JP2010229034A - Bicyclic pyrrole derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new compound that exhibits a renin-inhibiting action and is useful as a therapeutic agent for hypertension. <P>SOLUTION: A compound of formula (I) and a pharmaceutically acceptable salt thereof are provided. In the formula, G is a group represented by formula (a) or the like; R<SP>3a</SP>, R<SP>3b</SP>, R<SP>3c</SP>and R<SP>3d</SP>are each a hydrogen atom or the like; and n is 1 or the like. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to a bicyclic pyrrole derivative useful as a medicine. More specifically, the present invention relates to a bicyclic pyrrole derivative effective as a renin inhibitor. Furthermore, the present invention relates to an antihypertensive agent comprising a bicyclic pyrrole 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, in Patent Document 1, Patent Document 2, Patent Document 3 and Patent Document 4, it is reported that a derivative having a piperidine ring is effective as a renin inhibitor. Patent Document 5 reports 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 the amino group via a carbonyl or methylene chain. However, a compound group in which the nitrogen atom of pyrrolylcarbonylamino in the bicyclic pyrrole is directly bonded to the 3-position of the piperidine ring, that is, a compound group having 3- (2-pyrrolylcarbonylamino) piperidine or the like as a basic skeleton It has not been known to be 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. 07/006534 Pamphlet International Publication No. 07/077055 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.

[In the formula, G represents the following (a) to (c)

Any one group represented by:
R ^1a is 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 a substituted A heteroarylalkyl group which may be
R ^1b , R ^1c , R ^1d and R ^1e 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, a substituted 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, a substituted An optionally substituted heteroaryl group, an optionally substituted heteroarylalkyl group, an optionally substituted saturated heterocyclic group, an optionally substituted alkylthio group, an optionally substituted alkylsulfinyl group, an optionally substituted Alkylsulfonyl group, optionally substituted arylthio group, optionally substituted arylsulfinyl group, optionally substituted A reelsulfonyl 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 Heteroaryloxy group which may be substituted, heteroarylalkyloxy group which may be substituted, amino group which may be substituted, aminocarbonyl group which may be substituted, aminocarbonyloxy group which may be substituted, substituted Aminosulfonyl group, optionally substituted alkoxycarbonyl group, optionally substituted cycloalkyloxycarbonyl group, optionally substituted alkylcarbonyl group, optionally substituted cycloalkylcarbonyl group, optionally substituted An arylcarbonyl group or an optionally substituted heteroatom It is Lumpur carbonyl group;
R ^1f is a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, a substituted An optionally substituted cycloalkenyl group, an optionally substituted aryl group, an optionally substituted aralkyl group, an optionally substituted heteroaryl group, an optionally substituted heteroarylalkyl group, an optionally substituted saturated heteroalkyl group A cyclic group, an optionally substituted alkylthio group, an optionally substituted alkylsulfinyl group, an optionally substituted alkylsulfonyl group, an optionally substituted alkoxy group, an optionally substituted alkynyloxy group, and optionally substituted Good cycloalkyloxy group, optionally substituted aryloxy group, optionally substituted aralkyloxy group, substituted Heteroarylalkyloxy group which may be substituted, amino group which may be substituted, aminocarbonyl group which may be substituted, aminosulfonyl group which may be substituted, alkoxycarbonyl group which may be substituted, may be substituted A cycloalkyloxycarbonyl group, an optionally substituted alkylcarbonyl group, an optionally substituted cycloalkylcarbonyl group, an optionally substituted arylcarbonyl group, or an optionally substituted heteroarylcarbonyl 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 is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted aralkyl group, or an optionally substituted heteroaryl group. Yes;
When s is 0, 1 or 2 (-(CH ₂ ) _s N (R ⁴ )-, s is 0 or 2, and when-(CH ₂ ) _s CON (R ⁴ )- , S is 1 or 2.);
n is 0, 1, or 2. ]

Item 2: G is the following (a)

The compound of claim | item 1 which is group represented by these, or its salt.

Item 3: R ^1a is an optionally substituted C _1-10 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, or an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl C _1-4 alkyl group;
R ^1b , R ^1c , R ^1d and R ^1e 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, or an optionally substituted C _1-6 alkyl. Group, C _2-6 alkenyl group which may be substituted, C _3-6 alkynyl group which may be substituted, C _3-10 cycloalkyl group which may be substituted, C _5-6 cycloalkenyl which may be substituted A group, 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, substituted An optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl C _1-4 alkyl group, an optionally substituted 5- or 6-membered saturated heterocyclic group, an optionally substituted C _{1-; 6} alkylthio , Optionally substituted _{C 1-6} alkylsulfinyl group, optionally substituted _{C 1-6} alkylsulfonyl group, optionally substituted _{C 6-10} arylthio group, optionally substituted _{C 6-10} arylsulfinyl Group, optionally substituted C _6-10 arylsulfonyl group, optionally substituted C _1-6 alkoxy group, optionally substituted C _3-6 alkynyloxy group, optionally substituted C _3-10 cyclo An alkyloxy group, an optionally substituted C _6-10 aryloxy group, an _optionally substituted C _7-14 aralkyloxy group, an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl Oxy group, optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl C _1-4 alkyloxy group, optionally substituted amino group, substituted An optionally substituted aminocarbonyl group, an optionally substituted aminocarbonyloxy group, an optionally substituted aminosulfonyl group, an optionally substituted C _1-4 alkoxycarbonyl group, an optionally substituted C _3-10 cycloalkyloxy A carbonyl group, an optionally substituted C _1-4 alkylcarbonyl group, an optionally substituted C _3-10 cycloalkylcarbonyl group, an optionally substituted C _6-10 arylcarbonyl group, or an optionally substituted 5 A membered to 10-membered monocyclic or polycyclic heteroarylcarbonyl group;
R ^1f is a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, 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 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- to 10-membered monocyclic or polycyclic heteroaryl group, an 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, optionally substituted C _1-6 alkylsulfinyl group, optionally substituted C _{1- 6} alkylsulfonyl Group, optionally substituted _{C 1-6} alkoxy group, an optionally substituted _{C 3-6} alkynyloxy group, an optionally substituted _{C 3-10} cycloalkyl group, optionally substituted _{C 6- 10} aryloxy group, optionally substituted C _7-14 aralkyloxy group, optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl C _1-4 alkyloxy group, optionally substituted A good amino group, an optionally substituted aminocarbonyl group, an optionally substituted aminosulfonyl group, an optionally substituted C _1-4 alkoxycarbonyl group, an optionally substituted C _3-10 cycloalkyloxycarbonyl group, C _1-4 alkylcarbonyl group which may be substituted, C _3-10 cycloalkylcarbonyl group which may be substituted, C _6-10 aryl which may be substituted Item 3. The compound according to Item 1 or Item 2, or a pharmaceutically acceptable salt thereof, which is a carbonyl group, or an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroarylcarbonyl group.

Item 4: R ^1a is an optionally substituted C _1-10 alkyl group, an optionally substituted C _2-6 alkenyl group, an optionally substituted C _3-6 alkynyl group, or an optionally substituted 5 Item 6. The compound according to any one of Items 1 to 3, or a pharmaceutically acceptable salt thereof, which is a 10-membered monocyclic or polycyclic heteroaryl C _1-4 alkyl group.

Item 5: The compound according to Item 4, or a pharmaceutically acceptable salt thereof, wherein R ^1a is an optionally substituted C _1-10 alkyl group.

Item 6: The compound according to Item 5, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted C _1-10 alkyl group is an optionally substituted C _1-6 alkyl group.

Item 7: The compound according to Item 6, or a pharmaceutically acceptable salt thereof, wherein R ^1a is C _1-4 alkoxy, or a C _1-6 alkyl group optionally substituted with C _1-4 alkoxycarbonylamino. .

Item 8: The compound according to Item 7, 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 9: The compound according to Item 8, or a pharmaceutically acceptable salt thereof, wherein R ^1a is 4-methoxybutyl.

Item 10: The compound according to Item 7, or a pharmaceutically acceptable salt thereof, wherein R ^1a is a C _1-6 alkyl group optionally substituted with C _1-4 alkoxycarbonylamino.

Item 11: R ^1b , R ^1c , R ^1d and R ^1e are each independently the same or different and are a hydrogen atom, a halogen atom, a hydroxyl group, a carboxy group, a cyano group, or an optionally substituted C _1-6 alkyl A group, an optionally substituted mono- or polycyclic heteroaryl group having 10 to 10 members, an optionally substituted C _1-6 alkylsulfonyl group, an optionally substituted C _6-10 arylsulfonyl group, C _1-6 alkoxy group which may be substituted, C _3-10 cycloalkyloxy group which may be substituted, C _6-10 aryloxy group which may be substituted, C _7-14 aralkyloxy which may be substituted A group, an optionally substituted amino group, an optionally substituted aminocarbonyl group, an optionally substituted aminocarbonyloxy group, an optionally substituted aminosulfonyl group, or Item 11. The compound according to any one of Items 1 to 10, which is a C _1-4 alkoxycarbonyl group which may be substituted, or a pharmaceutically acceptable salt thereof.

Claim ^{12: R 1b} is a hydrogen atom, a halogen atom, a hydroxyl group, a carboxyl group, a cyano group, an optionally substituted _{C 1-6} alkyl group, optionally substituted _{C 1-6} alkoxy group, may be substituted Item 1 which is a C _3-10 cycloalkyloxy group, an optionally substituted C _7-14 aralkyloxy group, an optionally substituted aminocarbonyloxy group, or an optionally substituted C _1-4 alkoxycarbonyl group. Item 12. The compound according to any one of Items 11 or a pharmaceutically acceptable salt thereof.

Item 13: R ^1b is a hydrogen atom; hydroxyl group; carboxy group; cyano group; carboxy, cyano, hydroxy, C _1-4 alkoxy, mono- or di-substituted amino, 5-membered to 7-membered cyclic amino, C _1-4 Alkoxycarbonylamino, (C _1-6 alkyl) sulfonylamino, (C _1-6 alkyl) sulfonyl-N— (C _1-6 alkyl) -amino, mono- or di- (C _1-6 alkyl) aminosulfonylamino, Aminocarbonyl, mono- or di-substituted aminocarbonyl, 5- to 7-membered cyclic aminocarbonyl, mono- or di- (C _1-6 alkyl) aminocarbonyloxy, C _1-4 alkylsulfonyl, C _1-4 alkylcarbonyl amino or a 5- or a C _1-6 a be substituted may be substituted with hetero ring 6 membered saturated, Kokishi group; C _1-6 alkyl optionally substituted aminocarbonyl group be; or C _1-4 The compound according to claim 12 is an alkoxycarbonyl group, or a pharmaceutically acceptable salt thereof,.

Item 14: The compound according to Item 13, or a pharmaceutically acceptable salt thereof, wherein R ^1b is a hydrogen atom.

Item 15: The compound according to any one of Items 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R ^1c , R ^1d and R ^1e are each independently the same and are a hydrogen atom.

Item 16: R ^1f is a hydrogen atom, a halogen atom, a cyano group, an optionally substituted C _1-6 alkyl group, an _optionally substituted C _3-10 cycloalkyl group, or an _optionally substituted C _1-6. In any one of Items 1 to 14, which is an alkoxy group, an optionally substituted C _7-14 aralkyloxy group, an optionally substituted aminocarbonyl group, or an optionally substituted C _1-4 alkylcarbonyl group. Or a pharmaceutically acceptable salt thereof.

Item 17: R ^1f is a hydrogen atom; a halogen atom; a cyano group; a C _1-6 alkyl group; a C _1-4 alkoxy, a C _3-6 cycloalkyl, a 5-membered or 6-membered saturated heterocyclic ring, or an aminocarbonyl A C _1-6 alkoxy group optionally substituted by 1 to 3; a C _7-14 aralkyloxy group optionally substituted by 1 to 3 fluorine atoms; a C _1-6 alkylthio group; a hydroxyl group; a 5-membered or 6-membered hetero Item 18. The compound according to Item 16, or a salt thereof, which is an aryl C _1-4 alkoxy group; a C _1-6 alkylsulfonyl group; a C _2-6 alkenyl group; or a 5-membered or 6-membered heteroaryl group.

Item 18: The compound according to Item 17, or a pharmaceutically acceptable salt thereof, wherein R ^1f is a hydrogen atom or a halogen atom.

Item 19: 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 19. The compound according to any one of Items 1 to 18, or a pharmaceutically acceptable salt thereof, which is a 10-membered monocyclic or polycyclic heteroaryl group.

Item 20: The compound according to Item 19, 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 21: The compound according to Item 20, or a pharmaceutically acceptable salt thereof, wherein R ² is an optionally substituted C _1-6 alkyl group.

Item 22: The compound according to Item 21, or a pharmaceutically acceptable salt thereof, wherein R ² is an isopropyl group.

Item 23: 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 23. The compound according to any one of Items 1 to 22, or a pharmaceutically acceptable salt thereof, which is the same as 1.

Item 24: R ^3a , R ^3b , R ^3c and R ^3d are each independently the same, and the group: -AB
Item 23. The compound according to any one of Items 1 to 22, or a pharmaceutically acceptable salt thereof, wherein A is a single bond and B is a hydrogen atom.

Item 25: 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, substituted The compound according to any one of Items 1 to 23, which may be a C _7-14 aralkyl group, or an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group, or a compound thereof. A pharmaceutically acceptable salt.

Item 26: The compound according to Item 25 or a pharmaceutically acceptable salt thereof, wherein R ⁴ is a hydrogen atom, an optionally substituted C _1-6 alkyl group, or an optionally substituted C _3-10 cycloalkyl group. Salt.

Item 27: The compound according to any one of Items 1 to 22, wherein n is 1, or a pharmaceutically acceptable salt thereof.

Item 28: A compound represented by the formula (II), or a pharmaceutically acceptable salt thereof.

[Wherein, R ^12a is an optionally substituted C _1-10 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, an optionally substituted C _5-6 cycloalkenyl group, or an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl C _1-4 alkyl group;
R ^12b , R ^12c , R ^12d and R ^12e are each independently the same or different and are each a hydrogen atom, a halogen atom, a hydroxyl group, a carboxy group, a cyano group, an optionally substituted C _1-6 alkyl group or a substituted group. 5-membered to 10-membered monocyclic or polycyclic heteroaryl group, optionally substituted C _1-6 alkylsulfonyl group, optionally substituted C _6-10 arylsulfonyl group, substituted C _1-6 alkoxy group which may be substituted, C _3-6 cycloalkyloxy group which may be substituted, C _6-10 aryloxy group which may be substituted, C _7-14 aralkyloxy group which may be substituted, substituted An optionally substituted amino group, an optionally substituted aminocarbonyl group, an optionally substituted aminocarbonyloxy group, an optionally substituted aminosulfonyl group, or A C _1-4 alkoxycarbonyl group which may be _substituted ;
R ^12f is a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, an optionally substituted C _1-6 alkyl group, an optionally substituted C _3-10 cycloalkyl group, or an optionally substituted C _1-6 alkoxy. A group, an optionally substituted C _7-14 aralkyloxy group, an optionally substituted aminocarbonyl group, or an optionally substituted C _1-4 alkylcarbonyl 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 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, or an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group;
s ₂ is 0, 1 or _{2 (- (CH 2) s2} N (R 42) - in the case of, _{s 2} is 0 or _{2, - (CH 2) s2} CON (R 42) - For S ₂ is 1 or 2.) ]

Item 29: R ^12a is a C _3-6 cycloalkyl optionally substituted with a fluorine atom or C _1-4 alkoxy, C _1-4 alkoxy optionally substituted with C _1-4 alkoxy, a hydroxyl group, trifluoromethyl , Trifluoromethoxy, difluoromethoxy, monofluoromethoxy, C _1-4 alkylcarbonylamino, C _1-4 alkoxycarbonylamino, C _3-6 cycloalkyloxy, mono or di (C ₁₎ optionally substituted with fluorine atoms _-4 alkyl) _{aminocarbonyl, C 1-4 alkylsulfonylamino, C 1-4} alkylsulfonyl, selected amino optionally substituted, and from the group consisting of mono- or di _{(C 1-4} alkyl) aminocarbonylamino one good _{C 1-10} alkyl group optionally substituted by _{group, C 2-6} a Kenyir group, C _3-6 alkynyl group or compound according to claim 28, which is a monocyclic or polycyclic heteroaryl C _1-4 alkyl group optionally substituted 5-membered to 10-membered, or a pharmaceutically Acceptable salt.

Item 30: The compound or a pharmaceutically acceptable salt thereof according to Item 29, wherein the optionally substituted C _1-10 alkyl group is an optionally substituted C _1-6 alkyl group.

Item 31: The compound according to Item 29 or a pharmaceutically acceptable salt thereof, wherein R ^12a is C _1-4 alkoxy, or a C _1-6 alkyl group optionally substituted with C _1-4 alkoxycarbonylamino. .

Item 32: The compound according to Item 31 or a pharmaceutically acceptable salt thereof, wherein R ^12a is a C _1-6 alkyl group optionally substituted with C _1-4 alkoxy.

Claim ^{33: R 12a} is, 4-methoxy compound according to claim 32 which is butyl or a pharmaceutically acceptable salt thereof,.

Item 34: The compound according to Item 31, or a pharmaceutically acceptable salt thereof, wherein R ^12a is a C _1-6 alkyl group optionally substituted with C _1-4 alkoxycarbonylamino.

Item 35: R ^12b is a hydrogen atom; hydroxyl group; carboxy group; cyano group; carboxy, cyano, hydroxy, C _1-4 alkoxy, mono- or di-substituted amino, 5-membered to 7-membered cyclic amino, C _1-4 Alkoxycarbonylamino, (C _1-6 alkyl) sulfonylamino, (C _1-6 alkyl) sulfonyl-N— (C _1-6 alkyl) -amino, mono- or di- (C _1-6 alkyl) aminosulfonylamino, Aminocarbonyl, mono- or di-substituted aminocarbonyl, 5- to 7-membered cyclic aminocarbonyl, mono- or di- (C _1-6 alkyl) aminocarbonyloxy, C _1-4 alkylsulfonyl, C _1-4 alkylcarbonyl amino or optionally substituted may be substituted with heterocyclic 5-membered or 6-membered saturated, C _1-6 Alkoxy groups; C _1-6 good aminocarbonyl group which may be substituted by alkyl; A compound according to any one of or a C _1-4 alkoxy claim 28 to claim 34 is a carbonyl group, or a is pharmaceutically acceptable Salt.

36.: salt R ^12b A compound according to claim 35 is a hydrogen atom, or is a pharmaceutically acceptable.

Item 37: The compound according to any one of Items 28 to 36, or a pharmaceutically acceptable salt thereof, wherein R ^12c , R ^12d and R ^12e are each independently the same and a hydrogen atom.

Item 38: R ^12f is a hydrogen atom; a halogen atom; a cyano group; a C _1-6 alkyl group; a C _1-4 alkoxy, a C _3-6 cycloalkyl, a 5- or 6-membered saturated heterocyclic ring, or an aminocarbonyl A C _1-6 alkoxy group optionally substituted by 1 to 3; a C _7-14 aralkyloxy group optionally substituted by 1 to 3 fluorine atoms; a C _1-6 alkylthio group; a hydroxyl group; a 5-membered or 6-membered hetero The compound according to any one of Items 28 to 37, which is an aryl C _1-4 alkoxy group; a C _1-6 alkylsulfonyl group; a C _2-6 alkenyl group; or a 5-membered or 6-membered heteroaryl group, or Its pharmaceutically acceptable salt.

Item 39: The compound according to Item 38 or a pharmaceutically acceptable salt thereof, wherein R ^12f is a hydrogen atom or a halogen atom.

Item 40: The compound according to any one of Items 28 to 39, or a pharmaceutically acceptable salt thereof, wherein R ²² is an optionally substituted C _1-6 alkyl group.

Item 41: The compound according to Item 40 or a pharmaceutically acceptable salt thereof, wherein R ²² is an isopropyl group.

Item 42: 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, or _{- (CH 2)} s2 is O-, ^{B 2} is a hydrogen atom, substituted good _{C 6- 10} aryl group, optionally substituted C _7-14 aralkyl group or substituted monocyclic or polycyclic heteroaryl group which may 5- to 10-membered.) of claim 28 to claim 41 is, The compound according to any one of the above, or a pharmaceutically acceptable salt thereof.

Item 43: 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). 43. The compound according to 42, or a pharmaceutically acceptable salt thereof.

Claim ^{44: R 32c} is a group: ^{-A 2} -B 2 (wherein, ^{A 2} is _{- (CH 2)} s2 is O-, ^{B 2} is a hydrogen atom.) According to claim 42 which is Or a pharmaceutically acceptable salt thereof.

Item 45: 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)} -, and _{- (CH 2) s2 SO 2} N (R 42) - when the ^{combines R 42} and ^{B 2} together may form a ring). . 42. The compound according to any one of Items 28 to 41, or a pharmaceutically acceptable salt thereof.

Claim ^{46: 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 ( 46. The compound according to item 45, which is R ⁴² ) CON (R ⁴² ) —, or a pharmaceutically acceptable salt thereof.

Item 47: 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)} -, and _{- (CH 2) s2 SO 2} N (R 42) - in the case of ^{combines R 42} and ^{B 2} together may form a ring). . 42. The compound according to any one of Items 28 to 41, or a pharmaceutically acceptable salt thereof.

Claim ^{48: 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 ( 48. The compound according to item 47, which is R ⁴² ) CON (R ⁴² ) —, or a pharmaceutically acceptable salt thereof.

Item 49: R ^32a , R ^32b , R ^32c and R ^32d are each independently the same and have the group: —A ² —B ² (wherein A ² is a single bond, and B ² is hydrogen 42. The compound according to any one of Items 28 to 41 or a pharmaceutically acceptable salt thereof.

Item 50: A pharmaceutical comprising the compound according to any one of Items 1 to 49 or a pharmaceutically acceptable salt thereof as an active ingredient.

Item 51: A renin inhibitor comprising the compound according to any one of Items 1 to 49 or a pharmaceutically acceptable salt thereof as an active ingredient.

Item 52: A therapeutic agent for hypertension comprising the compound according to any one of Items 1 to 49 or a pharmaceutically acceptable salt thereof as an active ingredient.

Item 53: Use of the compound according to any one of Items 1 to 49 or a pharmaceutically acceptable salt thereof for the production of a renin inhibitor.

Item 54: Use of the compound according to any one of Items 1 to 49 or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic agent for hypertension.

Item 55: A method for treating hypertension, comprising administering an effective amount of the compound according to any one of Items 1 to 49 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 _1-10 alkyl group”, “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.

The “C _1-6 alkyl group” in “B” includes a group which forms a ring composed of C _{2 to} C ₄ on one carbon of a saturated hydrocarbon group. Specific examples include groups represented by the following groups.

“Alkenyl group” means a linear or branched unsaturated hydrocarbon group containing one double bond. For example, “C _2-6 alkenyl 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 _3-6 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.

The “C _3-10 cycloalkyl group” in “B” includes a saturated bicyclo ring. Specific examples include groups represented by the following groups.

“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”. Specific examples include 2-pyridylmethyl, 3- (1,3-oxazol-2-yl) propyl, 3- (1,3,4-oxadiazolin-2-yl) propyl, and the like.

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 “heteroarylalkyloxy group” means a group in which the “heteroaryl” part of the “heteroaryloxy group” is replaced with “heteroarylalkyl”. For example, “5- to 10-membered monocyclic or polycyclic heteroaryl C _1-4 alkyloxy 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.

_{"C 1-4} alkyl" moiety of the _{"C 1-4} alkylcarbonyloxy group" is the same as defined in the _{"C 1-4} alkyl group". Specific examples include methylcarbonyloxy, ethylcarbonyloxy, isopropylcarbonyloxy and the like.

