JP2010064982A - Alkylamino derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new compound having an excellent renin inhibitory activity. <P>SOLUTION: The compound is represented by formula (I) (wherein R<SP>1a</SP>and R<SP>1d</SP>are each independently the same or different and a halogen atom or the like; R<SP>1b</SP>is 1-6C alkyl which may be substituted or the like; R<SP>1c</SP>is a hydrogen atom, 1-6C alkyl which may be substituted or the like or may form a ring together with them; R<SP>2</SP>is alkyl which may be substituted or the like; R<SP>3a</SP>and R<SP>3b</SP>are each independently the same or different and a hydrogen atom, 1-6C alkyl which may be substituted or the like; R<SP>4a</SP>and R<SP>4b</SP>are each independently the same or different and a hydrogen atom, 1-6C alkyl which may be substituted or the like) or a pharmacologically acceptable salt thereof. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a derivative useful as a medicine. More specifically, the present invention relates to an alkylamino derivative effective as a renin inhibitor. Furthermore, the present invention relates to a therapeutic agent for hypertension comprising an alkylamino derivative effective as a renin inhibitor as an active ingredient.

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

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

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

  As a compound having an ethylenediamine skeleton as a partial structure, for example, Patent Document 1 reports an aminocarbonyl-substituted benzimidazole derivative.

[Wherein R ¹ is a C ₁ -C ₁₀ alkyl group or the like; R ² is —C (═NH) NH ₂ or the like; R ³ and R ⁴ are the same or different and are each a hydrogen atom, C ₁ -C ₆ alkyl group (the alkyl group is —NH ₂ , —NH (C ₁ -C ₄ alkyl), —N (C ₁ -C ₄ alkyl) ₂ , —NH (phenyl), —N (phenyl ) ₂ , -NH benzyl, -N (benzyl) _2, etc.). ]

  The literature includes:

The compounds of Example 278, Example 294, Example 310, and Example 342 in structure are specifically described. Both are common to the compounds of the present invention in that they have an ethylenediamine skeleton. However, the compound of Patent Document 1 is different in structure from the compound of the present invention in that it has benzimidazole substituted at the 2-position with a phenethyl group as a partial structure.

  On the other hand, Patent Document 2 reports a substituted-benzyloxybenzoic acid amide derivative.

Wherein R ¹ is a hydrogen atom, halogen or trifluoromethyl; R ² is a hydrogen atom or halogen; R ³ is a hydrogen atom or halogen; R ⁴ is a hydrogen atom, chlorine, Fluorine, nitro, trifluoromethyl, trifluoromethoxy, formyl, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy; R ⁵ is a hydrogen atom or halogen; R ⁶ is a hydrogen atom or C ₁ be -C ₄ alkyl; ^{R 7} _is an C 3 -C ₈ alkyl, such as; ^{R 8} is a hydrogen atom or a _C 1 -C ₄ alkyl; ^{R 9} _is C 1 -C ₆ alkyl (in which is amino, mono - _alkylamino, may be substituted with C 1 -C ₄ alkylcarbonylamino or _C 1 -C ₄ alkoxycarbonylamino) in there;. ^{R 10} is hydrogen atoms Or _C 1 -C ₄ alkyl. ]

  The literature includes:

The compound of Example 29 of the structure and the like are specifically described. The compound is common to the compound of the present invention in that it has an ethylenediamine skeleton. However, the compound of Patent Document 2 is characterized in that the phenyl of phenylcarbonyl is substituted with a benzyloxy group and is different from the phenyl substituent of the compound group of the present invention. Therefore, the structure of the compound of the present invention and the compound group of Patent Document 2 are different.

  Moreover, the compound group described in the said patent document is an application regarding the use different from a renin inhibitor. Therefore, it has not been known so far that a compound group having a phenylcarbonyl-ethylenediamine skeleton having a specific substituent as a partial structure like the compound group of the present invention is useful as a renin inhibitor.

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

International Publication No. 01/014342 Pamphlet International Publication No. 06/094763 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.

Item 1: A compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

[Wherein, R ^1a and R ^1d are the same or different and each independently 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 _2-6 alkenyl group, an optionally substituted C _2-6 alkynyl group, an optionally substituted C _3-10 cycloalkyl group, an _optionally substituted C _5-6 cycloalkenyl group, optionally substituted _{C 1-6} alkylthio group, optionally substituted _{C 1-6} alkylsulfinyl group, optionally substituted _{C 1-6} alkylsulfonyl group, optionally substituted _{C 1-6} alkoxy group, C _3-10 cycloalkoxy group which may be substituted, C _5-6 cycloalkenyloxy group which may be substituted, amino group which may be mono- or di-substituted, which may be substituted There 5- to 7-membered cyclic amino group, an optionally substituted amino group, optionally substituted C _1-4 alkoxycarbonyl group, an optionally substituted C _1-4 alkylcarbonyl group, optionally substituted A good C _6-10 aryl group, an optionally substituted C _6-10 aryloxy group, or an optionally substituted 5-10 membered monocyclic or polycyclic heteroaryl group;
R ^1b is an optionally substituted _{C 1-6} alkyl group, optionally substituted _{C 1-6} alkylsulfinyl group, optionally substituted _{C 1-6} alkylsulfonyl group, an optionally substituted _{C 1- 6} alkoxy group, C _3-6 alkynyloxy group which may be substituted, amino group which may be mono- or di-substituted, aminocarbonyl group which may be substituted, C _1-4 alkoxycarbonyl group which may be substituted Or an optionally substituted C _1-4 alkylcarbonyl group (wherein the optionally substituted C _1-6 alkyl group includes C _1-4 alkoxy, C _3-6 cycloalkoxy, and C _1-6 alkylcarbonylamino (said alkyl may be substituted with 1-3 fluorine atoms.) is one group selected from the group consisting of, optionally substituted Substituents have _{C 1-6} alkoxy groups, one to three fluorine atoms, _{hydroxy, C 1-4 alkoxy, C 3-6} cycloalkoxy, cyano, _{mono--C 1-6} alkylcarbonylamino, mono- -C _1-6 alkoxycarbonylamino, aminocarbonyl, C _1-6 alkylaminocarbonyloxy, C _1-4 alkoxycarbonyl, and one group selected from the group consisting of C _1-4 alkylcarbonyl).
R ^1c is 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 _3-6 cycloalkyl group, or optionally substituted. Good C _5-6 cycloalkenyl group, optionally substituted 5- or 6-membered saturated heterocyclic group, optionally substituted C _1-6 alkylthio group, optionally substituted C _1-6 alkylsulfinyl group , optionally substituted _{C 1-6} alkylsulfonyl group, optionally substituted _{C 6-10} arylthio group, optionally substituted _{C 6-10} arylsulfinyl group, optionally substituted _{C 6-10} arylsulfonyl Group, optionally substituted C _1-6 alkoxy group, optionally substituted C _3-6 cycloalkyloxy group, optionally substituted C _6-10 aryloxy group, substituted An optionally substituted amino group, an optionally substituted aminocarbonyl group, an optionally substituted C _1-4 alkoxycarbonyl group, an optionally substituted C _3-6 cycloalkyloxycarbonyl group, an optionally substituted C _1-4 alkylcarbonyl group, optionally substituted C _3-6 cycloalkylcarbonyl group, optionally substituted C _6-10 arylcarbonyl group, _optionally substituted 5 to 10 membered monocyclic or polycyclic A cyclic heteroarylcarbonyl group, an optionally substituted C _7-14 aralkyl group, an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group, or

A group represented by
R ^1e , R ^1f , R ^1g and R ¹ⁱ are each independently the same or different and are each a hydrogen atom, a halogen atom, a carboxy group, a cyano group, an optionally substituted C _1-6 alkyl group, or a substituted group. also a C _1-6 alkoxy group, an optionally substituted C _3-10 cycloalkyl group, optionally substituted C _3-10 cycloalkyl group, heterocyclic oxy group to saturation which may be substituted, is substituted An optionally substituted aminocarbonyl group, or an optionally substituted C _1-4 alkoxycarbonyl group;
R ^1h is a cyano group, a halogen atom, or a group: -AB
(Here, A 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 j) CO -, - N (R j) SO 2 -, - N (R j) COO -, - _{^{OCO -, - SO 2 N (}} R j) CO -, - OCH 2 CH 2 SO 2 -, - C (CH 3) (CH 3) CO-, or a _-CH 2 _OCH 2 CO-,
R ^j is a hydrogen atom, a C _1-4 alkylcarbonyl group, or an optionally substituted C _1-6 alkyl group,
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 _3-10 cycloalkyl group, a mono- or di-substituted An optionally substituted amino group, an optionally substituted 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 cyclic group It is a monocyclic or polycyclic heteroaryl group. (However, when A is —O—, —COO— or —N (R ^j ) COO—, B is not the amino group).
Alternatively, R ^1e , R ^1h and R ¹ⁱ are both hydrogen atoms, and R ^1f and R ^1g together form a condensed ring. Or R ^1b and R ^1c are taken together to form

A ring represented by (wherein
G ¹ is —N (R ^1k ) —, an oxygen atom, —CH (R ^1k ) —, or —C (R ^1k ) ^═ ,
G ² is —CH ₂ —, —CO—, —CS—, or —CH═;
G ³ is —C (R ^1m ) (R ¹ⁿ ) —, —N (R ^1k ) —, —CO—, or an oxygen atom,
G ⁴ is —C (R ^1m ) (R ¹ⁿ ) —, —N (R ^1k ) —, ^—SO— , —SO ₂ —, an oxygen atom, a sulfur atom, or an absent atom.
R ^1k is optionally substituted _{C 1-6} alkyl group, optionally substituted _{C 2-6} alkenyl group, an optionally substituted _{C 2-6} alkynyl group or substituted 5-membered to 10, Membered monocyclic or polycyclic heteroaryl C _1-4 alkyl group,
R ^1m and R ¹ⁿ are each independently the same or different and are each a hydrogen atom, a halogen atom, a hydroxyl group, a carboxy group, an optionally substituted C _2-6 alkenyl group, or an optionally substituted C _5-6 cycloalkenyl. Group, optionally substituted C _2-6 alkynyl group, optionally substituted C _1-6 alkyl group, optionally substituted C _3-6 cycloalkyl group, optionally substituted aminocarbonyl group, substituted Saturated heterocyclic group which may be substituted, C _1-6 alkoxy group which may be substituted, C _3-6 cycloalkoxy group which may be substituted, aminocarbonyl group which may be substituted, C ₁ which may be substituted _-4 alkoxycarbonyl group, C _1-4 alkylcarbonyl group which may be substituted, C _6-10 arylcarbonyl group which may be substituted, 5-membered to 10-membered monocycle which may be substituted Formula or polycyclic heteroaryl group, cyano group, optionally substituted C _6-10 aryloxy group, _optionally substituted 5 to 10 membered monocyclic or polycyclic heteroaryloxy group, substituted which may _{C 7-14} aralkyloxy group optionally, an optionally substituted _{C 7-14} aralkyl group or a group represented by formula,

A group represented by
R ^1o , R ^1p , R ^1q , R ^1r and R ^1s are each independently the same or different and are each independently a hydrogen atom, a halogen atom, a cyano group, a C _1-4 alkyl group (the group is a 5-membered or 6- A member of saturated heterocyclic oxy, or C _1-4 alkoxy (which may be substituted with C _1-4 alkoxy or C _3-6 alkoxy), a C _1-4 alkoxy group ( The group may be substituted with a halogen atom, C _1-4 alkoxy or C _1-6 alkylaminocarbonyl.), C _3-6 cycloalkoxy group (may be substituted with C _1-4 alkoxy) , 5-membered or 6-membered heterocyclic oxy group to saturated or a _{C 1-6} alkylaminocarbonyl group, or ^{R 1o,} is ^{R 1r} and ^{R 1s} are each independently a hydrogen ^atom, Oyo ^{R 1p} R ^1q together form a condensed ring. Or R ^1m and R ¹ⁿ together are

