JP2011037712A - 4-arylphenyl derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a novel 4-arylphenyl derivative effective as a renin inhibitor. <P>SOLUTION: The compound of formula (I) or a pharmaceutically acceptable salt thereof is provided. In formula (I), R<SP>1a</SP>represents a hydrogen atom or the like; R<SP>1b</SP>represents a substituted 1-6C alkyl group or the like; G represents a group represented by formula (I-A) or the like; R<SP>1c</SP>represents a hydrogen atom or the like; R<SP>1f</SP>represents a hydrogen atom or the like; R<SP>1g</SP>represents a hydrogen atom, a halogen atom or the like; R<SP>1d</SP>represents a group represented by the formula: -D-E or the like, wherein D represents a single bond, -CO- or the like, and E represents a hydrogen atom, an optionally monosubstituted or disubstituted amino group, an optionally substituted 4- to 7-membered cyclic amino group or the like; R<SP>1e</SP>represents a hydrogen atom or the like; R<SP>2</SP>represents an optionally substituted 1-6C alkyl group or the like; R<SP>3a</SP>, R<SP>3b</SP>, R<SP>3c</SP>and R<SP>3d</SP>are identical to or different from each other and independently represent a group represented by the formula: -A-B or the like, wherein A represents a single bond or the like, and B represents a hydrogen atom or the like; and n represents 0 or the like. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to a 4-arylphenyl derivative useful as a medicine. More specifically, it relates to a 4-arylphenyl derivative effective as a renin inhibitor. Furthermore, the present invention relates to an antihypertensive agent comprising a 4-arylphenyl derivative effective as a renin inhibitor as an active ingredient.

The renin-angiotensin (RA) system is an important hormone 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 (4-arylphenyl) carbonylamino is directly bonded to the 3-position of the piperidine ring, that is, a compound group having 3- (4-arylphenylcarbonylamino) piperidine as a basic skeleton is renin. To date, it has not been known to be useful as an 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.

[Wherein, R ^1a represents a hydrogen atom, a halogen atom, a hydroxyl group, a formyl group, a carboxy group, a cyano group, an optionally substituted C _1-6 alkyl group, an optionally substituted C _3-10 cycloalkyl group, Optionally substituted C _2-6 alkynyl group, optionally substituted C _2-6 alkenyl group, optionally substituted C _1-6 alkylthio group, optionally substituted C _1-6 alkylsulfinyl group, substituted A C _1-6 alkylsulfonyl group which may be substituted, a C _1-6 alkoxy group which may be substituted, a C _3-10 cycloalkoxy group which may be substituted, an amino group which may be mono- or di-substituted, optionally substituted 5- to 7-membered cyclic amino group, an optionally substituted carbamoyl group, an optionally substituted C _1-4 alkoxycarbonyl group or optionally substituted C _1-4 a also, It is Kill carbonyl group;
R ^1b is substituted _{C 1-8} alkyl group, optionally substituted _{C 1-6} alkylsulfinyl group, optionally substituted _{C 1-6} alkylsulfonyl group, a substituted _{C 1-6} alkoxy group, C _3-6 alkynyloxy group which may be substituted, amino group which may be mono- or di-substituted, carbamoyl group which may be substituted, C _1-4 alkoxycarbonyl group which may be substituted, or substituted An optionally substituted C _1-4 alkylcarbonyl group (wherein the substituted C _1-8 alkyl group is mono-C _1-6 alkoxycarbonylamino, C _1-4 alkoxy, C _3-6 cycloalkyl, C _1-4 substituted with one group selected from alkoxy _{C 1-4} group consisting of alkoxy and _{C 1-6} alkylsulfonyl, substituted _{C 1-6} Al The alkoxy group is substituted with one group selected from the group consisting of C _1-4 alkoxy, C _3-6 cycloalkyl and C _1-4 alkoxycarbonylamino.);
G is the following formula

Or an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group (wherein
R ^1c is a hydrogen atom, a halogen atom, an optionally substituted C _1-6 alkyl group, or an optionally substituted C _1-6 alkoxy group;
R ^1f is a hydrogen atom, a halogen atom, a carboxyl group, a cyano group, an optionally substituted C _1-6 alkyl group, optionally substituted C _1-6 alkoxy group, an optionally substituted carbamoyl group, or a substituted, A C _1-4 alkoxycarbonyl group which may be
R ^1g represents a hydrogen atom, a halogen atom, a carboxyl group, a cyano group, an optionally substituted C _1-6 alkyl group, optionally substituted C _1-6 alkoxy group, an optionally substituted carbamoyl group, or a substituted, A C _1-4 alkoxycarbonyl group which may be
R ^1d is a cyano group, a halogen atom, or a group: —DE
(Here, D is a single bond, —O—, —SO ₂ —, —CO—, —COO—, —CH ₂ SO ₂ —, —COCO—, —OCH ₂ CH ₂ CO—, —OCH ₂ CO _{-, - OC (CH 3)} (CH 3) CO -, - CH 2 OCO -, - N (R h) CO -, - N (R h) SO 2 -, - N (R h) COO -, - _{^{OCO -, - SO 2 N (}} R h) CO -, - OCH 2 CH 2 SO 2 -, - C (CH 3) (CH 3) CO-, or a _-CH 2 _OCH 2 CO-,
R ^h is a hydrogen atom, a C _1-4 alkoxycarbonyl group, or an optionally substituted C _1-6 alkyl group,
E represents a hydrogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C _2-6 alkenyl group, an optionally substituted C _3-10 cycloalkyl group, a mono- or di-substituted An optionally substituted amino group, an optionally substituted 4 to 7 membered cyclic amino group, an optionally substituted 5 or 6 membered saturated heterocyclic group, or an optionally substituted 5 to 10 membered It is a monocyclic or polycyclic heteroaryl group. (However, when D is —O—, —COO— or —N (R ^h ) COO—, E is not the amino group).
R ^1e represents a hydrogen atom, a halogen atom, a carboxyl group, a cyano group, an optionally substituted _{C 1-6} alkyl group, optionally substituted _{C 1-6} alkoxy group, an optionally _{C 3-10} cycloalkyl substituted An alkyl group, an optionally substituted C _3-10 cycloalkyloxy group, a saturated heterocyclic oxy group, an optionally substituted carbamoyl group, or an optionally substituted C _1-4 alkoxycarbonyl group,
Alternatively, R ^1d and R ^1e together form a fused ring. );
R ² is an optionally substituted C _1-6 alkyl group, an optionally substituted C _2-6 alkenyl group, an optionally substituted C _2-6 alkynyl group, an optionally substituted C _3-10 cyclo An alkyl group, an optionally substituted C _5-6 cycloalkenyl group, an optionally substituted C _6-10 aryl group, an optionally substituted C _7-14 aralkyl group, or an optionally substituted 5-10 membered A membered monocyclic or polycyclic 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 C _1-6 alkyl group, an optionally substituted C _2-6 alkenyl group, an optionally substituted C _2-6 alkynyl group, an optionally substituted C _{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) In the case of — and — (CH ₂ ) _s SO ₂ N (R ⁴ ) —, R ⁴ and B may be bonded together to form a ring. Or any two of R ^3a , R ^3b , R ^3c and R ^3d are hydrogen atoms and the remaining two together form a bridged ring with the piperidine ring;
R ⁴ represents a hydrogen atom, an optionally substituted C _1-6 alkyl group, an _optionally substituted C _3-10 cycloalkyl group, an _optionally substituted C _6-10 aryl group, or an _optionally substituted C _{A 7-14} aralkyl group or an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group;
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. ]

Term 2: G is the following formula

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

Item 3: R ^1a is a hydrogen atom, a halogen atom, a cyano group, an optionally substituted C _1-6 alkyl group, an optionally substituted C _3-6 cycloalkyl group, or an optionally substituted C _{1 A -6} alkoxy group;
R ^1b is substituted _{C 1-6} alkyl _{group, C 1-4} alkoxy or _{C 1-4} alkoxycarbonylamino substituted by a _{C 1-6} alkoxy group or an optionally substituted _{C 3-6} alkynyloxy, (Wherein the substituted C _1-6 alkyl groups are mono-C _1-4 alkoxycarbonylamino, C _1-4 alkoxy, C _1-4 alkoxy C _1-4 alkoxy and C _1-6 alkyl). Substituted with one group selected from the group consisting of sulfonyl);
R ^1c is a hydrogen atom, a halogen atom, or an optionally substituted C _1-6 alkoxy group;
R ^1f is a hydrogen atom, a halogen atom, a carboxyl group, a cyano group, an optionally substituted C _1-6 alkyl group, optionally substituted C _1-6 alkoxy group, an optionally substituted carbamoyl group, or a substituted, A C _1-4 alkoxycarbonyl group which may be
R ^1g represents a hydrogen atom, a halogen atom, a carboxyl group, a cyano group, an optionally substituted C _1-6 alkyl group, optionally substituted C _1-6 alkoxy group, an optionally substituted carbamoyl group, or a substituted, A C _1-4 alkoxycarbonyl group which may be
R ^1d is a cyano group, a halogen atom, or a group: —DE
(Here, D is a single bond, —O—, —SO ₂ —, —CO—, —COO—, —CH ₂ SO ₂ —, —COCO—, —OCH ₂ CH ₂ CO—, —OCH ₂ CO _{-, - OC (CH 3)} (CH 3) CO -, - CH 2 OCO -, - N (R h) CO -, - N (R h) SO 2 -, - N (R h) COO -, - _{^{OCO -, - SO 2 N (}} R h) CO -, - OCH 2 CH 2 SO 2 -, - C (CH 3) (CH 3) CO-, or a _-CH 2 _OCH 2 CO-,
R ^h is a hydrogen atom, a C _1-4 alkoxycarbonyl group, or an optionally substituted C _1-6 alkyl group,
E represents a hydrogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C _3-10 cycloalkyl group, a mono- or di-substituted amino group, and optionally substituted 4 A 5- to 7-membered cyclic amino group, an optionally substituted 5- or 6-membered saturated heterocyclic group, or an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group . );
R ^1e represents a hydrogen atom, a halogen atom, a carboxyl group, a cyano group, an optionally substituted _{C 1-6} alkyl group, optionally substituted _{C 1-6} alkoxy group, an optionally _{C 3-10} cycloalkyl substituted Item 3. The compound according to Item 1 or 2, wherein the compound is an alkyloxy group, a saturated heterocyclic oxy group, an optionally substituted carbamoyl group, or an optionally substituted C _1-4 alkoxycarbonyl group, or a pharmaceutically acceptable salt thereof. Salt.

Item 4: R ^1a and R ^1b are

Item 4. The compound according to Item 3, wherein the benzene ring is substituted at the substitution position represented by: or a pharmaceutically acceptable salt thereof.

Item 5: The compound according to Item 4, wherein R ^1a is a hydrogen atom, a halogen atom, a cyano group, an optionally substituted C _1-6 alkyl group, or an optionally substituted C _3-6 cycloalkyl group, Or a pharmaceutically acceptable salt thereof.

Item 6: The compound according to Item 5, or a pharmaceutically acceptable salt thereof, wherein R ^1a is a hydrogen atom, a halogen atom, a cyano group, or 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 a hydrogen atom.

Item 8: The compound according to Item 5, wherein R ^1a is a halogen atom, a cyano group, an optionally substituted C _1-6 alkyl group, or an optionally substituted C _3-6 cycloalkyl group, or a pharmaceutical thereof Top acceptable salt.

Item 9: The compound according to Item 6 or 8, wherein R ^1a is a halogen atom, a cyano group, or an optionally substituted C _1-6 alkyl group, or a pharmaceutically acceptable salt thereof.

Section ^{10: R 1b} _is, any one of _{C 1-4 C 1-6} alkoxy group substituted with an alkoxy claim 1 to claim 9 or a _{C 1-6} alkyl group substituted by _{C 1-4} alkoxy, Or a pharmaceutically acceptable salt thereof.

Item 11: The compound according to Item 10, or a pharmaceutically acceptable salt thereof, wherein R ^1b is a C _1-6 alkoxy group substituted with C _1-4 alkoxy.

Item 12: The compound according to Item 11, or a pharmaceutically acceptable salt thereof, wherein R ^1b is a 3-methoxypropyloxy group.

Item 13: The compound according to Item 10, or a pharmaceutically acceptable salt thereof, wherein R ^1b is a C _1-6 alkyl group substituted with C _1-4 alkoxy.

Item 14: The compound according to Item 13, or a pharmaceutically acceptable salt thereof, wherein R ^1b is 4-methoxybutyl.

Item 15: The compound according to any one of Items 1 to 14, wherein R ^1c , R ^1f , and R ^1g are each independently the same or different and are a hydrogen atom or a halogen atom, or a pharmaceutical thereof Top acceptable salt.

Item 16: R ^1d is a cyano group, a halogen atom, or a group: —DE
(Wherein, D is a single _{bond, -O -, - SO 2 -} , - CO -, - COO -, - N (R h) SO 2 -, or ^-N (R h) is COO-,
R ^h is a hydrogen atom or an optionally substituted C _1-6 alkyl group;
E is a hydrogen atom, an optionally substituted C _1-6 alkyl group, a mono- or di-substituted amino group, and an optionally substituted 4- to 7-membered cyclic amino group. The compound according to any one of Items 1 to 15, or a pharmaceutically acceptable salt thereof.

Item 17: The compound according to Item 16, or a pharmaceutically acceptable salt thereof, wherein R ^1d is a group: -DE.

Item 18: The compound according to Item 16 or Item 17, wherein D is a single bond, or a pharmaceutically acceptable salt thereof.

Item 19: The compound according to Item 18 or a pharmaceutically acceptable salt thereof, wherein E is a hydrogen atom or an optionally substituted 4- to 7-membered cyclic amino group.

Item 20: The compound according to Item 19, or a pharmaceutically acceptable salt thereof, wherein E is a hydrogen atom.

Item 21: The compound according to Item 16 or 17, or a pharmaceutically acceptable salt thereof, wherein D is —CO— or —N (R ^h ) COO—.

Item 22: The compound according to Item 21, or a pharmaceutically acceptable salt thereof, wherein D is -CO-.

Item 23: E is an optionally substituted C _1-6 alkyl group, an optionally substituted mono- or di-substituted amino group, or an optionally substituted 4- to 7-membered cyclic amino group. Or the compound according to item 22, or a pharmaceutically acceptable salt thereof.

Item 24: The compound according to Item 23 or a pharmaceutically acceptable salt thereof, wherein E is an amino group which may be di-substituted, or a 4- to 7-membered cyclic amino group which may be substituted.

Item 25: The compound according to Item 24, wherein E is an optionally substituted 4- to 7-membered cyclic amino group, or a pharmaceutically acceptable salt thereof.

Item 26: The compound according to any one of Items 1 to 25, or a pharmaceutically acceptable salt thereof, wherein R ^1h is a hydrogen atom.

Item 27: R ^1c , R ^1e and R ^1f are each independently a hydrogen atom;
R ^1g is a hydrogen atom or a halogen atom;
R ^1d is a group: —DE
Wherein D is a single bond, —CO—, or —N (R ^h ) COO—
R ^h is a hydrogen atom or an optionally substituted C _1-6 alkyl group,
E is a hydrogen atom, an optionally substituted C _1-6 alkyl group, a mono- or di-substituted amino group, or an optionally substituted 4- to 7-membered cyclic amino group. The compound according to any one of Items 4 to 14, or a pharmaceutically acceptable salt thereof.

Item 28: The compound according to item 27 or a pharmaceutically acceptable salt thereof, wherein R ^1g is a hydrogen atom.

Item 29: The compound according to Item 27 or a pharmaceutically acceptable salt thereof, wherein R ^1g is a halogen atom.

Item 30: R ^1d is a group: -DE
(Where D is -CO-,
E is an optionally substituted C _1-6 alkyl group, an mono- or di-substituted amino group, or an optionally substituted 4- to 7-membered cyclic amino group. The compound according to any one of Items 27 to 29, or a pharmaceutically acceptable salt thereof.

Item 31: The compound according to Item 30, or a pharmaceutically acceptable salt thereof, wherein E is an optionally substituted amino group, or an optionally substituted 4- to 7-membered cyclic amino group.

Item 32: R ^1d is a group: -DE
(Where D is a single bond,
Item 30. The compound according to any one of Items 27 to 29, or a pharmaceutically acceptable salt thereof, wherein E is a hydrogen atom.

Item 33: R ^1d is a group: -DE
(Where D is —N (R ^h ) COO—,
E is an optionally substituted C _1-6 alkyl group. The compound according to any one of Items 27 to 29, or a pharmaceutically acceptable salt thereof.

Item 34: The compound according to any one of Items 1 to 33, wherein R ² is an optionally substituted C _1-6 alkyl group, or an optionally substituted C _3-6 cycloalkyl group, or Its pharmaceutically acceptable salt.

Item 35: The compound according to Item 34 or a pharmaceutically acceptable salt thereof, wherein R ² is an optionally substituted C _1-6 alkyl group.

Item 36: The compound according to Item 35 or a pharmaceutically acceptable salt thereof, wherein R ² is an isopropyl group.

Item 37: R ^3a , R ^3b , R ^3c and R ^3d are

Item 36. The compound according to Item 1 to Item 36, or a pharmaceutically acceptable salt, which binds to the piperidine ring at the substitution position represented by

Item 38: R ^3a , R ^3b and R ^3d are each independently the same and are a group: -AB (where A is a single bond and B is a hydrogen atom). ;
Item 37. R ^37c is the group: -AB (wherein A is a single bond, and B is a hydrogen atom or an optionally substituted C _6-10 aryl group). Or a pharmaceutically acceptable salt thereof.

Item 39: The Item 38, wherein R ^3c is a group: -A-B (wherein A is a single bond, and B is an optionally substituted C _6-10 aryl group). A compound, or a pharmaceutically acceptable salt thereof.

Item 40: R ^3a , R ^3c, and R ^3d are each independently the same and are a group: -AB (where A is a single bond and B is a hydrogen atom). ;
R ^3b is a group: —AB (where A is a single bond, — (CH ₂ ) _s O—, — (CH ₂ ) _s N (R ⁴ ) —, — (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 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 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 _{7. A -14} aralkyl group, an optionally substituted mono- or polycyclic heteroaryl group of 10 to 10 members, or an optionally substituted 5- or 6-membered saturated heterocyclic group. 38. The compound according to Item 37, or a pharmaceutically acceptable salt thereof.

Item 41: B in R ^3b is 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 _optionally substituted A term that is a good C _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 40. The compound according to 40, or a pharmaceutically acceptable salt thereof.

Item 42: R ^3a , R ^3b and R ^3c are each independently the same and are a group: -AB (where A is a single bond, and B is a hydrogen atom). ;
R ^3d is a group: -A-B (wherein, A represents a single _{bond, - (CH 2) s O} -, - (CH 2) s N (R 4) -, - (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 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 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 _{7. A -14} aralkyl group, an optionally substituted mono- or polycyclic heteroaryl group of 10 to 10 members, or an optionally substituted 5- or 6-membered saturated heterocyclic group. 38. The compound according to Item 37, or a pharmaceutically acceptable salt thereof.

Item 43: B in R ^3d is 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 _optionally substituted A term that is a good C _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 43. The compound according to 42, or a pharmaceutically acceptable salt thereof.

Item 44: R ^3a , R ^3b , R ^3c and R ^3d are each independently the same and are the group: -A-B (wherein A is a single bond and B is a hydrogen atom). 38. The compound according to Item 37, or a pharmaceutically acceptable salt thereof.

Item 45: The compound according to any one of Items 1 to 36, wherein n is 1, or a pharmaceutically acceptable salt thereof.

Item 46: A compound represented by formula (II) or a pharmaceutically acceptable salt thereof.

[Wherein, R ^12a represents a hydrogen atom, a halogen atom, a cyano group, or an optionally substituted C _1-6 alkyl group;
R ^12b _is an _{C 1-4} alkoxy substituted _{C 1-6} alkyl or _{C 1-4} alkoxy or _{C 1-4} alkoxycarbonylamino with substituted _{C 1-6} alkoxy group;
R ^12d is a group: -D ² -E ²
(D ² is a single bond, —CO—, —COO—, —N (R ^h ) SO ₂ —, or —N (R ^h2 ) COO—,
R ^h2 is a hydrogen atom or an optionally substituted C _1-6 alkyl group;
E ² is a hydrogen atom, an optionally substituted C _1-6 alkyl group, a mono- or di-substituted amino group, an optionally substituted 4- to 7-membered cyclic amino group, or a substituted It may be a 5- to 10-membered monocyclic or polycyclic heteroaryl group. (However, when D ² is —COO— or —N (R ^h2 ) COO—, E ² is not the amino group);
R ^12g is a hydrogen atom or a halogen atom;
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: —AB
(Wherein, ^{A 2} is a single _{bond, - (CH 2) s2 O} -, - (CH 2) s2 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 _2-6 alkynyl group, or an optionally substituted C _{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 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 heterocyclic group 6 membered saturated ^{(a 2} is _{^{- (CH 2) s2 N (}} R 42) -, - (CH 2) s2 OCON (R 42) -, - (CH 2) s2 CON (R _{^{42) -, - (CH 2}} ) s2 N (R ²⁾ 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). . 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 _3-10 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 47: The compound according to Item 46 or a pharmaceutically acceptable salt thereof, wherein R ^12a is a hydrogen atom, a halogen atom, or an optionally substituted C _1-6 alkyl group.

Item 48: The compound according to Item 46 or a pharmaceutically acceptable salt thereof, wherein R ^12a is a cyano group.

Item 49: The compound according to Item 47 or a pharmaceutically acceptable salt thereof, wherein R ^12a is a hydrogen atom.

Item 50: The compound according to Item 47 or a pharmaceutically acceptable salt thereof, wherein R ^12a is a halogen atom or an optionally substituted C _1-6 alkyl group.

Item 51: The compound according to Item 50 or a pharmaceutically acceptable salt thereof, wherein R ^12a is a halogen atom.

Item 52: The compound according to Item 50 or a pharmaceutically acceptable salt thereof, wherein R ^12a is an optionally substituted C _1-6 alkyl group.

Item 53: The compound according to any one of Items 46 to 56, wherein R ^12b is a 3-methoxypropyloxy group, or a pharmaceutically acceptable salt thereof.

Item 54: The compound according to any one of Items 46 to 52, wherein R ^12a is a 4-methoxybutyl group, or a pharmaceutically acceptable salt thereof.

Item 55: R ^12d is a group: -D ² -E ²
(Where D ² is —CO—,
E ² is an optionally substituted C _1-6 alkyl group, a mono- or di-substituted amino group, or an optionally substituted 4- to 7-membered cyclic amino group. 55. The compound according to any one of Items 46 to 54, or a pharmaceutically acceptable salt thereof.

Item 56: The compound according to Item 55, wherein E ² is an optionally substituted mono- or di-substituted amino group, or an optionally substituted 4- to 7-membered cyclic amino group, or a pharmaceutically acceptable salt thereof. Salt.

Item 57: R ^12d is a group: -D ² -E ²
(Where D ² is a single bond,
55. The compound according to any one of Items 46 to 54, or a pharmaceutically acceptable salt thereof, wherein E ² is a hydrogen atom.

Item 58: R ^12d is a group: -D ² -E ²
(Where D ² is —N (R ^h2 ) COO—,
E ² is an optionally substituted C _1-6 alkyl group. 55. The compound according to any one of Items 46 to 54, or a pharmaceutically acceptable salt thereof.

Item 59: The compound according to any one of Items 46 to 58, wherein R ^12g is a hydrogen atom, or a pharmaceutically acceptable salt thereof.

Item 60: The compound according to any one of Items 46 to 58, wherein R ^12g is a halogen atom, or a pharmaceutically acceptable salt thereof.

Item 61: R ^32a , R ^32b and R ^32d are each independently the same, a group: —A ² —B ² (where A ² is a single bond, and B ² is a hydrogen atom) .);
R ^32c is a group: -A ² -B ² (wherein A ² is a single bond, B ² is a hydrogen atom or an _optionally substituted C _6-10 aryl group). 61. The compound according to any one of 46 to 60, or a pharmaceutically acceptable salt thereof.

Item 62: The term wherein 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). 61. The compound according to 61, or a pharmaceutically acceptable salt thereof.

Item 63: 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. The compound according to any one of Items 46 to 60, or a pharmaceutically acceptable salt thereof.

Item 64: B ² in R ^32b is an ^optionally substituted C _1-6 alkyl group, an optionally substituted C _3-6 cycloalkyl group, an _optionally substituted C _6-10 aryl group _{, an optionally} substituted An optionally substituted C _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. Item 64, or a pharmaceutically acceptable salt thereof.

Item 65: 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-membered or 6-membered saturated heterocyclic group. The compound according to any one of Items 46 to 60, or a pharmaceutically acceptable salt thereof.

Item 66: B ² in R ^32d is an ^optionally substituted C _1-6 alkyl group, an optionally substituted C _3-6 cycloalkyl group, an _optionally substituted C _6-10 aryl group _{, an optionally} substituted An optionally substituted C _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. Item 66, or a pharmaceutically acceptable salt thereof.

Item 67: 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 61. The compound according to any one of Items 46 to 60, or a pharmaceutically acceptable salt thereof.

Item 68: A compound represented by the formula (III), or a pharmaceutically acceptable salt thereof.

[Wherein, R ^13a represents a hydrogen atom, a halogen atom, a cyano group, or an optionally substituted C _1-6 alkyl group;
R ^13b _is an _{C 1-4} alkoxy substituted _{C 1-6} alkyl or _{C 1-4} alkoxy or _{C 1-4} alkoxycarbonylamino with substituted _{C 1-6} alkoxy group;
R ^13g is a hydrogen atom or a halogen atom;
E ³ is an amino group that may be mono- or di-substituted, or a 4- to 7-membered cyclic amino group that may be substituted. ]

Item 69: The compound according to Item 68 or a pharmaceutically acceptable salt thereof, wherein R ^13a is a hydrogen atom, a halogen atom, or an optionally substituted C _1-6 alkyl group.

Item 70: The compound according to Item 68, wherein R ^13a is a cyano group, or a pharmaceutically acceptable salt thereof.

Item 71: The compound according to item 69, wherein R ^13a is a hydrogen atom, or a pharmaceutically acceptable salt thereof.

Item 72: The compound according to Item 69, wherein R ^13a is a halogen atom, or an optionally substituted C _1-6 alkyl group, or a pharmaceutically acceptable salt thereof.

Item 73: The compound according to Item 72, wherein R ^13a is a halogen atom, or a pharmaceutically acceptable salt thereof.

Item 74: The compound according to Item 72 or a pharmaceutically acceptable salt thereof, wherein R ^13a is an optionally substituted C _1-6 alkyl group.

Item 75: The compound according to any one of Items 68 to 74, or a pharmaceutically acceptable salt thereof, wherein R ^13b is a 3-methoxypropyloxy group.

Item 76: The compound according to any one of Items 68 to 74, or a pharmaceutically acceptable salt thereof, wherein R ^13b is a 4-methoxybutyl group.

Item 77: The compound according to any one of Items 68 to 76, wherein R ^13g is a hydrogen atom, or a pharmaceutically acceptable salt thereof.

Item 78: The compound according to any one of Items 68 to 76, wherein R ^13g is a halogen atom, or a pharmaceutically acceptable salt thereof.

Item 79: The compound according to Item 78, wherein R ^13g is a fluorine atom, or a pharmaceutically acceptable salt thereof.

Item 80: A pharmaceutical comprising the compound according to any one of Items 1 to 79 or a pharmaceutically acceptable salt thereof as an active ingredient.

Item 82: A renin inhibitor comprising the compound according to any one of Items 1 to 79 or a pharmaceutically acceptable salt thereof as an active ingredient.

Item 83: A therapeutic agent for hypertension comprising the compound according to any one of items 1 to 79, or a pharmaceutically acceptable salt thereof as an active ingredient.

Item 84: Use of the compound according to any one of Items 1 to 79 or a pharmaceutically acceptable salt thereof for the production of a renin inhibitor.

Item 85: Use of the compound according to any one of Items 1 to 79 or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic agent for hypertension.

Item 86: A method for treating hypertension, comprising administering an effective amount of the compound according to any one of Items 1 to 79 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. Further, in the present specification, a substituent that does not particularly indicate the term “which may be substituted” or “substituted” means an “unsubstituted” substituent. For example, “C _1-6 alkyl” means “unsubstituted”.

  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 “may be substituted” or “substituted” is not particularly limited as long as substitution is possible, and is one 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.

“C _1-8 alkyl group” means a straight-chain or branched saturated hydrocarbon group. A “C _1-6 alkyl group” is preferable, and a “C _1-4 alkyl group” is more preferable. Specific examples of “C _1-8 alkyl group” include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, heptyl. Octyl, 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 that forms a ring composed of C _{2 to} C ₄ on one carbon of a saturated hydrocarbon group. The “C _1-6 alkyl group” in “E” includes a group forming a ring composed of C ₃ on one carbon of a saturated hydrocarbon group. Specific examples include groups represented by the following groups.

“C _2-6 alkenyl group” means a linear or branched unsaturated hydrocarbon group containing one double bond. Specific examples include vinyl, propenyl, methylpropenyl, butenyl and methylbutenyl.

The “C _2-6 alkynyl group” means a linear or branched unsaturated hydrocarbon group containing one triple bond. Preferably, " _C3-6 alkynyl group" etc. are mentioned. Specific examples include ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, pentynyl, hexynyl and the like.

“C _3-10 cycloalkyl group” means a cyclic saturated hydrocarbon group. For example, preferably, “C _3-6 cycloalkyl group” and the like can be mentioned. Specific examples of “C _3-10 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.

The “C _3-6 cycloalkyl C _1-4 alkyl group” means a group in which “C _3-6 cycloalkyl” is bonded to “C _1-4 alkyl”. Specific examples include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl and the like.

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

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

The “C _7-14 aralkyl group” (C _6-10 aryl C _1-4 alkyl group) means a group in which the “aryl group” is substituted on the “alkyl group”. Preferably. “C _7-11 aralkyl group” (C ₆ aryl C _1-4 alkyl group) and the like. Specific examples of “C _7-14 aralkyl group” include, for example, 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 “heteroaryl C _1-4 alkyl group” means a group obtained by substituting the “heteroaryl group” for the “C _1-4 alkyl group”. Examples of the heteroaryl moiety are the same as the specific examples exemplified as the heteroaryl group. An example is “heteroaryl C _1-4 alkyl”. Specifically, 2-pyridylmethyl etc. are mentioned, for example.

The “C _1-6 alkyl” part of the “C _1-6 alkoxy group” has the same _{meaning as} the above “C _1-6 alkyl”. Preferably, " _C1-4 alkoxy group" etc. are mentioned. Specific examples of “C _1-6 alkoxy group” include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.

The “C _1-4 alkoxy C _1-4 alkoxy group” means a group obtained by substituting the “C _1-4 alkoxy group” with a “C _1-4 alkoxy group”. Specific examples of “C _1-4 alkoxy C _1-4 alkoxy group” include, for example, 3-methoxypropyloxy, 4-methoxybutyloxy and the like.

The “C _3-6 alkynyl” part of the “C _3-6 alkynyloxy group” has the same meaning as the above “C _3-6 alkynyl”. Specific examples include 1-propynyloxy, 2-propynyloxy, 2-butynyloxy, pentynyloxy, hexynyloxy, and the like.

The “C _1-6 alkyl” part of the “C _1-6 alkylthio group” has the same meaning as the above “C _1-6 alkyl”. Preferably, " _C1-4 alkylthio group" etc. are mentioned. Specific examples of the “C _1-6 alkylthio group” include, for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio, hexylthio and the like.

The “C _1-6 alkyl” part of the “C _1-6 alkylsulfinyl group” has the same meaning as the above “C _1-6 alkyl”. Preferably, “C _1-4 alkylsulfinyl group” and the like can be mentioned. Specific examples of the “C _1-6 alkylsulfinyl group” include, for example, methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl, pentylsulfinyl, hexylsulfinyl and the like.

The “C _1-6 alkyl” part of the “C _1-6 alkylsulfonyl group” has the same meaning as the above “C _1-6 alkyl”. Preferably, " _C1-4 alkylsulfonyl group" etc. are mentioned. Specific examples of the “C _1-6 alkylsulfonyl group” include, for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, pentylsulfonyl, hexylsulfonyl and the like.

The “C _3-10 cycloalkyl” part of the “C _3-10 cycloalkoxy group” has the same _{meaning as} the above “C _3-10 cycloalkyl”. Preferably, " _C3-6 cycloalkoxy group" etc. are mentioned. Specific examples of “C _3-10 cycloalkoxy group” include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, adamantyloxy, norbornyloxy and the like.

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

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

The “C _1-4 alkylcarbonyloxy group” means a group in which the “C _1-4 alkylcarbonyl group” is bonded to an oxygen atom. Specific examples include acetyloxy, propionyloxy, butyryloxy and the like.

  Examples of the “saturated heterocyclic group” include 5- to 7-membered saturated heterocyclic groups 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 “saturated heterocycle” in which the above-mentioned 5-membered or 6-membered “saturated heterocyclic group” and 6-membered aromatic hydrocarbon or 6-membered unsaturated heterocycle are condensed. 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.

  The “saturated hetero ring” part of the “saturated hetero ring oxy group” has the same meaning as the “saturated hetero ring group”. Specific examples include 4-pyranyloxy and the like.

  The “saturated heterocyclic carbonyl group” means a group in which the “saturated heterocyclic group” is bonded to a carbonyl group. Specific examples include pyrrolidinocarbonyl and the like.

The “saturated heterocyclic C _1-4 alkyl group” means a group in which the “saturated heterocyclic group” is bonded to the “C _1-4 alkyl group”. Specific examples include 4-pyranylmethyl and the like.

“Amino group which may be mono-substituted” means “C _1-4 alkyl”, “C _3-10 cycloalkyl” (preferably C _3-6 cycloalkyl), “C _3-6 cycloalkyl C”. _From “ _1-4 alkyl”, “benzyl”, “C _1-4 alkylcarbonyl”, “C _3-6 cycloalkylcarbonyl”, “saturated heterocycle” and “saturated heterocycle C _1-4 alkyl” It means an amino group which may be substituted with one group selected from the group consisting of “C _1-4 alkyl”, “C _3-6 cycloalkyl”, “C _3-6 cycloalkyl C _1-4 alkyl”, “C _1-4 alkylcarbonyl”, “C _3-6 cycloalkylcarbonyl”, “Saturated hetero ring group” and “saturated hetero ring C _1-4 alkyl group” 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 _3-10 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.

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

Specific examples of “amino group substituted with mono- (C _3-6 cycloalkylcarbonyl)” include, for example, cyclopropylcarbonylamino, cyclobutylcarbonylamino, cyclopentylcarbonylamino and the like.

Specific examples of “amino group substituted with mono- (saturated heterocyclic group)” include, for example, compounds represented by the following.

Specific examples of the “mono- (amino group substituted with a saturated heterocyclic C _1-4 alkyl group)” include, for example, compounds represented by the following.

The “di-substituted amino group” means “C _1-4 alkyl”, “C _3-6 cycloalkyl”, “C _3-6 cycloalkyl C _1-4 alkyl”, “benzyl”, “ The same or different 2 selected from the group consisting of “C _1-4 alkylcarbonyl”, “C _3-6 cycloalkylcarbonyl”, “saturated heterocyclic group” and “saturated heterocyclic C _1-4 alkyl group” It means an amino group which may be substituted with a group. “C _1-4 alkyl”, “C _3-6 cycloalkyl”, “C _3-6 cycloalkyl C _1-4 alkyl”, “C _1-4 alkylcarbonyl”, “C _3-6 cycloalkylcarbonyl”, “Saturated hetero ring group” and “saturated hetero ring C _1-4 alkyl group” are as defined above. The “C _1-6 alkyl group” herein may be further substituted with C _1-4 alkoxy or a halogen atom. Specific examples of the “di-substituted amino group” include, for example, compounds selected from the following table.

Specific examples of “amino group substituted with di- (C _1-4 alkyl)” include, for example, compounds represented by the following.

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 _3-6 cycloalkyl) (C _1-4 alkyl)” include, for example, N-methyl-N-cyclopropylmethyl and the like.

Specific examples of “amino group substituted with (C _1-4 alkyl) (C _1-4 alkylcarbonyl)” include, for example, N-methyl-N-methylcarbonylamino, N-methyl-N-ethylcarbonylamino. Etc.

Specific examples of “amino group substituted with (C _1-4 alkyl) (C _3-6 cycloalkylcarbonyl)” include, for example, N-methyl-N-cyclopropylcarbonylamino, N-methyl-N-cyclo Examples include butylcarbonylamino, N-methyl-N-cyclopentylcarbonylamino 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 “amino group substituted with (C _3-6 cycloalkyl C _1-4 alkyl) (C _1-4 alkyl)” include, for example, compounds represented by the following. .

Specific examples of “amino group substituted with (saturated heterocycle) (C _1-4 alkyl)” include, for example, compounds represented by the following. .

Specific examples of “amino group substituted with (saturated heterocyclic C _1-4 alkyl) (C _1-4 alkyl)” include, for example, compounds represented by the following. .

The “optionally substituted 4- to 7-membered cyclic amino group” means a cyclic amino group consisting of a 4-membered ring, a 5-membered ring, a 6-membered ring or a 7-membered ring. Preferably, it is 5 to 7 members. The group is a halogen atom, a hydroxyl group, C _1-4 alkyl (which may be substituted with a halogen atom or C _1-4 alkoxy), C _1-4 alkoxy, C _3-6 cycloalkyl, carboxy, C _{1- It} may be substituted with ₄ alkoxycarbonyl, C _1-4 alkylcarbonyloxy, or oxo group. The cyclic amino group may contain at least one nitrogen atom, oxygen atom or sulfur atom which may be the same or different. The 5-membered or 6-membered ring of the group may form a condensed ring with a ring having at least one of the same or different atoms selected from a nitrogen atom, an oxygen atom or a sulfur atom. Specific examples of the “optionally substituted 4- to 7-membered cyclic amino group” include, for example, compounds selected from the following table.