_{"C 3-6} cycloalkyl" moiety of the _{"C 3-6} cycloalkyl carbonyl group" is the same as defined in the _{"C 3-6} cycloalkyl group". Specific examples include cyclopropylcarbonyloxy, cyclobutylcarbonyloxy, cyclopentylcarbonyloxy and the like.

The “C _1-6 alkylsulfonylamino group” means a group in which the “C _1-6 alkylsulfonyl group” is substituted with one amino group. Specific examples include methylsulfonylamino, ethylsulfonylamino and the like. The amino _is optionally substituted by _{C 1-6} alkyl _{((C 1-6} alkyl) _{sulfonyl-N-(C 1-6} alkyl) - amino).

The “alkylcarbonylamino group” means a group in which the “alkylcarbonyl group” is bonded to an amino group. For example, “C _1-4 alkylcarbonylamino group” and the like can be mentioned. Specific examples include methylcarbonylamino and the like. The amino may be further substituted with C _1-4 alkyl.

The “alkoxycarbonylamino group” means a group in which the “alkoxycarbonyl group” is bonded to an amino group. For example, “C _1-4 alkoxycarbonylamino group” and the like can be mentioned. Specific examples include methoxycarbonyl and the like.

The “alkylsulfonylamino group” means a group in which the “alkylsulfonyl group” is bonded to an amino group. For example, “C _1-4 alkylsulfonylamino group” and the like can be mentioned. Specific examples include methylsulfonylamino 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. Specific examples include “groups” represented by the following groups.

  The “5-membered or 6-membered saturated heterocyclic group” also includes a saturated bicyclo group and a saturated spiro ring group having “5-membered or 6-membered saturated heterocycle” as a basic skeleton. Specific examples include “groups” represented by the following groups.

  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.

“Mono-substituted amino group” is from the group consisting of “C _1-4 alkyl”, “C _3-6 cycloalkyl”, “C _3-6 cycloalkyl C _1-4 alkyl”, and “benzyl”. It means an amino group substituted with one selected group. “C _1-4 alkyl”, “C _3-6 cycloalkyl”, and “C _3-6 cycloalkyl C _1-4 alkyl” are as defined above.

Specific examples of “amino group substituted with mono- (C _1-4 alkyl)” include, for example, methylamino, ethylamino and the like.

Specific examples of “amino group substituted with mono- (C _3-6 cycloalkyl)” include, for example, cyclopropylamino, cyclobutylamino, cyclopentylamino and the like.

Specific examples of “amino group substituted with mono- (C _3-6 cycloalkyl C _1-4 alkyl)” include, for example, cyclopropylmethylamino, cyclobutylmethylamino, cyclopentylmethylamino and the like.

“Di-substituted amino group” means “C _1-4 alkyl”, “C _3-6 cycloalkyl”, “benzyl”, “C _1-4 alkylcarbonyl” and “C _3-6 cycloalkylcarbonyl”. An amino group substituted with two groups of the same or different types selected from the group consisting of “C _1-4 alkyl”, “C _3-6 cycloalkyl”, “C _1-4 alkylcarbonyl” and “C _3-6 cycloalkylcarbonyl” are as defined above.

Specific examples of “amino group substituted with di- (C _1-4 alkyl)” include, for example, dimethylamino, diethylamino and the like.

Specific examples of “amino group substituted with di- (C _3-6 cycloalkyl)” include, for example, dicyclopropylamino, dicyclobutylamino, cyclodipentylamino and the like.

Specific examples of “amino group substituted with (C _1-4 alkyl) (benzyl)” include, for example, N-methyl-N-benzylamino, N-ethyl-N-benzylamino and the like.

Specific examples of “amino group substituted with (C _3-6 cycloalkyl) (benzyl)” include, for example, N-cyclopropyl-N-benzylamino, N-cyclopentyl-N-benzylamino, N-cyclohexyl- N-benzylamino and the like can be mentioned.

Specific examples of the “5- to 7-membered cyclic amino group” include pyrrolidino, piperidino, morpholino, thiomorpholino, thiomorpholino oxide, thiomorpholino oxide, piperazino and the like. The ring may be substituted with C _1-4 alkyl or a hydroxyl group.

Examples of the substituent in the “optionally substituted alkyl group” include, for example,
(A) a halogen atom,
(B) a cyano group,
(C) a C _3-6 cycloalkyl group (this group may be substituted with a halogen atom, a hydroxyl group or C _1-4 alkoxy),
(D) a hydroxyl group,
(E) a C _1-4 alkoxy group (which may be substituted with a fluorine atom);
(F) a C _3-6 cycloalkyloxy group,
(G) a C ₆ aryloxy group (this group may be substituted with the same or different group selected from the group consisting of a halogen atom, cyano and C _1-4 alkoxy);
(H) a benzyloxy group,
(I) a formyl group,
(J) a C _1-4 alkylcarbonyl group,
(K) a C _3-6 cycloalkylcarbonyl group,
(L) a phenylcarbonyl group,
(M) a benzylcarbonyl group,
(N) formylcarbonyloxy group,
(O) a C _1-4 alkylcarbonyloxy group,
(P) a C _3-6 cycloalkylcarbonyloxy group,
(Q) a carboxyl group,
(R) a C _1-4 alkoxycarbonyl group,
(S) a C _3-6 cycloalkoxycarbonyl group,
(T) an amino group,
(U) a mono-substituted amino group (the group is
(U1) C _1-4 alkyl group,
(U2) C _3-6 cycloalkyl group,
(U3) substituted with a C _3-6 cycloalkyl C _1-4 alkyl group, or (u4) a benzyl group. ),
(V) a di-substituted amino group (the group is substituted with two same or different groups selected from the above (u1) to (u4));
(W) a 5- or 6-membered cyclic amino group,
(X) an optionally substituted aminocarbonyl group,
(Y) an optionally substituted aminocarbonyloxy group, or (z) a 5- or 6-membered saturated heterocyclic group (this group may be substituted with C _1-4 alkyl or C _1-4 alkoxy). Etc.). In addition, the amino in said (x) and (y) is said (u1)-(u3), (v), and (w).

  The “optionally substituted aminocarbonyl group” means that “optionally substituted amino” is bonded to carbonyl. As used herein, “substituted amino” refers to a mono-substituted amino group, a di-substituted amino group, or a 5- to 7-membered cyclic amino. Examples of the mono- or di-substituted amino substituent include the above-mentioned “substituted amino” substituent and a 5- or 6-membered saturated heterocyclic group.

Examples of the “mono-substituted aminocarbonyl group” include the above-mentioned “aminocarbonyl group substituted with mono- (C _1-4 alkyl)” or “mono- (C _3-6 cycloalkyl)”. Aminocarbonyl group "and the like.

Specific examples of “aminocarbonyl group substituted with mono- (C _1-4 alkyl)” include, for example, methylaminocarbonyl, ethylaminocarbonyl and the like.

Specific examples of “aminocarbonyl group substituted with mono- (C _3-6 cycloalkyl)” include, for example, cyclopropylaminocarbonyl, cyclobutylaminocarbonyl, cyclopentylaminocarbonyl and the like.

  Specific examples of the “mono- (5-membered or 6-membered saturated heterocyclic ring) aminocarbonyl group” include, for example, mono- (1,1-dioxide-1,3-thiazolidin-3-yl) Examples include aminocarbonyl.

Examples of the “di-substituted aminocarbonyl group” include “aminocarbonyl group substituted with (C _1-4 alkyl) (C _1-4 alkyl)”, “(C _1-4 alkyl) (C _{3 -6} cycloalkyl) aminocarbonyl group substituted by "," _{(C 1-4} alkyl) (aminocarbonyl group substituted by benzyl) ", or" _{(C 1-4 alkylcarbonyl) (C 1-4} alkyl And the like ".

Specific examples of “aminocarbonyl group substituted with (C _1-4 alkyl) (C _1-4 alkyl)” include, for example, N-methyl-N-methylaminocarbonyl, N-methyl-N-ethylaminocarbonyl Etc.

Specific examples of “aminocarbonyl group substituted with (C _1-4 alkyl) (C _3-6 cycloalkyl)” include, for example, N-methyl-N-cyclopropylcarbonylamino, N-methyl-N-cyclo. Examples include butylcarbonylamino, N-methyl-N-cyclopentylcarbonylamino and the like.

Specific examples of “aminocarbonyl group substituted with (C _1-4 alkyl) (benzyl)” include, for example, N-methyl-N-benzylamino, N-ethyl-N-benzylamino and the like.

Specific examples of the _{"(C 1-4 alkyl)} amino carbonyl group substituted with a _{(C 1-4} alkyl)" includes, for example, N- methylcarbonyl -N- methylamino, and the like.

The “5- to 7-membered cyclic aminocarbonyl group” may be substituted with C _6-10 aryloxy. Specific examples include 3-phenyloxypyrrolidinocarbonyl and the like.

  The “optionally substituted aminocarbonyl” part of the “optionally substituted aminocarbonyloxy group” has the same meaning as the “optionally substituted aminocarbonyl group”. Specific examples include aminocarbonyloxy and the like.

As the substituent of the “optionally substituted C _1-6 alkyl group” in “R ^1a ”, C _1-4 alkoxy is preferable.

As the substituent of the “optionally substituted C _1-6 alkyl group” in “R ² ”, a halogen atom or a C _3-6 cycloalkyl group is preferable. A halogen atom is more preferable, and a fluorine atom is still more preferable.

As a substituent of the “C _1-6 alkyl group which may be substituted” in “B”,
(A2) C _3-6 cycloalkyl (which may be substituted with a halogen atom, hydroxy, C _1-4 alkyl or C _1-4 alkoxy),
(B2) a hydroxyl group,
(C2) C ₆ aryloxy (which may be substituted with C _1-4 alkyl),
(D2) carboxy,
(E2) C _1-4 alkoxycarbonyl,
(F2) amino (optionally substituted with C _1-4 alkyl or benzyl),
(G2) aminocarbonyl (the amino moiety may be substituted with C _1-6 alkyl, C _3-6 cycloalkyl, or C _3-6 cycloalkyl C _1-4 alkyl), or (h2) 5 members Alternatively, a group selected from the group consisting of a 6-membered saturated heterocyclic group (which may be substituted with C _1-4 alkyl or C _1-4 alkoxy), is preferable.

When “B” is a C _1-6 alkyl group substituted with “amino group substituted with mono- (C _1-6 alkyl)”, “C _1-6 alkyl” of the amino moiety is carbamoyl May be substituted with a group, mono- or di- (C _1-6 alkyl) aminocarbonyl, or 5- or 6-membered cyclic aminocarbonyl, provided that “A” is a single bond and “B” is substituted. As long as it is a C _1-6 alkyl group, which may be substituted ((C _1-6 alkyl) amino and cyclic amino moieties are the same as described above). Specific examples of “C _1-6 alkyl” of the amino moiety include the following compounds.

The substituent of the “optionally substituted C _1-6 alkyl group” in “B” may be substituted with at least 1 to 3 groups of the same or different types selected from the above group. For example, when “A” is a single bond, the group may be simultaneously substituted with the two substituents (c) and (x). When “A” is other than a single bond, the group is simultaneously substituted with the two groups (a) and (z) or the two substituents (a) and (c). May

  Specific examples of the above include the following “groups”.

Examples of the substituent in the “optionally substituted alkoxy group” include one group selected from the group consisting of the above (a) to (z) (provided that R ^1b , R ^1c , R ^This is not the case for ^1d and R ^1e .)

The substituent of the “optionally substituted C _1-6 alkoxy group” in “R ^1f ” is the above-mentioned (c), (d), (e), (g), (h), (x) or ( z) is preferred (in the case where the substituent is (h), phenyl may be substituted with a halogen atom).

As the substituent in the “optionally substituted C _2-6 alkenyl group” and the “optionally substituted C _2-6 alkynyl group”, for example, from the above (a) to (s) and C _1-4 alkyl One group selected from the group consisting of the above groups and the like (herein, the C _1-4 alkyl group may be substituted with a hydroxyl group).

Examples of the substituent in the “ _optionally substituted C _3-10 cycloalkyl group” and the “optionally substituted C _3-10 cycloalkyloxy group” include the above (x), a halogen atom, and C _1-4. 1 group selected from the group consisting of alkyl and a C _6-10 aryl group (the aryl group may be substituted with a halogen atom, C _1-4 alkyl, hydroxyl group, or C _1-4 alkoxy). Etc.

Examples of the substituent in the “optionally substituted C _5-6 cycloalkenyl group” include one group selected from the group consisting of the above (a) to (s) and a nitro group.

Examples of the substituent in the “optionally substituted C _1-4 alkylcarbonyl group” and the “optionally substituted C _3-10 cycloalkylcarbonyl group” include those described above from (a) to (h) and a nitro group. One group selected from the group consisting of

"Optionally substituted C _1-6 alkylthio group", "optionally substituted C _1-6 alkylsulfinyl group", "optionally substituted C _1-6 alkylsulfonyl group" and "may be substituted Examples of the substituent in the “C _1-4 alkoxycarbonyl group” include a halogen atom, a hydroxyl group, a nitro group, a cyano group, or one group selected from the group consisting of the above (d) to (h). It is done.

  “Optionally substituted amino group” means an amino group, a mono-substituted amino group, a di-substituted amino group and a 5- to 7-membered cyclic amino group.

  The “optionally substituted amino group” in the “optionally substituted aminosulfonyl group” and the “optionally substituted aminocarbonyl group” is the same as 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 C _6-10 aryl group” and the “ _optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group” include, for example,
(A3) a halogen atom,
(B3) a cyano group,
(C3) a C _1-4 alkyl group,
(D3) C _1-4 alkoxy group,
(E3) C _6-10 aryl group (for example, the group is
(E31) a halogen atom,
(E32) cyano,
(E32) carboxy,
(E33) C _1-4 alkyl optionally substituted with carboxy, or (e34) optionally substituted with fluorine atom, hydroxyl group, or C _1-4 alkoxy optionally substituted with carboxy. ),
(F3) C ₆ aryloxy,
(G3) C _7-11 aralkyloxy (which may be substituted with C _1-4 alkoxy),
(H3) aminocarbonyl (the amino moiety may be substituted with _C1-4 alkyl), and (i3) the same or different selected from the group consisting of C1-4 alkylsulfonylamino 1-3 Individual groups and the like.

As the substituent of the “optionally substituted C _6-10 aryl group” in “B”, a group selected from the group consisting of the above (a3), (d3), and (e3) is preferable.

If "A" is a single bond, C ₆ aryl (substituents are the same.) C ₆ aryl group substituted by are preferred.

When “A” is other than a single bond, C ₆ aryl optionally substituted with 1 to 3 groups of the same or different types selected from the group consisting of (a3) and (d3) is preferable.

Examples of the substituent of the aryl moiety in the “ _optionally substituted C _7-14 aralkyl group” include the substituents of the “optionally substituted C _6-10 aryl group”, for example,
(A4) a halogen atom,
(B4) a cyano group,
(C4) C _1-4 alkyl group (may be substituted with 1 to 3 halogen atoms),
(D4) C _1-4 alkoxy group (may be substituted with 1 to 3 halogen atoms),
(E4) a carboxy group,
(F4) C _1-4 alkoxycarbonyl group,
(G4) C ₆ aryl group (may be substituted with C _1-4 alkoxy)
(H4) C ₆ aryloxy group,
(I4) C _7-11 aralkyloxy group,
(J4) an aminocarbonyl group,
And a group selected from the group consisting of (k4) C _1-4 alkylsulfonylamino group and (l4) C _1-4 alkylsulfonyl group.

As the substituent of the “optionally substituted C _7-14 aralkyl group” in “B”, 1 to 3 of the same or different groups selected from the group consisting of (b4), (j4), and (14) Are preferred.

As the substituent of the heteroaryl moiety of the “optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl C _1-4 alkyl group”, the “optionally substituted 5- to 10-membered” What was illustrated as a substituent in a "monocyclic or polycyclic heteroaryl group" is mentioned.

Examples of the substituents of “saturated heterocycle” and “saturated heterocycle” include,
(A5) a halogen atom,
(B5) a hydroxyl group,
(C5) a nitro group,
(D5) a cyano group,
(E5) C _1-4 alkyl group (may be substituted with 1 to 3 halogen atoms),
(F5) C _1-4 alkoxy group (may be substituted with 1 to 3 halogen atoms, etc.),
(G5) carboxyl group,
(H5) a C _1-4 alkoxycarbonyl group,
(I5) C _3-6 cycloalkoxycarbonyl group,
(J5) an amino group (which may be substituted with C _1-4 alkyl),
(K5) C ₆ aryl group,
(15) aminocarbonyl group,
(M5) an oxo group, or (n5) a thioxo group. The group may be substituted with two of the same or different groups in the substituent. Preferably, one group selected from the group consisting of a halogen atom, a hydroxyl group, a cyano group, a C _1-4 alkyl group, a C _1-4 alkoxy group, and amino is mentioned. Specific examples of the substituted saturated heterocyclic group include groups represented by the following groups.

  As the “saturated heterocyclic group which may be substituted” in “B”, for example, “5-membered or 6-membered having 1 to 3 of the same or different atoms selected from nitrogen atom, oxygen atom and sulfur atom” Is preferably a saturated heterocyclic group.

Examples of the substituent in the definition ^{"R 1a",} for example,
(A6) a C _2-6 alkenyl group,
(B6) a C _3-6 alkynyl group,
(C6) C _1-10 alkyl group (the group is
(C600) C _3-6 cycloalkyl (which may be substituted with a fluorine atom or C _1-4 alkoxy),
(C601) C _1-4 alkoxy (which may be substituted with C _1-4 alkoxy),
(C602) a hydroxyl group,
(C603) trifluoromethyl,
(C604) trifluoromethoxy,
(C605) difluoromethoxy,
(C606) monofluoromethoxy,
(C607) C _1-4 alkylcarbonylamino (the group may be substituted with 1 to 3 fluorine atoms),
(C608) C _1-4 alkoxycarbonylamino,
_{(C609) C 3-6} cycloalkyloxy,
(C610) mono- or di _{(C 1-4} alkyl) aminocarbonyl,
_{(C611) C 1-4} alkylsulfonylamino,
(C612) _C1-4 alkylsulfonyl,
(C613) optionally substituted amino, or (c614) mono- or di (C _1-4 alkyl) aminocarbonylamino, or (d6) 5-10 membered monocyclic or polycyclic heteroaryl C _{1- 4-} alkyl group and the like can be mentioned.

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 (Q125), 4-methoxy-3,3-difluoro-butyl (Q120), 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, 4- (cyclopropyl) butyl (Q110), 4- (2,2-difluorocyclopropyl) butyl (Q112). ), 3- (cyclopentyl) propyl (Q113), (3-isopropyloxycyclobutyl) methyl (Q118); 4- (methoxy) butyl (Q108), 3- (cyclopropyloxy) propyl (Q121), 3- ( Ethoxy) propyl (Q116), (2-methoxyethoxy) methyl (Q123), 2- (n-propyloxy) ethyl (Q124); 5- (hydroxy) pentyl (Q104); 5- (trifluoromethyl) pentyl ( Q105); 4- (trifluoromethoxy) butyl (Q106); 4- (difluoromethoxy) butyl 4- (monofluoromethoxy) butyl (Q122); 3- (methylcarbonylamino) propyl (Q109), 3- (trifluoromethylcarbonylamino) propyl (Q117); 2- (methoxycarbonylamino) ethyl (Q107); Q103), 3- (methoxycarbonylamino) propyl (Q184); 3- (N-methylaminocarbonyl) propyl (Q183); 3- (methylsulfonylamino) propyl (Q185); 4- (methylsulfonyl) butyl (Q186) ); 3- (2-pyrrolidone-1-yl) propyl (Q187), 3- (2-oxazolidon-1-yl) propyl (Q188); 3- (1,3-oxadiazol-2-yl) propyl (Q189), 3- (1,3,4-oxadiazolin-2-yl) propyl ( Q190); 3- (N-methylaminocarbonylamino) propyl (Q191) and the like.

As the substituents in the definitions “R ^1b ”, “R ^1c ”, “R ^1d ” and “R ^1e ”, for example,
(A7) a hydrogen atom,
(B7) a halogen atom,
(C7) hydroxyl group,
(D7) a carboxy group,
(E7) a cyano group,
(F7) C _1-6 alkyl group (this group may be substituted with C _1-4 alkoxy, or 1 to 3 fluorine atoms),
(G7) 5- to 10-membered monocyclic or polycyclic heteroaryl group,
(H7) a C _1-6 alkylsulfonyl group,
(I7) a C _6-10 arylsulfonyl group,
(J7) C _1-6 alkoxy group (the group is
(J701) 1 to 3 fluorine atoms,
(J702) carboxy,
(J703) cyano,
(J704) hydroxy,
(J702) C _1-4 alkoxy,
(J703) C _3-6 cycloalkyl optionally substituted with C _1-4 alkoxy,
(J707) mono- or di-substituted amino, wherein the group is the same or different 1-2 selected from the group consisting of C _1-6 alkyl optionally substituted with hydroxy, and C _3-6 cycloalkyl Substituted with a group).
(J708) 5- to 7-membered cyclic amino,
(J709) C _1-4 alkoxycarbonylamino,
(J710) (C _1-6 alkyl) sulfonylamino,
(J711) (C _1-6 alkyl) sulfonyl-N- (C _1-6 alkyl) -amino,
(J712) mono- or di- (C _1-6 alkyl) aminosulfonylamino,
(J713) aminocarbonyl (the amino may be substituted with the same substituent as the above (j707), C _1-4 alkylcarbonyl, or a 5- or 6-membered saturated heterocyclic group),
(J714) 5- to 7-membered cyclic aminocarbonyl,
(J715) mono- or di- (C _1-6 alkyl) aminocarbonyloxy,
(J716) C _1-4 alkylsulfonyl,
(J717) C _1-4 alkylcarbonylamino, or (j718) optionally substituted with a 5 or 6 membered saturated heterocycle. ),
(K7) C _3-6 cycloalkyloxy group (the group may be substituted with 1 to 2 fluorine atoms),
(17) C _6-10 aryloxy group (may be substituted with 1 to 3 halogen atoms),
(M7) C _7-14 aralkyloxy group,
(N7) an optionally substituted amino group,
(O7) an optionally substituted aminocarbonyl group,
(P7) an aminocarbonyloxy group which may be substituted (may be substituted with C _1-6 alkyl),
(Q7) An aminosulfonyl group which may be substituted, or (r7) a C _1-4 alkoxycarbonyl group and the like.

  Specific examples of the group include, for example, methyl (Q3), trifluoromethyl (Q4), 4-methoxybutyl (Q108), 3-methoxypropyl (Q210), 5-methoxypentyl (Q211); 5-oxazolyl ( Q25); methylsulfonyl (Q20); phenylsulfonyl (Q23); methyloxy (Q5), isopropyloxy (Q6), difluoromethyloxy (Q8), trifluoromethoxy (Q9), 2,2-difluoroethoxy (Q10) , Propyloxy (Q11), 3-methoxypropyloxy (Q12), cyclopropylmethyloxy (Q13), 2-methoxycyclopropylmethyloxy (Q48), 3-methoxypropyloxy (Q208), 4-methoxybutyloxy ( Q209); cyclopropyloxy (Q7) 2-fluorocyclopropyloxy (Q37); 4-fluorophenyloxy (Q14); benzyloxy (Q15); 2-pyrrolidone-1-yl (Q21); dimethylaminocarbonyl (Q18), morpholinocarbonyl (Q19); dimethyl Examples include aminosulfonyl (Q22), morpholinosulfonyl (Q24); ethoxycarbonyl (Q17), and the like.