In the group represented by (wherein, D represents an oxygen atom, a sulfur _{^{atom, -SO 2 -, - NR 5}} -, - NR 5 CO -, - NR 5 SO 2 -, - NR 5 CONR 5 -, - OCH (R ⁶ ) —, —CH (R ⁶ ) —, or —CH (R ⁶ ) CH ₂ —, wherein R ⁵ is a hydrogen atom, an optionally substituted C _1-6 alkyl group, or optionally substituted. A good C _1-4 alkylcarbonyl group, an optionally substituted C _1-4 alkoxycarbonyl group, an optionally substituted aminocarbonyl group, an optionally substituted C _1-4 alkylsulfonyl group, or an optionally substituted A C _6-10 arylsulfonyl group, R ⁶ is a hydrogen atom, an optionally substituted C _1-6 alkoxy group, an optionally substituted C _3-6 cycloalkoxy group, an optionally substituted C _{7- 14} aralkyloxy group, A conversion to an amino group which may, optionally substituted C _1-4 alkoxycarbonylamino group optionally or an optionally substituted aminocarbonyl group,, p and q are each independently, identical or different, 0, 1 or 2.). );
R 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. A -10} cycloalkyl group, an optionally substituted C _5-6 cycloalkenyl group, an optionally substituted C _6-10 aryl group, an optionally substituted C _7-14 aralkyl group, or an optionally substituted 5 A membered to 10-membered monocyclic or polycyclic heteroaryl group;
R ^3a and R ^3b are each independently the same or different and are each a hydrogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C _2-6 alkenyl group, or an optionally substituted C _2-6 alkynyl group, optionally substituted C _3-6 cycloalkyl group, _optionally substituted C _6-10 aryl group, _optionally substituted C _7-14 aralkyl group, optionally saturated A terocyclic group, or an optionally substituted 5- to 10-membered heteroaryl group;
R ^4a and R ^4b are each independently the same or different and are each a hydrogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C _2-6 alkenyl group, or an optionally substituted C _2-6 alkynyl group, optionally substituted _{C 3-6} cycloalkyl group, optionally substituted _{C 6-10} aryl group, optionally substituted _{C 7-14} aralkyl group, optionally substituted _{C 6 A -10} aryloxy group, an optionally substituted saturated heterocyclic group, or an optionally substituted 5- to 10-membered heteroaryl group, or R ^4a and R ^{4b taken} together

In a group represented by (wherein, M is an oxygen atom, a sulfur _{^{atom, -SO 2 -, - NR 7}} -, - NR 7 CO -, - NR 7 SO 2 -, - NR 7 CONR 7 -, - CH (R ⁸ ) —, or —CH (R ⁸ ) CH ₂ —, wherein R ⁷ is a hydrogen atom, an optionally substituted C _1-6 alkyl group, or an optionally substituted C _1-4 alkoxycarbonyl group. , An optionally substituted C _1-4 alkylsulfonyl group, or an optionally substituted C _6-10 arylsulfonyl group, and R ⁸ is a hydrogen atom, an optionally substituted C _1-6 alkoxy group, a substituted is an optionally C _3-6 cycloalkoxy group, a substituted an optionally C _7-14 aralkyloxy group or an optionally substituted aminocarbonyl group also,, R ⁹ is a hydrogen atom, it may be substituted C _1-6 alkyl Or a C _1-6 alkoxy group which may be substituted, and r and s are each independently the same or different and are 0, 1 or 2. ]

Item 2: R ^1a is a halogen atom; a cyano group; a C _1-6 alkyl group optionally substituted with a halogen atom, C _1-4 alkoxy or C _3-6 cycloalkyl; a C _2-6 alkynyl group; and a halogen Item 6. The compound according to Item 1, or a pharmaceutically acceptable salt thereof, which is one group selected from the group consisting of C _1-6 alkoxy groups that may be substituted with atoms.

Item 3: The compound according to Item 2, or a pharmaceutically acceptable salt thereof, wherein R ^1a is a hydrogen atom.

Item 4: The compound according to Item 2, or a pharmaceutically acceptable salt thereof, wherein R ^1a is a C _1-6 alkyl group optionally substituted with a halogen atom.

Item 5: The compound or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 4, wherein R ^1d is a hydrogen atom or a halogen atom.

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

Item 7: R ^1a , R ^1b , R ^1c and R ^1d are

Item 7. The compound according to any one of Items 1 to 6, or a pharmaceutically acceptable salt, wherein the benzene ring is substituted at a substitution position represented by:

Item 8: R ^1b is substituted with C _1-4 alkoxy, C _3-6 cycloalkoxy, or C _1-6 alkylcarbonylamino (the alkyl may be substituted with 1 to 3 fluorine atoms). A C _1-6 alkyl group; or 1-3 fluorine atoms, hydroxy, C _1-4 alkoxy, C _3-6 cycloalkoxy, cyano, mono-C _1-6 alkylcarbonylamino, mono-C _1- C ₁ substituted with one group selected from the group consisting of ₆ alkoxycarbonylamino, aminocarbonyl, C _1-6 alkylaminocarbonyloxy, C _1-4 alkoxycarbonyl, and C _1-4 alkylcarbonyl Item 8. The compound according to any one of Items 1 to 7, which is a _-6 alkoxy group, or a pharmaceutically acceptable salt thereof.

Item 9: The compound according to Item 8, or a pharmaceutically acceptable salt thereof, wherein R ^1b is a C _1-6 alkoxy group substituted with C _1-4 alkoxy.

Item 10: The compound of Item 9, or a pharmaceutically acceptable salt thereof, wherein R ^1b is a 3-methoxypropyloxy group.

Item 11: R ^1c is the following formula

Item 11. The compound according to any one of Items 1 to 10, or a pharmaceutically acceptable salt thereof, which is a group represented by:

Item 12: R ^1e , R ^1f , R ^1g and R ¹ⁱ are each independently the same or different and each has a hydrogen atom or a halogen atom;
R ^1h is a group: -A-B (wherein, A represents a single _{bond, -O -, - SO 2 -} , - CO -, - N (R 1j) CO- or ^{-N (R} 1j) SO ₂ −
R ^1j is a C _1-6 alkyl group or a C _3-6 cycloalkyl group,
B is a hydrogen atom; a C _1-6 alkyl group (the group includes 1 to 3 fluorine atoms, C _3-6 cycloalkyl, di- (C _1-6 alkyl) aminocarbonyl, 5-membered or 6-membered An aminocarbonyl which may be substituted with a saturated heterocycle, or a C _3-10 cycloalkylamino (which may be substituted with hydroxy); an amino group which may be di-substituted ( The group is C _1-6 alkyl (which may be substituted with 1 to 3 fluorine atoms or C _1-4 alkoxy), a 5- or 6-membered saturated heterocyclic ring, C _3-6 cycloalkyl, And optionally substituted by the same or different 1 or 2 groups selected from the group consisting of C _6-10 aryl); or a 5- to 7-membered cyclic amino group (the group is hydroxy or C _{1 -4} is substituted by alkoxy Is may be substituted with may be _{C 1-4} alkyl.). The compound according to any one of Items 1 to 11, or a pharmaceutically acceptable salt thereof.

Item 13: The compound according to any one of Items 1 to 12, wherein A is a single bond or —CO—, or a pharmaceutically acceptable salt thereof.

Item 14: B is a hydrogen atom; C _1-6 alkyl group (the group is represented by 1 to 3 fluorine atoms, C _3-6 cycloalkyl, di- (C _1-6 alkyl) aminocarbonyl, 5-membered or Aminocarbonyl optionally substituted with 6-membered saturated heterocycle, or optionally substituted with C _3-10 cycloalkylamino optionally substituted with hydroxy)); di- (C _1-6 alkyl) amino A group wherein the alkyl may be substituted with 1 to 3 fluorine atoms or C _1-4 alkoxy; N— (C _1-6 alkyl) -N— (5 or 6 membered saturated hetero Ring) amino group; N- (C _3-6 alkyl) -N- (5- or 6-membered saturated heterocyclic) amino group; N- (C _1-6 alkyl) -N- (C _6-10 aryl) An amino group; and a 5- to 7-membered cyclic amino group (the group is Any one of groups 1 to 13 which is one group selected from the group consisting of hydroxy and C _1-4 alkyl which may be substituted with hydroxy or C _1-4 alkoxy. Or a pharmaceutically acceptable salt thereof.

Item 15: The compound according to any one of Items 1 to 14, wherein A is a single bond and B is a hydrogen atom, or a pharmaceutically acceptable salt thereof.

Item 16: R ^1b and R ^1c are taken together to form the following formula:

The compound as described in any one of claim | item 1 -6 which forms the ring represented by these, or its pharmaceutically acceptable salt.

Item 17: G ¹ is —N (R ^1k ) —, G ² is —CO—, G ³ is —C (R ^1m ) (R ¹ⁿ ) —, and G ⁴ is Item 18. The compound according to Item 16 or a pharmaceutically acceptable salt thereof, which is —C (R ^1m ) (R ¹ⁿ ) —, —SO ₂ —, an oxygen atom, or a sulfur atom.

Item 18: The compound according to Item 17, or a pharmaceutically acceptable salt thereof, wherein G ⁴ is an oxygen atom.

Item 19: R ^1k is a C _1-6 alkyl group (the group is substituted with hydroxy, C _1-4 alkoxy (1 to 3 fluorine atoms, C _1-4 alkoxy, C _1-6 alkylaminocarbonyl) _Optionally substituted C _3-6 cycloalkyl, or optionally substituted with a 5 or 6 membered saturated heterocycle optionally substituted with C _1-4 alkyl.), Trifluoromethyl, difluoromethyl, C _{3 -6} cycloalkyl (1-2 fluorine _atoms, may be substituted with _{C 1-4} alkoxy which may be substituted with _{C 1-4} alkyl, or _{C 1-4 alkoxy.), C 3-6} cycloalkyl alkoxy, _{carboxyl, C 1-6} alkylcarbonylamino (1-5 fluorine atoms, _{hydroxy, C 1-4} alkoxy, or _{C 3-6} may be substituted with cycloalkyl.), N _{(C 1-4 alkylcarbonyl)-N-(C 1-6} alkyl) - _(. Which may be substituted with _{C 1-4 alkoxy) amino, C 3-6} cycloalkylcarbonyl _{amino, C 1-6} alkylthiocarbonyl Amino, C _1-4 alkoxycarbonylamino (optionally substituted with 1 to 3 fluorine atoms), N- (C _1-4 alkoxycarbonyl) -N- (C _1-6 alkyl) -amino, C _3-6 cycloalkoxycarbonylamino, mono- (C _1-6 alkyl) aminocarbonyloxy, di- (C _1-6 alkyl) aminocarbonyloxy, 4-membered to 7-membered cyclic aminocarbonyloxy (C _1-4 alkoxy) ), C _1-6 alkylaminocarbonyl (may be substituted with 1 to 3 fluorine atoms or C _3-6 cycloalkyl). C _3-6 cycloalkylaminocarbonyl, C _1-6 alkylaminocarbonylamino, C _1-4 alkylcarbonyl, C _1-4 alkylcarbonyloxy, C _1-4 alkoxycarbonyl, C _1-6 alkylsulfonyl. , C _1-6 alkylsulfonylamino, and substituted with one group selected from the group consisting of 5- or 6-membered saturated heterocyclic ring (which may be substituted with C _1-4 alkyl) C _2-6 alkenyl group (which may be substituted with a halogen atom); C _2-6 alkynyl group (which may be substituted with C _1-4 alkoxy); or 5-membered to 6-membered Item 19. The compound according to any one of Items 16 to 18, which is a heteroaryl C _1-4 alkyl group, or a pharmaceutically acceptable salt thereof.

Claim ^{20: R 1k} _is the compound or a pharmaceutically acceptable salt thereof, as claimed in claim 19 is _{C 1-6} alkoxy substituted by a _{C 1-6} alkyl group.

Item 21: The compound according to Item 20, or a pharmaceutically acceptable salt thereof, wherein R ^1k is a 4-methoxybutyl group.

Claim ^{22: R 1k} _{is, C 1-6} compound or a pharmaceutically acceptable salt thereof, according to _{C 1-6} section 19 is an alkyl group substituted with alkylcarbonylamino.

Item 23: The compound according to Item 22, or a pharmaceutically acceptable salt thereof, wherein R ^1k is a 2- (ethylcarbonylamino) ethyl group.

Item 24: R ^1m and R ¹ⁿ are each independently the same or different, a hydrogen atom; a halogen atom; a C _1-6 alkyl group (the group is represented by 1 to 3 fluorine atoms, C _1-4 alkoxy (the alkoxy is 1-3 optionally C _6-10 aryl optionally substituted with a group selected from the group consisting of halogen atoms and cyano, optionally substituted with 1 to 3 fluorine atoms C _{1- 4} alkoxy, C _3-6 cycloalkyl (C _3-6 cycloalkyl is substituted with C _6-10 aryl optionally substituted with 1 to 3 groups selected from the group consisting of halogen atoms and cyano. 5 or 6-membered saturated heterocycle, 5- or 6-membered saturated heterocyclic oxy, or N- (C _3-10 cycloalkyl optionally substituted with hydroxy) -N- ( C _1-6 alkyl) Optionally substituted with aminocarbonyl), C _3-6 cycloalkyl, C _3-6 cycloalkoxy, C _7-14 aralkyloxy (optionally substituted with a halogen atom), saturated heterocyclic oxy, N - _{(C 3-6 cycloalkyl)-N-(C 1-6} alkyl) amino _{(C 3-6} cycloalkyl substituted with one to three groups selected from the group consisting of halogen atoms and cyano _Or optionally substituted with C _6-10 aryl), N- (C _3-6 cycloalkyl C _1-4 alkyl) -N- (C _1-6 alkyl) aminocarbonyl, N- (C _{1- 4 alkylcarbonyl)-N-(C 1-6} alkyl) amino (the _{C 1-4 alkylcarbonyl,} substituted with heterocycle _{C 1-4} alkyl which may be substituted 5-membered or 6-membered saturated Good ), _{N-(C 1-4 alkoxycarbonyl)-N-(C 1-6} alkyl) amino, _{N-(C 3-6} cycloalkyl _{sulfonyl)-N-(C 1-6} alkyl) amino, 5-membered to 7-membered cyclic amino or 5- to 7-membered cyclic aminocarbonyl (1-3 fluorine atoms or _{C 1-4} alkoxy which may be substituted with _{C 1-4} alkyl, or substituted with _{C 1-4} alkoxy C _3-6 cycloalkyl group; aminocarbonyl group (the group may be substituted with C _1-6 alkyl); 5-10 members A monocyclic or polycyclic heteroaryl group (the group may be substituted with 1 to 3 fluorine atoms, C _1-4 alkyl, or cyano); C _7-14 An aralkyl group (which is substituted with a halogen atom) It may be. ); And the following formula

24. The compound according to any one of items 16 to 23, or a pharmaceutically acceptable salt thereof, which is a group represented by:

Item 25: One of R ^1m and R ¹ⁿ is a hydrogen atom, and the other is represented by the following formula:

Item 25. The compound according to Item 24, which is a group represented by: or a pharmaceutically acceptable salt thereof.