As the substituent in the “optionally substituted C _1-6 alkyl group”, 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, C _1-4 alkyl or C _1-4 alkoxy),
(D) a hydroxyl group,
(E) a C _1-4 alkoxy group (this group may be substituted with a halogen atom),
(F) a C _3-6 cycloalkyloxy group,
(G) a phenyloxy 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 C _1-4 alkoxy C _1-4 alkoxy group,
(J) a formyl group,
(K) a C _1-4 alkylcarbonyl group,
(L) a C _3-6 cycloalkylcarbonyl group,
(M) a phenylcarbonyl group,
(N) a benzylcarbonyl group,
(O) formylcarbonyloxy group,
(P) a C _1-4 alkylcarbonyloxy group,
(Q) a C _3-6 cycloalkylcarbonyloxy group,
(R) a carboxyl group,
(S) a C _1-4 alkoxycarbonyl group,
(T) a C _3-6 cycloalkoxycarbonyl group,
(U) an amino group (the group is
(U1) C _1-4 alkyl group,
(U2) C _3-6 alkyl group,
(U3) C _3-6 cycloalkyl C _1-4 alkyl group,
(U4) benzyl group,
(U5) C _1-4 alkylcarbonyl group, or (u6) the same or different 1-2 groups selected from C _3-6 cycloalkylcarbonyl group may be substituted. ),
(V) a 5- or 6-membered cyclic amino group,
(W) an aminocarbonyl group which may be substituted,
(X) an optionally substituted aminocarbonyloxy group,
(Y) a 5- or 6-membered saturated heterocyclic group (the group may be substituted with C _1-4 alkoxy), (z) C _1-4 alkoxycarbonylamino and the like.

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. Mono- or di-substituted amino substituents include C _1-4 alkyl, C _3-6 cycloalkyl, or benzyl.

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.

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 And} an aminocarbonyl group substituted with (C _1-4 alkyl) (benzyl) ”and the like.

In the “aminocarbonyl group substituted with (C _1-4 alkyl) (C _1-4 alkyl)”, one “C _1-4 alkyl” may be substituted with C _1-4 alkoxy. Specific examples include N-methyl-N-methylaminocarbonyl, N-methyl-N-ethylaminocarbonyl, N-ethyl-N- (2-methoxyethyl) aminocarbonyl, and the like.

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.

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.

Hereinafter, the preferable aspect of the substituent of "the C1-6 alkyl group which may be substituted" in each definition is _demonstrated .

As the substituent of the “optionally substituted C _1-6 alkyl group” in “R ^1a ”, a halogen atom or C _3-6 cycloalkyl is preferable.
Will be described.

Examples of the substituent of the “optionally substituted C _1-6 alkyl group” in “R ^1b ” include C _1-4 alkoxy, C _1-4 alkoxy C _1-4 alkoxy, C _1-4 alkoxycarbonylamino or C _1-4 alkylsulfonyl is preferred.

As the substituent of the “optionally substituted C _1-6 alkyl group” in “E”, a halogen atom, cyano, C _3-6 cycloalkyl, hydroxyl group, di- (C _1-6 alkyl) aminocarbonyl, or Saturated heterocycles are preferred.

As the substituent of the “optionally substituted C _1-6 alkyl group” in “R ^1g ”, a halogen atom 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”,
(A1) a halogen atom,
(B1) C _3-6 cycloalkyl (the group is
(B11) a halogen atom,
(B12) a hydroxyl group,
(B13) C _1-4 alkyl, or (b14) C _1-4 alkoxy may be substituted. ),
(C1) a hydroxyl group,
(D1) a carboxyl group,
(E1) a C _1-4 alkoxycarbonyl group,
(F1) a carbamoyl group (the group is
(F11) C _1-6 alkyl,
(F12) C _3-6 cycloalkyl, or (f13) C _3-6 cycloalkyl C _1-4 alkyl may be substituted. And a group selected from the group consisting of (g1) a 5- or 6-membered saturated heterocyclic group (which may be substituted with C _1-4 alkoxy).

Examples of the aminocarbonyl group include a carbamoyl group, a mono- or di- (C _1-6 alkyl) aminocarbonyl group, a mono- (C _3-6 cycloalkyl) aminocarbonyl, or a mono- (C _3-6 cycloalkyl). C _1-4 alkyl) aminocarbonyl.

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 (w). When “A” is other than a single bond, the group may be simultaneously substituted with the two substituents (a) and (y) or (c) and (e).

  Examples of the above include the following “groups”.

Examples of the substituent in the “optionally substituted C _1-6 alkoxy group” include one group selected from the group consisting of the above (a) to (y) (wherein (u The substituents of the mono-substituted amino group of) are limited to C _1-4 alkyl groups and C _3-6 alkyl groups, and the same applies to (v), (w) and (x).

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

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

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 (z) 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 a halogen atom, C _1-4 alkyl, hydroxyl group, C ₁ group selected from the group consisting of _1-4 alkoxy and C _6-10 aryl groups (the aryl group may be substituted with a halogen atom, a hydroxyl group, or C _1-4 alkoxy), and the like. It is done.

Examples of the substituent of the “optionally substituted C _3-6 cycloalkyl group” in “R ² ” include a halogen atom.

Examples of the substituent of the “optionally substituted C _3-6 cycloalkyl group” in “E” include a hydroxyl group and the like.

_Examples of the substituent of the “optionally substituted C _3-6 cycloalkyl group” in “B” include C _1-4 alkoxy.

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 (z) 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, for example, the group consisting of the above (a) to (z). One selected group and the like can be mentioned.

"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 one group selected from the group consisting of the above (a) to (z).

  “Optionally substituted amino group” means an amino group, a mono-substituted amino group, a di-substituted amino group and a 5- or 6-membered cyclic amino group. “Mono-substituted amino”, “di-substituted amino” and “5- or 6-membered cyclic amino” are as defined above.

As the substituent in the “optionally substituted C _6-10 aryl group”, for example,
(A2) a halogen atom,
(B2) a nitro group,
(C2) a cyano group,
(D2) C _1-4 alkyl group (the group may be substituted with, for example, a halogen atom, a hydroxyl group, or amino),
(E2) a hydroxyl group, and (f2) a C _1-4 alkoxy group (the group is
(F21) C _1-4 alkoxy,
(F22) C _3-6 cycloalkyloxy which may be substituted with C _1-4 alkyl, or (f13) C ₆ aryloxy which may be substituted with a halogen atom. ),
(G2) C _3-6 cycloalkyloxy group,
(H2) a phenyloxy 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);
(I2) C _6-10 aryl group (the group is, for example,
(I21) a halogen atom,
(I22) C _1-4 alkyl optionally substituted by carboxy,
(I23) It may be substituted with a C _1-4 alkoxy which may be substituted with a fluorine atom, a hydroxyl group, or carboxy. ),
(J2) a sulfonyl group,
(K2) C _1-4 alkoxysulfonyl group,
(L2) C _3-6 cycloalkoxysulfonyl group,
(M2) C ₆ aryloxysulfonyl group (the phenyl may be substituted with the same or different group selected from the group consisting of a halogen atom, cyano and C _1-4 alkoxy),
(N2) benzyloxysulfonyl group,
(O2) C _6-10 aryloxy group (this group may be substituted with a halogen atom or cyano),
(P2) 5- or 6-membered monocyclic heteroaryloxy group (the group may be substituted with C _1-4 alkyl),
(Q2) a saturated heterocyclic oxy group (the group is
(Q21) C ₆ aryl which may be substituted with a halogen atom, or (q22) may be substituted with a saturated heterocyclic carbonyl. ),
(R2) amino group (the group is
(R21) C _1-4 alkyl,
_{(R22) C 3-6} alkyl,
(R23) C _3-6 cycloalkyl C _1-4 alkyl,
(R24) benzyl,
(R25) C _1-4 alkylcarbonyl, or (r26) C _3-6 cycloalkylcarbonyl may be substituted with the same or different 1-2 groups selected. ),
(S2) a 5- to 7-membered cyclic amino group (which may be substituted with C ₆ aryl),
Examples thereof include a group selected from the group consisting of (t2) an aminocarbonyl group which may be substituted, and (u2) an aminocarbonyloxy group which may be substituted.

As the substituent of the “optionally substituted C _6-10 aryl group” in “B”, the group consisting of the above (a2); (f2); (h2); (p2); (q2) and (t2) A group selected from:

When “A” is a single bond, for example, a C ₆ aryl group substituted with the above (f2), (h2), (q2) or (t2) can be mentioned.

When “A” is other than a single bond, C ₆ aryl substituted with (a2), (f2) or (p2) can be mentioned.

Examples of the substituent of the aryl moiety in the “optionally substituted C _7-14 aralkyl group” include groups selected from the group consisting of the above (a2) to (u2) and C _1-4 alkylsulfonylamino. .

Examples of the substituent of the “optionally substituted C _7-14 aralkyl group” in “B” include (a2), (c2), (d2), (t2), C _1-4 alkylsulfonylamino and the like. .

The substituent of the “optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group” has the same meaning as the substituent of the “optionally substituted C _6-10 aryl group”.

  Examples of the substituent of the “optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group” in “E” include (a2) and (d2).

  Examples of the substituent of the “optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group” in “B” include (a1).

Examples of the substituent of the heteroaryl moiety of the “optionally substituted heteroaryl C _1-4 alkyl group” include those exemplified as the substituents in the “optionally substituted heteroaryl group”.

Examples of the substituent of the “saturated heterocyclic group” and “saturated heterocycle” include a halogen atom, a hydroxyl group, a nitro group, a cyano group, a C _1-4 alkyl group (the alkyl group is substituted with, for example, a halogen atom) C _1-4 alkoxy group (the alkoxy group may be substituted with, for example, a halogen atom), carboxyl group, C _1-4 alkoxycarbonyl group, C _3-6 cycloalkoxycarbonyl group, amino group, mono- - or di - (C _1-4 alkyl) substituted amino groups, C ₆ aryl group, a carbamoyl group, and oxo group or 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.

Examples of the substituent of “saturated heterocyclic group which may be substituted” in “E” include C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkoxycarbonyl and the like.

  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.

  The “optionally substituted carbamoyl group” means a carbamoyl group, a mono-substituted aminocarbonyl group, a di-substituted aminocarbonyl group, and a 5- or 6-membered cyclic aminocarbonyl group. “Mono-substituted aminocarbonyl”, “di-substituted aminocarbonyl” and “5- or 6-membered cyclic aminocarbonyl” are the same as described above.

  The definition of the compound represented by formula (I) will be described in detail.

“R ^1a ”
(A3) a hydrogen atom,
(B3) a halogen atom,
(C3) a cyano group,
(D3) C _1-6 alkyl group (which may be substituted with C _3-6 cycloalkyl),
1 group selected from the group consisting of (e3) C _3-6 cycloalkyl group and (f3) C _1-6 alkoxy group (which may be substituted with 1 to 3 fluorine atoms). It is done.

“R ^1a ” is preferably one group selected from the group consisting of a hydrogen atom, a halogen atom, a cyano group, and a C _1-6 alkyl group.

“R ^1a ” is preferably substituted at the position represented by the following formula.

“R ^1b ”
(A4) C _1-8 alkyl group (the group is
(A41) C _1-4 alkoxy,
(A42) C _3-6 cycloalkyl,
(A43) C _1-4 alkoxycarbonylamino,
(A44) C _1-4 alkylsulfonyl, or (a45) C _1-4 alkoxy may be substituted with C _1-4 alkoxy. ),
(B4) C _1-6 alkoxy group (the group is
(B41) C _1-4 alkoxy,
(B42) C _3-6 cycloalkyl, or (b43) C _1-4 alkoxycarbonylamino may be substituted. ), And (c4) one group selected from the group consisting of C _3-6 alkynyloxy groups.

_In the case of _{C 3-6 C 1-8} alkyl group substituted cycloalkyl, or _{C 3-6 C 1-6} alkoxy group substituted with a cycloalkyl, a ^{"R 1a"} _{is C 1-} Limited to ₆ alkyl groups.

The “C _1-6 alkoxy group substituted with C _1-4 alkoxy” in “R ^1b ” may be substituted with 1 to 3 fluorine atoms. Specific examples include 3-monofluoromethoxy-3-propyloxy, 3-methoxy-3,3-difluoro-propyloxy and the like.

^{"R 1b"} _{is, C 1-6} alkoxy group substituted by _{C 1-4} alkoxy or _{C 1-6} alkyl group substituted by _{C 1-4} alkoxy are preferred. Furthermore, a 3-methoxypropyloxy group or a 4-methoxybutyl group is preferable.

In the compound represented by the formula (I), G is
(The definitions in the formula are the same as those described above.)

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

“R ^1c ”
(A5) a hydrogen atom,
(B5) one group selected from the group consisting of a halogen atom and (c5) C _1-6 alkoxy group.

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

“R ^1d ” is preferably a group: —DE.

"E"
(A6) a hydrogen atom,
(B6) a cyano group,
(C6) C _1-6 alkyl group (the group is
(C61) 1 to 3 fluorine atoms,
(C62) cyano,
(C63) C _3-6 cycloalkyl,
(C64) a hydroxyl group,
(C65) Di- (C _1-6 alkyl) aminocarbonyl, or (c66) optionally substituted with a 5 or 6 membered saturated heterocyclic ring. ),
(D6) a C _3-6 cycloalkyl group (which may be substituted with hydroxy),
(E6) an amino group which may be mono-substituted (the group is
(E61) C _1-4 alkyl,
(E62) C _3-6 cycloalkyl (which may be substituted with a fluorine atom),
(E63) a 5- or 6-membered saturated heterocyclic ring (which may be substituted with C _1-4 alkyl or C _1-4 alkoxy), or (e64) a 5- or 6-membered saturated heterocyclic ring C _{1 -4} alkyl (which may be substituted with _C1-4 alkyl or _C1-4 alkoxy). ),
(F6) an amino group which may be di-substituted (the group is
(F61) C _1-4 alkyl (may be substituted with 1 to 3 fluorine atoms, cyano, hydroxy, or C _1-4 alkoxy),
(F62) 5-membered or 6-membered saturated heterocyclic ring (which may be substituted with C _1-4 alkyl or C _1-4 alkoxy),
(F63) C _3-6 cycloalkyl (which may be substituted with a fluorine atom),
(F64) C _3-6 cycloalkyl C _1-4 alkyl (which may be substituted with a fluorine atom or C _1-4 alkyl),
(F65) 5- or 6-membered saturated heterocyclic C _1-4 alkyl (which may be substituted with C _1-4 alkyl or C _1-4 alkoxy)),
(G6) a 5- to 7-membered cyclic amino group (the group is
(G61) a halogen atom,
(G62) a hydroxyl group,
(G63) fluorine atom, a hydroxyl group or a _{C 1-4} which may be _{C 1-4} alkyl substituted with alkoxy,
(G64) C _1-4 alkoxy,
_{(G65) C 3-6} cycloalkyl,
(G66) carboxy,
(G67) C _1-4 alkoxycarbonyl, or (g68) C _1-4 alkylcarbonyloxy may be substituted. ),
(H6) a saturated heterocyclic group (which may be substituted with C _1-4 alkyl, C _1-4 alkoxy or C _1-4 alkoxycarbonyl), or (i6) a 5- to 10-membered monocyclic or 1 group selected from the group consisting of a polycyclic heteroaryl group (which group may be substituted with _C1-4 alkyl).

“R ^1d ”
(I) D is a single bond, E is a hydrogen atom, or (ii) D is —CO—, and E is a mono- or di-substituted amino group, or optionally substituted 5 A group defined by a membered to 7-membered cyclic amino group is preferred.

“R ^1e ”
(A7) a hydrogen atom,
(B7) a halogen atom,
(C7) a carboxy group,
(D7) a cyano group,
(E7) a C _1-6 alkyl group,
(F7) C _1-6 alkoxy group (the group is
(F71) A fluorine atom, or (f72) C _1-4 alkoxy may be substituted. ),
(G7) C _3-6 cycloalkyloxy group,
(H7) a 5- or 6-membered saturated heterocyclic oxy group,
(I7) a carbamoyl group,
(J7) one group selected from the group consisting of mono- or di- (C _1-6 alkyl) -substituted aminocarbonyl group and (k7) C _1-4 alkoxycarbonyl group.

“R ^1e ” is particularly preferably a hydrogen atom.

“R ^1f ”
(A8) a hydrogen atom,
(B8) a halogen atom,
(C8) a carboxy group,
(D8) a cyano group,
(E8) a C _1-6 alkyl group,
(F8) C _1-6 alkoxy group,
(G8) a carbamoyl group,
(H8) one group selected from the group consisting of an aminocarbonyl group substituted with mono- or di- (C _1-6 alkyl), and (i8) a C _1-4 alkoxycarbonyl group.

“R ^1f ” is particularly preferably a hydrogen atom.

“R ^1g ”
(A9) a hydrogen atom,
(B9) a halogen atom,
(C9) a cyano group,
(D9) a carboxy group,
(E9) C _1-6 alkyl group (may be substituted with 1 to 3 fluorine atoms),
(F9) a C _1-6 alkoxy group (which may be substituted with 1 to 3 fluorine atoms), and (g9) one group selected from the group consisting of a C _1-4 alkoxycarbonyl group. It is done.

“R ^1g ” is preferably a hydrogen atom or a halogen atom. The halogen atom is more preferably a fluorine atom.

“R ^1d and R ^1e together form a fused ring” means that “R ^1d ” and “R ^1e ” together form “R ^1c ”, “R ^1g ” and “R ^1f ”. Means to form a bicyclic or tricyclic condensed ring with the substituted benzene ring. Specifically, it means a ring having one structure selected from the group represented by the following structure. In the following structure, a ring represented by a broken line means a benzene ring substituted by “R ^1c ”, “R ^1g ”, and “R ^1f ”. Further, the ring represented by a solid line means a ring in which “R ^1d ” and “R ^1e ” are combined to form a condensed ring with the benzene ring.

In the partial structure, ^{"R 6"} is _{hydrogen; C 1-4} to alkoxy or saturated optionally substituted by heterocyclic group _{C 1-6} alkyl _{group; C 3-6} cycloalkyl group; trifluoromethyl group And one group selected from the group consisting of C _1-4 alkoxy groups. However, when R ⁶ is a C _1-4 alkoxy group, it is not directly bonded to the nitrogen atom of the partial structure.

“R ² ” is preferably a C _1-6 alkyl group substituted with a halogen atom or a C _3-6 cycloalkyl group substituted with a halogen atom.

“R ² ” is more preferably a C _1-6 alkyl group, and particularly preferably an isopropyl 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 ( In the case of R ⁴ ) CON (R ⁴ ) — and — (CH ₂ ) _s SO ₂ N (R ⁴ ) —, R ⁴ and B are bonded together to form a ring. Examples thereof include pyrrolidino, piperidino, morpholino and the like. The ring may be substituted with the same substituent as the above-mentioned “saturated heterocyclic group”. When A is “— (CH ₂ ) _s N (R ⁴ ) CON (R ⁴ ) —”, R ⁴ and B of “CON (R ⁴ )” are bonded together to form a ring. Form. Specific examples include 4-hydroxypiperidino; 2-methoxymorpholino; 4-formyl-piperidino; 4-methoxycarbonylpiperidino; 4-aminocarbonylpiperidino; 4-N-methylaminopiperidino; 3 -Phenylpyrrolidino; 4-dimethylaminopiperidino and the like.

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

"B"
(Aa) a hydrogen atom,
(Ab) a C _1-6 alkyl group (the group is
(Ab1) a halogen atom,
(Ab2) C _3-6 cycloalkyl (which may be substituted with a fluorine atom, a hydroxyl group, C _1-4 alkyl, or C _1-4 alkoxy),
(Ab3) a hydroxyl group,
(Ab4) carboxyl,
(Ab5) C _1-4 alkoxycarbonyl,
(Ab6) carbamoyl (optionally substituted with C _1-6 alkyl, C _3-6 cycloalkyl or C _3-6 cycloalkyl C _1-4 alkyl), or (ab7) to 5 or 6 membered saturation A terocyclic group (which may be substituted with C _1-4 alkoxy)),
(Ac) C _3-6 cycloalkyl (optionally substituted with C _1-4 alkoxy),
(Ad) C ₆ aryl group (the group is
(Ad1) a halogen atom,
_(Ad2) is substituted by _{C 1-4} alkoxy _{(C 1-4} alkyl substituted optionally _{C 3-6 cycloalkyloxy, C 1-4} alkoxy or optionally _{C 6} aryloxy optionally substituted by a halogen atom, You may)
(Ad3) C ₆ aryloxy (which may be substituted with a halogen atom or cyano),
(Ad4) 5- or 6-membered saturated heterocyclic oxy (C ₆ aryl optionally substituted with a halogen atom, or optionally substituted with 5- or 6-membered saturated heterocyclic carbonyl),
(Ad5) 5-membered to 7-membered cyclic aminocarbonyl (optionally substituted with _{C 6} aryloxy.), Or (ad6) substituted with hetero aryloxy _{(C 1-4} alkyl 5-membered or 6-membered monocyclic )),
(Ae) a C _7-11 aralkyl group (the group is
(Ae1) a halogen atom,
(Ae2) cyano,
(Ae3) C _1-4 alkyl,
(Ae4) Carbamoyl, or (ae5) C _1-4 alkylsulfonyl may be substituted. ),
1) selected from the group consisting of (af) a 5- or 6-membered monocyclic heteroaryl group (which may be substituted with a halogen atom), and (ag) a 5- or 6-membered saturated heterocyclic group Groups.

The “C _1-6 alkoxy group substituted with C _1-4 alkoxy” which is the substituent of (ad) in “B” includes the following groups.

"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

In the formula (I), the following partial structure
The following definitions (i) to (iii) are preferable.

(I) “R ^1a ” is a C _1-6 alkyl group;
“R ^1b ” is “C _1-6 alkoxy group substituted with C _1-4 alkoxy”;
“R ^1c ” is a hydrogen atom;
“R ^1d ” means that D is a single bond and E is a hydrogen atom;
“R ^1e ” is a hydrogen atom;
“R ^1f ” is a hydrogen atom;
“R ^1g ” is a hydrogen atom.

(Ii) “R ^1a ” is a hydrogen atom, a cyano group, or a C _1-6 alkyl group;
“R ^1b ” is “C _1-6 alkoxy group substituted with C _1-4 alkoxy”;
“R ^1c ” is a hydrogen atom;
“R ^1d ” means that D is a single bond and E is a hydrogen atom;
“R ^1e ” is a hydrogen atom;
“R ^1f ” is a hydrogen atom;
“R ^1g ” is a fluorine atom.

(Iii) “R ^1a ” is a hydrogen atom, a halogen atom, or a C _1-6 alkyl group;
“R ^1b ” is “C _1-6 alkoxy group substituted with C _1-4 alkoxy”;
“R ^1c ” is a hydrogen atom;
“R ^1d ” is D is —CO— and E is a mono- or di-substituted amino group, or an optionally substituted 4- to 7-membered cyclic amino group;
“R ^1e ” is a hydrogen atom;
“R ^1f ” is a hydrogen atom;
“R ^1g ” is a fluorine atom.

  In formula (I),

In “R ^3a ” to “R ^3d ” in the partial structure represented by formula (A), A is a single bond; B is preferably a hydrogen atom.

The compound of the present invention is preferably a compound represented by the formula (I ′).
[Wherein, R ^1a , R ^1b , R ^1c , R ^1d , R ^1e , R ^1f and R ^1g are as defined above. ]

In the formula (I ′), R ^1a , R ^1b , R ^1c , R ^1d , R ^1e , R ^1f and R ^1g are preferably in the form described below.

“R ^1a ” is preferably a hydrogen atom, a halogen atom, a cyano group, or a C _1-6 alkyl group.

^{"R 1b"} _{is, C 1-6} alkoxy group substituted by _{C 1-4} alkoxy or _{C 1-6} alkyl group is preferably substituted with _{C 1-4} alkoxy, 3-methoxypropyl group or 4, More preferred is a methoxybutyl group.

“R ^1c ”, “R ^1e ” and “R ^1f ” are preferably each independently a hydrogen atom.

“R ^1g ” is preferably a hydrogen atom or a halogen atom, more preferably a hydrogen atom or a fluorine atom.

“R ^1d ” is a group: —DE
Wherein D is a single bond, —CO—, or —N (R ^h ) COO—
R ^h is a hydrogen atom or an optionally substituted C _1-6 alkyl group,
E is a hydrogen atom, an optionally substituted C _1-6 alkyl group, a mono- or di-substituted amino group, or an optionally substituted 4- to 7-membered cyclic amino group. ) Is preferred.

Furthermore, “E” means “amino group substituted with mono- (C _3-6 cycloalkyl)”, “amino group substituted with di- (C _1-4 alkyl)”, “(C _3-6 Cycloalkyl) (amino group substituted with (C _1-4 alkyl) ”,“ (amino group substituted with (saturated heterocycle) (C _1-4 alkyl) ”, or“ optionally substituted 4-membered to A “7-membered cyclic amino group” is preferred.

  The compound of the present invention is preferably a compound represented by the formula (IV).

[Wherein, R ^13a , R ^13g and E ³ are the same as described above. ]

In formula (IV):
“R ^13a ” is a hydrogen atom, a halogen atom, a cyano group, or a C _1-6 alkyl group;
“R ^13g ” is a fluorine atom;
“E ³ ” is preferably a compound that is a mono- or di-substituted amino group, or an optionally substituted 4- to 7-membered cyclic amino group.

Furthermore, the “C _1-6 alkyl group” in “R ^13a ” is particularly preferably a “C _2-4 alkyl group”.

Furthermore, “E ³ ” means “amino group substituted with mono- (C _3-6 cycloalkyl)”, “amino group substituted with di- (C _1-4 alkyl)”, “(C _{3-3 6-} cycloalkyl) (amino group substituted with (C _1-4 alkyl) ”,“ (saturated heterocycle) (amino group substituted with C _1-4 alkyl) ”, or“ optionally substituted 4-membered group ” The “˜7-membered cyclic amino group” is preferred.

  The compound of the present invention is preferably a compound represented by the formula (V).

[Wherein, R ^13a , R ^13g and E ³ are the same as described above. ]

In formula (V):
“R ^13a ” is a hydrogen atom;
“R ^13g ” is a fluorine atom;
“E ³ ” means “amino group substituted with di- (C _1-4 alkyl)”, “amino group substituted with (saturated heterocycle) (C _1-4 alkyl)”, or “substituted The compound which is a “4-7 membered cyclic amino group” may be preferable.

  The compound of the present invention is preferably a compound represented by the formula (VI).

[Wherein, R ^13a and R ^13g are the same as described above. ]

In the formula (VI), R ^13a and R ^13g are preferably in the form described below.

A compound in which “R ^13a ” is a C _1-6 alkyl group; and “R ^13g ” is a hydrogen atom is preferable. Furthermore, the “C _1-6 alkyl group” is more preferably a “C _2-4 alkyl group”.

A compound in which “R ^13a ” is a hydrogen atom, a cyano group, or a C _1-6 alkyl group; and a compound in which “R ^13g ” is a fluorine atom is preferable. Furthermore, the “C _1-6 alkyl group” is more preferably a “C _2-4 alkyl group”.

The compound of the formula (I) is preferably a compound having the following absolute configuration (the symbols in the formula have the same meaning as described above).

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

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

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

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

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

  The compounds of the present invention may exist as atropisomers due to axial asymmetry. Examples thereof include compounds represented by the following (IA) and (IB).

  These atropisomers are also included in the present invention.

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 : Q243; T ² : Q292; T ³ : H) means the following compound (free base of Example 1).

  The simplified symbol in the table means a partial structure appropriately selected from the group consisting of the partial structural formulas shown below.

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, G, R ^1a , R ^1b , R ^3a , R ^3b , R ^3c , R ^3d and R ² have the same meanings as described in the above item 1, X ¹ represents a hydroxyl group or a chlorine atom, ² represents an iodine atom, a bromine atom, a chlorine atom, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, or a p-toluenesulfonyloxy group, and X ³ and X ⁴ represent an iodine atom, a bromine atom, or trifluoromethanesulfonyloxy group. R ¹¹⁷ represents a fluorine atom or a C _1-3 alkyl group which may be substituted with C _1-3 alkoxy, or a C _3-6 cycloalkyl which may be substituted with a fluorine atom or C _1-3 alkoxy a ^{group, R 118} _represents a _{C 1-2} alkyl ^{group, R 119} may be substituted with a fluorine atom or a _{C 1-3} alkoxy _1-5 represents an alkyl group or a fluorine atom or _{C 1-3} optionally substituted alkoxy _{C 3-6} cycloalkyl ^{group,, R 120} represents a fluorine atom or a _{C 1-3} alkoxy _{group, m 104} is , 0, 1, 2 or 3, Y ¹ represents Cbz, Boc or Alloc, Z ¹ and Z ² are
(Wherein R ²⁰⁰ is a hydrogen atom or a C _1-4 alkyl group, or two R ²⁰⁰ together form 1,2-phenylene, and R ²⁰¹ , R ²⁰² , R ²⁰³ , R ²⁰⁴ , R ²⁰⁵ and R ²⁰⁶ are each independently a hydrogen atom or a C _1-2 alkyl group, m represents an integer of 0 or 1, and M ⁺ represents a potassium ion, a sodium ion or an ammonium ion. Represents). ]

1) Step 1
When X ¹ represents a hydroxyl group, the compound of the formula (1-3) is obtained by converting the compound of the formula (1-1) into an inert solvent using a condensing agent and optionally in the presence of a base. 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.

  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 , R ^3c and R ^3d which are the substituents of the compound (1-3) are produced using the production methods described in Production method 2 to Production method 18 and Production method 21 in Production method 2 It can also be converted to the substituent shown in Production Method 18.

2) Step 2
Compound (1-12) can be produced from compound (1-3) by a method similar to the production method described in the literature (for example, Chem. Rev. 95, 2457 (1995), EP1764365, etc.). Production examples are given below.
Compound (1-12) is a reaction of Compound (1-3) with Compound (1-11) wherein Z ¹ is B (OH) ₂ in the presence of a Pd catalyst and a base in an inert solvent. Can be manufactured. Examples of the inert solvent include water or ether solvents such as tetrahydrofuran, 1,4-dioxane, or 1,2-dimethoxyethane. Usually, a mixed solution of water and an ether solvent is used. Examples of the base include sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate and the like. Examples of the Pd catalyst include palladium diphenylphosphino dichloride, tetrakistriphenylphosphine palladium, and the like. The reaction temperature is selected from the range of about 50 ° C to about 150 ° C.

3) Step 3
Compound (1-2) can be produced from compound (1-4) by the same method as in Step 8 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 (eg 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 (I) can be produced from Compound (1-12) 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.
7) Step 7
Compound (1-7) can be produced from compound (1-1) by the same method as in Process 1 described in Production Method 1.

8) Step 8
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.
9) Step 9
Compound (1-13) can be produced from compound (1-3) by a method similar to the method described in literature (eg, Tetrahedron 57, 9813 (2001)).
10) Step 10
Compound (1-12) can be produced from compound (1-13) by the same method as in Process 2 described in Production Method 1.

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).
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 formula (1-4), the compound represented by 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).
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 as defined above, and R ¹⁰⁴ represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, a substituted group. 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. An aralkyl group, an optionally substituted heteroaryl group, or R ¹⁰⁴ and R ¹⁰⁵ are bonded together to form a ring, and X ⁴ is an iodine atom, odor An element atom, a chlorine atom, a methanesulfonyloxy 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).
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, an optionally substituted aralkyl group, or an optionally substituted heteroaryl group, wherein R ¹⁰⁴ and R ¹¹² may be combined to form a ring, and m _100a is 0 or 1 and 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.

Production 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, and R ¹¹³ is the same as (a) to (z) 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 formula (1-4), the compound represented by formula (21-3) 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
In the formula (1-1), when X ¹ is a hydroxyl group, the compound represented by the formula (22-4) or a salt thereof is produced, for example, by the method shown below.

[Wherein, X ³ and R ^1a are the same as described above, R ²⁰³ represents a C _1-4 alkyl group, and X ¹⁰ represents an iodine atom, a bromine atom, a chlorine atom, a methanesulfonyloxy group, a trifluoro group. It is a lomethanesulfonyloxy group or a p-toluenesulfonyloxy group, and R ²⁰⁴ represents an alkyl group substituted with C _1-4 alkoxy, C _3-6 cycloalkyl, or C _1-4 alkoxycarbonyl. ]

1) Step 1
Compound (22-3) can be produced from compound (22-1) by the same method as in Step 8 described in Production Method 1.
3) Step 2
Compound (22-4) can be produced from compound (22-3) by the same method as in Process 1 described in Production Method 6.

Manufacturing method 23
Among the compounds represented by formula (I), the compound represented by formula (23-3) or a salt thereof is produced, for example, by the method shown below.

[Wherein Y ¹ , G, R ^1b , R ^3a , R ^3b , R ^3c , R ^3d and R ² have the same meanings as described above, and X ⁶ represents a chlorine atom, a bromine atom and an iodine atom. ]

1) Step 1
Compound (23-2) is a compound selected from Compound (23-1) selected from N-chlorosuccinimide, N-bromosuccinimide, and N-iodosuccinimide in the presence of sodium acetate in an inert solvent. It can be produced by reacting with (23-1). Examples of the inert solvent include organic acids such as acetic acid and propionic acid. The reaction temperature is selected from the range of about 20 ° C to about 50 ° C.
2) Step 2
Compound (23-3) can be produced from compound (23-2) by the same method as in Process 6 described in Production Method 1.

Production method 24
Of the compounds represented by formula (I), the compounds represented by formula (24-4), formula (24-8) and formula (24-11) or salts thereof are produced by, for example, the method shown below. The

[Wherein, Z ¹ , Y ¹ , G, R ^1b , R ^3a , R ^3b , R ^3c , R ^3d and R ² are as defined above, and R ²⁰⁷ represents a C _1-2 alkyl group. , X ⁷ represents an iodine atom, bromine atom, chlorine atom, methanesulfonyloxy group, trifluoromethanesulfonyloxy group, or p-toluenesulfonyloxy group, R ²⁰⁹ represents a hydrogen atom and an alkyl group, and R ²⁰⁸ represents Represents a hydrogen atom and an alkyl group. ]
1) Step 1
Compound (24-3) can be produced by reacting compound (24-1) and alkyllithium in an inert solvent and then reacting with compound (24-2). Examples of the alkyl lithium include n-butyl lithium, sec-butyl lithium, tert-butyl lithium and the like. Examples of the inert solvent include tetrahydrofuran, ether solvents such as 1,4-dioxane, and 1,2-dimethoxyethane. The reaction temperature is selected from the range of about −100 ° C. to about −50 ° C. in the step of reacting compound (24-1) with alkyllithium, and about −10 ° C. in the step of reacting with compound (24-2). Is selected from the range of ~ 40 ° C.
2) Step 2
Compound (24-4) can be produced from compound (24-3) by the same method as in Process 6 described in Production Method 1.
3) Step 3
Literature (eg Eur. J. Org. Chem. EN 5, 1075 (2004), WO 07/39142, J. Org. Chem. 67, 8424 (2002), Organic Letters 4, 107 (2002), Organic Letters 3, 393 (2001), Tetrahedron 58, 465 (2002) etc.) The compound (24-6) can be produced from the compound (24-1) by a method similar to the production method described in the above. Production examples are given below.
Compound (24-6) is a reaction between Compound (24-1) and Compound (24-5) in which Z ¹ is B (OH) ₂ in the presence of a Pd catalyst and a base in an inert solvent. Can be manufactured. Examples of the inert solvent include water or ether solvents such as tetrahydrofuran, 1,4-dioxane, or 1,2-dimethoxyethane. Usually, a mixed solution of water and an ether solvent is used. Examples of the base include sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate and the like. Examples of the Pd catalyst include palladium diphenylphosphino dichloride, tetrakistriphenylphosphine palladium, and the like. The reaction temperature is selected from the range of about 50 ° C to about 150 ° C.
4) Step 4
Compound (24-7) can be produced by hydrogenating compound (24-6) in the presence of palladium on carbon or palladium hydroxide in an inert solvent. Examples of the inert solvent include alcohol solvents such as methanol, ethanol, or 2-propanol. The reaction temperature is selected from the range of about 0 ° C to about 50 ° C.
5) Step 5
Compound (24-8) can be produced from compound (24-7) by the same method as in Process 6 described in Production Method 1.
6) Step 6
Compound (24-10) can be produced by reacting compound (24-1) with compound (24-9) in the presence of a Pd catalyst and an inorganic base in an inert solvent. Examples of the inorganic base include sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate and the like. Examples of the Pd catalyst include [1,1′-bis (diphenylphosphino) ferrocene] palladium dichloride or [1,1′-bis (diphenylphosphino) ferrocene] palladium dichloride dichloromethane complex. Examples of the inert solvent include water, tetrahydrofuran, ether solvents such as 1,4-dioxane, and 1,2-dimethoxyethane. Usually, a mixed solution of water and an ether solvent is used. The reaction temperature is selected from the range of about 50 ° C to about 120 ° C.
7) Step 7
Compound (24-11) can be produced from compound (24-10) by the same method as in Process 6 described in Production Method 1.

Production method 25
Among the compounds represented by formula (I), the compound represented by formula (25-2) or a salt thereof is produced, for example, by the method shown below.

[Wherein Y ¹ , G, R ^1b , R ^3a , R ^3b , R ^3c , R ^3d and R ² have the same meanings as described above. ]
1) Step 1
Production methods described in literature (for example, Synth. Commun. 24, 887 (1994), Organic Letters 9, 1711 (2007), Tetrahedron Lett. 40, 8193 (1999), Tetrahedron Lett. 45, 1441 (2004), etc.) The compound (25-1) can be produced from the compound (24-1) by the same method.
2) Step 2
Compound (25-2) can be produced from compound (25-1) by the same method as in Process 6 described in Production Method 1.

Manufacturing method 26
Of the compounds represented by formula (I), the compound represented by formula (26-5) or a salt thereof is produced, for example, by the method shown below.

[Wherein Y ¹ , G, R ^1a , R ^1b , R ^3a , R ^3b , R ^3c , R ^3d and R ² are as defined above, and R ²¹⁰ represents a C _1-4 alkyl group. , R ²¹¹ and R ²¹² are each independently the same or different, an optionally substituted C _1-6 alkyl group, an optionally substituted 5- or 6-membered saturated heterocyclic group, An _optionally substituted C _3-6 cycloalkyl group, an optionally substituted C _3-6 cycloalkyl C _1-4 alkyl group, an _optionally substituted 5- or 6-membered saturated heterocyclic C _1-4 alkyl group Or R ²¹¹ and R ²¹² together are an optionally substituted 5- to 7-membered cyclic amino group. ]
1) Step 1
Compound (26-2) can be produced from compound (26-1) by the same method as in Step 2 described in Production Method 3.
2) Step 2
Compound (26-4) can be produced from compound (26-2) by the same method as in Process 1 described in Production Method 1.
3) Step 3
Compound (26-5) can be produced from compound (26-4) by the same method as in Process 6 described in Production Method 1.

Manufacturing method 27
Of the compounds represented by formula (I), the compound represented by formula (27-5) or a salt thereof is produced, for example, by the method shown below.