Examples of the substituent in the definition “R ^1f ” include, for example,
(A8) a hydrogen atom,
(B8) a halogen atom,
(C8) a cyano group,
(D8) C _1-6 alkyl group (the group is
(D81) 1 to 3 fluorine atoms,
(D82) C _1-4 alkoxy optionally substituted by 1 to 3 fluorine atoms,
(D83) C _3-6 cycloalkyl,
(D84) C _3-6 cycloalkyloxy,
(D85) aminocarbonyl, or (d86) may be substituted with a 5- to 7-membered cyclic aminocarbonyl. ),
(E8) C _1-6 alkoxy group (the group is
(E81) a hydroxyl group,
(E82) C _1-4 alkoxy,
(E83) C _3-6 cycloalkyl,
(E84) 5- or 6-membered saturated heterocycle,
(E85) C ₆ aryloxy optionally substituted with a halogen atom,
(E86) C ₇ aralkyloxy optionally substituted with a halogen atom, or (e87) optionally substituted with aminocarbonyl. ),
(F8) C _3-6 cycloalkyl group (this group may be substituted with 1 to 2 fluorine atoms),
(G8) C _7-14 aralkyloxy group (may be substituted with 1 to 3 fluorine atoms),
(H8) C _1-4 alkylcarbonyl group,
(I8) an aminocarbonyl group,
(J8) mono- or di (C _1-4 alkyl) aminocarbonyl group (the C _1-4 alkyl may be substituted with C _1-4 alkoxy, or 1 to 3 fluorine atoms);
(K8) C _1-6 alkylthio group,
(18) a hydroxyl group,
(M8) 5- or 6-membered heteroaryl C _1-4 alkoxy group,
(N8) C _1-4 alkylsulfonyl group,
(O8) C _2-6 alkenyl group, (p8) 5-membered or 6-membered heteroaryl group and the like.

  Specific examples of the group include, for example, ethoxymethyl (Q73), cyclopropyloxymethyl (Q75), 2- (trifluoromethyl) ethyl (Q76), cyclopropylmethyl (Q78), difluoromethoxymethyl (Q79), 2- (methoxy) ethyl (Q84) 2- (aminocarbonyl) ethyl (Q197), 2- (morpholinocarbonyl) ethyl (Q198), (2,2-difluoromethoxy) methyl (Q207), ethoxymethyl (Q206); Propyloxy (Q85), 3-hydroxy-3-methyl-butyloxy (Q86), 2- (methoxy) ethoxy (Q87), 2- (cyclopropyl) ethoxy (Q88), 2- (ethoxy) ethoxy (Q99), 4-pyranylmethyloxy (Q100), 3- (3-chlorophenyloxy) ) Propyloxy (Q199), 2- (4-fluorobenzyloxy) ethoxy (Q200); 2,2-difluorocyclopropyl (Q82); 4-fluorobenzyloxy (Q89); ethylcarbonyl (Q77), aminocarbonyl ( Q193); dimethylaminocarbonyl (Q194), N- (2-methoxyethyl) aminocarbonyl (Q195), N- (2,2,2-trifluoroethyl) aminocarbonyl (Q196) and the like.

As the substituent in the definition “R ² ”, for example,
(A9) C _1-6 alkyl group (this group may be substituted with 1 to 3 fluorine atoms or C _3-6 cycloalkyl), or (b9) C _3-6 cycloalkyl group ( The group may be substituted with 1 to 2 fluorine atoms).

  Specific examples of the group include cyclopropylmethyl (Q179), 2- (cyclobutyl) ethyl (Q180), 2,2-difluoro-isopropyl (Q181); 2-fluorocyclopropyl (Q182) and the like. .

"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, for example:

The compound etc. which are represented by these are mentioned.

  The ring may be substituted with the same substituent as the above-mentioned “saturated heterocyclic group”. 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 heterocycle and a piperidine 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

  The preferable aspect of the definition in the compound represented by Formula (I) is demonstrated.

  “G” is preferably a group represented by the formula (a).

Represented by (a) below

The preferred embodiment of the partial structure (the definitions in the formula are the same as those described above) will be described.

“R ^1a ” is preferably a C _1-6 alkyl group substituted with C _1-4 alkoxy or C _1-4 alkoxycarbonylamino.

“R ^1a ” is preferably 4-methoxybutyl as the C _1-6 alkyl group substituted by C _1-4 alkoxy.

“R ^1a ” is preferably 3- (methoxycarbonyl) propyl as the C _1-6 alkyl group substituted with C _1-4 alkoxycarbonylamino.

“R ^1a ” is more preferably 4-methoxybutyl.

“R ^1b ”
(A10) a hydrogen atom,
(B10) a hydroxyl group,
(C10) a carboxy group,
(D10) a cyano group,
(E10) C _1-6 alkoxy group (the group is
(E1001) carboxy,
(E1002) cyano,
(E1003) hydroxy,
(E1004) C _1-4 alkoxy,
(E1005) Mono- or di-substituted amino (the group is the same or different 1-2 selected from the group consisting of C _1-6 alkyl optionally substituted with hydroxy, and C _3-6 cycloalkyl) Substituted with a group).
(E1006) 5- to 7-membered cyclic amino,
(E1007) C _1-4 alkoxycarbonylamino,
(E1008) (C _1-6 alkyl) sulfonylamino,
(E1009) (C _1-6 alkyl) sulfonyl-N- (C _1-6 alkyl) -amino,
(E1010) mono- or di- (C _1-6 alkyl) aminosulfonylamino,
(E1011) aminocarbonyl (the amino may be substituted with the same substituent as the above (e1005), C _1-4 alkylcarbonyl, or a 5- or 6-membered saturated heterocyclic group),
(E1012) 5- to 7-membered cyclic aminocarbonyl,
(E1013) mono- or di- (C _1-6 alkyl) aminocarbonyloxy,
(E1014) C _1-4 alkylsulfonyl,
(E1015) C _1-4 alkylcarbonylamino, or (e1016) optionally substituted with a 5 or 6 membered saturated heterocycle. ), And (f10) an optionally substituted aminocarbonyloxy group (optionally substituted with C _1-6 alkyl), and (g10) one selected from the group consisting of C _1-4 alkoxycarbonyl groups Are preferred.

“R ^1c ” is preferably a hydrogen atom or a halogen atom.

“R ^1d ” is preferably a hydrogen atom or a halogen atom.

“R ^1e ” is preferably a hydrogen atom, a halogen atom, a C _1-6 alkyl group or a C _1-4 alkoxycarbonyl group, and more preferably a hydrogen atom.

“R ^1f ”
(A11) a hydrogen atom,
(B11) a halogen atom,
(C11) a cyano group,
(D11) a C _1-6 alkyl group,
(E11) C _1-6 alkoxy group (the group is
(E111) C _1-4 alkoxy,
(E112) C _3-6 cycloalkyl,
(E113) 5-membered or 6-membered saturated heterocyclic ring, or (e114) may be substituted with aminocarbonyl. ),
(G11) C _7-14 aralkyloxy group (may be substituted with 1 to 3 fluorine atoms),
(K11) C _1-6 alkylthio group,
(L11) a hydroxyl group,
(M11) a 5- or 6-membered heteroaryl C _1-4 alkoxy group,
(N11) C _1-6 alkylsulfonyl group,
One group selected from the group consisting of (o11) C _2-6 alkenyl group and (p11) 5-membered or 6-membered heteroaryl group is preferred.

“R ² ”
(A12) a C _1-6 alkyl group (which may be substituted with C _3-6 cycloalkyl),
(B12) a C _3-6 cycloalkyl group,
(C12) one selected from the group consisting of a C ₆ aryl group (which may be substituted with a halogen atom) and (d12) a C _7-11 aralkyl group (which may be substituted with a halogen atom) Groups.

“R ² ” is preferably a C _1-6 alkyl group, particularly preferably an isopropyl group.

"B"
(A13) a hydrogen atom,
(B13) C _1-6 alkyl group (this group may be substituted with one group selected from the group consisting of the above (a2) to (h2)),
(C13) C _3-6 cycloalkyl group (which may be substituted with C _1-4 alkoxy),
(D13) C ₆ aryl group (this group may be substituted with 1 to 3 groups of the same or different types selected from the group consisting of the above (a3) to (i3));
(E13) C _7-14 aralkyl group (this group may be substituted with 1 to 3 groups of the same or different types selected from the group consisting of the above (a4) to (l4)),
(F13) a 5- or 6-membered monocyclic heteroaryl group (which may be substituted with a halogen atom or C ₆ aryl), and (g13) a 5- or 6-membered saturated heterocyclic group One selected group is mentioned.

^{"R 4"} is a hydrogen _{atom, C 3-6 C 1-6} alkyl groups substituted with a _cycloalkyl, a _{C 3-6} 1 radicals selected from the group consisting of cycloalkyl group and _{C 7} aralkyl group preferable. A hydrogen atom or a C _3-6 cycloalkyl group is even more preferable.

  The compound of the present invention also includes a compound represented by the formula (III) or a salt thereof.

[Wherein, R ^13a is a C _3-6 cycloalkyl optionally substituted with a fluorine atom or C _1-4 alkoxy, C _1-4 alkoxy optionally substituted with C _1-4 alkoxy, a hydroxyl group, trifluoro Methyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, C _1-4 alkylcarbonylamino, C _1-4 alkoxycarbonylamino, C _3-6 cycloalkyloxy, mono or di (C _1-4 alkyl) aminocarbonyl, C _1-4 alkylsulfonylamino, C _1-4 alkylsulfonyl, optionally substituted amino, and mono or di (C _1-4 alkyl) aminocarbonylamino one good _{C 1-10} alkyl group optionally substituted with a group _{that; C 2-6} a It is or substituted by or monocyclic also be 5-membered to 10-membered polycyclic heteroaryl C _1-4 alkyl group; Kenyir group; C _3-6 alkynyl group;
R ^13b is a hydrogen atom; hydroxyl group; carboxy group; cyano group; carboxy, cyano, hydroxy, C _1-4 alkoxy, mono- or di-substituted amino, 5- to 7-membered cyclic amino, C _1-4 alkoxycarbonylamino , (C _1-6 alkyl) sulfonylamino, (C _1-6 alkyl) sulfonyl-N— (C _1-6 alkyl) -amino, mono- or di- (C _1-6 alkyl) aminosulfonylamino, aminocarbonyl, Mono- or di-substituted aminocarbonyl, 5- to 7-membered cyclic aminocarbonyl, mono- or di- (C _1-6 alkyl) aminocarbonyloxy, C _1-6 alkylsulfonyl, C _1-4 alkylcarbonylamino, or 5-membered or optionally substituted may be substituted with hetero ring 6 membered saturated C _1-6 alkoxy It is or _{C 1-4} alkoxycarbonyl group; _{group; C 1-6} alkyl optionally aminocarbonyl substituted oxy group;
R ^13c , R ^13d and R ^13e are each independently the same and a hydrogen atom;
R ^13f is substituted with a hydrogen atom; a halogen atom; a cyano group; a C _1-6 alkyl group; a C _1-4 alkoxy, a C _3-6 cycloalkyl, a 5- or 6-membered saturated heterocyclic ring, or an aminocarbonyl. An optionally substituted C _1-6 alkoxy group; a C _7-14 aralkyloxy group optionally substituted with 1 to 3 fluorine atoms; a C _1-6 alkylthio group; a hydroxyl group; a 5- or 6-membered heteroaryl C _{1 A -4} alkoxy group; a C _1-6 alkylsulfonyl group; a C _2-6 alkenyl group; or a 5- or 6-membered heteroaryl group;
R ²³ is a C _1-6 alkyl group or a C _3-10 cycloalkyl group;
R ^33a , R ^33b , R ^33c and R ^33d are each independently the same or different, and group: —A ³ —B ³ (wherein A ³ is a single bond, — (CH ₂ ) _s3 O— _{^{, - (CH 2) s3 N}} (R 43) -, - (CH 2) s3 N (R 43) CO -, - (CH 2) s3 N (R 43) SO 2 -, - (CH 2) s3 N (R ⁴³ ) COO—, — (CH ₂ ) _s3 OCON (R ⁴³ ) —, or — (CH ₂ ) _s3 N (R ⁴³ ) CON (R ⁴³ ) —,
B ³ 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 C 3 _{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 ³ There _{^{- (CH 2) s3 N (}} R 43) -, - (CH 2) s3 OCON (R 43) -, - (CH 2) s3 CON (R 43) -, and _{- (CH 2) s3 N (} R ⁴³⁾ CON ^{(R 43)} - in the case of ^may be ^{R 43} and ^{B 3} are bonded together to form a ring).. );
R ⁴³ is a hydrogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted cycloalkyl group, or an optionally substituted C _7-14 aralkyl group;
s ₃ is 0, 1 or _{2 (- (CH 2) s3} N (R 43) - in the case of, _{s 3} is 0 or _{2, - (CH 2) s3} CON (R 43) - For S3 is 1 or 2);
n ³ is 0, 1, or 2. ]

R ^13a is preferably a C _1-6 alkyl group which may be substituted with C _1-4 alkoxy.

R ^33a , R ^33b , R ^33c and R ^33d are each independently a group: —A ³ -B ³ (wherein A ³ is a single bond, and B ³ is a hydrogen atom. ) Is preferred.

  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).

  The compounds of formula (I) may have axial asymmetry. Accordingly, for example, isomers represented by the following structures are also encompassed in the present invention.

  “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.

The compound of the present invention can be specifically exemplified as the following compounds. In the table below, for example, No. The compound represented by 1 (T ¹ : Q108; T ² : Q218) means the following compound (free base of Example 1).

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 ^1e , R ^1f , R ^3a , R ^3b , R ^3c , R ^3d and R ² have the same ^meanings as described in item 1 above, and R ¹¹⁷ is a fluorine atom or a _{C 1-3} alkoxy substituted optionally _{C 1-3} alkyl group or a fluorine atom or _{C 1-3} optionally substituted alkoxy _{C 3-6} cycloalkyl ^{group,, R 118} _is a _{C 1-2} alkyl ^{group, R 119} is substituted which may _{C 1-5} alkyl group or a fluorine atom or a _{C 1-3} alkoxy, substituted with a fluorine atom or a _{C 1-3} alkoxy _{Represents a} good C _3-6 cycloalkyl 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, and X ¹ represents a hydroxyl group or salt 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- Such as 7-ene, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [5.4.0] undec-7-ene, pyridine, dimethylaminopyridine, or picoline 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 (Chemical Society of Japan, Maruzen) Vol. For example, 7- (azabenzotriazol-1-yloxy) -1,3-dimethylimidazolidinium hexafluorophosphate, dimethylimidazolidinium hexafluorophosphate, benzotriazol-1-yl-oxy-tris (dimethylamino) phosphonium hexa Fluorophosphate (cas No.:56602-33-6), N, N-bis (2-oxo-3-oxazolidinyl) phosphinic chloride (cas No.:68641-49-6), 1,1-carbonylbis-1H -Imidazole (cas No .: 530-62-1), 2-chloro-1,3-dimethylimidazolidinium tetrafluoroborate, 2-chloro-1,3-dimethylimidazolinium hexafluorophosphate (cas No .: 101385-69-7), N, N′-dicyclohexylcarbodiimide (cas No .: 538-75-0), 3- (diethoxy-phospho Ruoxy) -3H-benzo [d] [1,2,3] triazin-4-one (cas No.:165534-43-0), diethyl cyanophosphate (cas No.:2942-58-7), N, N′-diisopropylcarbodiimide (cas No.:693-13-0), diphenylphosphoryl azide (cas No.:26386-88-9), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (cas No. : 1892-57-5), N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (cas No .: 16357-59-8), O- (7-azabenzotriazol-1-yl) -1 , 1,3,3-Tetramethyluronium hexafluorophosphate (cas No.:148893-10-1), 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluro Hexafluorofluorophosphate (cas No .: 94790-37-1), 1- [bis- (dimethylamino) -methylene] -5-chloro-1H-benzotriazolium Hexafluorophosphate 3-oxide (cas No .: 330645-87-9), 6-chlorobenzotriazol-1-ol (cas No .: 26198-19-6), benzotriazol-1-yl-oxy-tris -Pyrrolidino-phosphonium hexafluorophosphate (cas No .: 128625-52-5), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (cas No .: 132705-51-2), 2- (1H-benzotriazole-1 -Yl) -1,1,3,3-tetramethyluronium tetrafluoroborate (cas No .: 125700-67-6), 2- (5-norbornene-2,3-dicarboximide) -tetramethyluro And nitro tetrafluoroborate (cas No .: 125700-73-4).

  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.
For this step, it is possible to refer to a method described in literature (for example, Tetrahedron 61, 10827 (2005)).
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 52, 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
The compound represented by the formula (22-4) where X ¹ is a hydroxyl group or a salt thereof is produced, for example, by the method shown below.

[Wherein, R ^1a , R ^1b , R ^1c , R ^1d , R ^1e and R ^1f are the same as described above, R ⁵⁰⁰ represents a C _1-4 alkyl group, X ⁶ represents an iodine atom, A bromine atom, a chlorine atom, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, or a p-toluenesulfonyloxy group is represented. ]

1) Step 1
Compound (23-3) can be produced by treating compound (22-1) with a base in an inert solvent and reacting with compound (22-2) in the presence or absence of an additive. it can. Examples of the additive include potassium iodide. Examples of the base include inorganic bases such as sodium hydride or potassium hydroxide. 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 −10 ° C. to about 150 ° C.
3) Step 2
Compound (22-4) can be produced by treating compound (22-3) 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
Among the compounds represented by the formula (22-1), the compound represented by the formula (23-2) or a salt thereof is produced, for example, by the method shown below.

[Wherein, R ^1b , R ^1c , R ^1d , R ^1e and R ⁵⁰⁰ are the same as described above, and R ⁵⁰¹ represents a chlorine atom and a bromine atom. ]

1) Step 1
Among the compounds represented by the compound (23-2), a compound in which R ⁵⁰¹ is a chlorine atom can be produced by reacting the compound (23-1) with sulfuryl chloride 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 130 ° C. In addition, compound (23-2) can be produced from compound (23-1) by a method similar to the production method described in the literature (for example, WO06 / 061493, WO99 / 007678).

Production method 24
Among the compounds represented by formula (1-1), wherein X ¹ is a hydroxyl group, the compound represented by formula (24-5) or a salt thereof, and the compound represented by formula (24-6) or a salt thereof Is produced, for example, by the method described below.

[Wherein, R ^1a , R ^1b , R ^1c , R ^1d , R ^1e , R ⁵⁰⁰ and X ⁶ are the same as described above, and R ⁵⁰² represents a hydrogen atom, a fluorine atom, or 1 to 3 fluorine atoms. in an optionally substituted alkyl group, an optionally substituted C _1-4 alkoxy group, optionally substituted C _3-6 cycloalkyl group, optionally substituted C _3-6 cycloalkyl group or a substituted, Represents an aminocarbonyl group and the like. ]
1) Step 1
Compound (24-1) can be produced from compound (23-1) by the same method as in Step 1 described in Production Method 22.
2) Step 2
By a method similar to the production method described in the literature (for example, Tetrahedron 61, 4989 (2005), Eur. J. Med. Chem. 30, 963 (1995)), compound (24-1) to compound (24- 2) can be produced.
3) Step 3
Compound (24-3) can be produced from compound (24-2) 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
Compound (24-4) can be produced by hydrogenating compound (24-3) in the presence of palladium on carbon in an inert solvent. Examples of the inert solvent include ethanol or alcohol solvents such as 2-propanol. The reaction temperature is selected from the range of about −10 ° C. to about 50 ° C.
5) Step 5
Compound (24-5) can be produced from compound (24-4) by the same method as in Process 2 described in Production Method 22.
6) Step 6
Compound (24-6) can be produced from compound (24-3) by the same method as in Step 2 described in Production Method 22.

Production method 25
Among the compounds represented by the formula (1-1) in which X ¹ is a hydroxyl group, the compound represented by the formula (25-3) or a salt thereof is produced, for example, by the method shown below.

[Wherein, R ^1a , R ^1b , R ^1c , R ^1d , R ^1e , R ⁵⁰⁰ and X ⁶ are the same as those described above, and R ⁵⁰³ is a hydrogen atom, a hydroxyl group, C _1-4 alkoxy, C _3-6 cycloalkyl, a 5-membered or 6-membered saturated heterocyclic ring, an optionally substituted C ₆ aryloxy or an optionally substituted C ₇ aralkyloxy may be substituted. ]
1) Step 1
Compound (25-1) can be produced from compound (23-1) by a method similar to the production method described in the literature (eg, WO06 / 023590).
2) Step 2
Compound (25-2) can be produced from compound (25-1) by the same method as in Process 1 described in Production Method 22.
3) Step 3
Compound (25-3) can be produced from compound (25-2) by the same method as in Step 2 described in Production Method 22.

Manufacturing method 26
Among the compounds represented by the formula (1-1) in which X ¹ is a hydroxyl group, the compound represented by the formula (26-7) or a salt thereof is produced, for example, by the method shown below.

[Wherein, R ^1a , R ^1b , R ^1c , R ^1d , R ^1e , R ⁵⁰⁰ and X ⁶ are the same as described above, and R ⁵⁰⁴ is a hydrogen atom, an optionally substituted alkyl group, or a substituted 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 C _7-14 aralkyl A group, a heteroaryl group which may be substituted, a heteroarylalkyl group which may be substituted, a saturated heterocyclic group which may be substituted, or the like; ]
1) Step 1 to Step 4
Compound (26-5) can be produced from compound (26-1) by a method similar to the production method described in the literature (eg, Tetrahedron Letters 43, 135 (2002)).
2) Step 5
Compound (26-6) can be produced from compound (26-5) by the same method as in Process 1 described in Production Method 22.
3) Step 6
Compound (26-7) can be produced from compound (26-6) by the same method as in Step 2 described in Production Method 22.

Manufacturing method 27
Among the compounds represented by formula (1-1), wherein X ¹ is a hydroxyl group, the compound represented by the compound represented by formula (27-4) or a salt thereof is produced, for example, by the method shown below. .

[Wherein, R ^1a , R ^1b , R ^1c , R ^1d , R ^1e and R ⁵⁰⁰ are the same as those described above, and R ⁵⁰⁵ is an optionally substituted alkyl group or an optionally substituted cycloalkyl. Represents a group. ]
1) Step 1
Compound (27-2) can be produced from compound (27-1) by a method similar to the production method described in the literature (for example, J. Med. Chem 44, 3545 (2001)).
2) Step 2
Compound (27-3) can be produced from compound (27-2) 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 (27-4) can be produced from compound (27-3) by the same method as in Step 2 described in Production Method 24.

Production method 28
Among the compounds represented by formula (1-1), wherein X ¹ is a hydroxyl group, the compound represented by the compound represented by formula (27-4) or a salt thereof is produced, for example, by the method shown below. .

[Wherein, R ^1a , R ^1b , R ^1c , R ^1d , R ^1e and R ⁵⁰⁰ are the same as described above. ]
1) Step 1
Compound (28-1) can be produced from compound (24-2) by a method similar to the production method described in the literature (for example, Eur. J. Med. Chem 30, 963 (1995)).
2) Step 2
Compound (28-2) can be produced from compound (28-1) by the same method as in Step 2 described in Production Method 24.

Production method 29
Among the compounds represented by the formula (1-4), the compound represented by the formula (29-3) 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 ⁵⁰⁶ represents a hydrogen atom, an alkyl group which may be substituted, an alkenyl group which may be substituted, or an alkynyl group which may be substituted. , 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 ⁵⁰⁷ 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 (29-2) 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 (29-3) is produced from the compound (29-2) 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, and introduction and removal of such a protecting group can be carried out according to ordinary methods. (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
Methyl (3-bromopropyl) carbamate

3-Bromoethylamine hydrobromide (5 g) was dissolved in methylene chloride (80 ml), and triethylamine (5.8 g) and methyl chlorocarbonate (2.4 g) were added at 0 ° C. Thereafter, the mixture was stirred at room temperature for 12 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. 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: hexane / ethyl acetate = 4/1) to give the title compound (2.8 g).