Item 26: R ^1o , R ^1p , R ^1q , R ^1r and R ^1s are each independently the same or different and represent a hydrogen atom, a cyano group, a C _1-4 alkyl group, or a C _1-4 alkoxy group ( The compound according to Item 24 or 25, wherein the group may be substituted with C _1-4 alkoxy, or a pharmaceutically acceptable salt thereof.

Item 27: The compound according to any one of Items 16 to 26, or a pharmaceutically acceptable salt thereof, wherein R ^1m and R ¹ⁿ are each independently a C _1-6 alkyl group.

Item 28: R ^1m and R ¹ⁿ together represent the following formula

Wherein D is an oxygen atom, —NR ⁵ —, —OCH (R ⁶ ) —, —CH (R ⁶ ) —, or —CH (R ⁶ ) CH ₂ —, ^5, one to three fluorine atoms or _{C 1-4} alkoxy which may be substituted with _{C 1-4} alkyl _{group, C 1-4} alkoxycarbonyl or _{C 1-4} may be substituted with alkoxy, a 4-membered to 7-membered cyclic amino group, ^{R 6} is a hydrogen _atom, it may be substituted with _{C 1-4} alkoxy _{C 1-6} alkyl group which _may be substituted by _{C 1-4} alkoxy C _1-6 alkoxy group, N- (C _1-6 alkylsulfonyl) -N- (C _1-6 alkyl) amino group, C _1-4 alkoxycarbonylamino group, mono- (C _1-6 alkyl) aminocarbonyloxy Group, or C ₆₋ Item 16 is a ₁₀ arylsulfonylamino group (wherein the aryl may be substituted with a halogen atom), and p and q are each independently the same or different and are 0, 1 or 2. 24. The compound according to any one of to 23, or a pharmaceutically acceptable salt thereof.

Item 29: R ² is a C _1-6 alkyl group (which may be substituted with a halogen atom or C _3-6 cycloalkyl); a C _2-6 alkenyl group (which may be substituted with a halogen atom); A C _2-6 alkynyl group (which may be substituted with a halogen atom); a C _3-6 cycloalkyl group (which may be substituted with a halogen atom, C _1-4 alkyl, or C _1-4 alkoxy); C ₆ aryl group (a halogen atom, a _{C 6-10} aryl optionally substituted by a halogen atom, or _{C 1-4} may be substituted with optionally _{C 6-10} aryloxy substituted with alkoxy.); C _{Item 10 is a 7-10} aralkyl group (which may be substituted with a halogen atom); and a 5- or 6-membered heteroaryl group (which may be substituted with C _1-4 alkyl). Z Compound or a pharmaceutically acceptable salt thereof, as claimed in or claim.

Item 30: The compound according to Item 29 or a pharmaceutically acceptable salt thereof, wherein R ² is a C _1-6 alkyl group.

Item 31: The compound according to Item 30, or a pharmaceutically acceptable salt thereof, wherein R ² is an isopropyl group.

Item 32: R ^3a and R ^3b are each independently the same or different and are each a hydrogen atom; a C _1-6 alkyl group (the group is a halogen atom, hydroxy, C _3-6 cycloalkyl, C _1-4 Alkoxy, N- (C _1-4 alkylcarbonyl) -N- (C _1-6 alkyl) amino, N- (C _1-6 alkylsulfonyl) -N- (C _1-6 alkyl) amino, N- (C _6-10 arylsulfonyl) -N- (C _1-6 alkyl) amino, N- (C _1-4 alkoxycarbonyl) -N- (C _1-6 alkyl) amino, or C _7-14 aralkyloxy (1- . 3 fluorine atoms, or _{C 1-4} may be substituted with good _{C 3-6} cycloalkoxy optionally substituted by alkoxy) may be _{substituted);. C 2-6} alkenyl _{group; C 2- 6} alkynyl ; _{C 3-6 (which} may be substituted with _{C 1-4 alkoxy.)} Cycloalkyl _{group; C 6-10} aryl group (said group may be substituted with halogen atom or _{C 1-4} alkoxy. C _7-10 aralkyl group (the group is a halogen atom, C _1-4 alkyl (the group is a 5- or 6-membered cyclic amino _optionally substituted with C _6-10 aryloxy) , Optionally substituted with 1 to 3 fluorine atoms), or 5- to 7-membered cyclic amino (optionally substituted with C _6-10 aryloxy optionally substituted with fluorine atoms). May be substituted), C _1-4 alkoxy (the group may be C _1-4 alkoxy, C _3-6 cycloalkyl (optionally substituted with C _1-4 alkoxy)), C _3-6 cyclo. Alkyloxy ( _substituted with C _1-4 alkyl) May be substituted), C _6-10 aryloxy (the group may be substituted with 1 to 3 fluorine atoms, or cyano), or C _1-4 alkoxy. C _7-14 aralkyloxy may be substituted), C _6-10 aryl (may be substituted with a halogen atom), C _6-10 aryloxy (may be substituted with a halogen atom or cyano). ), C _7-14 aralkyloxy (optionally substituted with C _1-4 alkoxy), 5- or 6-membered saturated heterocyclic oxy (5- or 6-membered saturated heterocyclic carbonyl, or fluorine atom) _Optionally substituted C _6-10 aryl), 5 or 6 membered heteroaryloxy (C _1-4 alkyl). ) May be substituted with a 5- to 7-membered cyclic aminocarbonyl (which may be substituted with a C _6-10 aryloxy which may be substituted with a fluorine atom). ); 5-membered or 6-membered saturated heterocyclic group; 5-membered to 10-membered heteroaryl group (the group may be substituted with 1 to 3 fluorine atoms, C _1-4 alkyl, C _{1- 4} alkoxy optionally substituted _{C 1-4} alkoxy, 5-membered or 6-membered saturated heterocyclic amino _{carbonyl, C 1-4} optionally _{C 6-10} aryl optionally substituted with alkoxy, and _{C 1-6} alkylamino And may be substituted with 1 to 2 groups selected from the group consisting of carbonyl.); And a C _6-10 aryloxy group (which may be substituted with C _6-10 aryloxy). Item 32. The compound according to any one of Items 1 to 31, which is one selected group, or a pharmaceutically acceptable salt thereof.

Item 33: R ^3a and R ^3b are each independently the same or different, a hydrogen atom; a C _1-6 alkyl group that may be substituted with hydroxy; a C _6-10 aryl group; or a C _1-4 alkoxy in optionally substituted _{C 7-10} aralkyl group (said _alkoxy optionally substituted by _{C 1-4} alkoxy may be substituted with may be _{C 7-14} aralkyloxy.) of claim 1 to claim 32 which is The compound according to any one of the above, or a pharmaceutically acceptable salt thereof.

Item 34: One of R ^3a and R ^3b is a hydrogen atom, and the other is a hydrogen atom, a C _1-6 alkyl group which may be substituted with hydroxy, a C _6-10 aryl group, or C _1- Item 1 to Item 1 which is a C _7-10 aralkyl group which may be substituted with ₄ alkoxy (the alkoxy may be substituted with C _7-14 aralkyloxy which may be substituted with C _1-4 alkoxy). 34. The compound according to any one of 33, or a pharmaceutically acceptable salt thereof.

Item 35: The compound according to any one of Items 32 to 34, or a pharmaceutically acceptable salt thereof, wherein R ^3a and R ^3b are both C _1-6 alkyl groups.

Item 36: R ^4a and R ^4b are each independently the same or different from each other; a hydrogen atom; a C _1-6 alkyl group (the group is a halogen atom, C _3-6 cycloalkyl, C _1-4 alkoxy (the The group may be substituted with C _1-4 alkoxy, 5- to 7-membered cyclic aminocarbonyl.) 5-membered or 6-membered saturated heterocycle, or N— (C _1-4 alkylcarbonyl) — N- (C _3-6 cycloalkyl) amino (C _1-4 alkylcarbonyl) may be substituted with a 5 or 6 membered saturated heterocyclic ring, or C _6-10 aryl optionally substituted with a halogen atom. C _2-6 alkenyl group (the group is C _6-10 aryl optionally substituted with C _1-4 alkoxy, or N- (C _1-4 alkylcarbonyl). ) -N- _{(C 3-} Cycloalkyl) amino (C _1-4 alkylcarbonyl may be substituted with 5-membered may be substituted with C _1-4 alkyl or a 6-membered to saturation may be substituted with hetero ring.).) ; _{C 2-6 (which} may be substituted with _{C 3-6 cycloalkyl.) alkynyl; C 3-6 (which} may be substituted with _{C 1-4 alkoxy.)} cycloalkyl _{group; C 6-10} aryl A group (the group may be substituted with di- (C _1-6 alkyl) aminocarbonyl, or C _1-4 alkyl); a C _7-10 aralkyl group (the group is a halogen atom, or cyano And a 5- or 6-membered saturated heterocyclic group; and a 5- to 10-membered heteroaryl group (which may be substituted with C _1-4 alkyl). Item 36. The compound according to any one of items 35. Or a pharmaceutically acceptable salt thereof.

Item 37: The compound according to any one of Items 1 to 36, wherein any one of R ^4a and R ^4b is a hydrogen atom, and the other is a hydrogen atom or a C _1-6 alkyl group, or Its pharmaceutically acceptable salt.

Item 38: The compound according to any one of Items 37, or a pharmaceutically acceptable salt thereof, wherein R ^4a and R ^4b are each independently a hydrogen atom.

Item 39: The compound according to Item 36 or a pharmaceutically acceptable salt thereof, wherein R ^4a and R ^4b are both C _1-6 alkyl groups.

Item 40: R ^4a and R ^4b together represent the following formula

Wherein M is an oxygen atom, —NR ⁷ —, —CH (R ⁷ ) —, or —CH (R ⁷ ) CH ₂ —, and R ⁷ is a C _1-4 alkoxy 36. The compound according to any one of Items 1 to 35, which is a carbonyl group, and r and s are each independently the same or different and are each represented by 0, 1 or 2. Or a pharmaceutically acceptable salt thereof.

Item 41: A pharmaceutical composition comprising the compound according to any one of Items 1 to 40 or a pharmaceutically acceptable salt thereof as an active ingredient.

Item 42: A renin inhibitor comprising the compound according to any one of Items 1 to 40 or a pharmaceutically acceptable salt thereof as an active ingredient.

Item 43: A therapeutic agent for hypertension comprising the compound according to any one of Items 1 to 40 or a pharmaceutically acceptable salt thereof as an active ingredient.

Item 44: Use of the compound according to any one of Items 1 to 40 or a pharmaceutically acceptable salt thereof for the production of a renin inhibitor.

Item 45: Use of the compound according to any one of Items 1 to 40 or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic agent for hypertension.

Item 46: A method for treating hypertension, comprising administering an effective amount of the compound according to any one of Items 1 to 40 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 _1-6 alkyl group” means a straight or branched saturated hydrocarbon group having 1 to 6 carbon atoms. Preferably, " _C1-4 alkyl group" etc. are mentioned. Specific examples of the “C _1-6 alkyl group” include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl. 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl and the like.

The “C _2-6 alkenyl group” means a linear or branched unsaturated hydrocarbon group having 2 to 10 carbon atoms and 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 having 2 to 6 carbon atoms and containing one triple bond. For example, 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 having 3 to 10 carbon atoms. 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 _3-6 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 having 6 to 10 carbon atoms. 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” means a “C _6-10 aryl C _1-4 alkyl group”, and means a group in which the “aryl group” is substituted on the “alkyl group”. Preferably, _{"C 7-10} aralkyl group" _{(C 6} aryl _{C 1-4} alkyl group). 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 in which the “heteroaryl group” is substituted on the “alkyl group”. Examples of the heteroaryl moiety are the same as the specific examples exemplified as the heteroaryl group. An example is “heteroaryl C _1-4 alkyl”. Specifically, 2-pyridylmethyl etc. are mentioned, for example.

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 _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 _3-6 cycloalkyl” part of the “C _3-6 cycloalkylsulfonyl group” has the same meaning as the above “C _3-6 cycloalkyl”. Specific examples of “C _3-6 cycloalkylsulfonyl group” include, for example, cyclopropylsulfonyl, cyclobutylsulfonyl and the like.