[Wherein Y ¹ , G, R ^1a , R ^1b , R ^3a , R ^3b , R ^3c , R ^3d and R ² have the same meanings as described above, and R ²¹³ may be substituted C _{1- 6 represents} an alkyl group, an optionally substituted C _3-10 cycloalkyl group, or an optionally substituted saturated heterocyclic group, R ²¹⁴ represents an optionally substituted C _1-6 alkyl group, and X ⁸ represents an iodine atom, a bromine atom, a chlorine atom, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, or a p-toluenesulfonyloxy group. ]
1) Step 1
Compound (27-2) can be produced from compound (26-2) by the same method as in Process 1 described in Production Method 1.
2) Step 2
Compound (27-4) can be produced from compound (27-2) by the same method as in Step 8 described in Production Method 1.
3) Step 3
Compound (27-5) can be produced from compound (27-4) by the same method as in Process 6 described in Production Method 1.

Production method 28
The compound represented by the formula (28-11) or a salt thereof in which X ¹ is a hydroxyl group is produced, for example, by the method shown below.

[Wherein Y ¹ , R ^1a , R ^3a , R ^3b , R ^3c , R ^3d and R ² are as defined above, and R ²¹⁵
_Represents a C _1-4 alkyl group, X ⁹ represents an iodine atom, a bromine atom, a chlorine atom, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, or a p-toluenesulfonyloxy group, and R ²¹⁶ represents a substituted group. Represents a C _1-4 alkyl group which may be _substituted , and m ₃₀₀ represents an integer of 0 or 1. ]
1) Step 1
Compound (28-2) can be produced from compound (28-1) 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
Production methods described in literature (for example, J. Org. Chem. 72, 2596 (2007), J. Org. Chem. 68, 7722 (2003), J. Med. Chem. 36, 1811 (1993), etc.) By a similar method, compound (28-4) can be produced from compound (28-2).
3) Step 3
Compound (28-6) can be produced from compound (28-4) by the same method as in Step 8 described in Production Method 1.
4) Step 4
Compound (28-7) can be produced from compound (28-6) by the same method as in Process 2 described in Production Method 3.
5) Step 5
Compound (28-8) can be produced from compound (28-7) by a method similar to the production method described in the literature (for example, Comprehensive Organic transformation, RC Laroc, VCH publisher Inc., 1989). .
6) Step 6
Compound (28-9) can be produced from compound (28-8) by the same method as in Process 1 described in Production Method 1.
7) Step 7
Compound (28-10) can be produced from compound (28-9) by the same method as in Step 4 described in Production Method 24.
8) Step 8
Compound (28-11) can be produced from compound (28-10) by the same method as in Step 6 described in Production Method 1.

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, It represents an aralkyl group that may be substituted, a heteroaryl group that may be substituted, and the like. ]
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 the method described in the literature (for example, Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.)). be able to.

Production method 30
Among the compounds represented by the formula (22-4), the compound represented by the formula (30-8) or a salt thereof is produced, for example, by the method shown below.

[Wherein, G, X ³ and Z ¹ are as defined above, and R ²¹⁷ represents an optionally substituted alkyl group. ]
1) Step 1
Compound (30-2) can be produced from compound (30-1) by the same method as in Step 2 described in Production Method 3.
2) Step 2
Compound (30-3) can be produced from compound (30-2) 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 (30-4) can be produced from compound (30-3) by the same method as in Process 2 described in Production Method 1.
4) Step 4
Compound (30-5) can be produced from compound (30-4) by the same method as in Process 1 described in Production Method 23.
5) Step 5
A method similar to the production method described in the literature (for example, J. Org. Chem. 64, 6499 (1999), Tetrahedron Lett. 43, 7091 (2002), J. Org. Chem. 68, 1843 (2003), etc.) Can produce the compound (30-6) from the compound (30-5).
6) Step 6
Compound (30-7) can be produced by reacting compound (30-6) with tetrabutylammonium fluoride in an inert solvent. Examples of the inert solvent include tetrahydrofuran, ether solvents such as 1,4-dioxane, and 1,2-dimethoxyethane. The reaction temperature is selected from the range of about 0 ° C to about 30 ° C.
7) Step 7
Compound (30-8) can be produced from compound (30-7) by the same method as in Step 4 described in Production Method 24.

  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 the therapeutic agent for diabetes include insulin preparations (eg, animal insulin preparations extracted from bovine and porcine pancreas; human insulin preparations genetically engineered 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. ), 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
Methyl 4-bromo-3- (3-methoxypropoxy) benzoate

  To a solution of methyl 4-bromo-3-hydroxybenzoate (2.83 g) in acetonitrile (20 ml) were added potassium carbonate (2.54 g) and 1-bromo-3-methoxypropane (2.25 g), and the mixture was heated to reflux. After 3 hours, the reaction solution was cooled to 25 ° C., water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 5/1) to give the title compound (3.49 g) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.59 (d, J = 8.2 Hz, 1H), 7.55 (d, J = 1.8 HZ, 1H), 7.49 (dd, J = 1.8, 8.2 Hz, 1H), 4.18 (t, J = 6.2 Hz, 2H), 3.91 (s, 3H), 3.61 (t, J = 6.1 Hz, 2H), 3.36 (s, 3H), 2.15-2.08 (m 2H).

Reference example 2
4-Bromo-3- (3-methoxypropoxy) benzoic acid

  The compound of Reference Example 1 (3.49 g) was dissolved in methanol (18 ml), 1N aqueous sodium hydroxide solution (17.3 ml) was added, and the mixture was stirred at 55 ° C. for 5 hours. The reaction mixture was concentrated under reduced pressure, 5% potassium hydrogen sulfate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (3.10 g) as a white solid.

¹ H-NMR (400MHz, CDCl ₃ ) 7.63 (1H, d, J = 8.2 Hz, 1H), 7.60 (d, J = 1.7 Hz, 1H), 7.56 (dd, J = 1.7, 8.2 Hz, 1H), 4.21 (t, J = 6.2 Hz, 2H), 3.63 (t, J = 6.1 Hz, 2H), 3.38 (s, 3H), 2.17-2.10 (m, 1H).

Reference example 3
4-Bromo-3- (3-methoxypropoxy) benzoyl chloride

  The compound of Reference Example 2 (3.10 g) was dissolved in dichloromethane (15 ml), oxalyl chloride (2.04 ml) and dimethylformamide (10 μl) were added, and the mixture was stirred at room temperature for 6 hours. After the solvent was distilled off, toluene was added and the mixture was concentrated under reduced pressure twice to give the title compound (3.57 g) as a white solid.

Reference example 4
tert-Butyl (3R) -3-[[4-Bromo-3- (3-methoxypropoxy) benzoyl] (isopropyl) amino] piperidine-1-carboxylate

  Dissolve the compound of Reference Example 3 (3.57 g) and tert-butyl (3R) -3- (isopropylamino) piperidine-1-carboxylate (2.79 g) in dichloromethane (15 ml), add triethylamine (4.00 ml), and add room temperature. Stir with. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with saturated brine, 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 (5.37 g) as a colorless oily compound.

MS (ESI +) 513, 515 (M ⁺ +1, 100).

Reference Example 5
tert-butyl (3R) -3- (isopropyl {[2- (3-methoxypropoxy) biphenyl-4-yl] carbonyl} amino) piperidine-1-carboxylate

  The compound of Reference Example 4 (79.0 mg) was dissolved in 1,2-dimethoxyethane (2 ml) and water (1 ml), sodium carbonate (48.9 mg), phenylboronic acid (37.5 mg), tetrakistriphenylphosphine palladium ( 34.9 mg) was added and heated to reflux. After 5 hours, the reaction solution was cooled to 25 ° C., saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3/1) to give the title compound (78.6 mg) as a colorless oily compound.

MS (ESI +) 511 (M ⁺ +1, 100%).

Reference Example 6
tert-Butyl (3R) -3- {Isopropyl [3- (3-methoxypropoxy) -4-pyrimidin-5-ylbenzoyl] amino} piperidine-1-carboxylate

The title compound (37.4 mg) was synthesized in the same manner as in Reference Example 5.
MS (ESI +) 513 (M + 1, 100%).

Reference Example 7
tert-Butyl (3R) -3-[{[2'-Fluoro-2- (3-methoxypropyl) biphenyl-4-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate

  The title compound (599 mg) was synthesized in the same manner as in Reference Example 5.

MS (ESI +) 529 (M + 1, 100%).

Reference Example 8
Methyl 4-bromo-3- {2-[(methoxycarbonyl) amino] ethoxy} benzoate

  To a solution of methyl 4-bromo-3-hydroxybenzoate (600 mg) in acetonitrile (7 ml) were added potassium carbonate (719 mg) and methyl (2-bromoethyl) carbamate (473 mg), and the mixture was heated to reflux. After 3 hours, the reaction solution was cooled to 25 ° C., water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium 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 (754 mg) as a white solid.

MS (ESI +) 332 (M + 1, 50%), 334 (M + 1, 50%).

Reference Example 9
4-Bromo-3- {2-[(methoxycarbonyl) amino] ethoxy} benzoic acid

  The title compound (658 mg) was synthesized in the same manner as in Reference Example 2.

MS (ESI +) 318 (M + 1, 50%), 320 (M + 1, 50%).

Reference Example 10
Methyl {2- [2-bromo-5- (chlorocarbonyl) phenoxy] ethyl} carbamate

The title compound (659 mg) was synthesized in the same manner as in Reference Example 3.

Reference Example 11
tert-butyl (3R) -3-[(4-bromo-3- {2-[(methoxycarbonyl) amino] ethoxy} benzoyl) (isopropyl) amino] piperidine-1-carboxylate

  The title compound (541 mg) was synthesized in the same manner as in Reference Example 4.

MS (ESI +) 542 (M + 1, 50%), 544 (M + 1, 50%).

Reference Example 12
tert-butyl (3R) -3-[[(2'-fluoro-2-{(methoxycarbonyl) amino] ethoxy} biphenyl-4-yl) carbonyl] (isopropyl) amino] piperidine-1-carboxylate

  The title compound (166 mg) was synthesized in the same manner as in Reference Example 5.

MS (ESI +) 558 (M + 1, 100%)

Reference Example 13
tert-butyl (3R) -3-[{[5 '-(ethoxycarbonyl) -2'-fluoro-2- (3-methoxypropoxy) biphenyl-4-yl] carbonyl} (isopropyl) amino] piperidine-1- Carboxylate

  The title compound (4.39 g) was synthesized in the same manner as in Reference Example 5.

MS (ESI +) 601 (M + 1, 100%).

Reference Example 14
4 '-{[[(3R) -1- (tert-butoxycarbonyl) piperidin-3-yl] (isopropyl) amino] carbonyl} -6-fluoro-2'-(3-methoxypropoxy) biphenyl-3-carboxylic acid

  The compound of Reference Example 13 (1.02 g) was dissolved in ethanol (2 ml) and tetrahydrofuran (2 ml), 1N aqueous sodium hydroxide solution (2.6 ml) was added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, 5% potassium hydrogen sulfate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (913 mg) as a white solid.

MS (ESI +) 573 (M + 1, 100%).

Reference Example 15
tert-butyl (3R) -3-[{[5 '-(aminocarbonyl) -2'-fluoro-2- (3-methoxypropoxy) biphenyl-4-yl] carbonyl} (isopropyl) amino] piperidine-1- Carboxylate

  The compound of Reference Example 14 (206 mg) was dissolved in dimethylformamide (2 ml), 1-hydroxybenzotriazole (165 mg), 1-ethyl-3- (dimethylaminopropyl) carbodiimide / hydrochloride (207 mg), triethylamine (151 μl) and ammonium chloride (57.8 mg) were added, and the mixture was stirred at room temperature for 5 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/3) to give the title compound (167 mg) as a white solid.

MS (ESI +) 572 (M + 1, 100%).

Reference Example 16
tert-butyl (3R) -3-[{[5'-cyano-2'-fluoro-2- (3-methoxypropoxy) biphenyl-4-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate

  The compound of Reference Example 15 (101 mg) was dissolved in dichloromethane (1.5 ml), trifluoroacetic anhydride (32.7 μl) and triethylamine (49.1 μl) were added at 0 ° C., and the mixture was stirred at room temperature for 4 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 sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3/1) to give the title compound (167 mg) as a white solid.

MS (ESI +) 554 (M + 1, 100%).

  The compounds of Reference Examples 17 to 39 were synthesized according to the methods described in the corresponding Reference Examples and Reference Example 5.

Reference Example 17
MS (ESI +) 545 (M + 1, 100%).

Reference Example 18
MS (ESI +) 545 (M + 1, 100%).

Reference Example 19
MS (ESI +) 545 (M + 1, 100%).

Reference Example 20
MS (ESI +) 563 (M + 1, 100%).

Reference Example 21
MS (ESI +) 579 (M + 1, 100%).

Reference Example 22
MS (ESI +) 525 (M + 1, 100%).

Reference Example 23
MS (ESI +) 525 (M + 1, 100%).

Reference Example 24
MS (ESI +) 525 (M + 1, 100%).

Reference Example 25
MS (ESI +) 529 (M + 1, 100%).

Reference Example 26
MS (ESI +) 529 (M + 1, 100%).

Reference Example 27
MS (ESI +) 529 (M + 1, 100%).

Reference Example 28
MS (ESI +) 547 (M + 1, 100%).

Reference Example 29
MS (ESI +) 547 (M + 1, 100%).

Reference Example 30
MS (ESI +) 583 (M + 1, 100%).

Reference Example 31
MS (ESI +) 569 (M + 1, 100%).

Reference Example 32
MS (ESI +) 569 (M + 1, 100%).

Reference Example 33
MS (ESI +) 601 (M + 1, 100%).

Reference Example 34
MS (ESI +) 579 (M + 1, 100%).

Reference Example 35
MS (ESI +) 595 (M + 1, 100%).

Reference Example 36
MS (ESI +) 559 (M + 1, 100%).

Reference Example 37
MS (ESI +) 559 (M + 1, 100%).

Reference Example 38
MS (ESI +) 573 (M + 1, 100%).

Reference Example 39
MS (ESI +) 587 (M + 1, 100%).

  The compounds of Reference Examples 40 to 44 were synthesized according to the methods described in the corresponding Reference Examples and Reference Example 14.

Reference Example 40
MS (ESI +) 555 (M + 1, 100%).

Reference Example 41
MS (ESI +) 555 (M + 1, 100%).

Reference Example 42
MS (ESI +) 555 (M + 1, 100%).

Reference Example 43
MS (ESI +) 573 (M + 1, 100%).

Reference Example 44
MS (ESI +) 573 (M + 1, 100%).

  The compounds of Reference Examples 45 to 53 were synthesized according to the methods described in the corresponding Reference Examples and Reference Example 15.

Reference Example 45
MS (ESI +) 554 (M + 1, 100%).

Reference Example 46
MS (ESI +) 582 (M + 1, 100%).

Reference Example 47
MS (ESI +) 572 (M + 1, 100%).

Reference Example 48
MS (ESI +) 600 (M + 1, 100%).

Reference Example 49
MS (ESI +) 600 (M + 1, 100%).

Reference Example 50
MS (ESI +) 572 (M + 1, 100%).

Reference Example 51
MS (ESI +) 600 (M + 1, 100%).

Reference Example 52
MS (ESI +) 554 (M + 1, 100%).

Reference Example 53
MS (ESI +) 582 (M + 1, 100%).

  The compounds of Reference Examples 54 to 56 were synthesized according to the methods described in the corresponding Reference Examples and Reference Example 16.

Reference Example 54
MS (ESI +) 536 (M + 1, 100%).

Reference Example 55
MS (ESI +) 554 (M + 1, 100%).

Reference Example 56
MS (ESI +) 554 (M + 1, 100%).

  The compounds of Reference Examples 57 to 63 were synthesized according to the methods described in the corresponding Reference Examples and Reference Example 5.

Reference Example 57
MS (ESI +) 512 (M + 1, 100%).

Reference Example 58
MS (ESI +) 512 (M + 1, 100%).

Reference Example 59
MS (ESI +) 530 (M + 1, 100%).

Reference Example 60
MS (ESI +) 517 (M + 1, 100%).

Reference Example 61
MS (ESI +) 517 (M + 1, 100%).

Reference Example 62
MS (ESI +) 515 (M + 1, 100%).

Reference Example 63
MS (ESI +) 502 (M + 1, 100%).

Reference Example 64
tert-butyl (3R) -3-[{[5-bromo-2'-fluoro-2- (methoxypropoxy) biphenyl-4-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate

  The compound of Reference Example 7 (428 mg) was dissolved in acetic acid (7 ml), sodium acetate (300 mg) and N-bromosuccinimide (360 mg) were added, and the mixture was stirred at room temperature for 14 hours. A saturated aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with 2N aqueous sodium hydroxide solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium 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 (454 mg) as a single yellow oily compound.

MS (ESI +) 607 (M + 1, 50%), 609 (M + 1, 50%).

Reference Example 65
tert-butyl (3R) -3-[{[2'-fluoro-2- (3-methoxypropoxy) -5-methylbiphenyl-4-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate

  The compound of Reference Example 64 (127 mg) was dissolved in tetrahydrofuran (2 ml), butyllithium (0.264 ml, 2.77M in Hexane) was added at −78 ° C., and the mixture was stirred for 30 minutes. Iodomethane (65.0 μl) was added, and the mixture was gradually brought to room temperature and stirred for 12 hours. A saturated aqueous ammonium chloride 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 sodium 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 (38.7 mg) as a single yellow oily compound.

MS (ESI +) 543 (M + 1, 100%).

Reference Example 66
tert-butyl (3R) -3-[{[5-chloro-2'-fluoro-2- (methoxypropoxy) biphenyl-4-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate

  The compound of Reference Example 7 (170 mg) was dissolved in acetic acid (3 ml), sodium acetate (264 mg) and N-chlorosuccinimide (431 mg) were added, and the mixture was stirred at room temperature for 40 hours. A saturated aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with 2N aqueous sodium hydroxide solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium 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 (111 mg) as a single yellow oily compound.

MS (ESI +) 563 (M + 1, 100%).

Reference Example 67
tert-Butyl (3R) -3-[({2'-Fluoro-2- (3-methoxypropoxy) -5-[(1E) -prop-1-en-1-yl] biphenyl-4-yl} carbonyl ) (Isopropyl) amino] piperidine-1-carboxylate

  The compound of Reference Example 64 (103 mg) was dissolved in dimethoxyethane (2 ml) and water (0.5 ml), trans-propenylboronic acid (21.9 mg), sodium carbonate (36.0 mg), palladium diphenylphosphino dichloride / dichloromethane complex. (27.8 mg) was added and heated under reflux for 3 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 sodium 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 (82.4 mg) as a single yellow oily compound.

MS (ESI +) 569 (M + 1, 100%).

Reference Example 68
tert-butyl (3R) -3-[{[2'-fluoro-2- (3-methoxypropoxy) -5-propylbiphenyl-4-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate

  The compound of Reference Example 67 (82.4 mg) was dissolved in methanol (3 ml), palladium-carbon (120 mg) was added, and the mixture was stirred under a hydrogen atmosphere for 5 hours. The reaction solution was filtered through celite 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 (70.0 mg) as a single yellow oily compound.

MS (ESI +) 571 (M + 1, 100%).

Reference Example 69
tert-butyl (3R) -3-[{[5-cyano-2'-fluoro-2- (3-methoxypropoxy) biphenyl-4-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate

  The compound of Reference Example 64 (584 mg) was dissolved in dimethylformamide (2.5 ml), zinc cyanide (67.7 mg) and ditributylphosphine palladium (98.2 mg) were added, and the mixture was heated to reflux for 3 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 sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give the title compound (82.4 mg) as a single yellow oily compound.

MS (ESI +) 554 (M + 1, 100%).

  The compounds of Reference Examples 70 to 75 were synthesized according to the methods described in the corresponding Reference Examples and Reference Example 15.

Reference Example 70
MS (ESI +) 628 (M + 1, 100%).

Reference Example 71
MS (ESI +) 612 (M + 1, 100%).

Reference Example 72
MS (ESI +) 656 (M + 1, 100%).

Reference Example 73
MS (ESI +) 626 (M + 1, 100%).

Reference Example 74
MS (ESI +) 640 (M + 1, 100%).

Reference Example 75
MS (ESI +) 642 (M + 1, 100%).

  The compounds of Reference Examples 76 to 96 were synthesized according to the methods described in the corresponding Reference Examples and Reference Example 15.

Reference Example 76
MS (ESI +) 634 (M + 1, 100%).

Reference Example 77
MS (ESI +) 638 (M + 1, 100%).

Reference Example 78
MS (ESI +) 676 (M + 1, 100%).

Reference Example 79
MS (ESI +) 676 (M + 1, 100%).

Reference Example 80
MS (ESI +) 662 (M + 1, 100%).

Reference Example 81
MS (ESI +) 692 (M + 1, 100%).

Reference Example 82
MS (ESI +) 706 (M + 1, 100%).

Reference Example 83
MS (ESI +) 646 (M + 1, 100%).

Reference Example 84
MS (ESI +) 690 (M + 1, 100%).

Reference Example 85
MS (ESI +) 674 (M + 1, 100%).

Reference Example 86
MS (ESI +) 704 (M + 1, 100%).

Reference Example 87
MS (ESI +) 692 (M + 1, 100%).

Reference Example 88
MS (ESI +) 746 (M + 1, 100%).

Reference Example 89
MS (ESI +) 732 (M + 1, 100%).

Reference Example 90
MS (ESI +) 732 (M + 1, 100%).

Reference Example 91
MS (ESI +) 660 (M + 1, 100%).

Reference Example 92
MS (ESI +) 678 (M + 1, 100%).

Reference Example 93
MS (ESI +) 718 (M + 1, 100%).

Reference Example 94
MS (ESI +) 678 (M + 1, 100%).

Reference Example 95
MS (ESI +) 714 (M + 1, 100%).

Reference Example 96
MS (ESI +) 676 (M + 1, 100%).

Reference Example 97
tert-butyl (3R) -3-[{[5-chloro-5 '-{[cyclopropyl (methyl) amino] carbonyl} -2'-fluoro-2- (3-methoxypropoxy) biphenyl-4-yl] Carbonyl} (isopropyl) amino] piperidine-1-carboxylate

  The compound of Reference Example 83 (531 mg) was dissolved in dimethylformamide (2.0 ml), sodium hydride (66 mg, 60% in oil) was added at 0 ° C., and the mixture was stirred for 30 minutes. After adding iodomethane (102 μl), the mixture was stirred at room temperature for 4 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution and saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/3) to give the title compound (489 mg) as a white solid.

MS (ESI +) 660 (M + 1, 100%).

Reference Example 98
tert-butyl (3R) -3-[[(5-chloro-2'fluoro-2- (3-methoxypropoxy) -5 '-{[methyl (tetrahydro-2H-pyran-4-yl) amino] carbonyl} Biphenyl-4-yl) carbonyl] (isopropyl) amino] piperidine-1-carboxylate

  The title compound (183 mg) was synthesized in the same manner as in Reference Example 97.

MS (ESI +) 704 (M + 1, 100%).

Reference Example 99
tert-Butyl (3R) -3-[{[5-Chloro-5 '-[(1,1-dioxidethiomorpholin-4-yl) carbonyl] -2'-fluoro-2- (3-methoxypropoxy) Biphenyl-4-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate

  The compound of Reference Example 87 (234 mg) was dissolved in chloroform (2.0 ml), m-chloroperbenzoic acid (250 mg) was added, and the mixture was stirred at room temperature for 15 hours. A saturated aqueous sodium thiosulfate 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 sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/3) to give the title compound (144 mg) as a white solid.

MS (ESI +) 724 (M + 1, 100%).

Reference Example 100
1-{[4 '{[[(3R) -1- (tert-butoxycarbonyl) piperidin-3-yl] (isopropyl) amino] carbonyl} -5'-chloro-6-fluoro-2'-(3- Methoxypropoxy) biphenyl-3-yl] carbonyl} (isopropyl) amino] piperidine-4-carboxylic acid

  The title compound (769 mg) was synthesized in the same manner as in Reference Example 14.

MS (ESI +) 718 (M + 1, 100%).

Reference Example 101
tert-Butyl (3R) -3-[{[5-Chloro-2'-fluoro-5 '{[4- (hydroxymethyl) piperidin-1-yl] carbonyl} -2- (3-methoxypropoxy) biphenyl- 4-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate

  The compound of Reference Example 100 (699 mg) was dissolved in tetrahydrofuran (4 ml), and triethylamine (542 μl) and ethyl chloroformate (233 μl) were added at 0 ° C. After stirring for 1 hour, sodium borohydride (194 mg) and water (2 ml) were added, and the mixture was stirred at room temperature for 4 hours. A saturated aqueous ammonium chloride 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 sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/3) to give the title compound (560 mg) as a white solid.

MS (ESI +) 704 (M + 1, 100%).

Reference Example 102
tert-Butyl (3R) -3-[{[5-Chloro-2'-fluoro-5 '{[4- (methoxymethyl) piperidin-1-yl] carbonyl} -2- (3-methoxypropoxy) biphenyl- 4-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate

  The title compound (130 mg) was synthesized in the same manner as in Reference Example 97.

MS (ESI +) 718 (M + 1, 100%).

Reference Example 103
tert-Butyl (3R) -3-[{[5-Chloro-2'-fluoro-5 '-[(4-hydroxypiperidin-1-yl) carbonyl] -2- (3-methoxypropoxy) biphenyl-4- Yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate

  The compound of Reference Example 90 (686 mg) was dissolved in methanol (3 ml), potassium carbonate (194 mg) was added, and the mixture was stirred for 4 hours. A saturated aqueous ammonium chloride 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 sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform / methanol = 10/1) to give the title compound (534 mg) as a white solid.

MS (ESI +) 690 (M + 1, 100%).

Reference Example 104
tert-butyl (3R) -3-[{[5-chloro-2'-fluoro-5 '-[(4-methoxypiperidin-1-yl) carbonyl] -2- (3-methoxypropoxy) biphenyl-4- Yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate

  The title compound (112 mg) was synthesized in the same manner as in Reference Example 97.

MS (ESI +) 704 (M + 1, 100%).

Reference Example 105
tert-butyl (3R) -3-[{[5-chloro-2'-fluoro-5 '-{[(3S) -3-hydroxypyrrolidin-1-yl] carbonyl} -2- (3-methoxypropoxy) Biphenyl-4-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate

  The title compound (191 mg) was synthesized in the same manner as in Reference Example 103.

MS (ESI +) 676 (M + 1, 100%).

Reference Example 106
tert-butyl (3R) -3-[[(5-chloro-2'-fluoro-2- (3-methoxypropoxy) -5 '-{[(3S) -3-methoxypyrrolidin-1-yl] carbonyl} Biphenyl-4-yl) carbonyl] (isopropyl) amino] piperidine-1-carboxylate

  The title compound (76.1 mg) was synthesized in the same manner as in Reference Example 97.

MS (ESI +) 690 (M + 1, 100%).

Reference Example 107
tert-butyl (3R) -3-[{[5-chloro-5 '-[(1,1-dioxide-1,3-thiazolidin-3-yl) carbonyl] -2'-fluoro-2- (3- Methoxypropoxy) biphenyl-4-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate

  The title compound (103 mg) was synthesized in the same manner as in Reference Example 99.

MS (ESI +) 710 (M + 1, 100%).

  The compounds of Reference Examples 108 to 110 were synthesized according to the methods described in the corresponding Reference Examples and Reference Example 15.

Reference Example 108
MS (ESI +) 642 (M + 1, 100%).

Reference Example 109
MS (ESI +) 684 (M + 1, 100%).

Reference Example 110
MS (ESI +) 712 (M + 1, 100%).

Reference Example 111
tert-Butyl (3S) -3- (acetyloxy) pyrrolidine-1-carboxylate

Dissolve (S) -1-N-Boc-3-hydroxypyrrolidine (2.00 g) in dichloromethane (20 ml), add dimethylaminopyridine (261 mg), triethylamine (1.64 μl), and acetic anhydride (1.51 ml) at room temperature. For 18 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3/1) to give the title compound (2.54 g) as a colorless oil.

MS (ESI +) 230 (M + 1, 100%).

Reference Example 112
(3S) -Pyrrolidin-3-yl acetate hydrochloride

 4N Hydrochloric acid / dioxane solution (10 ml) was added to a solution of Reference Example 111 (2.54 g) in 1,4-dioxane (10 ml), stirred at 25 ° C. for 2 hours, and concentrated under reduced pressure to give the title compound ( 2.12 g) was obtained.

MS (ESI +) 130 (M + 1, 100%).

Reference Example 113
tert-Butyl 4-hydroxypiperidine-1-carboxylate

   1-BOC-4-piperidone (1.67 g) was dissolved in ethanol (20 ml), sodium borohydride (380 mg) was added, and the mixture was stirred at room temperature for 18 hours. A saturated aqueous ammonium chloride 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 sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give the title compound (1.75 g) as a white solid.

MS (ESI +) 202 (M + 1, 100%).

Reference Example 114
tert-Butyl 4- (acetyloxy) piperidine-1-carboxylate

The title compound (2.04 g) was synthesized in the same manner as in Reference Example 111.

MS (ESI +) 244 (M + 1, 100%).

Reference Example 115
Piperidin-4-yl acetate hydrochloride

The title compound (1.37 g) was synthesized in the same manner as in Reference Example 112.

MS (ESI +) 144 (M + 1, 100%).

Reference Example 116
tert-butyl (3R) -3-[{[5 '-(azepan-1-ylcarbonyl) -2'-fluoro-2- (3-methoxypropoxy) biphenyl-4-yl] carbonyl} (isopropyl) amino] Piperidine-1-carboxylate

The title compound (105.9 mg) was synthesized from the corresponding compound by a method similar to that in Reference Example 15.

MS (ESI +) 654 (M ⁺ +1, 61%).

Reference Example 117
tert-butyl (3R) -3-[{[5 '-[(4,4-difluoropiperidin-1-yl) carbonyl] -2'-fluoro-2- (3-methoxypropoxy) biphenyl-4-yl] Carbonyl} (isopropyl) amino] piperidine-1-carboxylate

The title compound (46.4 mg) was synthesized from the corresponding compound by a method similar to that in Reference Example 15.

MS (ESI +) 676 (M ⁺ +1, 69%).

Reference Example 118
tert-Butyl (3R) -3-[{[2'-Fluoro-5 '-[(methoxycarbonyl) amino] -2- (3-methoxypropoxy) biphenyl-4-yl] carbonyl} (isopropyl) amino] piperidine -1-carboxylate

4 '-{[[(3R) -1- (tert-butoxycarbonyl) piperidin-3-yl] (isopropyl) amino] arbonyl} -6-fluoro 2'-(3-methoxypropoxy) biphenyl-3-carboxylic acid Triethylamine (98 μl) diphenylphosphoryl azide (76 μl) was added to a toluene solution (4 ml) of (168.6 mg), and the mixture was stirred for 1 hour with heating under reflux, then sodium methoxide (31.7 mg) was added, and the mixture was stirred for 1 hour. did. The reaction mixture was diluted with brine and extracted with ethyl acetate. The organic layers were combined, dried and concentrated. The concentrated residue was purified by column to give the title compound (37.7 mg).

MS (ESI +) 602 (M ⁺ +1, 36%).

Reference Example 119
tert-butyl (3R) -3-[{[2'-fluoro-5 '-[(4-hydroxypiperidin-1-yl) carbonyl] -2- (3-methoxypropoxy) biphenyl-4-yl] carbonyl} (Isopropyl) amino] piperidine-1-carboxylate

The title compound (41.9 mg) was synthesized from the corresponding compound by a method similar to that in Reference Example 15.

MS (ESI +) 656 (M ⁺ +1, 61%).

Reference Example 120
tert-butyl (3R) -3-[{[2'-fluoro-5 '-[(4-methoxypiperidin-1-yl) carbonyl] -2- (3-methoxypropoxy) biphenyl-4-yl] carbonyl} (Isopropyl) amino] piperidine-1-carboxylate

tert-butyl (3R) -3-[{[2'-fluoro-5 '-[(4-hydroxypiperidin-1-yl) carbonyl] -2- (3-methoxypropoxy) biphenyl-4-yl] carbonyl} Sodium hydride (10 mg) and methyl iodide (10 ml) were added to a tetrahydrofuran solution (4 ml) of (isopropyl) amino] piperidine-1-carboxylate (20.4 mg), and the mixture was stirred for 2 hours. Furthermore, sodium hydride (10 mg) and methyl iodide (10 ml) were added and stirred for 3 hours. After the reaction, water was added at 0 ° C., diluted with brine, and extracted with ethyl acetate. The organic layers were combined, dried and concentrated. The concentrated residue was purified by column to give the title compound (7 mg).

MS (ESI +) 670 (M ⁺ +1, 41%).

Reference Example 121
tert-butyl (3R) -3-[{[2'-fluoro-5 '-(1-hydroxy-1-methylethyl) -2- (3-methoxypropoxy) biphenyl-4-yl] carbonyl} (isopropyl) Amino] piperidine-1-carboxylate

tert-butyl (3R) -3-[{[5 '-(ethoxycarbonyl) -2'-fluoro-2- (3-methoxypropoxy) biphenyl-4-yl] carbonyl} (isopropyl) amino] piperidine-1- To a solution of carboxylate (123 mg) in tetrahydrofuran-diethyl ether (6 ml) was added methylmagnesium bromide (1.5 ml, 1.0 mol / l tetrahydrofuran solution) at 0 ° C, and the mixture was stirred for 6 hours while warming to room temperature. . After the reaction, saturated aqueous ammonium chloride was added at 0 ° C., diluted with water, and extracted with ethyl acetate. The organic layers were combined, dried and concentrated. The concentrated residue was purified by column to give the title compound (100 mg).

MS (ESI +) 587 (M ⁺ +1, 55%).

Reference Example 122
tert-Butyl (3R) -3-[{[5'-Acetyl-2'-fluoro-2- (3-methoxypropoxy) biphenyl-4-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate

N, N-dimethylformamide-water solution of tert-butyl (3R) -3-[[4-bromo-3- (3-methoxypropoxy) benzoyl] (isopropyl) amino] piperidine-1-carboxylate (384.4 mg) ( 6 ml), (5-acetyl-2-fluorophenyl) boronic acid, tetrakistrifehilphosphine palladium (173 mg) and sodium carbonate (227 mg) were heated and refluxed for 3 hours. After the reaction, saturated aqueous sodium chloride was added, diluted with water, and extracted with ethyl acetate. The organic layers were combined, dried and concentrated. The concentrated residue was purified by column to give the title compound (268.9 mg).

MS (ESI +) 571 (M ⁺ +1, 35%).

Reference Example 123
tert-Butyl (3R) -3-[{[2'-Fluoro-5 '-[(4-hydroxy-4-methylpiperidi-1-yl) carbonyl] -2- (3-methoxypropoxy) biphenyl-4-yl ] Carbonyl} (isopropyl) amino] piperidine-1-carboxylate

The title compound (122.5 mg) was synthesized from the corresponding compound by a method similar to that in Reference Example 15.

MS (ESI +) 670 (M ⁺ +1, 53%).

Reference Example 124
tert-Butyl (3R) -3-[{[2'-Fluoro-5 '-[(3-hydroxypyrrolidin-1-yl) carbonyl] -2- (3-methoxypropoxy) biphenyl-4-yl] carbonyl} (Isopropyl) amino] piperidine-1-carboxylate

The title compound (172 mg) was synthesized from the corresponding compound by a method similar to that in Reference Example 15.

MS (ESI +) 642 (M ⁺ +1, 45%).

Reference Example 125
tert-Butyl (3R) -3-[({2'-Fluoro-2- (3-methoxypropoxy) -5 '-[(tetrahydro-2H-pyran-4-ylamino) carbonyl] biphenyl-4-yl} carbonyl ) (Isopropyl) amino] piperidine-1-carboxylate

The title compound was synthesized from the corresponding compound by a method similar to that in Reference Example 15.

MS (ESI +) 656 (M ⁺ +1, 62%).

Reference Example 126
tert-butyl (3R) -3-[({2'-fluoro-2- (3-methoxypropoxy) -5 '-[(3-methoxypyrrolidin-1-yl) carbonyl] biphenyl-4-yl} carbonyl) (Isopropyl) amino] piperidine-1-carboxylate

The title compound (81.5 mg) was synthesized from the corresponding compound by a method similar to that in Reference Example 120.

MS (ESI +) 656 (M ⁺ +1, 34%).

Reference Example 127
tert-butyl (3R) -3-[[(2'-fluoro-2- (3-methoxypropoxy) -5 '-{[methyl (tetrahydro-2H-pyran-4-yl) amino] carbonyl} biphenyl-4 -Yl) carbonyl] (isopropyl) amino] piperidi-1-carboxylate

In the same manner as in Reference Example 120, the title compound (120 mg) was synthesized from the corresponding compound.

MS (ESI +) 670 (M ⁺ +1, 56%).

Reference Example 128
tert-Butyl (3R) -3-[{[2'-Fluoro-5 '-[(3-fluoropyrosidin-1-yl) carbonyl] -2- (3-methoxypropoxy) biphenyl-4-yl] carbonyl } (Isopropyl) amino] piperidine-1-carboxylate

In the same manner as in Reference Example 15, the title compound (140 mg) was synthesized from the corresponding compound.

MS (ESI +) 644 (M ⁺ +1, 18%).

Reference Example 129
tert-butyl (3R) -3-[{[5-cyano-5 '-[(dimethylamino) carbonyl] -2'-fluoro-2- (3-methoxypropoxy) biphenyl-4-yl] carbonyl} (isopropyl Amino] piperidine-1-carboxylate

The title compound (110 mg) was synthesized from the corresponding compound by a method similar to that in Reference Example 15.

MS (ESI +) 625 (M ⁺ +1, 22%).

Reference Example 130
tert-butyl (3R) -3-[{[5 '-{[(2R, 6S) -2,6-dimethylaminomorpholin-4-yl] carbonyl} -2'-fluoro-2- (3-methoxy Propoxy) biphenyll-4-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate

The title compound was synthesized from the corresponding compound with reference to Reference Example 15.

MS (ESI +) 670 (M ⁺ +1, 40%).

Reference Example 131
tert-butyl (3R) -3-[[(2'-fluoro-2- (3-methoxypropoxy) -5 '-{[methyl (tetrahydro-2H-pyran-4-yl) amino] carbonyl} -5- Propylbiphenyl-4-yl) carbonyl] (isopropyl) amino] piperidine-1-carboxylate

The title compound (78.0 mg) was synthesized in the same manner as in Reference Example 15.
MS (ESI +) 698 (M + 1, 100%).

MS (ESI +) 628 (M ⁺ +1, 34%).

Reference Example 132
tert-butyl (3R) -3-[{[5-cyano-5 '-(ethoxycarbonyl) -2'-fluoro-2- (3-methoxypropoxy) biphenyl-4-yl] carbonyl} (isopropyl) amino] Piperidine-1-carboxylate

tert-butyl (3R) -3-[{[5-bromo-5 '-(ethoxycarbonyl) -2'-fluoro-2- (3-methoxypropoxy) biphenyl-4-yl] carbonyl} (isopropyl) amino] Tetrakistriphenylphosphine palladium (430 mg) and dicyanozinc (132 mg) were added to an N-methylpiperidone solution (19 ml) of piperidine-1-carboxylate (1.28 g), and sales were increased at 105 ° C. for 10 hours. The reaction solution was filtered through celite, and the filtrate and washings were combined and concentrated, followed by column purification to obtain the title compound (810 mg).