MS (ESI +) 197 (M ⁺ +1, 30%).

Reference example 3
Ethyl 3-chloro-1H-indole-2-carboxylate

Ethyl 1H-indole-2-carboxylate (946 mg) was dissolved in toluene (40 ml), sulfuryl chloride (1.01 g) was added, and the mixture was heated with stirring at 100 ° C. for 4 min. The reaction mixture was allowed to cool, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 6/1) to give the title compound (875 mg).

MS (ESI +) 224 (M ⁺ +1, 100%).

Reference example 4
Ethyl 3-chloro-1- (4-methoxybutyl) -1H-indole-2-carboxylate

Dissolve ethyl 3-chloro-1H-indole-2-carboxylate (224 mg) in N, N-dimethylformamide (5 ml), add 55% sodium hydride (44 mg) at 0 ° C, and warm to room temperature. Warm up. After 30 minutes, potassium iodide (15 mg) was added, 1-chloro-4-methoxybutane (135 mg) was added dropwise, the temperature was raised to 100 ° C., and the mixture was heated and stirred for 3 hours. The reaction mixture is allowed to cool, saturated aqueous sodium chloride (10 ml) is added, and the mixture is extracted with ethyl acetate (100 ml). The organic layer is washed with water and saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated under reduced pressure. did. The obtained residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 6/1) to give the title compound (257 mg).

MS (ESI +) 310 (M ⁺ +1, 100%).

Reference Example 5
Ethyl 3-chloro-1- {3-[(methoxycarbonyl) amino] propyl} -1H-indole-2-carboxylate

Dissolve ethyl 3-chloro-1H-indole-2-carboxylate (500 mg) in N, N-dimethylformamide (10 ml), add 55% sodium hydride (107 mg) at 0 ° C, and warm to room temperature. Warm up. 30 minutes later, potassium iodide (101 mg) was added, the compound (438 mg) obtained in Reference Example 2 was added dropwise, the temperature was raised to 100 ° C., and the mixture was heated and stirred for 6 hours. The reaction mixture is allowed to cool, saturated aqueous sodium chloride (10 ml) is added, and the mixture is extracted with ethyl acetate (100 ml). The organic layer is washed with water and saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated under reduced pressure. did. The obtained residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 3/1) to give the title compound (450 mg).

MS (ESI +) 339 (M ⁺ +1, 51%).

Reference Example 6
Ethyl 1- (4-methoxybutyl) -1H-indole-2-carboxylate

In the same manner as in Reference Example 4, the title compound (8.32 g) was synthesized from the compound obtained in Reference Example 4.

MS (ESI +) 276 (M ⁺ +1, 100%).

Reference Example 7
3-Chloro-1- (4-methoxybutyl) -1H-indole-2-carboxylic acid

The compound (257 mg) obtained in Reference Example 4 was dissolved in ethanol (2 ml), 1N aqueous sodium hydroxide solution (2 ml) was added, and the mixture was stirred with heating at 80 ° C. for 4 hr. The reaction mixture was allowed to cool, ethanol was distilled off under reduced pressure, and 1N aqueous hydrogen chloride solution was added to adjust the pH to 1. After extraction with ethyl acetate (100 ml), the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (226 mg).

MS (ESI +) 282 (M ⁺ +1, 4%).

Reference Example 8
1- (4-Methoxybutyl) -1H-indole-2-carboxylic acid

The title compound (255 mg) was synthesized from the compound obtained in Reference Example 6 by a method similar to that of Reference Example 7.

MS (ESI +) 248 (M ⁺ +1, 100%).

Reference Example 9
3-Chloro-1- {3-[(methoxycarbonyl) amino] propyl} -1H-indole-2-carboxylic acid

In the same manner as in Reference Example 7, the title compound (320 mg) was synthesized from the compound obtained in Reference Example 5.

MS (ESI +) 311 (M ⁺ +1, 35%).

Reference Example 10
tert-Butyl (3R) -3-[{[3-Chloro-1- (4-methoxybutyl) -1H-indol-2-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate

The compound obtained in Reference Example 7 was dissolved in dichloromethane (6 ml), oxalyl chloride (103 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 above crude product was dissolved in dichloromethane (2 ml) and added dropwise to a dichloromethane solution (2 ml) in which the compound obtained in Reference Example 1 (175 mg) and triethylamine (100 μl) were mixed. Stir. Methanol (10 ml) and 1N aqueous sodium hydroxide solution (3 ml) were added to the reaction mixture, and the mixture was stirred for 30 minutes. Water was added and 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: eluent: hexane / ethyl acetate = 3/1) to give the title compound (241 mg) as a white amorphous product.

MS (ESI +) 506 (M ⁺ +1, 100%).

Reference Example 11
tert-butyl (3R) -3- (isopropyl {[1- (4-methoxybutyl) -1H-indol-2-yl] carbonyl} amino) piperidine-1-carboxylate

The title compound (174 mg) was synthesized in the same manner as in Reference Example 10 using the compounds obtained in Reference Example 1 and Reference Example 8.

MS (ESI +) 472 (M ⁺ +1, 100%).

Reference Example 12
tert-Butyl (3R) -3-[[(3-Chloro-1- {3-[(methoxycarbonyl) amino] propyl} -1H-indol-2-yl) carbonyl] (isopropyl) amino] piperidine-1- Carboxylate

The title compound (130 mg) was synthesized in the same manner as in Reference Example 10 using the compounds obtained in Reference Example 1 and Reference Example 9.

MS (ESI +) 535 (M ⁺ +1, 32%).

Reference Example 13
6-Fluoro-1H-indole-2-carboxylic acid ethyl ester

  To an ethanol solution (400 ml) of potassium ethoxide (57.1 g), diethyl oxalate (94.2 g) and 2-nitro-4-fluorotoluene (50.0 g) were successively added under ice cooling. After stirring at room temperature for 14 hours, ice water (1 L) and 12N-hydrochloric acid (100 mL) were added to the reaction mixture, and the mixture was extracted twice with toluene. The obtained organic layer was washed twice with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained extract was dissolved in acetic acid (400 mL) and added dropwise to toluene (400 mL) to which iron powder (54.0 g) was added at 90 ° C. with stirring for 1 hour. Subsequently, after stirring at the same temperature for 1 hour, iron powder (36 g) was added and further stirred for 1 hour. After standing to cool, insolubles in the reaction solution were filtered off through Celite, and the filtrate was separated and washed with 2N hydrochloric acid and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was washed with 50% diethyl ether-hexane to give the title compound (37.0 g) as a pale-yellow powder.

¹ H-NMR (300MHz, CDCl3) δ 8.99 (brs, 1H), 7.60 (dd, 1H, J = 8.7, 5.4 Hz), 7.30-7.00 (m, 2H), 7.00-6.80 (m, 1H), 4.39 (qt, 2H, J = 7.2 Hz), 1.40 (t, 3H, J = 6.9 Hz).

Reference Example 14
Ethyl 3-chloro-6-fluoro-1H-indole-2-carboxylate

N-chlorosuccinimide (644 mg) was added to a solution of ethyl 6-fluoro-1H-indole-2-carboxylate (1.0 g) in N, N-dimethylformamide (20 mL) at room temperature. After stirring at room temperature for 14 hours, saturated brine was poured into the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was separated and washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was washed with 50% diethyl ether-hexane to give the title compound (611 mg) as a white powder.
MS (ESI +) 242 (M ⁺ +1, 56%)

Reference Example 15
1- (4-Methoxybutyl) -3-chloro-6-fluoro-1H-indole-2-carboxylate

To a solution of ethyl 3-chloro-6-fluoro-1H-indole-2-carboxylate (600 mg) in N, N-dimethylformamide (20 mL) under ice cooling, sodium hydride (119 mg as 55% content), 4-chloride Methoxybutyl (608 mg) and sodium iodide (111 mg) were added sequentially. The mixture was stirred at 90 ° C. for 2 hours and then allowed to cool. A saturated saline solution was poured into the reaction solution, followed by separation and extraction twice with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography to give the title compound (603 mg) as a pale brown amorphous product.
MS (ESI +) 328 (M ⁺ +1, 48%)

Reference Example 16
1- (4-Methoxybutyl) -3-chloro-6-fluoro-1H-indole-2-carboxylic acid

Ethyl 1- (4-methoxybutyl) -3-chloro-6-fluoro-1H-indole-2-carboxylate (603 mg) was dissolved in ethanol (20 mL), and 2N aqueous sodium hydroxide solution (10 mL) was added. Stir at 60 ° C. for 1 hour. After allowing to cool, ice water and dilute hydrochloric acid were added to the reaction solution to make an acidic solution, and the mixture was extracted twice with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (530 mg) as a light brown solid.
MS (ESI +) 300 (M ⁺ +1, 48%)

Reference Example 17
tert-Butyl (3R) -3-[{[6-Fluoro-1- (4-methoxybutyl) -1H-indol-2-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate

To a solution of 1- (4-methoxybutyl) -3-chloro-6-fluoro-1H-indole-2-carboxylic acid (530 mg) in dichloromethane (10 mL) under ice-cooling, oxalyl chloride (0.23 mL) and N, N -Dimethylformamide (50 uL) was added. After stirring at room temperature for 2 hours, the solvent was distilled off under reduced pressure. Toluene (10 mL) was added to the residue, and then again distilled off under reduced pressure. Dissolve the resulting residue in dichloromethane (10 mL) and add tert-butyl (3R) -3- (isopropylamino) piperidine-1-carboxylate (430 mg) and triethylamine (0.25 mL) with stirring under ice cooling. did. After stirring at room temperature for 1 hour, saturated brine was poured into the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography to give the title compound (462 mg) as a pale brown amorphous product.

MS (ESI +) 524 (M ⁺ +1, 23%)

Reference Example 18
(2Z) -2-Hydroxy-3- (3-nitropyridin-4-yl) -ethyl acrylate

Under ice-cooling, diethyl oxalate (14.7 ml) was added to a 20% sodium ethoxide / ethanol solution (25 g), and the mixture was stirred at 0 ° C. for 30 min. Subsequently, 4-methyl-3-nitropyridine (5.0 g) was added, and the mixture was stirred at room temperature for 4 hours. After neutralizing to pH 1 with 6N hydrochloric acid, the mixture was stirred at 0 ° C. for 30 minutes. The precipitated solid was collected by filtration, washed with ethanol and isopropanol, and dried under reduced pressure to give the title compound (13.1 g) as a red solid.
MS (ESI +) 239 (M ⁺ +1, 100%).

Reference Example 19
1H-Pyrrolo [2,3-C] Pyridine-2-carboxylate

(2Z) -2-Hydroxy-3- (3-nitropyridin-4-yl) -ethyl acrylate (13.1 g), iron powder (10.6 g), acetic acid (4.3 g) in ethanol: water (2: 1) And the mixture was stirred with heating under reflux for 1 hour. After allowing to cool, the mixture was neutralized with sodium bicarbonate, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure gave the title compound (6.3 g) as yellow crystals.
MS (ESI +) 191 (M ⁺ +1, 100%).
Reference Example 20
Ethyl 5-fluoro-1- (4-methoxybutyl) -1H-indole-2-carboxylate

The title compound was synthesized in the same manner as in Reference Example 15.
MS (ESI +) 294 (M ⁺ +1, 100%).

Reference Example 21
Ethyl 6-fluoro-1- (4-methoxybutyl) -1H-indole-2-carboxylate

The title compound was synthesized in the same manner as in Reference Example 15.
MS (ESI +) 294 (M ⁺ +1, 100%).

Reference Example 22
1H-Pyrrolo [2,3-C] Pyridine-2-carboxylate

The title compound was synthesized in the same manner as in Reference Example 15.
MS (ESI +) 277 (M ⁺ +1, 100%).

Reference Example 23
Ethyl 5-fluoro-3-iodo-1- (4-methoxybutyl) -1H-indole-2-carboxylate

Ethyl 5-fluoro-1- (4-methoxybutyl) -1H-indole-2-carboxylate (2.9 g) was dissolved in chloroform (50 ml), then N-iodosuccinimide (2.5 g) was added, and 18 hours at room temperature. Stir for hours. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, a 10% aqueous sodium thiosulfate solution, water, and a saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (4.1 g) as a yellow amorphous.
MS (ESI +) 420 (M ⁺ +1, 100%)

Reference Example 24
Ethyl 5-fluoro-1- (4-methoxybutyl) -3- (methylthio) -1H-indole-2-carboxylate

Ethyl 5-fluoro-3-iodo-1- (4-methoxybutyl) -indole-2-carboxylate (4.1 g) was dissolved in tetrahydrofuran (44 ml) and stirred at −40 ° C. for 15 minutes. Subsequently, 1N isopropyl magnesium chloride / lithium chloride / tetrahydrofuran solution (21.3 ml) was added dropwise, and the mixture was stirred at −40 ° C. for 30 minutes. After adding dimethyl disulfide, the mixture was stirred at room temperature for 4 hours. A saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solvent: developing solvent: hexane / ethyl acetate = 10/1) to give the title compound (1.0 g) as a colorless amorphous product.
MS (ESI +) 340 (M ⁺ +1, 100%)

Reference Example 25
Ethyl 3-formyl-1- (4-methoxybutyl) -1H-indole-2-carboxylate

Phosphorus oxychloride (2.2 g) was dissolved in N, N-dimethylformamide (14 ml) and stirred at room temperature for 30 minutes. To this solution, a solution of ethyl 1- (4-methoxybutyl) -1H-indole-2-carboxylate (2.0 g) in N, N-dimethylformamide (14 ml) was added dropwise and heated at 85 ° C. for 2 hours. Stir. The reaction mixture was allowed to cool and concentrated under reduced pressure. To the residue was added 1N aqueous sodium acetate solution (20 ml), and the mixture was stirred at 50 ° C. for 30 min. After extraction with ethyl acetate (100 ml), the organic layer was washed with water and then with saturated brine, and then the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: developing solvent: hexane / ethyl acetate = 6/1) to obtain the title compound (1.58 g) as a colorless amorphous.
MS (ESI +) 304 (M ⁺ +1, 100%).

Reference Example 26
Ethyl 5-fluoro-3-formyl-1- (4-methoxybutyl) -1H-indole-2-carboxylate

The title compound was synthesized in the same manner as in Reference Example 25.
MS (ESI +) 322 (M ⁺ +1, 100%).

Reference Example 27
Ethyl 6-fluoro-3-formyl-1- (4-methoxybutyl) -1H-indole-2-carboxylate

The title compound was synthesized in the same manner as in Reference Example 25.
MS (ESI +) 322 (M ⁺ +1, 100%).

Reference Example 28
Ethyl 3-hydroxy-1- (4-methoxybutyl) -1H-indole-2-carboxylate

Ethyl 3-formyl-1- (4-methoxybutyl) -1H-indole-2-carboxylate (2.4 g) was dissolved in methylene chloride (77 ml) and stirred at 5-10 ° C. To this solution, 69% m-chloroperbenzoic acid (2.4 g) and p-toluenesulfonic acid (1.5 g) were added and stirred at 5-10 ° C. for 1 hour, and then 15 ml of 2N ammonia in ethanol was added to room temperature. Was stirred. After concentrating with care not to dry, saturated aqueous sodium hydrogen carbonate solution was added, extracted with chloroform, and the organic layer was washed with 10% aqueous sodium thiosulfate solution. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: developing solvent: hexane / ethyl acetate = 5/1) to give the title compound (1.6 g) as white crystals.
MS (ESI +) 292 (M ⁺ +1, 100%).

Reference Example 29
Ethyl 5-fluoro-3-hydroxy-1- (4-methoxybutyl) -1H-indole-2-carboxylate

The title compound was synthesized in the same manner as in Reference Example 28.
MS (ESI +) 310 (M ⁺ +1, 100%).

Reference Example 30
Ethyl 6-fluoro-3-hydroxy-1- (4-methoxybutyl) -1H-indole-2-carboxylate

The title compound was synthesized in the same manner as in Reference Example 28.
MS (ESI +) 310 (M ⁺ +1, 100%).

Reference Example 31
Ethyl 3- (benzyloxy) -1- (4-methoxybutyl) -1H-indole-2-carboxylate

Ethyl 3-hydroxy-1- (4-methoxybutyl) -1H-indole-2-carboxylate (1.6 g) was dissolved in N, N-dimethylformamide (10 ml), benzyl bromide (1.1 g), potassium carbonate ( 0.99 g) was added and stirred at 80 ° C. for 1.5 hours. After cooling to room temperature, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous sodium chloride solution. 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: eluent: hexane / ethyl acetate = 6/1) to give the title compound (1.75 g) as a colorless amorphous product.
MS (ESI +) 382 (M ⁺ +1, 100%).

Reference Example 32
Ethyl 3- (benzyloxy) -5-fluoro-1- (4-methoxybutyl) -1H-indole-2-carboxylate

The title compound was synthesized in the same manner as in Reference Example 31.
MS (ESI +) 400 (M ⁺ +1, 100%).

Reference Example 33
Ethyl 3- (ethoxy) -6-fluoro-1- (4-methoxybutyl) -1H-indole-2-carboxylate

The title compound was synthesized in the same manner as in Reference Example 31.
MS (ESI +) 338 (M ⁺ +1, 100%).

Reference Example 34
5-Fluoro-1- (4-methoxybutyl) -1H-indole-2-carboxylic acid

The title compound was synthesized in the same manner as in Reference Example 16.
MS (ESI +) 266 (M ⁺ +1, 100%)

Reference Example 35
3- (Benzyloxy) -1- (4-methoxybutyl) -1H-indole-2-carboxylic acid

The title compound was synthesized in the same manner as in Reference Example 16.
MS (ESI +) 354 (M ⁺ +1, 100%).

Reference Example 36
3- (Benzyloxy) -5-fluoro-1- (4-methoxybutyl) -1H-indole-2-carboxylic acid

The title compound was synthesized in the same manner as in Reference Example 16.
MS (ESI +) 372 (M ⁺ +1, 90%).

Reference Example 37
3- (Ethoxy) -6-fluoro-1- (4-methoxybutyl) -1H-indole-2-carboxylic acid

The title compound was synthesized in the same manner as in Reference Example 16.
MS (ESI +) 310 (M ⁺ +1, 100%).

Reference Example 38
5-Fluoro-1- (4-methoxybutyl) -3- (methylthio) -1H-indole-2-carboxylic acid

The title compound (876 mg) was synthesized in the same manner as in Reference Example 16.
MS (ESI +) 310 (M ⁺ +1, 100%).

Reference Example 39
1H-Pyrrolo [2,3-c] pyridine-2-carboxylic acid lithium salt

Ethyl 1H-pyrrolo [2,3-C] pyridine-2-carboxylate (553 mg) was dissolved in ethanol (10 ml), lithium hydroxide (96 mg) was added, and the mixture was stirred at 80 ° C. for 2 hr. The mixture was allowed to cool to room temperature, filtered, and the filtrate was concentrated under reduced pressure to synthesize the title compound (606 mg).
MS (ESI +) 249 (M ⁺ +1, 100%) (* as free carboxylic acid).

Reference Example 40
t-Butyl (3R) -3-[{[5-Fluoro-1- (4-methoxybutyl) -1H-indol-2-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate

The title compound was synthesized in the same manner as in Reference Example 17.
MS (ESI +) 490 (M ⁺ +1, 100%).

Reference Example 41
tert-butyl (3R) -3-[{[3- (benzyloxy) -1- (4-methoxybutyl) -1H-indol-2-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate

The title compound was synthesized in the same manner as in Reference Example 17.
MS (ESI +) 578 (M ⁺ +1, 100%).

Reference Example 42
tert-Butyl (3R) -3-[{[3- (Benzyloxy) -5-fluoro-1- (4-methoxybutyl) -1H-indol-2-yl] carbonyl} (isopropyl) amino] piperidine-1 -Carboxylate

The title compound was synthesized in the same manner as in Reference Example 17.
MS (ESI +) 596 (M ⁺ +1, 100%).

Reference Example 43
tert-butyl (3R) -3-[{[3-ethoxy-6-fluoro-1- (4-methoxybutyl) -1H-indol-2-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate

The title compound was synthesized in the same manner as in Reference Example 17.
MS (ESI +) 596 (M ⁺ +1, 100%).

Reference Example 44
tert-butyl (3R) -3-[{[5-fluoro-1- (4-methoxybutyl) -3- (methylthio) -1H-indol-2-yl] carbonyl} (isopropyl) amino] piperidine-1- Carboxylate

The title compound was synthesized in the same manner as in Reference Example 17.
MS (ESI +) 536 (M ⁺ +1, 100%).

Reference Example 45
tert-butyl (3R) -3- (isopropyl {[1- (4-methoxybutyl) -1H-pyrrolo [2,3-C] pyridin-2-yl] carbonyl} amino) piperidine-1-carboxylate

The title compound was synthesized in the same manner as in Reference Example 17.
MS (ESI +) 473 (M ⁺ +1, 100%).

Reference Example 46
tert-butyl (3R) -3-[{[3-hydroxy-1- (4-methoxybutyl) -1H-indol-2-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate

tert-butyl (3R) -3-[{[3- (benzyloxy) -1- (4-methoxybutyl) -1H-indol-2-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate ( 1.2 g) was dissolved in ethanol (10 ml), 10% palladium carbon (430 mg) was added, and the mixture was stirred at room temperature for 3 hours in a hydrogen atmosphere. After filtration through Celite, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: eluent: hexane / ethyl acetate = 6/1) to give the title compound (0.77 g) as a colorless amorphous product.
MS (ESI +) 488 (M ⁺ +1, 100%).

Reference Example 47
tert-butyl (3R) -3-[{[5-fluoro-3-hydroxy-1- (4-methoxybutyl) -1H-indol-2-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate

The title compound was synthesized in the same manner as in Reference Example 46.
MS (ESI +) 506 (M ⁺ +1, 100%).

Reference Example 48
tert-butyl (3R) -3-[{[3-methoxy-1- (4-methoxybutyl) -1H-indol-2-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate

tert-Butyl (3R) -3-[{[3-Hydroxy-1- (4-methoxybutyl) -1H-indol-2-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate (122 mg) Was dissolved in N, N-dimethylformamide (1 ml), methyl iodide (43 mg) and potassium carbonate (45 mg) were added, and the mixture was stirred at room temperature for 16 hours. Water was added and extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous sodium chloride solution, and the organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: developing solvent: hexane / ethyl acetate = 3/1) to give the title compound (72 mg) as a colorless amorphous product.
MS (ESI +) 502 (M ⁺ +1, 100%).

Reference Example 49
t-Butyl (3R) -3-[{[3-Ethoxy-1- (4-methoxybutyl) -1H-indol-2-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate

The title compound was synthesized in the same manner as in Reference Example 48.
MS (ESI +) 516 (M ⁺ +1, 100%).

Reference Example 50
tert-butyl (3R) -3- (isopropyl {[1- (4-methoxybutyl) -3-propoxy-1H-indol-2-yl] carbonyl} amino) piperidine-1-carboxylate

The title compound was synthesized in the same manner as in Reference Example 48.
MS (ESI +) 530 (M ⁺ +1, 100%).

Reference Example 51
tert-butyl (3R) -3-[{[3- (cyclopropylmethoxy) -1- (4-methoxybutyl) -1H-indol-2-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate

The title compound was synthesized in the same manner as in Reference Example 48.
MS (ESI +) 542 (M ⁺ +1, 100%).

