group, an optionally substituted aminosulfonyl group, an optionally substituted An alkoxycarbonyl group, an optionally substituted cycloalkyloxycarbonyl group, an optionally substituted alkylcarbonyl group, an optionally substituted cycloalkylcarbonyl group, an optionally substituted arylcarbonyl group, or an optionally substituted A teloarylcarbonyl group;
R ² represents an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, or an optionally substituted A good aryl group, an optionally substituted aralkyl group, or an optionally substituted heteroaryl group;
R ^3a , R ^3b , R ^3c and R ^3d are each independently the same or different and are each a halogen atom, a cyano group, or a group: -AB
(Wherein, A represents a single _{bond, - (CH 2) s O} -, - (CH 2) s N (R 4) -, - (CH 2) s SO 2 -, - (CH 2) s CO- _{, - (CH 2) s COO} -, - (CH 2) s N (R 4) CO -, - (CH 2) s N (R 4) SO 2 -, - (CH 2) s N (R 4) ^{_{COO -, - (CH 2)}} s OCON (R 4) -, - (CH 2) s O-CO -, - (CH 2) s CON (R 4) -, - (CH 2) s N (R 4 ) CON (R ⁴ ) —, or — (CH ₂ ) _s SO ₂ N (R ⁴ ) —,
B is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, a substituted An optionally substituted aryl group, an optionally substituted aralkyl group, an optionally substituted heteroaryl group, an optionally substituted heteroarylalkyl group, or an optionally substituted saturated heterocyclic group (A is — _{^{(CH 2) s N (R}} 4) -, - (CH 2) s OCON (R 4) -, - (CH 2) s CON (R 4) -, - (CH 2) s N (R 4) CON In the case of (R ⁴ ) — and — (CH ₂ ) _s SO ₂ N (R ⁴ ) —, R ⁴ and B may be bonded together to form a ring. Or any two of R ^3a , R ^3b , R ^3c and R ^3d are hydrogen atoms and the remaining two together form a bridged ring with the piperidine ring;
R ⁴ represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, a substituted aryl group which may or substituted also to good heteroaryl group;
s is 0, 1 or 2. ] R ^1a is an optionally substituted C _1-6 alkyl group, an optionally substituted C _2-6 alkenyl group, an optionally substituted C _3-6 alkynyl group, an optionally substituted C _3-10 cyclo An alkyl group or an optionally substituted C _5-6 cycloalkenyl group;
R ^1b , R ^1c and R ^1d are each independently the same or different and are each a hydrogen atom, a halogen atom, a hydroxyl group, a formyl group, a carboxy group, a cyano group, an optionally substituted C _1-6 alkyl group or a substituted group. An optionally substituted C _2-6 alkenyl group, an optionally substituted C _3-6 alkynyl group, an optionally substituted C _3-10 cycloalkyl group, an _optionally substituted C _5-6 cycloalkenyl group, a substituted An _optionally substituted C _6-10 aryl group, an _optionally substituted C _7-14 aralkyl group, an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group, optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl C _1-4 alkyl group, optionally substituted 5- or 6-membered saturated heterocyclic group, optionally substituted C _1-6 alkylthio group Replaced Is a _{C 1-6} alkylsulfinyl group optionally, optionally substituted _{C 1-6} alkylsulfonyl group, optionally substituted _{C 6-10} arylthio group, optionally substituted _{C 6-10} arylsulfinyl group, C _6-10 arylsulfonyl group which may be substituted, C _1-6 alkoxy group which may be substituted, C _3-6 alkynyloxy group which may be substituted, C _3-10 cycloalkyloxy which may be substituted Group, optionally substituted C _6-10 aryloxy group, _optionally substituted C _7-14 aralkyloxy group, optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryloxy group An optionally substituted mono- or polycyclic heteroarylalkyloxy group, an optionally substituted amino group, an optionally substituted aminocarbo Nyl group, optionally substituted aminosulfonyl group, optionally substituted C _1-4 alkoxycarbonyl group, optionally substituted C _3-10 cycloalkyloxycarbonyl group, optionally substituted C _1-4 alkyl To a carbonyl group, an optionally substituted C _3-10 cycloalkylcarbonyl group, an optionally substituted C _6-10 arylcarbonyl group, or an optionally substituted 5- to 10-membered monocyclic or polycyclic The compound according to claim 1, which is a teloarylcarbonyl group, or a pharmaceutically acceptable salt thereof. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R ^1a is an optionally substituted C _1-6 alkyl group or an optionally substituted C _3-6 alkynyl group. R ^1b , R ^1c and R ^1d are a hydrogen atom, a halogen atom, a carboxy group, a cyano group, an optionally substituted C _1-6 alkyl group, an optionally substituted 5- to 10-membered monocyclic or polyvalent heteroaryl group, optionally substituted C _1-6 alkylsulfonyl group, optionally substituted C _6-10 arylsulfonyl group, optionally substituted C _1-6 alkoxy group, an optionally substituted C _3-10 cycloalkyloxy group, C _6-10 aryloxy group which may be substituted, C _7-14 aralkyloxy group which may be substituted, amino group which may be substituted, aminocarbonyl group which may be substituted , optionally substituted aminosulfonyl group, a compound according to any one of claims 1 to 3 is optionally substituted C _1-4 alkoxycarbonyl group, or a drug Salt to be above acceptable. R ² is an optionally substituted C _1-6 alkyl group, an optionally substituted C _2-6 alkenyl group, an optionally substituted C _3-6 alkynyl group, an optionally substituted C _3-10 cyclo An alkyl group, an optionally substituted C _5-6 cycloalkenyl group, an optionally substituted C _6-10 aryl group, an optionally substituted C _7-14 aralkyl group, or an optionally substituted 5 member to 10 member It is a member monocyclic or polycyclic heteroaryl group, The compound as described in any one of Claims 1-4, or its pharmaceutically acceptable salt. The compound according to claim 5, or a pharmaceutically acceptable salt thereof, wherein R ² is an optionally substituted C _1-6 alkyl group or an optionally substituted C _3-10 cycloalkyl group. The compound according to claim 6, or a pharmaceutically acceptable salt thereof, wherein R ² is an optionally substituted C _1-6 alkyl group. The compound according to claim 7, or a pharmaceutically acceptable salt thereof, wherein R ² is an isopropyl group. R ⁴ is a hydrogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C _3-10 cycloalkyl group, an optionally substituted C _6-10 aryl group, or an optionally substituted group. Item 9. The compound according to any one of Items 1 to 8, or a pharmaceutically acceptable salt thereof, which is a 5- to 10-membered monocyclic or polycyclic heteroaryl group. ^{R 3a,} R 3b, R ^3c and ^{R 3d} are each independently the same or different, a halogen atom, a cyano group or a group,: -A-B
(Wherein, A represents a single _{bond, - (CH 2) s O} -, - (CH 2) s N (R 4) -, - (CH 2) s SO 2 -, - (CH 2) s CO- _{, - (CH 2) s COO} -, - (CH 2) s N (R 4) CO -, - (CH 2) s N (R 4) SO 2 -, - (CH 2) s N (R 4) ^{_{COO -, - (CH 2)}} s OCON (R 4) -, - (CH 2) s O-CO -, - (CH 2) s CON (R 4) -, - (CH 2) s N (R 4 ) CON (R ⁴ ) —, or — (CH ₂ ) _s SO ₂ N (R ⁴ ) —,
B represents a hydrogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C _2-6 alkenyl group, an optionally substituted C _3-6 alkynyl group, an optionally substituted C _{3-3- 10} cycloalkyl group, optionally substituted C _5-6 cycloalkenyl group, _optionally substituted C _6-10 aryl group, _optionally substituted C _7-14 aralkyl group, optionally substituted 5 membered to A 10-membered monocyclic or polycyclic heteroaryl group, an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl C _1-4 alkyl group, or an optionally substituted 5-membered or A 6-membered saturated heterocyclic group (A is — (CH ₂ ) _s N (R ⁴ ) —, — (CH ₂ ) _s OCON (R ⁴ ) —, — (CH ₂ ) _s CON (R ⁴ ) ^{_{-, - (CH 2) s}} N (R 4) CON (R 4) -, and _{- (CH 2) s SO 2} N (R 4) - in the case of may be bonded ^{R 4} and B together form a ring).. Or any two of R ^3a , R ^3b , R ^3c and R ^3d are hydrogen atoms and the remaining two together form a bridged ring with the piperidine ring, and s and R ⁴ are the term Item 10. The compound according to any one of Items 1 to 9, which is the same as 1, or a pharmaceutically acceptable salt thereof. R ^3a , R ^3b , R ^3c and R ^3d are each independently the same and have the group: -AB
(Here, A is a single bond, B is a hydrogen atom, The compound or its pharmaceutically acceptable salt as described in any one of Claims 1-9.