MS (ESI +) 626 (M ⁺ +1, 26%).

Reference Example 133
tert-butyl (3R) -3-[{[5 '-[(tert-butylamino) carbonyl] -5-chloro-2'-fluoro-2- (3-methoxypropoxy) biphenyl-4-yl] carbonyl} (Isopropyl) amino] piperidine-1-carboxylate

The title compound (279 mg) was synthesized in the same manner as in Reference Example 15.
MS (ESI +) 661 (M + 1, 100%).

MS (ESI +) 668 (M ⁺ +1, 66%).

Reference Example 134
tert-butyl (3R) -3-[({5-ethyl-2'-fluoro-2- (3-methoxypropoxy) -5 '-[(tetrahydro-2H-pyran-4-ylamino) carbonyl] biphenyl-4 -Yl} carbonyl) (isopropyl) amino] piperidine-1-carboxylate

The title compound (160 mg) was synthesized from the corresponding compound by a method similar to that in Reference Example 15.

MS (ESI +) 684 (M ⁺ +1, 75%).

Reference Example 135
N-cyclopropyl-N-tetrahydro-2H-pyran-4-ylamine hydrochloride

  Tetrahydro-4H-pyran-4-one (2.00 g) was dissolved in ethanol (30 ml), and acetic acid (1.20 ml) and cyclopropylamine (2.08 ml) were added. After stirring at 50 ° C. for 4 hours, sodium triacetoxyborohydride (8.48 g) was added and stirred for 3 hours. To the reaction mixture was added 1N aqueous sodium hydroxide solution, and the mixture was extracted 3 times with chloroform. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform / methanol = 10/1), 4N hydrochloric acid-dioxane was added, and the mixture was concentrated under reduced pressure to give the title compound (1.71 g) as a light brown solid.

¹ H NMR (400 MHz, CD ₃ OD) δ 4.01 (m, 2H), 3.48-3.46 (m, 3H), 2.77 (m, 1H), 2.08 (m, 2H), 1.65 (m, 2H), 0.92 -0.89 (m, 4H).
MS (ESI +) 142 (M + 1, 100%).

Reference Example 136
tert-butyl (3R) -3-[{[5-chloro-2'-fluoro-2- (3-methoxypropoxy) -5 '-(morpholin-4-ylcarbonyl) biphenyl-4-yl] carbonyl} ( Isopropyl) amino] piperidine-1-carboxylate

The title compound (345 mg) was synthesized in the same manner as in Reference Example 15.

MS (ESI +) 676 (M + 1, 20%).

Reference Example 137
tert-butyl (3R) -3-[{[5-chloro-5 '-{[cyclopropyl (tetrahydro-2H-pyran-4-yl) amino] carbonyl} -2'-fluoro-2- (3-methoxy Propoxy) biphenyl-4-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate

The title compound (764 mg) was synthesized in the same manner as in Reference Example 15.
MS (ESI +) 730 (M + 1, 100%).

Reference Example 138
tert-butyl (3R) -3-[{[5-chloro-5 '-{[ethyl (tetrahydro-2H-pyran-4-yl) amino] carbonyl} -2'-fluoro-2- (3-methoxypropoxy ) Biphenyl-4-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate

  The compound of Reference Example 83 (505 mg) was dissolved in dimethylformamide (2.0 ml), sodium hydride (88.0 mg, 60% in oil) was added at 0 ° C., and the mixture was stirred for 30 minutes. After adding iodoethane (175.6 μl), the mixture was stirred at room temperature for 4 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution and saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/3) to give the title compound (384.6 mg) as a white solid.

MS (ESI +) 718 (M + 1, 100%).

Reference Example 139
tert-butyl (3R) -3-[{[5-ethyl-5 '-{[ethyl (tetrahydro-2H-pyran-4-yl) amino] carbonyl} -2'-fluoro-2- (3-methoxypropoxy ) Biphenyl-4-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate

The title compound (323 mg) was synthesized from the corresponding compound by a method similar to that in Reference Example 138.

MS (ESI +) 712 (M ⁺ +1, 100%).

Reference Example 140
tert-butyl (3R) -3-[{[5-ethyl-2'-fluoro-5 '-{[4- (methoxymethyl) piperidin-1-yl] carbonyl} -2- (3-methoxypropoxy) biphenyl -4-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate

  The title compound (140 mg) was synthesized in the same manner as Reference Example 15, Reference Example 14, Reference Example 101, and Reference Example 97 in this order.

MS (ESI +) 712 (M + 1, 100%).

Reference Example 141
3- (3-Oxomorpholin-4-yl) phenyl trifluoromethanesulfonate

To a solution of 1-benzyloxy-3-bromobenzene (0.53 g, 2.01 mmol) in dioxane (4 ml), morpholin-3-one (0.23 g, 2.27 mmol), cesium carbonate (1.06 g, 3.25 mmol), 4, 5-bis (diphenylphosphino) -9,9-dimethylxanthene (0.71 g, 1.23 mmol) and palladium acetate (0.18 g, 0.80 mmol) were added, and the mixture was stirred at 100 ° C. for 4 hours under a nitrogen stream. After cooling to room temperature, it was diluted with chloroform and filtered. The crude product obtained by concentrating the filtrate was purified by silica gel column chromatography to obtain 4- [3- (benzyloxy) phenyl] morpholin-3-one (0.33 g). This was dissolved in methanol (5 ml), 10% palladium carbon (0.27 g) was added, and the mixture was vigorously stirred for 9 hours in a hydrogen atmosphere. After filtration through celite, the filtrate was concentrated to give 4- (3-hydroxyphenyl) morpholin-3-one (0.13 g). A suspension of this compound (116.6 mg, 0.60 mmol) in dichloromethane (2 ml) was ice-cooled, and triethylamine (0.33 ml, 2.4 mmol) and trifluoroacetic anhydride (0.13 ml, 0.78 mmol) were added thereto at 0 ° C. For 2 hours and at room temperature for 2 hours. Water was added to the reaction solution for liquid separation, and the organic layer was washed with saturated brine, dried and concentrated. The obtained crude product was purified by silica gel column chromatography to obtain the title compound (189.1 mg, 97%).

MS (ESI +) 326 (M ⁺ +1, 100%).

Reference Example 142
1- (3-Bromophenyl) piperidin-2-one

3-Bromoaniline (3.45 g) was dissolved in chloroform and then cooled in an ice bath. Triethylamine (3.05 g) and 5-bromovaleric acid chloride (4.78 g) were added thereto, and the mixture was stirred for 2 hours in an ice bath. After diluting the reaction solution by adding chloroform, the organic layer was washed with a saturated aqueous citric acid solution, water and saturated brine. The mixture was dried over magnesium sulfate and concentrated to give 4-bromo-N- (3-bromophenyl) butanamide (7.61 g).
This compound (0.38 g) was dissolved in THF (10 ml), cooled in an ice bath, potassium tert-butoxide (0.19 g) was added little by little, and the mixture was stirred at 0 ° C. for 2 hours. The reaction mixture was diluted with water and extracted with ethyl acetate, and the organic layer was washed with saturated brine. The crude product obtained after drying and concentration was purified by silica gel column chromatography to obtain the title compound (0.20 g).

MS (ESI +) 256 (M ⁺ +2, 100%), 254 (M ⁺ , 100%).

Reference Example 143
3- (2-oxo-1,3-oxazolidine-3-yl) phenyl trifluoromethanesulfonate

To a solution of 1-benzyloxy-3-bromobenzene (0.53 g) in dioxane (5 ml) 2-oxazolidinone (0.26 g), cesium carbonate (1.05 g), 4,5-bis (diphenylphosphino) -9,9 -Dimethylxanthene (0.36 g) and palladium acetate (0.10 g) were added, and the mixture was stirred at 100 ° C for 9 hours under a nitrogen stream. After cooling to room temperature, it was diluted with chloroform and filtered. The crude product obtained by concentrating the filtrate was purified by silica gel column chromatography to obtain 3- [3- (benzyloxy) phenyl] -1,3-oxazolidine-2-one (0.24 g). This was dissolved in methanol (10 ml), 10% palladium carbon (0.17 g) was added, and the mixture was vigorously stirred for 9 hours in a hydrogen atmosphere. After filtration through celite, the filtrate was concentrated to give 3- (3-hydroxyphenyl) -1,3-oxazolidine-2-one (0.12 g). A suspension of this compound (122.6 mg) in dichloromethane (5 ml) was ice-cooled, and triethylamine (0.38 ml) and trifluoroacetic anhydride (0.15 ml) were added thereto. Stir for hours. Water was added to the reaction solution for liquid separation, and the organic layer was washed with saturated brine, dried and concentrated. The obtained crude product was purified by silica gel column chromatography to obtain the title compound (195.9 mg, 93%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.66 (t, J = 2.29 Hz, 1H), 7.54 (ddd, J = 8.40, 2.12, 0.96 Hz, 1H), 7.47 (t, J = 8.40 Hz, 1H) , 7.07 (ddd, J = 8.20, 2.36, 0.84 Hz, 1H), 4.57-4.51 (m, 2H), 4.12-4.06 (m, 1H).

Reference Example 144
4-[(3-Bromophenyl) sulfonyl] morpholine

A chloroform solution of morpholine (0.80 g) was ice-cooled, triethylamine (1.66 ml) was added, and then 3-bromobenzenesulfonyl chloride (1.52 g) was added. After stirring at 0 ° C. for 1 hour, the mixture was warmed to room temperature and stirred for 14 hours. The reaction mixture was washed with water and saturated brine, dried and concentrated. The crude product obtained was recrystallized from chloroform / hexane to give the title compound (1.09 g) as white crystals.

MS (ESI +) 306 (M ⁺ +2, 100%), 304 (M ⁺ , 100%).

Reference Example 145
tert-butyl (3R) -3- {isopropyl [3- (3-methoxypropoxy) -4- (4,4,5,5, -tetramethyl-1,3,2-dioxaborolan-2-yl) benzoyl] Amino} piperidine-1-carboxylate

tert-butyl (3R) -3-{[4-bromo-3- (3-methoxypropoxy) benzoyl] (isopropyl) amino} piperidine-1-carboxylate (2.78 g, 5.41 mmol) in dioxane (40 ml) Bis (pinacolato) diboron (1.76 g, 6.93 mmol), potassium acetate (2.82 g, 28.7 mmol), [1,1'-bis (diphenylphosphino) ferrocene] palladium dichloride dichloromethane complex (1: 1) (0.71 g, 0.87 mmol) and DMSO (1 ml) were added, and the mixture was stirred at 100 ° C. for 9 hours under a nitrogen stream. After cooling to room temperature, water and sodium acetate were added and stirred, and insolubles were removed by Celite filtration. The filtrate was separated, and the organic layer was washed with water and saturated brine, dried and concentrated, and the resulting crude product was purified by silica gel column chromatography to obtain the title compound (2.08 g).

MS (ESI +) 561 (M ⁺ +1, 59%).

Reference Example 146
tert-butyl (3R) -3- (isopropyl {[2- (3-methoxypropoxy) -3 '-(3-oxomorpholin-4-yl) biphenyl-4-yl] carbonyl} amino) piperidine-1- Carboxylate

tert-butyl (3R) -3- {isopropyl [3- (3-methoxypropoxy) -4- (4,4,5,5, -tetramethyl-1,3,2-dioxaborolan-2-yl) benzoyl] Amino} piperidine-1-carboxylate (146.6 mg) in a mixed solvent (3 ml) solution of DME-H ₂ O (2/1) 3- (3-oxomorpholin-4-yl) phenyltrifluoromethanesulfonate (123.4 mg), sodium hydrogen carbonate (77.4 mg), tetrakistriphenylphosphine palladium (11.2 mg) were added, and the mixture was heated to reflux for 9 hours under a nitrogen stream. After cooling to room temperature, water and sodium acetate were added for liquid separation, and the organic layer was washed with water and saturated brine, dried and concentrated to give a crude product. This was purified by silica gel column chromatography to give the title compound (61.7 mg).

MS (ESI +) 610 (M ⁺ +1, 100%).

Reference Example 147
tert-butyl (3R) -3- (isopropyl {[2- (3-methoxypropoxy) -3 '-(2-oxopiperidin-1-yl) biphenyl-4-yl] carbonyl} amino) piperidine-1-carboxy rate

The title compound (131.9 mg) was synthesized from the corresponding compound with reference to Reference Example 146.

MS (ESI +) 608 (M ⁺ +1, 100%).

Reference Example 148
tert-butyl (3R) -3- (isopropyl {[2- (3-methoxypropoxy) -3 '-(2-oxo-1,3-oxazolidine-3-yl) biphenyl-4-yl] carbonyl} amino) Piperidine-1-carboxylate

The title compound (149.7 mg) was synthesized from the corresponding compound with reference to Reference Example 146.

MS (ESI +) 596 (M ⁺ +1, 100%).

Reference Example 149
tert-butyl (3R) -3- (isopropyl {[2- (3-methoxypropoxy) -3 '-(morpholin-4-ylsulfonyl) biphenyl-4-yl] carbonyl} amino) piperidine-1-carboxylate

The title compound (80.5 mg) was synthesized from the corresponding compound with reference to Reference Example 146.

MS (ESI +) 660 (M ⁺ +1, 100%).

Reference Example 150
2- (2-Fluoro-5-nitrophenyl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Add 3-bromo-4-fluoronitrobenzene (3.31 g), bis (pinacolato) diboron (4.21 g), potassium acetate (2.98 g) to dioxane (45 ml), DMSO (1 ml), and finally add [1,1 '-Bis (diphenylphosphino) ferrocene] palladium dichloride dichloromethane complex (1: 1) (0.92 g) was added and stirred at 90-95 ° C. for 13 hours under a nitrogen stream. After cooling to room temperature, dioxane was distilled off under reduced pressure, and 2N aqueous sodium hydroxide solution (50 ml) was added to the residue. After stirring for 10 minutes, the mixture was poured into ethyl acetate and separated. The aqueous layer was washed with ethyl acetate, adjusted to pH 5 with 20% aqueous hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried and filtered to give the title compound (2.85 g).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.64 (dd, J = 5.0, 3.0 Hz, 1H), 8.32 (ddd, J = 9.0, 5.0, 3.0 Hz, 1H), 7.17 (dd, J = 9.0, 9.0 Hz, 1H), 1.38 (s, 12H).

Reference Example 151
tert-butyl (3R) -3-[{[2'-fluoro-2- (3-methoxypropoxy) -5'-nitrobiphenyl-4-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate

tert-Butyl (3R) -3-{[4-bromo-3- (3-methoxypropoxy) benzoyl] (isopropyl) amino} piperidine-1-carboxylate (4.91 g, 9.56 mmol) in DME-H ₂ O ( 2/1) Add 2- (2-fluoro-5-nitrophenyl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.85 g, 10.7 mmol), sodium bicarbonate ( 2.16 g, 25.7 mmol) and tetrakistriphenylphosphine palladium (0.62 g) were added, and the mixture was heated to reflux for 3 hours under a nitrogen stream. After cooling overnight, tetrakistriphenylphosphine palladium (0.41 g) was added, and the mixture was heated to reflux for 9 hours under a nitrogen stream. The reaction mixture was cooled to room temperature, poured into water and ethyl acetate, and separated. The organic layer was washed with water and saturated brine, dried and concentrated to give a crude product. The crude product was purified by silica gel chromatography to obtain the title compound (1.68 g).

MS (ESI +) 574 (M ⁺ +1, 100%).

Reference Example 152
tert-Butyl (3R) -3-[{[5'-amino-2'-fluoro-2- (3-methoxypropoxy) biphenyl-4-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate

tert-butyl (3R) -3-[{[2'-fluoro-2- (3-methoxypropoxy) -5'-nitrobiphenyl-4-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate ( To a methanol solution (30 ml) of 1.43 g) were added ammonium formate (3.60 g) and 10% palladium carbon (0.95 g), and the mixture was stirred for 24 hours. After filtration through celite, the filtrate was concentrated, and water and ethyl acetate were added to the residue for liquid separation. The organic layer was washed with water and saturated brine, dried and concentrated to give a crude product, which was purified by silica gel chromatography to give the title compound (1.06 g).

MS (ESI +) 544 (M ⁺ +1, 100%).

Reference Example 153
tert-butyl (3R) -3-[({2'-fluoro-2- (3-methoxypropoxy) -5 '-[(methylsulfonyl) amino] biphenyl-4-yl} carbonyl) (isopropyl) amino] piperidine -1-carboxylate

tert-butyl (3R) -3-[{[5'-amino-2'-fluoro-2- (3-methoxypropoxy) biphenyl-4-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate ( To a solution of 0.36 g) in chloroform (7 ml), pyridine (0.26 g) was added and then ice-cooled, and methanesulfonic acid chloride (0.098 g) was slowly added dropwise. After stirring for 2 hours under ice-cooling, 1N-hydrochloric acid solution was added for liquid separation, the organic layer was dried and concentrated, and the resulting crude product was purified by silica gel chromatography to give the title compound (0.44 g). It was.

MS (ESI +) 622 (M ⁺ +1, 100%).

Reference Example 154
tert-Butyl (3R) -3-[({2'-Fluoro-2- (3-methoxypropoxy) -5 '-[methyl (methylsulfonyl) amino] biphenyl-4-yl} carbonyl) (isopropyl) amino] Piperidine-1-carboxylate

tert-butyl (3R) -3-[({2'-fluoro-2- (3-methoxypropoxy) -5 '-[(methylsulfonyl) amino] biphenyl-4-yl} carbonyl) (isopropyl) amino] piperidine Methyl iodide (78.1 mg) was added to a DMF solution of -1-carboxylate (125.7 mg), sodium hydride (60% oil suspension: 17.6 mg) was added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried and concentrated. The residue obtained was purified by silica gel chromatography (ethyl acetate / hexane = 1/1) to give the title compound (119.9 mg).

MS (ESI +) 636 (M ⁺ +1, 100%).

Reference Example 155
tert-Butyl (3R) -3-[{[2'-Fluoro-5 '-[(methoxycarbonyl) (methylsulfonyl) amino] -2- (3-methoxypropoxy) biphenyl-4-yl] carbonyl} (isopropyl Amino] piperidine-1-carboxylate

tert-butyl (3R) -3-[({2'-fluoro-2- (3-methoxypropoxy) -5 '-[(methylsulfonyl) amino] biphenyl-4-yl} carbonyl) (isopropyl) amino] piperidine Triethylamine (0.2 ml) was added to a chloroform solution of -1-carboxylate (147.0 mg), and methyl chloroformate (50.4 mg) was added dropwise under ice cooling. After stirring overnight at room temperature, the mixture was ice-cooled again, methyl chloroformate (60.5 mg) was added dropwise, and the mixture was stirred at room temperature for 8 hours. The reaction mixture was washed with 1N aqueous hydrochloric acid, and the organic layer was washed with water and saturated brine, dried and concentrated. The resulting crude product was purified by silica gel chromatography (ethyl acetate / hexane = 2/1, Rf = 0.45) gave the title compound (145.0 mg).

MS (ESI +) 680 (M ⁺ +1, 100%).

Reference Example 156
tert-butyl (3R) -3-[{[2'-fluoro-5 '-({[N-hydroxyethaneimidoyl] amino} carbonyl) -2- (3-methoxypropoxy) biphenyl-4-yl] carbonyl } (Isopropyl) amino] piperidine-1-carboxylate

4 '{[[(3R) -1- (tert-Bugoxycarbonyl) piperidin-3-yl] (isopropyl) amino] carbonyl} -6-fluoro-2'-(3-methoxypropoxy) biphenyl-3- To a DMF solution of carboxylic acid (0.30 g), HBTU (0.88 g), diidpropylethylamine (0.43 ml) and N-hydroxyacetamide (0.16 g) were added and stirred at room temperature for 22 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried and concentrated to give a crude product containing the title compound.

MS (ESI +) 629 (M ⁺ +1, 100%).

Reference Example 157
tert-butyl (3R) -3-[{[2'-fluoro-2- (3-methoxypropoxy) -5 '-(3-methyl-1,2,4-oxadiazol-5-yl) biphenyl- 4-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate

tert-butyl (3R) -3-[{[2'-fluoro-5 '-({[N-hydroxyethaneimidoyl] amino} carbonyl) -2- (3-methoxypropoxy) biphenyl-4-yl] carbonyl } (Isopropyl) amino] piperidine-1-carboxylate in DMF was added cesium carbonate (984.5 mg) and stirred at 100 ° C. for 3 hours. After cooling to room temperature, it was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried and concentrated to give a crude product which was purified by silica gel chromatography to obtain the title compound (295.5 mg).

MS (ESI +) 611 (M ⁺ +1, 100%).

Reference Example 158
1- (3-Bromo-4-fluorophenyl) piperidin-2-one

The title compound (1.90 g) was synthesized from the corresponding compound with reference to Reference Example 142.

¹ MS (ESI +) 274 (M ⁺ +2, 100%), 272 (M ⁺ , 100%).

Reference Example 159
1- (3-Bromo-4-fluorophenyl) pyrrolidin-2-one

The title compound (1.43 g) was synthesized from the corresponding compound with reference to Reference Example 142.

¹ MS (ESI +) 260 (M ⁺ +2, 100%), 258 (M ⁺ , 98%).

Reference Example 160
tert-butyl (3R) -3-[{[2'-fluoro-2- (3-methoxypropoxy) -5 '-(2-oxopiperidin-1-yl) biphenyl-4-yl] carbonyl} (isopropyl) Amino] piperidine-1-carboxylate

The title compound (131.9 mg) was synthesized from the corresponding compound with reference to Reference Example 146.

MS (ESI +) 626 (M ⁺ +1, 100%).

Reference Example 161
tert-Butyl (3R) -3-[{[2'-Fluoro-2- (3-methoxypropoxy) -5 '-(2-oxopyrrolidin-1-yl) biphenyl-4-yl] carbonyl} (isopropyl) Amino] piperidine-1-carboxylate

The title compound (55.5 mg) was synthesized from the corresponding compound with reference to Reference Example 146.

MS (ESI +) 612 (M ⁺ +1, 100%).

Reference Example 162
tert-Butyl (3R) -3-[{[2'-Fluoro-5-isopropenyl-2- (3-methoxypropoxy) biphenyl-4-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate

tert-Butyl (3R) -3-[{[5-Bromo-2'-fluoro-2- (3-methoxypropoxy) biphenyl-4-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate (124.3 mg) in DME-H ₂ O (1/1) solution Isopropenylboronic acid pinacol ester (73.9 mg), potassium carbonate (64.8 mg), [1,1'-bis (diphenylphosphino) ferrocene] palladium dichloride dichloromethane Complex (1: 1) (74.5 mg) was added, and the mixture was stirred at 80 ° C. for 13 hours under a nitrogen stream. After cooling to room temperature, water and ethyl acetate were added, and the resulting insoluble material was removed by celite filtration. After the filtrate was separated, the organic layer was washed with water and saturated brine, dried and concentrated, and the resulting crude product was purified by silica gel column chromatography (ethyl acetate / hexane = 1/2, Rf = 0.30). The title compound (97.0 mg) was obtained.

MS (ESI +) 569 (M ⁺ +1, 100%).

Reference Example 163
tert-butyl (3R) -3-[{[2'-fluoro-5-isopropyl-2- (3-methoxypropoxy) biphenyl-4-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate

tert-butyl (3R) -3-[{[2'-fluoro-5-isopropenyl-2- (3-methoxypropoxy) biphenyl-4-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate ( 97.0 mg) was dissolved in methanol (5 ml), 10% palladium carbon (126.9 mg) was added, and the mixture was vigorously stirred for 9 hours in a hydrogen atmosphere. After filtration through celite, the filtrate was concentrated to give the title compound.

MS (ESI +) 571 (M ⁺ +1, 100%).

Reference Example 164
tert-Butyl (3R) -3-[{[2'-Fluoro-5-isobutyl-2- (3-methoxypropoxy) biphenyl-4-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate

The title compound (32.3 mg) was synthesized from the corresponding compound with reference to Reference Example 162.

MS (ESI +) 585 (M ⁺ +1, 84%).

Reference Example 165
tert-butyl (3R) -3-[{[5-ethyl-2'-fluoro-2- (3-methoxypropoxy) biphenyl-4-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate

The title compound (37.9 mg) was synthesized from the corresponding compound with reference to Reference Example 162.

MS (ESI +) 557 (M ⁺ +1, 100%).

Reference Example 166
tert-butyl (3R) -3-{[2-chloro-5- (3-methoxypropoxy) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Benzoyl] (isopropyl) amino} piperidine-1-carboxylate

The title compound (469.8 mg) was synthesized from the corresponding compound with reference to Reference Example 145.

MS (ESI +) 595 (M ⁺ +1, 52%).

Reference Example 167
tert-Butyl (3R) -3-[{[5-Chloro-2'-fluoro-2- (3-methoxypropoxy) -5 '-(2-oxopyrrolidin-1-yl) biphenyl-4-yl] carbonyl } (Isopropyl) amino] piperidine-1-carboxylate

tert-butyl (3R) -3-{[2-chloro-5- (3-methoxypropoxy) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) 1- (3-Bromo-4-fluorophenyl) to a solution of benzoyl] (isopropyl) amino} piperidine-1-carboxylate (469.8 mg, 0.79 mmol) in DME-H ₂ O (3/1) mixed solvent (5 ml) ) Pyrrolidin-2-one (415.1 mg, 1.61 mmol), cesium fluoride (395.5 mg, 2.60 mmol), [1,1'-bis (diphenylphosphino) ferrocene] palladium dichloride dichloromethane complex (1: 1) (141.5 mg, 0.17 mmol) was added, and the mixture was stirred at 100 ° C. for 10 hours under a nitrogen stream. After cooling to room temperature, water and ethyl acetate were added, and the resulting insoluble material was removed by celite filtration. The filtrate was separated, and the organic layer was washed with water and saturated brine, dried and concentrated to give a crude product which was purified by silica gel chromatography to give the title compound (230.2 mg).

MS (ESI +) 646 (M ⁺ +1, 70%).

Reference Example 168
tert-Butyl (3R) -3- {Iropropyl [3- (3-methoxypropoxy) -4- (3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) benzoyl ] Amino} piperidine-1-carboxylate

The title compound (81.8 mg) was synthesized from the corresponding compound with reference to Reference Example 146.

MS (ESI +) 582 (M ⁺ +1, 100%).

Reference Example 169
tert-butyl (3R) -3-[[2-chloro-5- (3-methoxypropoxy) -4- (3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazole-5- Yl) benzoyl] (isopropyl) amino] piperidine-1-carboxylate

The title compound (218.9 mg) was synthesized from the corresponding compound with reference to Reference Example 146.

MS (ESI +) 616 (M ⁺ , 100%)

Reference Example 170
tert-butyl (3R) -3-[{[5-bromo-2'-fluoro-2- (3-methoxypropoxy) -5 '-(morpholin-4-ylcarbonyl) biphenyl-4-yl] carbonyl} (Isopropyl) amino] piperidine-1-carboxylate

tert-butyl (3R) -3-[{[5-bromo-5 '-(ethoxycarbonyl) -2'-fluoro-2- (3-methoxypropoxy) biphenyl-4-yl] carbonyl} (isopropyl) amino] Piperidine-1-carboxylate (0.58 g) was dissolved in methanol (20 ml), 4N-sodium hydroxide (10 ml) was added, and the mixture was stirred at 50 ° C. for 1 hr. After cooling to room temperature, methanol was distilled off under reduced pressure. The residue was diluted with water, adjusted to pH 4 with 1N aqueous hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried and concentrated to give 5'-bromo-4 '-{[[(3R) -1- (tert-butoxycarbonyl) piperidin-3-yl] (isopropyl) amino] Carbonyl} -6-fluoro-2 ′-(3-methoxypropoxy) biphenyl-3-carboxylic acid (533.6 mg) was obtained. This was dissolved in DMF, ice-cooled, morpholine (235.5 mg), triethylamine (0.35 ml), WCS · HCl (501.7 mg), HOBt (417.8 mg) were added, and the mixture was stirred at 0 ° C for 30 minutes, and then warmed to room temperature. And stirred for 23 hours. 10% aqueous hydrochloric acid was added, and the mixture was stirred for 10 minutes and separated. The organic layer was washed with water and saturated brine, dried and concentrated. The obtained crude product was purified by silica gel chromatography to obtain the title compound (672.6 mg).

MS (ESI +) 722 (M ⁺ +2, 57%), 720 (M ⁺ , 58%).

Reference Example 171
Benzyl 4-bromo-3- (3-methoxypropoxy) benzoate

The compound of Reference Example 2 (7.72 g) was dissolved in N, N′-dimethylformamide (50 ml), potassium carbonate (4.43 g) and benzyl bromide (3.5 ml) were added, and the mixture was stirred at 80 ° C. for 3 hours. The reaction solution was cooled to room temperature, water was added to the reaction mixture, and the mixture was extracted twice with diethyl ether. The organic layer was washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (10.2 g) as a pale yellow oily compound.

MS (ESI +) 379 (M ⁺ +1, 100%).

Reference Example 172
4'-Benzyl 3-ethyl-6-fluoro-2 '-(3-methoxypropoxy) biphenyl-3,4'-dicarboxylate

  The compound of Reference Example 171 (10.2 g) was dissolved in 1,2-dimethoxyethane (40 ml) and water (20 ml) to give 5-ethoxycarbonyl-2-fluorophenylboronic acid (6.8 g), sodium carbonate (5.7 g). , Tetrakistriphenylphosphine palladium (3.0 g) was added, and the mixture was stirred with heating under reflux for 6 hours. The reaction solution was cooled to room temperature, water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 5/1) to give the title compound (12.0 g) as a pale-yellow oily compound.

MS (ESI +) 467 (M ⁺ +1, 100%).

Reference Example 173
4'-benzyl 3-ethyl-6-fluoro-5'-iodo-2 '-(3-methoxypropoxy) biphenyl-3,4'-dicarboxylate

The compound of Reference Example 172 (2.0 g) was dissolved in chloroform (30 ml), and silver trifluorosulfonate (1.2 g) and iodine (1.2 mg) were added under ice cooling. Thereafter, the mixture was stirred at room temperature for 12 hours. An aqueous sodium thiosulfate solution was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with aqueous sodium thiosulfate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 5/1) to give the title compound (2.0 g) as a pale-yellow oily compound.

MS (ESI +) 593 (M ⁺ +1, 36%).

Reference Example 174
4'-Benzyl 3-ethyl-6-fluoro-2 '-(3-methoxypropoxy) -5'-[(trimethylsilyl) ethynyl] biphenyl-3,4'-dicarboxylate

  The compound of Reference Example 173 (2.0 g) was dissolved in triethylamine (20 ml), and dichlorobistriphenylphosphine palladium (118 mg), copper iodide (32 mg) and ethynyltrimethylsilane (1.7 g) were added under ice cooling. . Thereafter, the mixture was stirred at room temperature for 6 hours. The reaction solvent was evaporated under reduced pressure, ethyl acetate was added, and the mixture was filtered through celite. The organic layer was washed with aqueous citric acid solution and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 7/1) to give the title compound (1.5 g) as a pale-yellow oily compound.

MS (ESI +) 562 (M + 1, 100%).

Reference Example 175
4'-benzyl 3-ethyl 5'-ethynyl-6-fluoro-2 '-(3-methoxypropoxy) biphenyl-3,4'-dicarboxylate

The compound of Reference Example 174 (1.5 g) was dissolved in tetrahydrofuran (20 ml), and 1M tetrabutylammonium fluoride-tetrahydrofuran solution (4.0 ml) was added under ice cooling. Thereafter, the mixture was stirred at room temperature for 3 hours. The reaction solvent was distilled off under reduced pressure and ethyl acetate was added. The organic layer was washed with water three times, dried over magnesium 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 (850 mg) as a pale-yellow oily compound.

MS (ESI +) 491 (M + 1, 100%).

Reference Example 176
5 '-(Ethoxycarbonyl) -5-ethyl-2'-fluoro-2- (3-methoxypropoxy) biphenyl-4-carboxylic acid

  The compound of Reference Example 175 (850 mg) was dissolved in methanol (20 ml), and 20% palladium hydroxide (300 mg) was added. Thereafter, the mixture was stirred at room temperature for 8 hours under a hydrogen atmosphere. The reaction mixture was filtered through celite and concentrated under reduced pressure to give the title compound (560 mg) as a pale yellow oily compound.

MS (ESI +) 405 (M + 1, 48%).

Reference Example 177
Ethyl 4 '-(chlorocarbonyl) -5'-ethyl-6-fluoro-2'-(3-methoxypropoxy) biphenyl-3-carboxylate

  The compound of Reference Example 176 (560 mg) was dissolved in dichloromethane (10 ml), and oxalyl chloride (352 mg) and N, N′-dimethylformamide (5 μl) were added under ice cooling. Thereafter, the mixture was stirred at room temperature for 1 hour. After the solvent was distilled off, toluene was added and the mixture was concentrated under reduced pressure twice to give the title compound as a pale yellow oil.

Reference Example 178
tert-butyl (3R) -3-[{[5 '-(ethoxycarbonyl) -5-ethyl-2'-fluoro-2- (3-methoxypropoxy) biphenyl-4-yl] carbonyl (isopropyl) amino} piperidine -1-carboxylate

The compound of Reference Example 177 (570 mg) was dissolved in dichloromethane (10 ml), and ice-cooled, tert-butyl (3R) -3- (isopropylamino) piperidine-1-carboxylate (334 mg), triethylamine (280 mg) Was added. Thereafter, the mixture was stirred at room temperature for 12 hours. Water was added to the reaction mixture, and the mixture was extracted twice with chloroform. The organic layer was washed with aqueous sodium hydrogen carbonate solution, aqueous citric acid solution and saturated brine, dried over magnesium 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 (433 mg) as a pale-yellow oily compound.
MS (ESI +) 629 (M + 1, 62%).

Reference Example 179
4 '-{[[((3R) -1- (tert-butoxycarbonyl) piperidin-3-yl] (isopropyl) amino] carbonyl} -5'-ethyl-6-fluoro-2'-(3-methoxypropoxy) Biphenyl-3-carboxylic acid

The compound of Reference Example 178 (433 mg) was dissolved in tetrahydrofuran (3 ml), methanol (3 ml) and water (3 ml), sodium hydroxide (41 mg) was added, and the mixture was stirred at 60 ° C. for 2 hr. The reaction solution was cooled to room temperature, an aqueous potassium hydrogen sulfate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound (420 mg) as a white amorphous product.
MS (ESI +) 601 (M + 1, 49%).

Reference Example 180
tert-butyl (3R) -3-[{[5 '-[dimethylamino] carbonyl-5-ethyl-2'-fluoro-2- (3-methoxypropoxy) biphenyl-4-yl] carbonyl} (isopropyl) amino ] Piperidine-1-carboxylate

The title compound (110 mg) was synthesized in the same manner as in Reference Example 15.
MS (ESI +) 628 (M + 1, 33%).

Reference Example 181
tert-butyl (3R) -3-[{[5-ethyl-5 '-{[ethyl (methyl) aminocarbonyl-2'-fluoro-2- (3-methoxypropoxy) biphenyl-4-yl] carbonyl} ( Isopropyl) amino] piperidine-1-carboxylate

The compound of Reference Example 15 (80 mg) was dissolved in N, N′-dimethylformamide (5 ml), and N-ethylmethylamine (24 mg), triethylamine (40 mg), N- (3-dimethylaminopropyl)- N′-ethylcarbodiimide hydrochloride (77 mg) and 1-hydroxybenzotriazole (61 mg) were added. Thereafter, the mixture was stirred at room temperature for 12 hours. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution, aqueous citric acid solution and water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1/5) to give the title compound (60 mg) as a colorless oily compound.
MS (ESI +) 642 (M + 1, 50%).

Reference Example 182
tert-butyl (3R) -3-[{[5-ethyl-2'-fluoro-5 '-[(isopropylamino) carbonyl] -2- (3-methoxypropoxy) biphenyl-4-yl] carbonyl} (isopropyl Amino] piperidine-1-carboxylate

  The title compound (130 mg) was synthesized in the same manner as in Reference Example 15.

MS (ESI +) 642 (M + 1, 69%).

Reference Example 183
tert-butyl (3R) -3-[{[5-ethyl-2'-fluoro-5 '-{[isopropyl (methyl) amino] carbonyl] -2- (3-methoxypropoxy) biphenyl-4-yl] carbonyl } (Isopropyl) amino] piperidine-1-carboxylate

  The compound of Reference Example 182 (70 mg) was dissolved in N, N′-dimethylformamide (3 ml), sodium hydride (5 mg) and methyl iodide (19 mg) were added under ice cooling, and then at room temperature. Stir for 6 hours. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with water three times, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1/5) to give the title compound (50 mg) as a colorless oil.

MS (ESI +) 656 (M + 1, 81%).

Reference Example 184
tert-butyl (3R) -3-[{[5'-ethyl-2'-fluoro-2- (3-methoxypropoxy) -5 '-(morpholin-4-ylcarbonyl) biphenyl-4-yl] carbonyl } (Isopropyl) amino] piperidine-1-carboxylate

The title compound (69 mg) was synthesized in the same manner as in Reference Example 15.
MS (ESI +) 670 (M ⁺ +1, 60%).

Reference Example 185
tert-butyl (3R) -3-[{[5 '-(2,6-dimethylmorpholin-4-yl) carbonyl] -5-ethyl-2'-fluoro-2- (3-methoxypropoxy) biphenyl- 4-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate

The title compound (70 mg) was synthesized in the same manner as in Reference Example 15.
MS (ESI +) 698 (M ⁺ +1, 75%).

Reference Example 186
tert-butyl (3R) -3-[{[5 '-{[4- (acetyloxy) piperidin-1-yl] carbonyl] -5-ethyl-2'-fluoro-2- (3-methoxypropoxy) biphenyl- 4-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate

  The title compound (170 mg) was synthesized in the same manner as in Reference Example 15.

MS (ESI +) 726 (M ⁺ +1, 76%).

Reference Example 187
tert-butyl (3R) -3-[{[5-ethyl-2'-fluoro-5 '-[(4-hydroxypiperidin-1-yl) carbonyl] -2- (3-methoxypropoxy) biphenyl-4- Yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate

  The compound of Reference Example 186 (170 mg) was dissolved in methanol (5 ml) and water (0.5 ml), potassium carbonate (69 mg) was added, and the mixture was stirred at room temperature for 4 hours. The reaction solvent was distilled off under reduced pressure, water was added, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: ethyl acetate) to give the title compound (130 mg) as a white amorphous product.