Reference Example 52
tert-Butyl (3R) -3-[{[5-Fluoro-3-methoxy-1- (4-methoxybutyl) -1H-indol-2-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate

tert-butyl (3R) -3-[{[5-fluoro-3-hydroxy-1- (4-methoxybutyl) -1H-indol-2-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate (253 mg) was dissolved in N, N-dimethylformamide (2.5 ml), sodium hydride (24 mg as a 55% content) was added at 0 ° C., and the mixture was warmed to room temperature. After 30 minutes, methyl iodide (92 mg) was added, and the mixture was stirred at room temperature for 2 hours. Water (10 ml) was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 3/1) to give the title compound (186 mg).
MS (ESI +) 520 (M ⁺ +1, 100%).

Reference Example 53
tert-butyl (3R) -3-[{[3-ethoxy-5-fluoro-1- (4-methoxybutyl) -1H-indol-2-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate

The title compound was synthesized in the same manner as in Reference Example 52.
MS (ESI +) 534 (M ⁺ +1, 100%).

Reference Example 54
tert-Butyl (3R) -3-[{[5-Fluoro-1- (4-methoxybutyl) -3- (2-methoxyethoxy) -1H-indol-2-yl] carbonyl} (isopropyl) amino] piperidine -1-carboxylate

The title compound was synthesized in the same manner as in Reference Example 52.
MS (ESI +) 564 (M ⁺ +1, 100%).

Reference Example 55
tert-Butyl (3R) -3-[{[5-Fluoro-1- (4-methoxybutyl) -3- (2-methoxypropoxy) -1H-indol-2-yl] carbonyl} (isopropyl) amino] piperidine -1-carboxylate

The title compound was synthesized in the same manner as in Reference Example 52.
MS (ESI +) 578 (M ⁺ +1, 100%).

Reference Example 56
tert-Butyl (3R) -3-[{[5-Fluoro-1- (4-methoxybutyl) -3- (pyridin-3-ylmethoxy) -1H-indol-2-yl] carbonyl} (isopropyl) amino] Piperidine-1-carboxylate

The title compound was synthesized in the same manner as in Reference Example 52.
MS (ESI +) 597 (M ⁺ +1, 100%).

Reference Example 57
tert-Butyl (3R) -3-[{[5-Fluoro-1- (4-methoxybutyl) -3- (tetrahydrofuran-2-ylmethoxy) -1H-indol-2-yl] carbonyl} (isopropyl) amino] Piperidine-1-carboxylate

The title compound was synthesized in the same manner as in Reference Example 52.
MS (ESI +) 590 (M ⁺ +1, 100%)

Reference Example 58
tert-Butyl (3R) -3-[{[3- (2-Amino-oxoethoxy) -5-fluoro-1- (4-methoxybutyl)-1H-indol-2-yl] carbonyl} (isopropyl) Amino] piperidine-1-carboxylate

The title compound was synthesized in the same manner as in Reference Example 52.
MS (ESI +) 563 (M ⁺ +1, 100%)

Reference Example 59
tert-Butyl (3R) -3-[{[3-Iodo-1- (4-methoxybutyl) -1H-indol-2-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate

tert-butyl (3R) -3- (isopropyl {[1- (4-methoxybutyl) -1H-indol-2-yl] carbonyl} amino) piperidine-1-carboxylate (625 mg) in chloroform (7 ml) Then, N-iodosuccinimide (349 mg) was added, and the mixture was stirred at room temperature for 3 hours. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, a 10% aqueous sodium thiosulfate solution, water, and a saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (843 mg) as a yellow amorphous.
MS (ESI +) 598 (M ⁺ +1, 100%)

Reference Example 60
tert-Butyl (3R) -3-[{[5-Fluoro-3-iodo-1- (4-methoxybutyl) -1H-indol-2-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate

The title compound was synthesized in the same manner as in Reference Example 58.
MS (ESI +) 616 (M ⁺ +1, 100%)

Reference Example 61
tert-Butyl (3R) -3-[{[3-Cyano-1- (4-methoxybutyl) -1H-indol-2-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate

Tert-butyl (3R) -3-[{[3-iodo-1- (4-methoxybutyl) -1H-indol-2-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate under nitrogen atmosphere (843 mg), copper (I) cyanide (253 mg), and tetrabutylammonium cyanide (118 mg) were dissolved in a mixture (8 ml) of N, N-dimethylformamidetetrahydrofuran (1: 1), and the mixture was stirred at room temperature for 15 Stir for minutes. Next, trisdibenzylideneacetone palladium (256 mg) and diphenylphosphinoferrocene (416 mg) were added, and the mixture was stirred at 110 ° C. for 5 hours. After allowing to cool to room temperature, saturated aqueous sodium chloride solution (15 ml) was added and celite filtration was performed to remove insolubles. Next, after extraction with ethyl acetate, the organic layer was washed with water and saturated aqueous sodium chloride solution and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 3/1) to give the title compound (600 mg).
MS (ESI +) 497 (M ⁺ +1, 100%)

Reference Example 62
tert-Butyl (3R) -3-[{[3-Cyano-5-fluoro-1- (4-methoxybutyl) -1H-indol-2-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate

The title compound was synthesized in the same manner as in Reference Example 60.
MS (ESI +) 515 (M ⁺ +1, 100%)

Reference Example 63
tert-butyl (3R) -3-[{[5-fluoro-1- (4-methoxybutyl) -3- (methylsulfonyl) -1H-indol-2-yl] carbonyl} (isopropyl) amino] piperidine-1 -Carboxylate

tert-butyl (3R) -3-[{[5-fluoro-1- (4-methoxybutyl) -3- (methylthio) -1H-indol-2-yl] carbonyl} (isopropyl) amino] piperidine-1- Carboxylate (327 mg) was dissolved in chloroform (6 ml), then m-chloroperbenzoic acid was added and stirred at room temperature for 18 hours. Chloroform was added, and the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and a 10% aqueous sodium thiosulfate solution, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 1/1) to give 117 mg and 97 mg of the title compound as colorless amorphous, respectively.
MS (ESI +) 568 (M ⁺ +1, 100%)

Reference Example 64
tert-butyl (3R) -3-[{[3-chloro-1- (4-methoxybutyl) -1H-pyrrolo [2,3-c] pyridin-2-yl] carbonyl} (isopropyl) amino] piperidine- 1-carboxylate

tert-butyl (3R) -3- (isopropyl {[1- (4-methoxybutyl) -1H-pyrrolo [2,3-c] pyridin-2-yl] carbonyl} amino) piperidine-1-carboxylate (190 mg) was dissolved in chloroform (2 ml), N-chlorosuccinimide (192 mg) was added, and the mixture was stirred at room temperature for 21 hours. The organic layer was then washed with 1N aqueous sodium hydroxide. The organic layer is dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (developing solvent: chloroform / methanol = 97/3) to purify the title compound as a colorless amorphous (176 mg).
MS (ESI +) 507 (M ⁺ +1, 100%)

Reference Example 65
(2Z) -2-Azido-3-pyridin-3-yl ethyl acrylate

Nicotinaldehyde (4.0 g) and ethyl azide acetate (12.0 g) were dissolved in ethanol (100 ml), sodium ethoxide (6.3 g) was added, and the mixture was stirred at 0 ° C. for 15 hours under a nitrogen atmosphere. Ice water and ammonium chloride (10 g) were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1/1) to give the title compound (1.4 g).
MS (ESI +) 219 (M ⁺ +1, 10%).

Reference Example 66
1H-pyrrolo [2,3-b] pyridine-2-carboxylic acid ethyl ester

(2Z) -2-Azido-3-pyridin-3-yl acrylate (1.4 g) was dissolved in mesitylene (50 ml), and the mixture was stirred with heating under reflux for 25 minutes. The reaction solution was cooled to 0 ° C. and further stirred for 1 hour. The reaction mixture was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 1/1) and then recrystallized (hexane / ethyl acetate = 10/1) to give the title compound (183 mg) as a white powder. Got as a body.
MS (ESI +) 191 (M ⁺ +1, 33%).

Reference Example 67
1- (4-Methoxybutyl) -1H-pyrrolo [2,3-b] pyridine-2-carboxylate

Dissolve ethyl 1H-pyrrolo [2,3-b] pyridine-2-carboxylate (182 mg) in N, N-dimethylformamide (5 ml) and stir in a nitrogen atmosphere at 0 ° C. Sodium (44 mg) was added and allowed to act for 10 minutes. Then, sodium iodide (15 mg) and 4-methoxybutyl chloride (245 mg) were added to the reaction mixture and stirred at 100 ° C. for 2.5 hours. The reaction mixture was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1/1) to give the title compound (231 mg).
MS (ESI +) 277 (M ⁺ +1, 100%).

Reference Example 68
1- (4-Methoxybutyl) -1H-pyrrolo [2,3-b] pyridine-2-carboxylic acid

Dissolve ethyl 1- (4-methoxybutyl) -1H-pyrrolo [2,3-b] pyridine-2-carboxylate (231 mg) in ethanol (5 mL) and add potassium hydroxide (471 mg) with heating under reflux. Stir for 10 minutes. After allowing to cool, water was added, and separation and washing were performed with chloroform to remove impurities, and the obtained aqueous layer was adjusted to pH 1 with hydrochloric acid and extracted with chloroform (100 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (204 mg).
MS (ESI +) 249 (M ⁺ +1, 100%).

Reference Example 69
tert-butyl (3R) -3- (isopropyl {[1- (4-methoxybutyl) -1H-pyrrolo [2,3-b] pyridin-2-yl] carbonyl} amino) piperidine-1-carboxylate

Dissolve 1- (4-methoxybutyl) -1H-pyrrolo [2,3-b] pyridine-2-carboxylic acid (204.5 mg) in dichloromethane (5 ml), oxalyl chloride (126 mg), N, N-dimethyl Formamide (20 mg) was added, and the mixture was stirred at 25 ° C. for 5 min. The solvent was distilled off to obtain a crude product.
Dissolve the above crude product in dichloromethane (5 ml) and mix tert-butyl (3R) -3- (isopropylamino) piperidine-1-carboxylate (227 mg) and triethylamine (167 mg) in dichloromethane (5 ml ) Was added dropwise and stirred at 25 ° C. for 30 minutes. The solvent was distilled off, and the obtained residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1/1) to give the title compound (126 mg) as a colorless amorphous product.
MS (ESI +) 473 (M ⁺ +1, 95%).

Reference Example 70
tert-Butyl (3R) -3-[{[3-Chloro-1- (4-methoxybutyl) -1H-pyrrolo [2,3-b] pyridin-2-yl] carbonyl} (isopropyl) amino] piperidine- 1-carboxylate

tert-butyl (3R) -3- (isopropyl {[1- (4-methoxybutyl) -1H-pyrrolo [2,3-b] pyridin-2-yl] carbonyl} amino) piperidine-1-carboxylate (130 mg) in N, N-dimethylformamide (5.5 ml) was added N-chlorosuccinimide (40 mg) and stirred at 80 ° C. for 5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 2/1) to give the title compound (27 mg) as a colorless oil.
MS (ESI +) 507 (M ⁺ +1, 100%).

Reference Example 71
2-Nitro-3-benzyloxytoluene

To a N, N-dimethylformamide solution (200 mL) of 2-nitro-3-hydroxytoluene (10.0 g) was added potassium carbonate (18.0 g) and benzyl bromide (8.5 mL), and the mixture was stirred at 50 ° C. for 3 hours. Cold saturated brine was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The obtained organic layer was washed twice with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography to give the title compound (16.1 g) as a pale brown oil. NMR
¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.40-7.22 (m, 6H), 6.88 (d, 1H, J = 8.4 Hz), 6.85 (d, 1H, J = 7.7 Hz), 5.16 (s, 2H) , 2.31 (s, 3H).

Reference Example 72
Ethyl 7-benzyloxy-1H-indole-2-carboxylate

Sodium hydride (3.9 g, content 55%) was added to a dimethylformamide solution (400 ml) of 2-nitro-3-benzyloxytoluene (20.0 g) under ice cooling and stirred for 30 minutes. Diethyl oxalate (24.0 g) was added and stirred at 60 ° C. for 4 hours. After allowing to cool, the reaction solution was acidified with saturated brine and 2N-hydrochloric acid, and then extracted twice with toluene. The obtained organic layer was washed twice with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. An acetic acid (200 mL) solution of the obtained extract was added dropwise at 90 ° C. to toluene (200 mL), to which iron powder (23.0 g) was added and stirred vigorously over 1 hour. The mixture was further stirred at the same temperature for 1 hour. After standing to cool, insolubles in the reaction solution were filtered off through Celite, and the filtrate was separated and washed with 2N hydrochloric acid and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel chromatography to give the title compound (6.3 g) as a pale brown solid.
MS (ESI +) 296 (M ⁺ +1, 100%)

Reference Example 73
7-Benzyloxy-1- (4-methoxybutyl) -1H-indole-2-carboxylic acid

Ethyl 7-benzyloxy-1H-indole-2-carboxylate (49 g) in N, N-dimethylformamide solution (500 mL) under ice-cooling, sodium hydride (8.0 g as 55% content), 4-methoxybutyl chloride (26.4 g) and sodium iodide (5.0 g) were added sequentially. After stirring at 80 ° C. for 6 hours, the mixture was allowed to cool, saturated brine was poured into the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in ethanol (500 mL), 2N aqueous sodium hydroxide solution (250 mL) was added, and the mixture was stirred at 80 ° C. for 3 hr. After allowing to cool, ice water and dilute hydrochloric acid were added to the reaction solution to make an acidic solution, and the mixture was extracted twice with chloroform. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was washed with hexane and dried to give the title compound (36.6 g) as a pale brown solid.
MS (ESI +) 354 (M ⁺ +1, 88%)

Reference Example 74
tert-butyl (3R) -3-[{[7-benzyloxy-1- (4-methoxybutyl) -1H-indol-2-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate

To a solution of 7-benzyloxy-1- (4-methoxybutyl) -1H-indole-2-carboxylic acid (27.2 g) in dichloromethane (300 mL) under ice-cooling, oxalyl chloride (8.2 mL) and N, N-dimethyl Formamide (50 uL) was added. After stirring for 2 hours at room temperature, the solvent was distilled off under reduced pressure. Toluene (100 mL) was added to the residue, and then again distilled off under reduced pressure. The obtained residue was dissolved in dichloromethane (300 mL), and tert-butyl (3R) -3- (isopropylamino) piperidine-1-carboxylate (23.5 g) and triethylamine (14.8 mL) were added while stirring under ice-cooling. Added. After stirring at room temperature for 1 hour, saturated brine was poured into the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography to give the title compound (15.2 g) as a pale brown amorphous product.
MS (ESI +) 578 (M ⁺ +1, 44%)

Reference Example 75
tert-butyl (3R) -3-[{[7-hydroxy-1- (4-methoxybutyl) -1H-indol-2-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate

tert-Butyl (3R) -3-[{[7-benzyloxy-1- (4-methoxybutyl) -1H-indol-2-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate (8.0 g ) In ethanol solution (100 mL) at room temperature, 10% palladium carbon (8.0 g, 50% wet) and ammonium formate (8.7 g) were added and stirred at 80 ° C. for 2 hours. The insoluble material was filtered through celite, and the solvent was evaporated under reduced pressure. After adding chloroform (100 mL) to the residue, the residue was evaporated again under reduced pressure, and then dried under reduced pressure to obtain the title compound (3.7 g) as a light brown amorphous. MS (ESI +) 488 (M ⁺ +1, 82%)

Reference Example 76
tert-butyl (3R) -3-[{[7- (2-ethoxy-2-oxoethoxy) -1- (4-methoxybutyl) -1H-indol-2-yl] carbonyl} (isopropyl) amino] piperidine -1-carboxylate

tert-Butyl (3R) -3-[{[7-Hydroxy-1- (4-methoxybutyl) -1H-indol-2-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate (580 mg) Sodium hydride (71 mg) was added to a solution of N, N-dimethylformamide (6 mL) under ice cooling, and the mixture was stirred at 25 ° C. for 15 min. After 15 minutes, ethyl bromoacetate (0.26 ml) was added and stirred at 80 ° C. for 3 hours. After the reaction, water was added to the reaction solution and the mixture was extracted with ethyl acetate. The ethyl acetate solution was washed with water and brine, dried over magnesium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to give the title compound (400 mg) as a pale-yellow oil.
MS (ESI +) 546 (M ⁺ +1, 34%)

Reference Example 77
tert-butyl (3R) -3-[{[7- (2-{[(benzyloxy) carbonyl] amino} ethoxy) -1- (4-methoxybutyl) -1H-indol-2-yl] carbonyl} ( Isopropyl) amino] piperidine-1-carboxylate

tert-Butyl (3R) -3-[{[7-Hydroxy-1- (4-methoxybutyl) -1H-indol-2-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate (220 mg) Water (1 ml), benzyl (2-bromoethyl) carbamate (316 mg), cesium carbonate (671 mg), and potassium iodide (34 mg) were added to a solution of acetonitrile in 10 mL, and the mixture was stirred at 65 ° C. for 4 hours. did. After the reaction, water was added to the reaction solution and the mixture was extracted with ethyl acetate. The ethyl acetate solution was washed with water and brine, dried over magnesium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give the title compound (200 mg) as a colorless oil. MS (ESI +) 665 (M ⁺ +1, 45%)
The following compounds (Reference Examples 78 to 86) were synthesized with reference to Reference Example 76 or Reference Example 77.

Reference Example 78
tert-butyl (3R) -3-[{[3-propyl-7- [2- (diethylamino) -2-oxoethoxy] -1- (4-methoxybutyl-1H-indol-2-yl] carbonyl} ( Isopropyl) amino] piperidine-1-carboxylate
MS (ESI +) 643 (M ⁺ +1, 40%).

Reference Example 79
tert-Butyl (3R) -3-[{[7- (Benzyloxy) -1- (4-methoxybutyl) -1H-indol-2-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate
MS (ESI +) 578 (M ⁺ +1, 15%).

Reference Example 80
tert-butyl (3R) -3- (isopropyl {[1- (4-methoxybutyl) -7- (2-pyrrolidin-1-ylethoxy) -1H-indol-2-yl] carbonyl} amino) piperidine-1- Carboxylate
MS (ESI +) 585 (M ⁺ +1, 100%).

Reference Example 81
tert-butyl (3R) -3-[{[3-cyano-7-{[(ethylamino) carbonyl] oxy} -1- (4-methoxybutyl) -1H-indol-2-yl] carbonyl} (isopropyl Amino] piperidine-1-carboxylate
MS (ESI +) 584 (M ⁺ +1, 8%).

Reference Example 82
tert-Butyl (3R) -3- (Isopropyl {[1- (4-methoxybutyl) -7- (2-methoxyethoxy) -1H-indol-2-yl] carbonyl} amino) piperidine-1-carboxylate
MS (ESI +) 546 (M ⁺ +1, 35%).

Reference Example 83
tert-Butyl (3R) -3- (Isopropyl {[1- (4-methoxybutyl) -7- (3-methoxypropoxy) -1H-indol-2-yl] carbonyl} amino) piperidine-1-carboxylate
MS (ESI +) 560 (M ⁺ +1, 34%)

Reference Example 84
tert-butyl (3R) -3- [isopropyl ({1- (4-methoxybutyl) -7- [2- (2-oxopyrrolidin-1-yl) ethoxy] -1H-indol-2-yl} carbonyl) Amino] piperidine-1-carboxylate
MS (ESI +) 599 (M ⁺ +1, 55%).

Reference Example 85
tert-butyl (3R) -3- (isopropyl {[1- (4-methoxybutyl) -7- (3-methoxy-2,2-dimethyl-3-oxopropoxy) -1H-indol-2-yl] carbonyl } Amino) piperidine-1-carboxylate
MS (ESI +) 602 (M ⁺ +1, 21%).

Reference Example 86
tert-Butyl (3R) -3- [Isopropyl ({1- (4-methoxybutyl) -7-[(methylsulfonyl) methoxy] -1H-indol-2-yl} carbonyl) amino] piperidine-1-carboxylate
MS (ESI +) 548 (M ⁺ +1, 17%).

Reference Example 87
tert-butyl (3R) -3-[{[3-chloro-7- (2-ethoxy-2-oxo) -1- (4-methoxybutyl) -1H-indol-2-yl] carbonyl} (isopropyl) Amino] piperidine-1-carboxylate

tert-butyl (3R) -3-[{[7- (2-ethoxy-2-oxoethoxy) -1- (4-methoxybutyl) -1H-indol-2-yl] carbonyl} (isopropyl) amino] piperidine -1-carboxylate
N-chlorosuccinimide (179 mg) was added to a solution of (700 mg) in chloroform (6 mL), and the mixture was stirred at 50 ° C. for 3 days. After the reaction, the reaction solution was concentrated, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 2/1) to give the title compound (680 mg) as a colorless oil.
MS (ESI +) 608 (M ⁺ +1, 28%)
Hereinafter, the following compounds (Reference Examples 88 to 103) were synthesized with reference to Reference Example 87.

Reference Example 88
tert-butyl (3R) -3-[{[7- {2-[(aminosulfonyl) amino] ethoxy} -3-chloro-1- (4-methoxybutyl) -1H-indol-2-yl] carbonyl} (Isopropyl) amino] piperidine-1-carboxylate
MS (ESI +) 643 (M ⁺ +1, 57%).

Reference Example 89
tert-butyl (3R) -3-[{[3-chloro-7- [2- (ethylsulfonyl) ethoxy] -1- (4-methoxybutyl) -1H-indol-2-yl] carbonyl} (isopropyl) Amino] piperidine-1-carboxylate
MS (ESI +) 642 (M ⁺ +1, 35%).

Reference Example 90
tert-butyl (3R) -3-[{[3-chloro-7- (2-{[(dimethylamino) sulfonyl] amino} ethoxy) -1- (4-methoxybutyl) -1H-indol-2-yl ] Carbonyl} (isopropyl) amino] piperidine-1-carboxylate
MS (ESI +) 672 (M ⁺ +1, 34%).

Reference Example 91
tert-butyl (3R) -3-[{[3-chloro-7-fluoro-1- (4-methoxybutyl) -1H-indol-2-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate
MS (ESI +) 524 (M ⁺ +1, 15%).

Reference Example 92
tert-Butyl (3R) -3-[{[3-Chloro-1- (4-methoxybutyl) -7- (2-methoxyethoxy) -1H-indol-2-yl] carbonyl} (isopropyl) amino] piperidine -1-carboxylate
MS (ESI +) 580 (M ⁺ +1, 25%).

Reference Example 93
tert-butyl (3R) -3-[{[3-chloro-7- {2-[(ethylsulfonyl) amino] ethoxy} -1- (4-methoxybutyl) -1H-indol-2-yl] carbonyl} (Isopropyl) amino] piperidine-1-carboxylate
MS (ESI +) 657 (M ⁺ +1, 31%).

Reference Example 94
tert-butyl (3R) -3-[{[3-chloro-7- {2-[(isopropylsulfonyl) amino] ethoxy} -1- (4-methoxybutyl) -1H-indol-2-yl] carbonyl} (Isopropyl) amino] piperidine-1-carboxylate
MS (ESI +) 671 (M ⁺ +1, 33%).

Reference Example 95
tert-butyl (3R) -3-[[(3-chloro-1- (4-methoxybutyl) -7- {2- [methyl (methylsulfonyl) amino] ethoxy} -1H-indol-2-yl) carbonyl ] (Isopropyl) amino] piperidine-1-carboxylate
MS (ESI +) 657 (M ⁺ +1, 42%).

Reference Example 96
tert-butyl (3R) -3-[{[3-chloro-7- {2- [ethyl (methylsulfonyl) amino] ethoxy} -1- (4-methoxybutyl) -1H-indol-2-yl] carbonyl } (Isopropyl) aminopiperidine-1-carboxylate
MS (ESI +) 671 (M ⁺ +1, 42%).