The “C _6-10 aryl” part of the “C _6-10 arylthio group” has the same meaning as the above “C _6-10 aryl”. Specific examples of the “C _6-10 arylthio group” include phenylthio, 1-naphthylthio, 2-naphthylthio and the like.

The “C _6-10 aryl” part of the “C _6-10 arylsulfinyl group” has the same meaning as the above “C _6-10 aryl”. Specific examples of the “C _6-10 arylsulfinyl group” include phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl and the like.

The “C _6-10 aryl” part of the “C _6-10 arylsulfonyl group” has the same _{meaning as} the above “C _6-10 aryl”. Specific examples of the “C _6-10 arylsulfonyl group” include phenylsulfonyl, tosyl, 1-naphthylsulfonyl and 2-naphthylsulfonyl.

_{"C 1-4} alkoxy" moiety of the _{"C 1-4} alkoxy sulfonyl group" is the same as defined in the _{"C 1-4} alkoxy group". Specific examples include methoxysulfonyl and the like.

_{"C 3-6} cycloalkoxy" portion of the _{"C 3-6} cycloalkoxy sulfonyl group" is the same as defined in the _{"C 3-6} cycloalkoxy group". Specific examples include cyclopropyloxysulfonyl and the like.

_{"C 6-10} aryloxy" portion of the _{"C 6-10} aryloxy sulfonyl group" is the same as defined in the _{"C 6-10} aryloxy group". Specific examples include phenyloxysulfonyl 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.

The “C _5-6 cycloalkenyloxy” part of the “C _5-6 cycloalkenyloxy group” has the same meaning as the above “C _5-6 cycloalkenyloxy”. Specific examples include 1-cyclopentenyloxy and the like.

The “C _6-10 aryl” part of the “C _6-10 aryloxy group” has the same _{meaning as} the above “C _6-10 aryl”. “C ₆ aryloxy” (phenyloxy) is preferred. Specific examples of the “C _6-10 aryloxy group” include phenoxy, 1-naphthyloxy, 2-naphthyloxy and the like.

_{"C 7-14} aralkyl" moiety of the _{"C 7-14} aralkyloxy group" _{(C 6-10} aryl _{C 1-4} alkyloxy group) is the same as defined in the _{"C 7-14} aralkyl". Preferably, “C _7-10 aralkyloxy group” (“phenyl C _1-4 alkyl group”) and the like can be mentioned. Specific examples of the “C _7-14 aralkyloxy group” include, for example, benzyloxy, phenethyloxy, naphthylmethyloxy and the like.

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

“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 _3-6 cycloalkoxycarbonyl group” means a group in which the “C _3-6 cycloalkoxy group” is bonded to a carbonyl group. Specifically, as the C _3-6 cycloalkoxy moiety, those exemplified as the aforementioned cycloalkoxy group can be mentioned.

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 _3-10 cycloalkylcarbonyl group” means a group in which the “C _3-10 cycloalkyl group” is bonded to a carbonyl group. Preferable examples include “C _3-6 cycloalkylcarbonyl group”, and specific examples of “C _3-10 cycloalkylcarbonyl group” include cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, adamantylcarbonyl. Or norbornyl carbonyl etc. are mentioned.

The “C _6-10 arylcarbonyl group” means a group in which the “C _6-10 aryl group” is bonded to a carbonyl group. The “C _6-10 aryl” moiety has the same _{meaning as the} “C _6-10 aryl group”. Preferably, “C ₆ arylcarbonyl group” (phenylcarbonyl group) is used. Specific examples of “C _6-10 arylcarbonyl group” include benzoyl, 1-naphthoyl, 2-naphthoyl and the like.

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

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

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

The “C _1-4 alkylcarbonylamino group” means a group obtained by substituting one amino group with the above “C _1-4 alkylcarbonyl group”. Specific examples include methylcarbonylamino and the like. “C _1-4 alkyl” may be substituted with 1 to 3 fluorine atoms.

The “C _1-4 alkylthiocarbonylamino group” means a group in which the carbonyl of the “C _1-4 alkylcarbonyl group” is replaced with thiocarbonyl. Specific examples include methylthiocarbonylamino and the like.

The “C _3-6 cycloalkylcarbonylamino group” means a group in which the “C _3-6 cycloalkylcarbonyl group” is substituted with one amino group. Specific examples include cyclopropylcarbonylamino and the like.

The “C _1-4 alkoxycarbonylamino group” means a group obtained by substituting one amino group with the above “C _1-4 alkoxycarbonyl group”. Specific examples include methoxycarbonylamino, ethoxycarbonylamino and the like. “C _1-4 alkyl” may be substituted with 1 to 3 fluorine atoms.

The “C _1-6 alkylsulfonylamino group” means a group obtained by substituting one amino group with the above “C _1-4 alkylsulfonyl group”. Specific examples include methylsulfonylamino, ethylsulfonylamino and the like.

The “C _6-10 arylsulfonylamino group” means a group in which the above “C _6-10 arylsulfonyl group” is substituted with one amino group. Specific examples include phenylsulfonylamino and the like.

The “C _1-4 alkylsulfonylaminocarbonyl group” means a group in which the “C _1-4 alkylsulfonylamino group” is substituted with a carbonyl group. Specific examples include methylsulfonylamino and the like.

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

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

  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 4-pyranylcarbonyl and the like.

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

The “mono- or di-substituted amino group” includes “C _1-6 alkyl”, “C _3-6 cycloalkyl”, “C _3-6 cycloalkyl C _1-4 alkyl”, “benzyl”, “ “C _6-10 aryl”, “C _1-4 alkoxycarbonyl”, “C _1-4 alkylcarbonyl”, “saturated heterocycle”, “C _1-6 alkylsulfonyl”, “C _3-6 cycloalkylsulfonyl” And an amino group substituted with 1 to 2 groups of the same or different types selected from the group consisting of “C _6-10 arylsulfonyl”.

Specific examples of the “mono- or di-substituted amino group” include, for example,
“Mono- or di- (C _1-6 alkyl) amino group” (eg, methylamino, ethylamino, dimethylamino, diethylamino, etc.),
“Mono- or di- (C _3-6 cycloalkyl) amino group” (for example, cyclopropylamino, cyclobutylamino, cyclopentylamino, dicyclopropylamino, dicyclobutylamino, cyclodipentylamino, etc.),
“Mono- (C _3-6 cycloalkyl C _1-4 alkyl) amino group” (for example, cyclopropylmethylamino, cyclobutylmethylamino, cyclopentylmethylamino, etc.),
“N- (C _3-6 cycloalkyl C _1-4 alkyl) -N— (C _1-6 alkyl) -amino group” (eg, N-cyclopropylmethyl-N-methylamino and the like),
“(C _1-6 alkyl) (benzyl) amino group” (eg, N-methyl-N-benzylamino and the like),
“5-membered or 6-membered saturated heterocyclic amino group” (eg, 3-pyrrolidinylamino),
“N- (C _1-6 alkyl) -N- (C _3-6 cycloalkyl) -amino group” (eg, N-cyclopropyl-N-methylamino and the like),
“N- (C _1-6 alkyl) -N- (5 or 6-membered saturated heterocyclic) -amino group” (eg, N-methyl-N- (4-pyranyl) amino and the like),
“N- (C _3-6 cycloalkyl) -N- (5 or 6-membered saturated heterocyclic) -amino group” (eg, N-cyclopropyl-N- (4-pyranyl) amino and the like),
“N- (C _1-4 alkoxycarbonyl) -N- (C _1-6 alkyl) -amino group” (eg, N-methoxy-N-methyl-amino, etc.),
“N- (C _3-6 cycloalkoxycarbonyl) -N- (C _1-6 alkyl) -amino group” (eg, N-cyclopropyloxy-N-methylcarbonylamino, etc.),
“N- (C _3-6 cycloalkylsulfonyl) -N- (C _1-6 alkyl) -amino group” (eg, N-cyclopropylsulfonyl-N-methyl-amino and the like),
“N- (C _1-6 alkylsulfonyl) -N- (C _1-6 alkyl) -amino group” (eg, N-propylsulfonyl-N-methyl-amino, etc.),
“N- (C _6-10 aryl) -N— (C _1-6 alkyl) -amino group” (eg, N-phenyl-N-methyl-amino, etc.),
“N- (C _6-10 arylsulfonyl) -N— (C _1-6 alkyl) -amino group” (eg, N-phenylsulfonyl-N-methyl-amino, etc.),
“N- (C _1-4 alkylcarbonyl) -N— (C _1-6 alkyl) -amino group” (for example, N-methyl-N-ethylcarbonylamino and the like),
“N- (C _1-4 alkylcarbonyl) -N- (C _3-6 cycloalkyl) -amino group” (for example, N-methylcarbonyl-N-cyclopropyl-amino and the like) and the like can be mentioned.

The “C _1-6 alkyl” moiety in the “amino group substituted with mono- or di- (C _1-6 alkyl)” is C _1-6 alkoxy, mono-C _1-6 alkylcarbonylamino C _1-6 alkyl may be substituted with 1 to 3 fluorine atoms.), Or may be substituted with mono-C _1-6 alkoxycarbonylamino.

“4- to 7-membered cyclic amino group” means a 4- to 7-membered cyclic amino group. A group in which the nitrogen atom of the ring is a direct bond of the “group” is meant. Preferably, it is 5 to 7 members, more preferably 5 or 6 members. Specific examples include pyrrolidino, piperidino, morpholino, thiomorpholino, thiomorpholino oxide, thiomorpholino oxide, piperazino, 2-pyrrolidone-1-yl and the like. The ring may be substituted with, for example, a halogen atom, C _1-4 alkyl, or C ₆ aryl which may be substituted with C _1-4 alkoxy.

  The “5- to 7-membered cyclic amino group” may form a condensed ring with a 6-membered aromatic hydrocarbon or a 6-membered unsaturated heterocycle. Specific examples include “groups” shown below.

  Further, a 5-membered or 6-membered saturated hetero ring and a spiro ring may be formed. Specific examples include “groups” shown below.

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 or C _1-4 alkoxy),
(D) a hydroxyl group,
(E) C _1-4 alkoxy group (which may be substituted with a fluorine atom, C _1-4 alkoxy or C _3-6 cycloalkyl),
(F) a C _3-6 cycloalkyloxy group,
(G) a C ₆ aryloxy group (the group may be substituted with the same or different groups selected from the group consisting of a halogen atom, cyano and C _1-4 alkoxy);
(H) a benzyloxy group,
(I) a formyl group,
(J) a C _1-4 alkylcarbonyl group,
(K) a C _3-6 cycloalkylcarbonyl group,
(L) a phenylcarbonyl group,
(M) a benzylcarbonyl group,
(N) formylcarbonyloxy group,
(O) a C _1-4 alkylcarbonyloxy group,
(P) a C _3-6 cycloalkylcarbonyloxy group,
(Q) a carboxyl group,
(R) a C _1-4 alkoxycarbonyl group,
(S) a C _3-6 cycloalkoxycarbonyl group,
(T) an amino group,
(U) a mono-substituted amino group (the group is
(U1) a C _1-6 alkyl group,
(U2) C _3-6 cycloalkyl group,
(U3) a C _3-6 cycloalkyl C _1-4 alkyl group, or (u4) a benzyl group,
(U5) C _1-4 alkylcarbonyl group,
(U6) C _1-4 alkoxycarbonyl group,
(U7) a saturated heterocyclic group,
(U8) C _6-10 aryl group,
(U9) substituted with a C _3-6 cycloalkylsulfonyl group, or (u10) a C _1-6 alkylsulfonyl group. ),
(V) a di-substituted amino group (the group is substituted with two same or different groups selected from the above (u1) to (u10));
(W) a 5- to 7-membered cyclic amino group,
(X) an optionally substituted aminocarbonyl group,
(Y) an aminocarbonyloxy group that may be substituted, or (z) a saturated heterocyclic group (the ring may be substituted with, for example, C _1-4 alkyl). In addition, it is not limited to these substituent list | wrists. That is, in addition to the above list, (a700) to (a725) and (b101) to (b109) and (b111 to 115) described later are also included in the list of substituents.

  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.

  Specific examples of the “mono- or di-substituted aminocarbonyl group” include those in which the “mono- or di-aminocarbonyl” moiety is the same as the above-mentioned specific examples of “mono- or di-substituted amino”. Can be mentioned.

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 “C _1-6 alkylaminocarbonylamino group” means an amino group substituted with one “aminocarbonyl group substituted with mono- (C _1-6 alkyl)”. Specific examples include methylaminocarbonylamino 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.

  The “5- to 7-membered cyclic aminocarbonyl” part of the “5- to 7-membered cyclic aminocarbonyloxy” has the same meaning as described above. Specific examples include pyrrolidinocarbonyloxy and the like.

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 (z) and the like (here, (u ) The mono-substituted amino group substituents are limited to C _1-4 alkyl groups and C _3-6 alkyl groups, and the same applies to (v), (x) and (y).