MS (ESI +) 684 (M ⁺ +1, 82%).

Reference Example 188
tert-butyl (3R) -3-[{[5-ethyl-2'-fluoro-5 '-[(4- (1-hydroxy-1-methylethyl) piperidin-1-yl) carbonyl] -2- ( 3-methoxypropoxy) biphenyl-4-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate

  The title compound (129 mg) was synthesized in the same manner as in Reference Example 15.

MS (ESI +) 726 (M ⁺ +1, 100%).

Reference Example 189
tert-butyl (3R) -3-[{[5-ethyl-2'-fluoro-2- (3-methoxypropoxy) -5 '-(piperidin-1-ylcarbonyl) biphenyl-4-yl] carbonyl} ( Isopropyl) amino] piperidine-1-carboxylate

The title compound (110 mg) was synthesized in the same manner as in Reference Example 15.
MS (ESI +) 668 (M ⁺ +1, 66%).

Reference Example 190
tert-butyl (3R) -3-[{[5-ethyl-2'-fluoro-2- (3-methoxypropoxy) -5 '-[(tetrahydro-2H-pyran-4-ylamino) carbonyl] biphenyl-4 -Yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate

The title compound (160 mg) was synthesized in the same manner as in Reference Example 15.
MS (ESI +) 684 (M ⁺ +1, 75%).

Reference Example 191
tert-butyl (3R) -3-[{[5-ethyl-2'-fluoro-2- (3-methoxypropoxy) -5 '-{[methyl (tetrahydro-2H-pyran-4-yl) amino] carbonyl } Biphenyl-4-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate

The title compound (160 mg) was synthesized in the same manner as in Reference Example 97.
MS (ESI +) 698 (M ⁺ +1, 69%).

Reference Example 192
tert-butyl (3R) -3-[{[5-ethyl-2'-fluoro-2- (3-methoxypropoxy) -5 '-(pyrrolidin-1-ylcarbonyl) biphenyl-4-yl] carbonyl} ( Isopropyl) amino] piperidine-1-carboxylate

  The title compound (70 mg) was synthesized in the same manner as in Reference Example 15.

MS (ESI +) 654 (M ⁺ +1, 80%).

Reference Example 193
Methyl-3-bromo-4-hydroxybenzoate

  3-Bromo-4-hydroxybenzoic acid (2.5 g) was dissolved in methanol (20 ml), and thionyl chloride (2.1 g) was added dropwise over 5 minutes under ice cooling. Thereafter, the mixture was stirred at 80 ° C. for 4 hours. The reaction solution was cooled to room temperature, and the reaction solvent was removed under reduced pressure. Water was added to the residue, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and aqueous citric acid solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (2.1 g) as a white solid.

MS (ESI +) 230, 232 (M ⁺ +1, 36%).

Reference Example 194
Methyl 4- (benzyloxy) -3-bromobenzoate

  The compound of Reference Example 193 (2.1 g) was dissolved in N, N-dimethylformamide (25 ml), benzylboromide (1.7 g) and potassium carbonate (1.9 g) were added, and the mixture was stirred at 80 ° C. for 6 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted twice with ethyl acetate. The organic layer was washed 3 times with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 8/1) to give the title compound (2.3 g) as a white solid.

MS (ESI +) 321, 323 (M ⁺ +1, 100%).

Reference Example 195
Methyl 4- (benzyloxy) -3-[(1E) -4-hydroxybuten-1-yl] benzoate

The compound of Reference Example 194 (2.3 g) was dissolved in acetonitrile (25 ml), and 3-buten-1-ol (516 mg), tris (2-methylphenyl) phosphine (44 mg), palladium acetate (16 mg), Triethylamine (725 mg) was added, and the mixture was stirred for 14 hours with heating under reflux. The reaction solution was cooled to room temperature, and the reaction solvent was distilled off under reduced pressure. Water was added to the residue and the mixture was extracted twice with ethyl acetate. The organic layer was dried over magnesium 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 (1.4 g) as a pale-yellow oily compound.
MS (ESI +) 313 (M ⁺ +1, 100%).

Reference Example 196
Methyl 4- (benzyloxy) -3-[(1E) -4-methoxybuten-1-yl] benzoate

The compound of Reference Example 195 (1.0 g) was dissolved in dichloromethane (15 ml), 2,6-di-tert-butyl-4-methylpyridine (1.3 g), trifluoromethanesulfonic acid methyl ester (1.05 g) under ice cooling. ) Was added. Thereafter, the mixture was stirred at room temperature for 12 hours. An aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted twice with chloroform. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 8/1) to give the title compound (640 mg).
MS (ESI +) 327 (M ⁺ +1, 22%).

Reference Example 197
4- (Benzyloxy) -3-[(1E) -4-methoxybuten-1-yl] benzoic acid

The compound of Reference Example 196 (640 mg) was dissolved in tetrahydrofuran (5 ml), methanol (5 ml) and water (5 ml), sodium hydroxide (118 mg) was added, and the mixture was stirred at 60 ° C. for 2 hr. The reaction solution was cooled to room temperature, an aqueous potassium hydrogen sulfate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound (600 mg) as a white solid.
MS (ESI +) 313 (M ⁺ +1, 24%).

Reference Example 198
4- (Benzyloxy) -3-[(1E) -4-methoxybuten-1-yl] benzoyl chloride

  The compound of Reference Example 197 (600 mg) was dissolved in dichloromethane (10 ml), and oxalyl chloride (488 mg) and N, N′-dimethylformamide (5 μl) were added under ice cooling. Thereafter, the mixture was stirred at room temperature for 1 hour. After the solvent was distilled off, toluene was added and the mixture was concentrated under reduced pressure twice to give the title compound as a pale yellow oil.

Reference Example 199
tert-butyl 3-[{4- (benzyloxy) -3-[(1E) -4-methoxybuten-1-yl] benzoyl} (isopropyl) amino] piperidine-1-carboxylate

  The compound of Reference Example 198 (610 mg) was dissolved in dichloromethane (10 ml), and ice-cooled, tert-butyl (3R) -3- (isopropylamino) piperidine-1-carboxylate (465 mg), triethylamine (389 mg) Was added. Thereafter, the mixture was stirred at room temperature for 6 hours. Water was added to the reaction mixture, and the mixture was extracted twice with chloroform. The organic layer was washed with aqueous sodium hydrogen carbonate solution, aqueous citric acid solution and saturated brine, dried over magnesium 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 (750 mg) as a pale-yellow oily compound.

MS (ESI +) 537 (M + 1, 52%).

Reference Example 200
tert-Butyl (3R)-[[4-hydroxy-3- (4-methoxybutyl) benzoyl] (isopropyl) amino] piperidine-1-carboxylate

  The compound of Reference Example 199 (750 mg) was dissolved in methanol (15 ml), and 10% palladium on carbon (300 mg) was added. Thereafter, the mixture was stirred at room temperature for 6 hours under a hydrogen atmosphere. The reaction mixture was filtered through celite, and concentrated under reduced pressure to give the title compound (610 mg) as a pale yellow oily compound.

MS (ESI +) 449 (M + 1, 55%).

Reference Example 201
tert-Butyl (3R) -3- [isopropyl (3- (4-methoxybutyl) -4-{[trifluoromethyl] sulfonyl} oxy) benzoyl] amino] piperidine-1-carboxylate

  The compound of Reference Example 200 (610 mg) was dissolved in dichloromethane (10 ml), and triethylamine (212 mg) and trifluorosulfonic anhydride (473 mg) were added under ice cooling. Thereafter, the mixture was stirred at room temperature for 6 hours. An aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted twice with chloroform. The organic layer was dried over magnesium 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 (600 mg) as a pale-yellow oily compound.

MS (ESI +) 581 (M + 1, 21%).

Reference Example 202
tert-butyl (3R) -3-[{[5 '-(ethoxycarbonyl) -2'-fluoro-2- (4-methoxybutyl) biphenyl-4-yl] carbonyl} (isopropyl) amino] piperidine-1- Carboxylate

  The compound of Reference Example 201 (600 mg) was dissolved in 1,2-dimethoxyethane (6 ml) and water (3 ml), and 5-ethoxycarbonyl-2-fluorophenylboronic acid (329 mg), sodium carbonate (219 mg) ), Tetrakistriphenylphosphine palladium (239 mg) was added, and the mixture was stirred for 6 hours with heating under reflux. The reaction solution was cooled to room temperature, ethyl acetate was added to the reaction mixture, and the mixture was filtered through celite. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 5/1) to give the title compound (480 mg) as a colorless oily compound.

MS (ESI +) 599 (M + 1, 44%).

Reference Example 203
4 '-{[[((3R) -1- (tert-butoxycarbonyl) piperidin-3-yl] (isopropyl) amino] carbonyl} -6-fluoro-2'-(4-methoxybutyl) biphenyl-3-carboxy Rick Acid

  The compound of Reference Example 202 (480 mg) was dissolved in tetrahydrofuran (3 ml), methanol (3 ml) and water (3 ml), sodium hydroxide (48 mg) was added, and the mixture was stirred at 60 ° C. for 2 hr. The reaction solution was cooled to room temperature, an aqueous potassium hydrogen sulfate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound (440 mg) as a white amorphous product.

MS (ESI +) 571 (M + 1, 44%).

Reference Example 204
tert-butyl (3R) -3-[{[5 '-[dimethylamino] carbonyl] -2'-fluoro-2- (4-methoxybutyl) biphenyl-4-yl} carbonyl] (isopropyl) amino] piperidine- 1-carboxylate

  The compound of Reference Example 203 (120 mg) was dissolved in N, N′-dimethylformamide (5 ml), dimethylamine hydrochloride (51 mg), triethylamine (128 mg), N- (3-dimethylaminopropyl) -N '-Ethylcarbodiimide hydrochloride (121 mg) and 1-hydroxybenzotriazole (97 mg) were added. Thereafter, the mixture was stirred at room temperature for 8 hours. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution, aqueous citric acid solution and water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1/3) to give the title compound (90 mg) as a colorless oily compound.

MS (ESI +) 598 (M + 1, 35%).

Reference Example 205
tert-butyl (3R) -3-[{[2'-fluoro-5 '-[cyclopropylamino] carbonyl] -2- (4-methoxybutyl) biphenyl-4-yl} carbonyl] (isopropyl) amino] piperidine -1-carboxylate

The title compound (296 mg) was synthesized in the same manner as in Reference Example 204.
MS (ESI +) 610 (M + 1, 70%).

Reference Example 206
tert-butyl (3R) -3-[{[2'-fluoro-5 '-[cyclopropyl (methyl) amino] carbonyl] -2- (4-methoxybutyl) biphenyl-4-yl} carbonyl] (isopropyl) Amino] piperidine-1-carboxylate

The title compound (145 mg) was synthesized in the same manner as in Reference Example 97.
MS (ESI +) 624 (M + 1, 78%).

Reference Example 207
tert-butyl (3R) -3-[{[5 '-{[ethyl (2-methoxyethyl) amino] carbonyl] -2'-fluoro-2- (4-methoxybutyl) biphenyl-4-yl} carbonyl] (Isopropyl) amino] piperidine-1-carboxylate

  The title compound (184 mg) was synthesized in the same manner as in Reference Example 204.

MS (ESI +) 656 (M ⁺ +1, 55%).

Reference Example 208
tert-butyl (3R) -3-[{[2'-fluoro-5 '-{[isopropyl (2-methoxyethyl) amino] carbonyl] -2- (4-methoxybutyl) biphenyl-4-yl} carbonyl] (Isopropyl) amino] piperidine-1-carboxylate

  The title compound (184 mg) was synthesized in the same manner as in Reference Example 204.

MS (ESI +) 670 (M ⁺ +1, 86%).

Reference Example 209
tert-butyl (3R) -3-[{[2'-fluoro-2- (4-methoxybutyl) -5 '-(morpholin-4-ylcarbonyl] biphenyl-4-yl) carbonyl} (isopropyl) amino ] Piperidine-1-carboxylate

  The title compound (119 mg) was synthesized in the same manner as in Reference Example 204.

MS (ESI +) 642 (M + 1, 78%).

Reference Example 210
tert-butyl (3R) -3-[{[5 '-[(2,6-dimethylmorpholin-4-yl) carbonyl] -2'-fluoro-2- (4-methoxybutyl) biphenyl-4-yl ) Carbonyl} (isopropyl) amino] piperidine-1-carboxylate

  The title compound (140 mg) was synthesized in the same manner as in Reference Example 204.

MS (ESI +) 668 (M + 1, 93%).

Reference Example 211
tert-butyl (3R) -3-[{[2'-fluoro-2- (4-methoxybutyl) -5 '-(piperidin-1-ylcarbonyl] biphenyl-4-yl) carbonyl} (isopropyl) amino] Piperidine-1-carboxylate

  The title compound (100 mg) was synthesized in the same manner as in Reference Example 204.

MS (ESI +) 642 (M + 1, 70%).

Reference Example 212
tert-butyl (3R) -3-[{[2'-fluoro-5 '-(4-hydroxy-4-methylpiperidin-1-yl) -2-methoxybutyl) biphenyl-4-yl] carbonyl} (isopropyl ) Amino] piperidine-1-carboxylate

  The title compound (120 mg) was synthesized in the same manner as in Reference Example 204.

MS (ESI +) 668 (M + 1, 97%).

Reference Example 213
tert-Butyl (3R) -3-[{[2'-Fluoro-5 '-{[4- (1-hydroxy-1-methylethyl) piperidin-1-yl) carbonyl] -2- (4-methoxybutyl ) Biphenyl-4-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate

  The title compound (120 mg) was synthesized in the same manner as in Reference Example 204.

MS (ESI +) 696 (M + 1, 100%).

Reference Example 214
tert-butyl (3R) -3-[{[2'-fluoro-2- (4-methoxybutyl) -5 '-[tetrahydro-2H-pyran-4-ylamino] carbonyl] biphenyl-4-yl} carbonyl} (Isopropyl) amino] piperidine-1-carboxylate

  The title compound (119 mg) was synthesized in the same manner as in Reference Example 204.

MS (ESI +) 654 (M + 1, 97%).

Reference Example 215
tert-butyl (3R) -3-[{[2'-fluoro-2- (4-methoxybutyl) -5 '-{[methyl (tetrahydro-2H-pyran-4-ylamino] carbonyl] biphenyl-4-yl } Carbonyl} (isopropyl) amino] piperidine-1-carboxylate

  The title compound (72 mg) was synthesized in the same manner as in Reference Example 97.

MS (ESI +) 668 (M + 1, 100%).

Reference Example 216
tert-butyl (3R) -3-[{[2'-fluoro-2- (4-methoxybutyl) -5 '-(thiomorpholin-4-ylcarbonyl] biphenyl-4-yl) carbonyl} (isopropyl) Amino] piperidine-1-carboxylate

  The title compound (180 mg) was synthesized in the same manner as in Reference Example 204.

MS (ESI +) 656 (M + 1, 63%).

Reference Example 217
tert-butyl (3R) -3-[{[5 '-[(1,1'-dioxathiomorpholin-4-yl) carbonyl] -2'-fluoro-2- (4-methoxybutyl) biphenyl- 4-yl) carbonyl} (isopropyl) amino] piperidine-1-carboxylate

  The compound of Reference Example 216 (110 mg) was dissolved in chloroform (5 ml), and 75% metachloroperbenzoic acid (124 mg) was added under ice cooling. Thereafter, the mixture was stirred at room temperature for 6 hours. To the reaction solution were added an aqueous sodium hydrogen carbonate solution and an aqueous sodium thiosulfate solution, and the mixture was extracted twice with chloroform. The organic layer was washed with an aqueous sodium bicarbonate solution and an aqueous sodium thiosulfate solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1/2) to give the title compound (80 mg) as a white amorphous compound.

MS (ESI +) 688 (M + 1, 62%).

Reference Example 218
tert-butyl (3R) -3-[{[5-cyano-2'-fluoro-2- (3-methoxypropoxy) -5 '-(piperidin-1-ylcarbonyl) biphenyl-4-yl] carbonyl} ( Isopropyl) amino] piperidine-1-carboxylate

The title compound (355 mg) was synthesized from the corresponding compound by a method similar to that in Reference Example 15.

MS (ESI +) 665 (M ⁺ +1, 22%).

Reference Example 219
tert-butyl (3R) -3-[{[5-bromo-5 '-(ethoxycarbonyl) -2'-fluoro-2- (3-methoxypropoxy) biphenyl-4-yl] carbonyl} (isopropyl) amino] Piperidine-1-carboxylate

  The title compound (2.84 g) was synthesized from the corresponding compound by a method similar to that in Reference Example 64.

MS (ESI +) 679 (M + 1, 50%), 681 (M + 1, 50%).

Reference Example 220
tert-butyl (3R) -3-[{[5-chloro-5 '-(ethoxycarbonyl) -2'-fluoro-2- (3-methoxypropoxy) biphenyl-4-yl] carbonyl} (isopropyl) amino] Piperidine-1-carboxylate

  The title compound (1.08 g) was synthesized from the corresponding compound by a method similar to that in Reference Example 66.

MS (ESI +) 635 (M + 1, 100%).

Reference Example 221
4 '-{[[(3R) -1- (tert-butoxycarbonyl) piperidin-3-yl] (isopropyl) amino] carbonyl} -5'-chloro-6-fluoro-2'-(3-methoxypropoxy) Biphenyl-3-carboxylic acid

The title compound (954 mg) was synthesized from the corresponding compound by a method similar to that in Reference Example 14.
MS (ESI +) 607 (M + 1, 100%).

Reference Example 222
tert-butyl (3R) -3-[({5 '-(ethoxycarbonyl) -2'-fluoro-2- (3-methoxypropoxy) -5-[(1E) -prop-1-en-1-yl ] Biphenyl-4-yl} carbonyl) (isopropyl) amino] piperidine-1-carboxylate

The title compound (237 mg) was synthesized from the corresponding compound by a method similar to that in Reference Example 67.
MS (ESI +) 641 (M + 1, 100%).

Reference Example 223
tert-butyl (3R) -3-[{[5 '-(ethoxycarbonyl) -2'-fluoro-2- (3-methoxypropoxy) -5-propylbiphenyl-4-yl] carbonyl} (isopropyl) amino] Piperidine-1-carboxylate

The title compound (191 mg) was synthesized from the corresponding compound by a method similar to that in Reference Example 68.
MS (ESI +) 643 (M + 1, 100%).

Reference Example 224
4 '-{[[(3R) -1- (tert-butoxycarbonyl) piperidin-3-yl] (isopropyl) amino] carbonyl} -6-fluoro-2'-(3-methoxypropoxy) -5'-propyl Biphenyl-3-carboxylic acid

  The title compound (179 mg) was synthesized from the corresponding compound by a method similar to that in Reference Example 14.

MS (ESI +) 615 (M + 1, 100%).

Reference Example 225
4 '-{[[(3R) -1- (tert-butoxycarbonyl) piperidin-3-yl] (isopropyl) amino] carbonyl} -5'-cyano-6-fluoro-2'-(3-methoxypropoxy) Biphenyl-3-carboxylic acid

  The title compound (1209 mg) was synthesized from the corresponding compound by a method similar to that in Reference Example 14.

MS (ESI +) 598 (M + 1, 100%).

Reference Example 226
tert-Butyl (3R) -3-[{[2'-Fluoro-2- (4-methoxybutyl) biphenyl-4-yl] carbonyl} (isopropyl) amino] piperidine-1-carboxylate

  The title compound (280 mg) was synthesized in the same manner as in Reference Example 202.

MS (ESI +) 527 (M + 1, 21%).

Example 1
6-[(3R) -3-Aminopiperidin-1-yl] -5- (2-chlorobenzyl) -2- (3-ethoxyphenoxy) -3-methyl-4-oxo-4,5-dihydro-3H -Pyrrolo [3,2-d] pyrimidine-7-carbonitrile hydrochloride

tert-butyl {(3R) -1- [5- (2-chlorobenzyl) -7-cyano-2- (3-ethoxyphenoxy) -3-methyl-4-oxo-4,5-dihydro-3H-pyrrolo 4N hydrochloric acid / dioxane solution (2 ml) was added to a solution of [3,2-d] pyrimidin-6-yl] piperidin-3-yl} carbamate (78.6 mg) in 1,4-dioxane (2 ml) at 25 ° C. The mixture was stirred for 2 hours and then concentrated under reduced pressure to give the title compound (17.4 mg).
¹ H NMR (400 MHz, CD ₃ OD) δ 7.50-7.48 (m, 2H), 7.42-7.38 (m, 3H), 7.34-7.31 (m, 1H), 7.04 (s, 1H), 7.00 (d, J = 7.7 Hz, 1H), 4.10-4.07 (m, 4H), 3.68-3.64 (m, 1H), 3.44 (t, J = 6.2 Hz, 2H), 3.38-3.34 (m, 2H), 3.26 (s , 3H), 3.00-2.94 (m, 1H), 2.78 (brs, 1H), 2.11-2.04 (m, 1H), 1.97-1.88 (m, 4H), 1.27 (brs, 6H).
MS (ESI +) 411 (M ⁺ +1, 100%).

Example 2
6-[(3R) -3-Aminopiperidin-1-yl] -5- (2-chlorobenzyl) -1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H- Pyrrolo [3,2-d] pyrimidine-7-carbonitrile hydrochloride

In the same manner as in Example 1, the title compound (13.3 mg) was synthesized from the corresponding compound.
¹ H NMR (400 MHz, CD ₃ OD) δ 9.22 (s, 1H), 9.05 (s, 2H), 7.55 (d, J = 7.7 Hz, 1H), 7.11 (s, 1H), 7.10 (dd, J = 1.2, 7.7 Hz, 1H), 4.18 (t, J = 6.1 Hz, 2H), 4.11-4.08 (m, 2H), 3.67-3.64 (m, 1H), 3.47 (t, J = 6.0 Hz, 2H) , 3.39-3.34 (m, 2H), 3.30 (s, 3H), 2.97 (m, 1H), 2.78 (brs, 1H), 2.11-1.86 (m, 5H), 1.25 (brs, 6H).
MS (ESI +) 413 (M ⁺ +1, 100%).

Example 3
6-[(3R) -3-Aminopiperidin-1-yl] -5- (2-chlorobenzyl) -2-hydroxy-3-methyl-4-oxo-4,5-dihydro-3H-pyrrolo [3, 2-d] pyrimidine-7-carbonitrile hydrochloride

In the same manner as in Example 1, the title compound (96.1 mg) was synthesized from the corresponding compound.
¹ H NMR (400 MHz, CD ₃ OD) δ 7.38-7.31 (m, 3H), 7.24-7.20 (m, 1H), 7.17-7.12 (m, 1H), 7.04 (d, J = 1.3 Hz, 1H) , 7.01 (dd, J = 1.3, 7.6 Hz, 1H), 4.10-4.06 (m, 4H), 3.69-3.63 (m, 1H), 3.43-3.36 (m, 4H), 3.26 (s, 3H), 3.00 -2.94 (m, 1H), 2.78 (brs, 1H), 2.12-2.08 (m, 1H), 1.97-1.87 (m, 4H), 1.27 (brs, 6H).
MS (ESI +) 429 (M ⁺ +1, 100%).

Example 4
6-[(3R) -3-Aminopiperidin-1-yl] -5- (2-chlorobenzyl) -3-methyl-2- (methylsulfonyl) -4-oxo-4,5-dihydro-3H-pyrrolo [3,2-d] pyrimidine-7-carbonitrile hydrochloride

In the same manner as in Example 1, the title compound (144 mg) was synthesized from the corresponding compound.
¹ H NMR (400 MHz, CD ₃ OD) δ 7.40-7.33 (m, 3H), 7.24-7.20 (m, 1H), 7.17-7.12 (m, 1H), 7.09 (brs, 1H), 7.03 (dd, J = 1.4, 7.6 Hz, 1H), 4.09-4.06 (m, 4H), 3.61 (s, 3H), 3.59-3.56 (m, 1H), 3.39-3.37 (m, 4H), 3.30 (s, 3H) , 2.99-2.96 (m, 1H), 2.79 (brs, 1H), 2.12-2.07 (m, 1H), 1.97-1.87 (m, 2H), 1.28-1.26 (m, 6H).
MS (ESI +) 458 (M ⁺ +1, 100%).

Example 5
6- (3-Aminopiperidin-1-yl) -5- (2-chlorobenzyl) -1,3-dimethyl-1H-pyrrolo [3,2-d] pyrimidine-2,4 (3H, 5H) -dione Hydrochloride

In the same manner as in Example 1, the title compound (167 mg) was synthesized from the corresponding compound.
¹ H NMR (400 MHz, CD ₃ OD) δ 7.96-7.86 (m, 1H), 7.39 (d, J = 7.6 Hz, 1H), 7.28-7.24 (m, 1H), 7.07 (d, J = 1.3 Hz , 1H), 7.03 (dd, J = 1.3, 7.6 Hz, 1H), 4.11-4.04 (m, 4H), 3.68-3.64 (m, 1H), 3.43-3.35 (m, 4H), 3.26 (s, 3H ), 3.00-2.94 (m, 1H), 2.78 (brs, 1H), 2.12-2.08 (m, 1H), 1.97-1.87 (m, 4H), 1.27 (brs, 6H).
MS (ESI +) 472 (M ⁺ +1, 100%).

  The compounds of Examples 6 to 48 were synthesized according to the methods described in the corresponding Reference Examples and Example 1.

Example 6
¹ H NMR (400 MHz, CD ₃ OD) δ 7.48-7.46 (m, 1H), 7.36-7.33 (m, 2H), 7.29-7.23 (m, 2H), 7.04 (brs, 1H), 7.02-6.99 ( m, 1H), 4.08-4.05 (m, 4H), 3.70-3.64 (m, 1H), 3.39-3.33 (m, 4H), 3.24 (s, 3H), 2.99-2.93 (m, 1H), 2.78 ( brs, 1H), 2.10-2.02 (m, 1H), 1.96-1.83 (m, 4H), 1.27 (brs, 6H).
MS (ESI +) 446 (M ⁺ +1, 100%).

Example 7
¹ H NMR (400 MHz, CD ₃ OD) δ 7.54 (m, 1H), 7.42-7.37 (m, 3H), 7.35-7.33 (m, 1H), 7.06 (brs, 1H), 7.03-7.00 (m, 1H), 4.12-4.02 (m, 4H), 3.70-3.62 (m, 1H), 3.47 (t, J = 6.2 Hz, 2H), 3.39-3.34 (m, 2H), 3.30 (s, 3H), 2.99 -2.93 (m, 1H), 2.78 (brs, 1H), 2.10-2.04 (m, 1H), 1.99-1.93 (m, 4H), 1.26 (brs, 6H).
MS (ESI +) 446 (M ⁺ +1, 100%).

Example 8
¹ H NMR (400 MHz, CD ₃ OD) δ 7.51-7.48 (m, 2H), 7.41-7.38 (m, 3H), 7.05 (brs, 1H), 7.02-7.00 (m, 1H), 4.11-4.03 ( m, 4H), 3.69-3.64 (m, 1H), 3.44 (t, J = 6.2 Hz, 2H), 3.39-3.34 (m, 2H), 3.27 (s, 3H), 2.99-2.93 (m, 1H) , 2.78 (brs, 1H), 2.10-2.04 (m, 1H), 1.99-1.93 (m, 4H), 1.26 (brs, 6H).
MS (ESI +) 446 (M ⁺ +1, 100%).

Example 9
¹ H NMR (400 MHz, CD ₃ OD) δ 7.49-7.46 (m, 1H), 7.35-7.33 (m, 1H), 7.27-7.20 (m, 2H), 7.07 (brs, 1H), 7.04-7.02 ( m, 1H), 4.11-4.05 (m, 4H), 3.67-3.64 (m, 1H), 3.42-3.34 (m, 4H), 3.27 (s, 3H), 2.96 (m, 1H), 2.78 (brs, 1H), 2.07-2.03 (m, 1H), 1.96-1.84 (m, 4H), 1.27 (brs, 6H).
MS (ESI +) 464 (M ⁺ +1, 100%).

Example 10
¹ H NMR (400 MHz, CD ₃ OD) δ 7.54 (d, 1.9 Hz, 1H), 7.38 (dd, J = 1.9, 8.2 Hz, 1H), 7.29-7.24 (m, 2H), 7.05 (brs, 1H ), 7.01 (d, J = 7.7 Hz, 1H), 4.15-4.02 (m, 4H), 3.70-3.62 (m, 1H), 3.43-3.35 (m, 4H), 3.26 (s, 3H), 2.99- 2.93 (m, 1H), 2.78 (brs, 1H), 2.10-2.05 (m, 1H), 1.96-1.85 (m, 4H), 1.28 (brs, 6H).
MS (ESI +) 480 (M ⁺ +1, 100%).

Example 11
¹ H NMR (400 MHz, CD ₃ OD) δ 7.25-7.18 (m, 4H), 7.08 (d, = 7.1 Hz, 1H), 7.03 (d, J = 1.4 Hz, 1H), 7.00 (dd, J = 1.4, 7.1 Hz, 1H), 4.15-4.03 (m, 4H), 3.70-3.61 (m, 1H), 3.39-3.36 (m, 2H), 3.31-3.26 (m, 2H), 3.21 (s, 3H) , 3.00-2.94 (m, 1H), 2.78 (brs, 1H), 2.10 (s, 3H), 2.08 (brs, 1H), 1.97-1.81 (m, 4H), 1.28 (brs, 6H).
MS (ESI +) 425 (M ⁺ +1, 100%).

Example 12
¹ H NMR (400 MHz, CD ₃ OD) δ 7.36 (d, J = 7.6 Hz, 1H), 7.31 (s, 1H), 7.28-7.27 (m, 2H), 7.15 (m, 1H), 7.03 (s , 1H), 6.99 (d, J = 7.6 Hz, 1H), 4.17-4.06 (m, 4H), 3.70-3.63 (m, 1H), 3.45 (t, J = 6.2 Hz, 2H), 3.38-3.36 ( m, 2H), 3.27 (s, 3H), 2.99-2.93 (m, 1H), 2.78 (brs, 1H), 2.38 (s, 3H), 2.14-2.04 (m, 1H), 1.97-1.91 (m, 4H), 1.27 (brs, 6H).
MS (ESI +) 425 (M ⁺ +1, 100%).

Example 13
¹ H NMR (400 MHz, CD ₃ OD) δ 7.40-7.36 (m, 3H), 7.22-7.20 (m, 2H), 7.02 (d, J = 7.7Hz, 2H), 4.09-4.06 (m, 4H) , 3.69-3.66 (m, 1H), 3.46-3.43 (m, 2H), 3.38-3.35 (m, 2H), 3.27 (s, 3H), 2.99-2.93 (m, 1H), 2.78 (brs, 1H) , 2.37 (s, 3H), 2.10-2.07 (m, 1H), 1.96-1.87 (m, 4H), 1.26 (brs, 6H).
MS (ESI +) 425 (M ⁺ +1, 100%).

Example 14
¹ H NMR (400 MHz, CD ₃ OD) δ 7.43-7.40 (m, 2H), 7.32-7.26 (m, 2H), 7.10 -7.05 (m, 2H), 7.01 (dd, J = 1.5, 7.7 Hz, 1H), 4.13-4.02 (m, 4H), 3.70-3.63 (m, 1H), 3.46 (t, J = 6.2 Hz, 2H), 3.39-3.37 (m, 2H), 3.27 (s, 3H), 2.99 -2.93 (m, 1H), 2.78 (brs, 1H), 2.10-2.04 (m, 1H), 1.99-1.93 (m, 4H), 1.27 (brs, 6H).
MS (ESI +) 429 (M ⁺ +1, 100%).

Example 15
¹ H NMR (400 MHz, CD ₃ OD) δ 7.54-7.50 (m, 2H), 7.37 (d, J = 7.7 Hz, 1H), 7.16-7.11 (m, 2H), 7.04 (d, J = 1.4 Hz , 1H), 7.00 (dd, J = 1.4, 7.7 Hz, 1H), 4.16-4.04 (m, 4H), 3.69-3.61 (m, 1H), 3.44 (t, J = 6.2 Hz, 2H), 3.40- 3.34 (m, 2H), 3.27 (s, 3H), 2.99-2.93 (m, 1H), 2.78 (brs, 1H), 2.10-2.04 (m, 1H), 1.97-1.92 (m, 4H), 1.27 ( brs, 6H).
MS (ESI +) 425 (M ⁺ +1, 100%).

Example 16
¹ H NMR (400 MHz, CD ₃ OD) δ 7.42 (d, J = 7.7 Hz, 1H), 7.17-7.12 (m, 2H), 7.08 (d, J = 1.3 Hz, 1H), 7.02 (dd, 1.3 , 7.7 Hz, 1H), 6.96-6.91 (m, 1H), 4.16-4.00 (m, 4H), 3.70-3.62 (m, 1H), 3.48 (t, J = 6.2 Hz, 2H), 3.39-3.34 ( m, 2H), 3.30 (s, 3H), 2.99-2.93 (m, 1H), 2.78 (brs, 1H), 2.10-2.04 (m, 1H), 2.00-1.93 (m, 4H), 1.26 (brs, 6H).
MS (ESI +) 447 (M ⁺ +1, 100%).

Example 17
¹ H NMR (400 MHz, CD ₃ OD) δ 7.39-7.31 (m, 2H), 7.05-7.01 (m, 3H), 4.16-4.03 (m, 4H), 3.70-3.62 (m, 1H), 3.41- 3.34 (m, 4H), 3.27 (s, 3H), 2.97-2.94 (m, 1H), 2.78 (brs, 1H), 2.10-2.01 (m, 1H), 1.97-1.88 (m, 4H), 1.27 ( brs, 6H).
MS (ESI +) 447 (M ⁺ +1, 100%).

Example 18
¹ H NMR (400 MHz, CD ₃ OD) δ 7.43-7.39 (m, 2H), 7.08-7.01 (m, 4H), 4.11-4.08 (m, 4H), 3.67-3.64 (m, 1H), 3.39- 3.34 (m, 4H), 3.25 (s, 3H), 3.00-2.94 (m, 1H), 2.80 (brs, 1H), 2.11-2.08 (m, 1H), 1.97-1.85 (m, 4H), 1.29 ( brs, 6H).
MS (ESI +) 447 (M ⁺ +1, 100%).

Example 19
¹ H NMR (400 MHz, CD ₃ OD) δ 7.88 (d, J = 7.7 Hz, 1H), 7.67-7.53 (m, 1H), 7.48-7.44 (m, 1H), 7.30 (d, J = 7.0 Hz , 2H), 7.01 (d, J = 7.7 Hz, 1H), 6.95 (s, 1H), 4.10-4.05 (m, 4H), 3.98 (m, 2H), 3.70-3.63 (m, 1H), 3.38- 3.34 (m, 2H), 3.31-3.30 (m, 2H), 3.20 (s, 3H), 2.97 (m, 1H), 2.78 (brs, 1H), 2.11-2.04 (m, 1H), 1.96-1.80 ( m, 4H), 1.27 (brs, 6H), 1.04 (d, J = 7.0 Hz, 3H).
MS (ESI +) 483 (M ⁺ +1, 100%).

Example 20
¹ H NMR (400 MHz, CD ₃ OD) δ 7.92--7.89 (m, 1H), 7.60-7.57 (m, 1H), 7.46-7.42 (m, 1H), 7.30-7.28 (m, 2H), 7.00 -6.98 (m, 1H), 6.93 (s, 1H), 4.15-3.98 (m, 4H), 3.70-3.62 (m, 1H), 3.38-3.36 (m, 2H), 3.33-3.30 (m, 2H) , 3.21 (s, 3H), 2.96 (m, 1H). 2.78 (brs, 1H), 2.10-2.04 (m, 1H), 1.96-1.84 (m, 4H), 1.27 (brs, 6H).
MS (ESI +) 455 (M ⁺ +1, 100%).

Example 21
¹ H NMR (400 MHz, CD ₃ OD) δ 8.21-8.20 (m, 1H), 8.01-7.98 (m, 1H), 7.76-7.74 (m, 1H), 7.56-7.52 (m, 1H), 7.43 ( d, J = 7.6 Hz, 1H), 7.07 (brs, 1H), 7.03 (d, J = 7.6 Hz, 1H), 4.13-4.04 (m, 4H), 3.93 (s, 3H), 3.68-3.63 (m , 1H), 3.46 (t, J = 6.2 Hz, 2H), 3.41-3.37 (m, 2H), 3.28 (s, 3H), 2.97 (m, 1H), 2.78 (brs, 1H), 2.08-2.04 ( m, 1H), 1.99-1.92 (m, 4H), 1.27 (brs, 6H).
MS (ESI +) 469 (M ⁺ +1, 100%).

Example 22
¹ H NMR (400 MHz, CD ₃ OD) δ 8.22 (brs, 1H), 8.01-7.99 (m, 1H), 7.74-7.72 (m, 1H), 7.55-7.51 (m, 1H), 7.44-7.43 ( m, 1H), 7.07 (brs, 1H), 7.03 (dd, J = 1.1, 7.6 Hz, 1H), 4.13-4.04 (m, 4H), 3.70-3.65 (m, 1H), 3.47 (t, J = 6.2 Hz, 2H), 3.39-3.37 (m, 2H), 3.27 (s, 3H), 2.97 (m, 1H), 2.78 (brs, 1H), 2.11-2.04 (m, 1H), 1.99-1.93 (m , 4H), 1.28 (brs, 6H).
MS (ESI +) 455 (M ⁺ +1, 100%).

Example 23
¹ H NMR (400 MHz, CD ₃ OD) δ 8.05 (m, 1H), 7.89-7.84 (m, 1H), 7.72-7.69 (m, 1H), 7.53-7.50 (m, 1H), 7.45 (d, J = 7.6 Hz, 1H), 7.06 (d, 1.4 Hz, 1H), 7.04 (dd, J = 1.4, 7.6 Hz, 1H), 4.12-4.04 (m, 4H), 3.68-3.63 (m, 1H), 3.43 (t, J = 6.2 Hz, 2H), 3.40-3.36 (m, 2H), 3.27 (s, 3H), 2.97 (m, 1H), 2.78 (brs, 1H), 2.12-2.04 (m, 1H) , 1.98-1.86 (m, 4H), 1.27 (brs, 6H).
MS (ESI +) 454 (M ⁺ +1, 100%).

Example 24
¹ H NMR (400 MHz, CD ₃ OD) δ 7.62-7.60 (m, 1H), 7.58 (brs, 1H), 7.53-7.49 (m, 1H), 7.43-7.39 (m, 2H), 7.07 (brs, 1H), 7.02 (d, J = 7.7 Hz, 1H), 4.13-4.02 (m, 4H), 3.70-3.63 (m, 1H), 3.44 (t, J = 6.1 Hz, 2H), 3.39-3.37 (m , 2H), 3.27 (s, 3H), 3.12 (s, 3H), 3.05 (s, 3H), 2.96 (m, 1H), 2.78 (brs, 1H), 2.10-2.04 (m, 1H), 1.96- 1.92 (m, 4H), 1.27 (brs, 6H).
MS (ESI +) 482 (M ⁺ +1, 100%).