Reference Example 97
tert-butyl (3R) -3-[{[3-chloro-7- {2-[(ethylsulfonyl) (methyl) amino] ethoxy} -1- (4-methoxybutyl) -1H-indol-2-yl ] Carbonyl} (isopropyl) amino] piperidine-1-carboxylate
MS (ESI +) 671 (M ⁺ +1, 43%).

Reference Example 98
tert-Butyl (3R) -3-[({3-Chloro-1- (4-methoxybutyl) -7- [2- (methylsulfonyl) ethoxy] -1H-indol-2-yl} carbonyl) (isopropyl) Amino] piperidine-1-carboxylate
MS (ESI +) 628 (M ⁺ +1, 32%).

Reference Example 99
tert-butyl (3R) -3-[{[7- [2- (tert-butylsulfonyl) ethoxy] -3-chloro-1- (4-methoxybutyl) -1H-indol-2-yl] carbonyl} ( Isopropyl) amino] piperidine-1-carboxylate
MS (ESI +) 670 (M ⁺ +1, 42%).

Reference Example 100
tert-Butyl (3R) -3-[{[3-Chloro-7- [2- (1,1-dioxidethiomorpholin-4-yl) ethoxy] -1- (4-methoxybutyl) -1H-indole -2-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate
MS (ESI +) 683 (M ⁺ +1, 17%).

Reference Example 101
tert-Butyl (3R) -3-[{[3-Chloro-7- (3-hydroxypropoxy) -1- (4-methoxybutyl) -1H-indol-2-yl] carbonyl} (isopropyl) amino] piperidine -1-carboxylate
MS (ESI +) 580 (M ⁺ +1, 32%).

Reference Example 102
tert-Butyl (3R) -3-[{[3-Chloro-1- (4-methoxybutyl) -7- (3-methoxy-2,2-dimethyl-3-oxopropoxy) -1H-indole-2- Yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate
MS (ESI +) 636 (M ⁺ +1, 34%).

Reference Example 103
tert-Butyl (3R) -3-[{[3-Chloro-7- [3- (dimethylamino) -3-oxopropyl] -1- (4-methoxybutyl) -1H-indol-2-yl] carbonyl } (Isopropyl) amino] piperidine-1-carboxylate
MS (ESI +) 605 (M ⁺ +1, 28%).

Reference Example 104
{[2-{[[(3R) -1- (tert-butoxycarbonyl) piperidin-3-yl] (isopropyl) amino] carbonyl} -3-chloro-1- (4-methoxy) -1H-indole-7 -Il] oxy} acetic acid

tert-butyl (3R) -3-[{[3-chloro-7- (2-ethoxy-2-oxo) -1- (4-methoxybutyl) -1H-indol-2-yl] carbonyl} (isopropyl) To a solution of amino] piperidine-1-carboxylate (780 mg) in ethanol (10 mL) was added 2N aqueous sodium hydroxide solution (10 mg), and the mixture was stirred at 85 ° C. for 1 hr. After the reaction, the reaction solution was concentrated, 2N aqueous hydrochloric acid (10 ml) was added to the resulting residue, and the aqueous solution was extracted with ethyl acetate. The ethyl acetate solution was dried over anhydrous magnesium sulfate, filtered and concentrated. The obtained residue (520 mg) containing the title compound was directly used in the next reaction.
MS (ESI +) 580 (M ^{+ +} 1,28%)

Reference Example 105
tert-Butyl (3R) -3-[{[3-Chloro-7- [2- (dimethylamino) -2-oxoethoxy] -1- (4-methoxybutyl) -1H-indol-2-yl] carbonyl } (Isopropyl) amino] piperidine-1-carboxylate

{[2-{[[(3R) -1- (tert-butoxycarbonyl) piperidin-3-yl] (isopropyl) amino] carbonyl} -3-chloro-1- (4-methoxy) -1H-indole-7 -Il] oxy} acetic acid (150 mg) in chloroform (5 mL) solution with 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (100 mg), 1-hydroxybenzotriazole (70 mg), Triethylamine (0.10 ml) and dimethylamine (0.10 ml) were added and stirred at room temperature for 12 hours. After the reaction, the reaction solution was concentrated, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give the title compound (100 mg) as a colorless liquid.
MS (ESI +) 607 (M ⁺ +1, 32%)
Hereinafter, the following compounds (Reference Examples 106 to 111) were synthesized with reference to Reference Example 105.

Reference Example 106
tert-butyl (3R) -3-[{[7- [2- (dimethylamino) -2-oxoethoxy] -1- (4-methoxybutyl) -1H-indol-2-yl] carbonyl} (isopropyl) Amino] piperidine-1-carboxylate
MS (ESI +) 573 (M ⁺ +1, 41%).

Reference Example 107
tert-Butyl (3R) -3-[{[3-Chloro-7- [2- (isopropylamino) -2-oxoethoxy] -1- (4-methoxybutyl) -1H-indol-2-yl] carbonyl } (Isopropyl) amino] piperidine-1-carboxylate
MS (ESI +) 621 (M ⁺ +1, 30%).

Reference Example 108
tert-Butyl (3R) -3-[{[7- [2- (tert-Butylamino) -2-oxoethoxy] -3-chloro-1- (4-methoxybutyl) -1H-indol-2-yl ] Carbonyl} (isopropyl) amino] piperidine-1-carboxylate
MS (ESI +) 635 (M ⁺ +1, 30%).

Reference Example 109
tert-butyl (3R) -3-[{[3-chloro-7- {2-[(2-hydroxyethyl) amino] -2-oxoethoxy} -1- (4-methoxybutyl) -1H-indole- 2-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate
MS (ESI +) 623 (M ⁺ +1, 26%).

Reference Example 110
tert-Butyl (3R) -3-[[(3-Chloro-1- (4-methoxybutyl) -7- {2-[(methylsulfonyl) amino] -2-oxoethoxy} -1H-indole-2- Yl) carbonyl] (isopropyl) amino] piperidine-1-carboxylate
MS (ESI +) 657 (M ⁺ +1, 21%).

Reference Example 111
tert-butyl (3R) -3-[{[7- (3-amino-2,2-dimethyl-3-oxopropoxy) -3-chloro-1- (4-methoxybutyl) -1H-indole-2- Yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate
MS (ESI +) 621 (M ⁺ +1, 30%).

Reference Example 112
tert-Butyl (3R) -3-[{[7-Cyano-1- (4-methoxybutyl) -1H-indol-2-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate

tert-Butyl (3R) -3-[{[7-Hydroxy-1- (4-methoxybutyl) -1H-indol-2-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate (400 mg) To a methylene chloride solution (5 mL) was added anhydrous trifluoromethanesulfonyl (0.28 ml) and triethylamine (0.15 ml) under ice cooling, and the mixture was stirred at room temperature for 3 hours. After the reaction, water was added to the reaction solution, extracted with chloroform, dried over magnesium sulfate, filtered and concentrated.
To the obtained residue, zinc cyanide (96 mg), bis (ditert-butylphosphine) palladium (126 mg), N, N-dimethylformamide (5 ml) were added and stirred at 110 ° C. for 3 hours. After the reaction, water was added to the reaction solution, extracted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give the title compound (50 mg) as a red-purple oil.
MS (ESI +) 497 (M ⁺ +1, 13%)

Reference Example 113
tert-Butyl (3R) -3-[{[3-Iodo-7-methoxy-1- (4-methoxybutyl) -1H-indol-2-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate

tert-Butyl (3R) -3-[{[7-Methoxy-1- (4-methoxybutyl) -1H-indol-2-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate (520 mg) N-iodosuccinimide (256 mg) was added to a chloroform (5 mL) solution, and the mixture was stirred overnight at 25 ° C. After the reaction, the reaction solution was washed with an aqueous sodium thiosulfate solution, dried over magnesium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to give the title compound (570 mg) as a red oil.
MS (ESI +) 628 (M ⁺ +1, 36%)
Hereinafter, the following compound (Reference Example 114) was synthesized with reference to Reference Example 112.

Reference Example 114
tert-Butyl (3R) -3-[{[3-Iodo-7-fluoro-1- (4-methoxybutyl) -1H-indol-2-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate
MS (ESI +) 616 (M ⁺ +1, 25%).

Reference Example 115
tert-butyl (3R) -3-[{[3-cyano-7- (benzyloxy) -1- (4-methoxybutyl) -1H-indol-2-yl] carbonyl} (isopropyl) amino] piperidine-1 -Carboxylate

tert-butyl (3R) -3-[{[3-iodo-7- (benzyloxy) -1- (4-methoxybutyl) -1H-indol-2-yl] carbonyl} (isopropyl) amino] piperidine-1 -Carboxylate (4.26 g) was added to a mixed solution of tetrahydrofuran (20 mL) and N, N-dimethylformamide (20 ml), and copper cyanide (1.09 g) and tetrabutylammonium cyanate (473 mg) were added. The mixture was purged with nitrogen and stirred at 25 ° C. for 15 minutes. After 15 minutes, 1,1′-bis (diphenylphosphino) ferrocene (907 mg) and tris (dibenzylideneacetone) dipalladium (555 mg) were added, and the mixture was stirred at 120 ° C. for 5 hours. After the reaction, water was added to the reaction solution and extracted with an ethyl acetate solution. The ethyl acetate solution was washed with water and brine, dried over magnesium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to give the title compound (570 mg) as a yellow liquid.
MS (ESI +) 603 (M ⁺ +1, 24%)
The following compound (Reference Example 116) was synthesized with reference to Reference Example 115.

Reference Example 116
tert-butyl (3R) -3-[{[3-cyano-6-fluoro-1- (4-methoxybutyl) -1H-indol-2-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate
MS (ESI +) 514 (M ⁺ +1, 21%).

Reference Example 117
tert-Butyl (3R) -3-[({7- (Benzyloxy) -1- (4-methoxybutyl) -3-[(1E) -prop-1-en-1-yl] -1H-indole- 2-yl} carbonyl) (isopropyl) amino] piperidine-1-carboxylate

tert-butyl (3R) -3-[{[3-iodo-7- (benzyloxy) -1- (4-methoxybutyl) -1H-indol-2-yl] carbonyl} (isopropyl) amino] piperidine-1 -Carboxylate (5.4 g) was added into a mixed solution of dimethoxyethane (40 mL) and 2N aqueous sodium carbonate solution (7.6 ml), and trans-1-propen-1-yl-boronic acid (1.3 g), 1, 1′-bis (diphenylphosphino) ferrocenepalladium (1.3 g) was added, the atmosphere was replaced with nitrogen, and the mixture was stirred for 5 hours under reflux. After the reaction, water was added to the reaction solution and extracted with an ethyl acetate solution. The ethyl acetate solution was washed with water and brine, dried over magnesium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to give the title compound (2.2 g) as a red oil.
MS (ESI +) 618 (M ⁺ +1, 75%)
The following compound (Reference Example 118) was synthesized with reference to Reference Example 117.

Reference Example 118
tert-Butyl (3R) -3- [Isopropyl ({7-methoxy-1- (4-methoxybutyl) -3-[(1E) -prop-1-en-1-yl] -1H-indole-2- Yl} carbonyl) amino] piperidine-1-carboxylate
MS (ESI +) 542 (M ⁺ +1, 39%).

Reference Example 119
tert-butyl (3R) -3-[{[6-fluoro-1- (4-methoxybutyl) -3- (2H-tetrazol-5-yl) -1H-indol-2-yl] carbonyl} (isopropyl) Amino] piperidine-1-carboxylate

tert-butyl (3R) -3-[{[3-cyano-6-fluoro-1- (4-methoxybutyl) -1H-indol-2-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate (300 mg) was added to a N, N-dimethylformamide (5 ml) solution, sodium azide (454 mg) and ammonium chloride (405 mg) were added, and the mixture was stirred at 100 ° C. for 3 days. After the reaction, water was added to the reaction solution and extracted with an ethyl acetate solution. The ethyl acetate solution was washed with water and an aqueous solution, dried over magnesium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give the title compound (140 mg) as a yellow liquid.
MS (ESI +) 558 (M ⁺ +1, 36%)

Reference Example 120
tert-butyl (3R) -3-[({3-chloro-1- (4-methoxybutyl) -7- [3- (5-oxo-4,5-dihydro-1,2,4-oxadiazole -3-yl) propoxy] -1H-indol-2-yl} carbonyl) (isopropyl) amino] piperidine-1-carboxylate

tert-Butyl (3R) -3-[{[7- (3-Cyanopropoxy) -3-chloro 1- (4-methoxybutyl) -1H-indol-2-yl] carbonyl} (isopropyl) amino] piperidine- 1-Carboxylate (600 mg) was added to a 10% aqueous methanol (11 ml) solution, hydroxylammonium chloride (255 mg) and sodium carbonate (389 mg) were added, and the mixture was heated to reflux for 8 hours. After the reaction, water was added to the reaction solution and extracted with an ethyl acetate solution. The ethyl acetate solution was washed with water and an aqueous solution, dried over magnesium sulfate, filtered and concentrated. N, N′-carbonyldiimidazole (165 mg), 1,5-diazabicyclo (5,4,0) undec-5-ene (0.15 ml) and tetrahydrofuran (5 ml) were added to the resulting residue at 25 ° C. For 4 hours. After the reaction, water was added to the reaction solution and extracted with an ethyl acetate solution. The ethyl acetate solution was washed with water and an aqueous solution, dried over magnesium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give the title compound (550 mg) as a colorless amorphous.
MS (ESI +) 648 (M ⁺ +1, 11%)

Reference Example 121
tert-Butyl (3R) -3- [Isopropyl ({1- (4-methoxybutyl) -7-[(methylsulfonyl) methoxy] -1H-indol-2-yl} carbonyl) amino] piperidine-1-carboxylate

tert-butyl (3R) -3- [isopropyl ({1- (4-methoxybutyl) -7-[(methylthio) methoxy] -1H-indol-2-yl} carbonyl) amino] piperidine-1-carboxylate ( 180 mg) was added to the chloroform solution, m-chloroperbenzoic acid (243 mg) was added under ice cooling, and the mixture was stirred at 25 ° C. for 3 hours. After the reaction, an aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with an ethyl acetate solution. The ethyl acetate solution was washed with water and brine, dried over magnesium sulfate, filtered and concentrated. The obtained residue was purified by aminosilica gel column chromatography (hexane / ethyl acetate = 1/1) to give the title compound (47 mg) as a colorless liquid.
MS (ESI +) 580 (M ⁺ +1, 17%)
Hereinafter, the following compounds (Reference Examples 122 to 124) were synthesized with reference to Reference Example 121.

Reference Example 122
tert-Butyl (3R) -3- [Isopropyl ({1- (4-methoxybutyl) -7- [2- (methylsulfonyl) ethoxy] -1H-indol-2-yl} carbonyl) amino] piperidine-1- Carboxylate
MS (ESI +) 594 (M ⁺ +1, 33%).

Reference Example 123
tert-butyl (3R) -3-[{[7- [2- (tert-butylsulfonyl) ethoxy] -1- (4-methoxybutyl) -1H-indol-2-yl] carbonyl} (isopropyl) amino] Piperidine-1-carboxylate
MS (ESI +) 636 (M ⁺ +1, 41%).

Reference Example 124
tert-Butyl (3R) -3-[{[7- [2- (1,1-Dioxidethiomorpholin-4-yl) ethoxy] -1- (4-methoxybutyl) -1H-indol-2-yl ] Carbonyl} (isopropyl) amino] piperidine-1-carboxylate
MS (ESI +) 649 (M ⁺ +1, 19%).

Reference Example 125
tert-butyl (3R) -3-[[1- (4-methoxybutyl) -7- {2-[(methylsulfonyl) amino] ethoxy} -1H-indol-2-yl) carbonyl] (isopropyl) amino] Piperidine-1-carboxylate

tert-butyl (3R) -3-[{[7- (2-{[(benzyloxy) carbonyl] amino} ethoxy) -1- (4-methoxybutyl) -1H-indol-2-yl] carbonyl} ( Isopropyl) amino] piperidine-1-carboxylate (220 mg) was added to the methanol solution, 10% palladium carbon (110 mg) was added, and the mixture was stirred at 25 ° C. for 3 hours in the presence of hydrogen. After the reaction, the catalyst was removed by filtration, and the reaction solution was concentrated to obtain a residue (110 mg). Tetrahydrofuran (3 ml), triethylamine (0.080 ml) and methanesulfonyl chloride (0.021 ml) were added to the residue under ice-cooling, and then stirred at 25 ° C. overnight. After the reaction, an aqueous sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with an ethyl acetate solution. The ethyl acetate solution was washed with water and brine, dried over magnesium sulfate, filtered and concentrated. The obtained residue was purified by aminosilica gel column chromatography (hexane / ethyl acetate = 1/1) to give the title compound (47 mg) as a colorless liquid.
MS (ESI +) 609 (M ⁺ +1, 26%)

Reference Example 126
tert-butyl (3R) -3-[[1- (4-methoxybutyl) -7- {2- [ethyl (methylsulfonyl) amino] ethoxy} -1H-indol-2-yl) carbonyl] (isopropyl) amino ] Piperidine-1-carboxylate

tert-butyl (3R) -3-[[1- (4-methoxybutyl) -7- {2-[(methylsulfonyl) amino] ethoxy} -1H-indol-2-yl) carbonyl] (isopropyl) amino] Sodium hydride (43 mg) was added to a solution of piperidine-1-carboxylate (550 mg) in N, N-dimethylformamide (5 mL) under ice cooling, and the mixture was stirred at 25 ° C. for 20 minutes. Thereafter, iodoethane (0.10 ml) was added and the mixture was further stirred for 2 hours. After the reaction, water was added to the reaction solution and extracted with an ethyl acetate solution. The ethyl acetate solution was washed with water and brine, dried over magnesium sulfate, filtered and concentrated. The obtained residue was purified by amino silica gel column chromatography (hexane / ethyl acetate = 1/1) to give the title compound (424 mg) as a colorless amorphous.
MS (ESI +) 637 (M ⁺ +1, 39%)
The following compound (Reference Example 127) was synthesized with reference to Reference Example 126.

Reference Example 127
tert-butyl (3R) -3-[[1- (4-methoxybutyl) -7- {2- [methyl (ethylsulfonyl) amino] ethoxy} -1H-indol-2-yl) carbonyl] (isopropyl) amino ] Piperidine-1-carboxylate
MS (ESI +) 637 (M ⁺ +1, 41%).

Reference Example 128
tert-Butyl (3R) -3-[{[3-Fluoro-7- (2-ethoxy-2-oxo) -1- (4-methoxybutyl) -1H-indol-2-yl] carbonyl} (isopropyl) Amino] piperidine-1-carboxylate

tert-butyl (3R) -3-[{[7- (2-ethoxy-2-oxoethoxy) -1- (4-methoxybutyl) -1H-indol-2-yl] carbonyl} (isopropyl) amino] piperidine -1-carboxylate
1-Fluoropyridinium triflate (251 mg) was added to a solution of (530 mg) in chloroform (5 mL), and the mixture was stirred at 50 ° C. for 5 days. After the reaction, the reaction solution was concentrated, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3/1) to give the title compound (200 mg) as a colorless liquid.
MS (ESI +) 592 (M ⁺ +1, 34%)
The following compound (Reference Example 129) was synthesized with reference to Reference Example 128.

Reference Example 129
tert-butyl (3R) -3-[{[3-fluoro-7- {2- [methyl (methylsulfonyl) amino] ethoxy} -1- (4-methoxybutyl) -1H-indol-2-yl] carbonyl } (Isopropyl) amino] piperidine-1-carboxylate
MS (ESI +) 641 (M ⁺ +1, 38%).

Reference Example 130
tert-butyl (3R) -3-[{[7- [3- (dimethylamino) -3-oxopropyl] -1- (4-methoxybutyl) -1H-indol-2-yl] carbonyl} (isopropyl) Amino] piperidine-1-carboxylate

tert-butyl (3R) -3-[{[7-hydroxy-1- (4-methoxybutyl) -1H-indol-2-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate (500 mg) To a methylene chloride solution (6 mL) was added anhydrous trifluoromethanesulfonyl (0.21 ml) and triethylamine (0.29 ml) at 0 ° C., and the mixture was stirred at room temperature for 3 hours. After the reaction, water was added to the reaction solution, extracted with chloroform, dried over magnesium sulfate, filtered and concentrated.
N, N-dimethylacrylamide (0.32 ml), palladium acetate (92 mg), tris (2-methylphenyl) phosphine (250 mg), diisopropylethylamine (0.54 ml), N, N-dimethylformamide ( 5 ml) was added and stirred at 120 ° C. for 3 hours. After the reaction, water was added to the reaction solution, extracted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to obtain a mixture (300 mg) containing the desired product. Methanol (5 ml) and 10% palladium carbon (150 mg) were added to this mixture, and the mixture was stirred at 25 ° C. for 3 hours in the presence of hydrogen. After the reaction, the catalyst was removed by filtration and concentrated. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give the title compound (12 mg) as a red-purple liquid.
MS (ESI +) 571 (M ⁺ +1, 26%)

Example 1
3-Chloro-N-isopropyl-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -1H-indole-2-carboxamide hydrochloride

The compound (241 mg) obtained in Reference Example 10 was dissolved in methanol (0.5 ml), 4N hydrochloric acid / 1,4-dioxane solution (0.5 mL) was added, and the mixture was stirred at 25 ° C. for 3 hr. The reaction solution was concentrated under reduced pressure to give the title compound (212 mg) as a white amorphous.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.61 (d, 1H, J = 8.0 Hz), 7.38-7.29 (m, 2H), 7.23-7.19 (m, 1H), 4.23-3.92 (m, 5H), 3.51-3.32 (m, 4H), 3.30 (d, 3H), 3.05-2.85 (m, 2H), 2.16-1.85 (m, 5H), 1.64-1.60 (m, 2H), 1.47-1.38 (m, 3H ), 1.26-1.15 (m, 3H).

MS (ESI +) 406 (M ⁺ +1, 100%).

Example 2
N-isopropyl-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -1H-indole-2-carboxamide hydrochloride

In the same manner as in Example 1, the title compound (174 mg) was synthesized from the compound obtained in Reference Example 11.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.61 (d, 1H, J = 8.0 Hz), 7.37 (d, 2H, J = 8.4 Hz), 7.29-7.24 (m, 1H), 7.12 (t, 1H, J = 7.4 Hz), 6.54 (s, 1H), 4.55-4.48 (m, 1H), 4.30-4.17 (m, 3H), 3.92-3.86 (m, 1H), 3.50-3.41 (m, 2H), 3.34 (t, 2H, J = 6.3 Hz), 3.29 (s, 3H), 2.96-2.86 (m, 2H), 2.16-1.80 (m, 5H), 1.58-1.51 (m, 2H), 1.34 (d, 3H , J = 6.68 Hz), 1.27 (d, 3H, J = 6.68 Hz).

MS (ESI +) 372 (M ⁺ +1, 100%).

Example 3
Methyl {3- [3-chloro-2-({isopropyl [(3R) -piperidin-3-yl] amino} carbonyl) -1H-indol-1-yl] propyl} carbamate hydrochloride

In the same manner as in Example 1, the title compound (88 mg) was synthesized from the compound obtained in Reference Example 12.

MS (ESI +) 435 (M ⁺ +1, 100%).

Example 4
3-Chloro-6-fluoro-N-isopropyl-1- (4-methoxybutyl-l) -N-[(3R) -piperidin-3-yl] -1H-indole-2-carboxamide hydrochloride

  tert-Butyl (3R) -3-[{[6-Fluoro-1- (4-methoxybutyl) -1H-indol-2-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate (460 mg) 4M hydrochloric acid / 1,4-dioxane solution (5 ml) was added to a methanol solution (10 mL) and stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure to give the title compound (402 mg) as a white powder. Got as a body.