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

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

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

Examples of the substituent in the “optionally substituted C _1-4 alkylcarbonyl group” and the “optionally substituted C _3-10 cycloalkylcarbonyl group” include the above (a) to (h), a nitro group, like one group selected from C _1-4 alkyl carbonyl amino group and C _1-4 alkoxy group consisting of a carbonyl amino group.

As the substituent in the “optionally substituted C _1-6 alkylthio group”, the “optionally substituted C _1-6 alkylsulfonyl group”, and the “optionally substituted C _1-4 alkoxycarbonyl group”, Examples thereof include a halogen atom, a hydroxyl group, a nitro group, a cyano group, or one group selected from the group consisting of the above (d) to (h).

“Optionally substituted C _6-10 aryl group”, “ _optionally substituted C _6-10 aryloxy group”, “optionally substituted C _6-10 arylcarbonyl group”, “optionally substituted” Examples of the substituent in the “5- to 10-membered monocyclic or polycyclic heteroaryl group” and “the optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryloxy group” include, 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 cycloalkyl optionally substituted with C _1-4 alkyl, or (f23) optionally substituted with C ₆ aryloxy optionally substituted with a halogen atom. ),
(G2) C _3-6 cycloalkyloxy group,
(H2) a C _6-10 aryloxy group (the group may be substituted with the same or different groups selected from the group consisting of a halogen atom, cyano and C _1-4 alkoxy);
(I2) a C _6-10 aryl group (the group may be substituted with a halogen atom),
(J2) a sulfonyl group,
(K2) C _1-4 alkoxysulfonyl group,
(L2) C _3-6 cycloalkoxysulfonyl group,
(M2) C _6-10 aryloxysulfonyl group,
(N2) benzyloxysulfonyl group,
(O2) 5- or 6-membered monocyclic heteroaryloxy group (the group may be substituted with C _1-4 alkyl),
(P2) an amino group (the group may be substituted with one or two of the same or different species selected from the aforementioned u1 to u10),
(Q2) a 5- to 7-membered cyclic amino group,
A group selected from the group consisting of (r2) an optionally substituted aminocarbonyl group and (s2) an optionally substituted aminocarbonyloxy group; and the like.

Examples of the substituent of the aryl moiety in the “optionally substituted C _7-14 aralkyl group” and the “optionally substituted C _7-14 aralkyloxy group” include, for example,
(A3) a halogen atom,
(B3) a cyano group,
(C3) C _1-4 alkyl group (may be substituted with 1 to 3 halogen atoms),
(D3) a hydroxyl group,
(E3) C _1-4 alkoxy group (may be substituted with 1 to 3 halogen atoms),
(F3) C _3-6 cycloalkoxy group (may be substituted with 1 to 2 halogen atoms),
(G3) a carboxy group,
(H3) a C _1-4 alkoxycarbonyl group,
(I3) C _6-10 aryl group (which may be substituted with 1 to 3 halogen atoms or C _1-4 alkoxy),
(J3) a C _6-10 aryloxy group,
(K3) C _7-10 aralkyloxy group,
(L3) aminocarbonyl group (the amino moiety may be substituted with C _1-6 alkyl),
And (m3) a C _1-4 alkylsulfonylamino group, and a group selected from the group consisting of (n3) C _1-4 alkylsulfonyl groups.

The substituents (a3) to (n3) may be substituted with a C _1-4 alkyl moiety in a C _7-14 aralkyl group (C _6-10 aryl C _1-4 alkyl group). In addition, it is not limited to these substituent list | wrists. That is, in addition to the above list, (g101) to (g110) described later are also included in the list of substituents.

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

Examples of the substituents of “saturated heterocycle” and “saturated heterocycle” include,
(A4) a halogen atom,
(B4) a hydroxyl group,
(C4) a nitro group,
(D4) a cyano group,
(E4) C _1-4 alkyl group (may be substituted with 1 to 3 halogen atoms or C _1-4 alkoxy),
(F4) C _1-4 alkoxy group (may be substituted with 1 to 3 halogen atoms, etc.),
(G4) carboxyl group,
(H4) C _1-4 alkoxycarbonyl group,
(I4) C _3-6 cycloalkoxycarbonyl group,
(J4) an amino group (which may be substituted with C _1-6 alkyl),
(K4) C ₆ aryl group,
(14) aminocarbonyl group,
(M4) C _1-4 alkylcarbonylamino group,
(N4) an oxo group, or (o4) a thioxo group.
In the “saturated heterocyclic group” or “saturated heterocyclic ring”, two of the above-mentioned substituents may be substituted with the same or different groups.

  Each definition in the compound represented by formula (I) will be described in more detail.

The bonding positions of “A” and “B” in “group: -A-B” will be described. For example, when “A” is —N (R ^1j ) CO—, it means “−N (R ^1j ) CO-B”.

^{"R 1e, R 1h} and ^{R 1i} are both hydrogen ^{atom, R 1f} and ^{R 1g} form a fused ring together" and ^{"R 1f"} and ^{"R 1g"} is together In other ^words , “R ^1e ”, “R ^1h ” and “R ¹ⁱ ” mean that a substituted benzene ring forms a bicyclic or tricyclic condensed ring. Specifically, it means a ring having one structure selected from the group represented by the following structure. In addition, the ring represented by the broken line in the following structure means a benzene ring substituted by “R ^1e ”, “R ^1h ” and “R ¹ⁱ ”. Furthermore, the ring represented by a solid line means a ring in which “R ^1f ” and “R ^1g ” together form a condensed ring with the benzene ring.

In the partial structure, ^{"R x"} is a hydrogen _{atom; 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 ^x is a C _1-4 alkoxy group, it is not directly bonded to the nitrogen atom of the partial structure.

In G ¹ , G ² , G ³ and G ⁴ , when at least two of G ¹ , G ³ and G ⁴ are —N (R ^1k ) —, —CH (R ^1k ) —, or G ³ and G 4 ^{When 4} is —C (R ^1m ) (R ¹ⁿ ) —, each “R ^1k ”, “R ^1m ” and “R ¹ⁿ ” are independent.

In G ¹ , G ² , G ³ and G ⁴ , when G ¹ is —C (R ^1k ) =, only when G ² is —CH═. Such a definition means that it is a definition expressed below. Incidentally, the ring represented by a broken line ^means a benzene ring which ring represented by G ^1, G 2, ^{G 3} and ^{G 4} are condensed.

In G ¹ , G ² , G ³ and G ⁴ , when G ³ and G ⁴ are —C (R ^1m ) (R ¹ⁿ ) —, R ¹ⁿ may be taken together. That is, in such a case,

Means a structure represented by Incidentally, the ring represented by a broken line ^means a benzene ring which ring represented by G ^1, G 2, ^{G 3} and ^{G 4} are condensed.

In G ¹ , G ² , G ³ and G ⁴ , “R ^1o , R ^1r and R ^1s are each independently a hydrogen atom, and R ^1p and R ^1q together form a condensed ring” , “R ^1p ” and “R ^1q ” together form a bicyclic or tricyclic condensed ring with a benzene ring substituted with “R ^1o ”, “R ^1r ” and “R ^1s ” Means. A specific example is the same as the above-described illustration of “R ^1e , R ^1h and R ¹ⁱ are all hydrogen atoms, and R ^1f and R ^1g together form a condensed ring”.
Following formula
The group represented by will be described. In the formula, the broken line part means a part of the benzene ring substituted by “R ^1m ” and “R ¹ⁿ ”.

When “D” is “—NR ⁵ CONR ⁵ —”, each “R ⁵ ” is an independent definition. When “D” is an oxygen atom or a sulfur atom and p and q are 0, it means that R ^1m and R ¹ⁿ are taken together to form an oxo group or a thixo group. “—CH (R ⁶ ) CH ₂ —” in “D” may be “—CH ₂ CH (R ⁶ ) —”. Incidentally, _{^{"D", -SO 2 -, - NR 5}} CO -, - NR 5 SO 2 -, - NR 5 CONR 5 - in the case of the "p" and "q" are not both 0.

Specific examples of the group represented by Chemical Formula 24 include structural formulas represented by the following groups. The broken line portion, ^{"R 1 m"} and ^{"R 1n"} means ring substituted.

Following formula
The group represented by will be described.

When “M” is “—NR ⁷ CONR ⁷ —”, each “R ⁷ ” is an independent definition. When “M” is an oxygen atom or a sulfur atom and r and s are 0, it means that R ^4a and R ^4b are together an oxo group or a thixo group. “—CH (R ⁸ ) CH ₂ —” in “M” may be “—CH ₂ CH (R ⁸ ) —”. Note that _{^{"M", -SO 2 -, - NR 7}} CO -, - NR 7 SO 2 -, - NR 7 CONR 7 - in the case of "r" and "s" are not both 0.

“R ⁹ ” is a group substituted on a carbon atom other than M. However, when both r and s are 0, “R ⁹ ” is a non-existing group.

  With respect to each substituent in the compound represented by the formula (I), further preferred embodiments will be described below.

The following partial structure:
In the group represented by “R ^1a ”,
The group substituted at the position represented by is preferable. In such a case, the preferred groups R ^1a , R ^1b , R ^1c and R ^1d are as follows.

“R ^1a ”
(A5) a halogen atom,
(B5) a cyano group,
(C5) C _1-6 alkyl group (the group is
(C51) a halogen atom,
(C52) C _1-4 alkoxy, or (c53) C _3-6 cycloalkyl may be substituted. ),
1 group selected from the group consisting of (d5) C _2-6 alkynyl group and (e5) C _1-6 alkoxy group (the group may be substituted with a halogen atom).

“R ^1a ” is more preferably a C _1-6 alkyl group which may be substituted with 1 to 3 halogen atoms.

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

“R ^1b ” is substituted with C _1-4 alkoxy, C _3-6 cycloalkoxy, or C _1-6 alkylcarbonylamino (wherein the alkyl may be substituted with 1 to 3 fluorine atoms). A C _1-6 alkyl group; or 1-3 fluorine atoms, hydroxy, C _1-4 alkoxy, C _3-6 cycloalkoxy, cyano, mono-C _1-6 alkylcarbonylamino, mono-C _1-6 C _1-6 alkoxy groups substituted with alkoxycarbonylamino, aminocarbonyl, C _1-6 alkylaminocarbonyloxy, C _1-4 alkoxycarbonyl, or C _1-4 alkylcarbonyl are preferred.

“R ^1b ” is preferably a C _1-6 alkoxy group substituted with C _1-4 alkoxy, and more preferably a 3-methoxypropyloxy group.

“R ^1c ” has the following formula:

(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 ^1e ”, “R ^1f ”, “R ^1g ” and “R ¹ⁱ ” are each independently the same or different, preferably a hydrogen atom or a halogen atom, and more preferably a hydrogen atom.

“R ^1h ” is preferably a group: —AB.

"A" is a single _{bond, -O -, - SO 2 -} , - CO -, - N (R 1j) CO- or ^{-N (R} 1j) SO ₂ -, more preferably a single bond or -CO- is preferable .

“R ^1j ” is preferably a C _1-6 alkyl group or a C _3-6 cycloalkyl group.

"B"
(A6) a hydrogen atom,
(B6) a C _1-6 alkyl group (the group is
(B61) 1 to 3 fluorine atoms,
(B62) C _3-6 cycloalkyl,
(B63) di- (C _1-6 alkyl) aminocarbonyl,
(B64) 5-membered or 6-membered optionally aminocarbonyl substituted with heterocyclic ring saturated, or (b65) C _3-10 (which may be substituted with hydroxy.) Cycloalkylamino may be substituted with. ),
(C6) an amino group which may be di-substituted (the group is
(C61) C _1-6 alkyl (may be substituted with 1 to 3 fluorine atoms or C _1-4 alkoxy),
(C62) 5- or 6-membered saturated heterocycle,
(C63) C _3-6 cycloalkyl, and (c64) C _6-10 aryl may be substituted with the same or different 1 or 2 groups selected from the group consisting of aryl. ), Or (d6) 5-membered to 7-membered cyclic amino group (said group from the group consisting of substituted by hydroxy or _{C 1-4} alkoxy may be substituted also a good _{C 1-4} alkyl.) One group selected is preferred.

“B” represents a hydrogen atom; a C _1-6 alkyl group (the group is represented by 1 to 3 fluorine atoms, C _3-6 cycloalkyl, di- (C _1-6 alkyl) aminocarbonyl, 5-membered or 6 A di- (C _1-6 alkyl) amino group which may be substituted with an aminocarbonyl which may be substituted with a membered saturated heterocyclic ring, or a C _3-10 cycloalkylamino which may be substituted with hydroxy. (The alkyl may be substituted with 1 to 3 fluorine atoms or C _1-4 alkoxy); N- (C _1-6 alkyl) -N- (C _3-6 cycloalkyl) amino group; N- (C _1-6 alkyl) -N- (5- or 6-membered saturated heterocycle) amino group; N- (C _3-6 cycloalkyl) -N- (5- or 6-membered saturated heterocycle) ring) amino group; N- _{(C 1-6} alkyl) -N- ( _6-10 aryl) amino group;. And 5-membered to 7-membered cyclic amino group (the group may which may be substituted also a good _{C 1-4} alkyl substituted by hydroxy or _{C 1-4} alkoxy from) Even more preferred is a single group selected from the group consisting of

  “B” is more preferably a hydrogen atom.