Example 25
¹ H NMR (400 MHz, CD ₃ OD) δ 7.90 (m, 1H), 7.82 (m, 1H), 7.70 (m, 1H), 7.61 (m, 1H), 7.43 (m, 1H), 7.07 (m , 1H), 7.03 (m, 1H), 4.15-4.01 (m, 4H), 3.69-3.66 (m, 1H), 3.48-3.37 (m, 4H), 3.30 (s, 3H), 2.99-2.94 (m , 1H), 2.78 (brs, 1H), 2.10-2.07 (m, 1H), 2.00-1.94 (m, 4H), 1.27 (brs, 6H).
MS (ESI +) 436 (M ⁺ +1, 100%).

Example 26
¹ H NMR (400 MHz, CD ₃ OD) δ 8.06 (dd, J = 1.7, 6.7 Hz, 2H), 7.64 (dd, J = 1.8, 6.7 Hz, 2H), 7.43 (d, J = 7.7 Hz, 1H ), 7.08 (d, J = 1.2 Hz, 1H), 7.04 (d, J = 1.2, 7.7 Hz, 1H), 4.13-4.01 (m, 4H), 3.93 (s, 3H), 3.68-3.63 (m, 1H), 3.44 (t, J = 6.1 Hz, 2H), 3.39-3.36 (m, 2H), 3.27 (s, 3H), 2.96 (m, 1H), 2.78 (brs, 1H), 2.07-2.05 (m , 1H), 1.99-1.93 (m, 4H), 1.26 (brs, 6H).
MS (ESI +) 469 (M ⁺ +1, 100%).

Example 27
¹ H NMR (400 MHz, CD ₃ OD) δ 8.06 (d, J = 8.3 Hz, 2H), 7.62 (d, J = 8.3 Hz, 2H), 7.44 (d, J = 7.6 Hz, 1H), 7.08 ( s, 1H), 7.03 (d, J = 7.6 Hz, 1H), 4.13-4.04 (m, 4H), 3.68-3.64 (m, 1H), 3.45 (t, J = 6.1 Hz, 2H), 3.39-3.36 (M, 2H), 3.27 (s, 3H), 3.00-2.94 (m, 1H), 2.80 (brs, 1H), 2.12-2.05 (m, 1H), 1.99-1.93 (m, 4H), 1.28 (brs , 6H).
MS (ESI +) 455 (M ⁺ +1, 100%).

Example 28
¹ H NMR (400 MHz, CD ₃ OD) δ 7.92 (d, J = 8.3 Hz, 2H), 7.62 (d, J = 8.3 Hz, 2H), 7.43 (d, J = 7.6 Hz, 1H), 7.08 ( brs, 1H), 7.03 (d, J = 7.6 Hz, 1H), 4.13-4.04 (m, 4H), 3.70-3.64 (m, 1H), 3.44 (t, J = 6.1 Hz, 2H), 3.39-3.37 (m, 2H), 3.27 (s, 3H), 3.00-2.94 (m, 1H), 2.79 (brs, 1H), 2.11-2.08 (m, 1H), 1.97-1.94 (m, 4H), 1.26 (brs , 6H).
MS (ESI +) 454 (M ⁺ +1, 100%).

Example 29
¹ H NMR (400 MHz, CD ₃ OD) δ 7.63-7.60 (m, 2H), 7.50-7.48 (m, 2H), 7.43 (d, J = 7.6 Hz, 1H), 7.07 (d, J = 1.4 Hz , 1H), 7.03 (dd, J = 1.4, 7.6 Hz, 1H), 4.13-4.04 (m, 4H), 3.68-3.64 (m, 1H), 3.44 (t, J = 6.2 Hz, 2H), 3.27 ( s, 3H), 3.13 (s, 3H), 3.06 (s, 3H), 2.97 (m, 1H), 2.79 (brs, 1H), 2.11-2.04 (m, 1H), 1.98-1.93 (m, 4H) , 1.26 (brs, 6H).
MS (ESI +) 482 (M ⁺ +1, 100%).

Example 30
¹ H NMR (400 MHz, CD ₃ OD) δ 7.79-7.77 (d, J = 8.4 Hz, 2H), 7.72-7.70 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 7.7 Hz, 1H ), 7.09 (d, J = 1.4 Hz, 1H), 7.04 (dd, J = 1.4, 7.7 Hz, 1H), 4.11 (t, J = 6.2 Hz, 2H), 4.06-4.02 (m, 2H), 3.68 -3.64 (m, 1H), 3.44 (t, J = 6.1 Hz, 2H), 3.39-3.36 (m, 2H), 3.28 (s, 3H), 3.00-2.94 (m, 1H), 2.79 (brs, 1H ), 2.11-2.08 (m, 1H), 2.00-1.93 (m, 4H), 1.25 (brs, 6H).
MS (ESI +) 436 (M ⁺ +1, 100%).

Example 31
¹ H NMR (400 MHz, CD ₃ OD) δ 8.08-8.02 (m, 2H), 7.37 (d, J = 7.6 Hz, 1H), 7.31-7.26 (m, 1H), 7.07 (d, J = 1.2 Hz , 1H), 7.04 (dd, J = 1.2, 7.6 Hz, 1H), 4.12-4.03 (m, 4H), 3.91 (s, 3H), 3.70-3.62 (m, 1H), 3.41-3.38 (m, 4H ), 3.26 (s, 3H), 2.97 (m, 1H), 2.78 (brs, 1H), 2.10-2.01 (m, 1H), 1.93-1.87 (m, 4H), 1.27 (brs, 6H).
MS (ESI +) 487 (M ⁺ +1, 100%).

Example 32
¹ H NMR (400 MHz, CD ₃ OD) δ 8.06-8.03 (m, 2H), 7.38 (d, J = 7.6 Hz, 1H), 7.30-7.25 (m, 1H), 7.08 (d, J = 1.3 Hz , 1H), 7.04 (dd, J = 1.3, 7.6 Hz, 1H), 4.12-4.09 (m, 4H), 3.68-3.65 (m, 1H), 3.42-3.39 (m, 4H), 3.26 (s, 3H ), 2.99-2.97 (m, 1H), 2.79 (brs, 1H), 2.11-2.05 (m, 1H), 1.94-1.88 (m, 4H), 1.28 (brs, 6H).
MS (ESI +) 473 (M ⁺ +1, 100%).

Example 33
¹ H NMR (400 MHz, CD ₃ OD) δ 7.51-7.48 (m, 1H), 7.45 (dd, J = 2.2, 6.9 Hz, 1H), 7.37 (d, J = 7.6 Hz, 1H), 7.29-7.24 (m, 1H), 7.07 (d, J = 1.4 Hz, 1H), 7.03 (dd, J = 1.4, 7.6 Hz, 1H), 4.12-4.04 (m, 4H), 3.67-3.65 (m, 1H), 3.41-3.36 (m, 4H), 3.26 (s, 3H), 3.10 (s, 3H), 3.06 (s, 3H), 2.97 (m, 1H), 2.78 (brs, 1H), 2.12-2.08 (m, 1H), 1.97-1.87 (m, 4H), 1.26 (brs, 6H).
MS (ESI +) 500 (M ⁺ +1, 100%).

Example 34
¹ H NMR (400 MHz, CD ₃ OD) δ 7.83-7.79 (m, 2H), 7.41-7.37 (m, 2H), 7.09 (d, J = 1.2 Hz, 1H), 7.04 (dd, J = 1.2, 7.6 Hz, 1H), 4.13-4.03 (m, 4H), 4.00 (t, J = 6.2 Hz, 2H), 3.68-3.64 (m, 1H), 3.39-3.31 (m, 2H), 3.00-2.94 (m , 1H), 2.81 (brs, 1H), 2.12-2.08 (m, 1H), 1.96-1.88 (m, 4H), 1.27 (brs, 6H).
MS (ESI +) 445 (M ⁺ +1, 100%).

Example 35
¹ H NMR (400 MHz, CD ₃ OD) δ 7.93-7.90 (m, 1H), 7.56-7.53 (m, 1H), 7.36-7.30 (m, 2H), 7.07-7.03 (m, 2H), 4.38 ( q, J = 7.0 Hz, 2H), 4.11-4.08 (m, 4H), 3.67-3.66 (m, 1H), 3.41-3.38 (m, 4H), 3.26 (s, 3H), 2.97 (m, 1H) , 2.82 (brs, 1H), 2.11-2.08 (m, 1H), 1.93-1.88 (m, 4H), 1.38 (t, J = 7.0 Hz, 3H), 1.27 (brs, 6H).
MS (ESI +) 501 (M ⁺ +1, 100%).

Example 36
¹ H NMR (400 MHz, CD ₃ OD) δ 7.96-7.91 (m, 1H), 7.54-7.51 (m, 1H), 7.36 (d, J = 7.6 Hz, 1H), 7.33-7.29 (m, 1H) , 7.06 (d, J = 1.2 HZ, 1H), 7.03 (dd, J = 1.2, 7.6 Hz, 1H), 4.11-4.04 (m, 4H), 3.68-3.64 (m, 1H), 3.41 (t, J = 6.2 Hz, 2H), 3.39-3.34 (m, 2H), 3.27 (s, 3H), 3.00-2.94 (m, 1H), 2.78 (brs, 1H), 2.12-2.08 (m, 1H), 1.96- 1.87 (m, 4H), 1.27 (brs, 6H).
MS (ESI +) 473 (M ⁺ +1, 100%).

Example 37
¹ H NMR (400 MHz, CD ₃ OD) δ 7.82-7.79 (m, 1H), 7.51-7.48 (m, 1H), 7.38-7.31 (m, 2H), 7.07 (brs, 1H), 7.02 (d, J = 7.4 Hz, 1H), 4.11-4.04 (m, 4H), 3.70-3.66 (m, 1H), 3.40-3.37 (m, 4H), 3.26 (s, 3H), 2.99-2.94 (m, 1H) , 2.80 (brs, 1H), 2.11-2.08 (m, 1H), 1.93-1.89 (m, 4H), 1.27 (brs, 6H).
MS (ESI +) 472 (M ⁺ +1, 100%).

Example 38
¹ H NMR (400 MHz, CD ₃ OD) δ 7.43-7.32 (m, 4H), 7.06 (d, J = 1.4 Hz, 1H), 7.03 (dd, J = 1.4, 7.6 Hz, 1H), 4.11-4.04 (m, 4H), 3.68-3.64 (m, 1H), 3.43-3.36 (m, 4H), 3.25 (s, 3H), 3.13 (s, 3H), 2.99 (s, 3H), 2.99-2.94 (m , 1H), 2.78 (brs, 1H), 2.11-2.08 (m, 1H), 1.97-1.86 (m, 4H), 1.27 (brs, 6H).
MS (ESI +) 500 (M ⁺ +1, 100%).

Example 39
¹ H NMR (400 MHz, CD ₃ OD) δ 7.78-7.76 (m, 1H), 7.71-7.68 (m, 1H), 7.44 (d, J = 7.6Hz, 1H), 7.41-7.37 (m, 1H) , 7.09 (d, J = 1.4 Hz, 1H), 7.05 (dd, J = 1.4, 7.6 Hz, 1H), 4.13-4.04 (m, 4H), 3.68-3.64 (m, 1H), 3.42-3.36 (m , 4H), 3.30 (s, 3H), 2.97 (m, 1H), 2.78 (brs, 1H), 2.12-2.08 (m, 1H), 1.95-1.89 (m, 4H), 1.27 (brs, 6H).
MS (ESI +) 454 (M ⁺ +1, 100%).

Example 40
¹ H NMR (400 MHz, CD ₃ OD) δ 7.76 (d, J = 7.6 Hz, 1H), 7.66-7.62 (m, 1H), 7.57-7.53 (m, 1H), 7.29 (d, J = 7.5 Hz , 1H), 7.22 (d, J = 7.7 Hz, 1H), 7.03 (brs, 1H), 6.98 (d, J = 7.5 Hz, 1H), 4.08-3.97 (m, 4H), 3.72-3.64 (m, 1H), 3.38-3.30 (m, 2H), 3.24 (t, J = 6.2 Hz, 2H), 3.21 (s, 3H), 3.00-2.94 (m, 1H), 2.78 (brs, 1H), 2.12-2.08 (m, 1H), 1.97-1.77 (m, 4H), 1.28 (brs, 6H).
MS (ESI +) 479 (M ⁺ +1, 100%).

Example 41
¹ H NMR (400 MHz, CD ₃ OD) δ 7.47-7.36 (m, 4H), 7.29 (d, J = 7.6 Hz, 1H), 7.06 (d, J = 1.2 Hz, 1H), 7.01 (dd, J = 1.2, 7.6 Hz, 1H), 4.08-4.05 (m, 4H), 3.68-3.64 (m, 1H), 3.38-3.32 (m, 4H), 3.24 (s, 3H), 3.00-2.94 (m, 1H ), 2.79 (brs, 1H), 2.12-2.08 (m, 1H), 1.97-1.84 (m, 4H), 1.27 (brs, 6H).
MS (ESI +) 495 (M ⁺ +1, 100%).

Example 42
¹ H NMR (400 MHz, CD ₃ OD) δ 7.33 (d, J = 7.6 Hz, 1H), 7.08-7.04 (m, 2H), 7.00 (dd, J = 1.6, 7.6 Hz, 1H), 6.94-6.90 (m, 1H), 6.87-6.85 (m, 1H), 4.10-4.00 (m, 4H), 3.79 (s, 3H), 3.68-3.57 (m, 1H), 3.44-3.37 (m, 4H), 3.27 (s, 3H), 2.99-2.94 (m, 1H), 2.79 (brs, 1H), 2.11-2.07 (m, 1H), 1.94-1.88 (m, 4H), 1.27 (brs, 6H).
MS (ESI +) 459 (M ⁺ +1, 100%).

Example 43
¹ H NMR (400 MHz, CD ₃ OD) δ 7.33-7.31 (m, 1H), 7.16-7.08 (m, 2H), 7.04 (brs, 1H), 7.00 (dd, J = 1.3, 7.6 Hz, 1H) , 6.88-6.85 (m, 1H), 4.09-4.06 (m, 4H), 3.90 (s, 3H), 3.60-3.56 (m, 1H), 3.41-3.34 (m, 4H), 3.27 (s, 3H) , 2.99-2.93 (m, 1H), 2.78 (brs, 1H), 2.11-2.04 (m, 1H), 1.96-1.87 (m, 4H), 1.26 (brs, 6H).
MS (ESI +) 459 (M ⁺ +1, 100%).

Example 44
¹ H NMR (400 MHz, CD ₃ OD) δ 7.34-7.28 (m, 1H), 7.25 (d, J = 7.6 Hz, 1H), 7.03-7.02 (m, 1H), 6.99-6.97 (m, 1H) , 6.85 (m, 1H), 6.77-6.73 (m, 1H), 4.10-3.96 (m, 6H), 3.59-3.56 (m, 1H), 3.41-3.33 (m, 4H), 3.24 (s, 3H) , 3.00-2.93 (m, 1H), 2.78 (brs, 1H), 2.11-2.04 (m, 1H), 1.96-1.82 (m, 4H), 1.27 (brs, 6H), 1.20 (t, J = 7.0 Hz , 3H).
MS (ESI +) 473 (M ⁺ +1, 100%).

Example 45
¹ H NMR (400 MHz, CD ₃ OD) δ 7.88 (dd, J = 1.4, 8.0 Hz, 1H), 7.76 (dd, J = 1.2, 10.3 Hz, 1H), 7.50-7.46 (m, 1H), 7.37 (d, J = 7.6 Hz, 1H), 7.08 (brs, 1H), 7.03 (d, J = 7.6 Hz, 1H), 4.12-4.10 (m, 4H), 3.94 (s, 3H), 3.61-3.56 ( m, 1H), 3.47-3.37 (m, 4H), 3.26 (s, 3H), 2.99-2.94 (m, 1H), 2.79 (brs, 1H), 2.11-2.08 (m, 1H), 2.01-1.89 ( m, 4H), 1.27 (brs, 6H).
MS (ESI +) 487 (M ⁺ +1, 100%).

Example 46
¹ H NMR (400 MHz, CD ₃ OD) δ 7.88 (dd, J = 1.4, 7.9 Hz, 1H), 7.75 (dd, J = 1.2, 10.4 Hz, 1H), 7.49-7.45 (m, 1H), 7.37 (d, J = 7.6 Hz, 1H), 7.08 (d, J = 1.0 Hz, 1H), 7.04 (dd, J = 1.2, 7.6 Hz, 1H), 4.12-4.06 (m, 4H), 3.70-3.64 ( m, 1H), 3.41-3.34 (m, 4H), 3.26 (s, 3H), 3.00-2.94 (m, 1H), 2.79 (brs, 1H), 2.08-2.05 (m, 1H), 1.97-1.88 ( m, 4H), 1.27 (brs, 6H).
MS (ESI +) 473 (M ⁺ +1, 100%).

Example 47
¹ H NMR (400 MHz, CD ₃ OD) δ 7.75 (dd, J = 1.4, 7.9 Hz, 1H), 7.68 (d, J = 10.6 Hz, 1H), 7.47-7.44 (m, 1H), 7.37 (d , J = 7.6 Hz, 1H), 7.08 (brs, 1H), 7.03 (d, J = 7.6 Hz, 1H), 4.12-4.09 (m, 4H), 3.59-3.56 (m, 1H), 3.47-3.34 ( m, 4H), 3.26 (s, 3H), 3.00-2.94 (m, 1H), 2.79 (brs, 1H), 2.11-2.08 (m, 1H), 1.94-1.90 (m, 4H), 1.27 (brs, 6H).
MS (ESI +) 472 (M ⁺ +1, 100%).

Example 48
¹ H NMR (400 MHz, CD ₃ OD) δ 7.47-7.43 (m, 1H), 7.37 (d, J = 7.6 Hz, 1H), 7.32-7.26 (m, 2H), 7.07 (d, J = 1.2 Hz , 1H), 7.03 (dd, J = 1.4, 7.6 Hz, 1H), 4.12-4.06 (m, 4H), 3.59-3.56 (m, 1H), 3.44-3.34 (m, 4H), 3.26 (s, 3H ), 3.12 (s, 3H) .3.06 (s, 3H), 3.00-2.94 (m, 1H), 2.79 (brs, 1H), 2.08-2.01 (m, 1H), 1.97-1.87 (m, 4H), 1.27 (brs, 6H).
MS (ESI +) 500 (M ⁺ +1, 100%).

Example 49
6- fluoride -N ⁴ '- isopropyl-2' - (3-methoxypropoxy) -N ³ - methyl -N ⁴ '- [(3R) - piperidin-3-yl] -5-propyl -N ³ - ( Tetrahydro-2H-pyran-4-yl) biphenyl-3,4'-dicarboxamide hydrochloride

The title compound (67.8 mg) was synthesized from the corresponding compound by a method similar to that in Example 1.
¹ H NMR (400 MHz, CD ₃ OD) δ 7.46-7.41 (m, 2H), 7.29-7.23 (m, 2H), 6.91-6.87 (m, 1H), 4.17-3.84 (m, 6H), 3.74- 3.48 (m, 3H), 3.41-3.38 (m, 5H), 3.26 (s, 3H), 2.96-2.83 (m, 5H), 2.60-2.49 (m, 2H), 2.14-2.10 (m, 1H), 1.96-1.86 (m, 6H), 1.71-1.56 (m, 4H), 1.29-1.22 (m, 6H), 0.99-0.88 (m, 3H).
MS (ESI +) 611 (M ⁺ +1, 100%).

Example 50
N ^3- (tert-butyl) -5'-chloro-6-fluoro-N ⁴ '-isopropyl-2'-(3-methoxypropoxy) -N ⁴ '-[(3R) -piperidin-3-yl] biphenyl -3,4'-Dicarboxamide hydrochloride

In the same manner as in Example 1, the title compound (227 mg) was synthesized from the corresponding compound.
¹ H NMR (400 MHz, CD ₃ OD) δ 7.84-7.77 (m, 2H), 7.44 (m, 1H), 7.26-7.22 (m, 1H), 7.11-7.06 (m, 1H), 4.16-4.06 ( m, 3H), 3.84-3.79 (m, 1H), 3.67-3.62 (m, 1H), 3.43-3.36 (m, 4H), 3.26 (s, 3H), 3.00-2.98 (m, 1H), 2.88- 2.82 (m, 1H), 2.13-2.09 (m, 1H), 2.00-1.83 (m, 4H), 1.45 (s, 9H), 1.34-1.22 (m, 6H).
MS (ESI +) 561 (M ⁺ +1, 100%).

Example 51
5'-chloro -N ³ - cyclopropyl-6-fluoro--N ⁴ '- isopropyl-2' - ^{(3-methoxypropoxy) -N 4 '- [(3R} ) - piperidin-3-yl] -N ³ - (Tetrahydro-2H-pyran-4-yl) biphenyl-3,4'-dicarboxamide hydrochloride

In the same manner as in Example 1, the title compound (690 mg) was synthesized from the corresponding compound.
¹ H NMR (400 MHz, CD ₃ OD) δ 7.61-7.58 (m, 1H), 7.53 (dd, J = 2.2, 6.9 Hz, 1H), 7.39 (d, J = 2.4 Hz, 1H), 7.28-7.23 (m, 1H), 7.11-7.06 (m, 1H), 4.29 (m, 1H), 4.13-4.01 (m, 5H), 3.84-3.80 (m, 1H), 3.66-3.48 (m, 3H), 3.43 -3.37 (m, 4H), 3.26 (s, 3H), 3.00-2.98 (m, 1H), 2.83-2.80 (m, 2H), 2.25-2.20 (m, 2H), 2.13-2.09 (m, 1H) , 1.98-1.85 (m, 6H), 1.33-1.21 (m, 6H), 0.68-0.67 (m, 2H), 0.54-0.53 (m, 2H).
MS (ESI +) 629 (M ⁺ +1, 100%).

Example 52
5'-chloro -N ³ - ethyl-6-fluoro--N ⁴ '- isopropyl-2' - ^{(3-methoxypropoxy) -N 4 '- [(3R} ) - piperidin-3-yl] -N ³ - ( Tetrahydro-2H-pyran-4-yl) biphenyl-3,4'-dicarboxamide hydrochloride

In the same manner as in Example 1, the title compound (269 mg) was synthesized from the corresponding compound.
¹ H NMR (400 MHz, CD ₃ OD) δ 7.46-7.44 (m, 1H), 7.42-7.39 (m, 2H), 7.32-7.27 (m, 1H), 7.13-7.08 (m, 1H), 4.13- 4.07 (m, 3H), 3.97 (brs, 2H), 3.84-3.79 (m, 2H), 3.66-3.63 (m, 1H), 3.49-3.37 (m, 7H), 3.26 (s, 3H), 3.21 ( m, 1H), 3.00-2.97 (m, 1H), 2.84 (m, 1H), 2.13-1.83 (m, 7H), 1.70 (m, 2H), 1.33-1.14 (m, 9H).
MS (ESI +) 617 (M ⁺ +1, 100%).

Example 53
¹ H NMR (400 MHz, CD ₃ OD) δ 8.88-8.86 (m, 2H), 8.36-8.35 (m, 2H), 7.71 (d, J = 7.8 Hz, 2H), 7.23 (m, 1H), 7.15 (d, J = 7.8 Hz, 2H), 4.25 (t, J = 6.3 Hz, 2H), 4.15-4.04 (m, 1H), 3.99-3.91 (m, 1H), 3.68-3.64 (m, 1H), 3.50 (t, J = 6.1 Hz, 2H), 3.41-3.34 (m, 2H), 3.30 (s, 3H), 3.01-2.94 (m, 1H), 2.80 (brs, 1H), 2.21-1.85 (m, 5H), 1.26 (brs, 6H).
MS (ESI +) 412 (M ⁺ +1, 100%).

Example 54
¹ H NMR (400 MHz, CD ₃ OD) δ 9.14 (s, 1H), 8.86-8.83 (m, 2H), 8.19-8.15 (m, 1H), 7.65-7.63 (d, J = 7.7 Hz, 1H) , 7.20-7.19 (m, 1H), 7.15-7.10 (m, 1H), 4.23 (t, J = 6.2 Hz, 2H), 4.10-4.08 (m, 1H), 3.96 (m, 1H), 3.71-3.64 (m, 1H), 3.47 (t, J = 6.0 Hz, 2H), 3.45-3.39 (m, 2H), 3.30 (s, 3H), 3.00-2.94 (m, 1H), 2.80 (brs, 1H), 2.10-1.94 (m, 5H), 1.26 (brs, 6H).
MS (ESI +) 412 (M ⁺ +1, 100%).

Example 55
¹ H NMR (400 MHz, CD ₃ OD) δ 8.87-8.46 (m, 2H), 7.57-7.53 (m, 1H), 7.48-7.43 (m, 1H), 7.14 (d, J = 10.8 Hz, 1H) , 7.09-7.06 (m, 1H), 4.16-4.09 (m, 4H), 3.63-3.56 (m, 1H), 3.43-3.37 (m, 4H), 3.27 (s, 3H), 2.97 (m, 1H) , 2.78 (brs, 1H), 2.12-2.08 (m, 1H), 1.99-1.90 (m, 4H), 1.25 (brs, 6H).
MS (ESI +) 430 (M ⁺ +1, 100%).

Example 56
¹ H NMR (400 MHz, CD ₃ OD) δ 7.74-7.72 (m, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.48-7.42 (m, 2H), 7.04 (d, J = 1.5 Hz , 1H), 6.97 (dd, J = 1.5, 7.8 Hz, 1H), 4.18-4.03 (m, 4H), 3.74-3.66 (m, 1H), 3.54 (t, J = 6.3 Hz, 2H), 3.38- 3.31 (m, 2H), 3.30 (s, 3H), 3.00-2.92 (m, 1H), 2.77 (brs, 1H), 2.10-1.92 (m, 5H), 1.27 (brs, 6H).
MS (ESI +) 417 (M ⁺ +1, 100%).

Example 57
MS (ESI +) 417 (M ⁺ +1, 100%).

Example 58
¹ H NMR (400 MHz, CD ₃ OD) δ 8.17 (brs, 1H), 8.06-8.05 (m, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.03 (s, 1H), 6.95 (d , J = 7.8 Hz, 1H), 4.33-4.29 (m, 1H), 4.21 (t, J = 6.1 Hz, 2H), 4.04-4.01 (m, 1H), 3.97 (s, 3H), 3.75-3.64 ( m, 1H), 3.59 (t, J = 6.1 Hz, 2H), 3.37-3.35 (m, 2H), 3.34 (s, 3H), 2.96 (m, 1H), 2.78 (brs, 1H), 2.17-2.05 (m, 3H), 1.95-1.88 (m, 2H), 1.25 (brs, 6H).
MS (ESI +) 415 (M ⁺ +1, 100%).

Example 59
¹ H NMR (400 MHz, CD ₃ OD) δ 9.18 (s, 1H), 8.94 (s, 1H), 8.12 (s, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.09 (d, J = 1.3 Hz, 1H), 7.01 (dd, J = 1.3, 7.8 Hz, 1H), 4.31-4.29 (m, 2H), 4.26 (t, J = 6.4 Hz, 2H), 3.70-3.64 (m, 1H) , 3.59 (t, J = 5.9 Hz, 2H), 3.35-3.33 (m, 2H), 3.34 (s, 3H), 2.97 (m, 1H), 2.78 (brs, 1H), 2.19-2.05 (m, 3H ), 1.96-1.88 (m, 2H), 1.24 (brs, 6H).
MS (ESI +) 402 (M ⁺ +1, 100%).

  The compounds of Examples 60 to 64 were synthesized according to the methods described in the corresponding Reference Examples and Example 1.

Example 60
¹ H NMR (400 MHz, CD ₃ OD) δ 7.50-7.49 (m, 1H), 7.44-7.39 (m, 1H), 7.36-7.32 (m, 1H), 7.26-7.22 (m, 1H), 7.19- 7.14 (m, 1H), 7.08 (s, 0.5H), 7.03 (s, 0.5H), 4.13-4.05 (m, 3H), 3.84-3.81 (m, 1H), 3.67-3.66 (m, 1H), 3.42-3.36 (m, 4H), 3.25 (s, 3H), 3.00-2.98 (m, 1H), 2.85 (m, 1H), 2.13-2.10 (m, 1H), 2.00-1.97 (m, 1H), 1.92-1.86 (m, 3H), 1.34 (t, J = 6.4 Hz, 3H), 1.23 (t, J = 6.4 Hz, 3H).
MS (ESI +) 507, 509 (M ⁺ +1, 100%).

Example 61
¹ H NMR (400 MHz, CD ₃ OD) δ 7.35-7.29 (m, 2H), 7.25-7.21 (m, 1H), 7.16 (brs, 1H), 7.13-7.11 (m, 1H), 6.89 (s, 0.5H), 6.85 (s, 0.5H), 4.18-4.12 (m, 1H), 4.02 (t, J = 5.9 Hz, 2H), 3.90-3.86 (m, 1H), 3.68-3.64 (m, 1H) , 3.43-3.36 (m, 4H), 3.25 (s, 3H), 2.99 (m, 1H), 2.87 (m, 1H), 2.26 (m, 3H), 2.13-2.10 (m, 1H), 1.90-1.84 (m, 4H), 1.29-1.19 (m, 6H).
MS (ESI +) 443 (M ⁺ +1, 100%).

Example 62
¹ H NMR (400 MHz, CD ₃ OD) δ 7.41-7.39 (m, 1H), 7.37-7.32 (m, 2H), 7.26-7.22 (m, 1H), 7.19-7.14 (m, 1H), 7.08 ( s, 0.5H), 7.04 (s, 0.5 H), 4.13-4.05 (m, 3H), 3.85-3.82 (m, 1H), 3.67-3.62 (m, 1H), 3.43-3.31 (m, 4H), 3.25 (s, 3H), 2.99-2.98 (m, 1H), 2.88-2.84 (m, 1H), 2.13-2.09 (m, 1H), 1.97-1.86 (m, 4H), 1.32 (t, J = 6.6 Hz, 3H), 1.23 (m, 3H).
MS (ESI +) 463 (M ⁺ +1, 100%).

Example 63
¹ H NMR (400 MHz, CD ₃ OD) δ 7.40-7.30 (m, 2H), 7.23-7.11 (m, 3H), 6.88 (s, 0.5H), 6.83 (s, 0.5H), 4.18-4.12 ( m, 1H), 4.05-4.01 (m, 2H), 3.90-3.87 (m, 1H), 3.43-3.36 (m, 4H), 3.25 (s, 3H), 3.04-2.95 (m, 1H), 2.88- 2.82 (m, 1H), 2.58-2.51 (m, 2H), 2.10 (m, 1H), 1.95-1.85 (m, 4H), 1.70-1.58 (m, 3H), 1.26-1.22 (m, 6H), 0.99-0.95 (m, 3H).
MS (ESI +) 471 (M ⁺ +1, 100%).

Example 64
¹ H NMR (400 MHz, CD ₃ OD) δ 7.72 (s, 1H), 7.46-7.42 (m, 1H), 7.39-7.35 (m, 1H), 7.28-7.25 (m, 2H), 7.21-7.17 ( m, 1H), 4.18 (t, J = 6.0 Hz, 2H), 4.15-4.09 (m, 1H), 3.83-3.80 (m, 1H), 3.68-3.64 (m, 1H), 3.43-3.37 (m, 4H), 3.26 (s, 3H), 3.00-2.99 (m, 1H), 2.88-2.81 (m, 1H), 2.14-2.10 (m, 1H), 2.02-1.99 (m, 1H), 1.95-1.87 ( m, 3H), 1.26 (s, 3H).
MS (ESI +) 454 (M ⁺ +1, 100%).

  The compounds of Examples 65 to 70 were synthesized according to the methods described in the corresponding Reference Examples and Example 1.

Example 65
¹ H NMR (400 MHz, CD ₃ OD) δ 7.48-7.42 (m, 1H), 7.39-7.37 (m, 2H), 7.29-7.25 (m, 1H), 7.07 (d, J = 1.3 Hz, 1H) , 7.03 (dd, J = 1.3, 7.6 Hz, 1H), 4.12-4.09 (m, 4H), 3.59-3.56 (m, 3H). 3.48-3.38 (m, 6H), 3.26 (s, 3H), 3.00 -2.94 (m, 1H), 2.79 (m, 1H), 2.11-2.08 (m, 1H), 1.93-1.87 (m, 4H), 1.26 (brs, 6H), 1.16 (brs, 6H).
MS (ESI +) 528 (M ⁺ +1, 100%).

Example 66
¹ H NMR (400 MHz, CD ₃ OD) δ 7.87-7.83 (m. 2H), 7.38 (d, 7.6 Hz, 1H), 7.26-7.22 (m, 1H), 7.07 (d, J = 1.3 Hz, 1H ), 7.04 (dd, J = 1.3, 7.6 Hz, 1H), 4.11-4.03 (m, 4H), 3.59-3.57 (m, 1H) .3.43-3.37 (m, 4H), 3.26 (s, 3H), 3.00-2.94 (m, 1H), 2.87-2.79 (m, 2H), 2.11-2.08 (m, 1H), 1.98-1.87 (m, 4H), 1.26 (brs, 6H), 0.83-0.78 (m, 2H ), 0.65-0.61 (m, 2H).
MS (ESI +) 512 (M ⁺ +1, 100%).

Example 67
¹ H NMR (400 MHz, CD ₃ OD) δ 7.40-7.36 (m, 2H), 7.31-7.24 (m, 2H), 7.07 (brs, 1H)., 7.04-7.03 (m, 1H), 4.11-4.09 (m, 4H), 3.80-3.58 (m, 3H) .3.43-3.35 (m, 4H), 3.30 (s, 3H), 2.97-2.94 (m, 1H), 2.79 (brs, 1H), 2.11-2.08 (m, 1H), 1.97-1.88 (m, 4H), 1.25 (m, 12H).
MS (ESI +) 556 (M ⁺ +1, 100%).

Example 68
¹ H NMR (400 MHz, CD ₃ OD) δ 7.62-7.58 (m, 1H), 7.55 (dd, J = 2.2, 6.9 Hz, 1H), 7.37 (d, J = 7.6 Hz, 1H), 7.28-7.24 (m, 1H), 7.07 (d, J = 1.4 Hz, 1H), 7.03 (dd, J = 1.4, 7.6 Hz, 1H), 4.12-4.06 (m, 4H), 3.61-3.57 (m, 3H), 3.54-3.51 (m, 2H), 3.43-3.38 (m, 4H), 3.26 (s, 3H), 3.00-2.94 (m, 1H), 2.80 (brs, 1H), 2.11-2.07 (m, 1H), 2.04-1.87 (m, 8H), 1.27 (brs, 6H).
MS (ESI +) 526 (M ⁺ +1, 100%).

Example 69
¹ H NMR (400 MHz, CD ₃ OD) δ 7.65-7.62 (m, 1H), 7.48-7.44 (m, 1H), 7.40 (dd, J = 2.1, 6.8 Hz, 1H), 7.37 (d, J = 7.6 Hz, 1H), 7.29-7.24 (m, 1H), 7.07 (d, J = 1.3 Hz, 1H), 7.04-7.01 (dd, J = 1.3, 7.6 Hz, 1H), 4.12-4.09 (m, 4H ), 3.75-3.64 (m, 3H), 3.46 (m, 2H), 3.39-3.36 (m, 4H), 3.26 (s, 3H), 3.00-2.93 (m, 1H), 2.78 (brs, 1H), 2.11-2.08 (m, 1H), 1.93-1.87 (m, 4H), 1.72-1.57 (m, 6H), 1.27 (brs, 6H).
MS (ESI +) 540 (M ⁺ +1, 100%).

Example 70
¹ H NMR (400 MHz, CD ₃ OD) δ 7.52-7.48 (m, 1H), 7.46-7.45 (m, 1H), 7.37 (d, J = 7.6Hz, 1H), 7.30-7.26 (m, 1H) , 7.07 (s, 1H), 7.03 (d, J = 7.6 Hz, 1H), 4.12-4.09 (m, 4H), 3.72-3.58 (m, 9H), 3.41-3.36 (m, 4H), 3.26 (s , 3H), 2.97 (m, 1H), 2.79 (brs, 1H), 2.11-2.08 (m, 1H), 1.97-1.87 (m, 4H), 1.26 (brs, 6H).
MS (ESI +) 542 (M ⁺ +1, 100%).

  The compounds of Examples 71 to 102 were synthesized according to the methods described in the corresponding Reference Examples and Example 1.

Example 71
¹ H NMR (400 MHz, CD ₃ OD) δ 7.53-7.50 (m, 1H), 7.48-7.46 (m, 1H), 7.42 (brs, 1H), 7.31-7.26 (m, 1H), 7.11 (s, 0.5H), 7.07 (s, 0.5H), 4.16-4.07 (m, 3H), 3.84-3.79 (m, 1H), 3.619-3.58 (m, 1H), 3.42-3.36 (m, 4H), 3.26 ( s, 3H), 3.10 (s, 3H), 3.06 (s, 3H), 3.02-2.99 (m, 1H), 2.87-2.81 (brs, 1H), 2.13-2.10 (m, 1H), 1.97-1.85 ( m, 4H), 1.33-1.30 (m, 3H), 1.27-1.24 (m, 3H).
MS (ESI +) 535 (M ⁺ +1, 100%).

Example 72
¹ H NMR (400 MHz, CD ₃ OD) δ 7.48-7.40 (m, 3H), 7.27 (m, 1H), 7.12-7.07 (m, 1H), 4.13-4.07 (m, 3H), 3.84 -3.79 ( m, 1H), 3.72-3.58 (m, 4H), 3.51 (m, 2H), 3.43-3.37 (m, 4H), 3.26 (s, 3H), 3.02-2.98 (m, 1H), 2.88-2.80 ( m, 1H), 2.12-2.09 (m, 1H), 1.97-1.88 (m, 4H), 1.33-1.12 (m, 8H).
MS (ESI +) 548 (M ⁺ +1, 100%).

Example 73
¹ H NMR (400 MHz, CD ₃ OD) δ 7.47-7.38 (m, 3H), 7.31-7.26 (m, 1H), 7.13-7.07 (m, 1H), 4.16-4.07 (m, 3H), 3.84- 3.81 (m, 1H), 3.66-3.64 (m, 1H), 3.56-3.55 (m, 1H), 3.48-3.37 (m, 7H), 3.00-2.98 (m, 1H), 2.89-2.81 (m, 1H ), 2.12-2.09 (m, 1H), 1.97-1.84 (m, 4H), 1.72-1.56 (m, 3H), 1.33-1.19 (m, 7H), 1.13-0.78 (m, 3H).
MS (ESI +) 576 (M ⁺ +1, 100%).