¹ H-NMR (400 MHz, DMSO-d6) δ 9.40-9.00 (brm, 2H), 7.65-7.50 (m, 2H), 7.08 (dt, 1H, J = 9.5, 2.2 Hz), 4.30-4.10 (m, 1H), 4.10-3.75 (m, 3H), 3.40-3.00 (m, 7H), 2.90-2.55 (m, 2H), 2.10-1.60 (m, 5H), 1.60-1.40 (m, 3H), 1.35- 1.05 (m, 6H).
MS (ESI +) 424 (M ⁺ +1, 100%).

Example 5
5-Fluoro-N-isopropyl-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -1H-indole-2-carboxamide hydrochloride

The title compound was synthesized in the same manner as in Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.30-7.23 (m, 2H), 7.02 (ddd, 1H, J = 9.1, 2.5 Hz), 6.49 (s, 1H), 4.48-4.45 (m, 1H), 4.29-4.16 (m, 3H), 3.92-3.87 (m, 1H), 3.50-3.32 (m, 4H), 3.29 (d, 3H), 2.95-2.85 (m, 2H), 2.19-1.78 (m, 5H ), 1.56-1.50 (m, 2H), 1.35 (d, 3H, J = 6.6 Hz), 1.27 (d, 3H, J = 6.6 Hz).
MS (ESI +) 390 (M ⁺ +1, 100%).

Example 6
3- (Benzyloxy) -N-isopropyl-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -1H-indole-2-carboxamide hydrochloride

The title compound was synthesized in the same manner as in Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.59 (d, 1H, J = 8.0 Hz), 7.34-7.23 (m, 7H), 7.08 (t, 1H, J = 7.2 Hz), 5.14-5.07 (br, 2H), 4.34-3.76 (m, 5H), 3.44-3.28 (m, 4H), 3.23 (s, 3H), 2.99-2.62 (m, 2H), 2.06-1.76 (m, 5H), 1.57 (m, 2H), 1.42-1.01 (m, 6H).
MS (ESI +) 478 (M ⁺ +1, 100%).

Example 7
3-Ethoxy-6-fluoro-N-isopropyl-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -1H-indole-2-carboxamide hydrochloride

The title compound was synthesized in the same manner as in Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.54-7.50 (m, 1H), 7.00-6.96 (dd, 1H, J = 6.4, 4.4 Hz), 7.02 (ddd, 1H, J = 9.2, 9.2, 2.2 Hz ), 4.34-3.86 (m, 7H), 3.51-3.32 (m, 4H), 3.30 (s, 3H), 2.96-2.90 (m, 2H), 2.21-1.72 (m, 5H), 1.56-1.50 (m , 2H), 1.45-1.14 (m, 9H)
MS (ESI +) 434 (M ⁺ +1, 100%).

Example 8
5-Fluoro-N-isopropyl-1- (4-methoxybutyl) -3- (methylthio) -N-[(3R) -piperidin-3-yl] -1H-indole-2-carboxamide hydrochloride

The title compound was synthesized in the same manner as in Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.41-7.37 (m, 1H), 7.32-7.28 (m, 1H), 7.06-7.01 (ddd, 1H, J = 9.0, 9.0, 2.4 Hz), 4.31-4.10 (m, 2H), 3.97-3.80 (m, 3H), 3.54-3.34 (m, 4H), 3.31 (s, 3H), 3.04-2.91 (m, 2H), 2.28 (s, 3H), 2.21-1.80 (m, 5H), 1.64-1.58 (m, 2H), 1.43-1.16 (m, 6H)

MS (ESI +) 436 (M ⁺ +1, 100%).

Example 9
N-isopropyl-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -1H-pyrrolo [2,3-c] pyridine-2-carboxamide hydrochloride

The title compound was synthesized in the same manner as in Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 9.59 (s, 1H), 8.28 (d, 1H, J = 5.8 Hz), 7.93 (d, 1H, J = 5.8 Hz), 7.84 (s, 1H), 4.51 (br, 2H), 4.14-4.01 (m, 3H), 3.54-3.37 (m, 4H), 3.30 (s, 3H), 2.94-2.83 (m, 2H), 2.25-1.90 (m, 5H), 1.63 -1.60 (m, 2H), 1.43-1.29 (m, 6H)
MS (ESI +) 373 (M ⁺ +1, 5%).

Example 10
3-Hydroxy-N-isopropyl-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -1H-indole-2-carboxamide

The title compound was synthesized in the same manner as in Example 1.

MS (ESI +) 388 (M ⁺ +1, 100%).

Example 11
N-isopropyl-3-methoxy-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -1H-indole-2-carboxamide hydrochloride

The title compound was synthesized in the same manner as in Reference Example 1.

MS (ESI +) 402 (M ⁺ +1, 100%).

Example 12
3-Ethoxy-N-isopropyl-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -1H-indole-2-carboxamide hydrochloride

The title compound was synthesized in the same manner as in Example 1.

MS (ESI +) 416 (M ⁺ +1, 100%).

Example 13
N-isopropyl-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -3-propoxy-1H-indole-2-carboxamide hydrochloride

The title compound was synthesized in the same manner as in Example 1.

MS (ESI +) 430 (M ⁺ +1, 100%).

Example 14
3- (Cyclopropylmethoxy) -N-isopropyl-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -1H-indole-2-carboxamide hydrochloride

The title compound was synthesized in the same manner as in Example 1.

MS (ESI +) 442 (M ⁺ +1, 100%).

Example 15
5-Fluoro-N-isopropyl-3-methoxy-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -1H-indole-2-carboxamide hydrochloride

The title compound was synthesized in the same manner as in Example 1.

MS (ESI +) 420 (M ⁺ +1, 100%).

Example 16
3-Ethoxy-5-fluoro-N-isopropyl-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -1H-indole-2-carboxamide hydrochloride

The title compound was synthesized in the same manner as in Example 1.

MS (ESI +) 434 (M ⁺ +1, 100%).

Example 17
5-Fluoro-N-isopropyl-1- (4-methoxybutyl) -3- (2-methoxyethoxy) -N-[(3R) -piperidin-3-yl] -1H-indole-2-carboxamide hydrochloride

The title compound was synthesized in the same manner as in Example 1.

MS (ESI +) 464 (M ⁺ +1, 100%).

Example 18
5-Fluoro-N-isopropyl-1- (4-methoxybutyl) -3- (2-methoxypropoxy) -N-[(3R) -piperidin-3-yl] -1H-indole-2-carboxamide hydrochloride

The title compound was synthesized in the same manner as in Example 1.

MS (ESI +) 478 (M ⁺ +1, 100%).

Example 19
5-Fluoro-N-isopropyl-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -3- (pyridin-3-ylmethoxy) -1H-indole-2-carboxamide Hydrochloride

The title compound was synthesized in the same manner as in Example 1.

MS (ESI +) 497 (M ⁺ +1, 13%).

Example 20
5-Fluoro-N-isopropyl-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -3- (tetrahydrofuran-2-ylmethoxy) -1H-indole-2-carboxamide Hydrochloride salt

The title compound was synthesized in the same manner as in Example 1.

MS (ESI +) 490 (M ⁺ +1, 100%).

Example 21
3- (2-Amino-2-oxoethoxy) -5-fluoro-N-isopropyl-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -1H-indole-2- Carboxamide hydrochloride

The title compound was synthesized in the same manner as in Example 1.

MS (ESI +) 463 (M ⁺ +1, 100%).

Example 22
3-Cyano-N-isopropyl-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -1H-indole-2-carboxamide hydrochloride

The title compound was synthesized in the same manner as in Example 1.

MS (ESI +) 397 (M ⁺ +1, 100%).

Example 23
3-Cyano-5-fluoro-N-isopropyl-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -1H-indole-2-carboxamide hydrochloride

The title compound was synthesized in the same manner as in Example 1.

MS (ESI +) 415 (M ⁺ +1, 100%).

Example 24
5-Fluoro-N-isopropyl-1- (4-methoxybutyl) -3- (methoxysulfonyl) -N-[(3R) -piperidin-3-yl] -1H-indole-2-carboxamide hydrochloride

The title compound was synthesized in the same manner as in Example 1.

MS (ESI +) 468 (M ⁺ +1, 100%).

Example 25
5-Fluoro-N-isopropyl-1- (4-methoxybutyl) -3- (methoxysulfonyl) -N-[(3R) -piperidin-3-yl] -1H-indole-2-carboxamide hydrochloride

The title compound was synthesized in the same manner as in Example 1.
MS (ESI +) 468 (M ⁺ +1, 100%).

Example 26
3-Chloro-N-isopropyl-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -1H-pyrrolo [2,3-c] pyridine-2-carboxamide hydrochloride

The title compound was synthesized in the same manner as in Example 1.

MS (ESI +) 407 (M ⁺ +1, 2%).

Example 27
N-isopropyl-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -1H-pyrrolo [2,3-b] pyridine-2-carboxamide dihydrochloride

tert-Butyl (3R) -3- (Isopropyl {[1- (4-methoxybutyl) -1H-pyrrolo [2,3-b] pyridin-2-yl] carbonyl} amino) piperidine-1-carboxylate (126.3 mg) was dissolved in 1,4-dioxane (3 ml), 4M hydrochloric acid / 1,4-dioxane solution (3 mL) was added, and the mixture was stirred at 25 ° C. for 30 min. After the reaction solution was concentrated under reduced pressure, toluene was added and azeotroped to completely remove dioxane. Solidification with chloroform / hexane (1/4) gave the title compound (110 mg) as a white solid.

MS (ESI +) 373 (M ⁺ +1, 100%).

Example 28
3-Chloro-N-isopropyl-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -1H-pyrrolo [2,3-b] pyridine-2-carboxamide trifluoroacetate

tert-Butyl (3R) -3-[{[3-Chloro-1- (4-methoxybutyl) -1H-pyrrolo [2,3-b] pyridin-2-yl] carbonyl} (isopropyl) amino] piperidine- To a solution of 1-carboxylate (27 mg) in chloroform (1 ml) was added a trifluoroacetic acid solution (1 ml), stirred at 25 ° C. for 2 hours, and then concentrated under reduced pressure to give the title compound (27 mg). Obtained.

¹ H NMR (400 MHz, CD ₃ OD) δ 9.40-8.85 (m, 2H), 8.49 (d, J = 4.5 Hz, 1H), 8.04 (d, J = 7.8 Hz, 1H), 7.31-7.20 (m , 1H), 4.40-4.26 (m, 1H), 4.25-4.02 (m, 2H), 4.01-3.85 (m, 1H), 3.82-3.68 (m, 1H), 3.48-3.28 (m, 3H), 3.23 (s, 2H), 3.22 (s, 1H), 3.12-2.85 (m, 1H), 2.85-2.69 (m, 1H), 2.08-1.70 (m, 6H), 1.64-1.48 (m, 2H), 1.38 -1.23 (m, 3H), 1.18-1.08 (d, J = 6.0 Hz, 3H).
MS (ESI +) 407 (M ⁺ +1, 100%).

Example 29
3-Chloro-7- [2- (dimethylamino) -2-oxoethoxy] -N-isopropyl-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -1H-indole -2-carboxamide hydrochloride

tert-Butyl (3R) -3-[{[3-Chloro-7- [2- (dimethylamino) -2-oxoethoxy] -1- (4-methoxybutyl) -1H-indol-2-yl] carbonyl } (Isopropyl) amino] piperidine-1-carboxylate (100 mg) added with 4N hydrochloric acid / ethyl acetate solution (5 ml), stirred at 25 ° C. for 15 min, and concentrated under reduced pressure to give the title compound (60 mg) Was obtained as white crystals.

¹ H NMR (300 MHz, DMSO-d6) δ 1.12-1.27 (m, 6H), 1.46-1.51 (m, 3H), 1.78-1.97 (m, 5H), 2.86 (s, 3H), 3.01 (s, 3H), 3.16-3.46 (m, 6H), 3.75-4.13 (m, 4H), 4.54-4.63 (m, 1H), 4.96 (s, 2H), 6.54 (s, 2H), 6.80-6.82 (m, 1H), 7.03-7.07 (m, 2H), 9.12-9.38 (m, 2H).
MS (ESI +) 507 (M ⁺ +1, 100%).

Example 30
3-chloro-N-isopropyl-1- (4-methoxybutyl) -7- {2-[(methylsulfonyl) amino] ethoxy} -N-[(3R) -piperidin-3-yl] -1H-indole- 2-carboxamide trifluoroacetate

tert-butyl (3R) -3-[[(3-chloro-1- (4-methoxybutyl) -7- {2-[(methylsulfonyl) amino] ethoxy} -1H-indol-2-yl) carbonyl] (Isopropyl) amino] piperidine-1-carboxylate (806 mg) was added with trifluoroacetic acid (5 ml), stirred at 25 ° C. for 15 minutes, and concentrated under reduced pressure to give the title compound (660 mg) as white crystals. Obtained.

¹ H NMR (300 MHz, DMSO-d6) δ 1.12-1.25 (m, 6H), 1.47-1.56 (m, 3H), 1.75-1.93 (m, 5H), 2.57 (s, 3H), 2.97 (s, 3H), 3.28-3.35 (m, 3H), 3.42-4.44 (m, 2H), 3.62-4.47 (m, 9H), 6.83-6.86 (m, 1H), 7.09-7.11 (m, 2H), 7.31- 7.33 (m, 1H), 8.58-9.00 (m, 2H).
MS (ESI +) 543 (M ⁺ +1, 100%).

Hereinafter, the title compounds (Examples 31 to 144) were synthesized with reference to Example 29 or Example 30.

Example 31
6-Fluoro-N-isopropyl-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -1H-indole-2-carboxamide hydrochloride

MS (ESI +) 390 (M ^{+ +} 1,100%).

Example 32
6-Fluoro-N-isopropyl-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -3-[(1E) -prop-1-en-1-yl] -1H -Indole-2-carboxamide hydrochloride

MS (ESI +) 431 (M ^{+ +} 1,100%).

Example 33
6-Fluoro-N-isopropyl-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -3-propyl-1H-indole-2-carboxamide hydrochloride

MS (ESI +) 432 (M ⁺ + 1,100%).

Example 34
3-Ethyl-6-fluoro-N-isopropyl-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -1H-indole-2-carboxamide hydrochloride

MS (ESI +) 418 (M ⁺ + 1,100%).

Example 35
3-Chloro-6-fluoro-N-isopropyl-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -1H-indole-2-carboxamide hydrochloride

MS (ESI +) 424 (M ⁺ + 1,100%).

Example 36
6-Fluoro-N-isopropyl-1- (4-methoxybutyl) -3-[(1E) -pent-1-en-1-yl] -N-[(3R) -piperidin-3-yl] -1H -Indole-2-carboxamide hydrochloride

MS (ESI +) 458 (M ⁺ + 1,100%).

Example 37
6-Fluoro-N-isopropyl-1- (4-methoxybutyl) -3-pentyl-N-[(3R) -piperidin-3-yl] -1H-indole-2-carboxamide hydrochloride

MS (ESI +) 460 (M ⁺ + 1,100%).

Example 38
3-Cyano-6-fluoro-N-isopropyl-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -1H-indole-2-carboxamide hydrochloride

MS (ESI +) 416 (M ⁺ + 1,100%).

Example 39
3-Cyano-4-fluoro-N-isopropyl-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -1H-indole-2-carboxamide hydrochloride

MS (ESI +) 415 (M ⁺ + 1,100%).

Example 40
3-Chloro-7-fluoro-N-isopropyl-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -1H-indole-2-carboxamide hydrochloride

MS (ESI +) 424 (M ⁺ + 1,100%).

Example 41
7-Fluoro-N-isopropyl-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -1H-indole-2-carboxamide hydrochloride

MS (ESI +) 390 (M ⁺ + 1,100%).

Example 42
7-Fluoro-N-isopropyl-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -3-propyl-1H-indole-2-carboxamide hydrochloride

MS (ESI +) 432 (M ⁺ + 1,100%).

Example 43
3-Cyano-7-fluoro-N-isopropyl-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -1H-indole-2-carboxamide hydrochloride

MS (ESI +) 415 (M ⁺ + 1,100%).

Example 44
N-isopropyl-7-methoxy-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -1H-indole-2-carboxamide hydrochloride

MS (ESI +) 402 (M ⁺ + 1,100%).

Example 45
3-Chloro-N-isopropyl-7-methoxy-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -1H-indole-2-carboxamide hydrochloride

MS (ESI +) 436 (M ⁺ + 1,100%).

Example 46
N-isopropyl-7-methoxy-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -3-propyl-1H-indole-2-carboxamide hydrochloride

MS (ESI +) 444 (M ⁺ + 1,100%).

Example 47
3-Cyano-N-isopropyl-7-methoxy-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -1H-indole-2-carboxamide hydrochloride

MS (ESI +) 427 (M ⁺ + 1,100%).

Example 48
3-Cyano-7-ethoxy-N-isopropyl-7-methoxy-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -1H-indole-2-carboxamide hydrochloride

MS (ESI +) 441 (M ⁺ + 1,100%).

Example 49
4-Fluoro-N-isopropyl-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -3-[(1E) -prop-1-en-1-yl] -1H -Indole-2-carboxamide hydrochloride

MS (ESI +) 430 (M ⁺ + 1,100%).

Example 50
7- (Benzyloxy) -N-isopropyl-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -1H-indole-2-carboxamide hydrochloride

MS (ESI +) 478 (M ⁺ + 1,100%).

Example 51
7-Hydroxy-N-isopropyl-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -1H-indole-2-carboxamide hydrochloride

MS (ESI +) 388 (M ⁺ + 1,100%).

Example 52
N-isopropyl-1- (4-methoxybutyl) -7- [2- (dimethylamino) -2-oxoethoxy] -N-[(3R) -piperidin-3-yl] -1H-indole-2-carboxamide Hydrochloride

MS (ESI +) 473 (M ⁺ + 1,100%).

Example 53
N-isopropyl-1- (4-methoxybutyl) -7- (2-oxo-2-pyrrolidin-1-ylethoxy) -N-[(3R) -piperidin-3-yl] -1H-indole-2-carboxamide Hydrochloride

MS (ESI +) 499 (M ⁺ + 1,100%).

Example 54
N-isopropyl-1- (4-methoxybutyl) -7- (2-morpholin-4-yl-2-oxoethoxy) -N-[(3R) -piperidin-3-yl] -1H-indole-2- Carboxamide hydrochloride

MS (ESI +) 515 (M ⁺ + 1,100%).

Example 55
3,4-dichloro-7- [2- (dimethylamino) -2-oxoethoxy] -N-isopropyl-1- (4-methoxybutyl-l) -N-[(3R) -piperidin-3-yl]- 1H-indole-2-carboxamide hydrochloride

MS (ESI +) 541 (M ⁺ + 1,100%).

Example 56
3-Chloro-N-isopropyl-1- (4-methoxybutyl) -7- (2-oxo-2-pyrrolidin-1-ylethoxy) -N-[(3R) -piperidin-3-yl] -1H-indole -2-carboxamide hydrochloride

MS (ESI +) 533 (M ⁺ + 1,100%).

Example 57
N-isopropyl-1- (4-methoxybutyl) -7- (2-pyrrolidin-1-ylethoxy) -N-[(3R) -piperidin-3-yl] -1H-indole-2-carboxamide dihydrochloride

MS (ESI +) 485 (M ⁺ +1, 11%).

Example 58
{[3-Chloro-2-({isopropyl [(3R) -piperidin-3-yl] amino} carbonyl) -1- (4-methoxybutyl) -1H-indol-7-yl] oxy} acetic acid hydrochloride

MS (ESI +) 482 (M ⁺ + 1,100%).

Example 59
7-Cyano-N-isopropyl-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -1H-indole-2-carboxamide hydrochloride

MS (ESI +) 397 (M ⁺ + 1,100%).

Example 60
{[2-({Isopropyl [(3R) -piperidin-3-yl] amino} carbonyl) -1- (4-methoxybutyl) -1H-indol-7-yl] oxy} acetic acid hydrochloride

MS (ESI +) 446 (M ⁺ + 1,100%).

Example 61
N-isopropyl-1- (4-methoxybutyl l) -7- [2- (diethylamino) -2-oxoethoxy] -N-[(3R) -piperidin-3-yl] -1H-indole-2-carboxamide Hydrochloride

MS (ESI +) 501 (M ⁺ + 1,100%).

Example 62
N-isopropyl-1- (4-methoxybutyl) -3-propyl-7- [2- (diethylamino) -2-oxoethoxy] -N-[(3R) -piperidin-3-yl] -1H-indole- 2-carboxamide hydrochloride

MS (ESI +) 543 (M ⁺ + 1,100%).

Example 63
2-({Isopropyl [(3R) -piperidin-3-yl] amino} carbonyl) -1- (4-methoxybutyl) -1H-indol-7-yl diethylcarbamate hydrochloride

MS (ESI +) 487 (M ⁺ + 1,100%).

Example 64
2-({Isopropyl [(3R) -piperidin-3-yl] amino} carbonyl) -1- (4-methoxybutyl) -3-propyl-1H-indol-7-yl diethylcarbamate hydrochloride

MS (ESI +) 529 (M ⁺ + 1,100%).

Example 65
3-cyano-2-({isopropyl [(3R) -piperidin-3-yl] amino} carbonyl) -1- (4-methoxybutyl) -1H-indol-7-yl diethylcarbamate hydrochloride

MS (ESI +) 513 (M ⁺ + 1,100%).

Example 66
2-({Isopropyl [(3R) -piperidin-3-yl] amino} carbonyl) -1- (4-methoxybutyl) -1H-indol-7-yl ethylcarbamate hydrochloride

MS (ESI +) 459 (M ⁺ + 1,100%).

Example 67
2-({Isopropyl [(3R) -piperidin-3-yl] amino} carbonyl) -1- (4-methoxybutyl) -3-propyl-1H-indol-7-ylethylcarbamate hydrochloride

MS (ESI +) 501 (M ⁺ + 1,100%).

Example 68
3-cyano-2-({isopropyl [(3R) -piperidin-3-yl] amino} carbonyl) -1- (4-methoxybutyl) -1H-indol-7-yl ethylcarbamate hydrochloride

MS (ESI +) 484 (M ⁺ + 1,100%).

Example 69
N-isopropyl-1- (4-methoxybutyl l) -7- [2- (methylamino) -2-oxoethoxy] -N-[(3R) -piperidin-3-yl] -1H-indole-2- Carboxamide hydrochloride

MS (ESI +) 459 (M ⁺ + 1,100%).

Example 70
N-isopropyl-1- (4-methoxybutyl l) -7- [2- (ethylamino) -2-oxoethoxy] -N-[(3R) -piperidin-3-yl] -1H-indole-2- Carboxamide hydrochloride

MS (ESI +) 473 (M ⁺ + 1,100%).

Example 71
N-isopropyl-1- (4-methoxybutyl l) -7- [2- (isopropylamino) -2-oxoethoxy] -N-[(3R) -piperidin-3-yl] -1H-indole-2- Carboxamide hydrochloride

MS (ESI +) 487 (M ⁺ + 1,100%).

Example 72
N-isopropyl-1- (4-methoxybutyl) -7- (2-oxo-2-piperidin-1-ylethoxy) -N-[(3R) -piperidin-3-yl] -1H-indole-2-carboxamide Hydrochloride

MS (ESI +) 513 (M ⁺ + 1,100%).

Example 73
6-Fluoro-N-isopropyl-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -3- (2H-tetrazol-5-yl) -1H-indole-2-carboxamide Dihydrochloride

MS (ESI +) 458 (M ⁺ +1, 62%).

Example 74
3-Chloro-7- [2- (methylamino) -2-oxoethoxy] -N-isopropyl-1- (4-methoxybutyl-l) -N-[(3R) -piperidin-3-yl] -1H- Indole-2-carboxamide hydrochloride

MS (ESI +) 493 (M ⁺ + 1,100%).