“R ^1b ” and “R ^1c ” are taken together to form the following formula:

It is preferable to form a ring represented by

Preferred embodiments of “G ¹ ”, “G ² ”, “G ³ ” and “G ⁴ ” in the ring will be described.

In the partial structure, “G ¹ ” is —N (R ^1k ) —, or —C (R ^1k ) ^═ ,
“G ² ” is —CH ₂ —, —CO—, —CS—, or —CH═;
“G ³ ” is —C (R ^1m ) (R ¹ⁿ ) —, —N (R ^1k ) —, —CO—, or an oxygen atom,
“G ⁴ ” is preferably a ring represented by —C (R ^1m ) (R ¹ⁿ ) —, —N (R ^1k ) —, ^—SO— , —SO ₂ —, an oxygen atom, or a sulfur atom.

Examples of the ring represented by the partial structure include the following:
And a ring selected from the group represented by:

“G ¹ ” is —N (R ^1k ) —, “G ² ” is —CO—, “G ³ ” is —C (R ^1m ) (R ¹ⁿ ) —, ⁴ "is more preferably a ring represented by an oxygen atom.

“R ^1k ”
(A7) a C _1-6 alkyl group (the group is
(A700) hydroxy,
(A701) C _1-4 alkoxy (1 to 3 fluorine atoms, C _1-4 alkoxy, C _3-6 cycloalkyl optionally substituted with C _1-6 alkylaminocarbonyl, or C _1-4 alkyl Optionally substituted 5 or 6 membered saturated heterocycle).
(A702) trifluoromethyl,
(A703) difluoromethyl,
_{(A704) C 3-6} cycloalkyl (1-2 fluorine _atoms, may be substituted with _{C 1-4} alkoxy which may be substituted with _{C 1-4} alkyl, or _{C 1-4} alkoxy.),
(A705) C _3-6 cycloalkoxy,
(A706) carboxyl,
(A707) C _1-6 alkylcarbonylamino (may be substituted with 1 to 5 fluorine atoms, hydroxy, C _1-4 alkoxy, or C _3-6 cycloalkyl),
_(A708) N- _{(C 1-4 alkylcarbonyl)-N-(C 1-6} alkyl) - amino,
(A709) C _3-6 cycloalkylcarbonylamino (optionally substituted with C _1-4 alkoxy),
(A710) C _1-6 alkylthiocarbonylamino,
(A711) C _1-4 alkoxycarbonylamino (may be substituted with 1 to 3 fluorine atoms),
_(A712) N- _{(C 1-4 alkoxycarbonyl)-N-(C 1-6} alkyl) - amino,
(A713) C _3-6 cycloalkoxycarbonylamino,
(A714) mono- (C _1-6 alkyl) aminocarbonyloxy,
(A715) di- (C _1-6 alkyl) aminocarbonyloxy,
(A716) 4- to 7-membered cyclic aminocarbonyloxy (which may be substituted with C _1-4 alkoxy),
(A717) C _1-6 alkylaminocarbonyl (may be substituted with 1 to 3 fluorine atoms or C _3-6 cycloalkyl),
_{(A718) C 3-6} cycloalkyl-aminocarbonyl,
(A719) C _1-6 alkylaminocarbonylamino,
(A720) C _1-4 alkylcarbonyl,
(A721) C _1-4 alkylcarbonyloxy,
(A722) C _1-4 alkoxycarbonyl,
(A723) C _1-6 alkylsulfonyl,
One group selected from the group consisting of (a724) C _1-6 alkylsulfonylamino, and (a725) a 5- or 6-membered saturated heterocyclic ring (which may be substituted with C _1-4 alkyl). May be substituted. ),
(B7) C _2-6 alkenyl group (may be substituted with a halogen atom),
(C7) C _2-6 alkynyl group (which may be substituted with C _1-4 alkoxy), or (d7) a 5- to 6-membered heteroaryl C _1-4 alkyl group.

“R ^1k ” means “C _1-6 alkyl group substituted with C _1-4 alkoxy” may be substituted with 1 to 3 fluorine atoms. Specific examples include 3-monofluoromethoxy-4-butyl, 4-methoxy-3,3-difluoro-butyl and the like.

“R ^1k ” is preferably a C _1-6 alkyl group substituted with C _1-4 alkoxy, more preferably a 3-methoxypropyl group or a 4-methoxybutyl group.

^{"R 1k"} is _{preferably C 1-6 C 1-6} alkyl group substituted with alkylcarbonylamino, 2- (ethylcarbonylamino) ethyl group is more preferable.

R ^1m and R ¹ⁿ are each independently the same or different,
(A8) a hydrogen atom,
(B8) a halogen atom,
(C8) C _1-6 alkyl group (the group is
(C801) 1-3 fluorine atoms,
(C802) C _1-4 alkoxy (the group is
(I) C _6-10 aryl optionally substituted with 1 to 3 groups selected from the group consisting of halogen atoms and cyano,
(Ii) C _1-4 alkoxy optionally substituted by 1 to 3 fluorine atoms,
(Iii) C _3-6 cycloalkyl (C _3-6 cycloalkyl is substituted with C _6-10 aryl optionally substituted with 1 to 3 groups selected from the group consisting of a halogen atom and cyano. May be good),
(Iv) 5- or 6-membered saturated heterocycle,
(V) 5- or 6-membered saturated heterocyclic oxy, or (vi) substituted with N- (C _3-10 cycloalkyl optionally substituted with hydroxy) -N- (C _1-6 alkyl) aminocarbonyl May be. ),
_{(C803) C 3-6} cycloalkyl,
_{(C804) C 3-6} cycloalkoxy,
(C805) C _7-14 aralkyloxy (which may be substituted with a halogen atom),
(C806) saturated heterocyclic oxy,
(C807) N- (C _3-6 cycloalkyl) -N- (C _1-6 alkyl) amino (C _3-6 cycloalkyl is 1 to 3 groups selected from the group consisting of halogen atoms and cyano. And may be substituted with C _6-10 aryl, which may be substituted with
(C808) N- (C _3-6 cycloalkyl C _1-4 alkyl) -N- (C _1-6 alkyl) aminocarbonyl,
(C809) N- (C _1-4 alkylcarbonyl) -N- (C _1-6 alkyl) amino (wherein the C _1-4 alkylcarbonyl may be substituted with C _1-4 alkyl) Or a saturated heterocycle of
_(C810) N- _{(C 1-4 alkoxycarbonyl)-N-(C 1-6} alkyl) amino,
(C811) N- (C _3-6 cycloalkylsulfonyl) -N- (C _1-6 alkyl) amino,
(C812) 5-membered to 7-membered cyclic amino, or (c813) 5-membered to 7-membered cyclic aminocarbonyl (1-3 fluorine atoms or _{C 1-4} optionally _{C 1-4} alkyl optionally substituted with alkoxy , Or may be substituted with C _1-4 alkoxy. ),
(D8) C _3-6 cycloalkyl group,
(E8) an aminocarbonyl group (this group may be substituted with C _1-6 alkyl),
(F8) a 5- to 10-membered monocyclic or polycyclic heteroaryl group (the group may be substituted with 1 to 3 fluorine atoms, C _1-4 alkyl, or cyano; And (g8) a C _7-14 aralkyl group (the group may be substituted with a halogen atom), or (h8)

A group selected from the group consisting of groups represented by the formula (the definitions in the formula are the same as in item 1) is preferred.

Following formula

In the group represented by
^{R 1o, R 1p, R 1q} , R 1r and ^{R 1s} are each independently the same or different, a hydrogen atom, from a good _{C 1-4} alkoxy group optionally substituted by cyano and _{C 1-4} alkoxy The same or different 1 to 5 groups selected from the group consisting of

R ^1m and R ¹ⁿ together represent the following formula

(D is an oxygen atom, —NR ⁵ —, —OCH (R ⁶ ) —, —CH (R ⁶ ) —, or —CH (R ⁶ ) CH ₂ —, wherein R ⁵ is C _1-4 alkylcarbonyl group, C _1-4 alkoxycarbonyl group, which may be substituted with 1 to 3 fluorine atoms or C _1-4 alkoxy, or 4-membered which may be substituted with C _1-4 alkoxy A 7-membered cyclic aminocarbonyl group, wherein R ⁶ is a C _1-6 alkyl group optionally substituted with a hydrogen atom, a saturated heterocyclic ring optionally substituted with C _1-4 alkoxy or hydroxy, C _1- C _1-6 alkoxy group optionally substituted by ₄ alkoxy, N- (C _1-6 alkylsulfonyl) -N- (C _1-6 alkyl) amino group, C _1-4 alkoxycarbonylamino group, or mono- _{(C 1-6} alkyl) Amino carbonyl group or C _6-10 arylsulfonylamino group, (the aryl may. Be substituted by a halogen atom) Yes, p and q are each independently the same or different, 0, 1, or 2).

R ^1m and R ¹ⁿ are both more preferably a C _1-6 alkyl group.

Preferred “R ² ” in formula (I) is
(A9) a C _1-6 alkyl group (which may be substituted with a halogen atom or C _3-6 cycloalkyl),
(B9) C _2-6 alkenyl group (which may be substituted with a halogen atom),
(C9) C _2-6 alkynyl group (may be substituted with a halogen atom)
(D9) C _3-6 cycloalkyl group (which may be substituted with a halogen atom, C _1-4 alkyl, or C _1-4 alkoxy),
(E9) C ₆ aryl group (halogen atom, C _6-10 aryl which may be substituted with a halogen atom, or C _6-10 aryloxy which may be substituted with C _1-4 alkoxy may be substituted. ),
(F9) a C _7-10 aralkyl group (which may be substituted with a halogen atom), and (g9) a 5- or 6-membered heteroaryl group (which may be substituted with C _1-4 alkyl). One group selected from the group is mentioned.

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

Preferred “R ^3a ” and “R ^3b ” in formula (I) are each independently the same or different,
(A10) a hydrogen atom,
(B10) a C _1-6 alkyl group (the group is
(B101) a halogen atom,
(B102) hydroxy,
(B103) C _3-6 cycloalkyl,
(B104) C _1-4 alkoxy,
_(B105) N- _{(C 1-4 alkylcarbonyl)-N-(C 1-6} alkyl) amino,
(B106) N- (C _1-6 alkylsulfonyl) -N- (C _1-6 alkyl) amino,
(B107) N- (C _6-10 arylsulfonyl) -N- (C _1-6 alkyl) amino,
(B108) N- (C _1-4 alkoxycarbonyl) -N- (C _1-6 alkyl) amino, or (b109) C _7-14 aralkyloxy (1 to 3 fluorine atoms, or C _1-4 alkoxy And optionally substituted with C _3-6 cycloalkoxy. ),
(C10) C _2-6 alkenyl group,
(D10) a C _2-6 alkynyl group,
(E10) C _3-6 cycloalkyl group (which may be substituted with C _1-4 alkoxy),
(F10) C _6-10 aryl group (the group is
(F101) may be substituted with a halogen atom, or (f102) C _1-4 alkoxy. ),
(G10) C _7-10 aralkyl group (the group is
(G101) a halogen atom,
(G102) C _1-4 alkyl (the group is
(I) 5- or 6-membered cyclic amino optionally substituted with C _6-10 aryloxy (the aryl may be substituted with 1 to 3 fluorine atoms), or (ii) 5-membered It may be substituted with ˜7-membered cyclic amino (which may be substituted with C _6-10 aryloxy which may be substituted with fluorine atom). ),
(G103) C _1-4 alkoxy (the group is
(I) C _1-4 alkoxy,
(Ii) C _3-6 cycloalkyl (which may be substituted with C _1-4 alkoxy),
(Iii) C _3-6 cycloalkyloxy (which may be substituted with C _1-4 alkyl),
(Iv) C _6-10 aryloxy (the group may be substituted with 1 to 3 fluorine atoms or cyano), or (v) C ₇ optionally substituted with C _1-4 alkoxy. _It may be substituted with _-14 aralkyloxy. ),
(G104) C _6-10 aryl (may be substituted with a halogen atom),
(G105) C _6-10 aryloxy (which may be substituted with a halogen atom or cyano),
(G107) C _7-14 aralkyloxy (which may be substituted with C _1-4 alkoxy),
(G108) 5-membered or 6-membered saturated heterocyclic oxy (may be substituted with 5- or 6-membered saturated heterocyclic carbonyl, or C _6-10 aryl optionally substituted with a fluorine atom),
(G109) 5-membered or 6-membered heteroaryloxy (optionally substituted with C _1-4 alkyl),
(G110) A 5- to 7-membered cyclic aminocarbonyl (which may be substituted with a C _6-10 aryloxy which may be substituted with a fluorine atom) may be substituted. ),
(H10) a 5- or 6-membered saturated heterocyclic group,
(I10) a 5- to 10-membered heteroaryl group (the group is
(I101) C _1-4 alkyl optionally substituted by 1 to 3 fluorine atoms,
(I102) C _1-4 alkoxy optionally substituted with C _1-4 alkoxy,
(I103) 5- or 6-membered saturated heterocyclic aminocarbonyl,
(I104) C _6-10 aryl optionally substituted with C _1-4 alkoxy, and (i103) optionally substituted with 1-2 groups selected from the group consisting of C _1-6 alkylaminocarbonyl . And a group selected from the group consisting of (j10) C _6-10 aryloxy group (which may be substituted with C _6-10 aryloxy).