Example 74
¹ H NMR (400 MHz, CD ₃ OD) δ 7.48-7.39 (m, 3H), 7.31-7.27 (m, 1H), 7.13-7.07 (m, 1H), 4.16-4.07 (m, 3H), 3.84- 3.81 (m, 1H), 3.67-3.64 (m, 1H), 3.43-3.33 (m, 5H), 3.26 (s, 3H), 3.23-3.21 (m, 1H), 3.06-2.98 (m, 4H), 2.89-2.84 (m, 1H), 2.13-2.09 (m, 1H), 2.00-1.84 (m, 5H), 1.34-1.22 (m, 6H), 0.99 (d, J = 6.8 Hz, 3H), 0.78 ( d, J = 6.4 Hz, 3H).
MS (ESI +) 576 (M ⁺ +1, 100%).

Example 75
¹ H NMR (400 MHz, CD ₃ OD) δ 7.49-7.41 (m, 3H), 7.31-7.26 (m, 1H), 7.12-7.07 (m, 1H), 4.10 (m, 3H), 3.83 (m, 1H), 3.67-3.66 (m, 1H), 3.53-3.49 (m, 1H), 3.43-3.38 (m, 5H), 3.26 (s, 3H), 3.07-2.99 (m, 4H), 2.88-2.81 ( m, 1H), 2.13-2.09 (m, 1H), 1.97-1.89 (m, 4H), 1.72-1.70 (m, 2H), 1.34-1.22 (m, 6H), 1.01-0.77 (m, 3H).
MS (ESI +) 562 (M ⁺ +1, 100%).

Example 76
¹ H NMR (400 MHz, CD ₃ OD) δ 7.49-7.41 (m, 3H), 7.31-7.26 (m, 1H), 7.12-7.07 (m, 1H), 4.12-4.07 (m, 3H), 3.84 3.81 (m, 1H), 3.66-3.57 (m, 2H), 3.43-3.34 (m, 6H), 3.30 (s, 3H), 3.26 (s, 3H), 3.07-2.98 (m, 4H), 2.87- 2.84 (m, 1H), 2.12-2.09 (m, 1H), 1.99-1.86 (m, 4H), 1.34-1.22 (m, 9H).
MS (ESI +) 592 (M ⁺ +1, 100%).

Example 77
¹ H NMR (400 MHz, CD ₃ OD) δ 7.47-7.44 (m, 1H), 7.41-7.39 (m, 2H), 7.29 (m, 1H), 7.12-7.07 (m, 1H), 4.13-4.07 ( m, 4H), 3.84-3.81 (m, 1H), 3.67-3.55 (m, 5H), 3.43-3.35 (m, 6H), 3.30 (s, 3H), 3.26 (s, 3H), 2.99 (m, 1H), 2.92-2.77 (m, 1H), 2.13-2.09 (m, 1H), 1.99-1.87 (m, 4H), 1.33-1.22 (m, 12H).
MS (ESI +) 606 (M ⁺ +1, 100%).

Example 78
¹ H NMR (400 MHz, CD ₃ OD) δ 7.91-7.87 (m, 1H), 7.85-7.83 (m, 1H), 7.44-7.43 (m, 1H), 7.29-7.24 (m, 1H), 7.12- 7.07 (m, 1H), 4.13-4.06 (m, 3H), 3.83-3.80 (m, 1H), 3.66-3.64 (m, 1H), 3.40-3.35 (m, 4H), 3.26 (s, 3H), 2.99 (m, 1H), 2.88-2.82 (m, 2H), 2.09 (m, 1H), 1.91-1.87 (m, 4H), 1.34-1.22 (m, 6H), 0.83-0.78 (m, 2H), 0.65-0.61 (m, 2H).
MS (ESI +) 546 (M ⁺ +1, 100%).

Example 79
¹ H NMR (400 MHz, CD ₃ OD) δ 7.63-7.54 (m, 2H), 7.40-7.39 (m, 1H), 7.28-7.24 (m, 1H), 7.12-7.06 (m, 1H), 4.16- 4.07 (m, 3H), 3.84-3.79 (m, 1H), 3.67-3.63 (m, 1H), 3.43-3.34 (m, 4H), 3.26 (s, 3H), 3.10 (s, 3H), 2.99- 2.95 (m, 2H), 2.87-2.84 (m, 1H), 2.12-2.08 (m, 1H), 1.98-1.86 (m, 4H), 1.34-1.22 (m, 6H).
MS (ESI +) 560 (M ⁺ +1, 100%).

Example 80
¹ H NMR (400 MHz, CD ₃ OD) δ 7.93-7.86 (m, 2H), 7.44 (m, 1H), 7.30-7.25 (m, 1H), 7.12-7.07 (m, 1H), 4.16-4.07 ( m, 4H), 4.00-3.97 (m, 2H), 3.85-3.78 (m, 1H), 3.66-3.59 (m, 1H), 3.55-3.49 (m, 2H), 3.42-3.35 (m, 4H), 3.25 (s, 3H), 3.02-2.96 (m, 1H), 2.88-2.81 (m, 1H), 2.13-2.10 (m, 1H), 1.98-1.86 (m, 6H), 1.72-1.58 (m, 2H ), 1.34-1.22 (m, 2H).
MS (ESI +) 590 (M ⁺ +1, 100%).

Example 81
¹ H NMR (400 MHz, CD ₃ OD) δ 7.49-7.41 (m, 3H), 7.32-7.27 (m, 1H), 7.12-7.07 (m, 1H), 4.13-3.99 (m, 5H), 3.84- 3.81 (m, 1H), 3.66-3.59 (m, 1H), 3.43-3.37 (m, 4H), 3.30 (s, 3H), 3.26 (s, 3H), 3.01-2.84 (m, 5H), 2.13- 2.09 (m, 1H), 1.98-1.86 (m, 6H), 1.68-1.56 (m, 2H), 1.33-1.22 (m, 6H).
MS (ESI +) 604 (M ⁺ +1, 100%).

Example 82
¹ H NMR (400 MHz, CD ₃ OD) δ 7.48-7.46 (m, 1H), 7.43-7.41 (m, 2H), 7.31-7.26 (m, 1H), 7.12 (s, 0.5H), 7.07 (s , 0.5H), 4.13-4.07 (m, 3H), 3.83-3.81 (m, 1H), 3.74-3.58 (m, 3H), 3.48-3.36 (m, 6H), 3.26 (s, 3H), 3.04- 2.95 (m, 1H), 2.90-2.80 (m, 1H), 2.13-2.10 (m, 1H), 2.01-1.85 (m, 4H), 1.73-1.56 (m, 6H), 1.33-1.27 (m, 3H ), 1.25-1.21 (m, 3H).
MS (ESI +) 575 (M ⁺ +1, 100%).

Example 83
¹ H NMR (400 MHz, CD ₃ OD) δ 7.53-7.49 (m, 1H), 7.47-7.45 (m, 1H), 7.42-7.41 (m, 1H), 7.32-7.27 (m, 1H), 7.12- 7.08 (m, 1H), 4.49 (m, 1H), 4.13-4.07 (m, 3H), 3.84-3.81 (m, 1H), 3.67-3.61 (m, 4H), 3.26 (s, 3H), 3.00- 2.84 (m, 3H), 2.58 (m, 1H), 2.12-2.09 (m, 1H), 1.99-1.87 (m, 4H), 1.33-1.09 (m, 12H).
MS (ESI +) 604 (M ⁺ +1, 100%).

Example 84
¹ H NMR (400 MHz, CD ₃ OD) δ 7.52-7.48 (m, 1H), 7.46-7.44 (m, 1H), 7.42-7.41 (m, 1H), 7.32-7.27 (m, 1H), 7.13- 7.08 (m, 1H), 4.16-4.07 (m, 3H), 3.99 (m, 2H), 3.85-3.73 (m, 3H), 3.67-3.65 (m, 1H), 3.43-3.34 (m, 4H), 3.26 (s, 3H), 3.00-2.98 (m, 1H), 2.88-2.81 (m, 1H), 2.71-2.66 (m, 4H), 2.12-2.09 (m, 1H), 1.97-1.86 (m, 4H ), 1.33-1.22 (m, 6H).
MS (ESI +) 592 (M ⁺ +1, 100%).

Example 85
¹ H NMR (400 MHz, CD ₃ OD) δ 7.61-7.56 (m, 2H), 7.47-7.43 (m, 1H), 7.33-7.29 (m, 1H), 7.13-7.08 (m, 1H), 4.16- 4.07 (m, 6H), 3.83-3.80 (m, 1H), 3.68-3.65 (m, 2H), 3.44-3.34 (m, 4H), 3.26-3.23 (m, 7H), 3.00-2.98 (m, 1H ), 2.88-2.81 (m, 1H), 2.12-2.09 (m, 1H), 1.97-1.87 (m, 4H), 1.33-1.22 (m, 6H).
MS (ESI +) 624 (M ⁺ +1, 100%).

Example 86
¹ H NMR (400 MHz, CD ₃ OD) δ 7.52-7.48 (m, 1H), 7.46-7.42 (m, 2H), 7.32-7.27 (m, 1H), 7.12-7.08 (m, 1H), 4.48 ( m, 1H), 4.17-4.07 (m, 5H), 3.85-3.80 (m, 2H), 3.66-3.61 (m, 1H), 3.43-3.35 (m, 4H), 3.26 (s, 3H), 3.13- 2.94 (m, 2H), 2.92-2.81 (m, 1H), 2.69-2.65 (m, 1H), 2.13-2.09 (m, 1H), 2.04-1.86 (m, 6H), 1.68-1.56 (m, 2H ), 1.33-1.22 (m, 9H).
MS (ESI +) 646 (M ⁺ +1, 100%).

Example 87
¹ H NMR (400 MHz, CD ₃ OD) δ 7.52-7.48 (m, 1H), 7.46-7.43 (m, 2H), 7.32-7.27 (m, 1H), 7.12-7.08 (m, 1H), 4.46 ( brs, 1H), 4.13-4.07 (m, 3H), 3.85-3.74 (m, 2H), 3.67-3.59 (m, 1H), 3.43-3.35 (m, 4H), 3.26 (m, 4H), 3.13- 2.94 (m, 2H), 2.91-2.76 (m, 1H), 2.66-2.64 (m, 1H), 2.13-1.87 (m, 7H), 1.72-1.56 (m, 2H), 1.33-1.22 (m, 6H ).
MS (ESI +) 618 (M ⁺ +1, 100%).

Example 88
¹ H NMR (400 MHz, CD ₃ OD) δ 7.50-7.46 (m, 1H), 7.45-7.42 (m, 2H), 7.31-7.27 (m, 1H), 7.12-7.07 (m, 1H), 4.13- 4.07 (m, 3H), 3.85-3.81 (m, 2H), 3.75-3.58 (m, 3H), 3.42-3.37 (m, 4H), 3.26 (m, 4H), 3.13-3.12 (m, 1H), 3.02-2.94 (m, 1H), 2.88-2.77 (m, 2H), 2.13-2.10 (m, 1H), 1.98-1.80 (m, 6H), 1.63-1.56 (m, 2H), 1.33-1.22 (m , 6H), 1.18 (s, 6H).
MS (ESI +) 632 (M ⁺ +1, 100%).

Example 89
¹ H NMR (400 MHz, CD ₃ OD) δ 7.49-7.47 (m, 1H), 7.44-7.41 (m, 2H), 7.31-7.23 (m, 1H), 7.12-7.07 (m, 1H), 4.65 ( m, 1H), 4.13-4.07 (m, 3H), 3.86-3.79 (m, 2H), 3.66-3.62 (m, 1H), 3.45-3.43 (m, 2H), 3.39-3.36 (m, 3H), 3.26 (s, 3H), 3.21-3.12 (m, 1H), 3.00-2.97 (m, 1H), 2.88-2.83 (m, 2H), 2.13-2.09 (m, 1H), 2.03-1.76 (m, 7H ), 1.33-1.17 (m, 6H).
MS (ESI +) 604 (M ⁺ +1, 100%).

Example 90
¹ H NMR (400 MHz, CD ₃ OD) δ 7.49-7.46 (m, 1H), 7.44-7.41 (m, 2H), 7.31-7.26 (m, 1H), 7.12-7.07 (m, 1H), 4.61 ( m, 1H), 4.13-4.07 (m, 3H), 3.84-3.79 (m, 2H), 3.68-3.59 (m, 1H), 3.43-3.12 (m, 11H), 3.26 (s, 3H), 3.00- 2.98 (m, 1H), 2.88-2.81 (m, 2H), 2.13-2.09 (m, 1H), 2.05-1.83 (m, 6H), 1.74 (m, 1H), 1.33-1.22 (m, 7H).
MS (ESI +) 618 (M ⁺ +1, 100%).

Example 91
¹ H NMR (400 MHz, CD ₃ OD) δ 7.53-7.50 (m, 1H), 7.48-7.45 (m, 1H), 7.43-7.42 (m, 1H), 7.32-7.27 (m, 1H), 7.12- 7.08 (m, 1H), 5.03-5.01 (m, 1H), 4.13-4.07 (m, 3H), 3.99 (brs, 1H), 3.84-3.81 (m, 1H), 3.66-3.59 (m, 3H), 3.48-3.34 (m, 4H), 3.26 (s, 3H), 3.03-2.95 (m, 1H), 2.91-2.78 (m, 1H), 2.10-2.07 (m, 1H), 2.05 (s, 3H), 1.99-1.82 (m, 6H), 1.73-1.69 (m, 2H), 1.33-1.22 (m, 7H).
MS (ESI +) 632 (M ⁺ +1, 100%).

Example 92
¹ H NMR (400 MHz, CD ₃ OD) δ 7.50-7.48 (m, 1H), 7.45-7.42 (m, 2H), 7.31-7.27 (m, 1H), 7.12-7.07 (m, 1H), 4.16- 4.07 (m, 4H), 3.92-3.61 (m, 5H), 3.42-3.30 (m, 5H), 3.26 (s, 3H), 3.00-2.97 (m, 1H), 2.84-2.78 (m, 1H), 2.15-2.09 (m, 1H), 1.97-1.85 (m, 6H), 1.61-1.45 (m, 2H), 1.33-1.22 (m, 6H).
MS (ESI +) 590 (M ⁺ +1, 100%).

Example 93
¹ H NMR (400 MHz, CD ₃ OD) δ 7.51-7.48 (m, 1H), 7.46-7.41 (m, 2H), 7.31-7.27 (m, 1H), 7.12-7.07 (m, 1H), 4.13- 4.07 (m, 3H), 4.00 (m, 1H), 3.84-3.80 (m, 1H), 3.67-3.61 (m, 2H), 3.55-3.48 (m, 2H), 3.42-3.30 (m, 8H), 3.26 (s, 3H), 2.99 (m, 1H), 2.88-2.78 (m, 1H), 2.12-2.09 (m, 1H), 1.98-1.82 (m, 6H), 1.61 (m, 2H), 1.33- 1.22 (m, 6H).
MS (ESI +) 604 (M ⁺ +1, 100%).

Example 94
¹ H NMR (400 MHz, CD ₃ OD) δ 7.62-7.60 (m, 1H), 7.58-7.55 (m, 1H), 7.45-7.41 (m, 1H), 7.30-7.26 (m, 1H), 7.12- 7.07 (m, 1H), 4.16-4.07 (m, 3H), 3.84-3.81 (m, 1H), 3.67-3.51 (m, 4H), 3.43-3.34 (m, 4H), 3.26 (s, 3H), 3.00-2.97 (m, 1H), 2.84 (m, 1H), 2.12-2.09 (m, 1H), 2.03-1.85 (m, 8H), 1.34-1.22 (m, 6H).
MS (ESI +) 560 (M ⁺ +1, 100%).

Example 95
¹ H NMR (400 MHz, CD ₃ OD) δ 7.71-7.57 (m, 2H), 7.42 (m, 1H), 7.32-7.28 (m, 1H), 7.12-7.08 (m, 1H), 4.13-4.07 ( m, 3H), 3.87-3.62 (m, 6H), 3.62-3.36 (m, 4H), 3.26 (s, 3H), 3.00-2.98 (m, 1H), 2.84 (m, 1H), 2.32-2.09 ( m, 3H), 1.99-1.86 (m, 4H), 1.33-1.22 (m, 7H).
MS (ESI +) 578 (M ⁺ +1, 100%).

Example 96
¹ H NMR (400 MHz, CD ₃ OD) δ 7.64-7.57 (m, 2H), 7.43-7.42 (m, 1H), 7.32-7.27 (m, 1H), 7.12-7.08 (m, 1H), 4.13- 4.07 (m, 3H), 3.87-3.65 (m, 7H), 3.43-3.36 (m, 4H), 3.26 (s, 3H), 3.03-2.94 (m, 1H), 2.88-2.78 (m, 1H), 2.23-1.97 (m, 7H), 1.94-1.85 (m, 3H), 1.33-1.22 (m, 6H).
MS (ESI +) 618 (M ⁺ +1, 100%).

Example 97
¹ H NMR (400 MHz, CD ₃ OD) δ 7.64-7.56 (m, 2H), 7.42-7.41 (m, 1H), 7.31-7.26 (m, 1H), 7.12-7.07 (m, 1H), 4.13- 4.07 (m, 3H), 3.85-3.56 (m, 6H), 3.41-3.37 (m, 4H), 3.26 (s, 3H), 3.03-2.93 (m, 1H), 2.88-2.83 (m, 1H), 2.10-1.85 (m, 7H), 1.33-1.22 (m, 7H).
MS (ESI +) 576 (M ⁺ +1, 100%).

Example 98
¹ H NMR (400 MHz, CD ₃ OD) δ 7.63-7.60 (m, 1H), 7.58-7.56 (m, 1H), 7.43-7.42 (m, 1H), 7.31-7.26 (m, 1H), 7.12- 7.07 (m, 1H), 4.13-4.07 (m, 3H), 3.84-3.81 (m, 1H), 3.72-3.49 (m, 5H), 3.39-3.26 (m, 11H), 3.04-2.93 (m, 1H ), 2.91-2.78 (m, 1H), 2.15-1.87 (m, 7H), 1.33-1.22 (m, 6H).
MS (ESI +) 590 (M ⁺ +1, 100%).

Example 99
¹ H NMR (400 MHz, CD ₃ OD) δ 7.64-7.55 (m, 2H), 7.47-7.43 (m, 1H), 7.33-7.28 (m, 1H), 7.13-7.08 (m, 1H), 4.62 ( m, 2H), 4.13-4.07 (m, 3H), 3.86-3.81 (m, 3H), 3.67-3.64 (m, 1H), 3.43-3.33 (m, 4H), 3.26 (s, 3H), 3.15- 2.98 (m, 3H), 2.88-2.84 (m, 1H), 2.13-2.08 (m, 1H), 1.97-1.86 (m, 4H), 1.34-1.21 (m, 6H).
MS (ESI +) 578 (M ⁺ +1, 100%).

Example 100
¹ H NMR (400 MHz, CD ₃ OD) δ 7.64-7.55 (m, 2H), 7.46-7.45 (m, 1H), 7.36-7.31 (m, 1H), 7.13-7.09 (m, 1H), 4.67 ( s, 2H), 4.20-4.16 (m, 2H), 4.13-4.08 (m, 3H), 3.84-3.81 (m, 1H), 3.67-3.63 (m, 1H), 3.43-3.34 (m, 6H), 3.26 (s, 3H), 2.99 (m, 1H), 2.84 (m, 1H), 2.13-2.09 (m, 1H), 1.99-1.87 (m, 4H), 1.33-1.21 (m, 6H).
MS (ESI +) 610 (M ⁺ +1, 100%).

Example 101
¹ H NMR (400 MHz, CD ₃ OD) δ 7.48-7.46 (m, 1H), 7.43-7.41 (m, 2H), 7.31-7.27 (m, 1H), 7.12-7.08 (m, 1H), 4.16- 4.07 (m, 3H), 3.89-3.81 (m, 3H), 3.66-3.59 (m, 3H), 3.43-3.36 (m, 4H), 3.25 (s, 3H), 3.00-2.98 (m, 1H), 2.84 (m, 1H), 2.17-2.07 (m, 2H), 1.99-1.86 (m, 5H), 1.82-1.72 (m, 8H), 1.33-1.22 (m, 6H).
MS (ESI +) 614 (M ⁺ +1, 100%).

Example 102
¹ H NMR (400 MHz, CDCl3) δ10.05-9.65 (brs, 2H), 7.46-7.37 (m, 2H), 7.32-7.23 (m, 1H), 7.21-7.13 (m, 1H), 6.88-6.78 (brs, 0.5H), 6.76 (s, 0.5H), 4.33-4.13 (brs, 1H), 4.12-3.97 (m, 2H), 3.98-3.82 (brs, 1H), 3.86-3.32 (m, 12H) , 3.27 (s, 3H), 3.14-2.81 (brs, 2H), 2.30-1.99 (m, 2H), 1.98-1.81 (m, 3H), 1.80-1.51 (brs, 3H), 1.49-1.38 (m, 1H), 1.37-1.20 (m, 3H), 1.21-1.13 (m, 1H).
MS (ESI +) 576 (M ⁺ +1, 100%).

  The compounds of Examples 103 to 105 were synthesized according to the methods described in the corresponding Reference Examples and Example 1.

Example 103
¹ H NMR (400 MHz, CD ₃ OD) δ 7.48-7.46 (m, 1H), 7.45-7.43 (m, 1H), 7.28-7.23 (m, 2H), 6.91 (s, 0.5H), 6.86 (s , 0.5H), 4.17-4.03 (m, 3H), 3.89-3.86 (m, 1H), 3.42-3.37 (m, 4H), 3.26 (s, 3H), 3.10 (s, 3H), 3.07 (s, 3H), 3.00-2.98 (m, 1H), 2.85-2.83 (m, 1H), 2.58-2.51 (m, 2H), 2.13-2.10 (m, 1H), 1.96-1.85 (m, 4H), 1.71- 1.58 (m, 3H), 1.29-1.22 (m, 6H), 0.97 (t, J = 7.1 Hz, 3H).
MS (ESI +) 542 (M ⁺ +1, 100%).

Example 104
¹ H NMR (400 MHz, CD ₃ OD) δ 7.50-7.44 (m, 2H), 7.29-7.24 (m, 2H), 6.92-6.87 (m, 1H), 4.17-4.04 (m, 3H), 3.89- 3.86 (m, 1H), 3.74-3.57 (m, 8H), 3.43-3.37 (m, 4H), 3.26 (s, 3H), 3.00 (m, 1H), 2.58 (m, 1H), 2.58-2.51 ( m, 2H), 2.14-2.10 (m, 1H), 2.00-1.85 (m, 1H), 1.73-1.58 (m, 2H), 1.29-1.22 (m, 6H), 0.99-0.90 (m, 3H).
MS (ESI +) 584 (M ⁺ +1, 100%).

Example 105
¹ H NMR (400 MHz, CD ₃ OD) δ 7.47-7.42 (m, 2H), 7.29-7.23 (m, 2H), 6.92-6.87 (m, 1H), 4.50 (brs, 1H), 4.15-4.04 ( m, 3H), 3.87-3.86 (m, 1H), 3.66-3.58 (m, 4H), 3.43-3.37 (m, 4H), 3.26 (s, 3H), 3.04-2.83 (m, 3H), 2.58- 2.53 (m, 3H), 2.10 (m, 1H), 1.96-1.86 (m, 4H), 1.69-1.60 (m, 2H), 1.29-1.10 (m, 12H), 0.99-0.95 (m, 3H).
MS (ESI +) 612 (M ⁺ +1, 100%).

Example 106
5'-cyano-6-fluoro-N ⁴ '-isopropyl-2'-(3-methoxypropoxy) -N ³ , N ³ -dimethyl-N ⁴ '-[(3R) -piperidin-3-yl] biphenyl- 3,4'-dicarboxamide hydrochloride

tert-butyl (3R) -3-[{[5-cyano-5 '-[(dimethylamino) carbonyl] -2'-fluoro-2- (3-methoxypropoxy) biphenyl-4-yl] carbonyl} (isopropyl ) Amino] piperidine-1-carboxylate in chloroform was added trifluoroacetic acid (141 ml), stirred for 3 hours, and then trifluoroacetic acid (100 ml) was added. After further stirring for 2 hours, trifluoroacetic acid (100 ml) was further added. After stirring for 20 hours, the mixture was diluted with toluene and concentrated. The residue was diluted with saturated aqueous sodium hydrogen carbonate, extracted with ethyl acetate, the organic layers were combined, dried and concentrated. 1M HCl / dioxane (183 ml) was added to the residue and concentrated to obtain the title compound (95.8 mg).

¹ H NMR (400 MHz, MeOD) δ 1.28 (m, 5H), 1.57 (t, J = 6.1 Hz, 2H), 1.61-1.73 (m, 1H), 1.85-1.95 (m, 4H), 2.56 (td , J = 2 Hz, 12.6 Hz, 1H), 2.8 (d, J = 11 Hz, 2H), 2.98 (d, J = 12 Hz, 1H), 3.06 (s, 3H), 3.10 (s, 3H), 3.26 (s, 3H), 3.39 (t, J = 6.1 Hz, 3H), 3.71-3.79 (m, 2H), 4.19 (t, J = 6.0 Hz, 2H), 7.19 (s, 1H), 7.29 (t , J = 8.5 Hz, 1H), 7.49 (dd, J = 2.0 Hz, 7 Hz, 1H), 7.52-7.56 (m, 1H), 7.75 (s. 1H).
MS (ESI +) 528 (M ⁺ +1, 100%).

Example 107
¹ H NMR (400 MHz, CDCl ₃ ) δ 9.86 (brs, 1H), 9.78 (brs, 1H), 7.57-7.73 (m, 3H), 7.35-7.30 (m, 2H), 7.27 (s, 1H), 4.36 (s, 2H), 4.26-4.11 (brs, 1H), 4.12-4.02 (m, 5H), 3.95-3.84 (brs, 1H), 3.82-3.79 (m, 2H), 3.53-3.40 (m, 4H ), 3.31 (s, 3H), 2.90 (brs, 2H), 2.22-2.08 (m, 1H), 2.07-1.97 (m, 3H), 1.92-1.79 (m, 2H), 1.34 (d, J = 5.9 Hz, 3H), 1.23 (d, J = 6.4 Hz, 3H).
MS (ESI +) 510 (M ⁺ +1, 100%).

Example 108
¹ H NMR (400 MHz, CDCl ₃ ) δ 10.0 (brs, 1H), 9.60 (brs, 1H), 7.45-7.40 (m, 3H), 7.38-7.31 (m, 1H), 6.92 (s, 2H), 4.15-4.07 (m, 4H), 3.89-3.81 (m, 1H), 3.70 (s, 2H), 3.48 (t, J = 5.60 Hz, 4H), 3.46-3.34 (m, 1H), 3.32 (s, 3H), 2.98-2.84 (m, 2H), 2.60 (brs, 2H), 2.12-1.87 (m, 9H), 1.33-1.28 (m, 3H), 1.24 (d, J = 6.2 Hz, 3H).
MS (ESI +) 508 (M ⁺ +1, 100%).

Example 109
¹ H NMR (400 MHz, CDCl ₃ ) δ 9.81 (brs, 1H), 9.65 (brs, 1H), 7.73-7.71 (m, 1H), 7.55-7.51 (m, 1H), 7.42 (t, J = 7.84 Hz, 1H), 7.35-7.27 (m, 2H), 6.94-6.92 (m, 2H), 4.54-4.47 (m, 2H), 4.22-4.12 (m, 1H), 4.12-4.01 (m, 5H), 3.93-3.82 (m, 1H), 3.53-3.46 (m, 1H), 3.45 (t, J = 6.2 Hz, 3H), 3.30 (s, 3H), 3.01-2.92 (m, 2H), 2.17-2.10 ( m, 1H), 2.06-1.96 (m, 3H), 1.90-1.86 (m, 1H), 13.35-1.33 (m, 3H), 1.26-1.20 (m, 3H).
MS (ESI +) 496 (M ⁺ +1, 100%).

Example 110
¹ H NMR (400 MHz, CDCl ₃ ) δ 9.80 (brs, 2H), 7.96 (t J = 1.54 Hz, 1H), 7.76 (d, J = 7.80 Hz, 1H), 7.72 (dt, J = 7.84, 1.52 Hz, 2H), 7.34 (d, J = 7.88 Hz, 1H), 6.98-6.96 (m, 2H), 4.22-4.12 (m, 1H), 4.11 (t, J = 6.16 Hz, 2H), 4.05-4.01 (m, 1H), 3.95-3.84 (m, 1H), 3.79-3.75 (m, 4H), 3.56-3.48 (m, 1H), 3.45 (t, J = 6.12 Hz, 3H), 3.30 (s, 3H ), 3.06-3.03 (m, 4H), 2.99-2.81 (m, 2H), 2.21-2.11 (m, 1H), 2.06-1.94 (m, 3H), 1.90-1.87 (m, 1H), 1.37-1.34 (m, 3H), 1.25-1.23 (m, 3H).
MS (ESI +) 560 (M ⁺ +1, 100%).

Example 111
¹ H NMR (400 MHz, CDCl ₃ ) δ 1.19-1.25 (m, 3H), 1.34 (s, 3H), 1.85-2.13 (m, 5H), 2.56 (s, 1H), 2.88 (s, 1H), 3.27 (s, 3H), 3.40 (t, J = 6.0 Hz, 2H), 3.63-3.65 (m, 3H), 3.70 (s, 3H), 3.73 (s, 1H), 3.85-3.90 (m, 1H) , 4.05 (s, 3H), 4.15 (s, 1H), 6.91 (s, 1H), 7.04 (t, 9 Hz, 2H), 7.23-7.37 (m, 2H)
MS (ESI +) 502 (M ⁺ +1, 100%).

Example 112
¹ H NMR (400 MHz, CDCl ₃ ) δ 9.77 (brs, 1H), 9.45 (brs, 1H), 7.74 (brs, 1H), 7.36-7.18 (m, 1H), 7.10 (t, J = 8.4 Hz, 2H), 7.01-6.79 (m, 3H), 4.28-4.14 (m, 1H), 4.12 (brs, 3H), 3.95-3.84 (m, 1H), 3.62-3.43 (m, 1H), 3.42 (brs, 3H), 3.29 (s, 3H), 3.01 (s, 3H), 2.98-2.68 (m, 1H), 2.22-1.98 (m, 2H), 1.94 (brs, 1H), 1.35 (brs, 3H), 1.23 (brs, 3H).
MS (ESI +) 522 (M ⁺ +1, 100%).

Example 113
¹ H NMR (400 MHz, CDCl ₃ ) δ 9.83 (brs, 1h), 9.74 (brs, 1H), 7.41-7.33 (m, 2H), 7.31-7.27 (m, 1H), 7.15 (t J = 8.85 Hz , 1H), 6.95-6.92 (m, 2H), 4.26-4.13 (m, 1H), 4.11-4.01 (m, 3H), 3.94-3.86 (m, 1H), 3.54-3.47 (m, 1H), 3.41 (t, J = 6.16 Hz, 2H), 3.33 (s, 3H), 3.29 (s, 3H), 2.99-2.82 (m, 1H), 2.88 (s, 3H), 2.22-2.11 (m, 1H), 2.08-1.99 (m, 1H), 1.95 (quint, J = 6.12 Hz, 2H), 1.90-1.85 (m, 1H), 1.34 (d, J = 6.60 Hz, 3H), 1.25 (d, J = 6.60 Hz , 3H).
MS (ESI +) 536 (M ⁺ +1, 100%).

Example 114
¹ H NMR (400 MHz, CDCl ₃ ) δ 9.84 (brs, 1H), 9.70 (brs, 1H), 7.32-7.15 (m, 4H), 6.95-6.91 (m, 2H), 4.24-4.13 (m, 1H ), 4.10-4.01 (m, 3H), 3.96-3.81 (m, 1H), 3.82 (s, 3H), 3.54-3.45 (m, 4H), 3.42-3.38 (m, 3H), 3.28 (s, 3H ), 2.96-2.82 (m, 2H), 2.21-2.08 (m, 1H), 2.07-1.99 (m, 1H), 1.95 (quint, J = 5.96 Hz, 2H), 1.90-1.85 (m, 1H), 1.34 (d, J = 6.44 Hz, 3H), 1.26 (d, J = 6.56 Hz, 3H).
MS (ESI +) 580 (M ⁺ +1, 100%).

Example 115
¹ H NMR (400 MHz, CDCl ₃ ) δ 9.91-9.75 (brs, 2H), 8.18-8.10 (m, 2H), 7.41-7.22 (m, 1H), 7.28 (t, J = 8.97 Hz, 1H), 6.96 (s, 2H), 4.26-4.05 (m, 4H), 3.90 (brs, 1H), 3.56-3.35 (m, 4H), 3.28 (s, 3H), 2.92 (brs, 2H), 2.47 (s, 3H), 2.22-2.01 (m, 2H), 2.00-1.86 (m, 3H), 1.36 (brs, 3H), 1.27-1.24 (m, 3H).
MS (ESI +) 511 (M ⁺ +1, 100%).

Example 116
¹ H NMR (400 MHz, CDCl ₃ ) δ 9.90 (brs, 1H), 9.78 (brs, 1H), 7.32 (d, J = 7.09 Hz, 1H), 7.25-7.21 (m, 2H), 7.14 (t, J = 8.4 Hz, 1H), 6.96-9.87 (m, 2H), 4.23-4.12 (m, 1H), 4.10-4.02 (m, 3H), 3.87-3.83 (m, 1H), 3.69-3.65 (m, 2H), 3.49-3.40 (m, 4H), 3.30 (s, 3H), 2.99-2.81 (m, 2H), 2.57 (brs, 2H), 2.18-1.82 (m, 9H), 1.35-1.31 (m, 3H), 1.24-1.21 (m, 3H).
MS (ESI +) 526 (M ⁺ +1, 100%).

Example 117
¹ H NMR (400 MHz, CDCl ₃ ) δ 9.81 (brs, 1H), 9.65 (brs, 1H), 7.66-7.62 (m, 1H), 7.54-7.50 (m, 1H), 7.11 (t, J = 9.05 Hz, 1H), 6.92 (brs, 2H), 4.20 (brs, 1H), 4.07 (brs, 3H), 3.88-3.81 (m, 3H), 3.52-3.35 (m, 4H), 3.28 (s, 3H) , 2.90 (brs, 2H), 2.62 (t, J = 7.80 Hz, 2H), 2.19-1.82 (m, 8H), 1.35 (brs, 3H), 1.28-1.23 (m, 3H).
MS (ESI +) 512 (M ⁺ +1, 100%).

Example 118
2'-Fluoro-5 '-(1-hydroxy-1-methylethyl) -N-isopropyl-2- (3-methoxypropoxy) -N-[(3R) -piperidin-3-yl] biphenyl-4-carboxy Amide hydrochloride
¹ H NMR (400 MHz, MeOD) δ 1.26 (s, 5H), 1.55 (s, 6H), 1.87-1.93 (m, 5H), 2.04 (s, 1H), 2.83 (s, 1H), 3.26 (s , 3H), 3.30-3.31 (m, 6H), 3.42 (t, J = 5.5 Hz, 2H), 3.56-3.61 (m, 1H), 4.05 (s, 1H), 4.08 (t, J = 6.08 Hz, 2H), 6.98-7.03 (m, 2H), 7.08 (t, J = 9.6 Hz, 1H), 7.33 (d, J = 7.6 Hz, 1H), 7.44-7.51 (m, 2H)
MS (ESI +) 487 (M ⁺ +1, 100%).

Example 119
5'-acetyl-2'-fluoro-N-isopropyl-2- (3-methoxypropoxy) -N-[(3R) -piperidin-3-yl] biphenyl-4-carboxamide hydrochloride
¹ H NMR (400 MHz, MeOD) δ 1.27 (s, 6H), 1.87-1.99 (m, 4H), 2.06-2.10 (m, 1H), 2.61 (s, 3H), 2.77-2.81 (m, 1H) , 2.96 (t, J = 12 Hz, 1H), 3.26 (s, 3H), 3.30-3.43 (m, 2H), 3.39 (t, J = 6.2 Hz, 2H), 3.65-3.75 (m, 1H), 4.07 (s, 1H), 4.10 (t, J = 6 Hz, 2H), 7.04 (dd, J = 7.6, 1.1 Hz, 1H), 7.09 (s, 1H), 7.30 (t, J = 9.3 Hz, 1H ), 7.38 (d, J = 9.3 Hz, 1H), 8.00-8.08 (m, 2H)
MS (ESI +) 471 (M ⁺ +1, 100%).

Example 120
¹ H NMR (400 MHz, CDCl ₃ ) δ 9.87 (brs, 1H), 9.77 (brs, 1H), 7.38-7.31 (m, 2H), 7.25-7.17 (m, 2H), 7.13 (t, J = 9.88 Hz, 1H), 6.66 (s, 0.35H), 6.61 (s, 0.65H), 4.26 (brs, 1H), 4.05-3.98 (m, 2H), 3.94-3.87 (m, 2H), 3.56-3.46 ( m, 1H), 3.45-3.34 (m, 2H), 3.28 (s, 3H), 3.04-2.91 (m, 2H), 2.91-2.78 (m, 1H), 2.22-2.11 (m, 1H), 2.12- 2.00 (m, 1H), 1.95-1.87 (m, 4H), 1.32-1.30 (m, 3H), 1.26-1.17 (m, 9H).
MS (ESI +) 471 (M ⁺ +1, 100%).

Example 121
¹ H NMR (400 MHz, CDCl ₃ ) δ 9.95-9.71 (m, 2H), 7.37-7.31 (m, 2H), 7.21-7.15 (m, 1H), 7.15-7.10 (m, 2H), 6.72 (s , 0.6H), 6.67 (s, 0.4H), 4.27 (m, 1H), 4.08-3.99 (m, 2H), 3.91-3.83 (m, 2H), 3.53-3.44 (m, 1H), 3.44-3.36 (m, 3H), 3.28 (s, 3H), 2.98-2.95 (m, 2H), 2.50-2.32 (m, 2H), 2.22-2.09 (m, 1H), 2.07-2.01 (m, 1H), 1.96 -1.85 (m, 4H), 1.35-1.26 (m, 3H), 1.25-1.87 (m, 3H), 0.95-0.88 (m, 6H).
MS (ESI +) 485 (M ⁺ +1, 100%).

Example 122
¹ H NMR (400 MHz, CDCl ₃ ) δ 9.96-9.72 (m, 2H), 7.36-7.30 (m, 2H), 7.21-7.10 (m, 3H), 6.72 (s, 0.5H), 6.66 (s, 0.5H), 4.33-4.18 (m, 1H), 4.10-3.99 (m, 2H), 3.94-3.83 (m, 2H), 3.56-3.46 (m, 1H), 3.45-3.4 (m, 3H), 3.28 (s, 3H), 3.03-2.89 (m, 2H), 2.62-2.52 (m, 2H), 2.22-2.12 (m, 1H), 2.10-2.02 (m, 1H), 1.98-1.84 (m, 3H) , 1.35-1.27 (m, 3H), 1.26-1.17 (m, 6H).
MS (ESI +) 457 (M ⁺ +1, 100%).