Example 75
3-Chloro-7- [2- (isopropylamino) -2-oxoethoxy] -N-isopropyl-1- (4-methoxybutyl l) -N-[(3R) -piperidin-3-yl] -1H- Indole-2-carboxamide hydrochloride

MS (ESI +) 523 (M ⁺ + 1,100%).

Example 76
3-Chloro-7- [2- (diethylamino) -2-oxoethoxy] -N-isopropyl-1- (4-methoxybutyll) -N-[(3R) -piperidin-3-yl] -1H-indole -2-carboxamide hydrochloride

MS (ESI +) 535 (M ⁺ + 1,100%).

Example 77
3-Chloro-2-({isopropyl [(3R) -piperidin-3-yl] amino} carbonyl) -1- (4-methoxybutyl) -1H-indol-7-yl ethylcarbamate hydrochloride

MS (ESI +) 484 (M ⁺ + 1,100%).

Example 78
Methyl 7-hydroxy-2-({isopropyl [(3R) -piperidin-3-yl] amino} carbonyl) -1- (4-methoxybutyl) -1H-indole-4-carboxamide hydrochloride

MS (ESI +) 446 (M ⁺ + 1,100%).

Example 79
7-Hydroxy-N-isopropyl-1- (4-methoxybutyl) -4-methyl lN-[(3R) -piperidin-3-yl] -1H-indole-2-carboxamide hydrochloride

MS (ESI +) 402 (M ⁺ + 1,100%).

Example 80
7- (2-Methoxyethoxy) -N-isopropyl-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -1H-indole-2-carboxamide hydrochloride

MS (ESI +) 446 (M ⁺ + 1,100%).

Example 81
7- (2-Methoxypropoxy) -N-isopropyl-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -1H-indole-2-carboxamide hydrochloride

MS (ESI +) 460 (M ⁺ + 1,100%).

Example 82
7- (2-Methoxyethoxy) -N-isopropyl-1- (4-methoxybutyl) -4-methyl-N-[(3R) -piperidin-3-yl] -1H-indole-2-carboxamide hydrochloride

MS (ESI +) 460 (M ⁺ + 1,100%).

Example 83
7- [2- (Diethylamino) -2-oxoethoxy] -N-isopropyl-1- (4-methoxybutyl) -4-methyl-N-[(3R) -piperidin-3-yl] -1H-indole- 2-carboxamide hydrochloride

MS (ESI +) 515 (M ⁺ + 1,100%).

Example 84
3-Chloro-N-isopropyl-1- (4-methoxybutyl) -7- (2-methoxyethoxy) -N-[(3R) -piperidin-3-yl] -1H-indole-2-carboxamide hydrochloride

MS (ESI +) 482 (M ⁺ + 1,100%).

Example 85
3-Chloro-N-isopropyl-1- (4-methoxybutyl) -7- (2-methoxypropoxy) -N-[(3R) -piperidin-3-yl] -1H-indole-2-carboxamide hydrochloride

MS (ESI +) 496 (M ⁺ + 1,100%).

Example 86
N-isopropyl-1- (4-methoxybutyl) -7- [2- (2-oxopyrrolidin-1-yl) ethoxy] -N-[(3R) -piperidin-3-yl] -1H-indole-2 -Carboxamide hydrochloride

MS (ESI +) 499 (M ⁺ + 1,100%).

Example 87
Methyl (2-{[2-({isopropyl [(3R) -piperidin-3-yl] amino} carbonyl) -1- (4-methoxybutyl) -1H-indol-7-yl] oxy} ethyl) carbamate hydrochloric acid salt

MS (ESI +) 489 (M ⁺ + 1,100%).

Example 88
Ethyl {[3-chloro-2-({isopropyl [(3R) -piperidin-3-yl] amino} carbonyl) -1- (4-methoxybutyl) -1H-indol-7-yl] oxy} acetic acid hydrochloride

MS (ESI +) 508 (M ⁺ + 1,100%).

Example 89
3-Chloro-7- (3-hydroxypropoxy) -N-isopropyl-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -1H-indole-2-carboxamide hydrochloride

MS (ESI +) 482 (M ⁺ + 1,100%).

Example 90
3-Chloro-7- [2- (tert-butylamino) -2-oxoethoxy] -N-isopropyl-1- (4-methoxybutyl-l) -N-[(3R) -piperidin-3-yl]- 1H-indole-2-carboxamide hydrochloride

MS (ESI +) 535 (M ⁺ + 1,100%).

Example 91
Methyl (2-{[3-chloro-2-({isopropyl [(3R) -piperidin-3-yl] amino} carbonyl) -1- (4-methoxybutyl) -1H-indol-7-yl] oxy} Ethyl) carbamate hydrochloride

MS (ESI +) 523 (M ⁺ + 1,100%).

Example 92
2-{[2-({Isopropyl [(3R) -piperidin-3-yl] amino} carbonyl) -1- (4-methoxybutyl) -1H-indol-7-yl] oxy} ethyldimethylcarbamate hydrochloride

MS (ESI +) 503 (M ⁺ + 1,100%).

Example 93
2-{[2-({Isopropyl [(3R) -piperidin-3-yl] amino} carbonyl) -1- (4-methoxybutyl) -1H-indol-7-yl] oxy} propyldimethylcarbamate hydrochloride

MS (ESI +) 517 (M ⁺ + 1,100%).

Example 94
N-isopropyl-1- (4-methoxybutyl) -7- [2- (methylsulfonyl) methoxy] -N-[(3R) -piperidin-3-yl] -1H-indole-2-carboxamide trifluoroacetate

MS (ESI +) 480 (M ⁺ + 1,100%).

Example 95
7- (3-Cyanopropyl) -N-isopropyl-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -1H-indole-2-carboxamide hydrochloride

MS (ESI +) 455 (M ⁺ + 1,100%).

Example 96
3,4-dichloro-N-isopropyl-1- (4-methoxybutyl) -7- {2-[(methylsulfonyl) amino] ethoxy} -N-[(3R) -piperidin-3-yl] -1H- Indole-2-carboxamide hydrochloride

MS (ESI +) 577 (M ⁺ + 1,100%).

Example 97
3-Chloro-7- [2- (ethylamino) -2-oxoethoxy] -N-isopropyl-1- (4-methoxybutyl-l) -N-[(3R) -piperidin-3-yl] -1H- Indole-2-carboxamide hydrochloride

MS (ESI +) 495 (M ⁺ + 1,100%).

Example 98
2-{[3-Chloro-2-({isopropyl [(3R) -piperidin-3-yl] amino} carbonyl) -1- (4-methoxybutyl) -1H-indol-7-yl] oxy} ethyldimethyl Carbamate hydrochloride

MS (ESI +) 537 (M ⁺ + 1,100%).

Example 99
7- [2- (Diethylamino) ethoxy] -N-isopropyl-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -1H-indole-2-carboxamide dihydrochloride

MS (ESI +) 487 (M ⁺ +1, 12%).

Example 100
2-{[3-Chloro-2-({isopropyl [(3R) -piperidin-3-yl] amino} carbonyl) -1- (4-methoxybutyl) -1H-indol-7-yl] oxy} propyldimethyl Carbamate hydrochloride

MS (ESI +) 551 (M ⁺ + 1,100%).

Example 101
3-Chloro-7- (3-cyanopropyl) -N-isopropyl-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -1H-indole-2-carboxamide hydrochloride

MS (ESI +) 489 (M ⁺ + 1,100%).

Example 102
3-Chloro-7- [2- (diethylamino) ethoxy] -N-isopropyl-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -1H-indole-2-carboxamide 2 Hydrochloride

MS (ESI +) 521 (M ⁺ +1, 10%).

Example 103
3-Chloro-N-isopropyl-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -7- (2-pyrrolidin-1-ylethoxy) -1H-indole-2-carboxamide Dihydrochloride

MS (ESI +) 519 (M ⁺ +1, 13%).

Example 104
3-Chloro-7- {2-[(2,2-dimethylpropanoyl) amino] ethoxy} -N-isopropyl-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -1H-indole-2-carboxamide hydrochloride

MS (ESI +) 549 (M ⁺ + 1,100%).

Example 105
3-Chloro-7- [2- (cyclopropylamino) -2-oxoethoxy] -N-isopropyl-1- (4-methoxybutyl-l) -N-[(3R) -piperidin-3-yl] -1H -Indole-2-carboxamide hydrochloride

MS (ESI +) 519 (M ⁺ + 1,100%).

Example 106
7- (2-Amino-2-oxoethoxy) -3-chloro-N-isopropyl-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -1H-indole-2- Carboxamide hydrochloride

MS (ESI +) 479 (M ⁺ + 1,100%).

Example 107
7- [2- (4-Hydroxyethylamino) -2-oxoethoxy] -3-chloro-N-isopropyl-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl]- 1H-indole-2-carboxamide hydrochloride

MS (ESI +) 523 (M ⁺ + 1,100%).

Example 108
N-isopropyl-1- (4-methoxybutyl) -7- [2- (methylsulfonyl) ethoxy] -N-[(3R) -piperidin-3-yl] -1H-indole-2-carboxamide trifluoroacetate

MS (ESI +) 494 (M ⁺ + 1,100%).

Example 109
3-Chloro-7- [3- (dimethylamino) -3-oxopropyl] -N-isopropyl-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -1H-indole -2-carboxamide hydrochloride

MS (ESI +) 505 (M ⁺ + 1,100%).

Example 110
3-Chloro-7- [2- (dimethylamino) ethoxy] -N-isopropyl-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -1H-indole-2-carboxamide Dihydrochloride

MS (ESI +) 493 (M ⁺ +1, 16%).

Example 111
3-Chloro-N-isopropyl-1- (4-methoxybutyl) -7- [2- (methylsulfonyl) ethoxy] -N-[(3R) -piperidin-3-yl] -1H-indole-2-carboxamide Trifluoroacetate

MS (ESI +) 528 (M ⁺ + 1,100%).

Example 112
3-Chloro-N-isopropyl-1- (4-methoxybutyl) -7- {2-[(methylsulfonyl) amino] -2-oxoethoxy} -N-[(3R) -piperidin-3-yl]- 1H-indole-2-carboxamide hydrochloride

MS (ESI +) 557 (M ⁺ + 1,100%).

Example 113
7- [2- (tert-Butylsulfonyl) ethoxy] -3-chloro-N-isopropyl-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -1H-indole-2 -Carboxamide trifluoroacetate

MS (ESI +) 571 (M ⁺ +1, 100%).

Example 114
3-Chloro-N-isopropyl-1- (4-methoxybutyl) -7- {2- [methyl (methylsulfonyl) amino] -2-oxoethoxy} -N-[(3R) -piperidin-3-yl] -1H-indole-2-carboxamide hydrochloride

MS (ESI +) 571 (M ⁺ + 1,100%).

Example 115
7- (2-{[Methylsulfonyl] amino} ethoxy) -N-isopropyl-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -1H-indole-2-carboxamide Tri Fluoroacetate

MS (ESI +) 509 (M ⁺ + 1,100%).

Example 116
7- [2- (tert-Butylsulfonyl) ethoxy] -N-isopropyl-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -1H-indole-2-carboxamide trifluoro Acetate

MS (ESI +) 536 (M ⁺ + 1,100%).

Example 117
3-{[3-Chloro-2-({isopropyl [(3R) -piperidin-3-yl] amino} carbonyl) -1- (4-methoxybutyl) -1H-indol-7-yl] oxy} -2 , 2-Dimethylpropanoic acid hydrochloride

MS (ESI +) 522 (M ⁺ + 1,100%).

Example 118
7- (3-Amino-2,2-dimethyl-3-oxopropoxy) -3-chloro-N-isopropyl-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl]- 1H-indole-2-carboxamide hydrochloride

MS (ESI +) 521 (M ⁺ + 1,100%).

Example 119
3-Chloro-7- [2- (1,1-dioxide-1,3-thiazolidin-3-yl) -amino-2-oxoethoxy] -N-isopropyl-1- (4-methoxybutyl) -N- [(3R) -piperidin-3-yl] -1H-indole-2-carboxamide trifluoroacetate

MS (ESI +) 597 (M ⁺ + 1,100%).

Example 120
7- (2- {Methyl [methylsulfonyl] amino} ethoxy) -N-isopropyl-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -1H-indole-2-carboxamide Trifluoroacetate

MS (ESI +) 523 (M ⁺ + 1,100%).

Example 121
7- (2- {Ethyl [methylsulfonyl] amino} ethoxy) -N-isopropyl-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -1H-indole-2-carboxamide Trifluoroacetate

MS (ESI +) 537 (M ⁺ + 1,100%).

Example 122
7- (2-{[Ethylsulfonyl] amino} ethoxy) -N-isopropyl-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -1H-indole-2-carboxamide Tri Fluoroacetate

MS (ESI +) 523 (M ⁺ + 1,100%).

Example 123
7- (2- {Methyl [ethylsulfonyl] amino} ethoxy) -N-isopropyl-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -1H-indole-2-carboxamide Trifluoroacetate

MS (ESI +) 537 (M ⁺ + 1,100%).

Example 124
7- (2-{[isopropylsulfonyl] amino} ethoxy) -N-isopropyl-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -1H-indole-2-carboxamide Tri Fluoroacetate

MS (ESI +) 537 (M ⁺ + 1,100%).

Example 125
7- (2-{[(Dimethylamino) sulfonyl] amino} ethoxy) -N-isopropyl-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -1H-indole-2 -Carboxamide trifluoroacetate

MS (ESI +) 538 (M ⁺ + 1,100%).

Example 126
7- {2- [Acetyl (methyl) amino] -2-oxoethoxy} -3-chloro-N-isopropyl-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl]- 1H-indole-2-carboxamide hydrochloride

MS (ESI +) 535 (M ⁺ + 1,100%).

Example 127
3-Chloro-7- [2- (1,1-dioxidethiomorpholin-4-yl) ethoxy] -N-isopropyl-1- (4-methoxybutyl) -N-[(3R) -piperidine-3- IL] -1H-indole-2-carboxamide hydrochloride

MS (ESI +) 583 (M ⁺ +1, 14%).

Example 128
3-Chloro-N-isopropyl-1- (4-methoxybutyl) -7- {2- [methyl (methylsulfonyl) amino] ethoxy} -N-[(3R) -piperidin-3-yl] -1H-indole -2-carboxamide trifluoroacetate

MS (ESI +) 557 (M ⁺ + 1,100%).

Example 129
3-Chloro-N-isopropyl-1- (4-methoxybutyl) -7- {2- [ethyl (methylsulfonyl) amino] ethoxy} -N-[(3R) -piperidin-3-yl] -1H-indole -2-carboxamide trifluoroacetate

MS (ESI +) 571 (M ⁺ + 1,100%).

Example 130
3-chloro-N-isopropyl-7- {2-[(ethylsulfonyl) amino] ethoxy} -1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -1H-indole- 2-carboxado trifluoroacetate

MS (ESI +) 557 (M ⁺ + 1,100%).

Example 131
3-Chloro-N-isopropyl-1- (4-methoxybutyl) -7- {2- [methyl (ethylsulfonyl) amino] ethoxy} -N-[(3R) -piperidin-3-yl] -1H-indole -2-carboxamide trifluoroacetate

MS (ESI +) 571 (M ⁺ + 1,100%).

Example 132
3-chloro-N-isopropyl-7- {2-[(isopropylsulfonyl) amino] ethoxy} -1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -1H-indole- 2-carboxamide trifluoroacetate

MS (ESI +) 571 (M ⁺ + 1,100%).

Example 133
3-Chloro-7- (2-{[(dimethylamino) sulfonyl] amino} ethoxy) -N-isopropyl-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -1H -Indole-2-carboxamide trifluoroacetate

MS (ESI +) 572 (M ⁺ + 1,100%).

Example 134
7- [2- (Ethylsulfonyl) ethoxy] -3-chloro-N-isopropyl-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -1H-indole-2-carboxamide Trifluoroacetate

MS (ESI +) 542 (M ⁺ + 1,100%).

Example 135
3-Fluoro-7- [2- (dimethylamino) -2-oxoethoxy] -N-isopropyl-1- (4-methoxybutyll) -N-[(3R) -piperidin-3-yl] -1H- Indole-2-carboxamide hydrochloride

MS (ESI +) 491 (M ⁺ + 1,100%).

Example 136
3-Fluoro-N-isopropyl-1- (4-methoxybutyl) -7- {2- [methyl (methylsulfonyl) amino] ethoxy} -N-[(3R) -piperidin-3-yl] -1H-indole -2-carboxamide trifluoroacetate

MS (ESI +) 541 (M ⁺ + 1,100%).

Example 137
3-Chloro-7- [2- (1,1-dioxidethiomorpholin-4-yl) -2-oxoethoxy] -N-isopropyl-1- (4-methoxybutyl) -N-[(3R)- Piperidin-3-yl] -1H-indole-2-carboxamide trifluoroacetate

MS (ESI +) 597 (M ⁺ + 1,100%).

Example 138
3-Chloro-N-isopropyl-1- (4-methoxybutyl) -7-[(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) methoxy] -N- [(3R) -piperidin-3-yl] -1H-indole-2-carboxamide hydrochloride

MS (ESI +) 520 (M ⁺ + 1,100%).

Example 139
7- (2-{[Methylsulfonyl] amino} propoxy) -N-isopropyl-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -1H-indole-2-carboxamide Tri Fluoroacetate MS

(ESI +) 523 (M ⁺ + 1,100%).

Example 140
7- (2-{[Ethylsulfonyl] amino} ethoxy) -N-isopropyl-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -1H-indole-2-carboxamide Tri Fluoroacetate

MS (ESI +) 537 (M ⁺ + 1,100%).

Example 141
7- (2-{[isopropylsulfonyl] amino} ethoxy) -N-isopropyl-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -1H-indole-2-carboxamide Tri Fluoroacetate

MS (ESI +) 551 (M ⁺ + 1,100%).

Example 142
7- (2-{[(Dimethylamino) sulfonyl] amino} propoxy) -N-isopropyl-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -1H-indole-2 -Carboxamide trifluoroacetate

MS (ESI +) 552 (M ⁺ + 1,100%).

Example 143
7- [2- (Isopropylsulfonyl) ethoxy] -N-isopropyl-1- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] -1H-indole-2-carboxado trifluoroacetate

MS (ESI +) 522 (M ⁺ + 1,100%).

Example 144
3-Chloro-N-isopropyl-1- (4-methoxybutyl) -7-[(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) propoxy] -N- [(3R) -piperidin-3-yl] -1H-indole-2-carboxamide hydrochloride

MS (ESI +) 548 (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.

Test compound
Human renin inhibitory activity
IC ₅₀ (μM)

Example 1
0.00081

Example 2
0.0053

Example 3
0.036

Example 4
0.0041

Example 7
0.00017

Example 8
0.00051

Example 13
0.0029

Example 14
0.0087

Example 15
0.0036

Example 16
0.00086

Example 32
0.0078

Example 34
0.0058

Example 35
0.0013

Example 38
0.0018

Example 40
0.0022

Example 41
0.0015

Example 48
0.0033

Example 49
0.00083

Example 55
0.0037

Example 70
0.0038

Example 71
0.0032

Example 72
0.0027

Example 74
0.0042

Example 75
0.00025

Example 84
0.00077

Example 85
0.00028

Example 86
0.0037

Example 91
0.00015

Example 92
0.00312

Example 97
0.0043

Example 104
0.000069

Example 106
0.00029

Example 107
0.00023

Example 109
0.00018

Example 110
0.00046

Example 111
0.00029

Example 116
0.00071

Example 119
0.00062

Example 123
0.00095

Example 124
0.00043

Example 126
0.00017

Example 127
0.00106

Example 129
0.00029

Example 131
0.00131

  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 (9)

A compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

[In the formula, G represents the following (a) to (c)

Any one group represented by:
R ^1a is 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 a substituted A heteroarylalkyl group which may be
R ^1b , R ^1c , R ^1d and R ^1e 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, a substituted 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, a substituted An optionally substituted heteroaryl group, an optionally substituted heteroarylalkyl group, an optionally substituted saturated heterocyclic group, an optionally substituted alkylthio group, an optionally substituted alkylsulfinyl group, an optionally substituted Alkylsulfonyl group, optionally substituted arylthio group, optionally substituted arylsulfinyl group, optionally substituted A reelsulfonyl 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 Heteroaryloxy group which may be substituted, heteroarylalkyloxy group which may be substituted, amino group which may be substituted, aminocarbonyl group which may be substituted, aminocarbonyloxy group which may be substituted, substituted Aminosulfonyl group, optionally substituted alkoxycarbonyl group, optionally substituted cycloalkyloxycarbonyl group, optionally substituted alkylcarbonyl group, optionally substituted cycloalkylcarbonyl group, optionally substituted An arylcarbonyl group or an optionally substituted heteroatom It is Lumpur carbonyl group;
R ^1f is a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, a substituted An optionally substituted cycloalkenyl group, an optionally substituted aryl group, an optionally substituted aralkyl group, an optionally substituted heteroaryl group, an optionally substituted heteroarylalkyl group, an optionally substituted saturated heteroalkyl group A cyclic group, an optionally substituted alkylthio group, an optionally substituted alkylsulfinyl group, an optionally substituted alkylsulfonyl group, an optionally substituted alkoxy group, an optionally substituted alkynyloxy group, and optionally substituted Good cycloalkyloxy group, optionally substituted aryloxy group, optionally substituted aralkyloxy group, substituted Heteroarylalkyloxy group which may be substituted, amino group which may be substituted, aminocarbonyl group which may be substituted, aminosulfonyl group which may be substituted, alkoxycarbonyl group which may be substituted, may be substituted A cycloalkyloxycarbonyl group, an optionally substituted alkylcarbonyl group, an optionally substituted cycloalkylcarbonyl group, an optionally substituted arylcarbonyl group, or an optionally substituted heteroarylcarbonyl 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 is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted aralkyl group, or an optionally substituted heteroaryl group. Yes;
When s is 0, 1 or 2 (-(CH ₂ ) _s N (R ⁴ )-, s is 0 or 2, and when-(CH ₂ ) _s CON (R ⁴ )- , S is 1 or 2.);
n is 0, 1, or 2. ] G is the following (a)

The compound according to claim 1, or a salt thereof. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R ^1a is C _1-4 alkoxy, or a C _1-6 alkyl group optionally substituted with C _1-4 alkoxycarbonylamino. . R ^1b is a hydrogen atom, a halogen atom, a hydroxyl group, a carboxyl group, a cyano group, an optionally substituted _{C 1-6} alkyl group, optionally substituted _{C 1-6} alkoxy group, an optionally substituted _{C 3- 10. A} cycloalkyloxy group, an optionally substituted C _7-14 aralkyloxy group, an optionally substituted aminocarbonyloxy group, or an optionally substituted C _1-4 alkoxycarbonyl group. The compound according to any one of the above, or a pharmaceutically acceptable salt thereof. R ^<1c> , R ^<1d> and R ^<1e> are respectively independently the same, and are a hydrogen atom, The compound as described in any one of Claims 1-4, or its pharmacologically acceptable salt. R ^1f is a hydrogen atom, a halogen atom, a cyano group, an optionally substituted _{C 1-6} alkyl group, optionally substituted _{C 3-10} cycloalkyl group, an optionally substituted _{C 1-6} alkoxy group, The C _7-14 aralkyloxy group which may be substituted, the aminocarbonyl group which may be substituted, or the C _1-4 alkylcarbonyl group which may be substituted. A compound, or a pharmaceutically acceptable salt thereof. Item 7. The compound according to any one of Items 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R ² is an optionally substituted C _1-6 alkyl group. R ^3a , R ^3b , R ^3c and R ^3d are each independently the same and are the group: -AB (where A is a single bond and B is a hydrogen atom). The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof. n is 1, The compound as described in any one of Claims 1-8, or its pharmaceutically acceptable salt.