Further preferred ^{"R 3a"} and ^{"R 3b} 'are each independently the same or different, a hydrogen atom; a _{C 1-6} alkyl group optionally substituted by _{hydroxy; C 6-10} aryl _{group; C 1- A} C _7-10 aralkyl group optionally substituted with ₄ alkoxy (the alkoxy may be substituted with C _7-14 aralkyloxy optionally substituted with C _1-4 alkoxy).

More preferable “R ^3a ” and “R ^3b ” are any one of which is a hydrogen atom and the other is a hydrogen atom, a C _1-6 alkyl group which may be substituted with hydroxy, a C _6-10 aryl group , or _{C 1-4} optionally _{C 7-10} aralkyl group optionally substituted by alkoxy (said _{alkoxy, C 1-4} substituted alkoxy may be substituted with may be _{C 7-14} aralkyloxy.) in Or both are C _1-6 alkyl groups.

Preferred “R ^4a ” and “R ^4b ” in formula (I) are each independently the same or different,
(A11) a hydrogen atom,
(B11) a C _1-6 alkyl group (the group is
(B111) a halogen atom,
(B112) C _3-6 cycloalkyl,
(B113) C _1-4 alkoxy (the group is
(I) C _1-4 alkoxy,
(Ii) It may be substituted with a 5- to 7-membered cyclic aminocarbonyl. ),
(B114) 5- or 6-membered saturated heterocyclic ring, or (b115) N- (C _1-4 alkylcarbonyl) -N- (C _3-6 cycloalkyl) amino (C _1-4 alkylcarbonyl) is 5 A 6- or 6-membered saturated heterocyclic ring, or a C _6-10 aryl optionally substituted with a halogen atom. ),
(C11) C _2-6 alkenyl group (the group is
(C111) C _6-10 aryl optionally substituted with C _1-4 alkoxy, or (c112) N- (C _1-4 alkylcarbonyl) -N- (C _3-6 cyclylalkyl) amino (C _{1- 4-} alkylcarbonyl may be substituted with a 5- or 6-membered saturated heterocyclic ring which may be substituted with C _1-4 alkyl. ),
(D11) C _2-6 alkynyl group (which may be substituted with C _3-6 cycloalkyl),
(E11) C _3-6 cycloalkyl group (which may be substituted with C _1-4 alkoxy),
(E11) C _6-10 aryl group (the group is
(E111) di - _{(C 1-6} alkyl) amino carbonyl, or _{(e112) C 1-4} may be substituted with alkyl. ),
(F11) C _7-10 aralkyl group (the group is
(F111) a halogen atom,
(F112) It may be substituted with cyano. ),
(G11) 1 selected from the group consisting of a 5- or 6-membered saturated heterocyclic group and (h10) a 5- to 10-membered heteroaryl group (which may be substituted with C _1-4 alkyl) Groups.

R ^4a and R ^4b together form the following formula

In the group represented by formula (I), M is an oxygen atom, —NR ⁷ —, —CH (R ⁷ ) —, or —CH (R ⁷ ) CH ₂ —, and R ⁷ is a C _1-4 alkoxycarbonyl group. R ⁹ is an oxygen atom, and r and s are independently the same or different, and a group represented by 0, 1 or 2 is preferable.

More preferable “R ^4a ” and “R ^4b ” are either one of which is a hydrogen atom and the other is a hydrogen atom or a C _1-6 alkyl group, or both are a C _1-6 alkyl group. .

  “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. Also included are solvates such as this hydrate or ethanol solvate. Further, all forms of crystal forms are also included.

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

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

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

The compound of the present invention can be specifically exemplified as the following compounds. In the table below, for example, No. The compound represented by 1 (T ¹ : Q211; T ² : Q1; T ³ : Q104; T ⁴ : Q296) means the following compound.

  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 pharmaceutically acceptable salt is produced, for example, by the method shown below.

[Wherein, R ^1a , R ^1b , R ^1c , R ^1d , R ^3a , R ^3b , R ^4a , R ^4b and R ² have the same meanings as described in the above item 1, and R ²⁰⁰ may be substituted. a _{C 1-6} alkyl group, an optionally substituted _{C 3-6} alkenyl group, optionally substituted _{C 3-6} alkynyl or optionally substituted _{C 3-5} cycloalkyl ^{group,, R 201} 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 cycloalkyl group , An optionally substituted C _5-6 cycloalkenyl group, an optionally substituted C _6-10 aryl group, an optionally substituted C _7-14 aralkyl group, or an optionally substituted 5-10 membered Monocyclic or polycyclic heteroaryl The ^{stands, R 202} is a hydrogen atom, an optionally substituted _{C 1-6} alkyl group, optionally substituted _{C 2-6} alkenyl group, optionally substituted _{C 2-6} alkynyl group, optionally substituted A good C _3-10 cycloalkyl group, an optionally substituted C _5-6 cycloalkenyl group, an optionally substituted C _6-10 aryl group, an optionally substituted C _7-14 aralkyl group, or a substituted Represents a 5-membered to 10-membered monocyclic or polycyclic heteroaryl group, R ²⁰³ represents a hydrogen atom, a fluorine atom, or a C _1-3 alkoxy group, and X ² represents an iodine atom or a bromine atom. represents a chlorine atom, a methanesulfonyloxy group, trifluoromethanesulfonyloxy group or a p- toluenesulfonyloxy _{group,, m 100} is an integer of 0, 1, 2 or 3,, ^{Y 1} is Cbz, representing a Boc or Alloc. ]

1) Step 1
When X ¹ represents a hydroxyl group, the compound of formula (1-3), the compound of formula (1-1), in an inert solvent, using a condensing agent, in the presence of a base, if necessary the formula It can be synthesized by reacting with the compound (1-2). In some cases, a phase transfer catalyst can also be used.

  The base is not particularly limited as long as it is used as a base in a normal reaction. For example, N-methylmorpholine, triethylamine, diisopropylethylamine, tributylamine, 1,8-diazabicyclo [5.4.0] undeca- Such as 7-ene, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [5.4.0] undec-7-ene, pyridine, dimethylaminopyridine, or picoline Organic bases or inorganic bases such as sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, or sodium hydride can be used. Examples of the phase transfer catalyst include quaternary ammonium salts such as tetrabutylammonium bromide or benzyltriethylammonium bromide, or crown ethers such as 18-crown-6-ether.

  Examples of the condensing agent include those described in Experimental Chemistry Course (Chemical Society of Japan, Maruzen) Vol.

  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)).

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

3) Step 3
Compound (1-5) can be produced from compound (1-1) by the same method as in Process 1 described in Production Method 1.

4) Step 4
Compound (1-3) can be produced by reacting compound (1-5) with compound (1-6) in the presence of a base in an inert solvent. Examples of the base include alkali metal salts such as sodium hydrogen carbonate, potassium carbonate, cesium carbonate or sodium hydroxide, organic bases such as triethylamine or 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU). , Alkali metal hydrides such as sodium hydride or potassium hydride, alkoxyalkali metals such as potassium t-butoxy, and the like. 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.
5) Step 5
Compound (1-2) can be produced from compound (1-4) by the same method as in Step 4 described in Production Method 1. In addition, when R ^{2 of} the compound (1-6) 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.
6) Step 6
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 (1-7), Compound (1-8), and Compound (1-9) 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.

Manufacturing method 2
Among the compounds represented by formula (1-1), the compound represented by formula (2-9) or a salt thereof is produced, for example, by the method shown below.

[Wherein, R ^1a , R ^1d , R ^1k , R ^1m , and R ¹ⁿ are as defined above, R ¹⁰⁰ and R ¹⁰¹ represent a C _1-6 alkyl group, and X ³ and X ⁴ represent , An iodine atom, a bromine atom, a chlorine atom, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, or a p-toluenesulfonyloxy group. ]
1) Step 1
Compound (2-2) can be produced by reacting compound (2-1) with nitric acid in an inert solvent in the presence of concentrated sulfuric acid. Examples of the inert solvent include organic acids such as acetic acid or propionic acid. The reaction temperature is selected from the range of about 30 ° C to about 100 ° C.
2) Step 2
Compound (2-3) can be produced by hydrogenating compound (2-2) 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, and 2-propanol, and ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane, and 1,2-dimethoxyethane. . The reaction temperature is selected from the range of about 0 ° C to about 50 ° C.
3) Step 3
Compound (2-5) can be produced by reacting compound (2-3) with compound (2-4) in the presence of a base in an inert solvent. Examples of the base include sodium bicarbonate, potassium carbonate, cesium carbonate, alkali metal salts such as sodium hydroxide, and the like. Examples of the inert solvent include ether solvents such as tetrahydrofuran and 1,4-dioxane, aprotic solvents such as dimethylformamide and dimethyl sulfoxide, and water. A mixed solvent thereof may be used. The reaction temperature is selected from the range of about −10 ° C. to about 50 ° C.
4) Step 4
Compound (2-6) can be produced by treating compound (2-5) with a base in an inert solvent. Examples of the base include alkali metal salts such as sodium hydrogen carbonate, potassium carbonate, or sodium hydroxide. Examples of the inert solvent include aprotic solvents such as dimethylformamide or dimethyl sulfoxide. The reaction temperature is selected from the range of about 30 ° C to about 100 ° C.
5) Step 5
Compound (2-8) can be produced by reacting compound (2-6) with compound (2-7) in the presence of a base in an inert solvent. Examples of the base include alkali metal salts such as sodium hydrogen carbonate, potassium carbonate, cesium carbonate, or sodium hydroxide, alkali metal hydrides such as sodium hydride or potassium hydride, or alkoxy alkali metals such as t-butoxy potassium. Can be mentioned. Further, when X ⁴ is a chlorine atom or a bromine atom, an additive such as lithium iodide, sodium iodide, or potassium iodide can be used. Examples of the inert solvent include ether solvents such as tetrahydrofuran and 1,4-dioxane, aprotic solvents such as dimethylformamide and dimethyl sulfoxide, and a mixed solvent thereof. The reaction temperature is selected from the range of about 30 ° C to about 150 ° C.
6) Step 6
Compound (2-9) is produced from Compound (2-8) 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.

Production method 3
The compound represented by formula (2-6) or a salt thereof in Production Method 2 is produced, for example, by the method shown below.

[Wherein, R ^1a , R ¹⁰⁰ , R ^1d , R ^1m , and R ¹ⁿ have the same ^meanings as described above, and R ¹⁰² represents a C _1-6 alkyl group. ]
1) Step 1
Compound (3-2) can be produced by reacting compound (2-2) with compound (3-1) in the presence of phosphine and a condensing agent in an inert solvent. Examples of the phosphine include triphenylphosphine, and examples of the inert solvent include ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane, or 1,2-dimethoxyethane, and a condensing agent. Examples thereof include azodicarboxylic acid diisopropyl ester. The reaction temperature is selected from the range of about 0 ° C to about 80 ° C.
2) Step 2
For example, it can be carried out by the following production method (i. Or ii.).
i. Compound (2-6) can be produced by reacting iron and compound (3-2) in an inert solvent. Examples of the inert solvent include water, acetic acid, or alcohol solvents such as methanol, ethanol, or 2-propanol, and a mixed solvent thereof may be used. The reaction temperature is selected from the range of about 30 ° C to about 100 ° C.
ii. Compound (2-6) can be produced by hydrogenating compound (3-2) 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, and 2-propanol, and ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane, and 1,2-dimethoxyethane. . The reaction temperature is selected from the range of about 0 ° C to about 50 ° C.

Manufacturing method 4
Among the compounds represented by formula (1-14), the compound represented by formula (26-5) or a salt thereof is produced, for example, by the method shown below.

[Wherein, R ^1a , R ^1d , R ^1k , R ^1m , R ¹ⁿ , and X ⁴ have the same meanings as described above, X ⁵ represents a chlorine atom, a bromine atom, or an iodine atom, and R ¹⁰³ represents And C _1-3 alkyl group. ]
1) Step 1
Compound (4-2) is produced by reacting Compound (4-1) with Compound (3-1) in the presence of crown ether in the presence or absence of sodium hydride in an inert solvent. Can do. Examples of the crown ether include 15-crown, and examples of the inert solvent include ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane, or 1,2-dimethoxyethane. The reaction temperature is selected from the range of about 0 ° C to about 50 ° C.
2) Step 2
Compound (4-3) can be produced from compound (4-2) by the same method as in Step 2 described in Production Method 3.
3) Step 3
Compound (4-4) can be produced from compound (4-3) by the same method as in Process 5 described in Production Method 2.
4) Step 4
Compound (4-5) is produced by reacting Compound (4-4) in an inert solvent in the presence of methanol or ethanol, an organic base, an auxiliary ligand, and palladium acetate in a carbon monoxide atmosphere. Can do. Examples of the auxiliary ligand include diphenylphosphinopropane. Examples of the organic base include N, N-diisopropylethylamine. Examples of the inert solvent include amide solvents such as dimethylacetamide. The reaction temperature is selected from the range of about 70 ° C to about 150 ° C.
5) Step 5
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
The compound represented by formula (2-6) or a salt thereof in Production Method 2 is produced, for example, by the method shown below.