Example 123
5 '-{[(2R, 6S) -2,6-Dimethylmorpholin-4-yl] carbonyl} -2'-fluoro-N-isopropyl-2- (3-methoxypropoxy) -N-[(3R) -Piperidin-3-yl] biphenyl-4-carboxamide hydrochloride
¹ H NMR (400 MHz, MeOD) δ 1.09-1.28 (m, 1H), 1.52 (s, 1H), 1.87-1.93 (m, 4H), 2.01 (s, 1H), 2.58 (s, 2H), 2.80 -3.13 (m, 3H), 3.26 (s, 3H), 3.30-3.31 (m, 2H), 3.39 (t, J = 6 Hz, 2H), 3.62 (s, 4H), 4.03 (s, 2H), 4.11 (t, J = 6 Hz, 2H), 4.47 (s, 1H), 7.02 (dd, J = 1.2, 24 Hz, 1H), 7.07 (s, 1H), 7.28 (t, J = 9.6 Hz, 1H ), 7.36 (d, J = 7.6 Hz, 1H), 7.44-7.49 (m, 2H)
MS (ESI +) 570 (M ⁺ +1, 100%).

Example 124
2'-Fluoro-5 '-[(4-hydroxypiperidin-1-yl) carbonyl] -N-isopropyl-2- (3-methoxypropoxy) -N-[(3R) -piperidin-3-yl] biphenyl- 4-Carboxamide hydrochloride
¹ H NMR (400 MHz, CDCl ₃ ) δ 1.19-1.42 (m, 5H), 1.55-1.65 (m, 2H), 1.65-2.09 (m, 5H), 2.18 (s, 5H), 2.87 (s, 1H ), 3.27 (s, 3H), 3.39-3.50 (m, 3H), 3.62-3.68 (m, 2H), 3.71 (s, 1H), 3.73-3.79 (m, 3H), 3.86-4.11 (m, 6H ), 6.94 (s, 2H), 7.15 (t, J = 8.5 Hz, 1H), 7.32 (s, 1H), 7.40 (s, 2H)
MS (ESI +) 556 (M ⁺ +1, 100%).

Example 125
2'-Fluoro-N-isopropyl-5 '-[(4-methoxypiperidin-1-yl) carbonyl] -2- (3-methoxypropoxy) -N-[(3R) -piperidin-3-yl] biphenyl- 4-Carboxamide hydrochloride
¹ H NMR (400 MHz, CDCl ₃ ) δ 0.83-1.07 (m, 10H), 3.29 (s, 3H), 3.37-3.57 (m, 12H), 3.63-3.83 (m, 12H), 4.09-4.11 (m , 2H), 6.95-7.01 (m, 2H), 7.16 (s, 1H), 7.29-7.32 (m, 1H), 7.41 (s, 2H)
MS (ESI +) 570 (M ⁺ +1, 100%).

Example 126
2'-Fluoro-5 '-[(4-hydroxy-4-methylpiperidin-1-yl) carbonyl] -N-isopropyl-2- (3-methoxypropoxy) -N-[(3R) -piperidine-3- Yl] biphenyl-4-carboxamide hydrochloride
¹ H NMR (400 MHz, MeOD) δ 1.22-1.31 (m, 7H), 1.55-1.67 (m, 6H), 1.82-1.93 (m, 4H), 2.79-2.93 (m, 3H), 3.26 (s, 3H), 3.30-3.31 (m, 7H), 3.39 (t, J = 6.2 Hz, 3H), 3.55 (m, 2H), 4.09 (t, J = 6.1 Hz, 2H), 4.21 (s, 1H), 6.98 (d, J = 7.6 Hz, 1H), 7.02 (s, 1H), 7.26 (dd, J = 8.5, 8.5 Hz, 1H), 7.35 (d, J = 7.6 Hz, 1H), 7.41-7.46 (m , 2H)
MS (ESI +) 493 (M ⁺ +1, 84%).

Example 127
5 '-[(4,4-Difluoropiperidin-1-yl) carbonyl] -2'-fluoro-N-isopropyl-2- (3-methoxypropoxy) -N-[(3R) -piperidin-3-yl] Biphenyl-4-carboxamide hydrochloride
¹ H NMR (400 MHz, MeOD) δ 1.18-1.28 (m, 6H), 1.87-2.06 (m, 9H), 2.80 (s, 1H), 2.95 (m, 1H), 3.26 (s, 3H), 3.29 −3.31 (m, 1H), 3.39 (m, 1H), 3.65-3.75 (m, 9H), 4.11 (t, J = 5.9 Hz, 2H), 7.03 (d, J = 7.5 Hz, 1H), 7.07 ( s, 1H), 7.28 (dd, J = 8.7, 8.7 Hz, 1H), 7.38 (d, J = 5.4 Hz, 1H), 7.49-7.54 (m, 2H)
MS (ESI +) 576 (M ⁺ +1, 100%).

Example 128
2'-Fluoro-5 '-[(3-hydroxypyrrolidin-1-yl) carbonyl] -N-isopropyl-2- (3-methoxypropoxy) -N-[(3R) -piperidin-3-yl] biphenyl- 4-Carboxamide hydrochloride
¹ H NMR (400 MHz, MeOD) δ 1.26-1.28 (m, 8H), 1.89-2.11 (m, 7H), 2.93-2.99 (m, 1H), 3.26 (s, 3H), 3.34-3.41 (m, 5H), 3.56-3.75 (m, 7H), 4.08-4.15 (m, 4H), 7.02 (d, 7.6 Hz, 1H), 7.06 (s, 1H), 7.27 (t, J = 8.4 Hz, 1H), 7.37 (d, J = 7.6 Hz, 1H), 7.55- 7.61 (m, 2H)
MS (ESI +) 542 (M ⁺ +1, 100%).

Example 129
2'-Fluoro-N-isopropyl-2- (3-methoxypropoxy) -5 '-[(3-methoxypyrrolidin-1-yl) carbonyl] -N-[(3R) -piperidin-3-yl] biphenyl- 4-Carboxamide hydrochloride
¹ H NMR (400 MHz, MeOD) δ 1.26-1.28 (m, 7H), 1.89-2.07 (m, 7H), 2.78-2.80 (m, 4H), 2.96 (t, J = 11 Hz, 1H), 3.25 (s, 3H), 3.27 (s, 1H), 3.36 (s, 3H), 3.39 (t, J = 6.1 Hz, 2H), 3.55-3.74 (m, 5H), 3.99-4.12 (m, 5H), 7.02 (dd, J = 7.6 Hz, 0.6 Hz, 1H), 7.08 (s, 1H), 7.15-7.20 (m, 1H), 7.36-7.38 (m, 1H), 7.56-7.61 (m, 2H)
MS (ESI +): 556 (M ⁺ +1, 100%)

Example 130
2'-Fluoro-5 '-[(3-fluoropyrrolidin-1-yl) carbonyl] -N-isopropyl-2- (3-methoxypropoxy) -N-[(3R) -piperidin-3-yl] biphenyl- 4-Carboxamide hydrochloride
¹ H NMR (400 MHz, MeOD) δ 1.27 (m, 6H), 1.87-1.95 (m 4H), 2.01-2.25 (m, 2H), 2.78-2.81 (m, 1H), 2.96 (t, J = 12 Hz, 1H), 3.08 (d, J = 6 Hz, 4H), 3.26 (s, 3H), 3.94 (t, J = 6 Hz, 4H), 3.65 -3.87 (m, 5H), 3.95-4.19 (m , 2H), 4.10 (t, J = 6 Hz, 2H), 7.03 (d, J = 7.6 Hz, 1H), 7.08 (s, 4H), 7.10-7.21 (m, 1H), 7.25-7.30 (m, 1H), 7.37-7.39 (m, 1H), 7.45-7.49 (m, 1H)
MS (ESI +): 544 (M ⁺⁺ 1, 83%).

Example 131
5 '-(Azepan-1-ylcarbonyl) -2'-fluoro-N-isopropyl-2- (3-methoxypropoxy) -N-[(3R) -piperidin-3-yl] biphenyl-4-carboxamide hydrochloride salt
¹ H NMR (400 MHz, MeOD) δ 1.26 (s, 6H), 1.65 (s, 6H), 1.82-1.90 (m, 5H), 2.06 (s, 1H), 2.78 (s, 1H), 2.95 (s , 1H), 3.24-3.30 (m, 5H), 3.28 (s, 4H), 3.47 (s, 2H), 3.56-3.72 (m, 4H), 4.09 (s, 3H), 7.01-7.08 (m, 2H ), 7.24-7.26 (m, 1H), 7.36-7.43 (m, 3H)
MS (ESI +) 554 (M ⁺ +1, 100%).

Example 132
6-Fluoro--N ⁴ '- isopropyl-2' - (3-methoxypropoxy) -N ⁴ '- [(3R) - piperidin-3-yl] -N ³ - (tetrahydro -2H- pyran-4-yl) Biphenyl-3,4'-dicarboxamide hydrochloride
¹ H NMR (400 MHz, MeOD) δ 1.27 (s, 5H), 1.62-1.72 (m, 2H), 1.87-1.92 (m, 5H), 1.95-2.09 (m 1H), 2.79-2.80 (m, 1H ), 2.96 (t, J = 12 Hz, 1H), 3.25 (s, 3H), 3.38 (t, J = 6.2 Hz, 3H), 3.50 (td, J = 2, 11 HZ, 2H), 3.65 (s , 7H), 3.74-3.99 (m, 3H), 4.06-4.13 (m, 3H), 7.03 (dd, J = 7.6 Hz, 1,2 Hz, 1H), 7.08 (s, 1H), 7.25 (t, J = 9.3 Hz, 1H), 7.38 (d, J = 7.6 Hz, 1H), 7.86-7.91 (m, 2H)
MS (ESI +) 556 (M ⁺ +1, 100%).

Example 133
6-Fluoro--N ⁴ '- Iropuropiru -2' - (3-methoxypropoxy) -N ³ - methyl -N ⁴ '- [(3R) - piperidin-3-yl] -N ³ - (tetrahydro -2H- pyran -4-yl) biphenyl-3,4'-dicarboxamide hydrochloride
¹ H NMR (400 MHz, MeOD) δ 1.26-1.29 (m, 6H), 1.68 (s, 2H), 1.87-1.94 (m, 6H), 2.04-2.10 (m, 1H), 2.79 (s, 1H) , 2.96 (s, 4H), 3.26 (s, 3H), 3.29-3.31 (m, 1H), 3.40 (t, J 6.2 Hz, 4H), 3.56-3.75 (m, 4H), 4.02 (s, 3H) , 4.10 (t, 6.1 Hz, 3H), 7.03 (dd, J = 1.2 Hz, 7.6 Hz, 1H), 7.07 (s, 1H), 7.27 (t, J = 9.44 Hz, 1H), 7.37 (d, J = 7.6 Hz, 1H), 7.41-7.46 (m, 2H)
MS (ESI +): 570 (M ⁺ +1, 100%).

Example 134
5'-ethyl-6-fluoro-N ⁴ '-isopropyl-2'-(3-methoxypropoxy) -N ³ , N ³ -dimethyl-N ⁴ '-[(3R) -piperidin-3-yl] biphenyl- 3,4'-dicarboxamide hydrochloride
¹ H NMR (400 MHz, MeOD) δ 1.22-1.26 (m, 9H), 1.87-1.96 (m, 4H), 2.09-2.12 (m, 1H), 2.57-2.61 (m, 2H), 2.83-2.86 ( m, 1H), 2.95-2.98 (m, 1H), 3.07 (d, J = 14 Hz, 6H), 3.26 (s, 3H), 3.36-3.43 (m, 4H), 3.36-3.43 (m, 4H) , 3.66-3.74 (m, 2H), 3.85-3.89 (m, 1H), 4.05-4.17 (m, 3H), 6.88 (d, J = 22 Hz, 1H), 7.25 (t, J = 9.5 Hz, 2H ), 7.44-7.48 (m, 2H)
MS (ESI +) 528 (M ⁺ +1, 100%).

Example 135
MS (ESI +) 542 (M ⁺ +1, 100%).

Example 136
MS (ESI +) 542 (M ⁺ +1, 100%).

Example 137
MS (ESI +) 5556 (M ⁺ +1, 100%).

Example 138
MS (ESI +) 570 (M ⁺ +1, 100%).

Example 139
MS (ESI +) 598 (M ⁺ +1, 100%).

Example 140
MS (ESI +) 584 (M ⁺ +1, 100%).

Example 141
¹ H NMR (400 MHz, MeOD) δ 1.16 (s, 6H), 1.22-1.28 (m, 12H), 1.57-1.63 (m, 2H), 1.80-1.99 (m, 5H), 2.08-2.12 (m, 1H), 2.54-2.63 (m, 2H), 2.80-2.89 (m, 2H), 2.94-2.99 (m, 2H), 3.26 (s, 3H), 3.37-3.43 (m, 4H), 3.66-3.67 ( m, 2H), 3.86-3.89 (m, 2H), 4.05-4.17 (m, 3H), 6.89 (d, J = 24 Hz, 1H), 7.24-7.29 (m, 2H), 7.40-7.48 (m, 2H)
MS (ESI +) 726 (M ⁺ +1, 100%).

Example 142
5-ethyl-2'-fluoro-N-isopropyl-2- (3-methoxypropoxy) -N-[(3R) -piperidin-6-3-yl] -5 '-(piperidin-1-ylcarbonyl) biphenyl- 4-Carboxamide hydrochloride
¹ H NMR (400 MHz, MeOD) δ 1.22-1.28 (m, 9H), 1.58-1.72 (m, 7H), 1.86-1.99 (m, 4H), 2.04-2.12 (m, 1H), 2.54-2.63 ( m, 2H), 2.83-2.86 (m, 1H), 2.95-3.02 (m, 1H), 3.26 (s, 3H), 3.38 (t, J = 6.2 Hz, 2H), 3.43-3.36 (m, 3H) , 3.63-3.74 (m, 4H), 3.74-3.88 (m, 1H), 4.04-4.07 (m, 1H), 4.14 (t, J = 12 Hz, 2H), 6.88 (d, J = 24 Hz, 1H ), 7.24-7.28 (m, 2H), 7.39-7.47 (m, 2H)
MS (ESI +) 568 (M ⁺ +1, 100%).

Example 143
5'-ethyl-6-fluoro--N ⁴ '- isopropyl-2' - (3-methoxypropoxy) -N ³ - methyl -N ⁴ '- [(3R) - piperidin-3-yl] -N ³ - ( Tetrahydro-2H-pyran-4-yl) biphenyl-3,4'-dicarboxamide hydrochloride
¹ H NMR (400 MHz, MeOD) δ 1.21-1.28 (m, 10H), 1.56-1.67 (m, 3H), 1.86-1.96 (m, 6H), 2.08-2.12 (m, 1H), 2.54-2.61 ( m, 2H), 2.83-2.85 (m, 1H), 2.96-2.99 (m, 4H), 3.25 (s, 3H), 3.37-3.43 (m, 4H), 3.52-3.65 (m, 3H), 3.74- 3.88 (m, 1H), 4.04-4.06 (m, 4H), 4.04-4.06 (m, 4H), 4.14 (t, J = 12Hz, 1H), 6.89 (d, J = 24 z, 1H), 7.15- 7.29 (m, 2H), 7.41-7.45 (m, 2H)
MS (ESI +): 598 (M ⁺ +1, 100%)

Example 144
MS (ESI +) 554 (M ⁺ +1, 100%).

Example 145
MS (ESI +) 498 (M ⁺ +1, 100%).
Example 146
¹ H NMR (400 MHz, CDCl3) δ 10.1-9.82 (brs, 1H), 9.84-9.65 (brs, 1H), 7.90-7.79 (m, 1H), 7.65-7.55 (m, 1H), 7.32-7.11 ( m, 3H), 6.54-6.45 (brs, 1H), 4.22-4.07 (brs, 1H), 4.08-3.93 (brs, 1H), 3.95-3.80 (brs, 1H), 3.55-3.32 (m, 1H), 3.22 (s, 3H), 3.01-2.78 (m, 3H), 2.53-2.43 (m, 1H), 2.13-1.95 (m, 2H), 1.92-1.75 (m, 2H), 1.57-1.39 (m, 4H ), 1.39-1.28 (m, 3H), 1.27-1.18 (m, 3H), 0.91-0.80 (m, 2H), 0.67-0.55 (m, 2H).
MS (ESI +) 510 (M ⁺ +1, 100%).

Example 147
¹ H NMR (400 MHz, CDCl3) δ 10.2-9.85 (brs, 1H), 9.84-9.65 (brs, 1H), 7.59-7.50 (m, 1H), 7.42-7.33 (m, 1H), 7.31-7.22 ( m, 1H), 7.23-7.12 (m, 3H), 4.26-4.10 (brs, 1H), 4.09-3.92 (brs, 1H), 3.92-3.77 (brs, 1H), 3.54-3.33 (m, 2H), 3.28-3.22 (m, 1H), 3.24 (s, 3H), 3.09 (s, 3H), 3.02-2.66 (m, 3H), 2.53 (brt, J = 9.2Hz, 2H), 2.21-1.97 (m, 2H), 1.93-1.83 (m, 1H), 1.60-1.40 (m, 4H), 1.39-1.28 (m, 3H), 1.29-1.18 (m, 3H), 0.75-0.59 (m, 2H), 0.58- 0.41 (m, 2H).
MS (ESI +) 524 (M ⁺ +1, 100%).

Example 148
¹ H NMR (400 MHz, CD3OD) δ7.55-7.46 (m, 1H), 7.48-7.25 (m, 3H), 7.25-7.17 (m, 1H), 7.16-7.08 (m, 1H), 4.18-4.05 (brs, 1H), 4.05-3.91 (brs, 1H), 3.76-3.31 (m, 10H), 3.31 (s, 3H), 3.22 (s, 3H), 3.19-3.08 (m, 1H), 2.97 (brt , J = 12.8Hz, 1H), 2.59 (brt, J = 7.1Hz, 2H), 2.14-2.05 (m, 1H), 2.02-1.72 (m, 2H), 1.55-1.46 (m, 4H), 1.42- 1.08 (m, 9H).
MS (ESI +) 556 (M ⁺ +1, 100%).

Example 149
¹ H NMR (400 MHz, CD3OD) δ7.52-7.45 (m, 1H), 7.38-7.27 (m, 3H), 7.24-7.19 (m, 1H), 7.18-7.08 (m, 1H), 4.18-3.92 (m, 3H), 3.61-3.45 (m, 5H), 3.48-3.25 (m, 2H), 3.31 (s, 3H), 3.21 (s, 3H), 3.18-3.08 (m, 1H), 2.97 (brt , J = 12.8Hz, 1H), 2.93-2.72 (m, 1H), 2.59 (brt, J = 7.2Hz, 2H), 2.16-2.05 (m, 1H), 2.00-1.72 (m, 2H), 1.57- 1.33 (m, 4H), 1.43-1.13 (m, 13H) ,.
MS (ESI +) 570 (M ⁺ +1, 100%).

Example 150
MS (ESI +) 540 (M ⁺ +1, 100%).

Example 151
MS (ESI +) 568 (M ⁺ +1, 100%).

Example 152
MS (ESI +) 5640 (M ⁺ +1, 100%).

Example 153
MS (ESI +) 5968 (M ⁺ +1, 100%).

Example 154
MS (ESI +) 596 (M ⁺ +1, 100%).

Example 155
MS (ESI +) 554 (M ⁺ +1, 100%).

Example 156
MS (ESI +) 568 (M ⁺ +1, 100%).

Example 157
MS (ESI +) 556 (M ⁺ +1, 100%).

Example 158
MS (ESI +) 588 (M ⁺ +1, 100%).

Example 159
5-Chloro-2'-fluoro-N-isopropyl-2- (3-methoxypropoxy) -5 '-(2-oxopyrrolidin-1-yl) -N-[(3R) -piperidin-3-yl] biphenyl -4-Carboxamide hydrochloride

In the same manner as in Example 1, the title compound (248.6 mg) was synthesized from the corresponding compound.
¹ H NMR (400 MHz, CDCl ₃ ) δ 9.84 (brs, 2H), 7.68-7.60 (m, 1H), 7.57-7.51 (m, 1H), 7.29-7.27 (m, 1H), 7.12 (t, J = 9.05 Hz, 1H), 6.83 (s, 0.5H), 6.75 (s, 0.5H), 4.21 (brs, 1H), 4.05-4.01 (m, 2H), 3.93-3.77 (m, 4H), 3.56- 3.42 (m, 1H), 3.44-3.33 (m, 2H), 3.28 (s, 1.5H), 3.27 (s, 1.5H), 3.04-2.86 (m, 2H), 2.62 (t, J = 8.00 Hz, 2H), 2.16 (q, J = 7.36 Hz, 2H), 2.08-1.98 (m, 2H), 1.94-1.91 (m, 3H), 1.42 (d, J = 6.36 Hz, 1.5H), 1.32-1.24 ( m, 3H), 1.17 (d, J = 6.48 Hz, 1.5H), 0.89 (t, J = 6.64 Hz, 1H).
MS (ESI +) 546 (M ⁺ +1, 100%).

Example 160
N-isopropyl-3- (3-methoxypropoxy) -4- (3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) -N-[(3R) -piperidine -3-yl] benzamide hydrochloride

In the same manner as in Example 1, the title compound (73.0 mg) was synthesized from the corresponding compound.
¹ H NMR (400 MHz, CDCl ₃ ) δ 9.78 (brs, 2H), 7.31 (d, J = 7.72 Hz, 1H), 7.25-7.20 (m, 2H), 7.14 (s, 1H), 6.95-6.92 ( m, 2H), 4.17 (brs, 1H), 4.13-3.96 (m, 3H), 3.95-3.84 (m, 1H), 3.51 (brs, 1H), 3.47-3.42 (m, 3H), 3.41 (s, 3H), 3.29 (s, 3H), 2.98-2.82 (m, 2H), 2.21-2.08 (m, 1H), 2.06-1.96 (m, 3H), 1.90-1.85 (m, 1H), 1.34 (d, J = 6.36 Hz, 3H), 1.23 (d, J = 6.32 Hz, 3H).
MS (ESI +) 482 (M ⁺ +1, 100%).

Example 161
2-Chloro-N-isopropyl-5- (3-methoxypropoxy y) -4- (3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) -N- [ (3R) -Piperidin-3-yl] benzamide hydrochloride

In the same manner as in Example 1, the title compound (187.1 mg) was synthesized from the corresponding compound.
H NMR (400 MHz, CDCl ₃ ) δ 9.83-9.70 (brs, 2H), 7.33 (d, J = 2.12 Hz, 1H), 7.24 (s, 1H), 7.14-7.12 (m, 1H), 6.84 (s , 0.5H), 6.78 (s, 0.5H), 4.25-4.14 (m, 1H), 4.10-4.03 (m, 2H), 3.976-3.84 (m, 1H), 3.83-3.75 (m, 1H), 3.55 -3.49 (m, 1H), 3.50 (s, 3H), 3.49-3.41 (m, 5H), 3.30 (s, 3H), 3.00-2.86 (m, 2H), 2.11-2.04 (m, 1H), 1.98 (quint.J = 5.88 Hz, 2H), 1.95-1.87 (m, 1H), 1.42 (d, J = 6.76 Hz, 1.5H), 1.33-1.27 (m, 3H), 1.17 (d, J = 6.64 Hz , 1.5H).
MS (ESI +) 515 (M ⁺ , 100%).

Example 162
5-Cyano-2'-fluoro-N-isopropyl-2- (3-methoxypropoxy) -N-[(3R) -piperidin-3-yl] -5 '-(piperidin-1-ylcarbonyl) biphenyl-4 -Carboxamide hydrochloride

The title compound (306 mg) was synthesized from the corresponding compound by a method similar to that in Example 106.
¹ H NMR (400 MHz, CD ₃ OD) δ 1.29 (m, 6H), 1.58-1.73 (m, 7H), 1.86-2.01 (m, 4H), 2.08-2.14 (m, 1H), 2.82-2.86 ( m, 1H), 2.97-3.02 (m, 1H), 3.37-3.48 (m, 6H), 3.63-3.70 (m, 3H), 3.78-3.85 (m, 1H), 4.11 (t, J = 12 Hz, 1H), 4.20 (t, J = 6 Hz, 2H), 7.28-7.33 (m, 2H), 7.45 (dd, J = 2.1, 6.8 Hz, 1H), 7.49-7.53 (m, 1H), 7.78 (s , 1H)
MS (ESI +) 565 (M ⁺ +1, 100%).

Example 163
5-Bromo-2'-fluoro-N-isopropyl-2- (3-methoxypropoxy) -5 '-(morpholin-4-ylcarbonyl) -N-[(3R) -piperidin-3-yl] biphenyl- 4-Carboxamide hydrochloride

In the same manner as in Example 1, the title compound (167.4 mg) was synthesized from the corresponding compound.
¹ H NMR (400 MHz, CDCl ₃ ) δ 9.75 (brs, 2H), 8.03 (s, 1H), 7.45-7.38 (m, 2H), 7.18 (t, J = 8.85 Hz, 1H), 6.85 (s, 0.47H)), 6.76 (s, 0.53H), 4.21 (brs, 1H), 4.12-4.00 (m, 2H), 3.93 (brs, 1H), 3.86-3.64 (m, 8H), 3.61-3.43 (m , 2H), 3.42-3.32 (m, 2H), 3.31 (s, 1.6H), 3.29 (s, 1.4H), 3.02-2.87 (m, 2H), 2.35-2.00 (m, 3H), 2.01-1.86 (m, 3H), 1.45 (d, J = 6.04 Hz, 1.5H), 1.35-1.25 (m, 3H), 1.77 (d, J = 6.48 Hz, 1.5H).
MS (ESI +) 620 (M ⁺ , 100%), 618 (M ⁺ +2, 100%).

Example 164
2'-Fluoro-N-isopropyl-2- (4-methoxybutyl) -N-[(3R) -piperidin-3-yl] biphenyl-4-carboxamide hydrochloride

In the same manner as in Example 1, the title compound (71 mg) was synthesized from the corresponding compound.
MS (ESI +) 427 (M ⁺ +1, 100%).

Example 165
5'-ethyl-6-fluoro--N ⁴ '- isopropyl-2' - ^{(3-methoxypropoxy) -N 4 '- [(3R} ) - piperidin-3-yl] -N ³ - (tetrahydro -2H- pyran -4-yl) biphenyl-3,4'-dicarboxamide hydrochloride

In the same manner as in Example 1, the title compound (78 mg) was synthesized from the corresponding compound.
¹ H NMR (400 MHz, MeOD) δ 1.21-1.32 (m, 9H), 1.58-1.72 (m, 2H), 1.84-1.98 (m, 6H), 2.10-2.13 (m, 1H), 2.57-2.64 ( m, 2H), 2.81-2.86 (m, 2H), 2.91-2.99 (m, 1H), 3.25 (s, 3H), 3.29-3.38 (m, 4H), 3.49-3.64 (m, 6H), 3.75- 4.14 (m, 6H), 6.87 (d, J = 20 Hz, 1H), 7.22-7.28 (m, 2H), 7.84-7.89 (m, 2H)
MS (ESI +): 584 (M ⁺⁺ 1, 100%).

Example 166
5-ethyl-2'-fluoro-N-isopropyl-5 '-{[4- (methoxymethyl) piperidin-1-yl] carbonyl} -2- (3-methoxypropoxy) -N-[(3R) -piperidine -3-yl] biphenyl-4-carboxamide hydrochloride

In the same manner as in Example 1, the title compound (120 mg) was synthesized from the corresponding compound.
¹ H NMR (400 MHz, CD ₃ OD) δ 7.47-7.39 (m, 2H), 7.28-7.24 (m, 2H), 6.91-6.86 (m, 1H), 4.61 (brs, 1H), 4.17-4.04 ( m, 3H), 3.91-3.82 (m, 2H), 3.66-3.57 (m, 1H), 3.43-3.37 (m, 4H), 3.32-3.13 (m, 9H), 3.02-2.96 (m, 1H), 2.89-2.80 (m, 2H), 2.63-2.56 (m, 2H), 2.13-2.09 (m, 1H), 2.03-1.72 (m, 7H), 1.29-1.22 (m, 11H).
MS (ESI +) 612 (M ⁺ +1, 100%).

Example 167
N ^3, 5'-diethyl-6-fluoro--N ⁴ '- isopropyl-2' - ^{(3-methoxypropoxy) -N 4 '- [(3R} ) - piperidin-3-yl] -N ³ - (tetrahydro - 2H-pyran-4-yl) biphenyl-3,4'-dicarboxamide hydrochloride

In the same manner as in Example 1, the title compound (290 mg) was synthesized from the corresponding compound.
¹ H NMR (400 MHz, CD ₃ OD) δ 7.43-7.40 (m, 1H), 7.38-7.36 (m, 1H), 7.29-7.24 (m, 2H), 6.91-6.86 (m, 1H), 4.17- 3.86 (m, 7H), 3.62-3.57 (m, 1H), 3.48-3.38 (m, 6H), 3.26 (s, 3H), 3.22 (m, 1H), 2.99-2.97 (m, 1H), 2.86- 2.83 (m, 1H), 2.63-2.58 (m, 2H), 2.13-1.82 (m, 7H), 1.67-1.56 (m, 2H), 1.29-1.22 (m, 12H).
MS (ESI +) 612 (M ⁺ +1, 100%).

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

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

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

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

Claims (8)

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

[Wherein, R ^1a represents a hydrogen atom, a halogen atom, a hydroxyl group, a formyl group, a carboxy group, a cyano group, an optionally substituted C _1-6 alkyl group, an optionally substituted C _3-10 cycloalkyl group, Optionally substituted C _2-6 alkynyl group, optionally substituted C _2-6 alkenyl group, optionally substituted C _1-6 alkylthio group, optionally substituted C _1-6 alkylsulfinyl group, substituted A C _1-6 alkylsulfonyl group which may be substituted, a C _1-6 alkoxy group which may be substituted, a C _3-10 cycloalkoxy group which may be substituted, an amino group which may be mono- or di-substituted, optionally substituted 5- to 7-membered cyclic amino group, an optionally substituted carbamoyl group, an optionally substituted C _1-4 alkoxycarbonyl group or optionally substituted C _1-4 a also, It is Kill carbonyl group;
R ^1b is substituted _{C 1-8} alkyl group, optionally substituted _{C 1-6} alkylsulfinyl group, optionally substituted _{C 1-6} alkylsulfonyl group, a substituted _{C 1-6} alkoxy group, C _3-6 alkynyloxy group which may be substituted, amino group which may be mono- or di-substituted, carbamoyl group which may be substituted, C _1-4 alkoxycarbonyl group which may be substituted, or substituted An optionally substituted C _1-4 alkylcarbonyl group (wherein the substituted C _1-8 alkyl group is mono-C _1-6 alkoxycarbonylamino, C _1-4 alkoxy, C _3-6 cycloalkyl, C _1-4 substituted with one group selected from alkoxy _{C 1-4} group consisting of alkoxy and _{C 1-6} alkylsulfonyl, substituted _{C 1-6} Al The alkoxy group is substituted with one group selected from the group consisting of C _1-4 alkoxy, C _3-6 cycloalkyl and C _1-4 alkoxycarbonylamino.);
G is the following formula

Or an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group (wherein
R ^1c is a hydrogen atom, a halogen atom, an optionally substituted C _1-6 alkyl group, or an optionally substituted C _1-6 alkoxy group;
R ^1f is a hydrogen atom, a halogen atom, a carboxyl group, a cyano group, an optionally substituted C _1-6 alkyl group, optionally substituted C _1-6 alkoxy group, an optionally substituted carbamoyl group, or a substituted, A C _1-4 alkoxycarbonyl group which may be
R ^1g represents a hydrogen atom, a halogen atom, a carboxyl group, a cyano group, an optionally substituted C _1-6 alkyl group, optionally substituted C _1-6 alkoxy group, an optionally substituted carbamoyl group, or a substituted, A C _1-4 alkoxycarbonyl group which may be
R ^1d is a cyano group, a halogen atom, or a group: —DE
(Here, D is a single bond, —O—, —SO ₂ —, —CO—, —COO—, —CH ₂ SO ₂ —, —COCO—, —OCH ₂ CH ₂ CO—, —OCH ₂ CO _{-, - OC (CH 3)} (CH 3) CO -, - CH 2 OCO -, - N (R h) CO -, - N (R h) SO 2 -, - N (R h) COO -, - _{^{OCO -, - SO 2 N (}} R h) CO -, - OCH 2 CH 2 SO 2 -, - C (CH 3) (CH 3) CO-, or a _-CH 2 _OCH 2 CO-,
R ^h is a hydrogen atom, a C _1-4 alkoxycarbonyl group, or an optionally substituted C _1-6 alkyl group,
E represents a hydrogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C _2-6 alkenyl group, an optionally substituted C _3-10 cycloalkyl group, a mono- or di-substituted An optionally substituted amino group, an optionally substituted 4 to 7 membered cyclic amino group, an optionally substituted 5 or 6 membered saturated heterocyclic group, or an optionally substituted 5 to 10 membered It is a monocyclic or polycyclic heteroaryl group. (However, when D is —O—, —COO— or —N (R ^h ) COO—, E is not the amino group).
R ^1e represents a hydrogen atom, a halogen atom, a carboxyl group, a cyano group, an optionally substituted _{C 1-6} alkyl group, optionally substituted _{C 1-6} alkoxy group, an optionally _{C 3-10} cycloalkyl substituted An alkyl group, an optionally substituted C _3-10 cycloalkyloxy group, a saturated heterocyclic oxy group, an optionally substituted carbamoyl group, or an optionally substituted C _1-4 alkoxycarbonyl group,
Alternatively, R ^1d and R ^1e together form a fused ring. );
R ² is an optionally substituted C _1-6 alkyl group, an optionally substituted C _2-6 alkenyl group, an optionally substituted C _2-6 alkynyl group, an optionally substituted C _3-10 cyclo An alkyl group, an optionally substituted C _5-6 cycloalkenyl group, an optionally substituted C _6-10 aryl group, an optionally substituted C _7-14 aralkyl group, or an optionally substituted 5-10 membered A membered monocyclic or polycyclic 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 C _1-6 alkyl group, an optionally substituted C _2-6 alkenyl group, an optionally substituted C _2-6 alkynyl group, an optionally substituted C _{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) In the case of — and — (CH ₂ ) _s SO ₂ N (R ⁴ ) —, R ⁴ and B may be bonded together to form a ring. Or any two of R ^3a , R ^3b , R ^3c and R ^3d are hydrogen atoms and the remaining two together form a bridged ring with the piperidine ring;
R ⁴ represents a hydrogen atom, an optionally substituted C _1-6 alkyl group, an _optionally substituted C _3-10 cycloalkyl group, an _optionally substituted C _6-10 aryl group, or an _optionally substituted C _{A 7-14} aralkyl group or an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group;
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. ] R ^1a is a hydrogen atom, a halogen atom, a cyano group, an optionally substituted _{C 1-6} alkyl group, an optionally substituted _{C 3-6} cycloalkyl group or an optionally substituted _{C 1-6} alkoxy group, Is;
R ^1b is substituted _{C 1-6} alkyl _{group, C 1-4} alkoxy or _{C 1-4} alkoxycarbonylamino substituted by a _{C 1-6} alkoxy group or an optionally substituted _{C 3-6} alkynyloxy, (Wherein the substituted C _1-6 alkyl groups are mono-C _1-4 alkoxycarbonylamino, C _1-4 alkoxy, C _1-4 alkoxy C _1-4 alkoxy and C _1-6 alkyl). Substituted with one group selected from the group consisting of sulfonyl);
R ^1c is a hydrogen atom, a halogen atom, or an optionally substituted C _1-6 alkoxy group;
R ^1f is a hydrogen atom, a halogen atom, a carboxyl group, a cyano group, an optionally substituted C _1-6 alkyl group, optionally substituted C _1-6 alkoxy group, an optionally substituted carbamoyl group, or a substituted, A C _1-4 alkoxycarbonyl group which may be
R ^1g represents a hydrogen atom, a halogen atom, a carboxyl group, a cyano group, an optionally substituted C _1-6 alkyl group, optionally substituted C _1-6 alkoxy group, an optionally substituted carbamoyl group, or a substituted, A C _1-4 alkoxycarbonyl group which may be
R ^1d is a cyano group, a halogen atom, or a group: —DE
(Here, D is a single bond, —O—, —SO ₂ —, —CO—, —COO—, —CH ₂ SO ₂ —, —COCO—, —OCH ₂ CH ₂ CO—, —OCH ₂ CO _{-, - OC (CH 3)} (CH 3) CO -, - CH 2 OCO -, - N (R h) CO -, - N (R h) SO 2 -, - N (R h) COO -, - _{^{OCO -, - SO 2 N (}} R h) CO -, - OCH 2 CH 2 SO 2 -, - C (CH 3) (CH 3) CO-, or a _-CH 2 _OCH 2 CO-,
R ^h is a hydrogen atom, a C _1-4 alkoxycarbonyl group, or an optionally substituted C _1-6 alkyl group,
E represents a hydrogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C _3-10 cycloalkyl group, a mono- or di-substituted amino group, and optionally substituted 4 A 5- to 7-membered cyclic amino group, an optionally substituted 5- or 6-membered saturated heterocyclic group, or an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group . );
R ^1e represents a hydrogen atom, a halogen atom, a carboxyl group, a cyano group, an optionally substituted _{C 1-6} alkyl group, optionally substituted _{C 1-6} alkoxy group, an optionally _{C 3-10} cycloalkyl substituted The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is an alkyloxy group, a saturated heterocyclic oxy group, an optionally substituted carbamoyl group, or an optionally substituted C _1-4 alkoxycarbonyl group. . The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R ^1a is a halogen atom, a cyano group, or an optionally substituted C _1-6 alkyl group. R ^1b _is, according to any one of claims 1 to 3 is a _{C 1-4 C 1-6} alkoxy group substituted with an alkoxy or _{C 1-6} alkyl group substituted by _{C 1-4} alkoxy, Or a pharmaceutically acceptable salt thereof. R < ² _{> is the} C1-6 alkyl group which may be substituted, The compound as described in any one of Claims 1-4, or its pharmaceutically acceptable salt. The compound according to claim 5, wherein R ² is an isopropyl group, or a pharmaceutically acceptable salt thereof. 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 6, or a pharmaceutically acceptable salt thereof. n is 1, The compound as described in any one of Claims 1-7, or its pharmacologically acceptable salt.