[Wherein, R ^1a , R ^1e , R ^1m , R ¹ⁿ , R ¹⁰⁰ , R ¹⁰¹ , and X ³ are as defined above. ]
1) Step 1
Compound (2-6) can be produced from compound (2-3) by a method similar to the production method described in the literature (for example, Chem. Pharm. Bull. 46, 1716 (1998)).

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

[Wherein, R ^1a , R ^1d , R ^1k , R ^1m , R ¹ⁿ , R ¹⁰⁰ , R ¹⁰¹ , X ³ , and X ⁴ are as defined above, and R ¹⁰⁴ is a C _1-6 alkyl group. Represents. ]
1) Step 1
From compound (6-1) to compound by a method similar to the production method described in the literature (for example, Synth. Commun. 27, 2943 (1997), J. Chem. Soc. Perkin Trans 2, 691 (1988), etc.) (6-2) can be manufactured.
2) Step 2 and Step 3
Compound (6-4) can be produced from compound (6-2) by a method similar to the production method described in the literature (for example, WO2005 / 082872 etc.).
3) Step 4
Compound (6-5) can be produced from compound (6-4) by the same method as in Process 5 described in Production Method 2.
4) Step 5
The compound (6-6) is produced from the compound (6-5) 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 7
Among the compounds represented by formula (1-1), the compound represented by formula (7-4) or a salt thereof is produced, for example, by the method shown below.

[Wherein, R ^1a , R ^1d , R ^1k , R ^1m , R ¹⁰⁰ , R ¹⁰⁴ , and X ⁴ are as defined above, and R ¹⁰⁵ represents a C _1-6 alkyl group. ]
1) Step 1
Production methods described in literature (for example, J. Am. Chem. Soc. 123, 6989 (2001), J. Org. Chem. 70, 4360 (2005), Synth. Commun. 29, 591 (1999), etc.) By a similar method, compound (7-1) can be produced from compound (6-1).
2) Step 2
Compound (7-2) can be produced from compound (7-1) by the same method as in Step 2 described in Production Method 3.
3) Step 3
Compound (7-3) can be produced from compound (7-2) by the same method as in Step 4 described in Production Method 1.
4) Step 4
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.

Manufacturing method 8
Among the compounds represented by formula (1-1), the compound represented by formula (8-7) or a salt thereof is produced, for example, by the method shown below.

[Wherein, R ^1a , R ^1d , R ^1k , R ^1m , R ¹ⁿ , and X ⁴ are as defined above, and X ⁷ represents an iodine atom, a bromine atom, a chlorine atom, a methanesulfonyloxy group, a trifluoro group, It represents a lomethanesulfonyloxy group or a p-toluenesulfonyloxy group, and R ¹⁰⁵ and R ¹⁰⁶ represent a C _1-6 alkyl group. ]
1) Step 1
Compound (8-1) is converted from Compound (8-1) to Compound (8-3) by a method similar to the production method described in the literature (for example, Pharmazie 59, 93-98 (2004), Chimia 47, 19-21 (1993), etc.). Can be manufactured.
2) Step 2
Compound (8-4) can be produced from compound (8-3) by the same method as in Process 1 described in Production Method 2.
3) Step 3
Documents (for example, J. Am. Chem. Soc. 129, 14860-14861 (2007), Pharmazie 61, 901-907 (2006), Organic & Biomolecular Chemistry 4, 3960-3965 (2006), WO06 / 041830, etc.) Compound (8-5) can be produced from compound (8-4) by the same production method as described above.
4) Step 4
Compound (8-6) can be produced from compound (8-5) by the same method as in Process 5 described in Production Method 2.
5) Step 5
Compound (8-7) is produced from Compound (8-6) 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 9
Among the compounds represented by the formula (1-1), the compound represented by the formula (9-3) or a salt thereof is produced, for example, by the method shown below.

[Wherein, R ^1d , R ^1k , R ^1m , R ¹ⁿ , and G ⁴ have the same meanings as described above, X ⁸ represents a chlorine atom, a bromine atom, or an iodine atom, and R ¹⁰⁷ represents C _{1 -6} represents an alkyl group. ]

1) Step 1
Compound (9-2) is obtained by reacting Compound (9-1) with a compound selected from N-chlorosuccinimide, N-bromosuccinimide, and N-iodosuccinimide in the presence of sodium acetate in an inert solvent. Can be manufactured. 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
The compound (9-3) is produced from the compound (9-2) 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.

Manufacturing method 10
Among the compounds represented by formula (1-1), the compounds represented by formula (10-7) and formula (10-8) or their salts are produced, for example, by the method shown below.

[Wherein, R ^1d , R ^1k , R ^1m , R ¹ⁿ , and G ⁴ have the same meanings as described above, R ¹⁰⁹ represents an alkyl group, and R ¹¹⁰ and R ¹¹¹ represent a hydrogen atom or an alkyl group. R ¹⁰⁸ represents a C _1-6 alkyl group, Z ¹ is

(Wherein R ³⁰⁰ represents a hydrogen atom or a C _1-4 alkyl group, or two R ³⁰⁰ together form 1,2-phenylene, and R ³⁰¹ , R ³⁰² , R ³⁰³ , R ³⁰⁴ , R ³⁰⁵ , and R ³⁰⁶ are each independently a hydrogen atom or a C _1-2 alkyl group, m represents an integer of 0 or 1, and M ⁺ represents potassium ion, sodium ion, or ammonium Represents an ion). ]
1) Step 1
Compound (10-3) can be produced by reacting compound (10-1) with compound (10-2) 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.
2) Step 2
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 (10-5) can be produced from the compound (10-1) by a method similar to the production method described. Production examples are given below.
Compound (10-5) is a reaction between Compound (10-1) and Compound (10-4) 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 and tetrakistriphenylphosphine palladium. The reaction temperature is selected from the range of about 50 ° C to about 150 ° C.
3) Step 3
Compound (10-6) can be produced by hydrogenating compound (10-5) 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.
4) Step 4 and Step 5
The compound (10-3) to the compound (10-7) can also be obtained from a compound (10-3) by a method similar to that described in the literature (for example, Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.)). Compound (10-8) can be produced from compound (10-6).

Manufacturing method 11
Among the compounds represented by formula (1-1), the compound represented by formula (11-2) or a salt thereof is produced, for example, by the method shown below.

[Wherein, R ^1d , R ^1k , R ^1m , R ¹ⁿ , R ¹⁰⁸ , and G ⁴ are as defined 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 (11-1) can be produced from the compound (10-1) by the same method.
2) Step 2
The compound (11-2) is produced from the compound (11-1) 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 12
Among the compounds represented by formula (1-1), the compound represented by formula (12-5) or a salt thereof is produced, for example, by the method shown below.

[Wherein, R ^1a , R ^1c , and R ^1d have the same meanings as described above, R ¹¹² represents a C _1-6 alkyl group, R ¹¹³ represents a fluorine atom, a hydroxyl group, or a C _1-4 alkoxy group. , C _3-6 cycloalkoxy group, cyano group, mono-C _1-6 alkylcarbonylamino group, mono-C _1-6 alkoxycarbonylamino group, aminocarbonyl group, C _1-6 alkylaminocarbonyloxy group, C _{1 4} represents an alkoxycarbonyl group, or a _C1-4 alkylcarbonyl group, m ₁₀₁ represents an integer of 0, 1, 2, or 3, and X ⁹ represents an iodine atom, a bromine atom, a chlorine atom, methanesulfonyloxy Represents a group, a trifluoromethanesulfonyloxy group, or a p-toluenesulfonyloxy group. ]

1) Step 1
The compound (12-2) is produced from the compound (12-1) 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.

2) Step 2
Compound (12-4) can be produced from compound (12-2) by the same method as in Process 5 described in Production Method 2.
3) Step 3
Production of compound (12-5) from compound (12-4) 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 13
Among the compounds represented by formula (1-1), the compound represented by formula (13-5) or a salt thereof is produced, for example, by the method shown below.

[Wherein, R ^1a , R ¹¹³ , X ⁹ , Z ¹ , m ₁₀₁ , and R ^1m have the same meanings as described above, R ¹¹⁵ represents an optionally substituted C _6-10 aryl group, and It may represent a 5-membered to 10-membered monocyclic or polycyclic heteroaryl group, and R ¹¹⁴ represents a C _1-6 alkyl group. ]

1) Step 1
Compound (13-2) can be produced from compound (13-1) by the same method as in Process 5 described in Production Method 2.
2) Step 2
Compound (13-4) can be produced from compound (13-2) by the same method as in Step 2 described in Production Method 10.
3) Step 3
The compound (13-5) is produced from the compound (13-4) 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 14
Among the compounds represented by the formula (1-1), the compound represented by the formula (14-5) or a salt thereof is produced, for example, by the method shown below.

[Wherein R ¹¹⁰ , R ¹¹¹ , R ¹¹³ , R ¹¹⁴ , R ¹¹⁵ , Z ¹ , m ₁₀₁ , and R ^1d are as defined above, and X ¹¹ represents a chlorine atom, an iodine atom, or a bromine atom. Represents. ]

1) Step 1
Compound (14-2) can be produced from compound (14-1) by the same method as in Process 1 described in Production Method 9.
2) Step 2
Compound (14-3) can be produced from compound (14-2) by the same method as in Process 2 described in Production Method 10.
3) Step 3
Compound (14-4) can be produced from compound (14-3) by the same method as in Process 3 described in Production Method 10.
4) Step 4
The compound (14-5) is produced from the compound (14-4) 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 15
Among the compounds represented by formula (1-1), the compound represented by formula (15-2) or a salt thereof is produced, for example, by the method shown below.

[Wherein, R ¹¹³ , R ¹¹⁴ , R ¹¹⁵ , m ₁₀₁ , X ¹¹ , and R ^1d have the same meanings as described above. ]

1) Step 1
Literature (for example, Bioorganic & Medicinal Chemistry Letters 15, 3006-3011 (2005), WO07 / 099200, WO05 / 075424, Chemistry-A European Journal 13, 6249-6254 (2007), Organic Letters 7, 95-98 (2005), J. Org. Chem. 69, 3620 (2004), etc.) can be used to produce compound (15-1) from compound (14-2).
2) Step 2
The compound (15-2) is produced from the compound (15-1) 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 16
Among the compounds represented by formula (1-1), the compound represented by formula (16-3) or a salt thereof is produced, for example, by the method shown below.

[Wherein, R ¹⁰⁹ , R ¹¹³ , R ¹¹⁴ , R ¹¹⁵ , m ₁₀₁ , Z ¹ , and R ^1m are as defined above. ]

1) Step 1
Compound (16-2) can be produced from compound (16-1) by the same method as in Process 1 described in Production Method 10.
2) Step 2
The compound (16-3) is produced from the compound (16-2) 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.

Manufacturing method 17
Among the compounds represented by formula (1-2), the compound represented by formula (17-8) or a salt thereof is produced, for example, by the method shown below.

[Wherein, R ² , R ^3a , R ^3b , R ¹¹⁷ , R ¹¹⁸ , R ¹¹⁹ , R ¹²⁰ , and m ₁₀₀ are as defined above. ]

1) Step 1
Compound (17-2) can be produced from compound (17-1) by the same method as in Process 6 described in Production Method 1.
2) Step 2 to Step 3
The compound (17-4) is produced from the compound (17-2) 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.
3) Step 4
Compound (17-5) can be produced from compound (17-4) by the same method as in Process 1 described in Production Method 1. Compound (17-5) is synthesized with Compound (17-4) in the presence of 1-hydroxybenzotriazole, 1-ethyl-3- (dimethylaminopropyl) carbodiimide / hydrochloride, and triethylamine in an inert solvent. It can be produced by reacting with ammonium chloride. Examples of the inert solvent include aprotic solvents such as dimethylformamide. The reaction temperature is selected from the range of about 10 ° C to about 50 ° C.
4) Step 5
Compound (17-6) can be produced by reacting compound (17-5) with borane-dimethylsulfide complex in an inert solvent. Examples of the inert solvent include ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane, or 1,2-dimethoxyethane. The reaction temperature is selected from the range of about 50 ° C to about 100 ° C.
5) Step 6 to Step 7
Production of compound (17-8) from compound (17-6) 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 18
Among the compounds represented by formula (1-2), the compound represented by formula (17-8) or a salt thereof is produced, for example, by the method shown below.

[Wherein, R ² , R ^3a , R ^3b , R ¹¹⁷ , R ¹¹⁸ , R ¹¹⁹ , R ¹²⁰ , and m ₁₀₀ are as defined above. ]

1) Step 1
Compound (18-2) can be produced from compound (18-1) by the same method as in Process 5 described in Production Method 17.
2) Step 2
The compound (18-3) is produced from the compound (18-2) 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.
3) Step 3
Compound (18-4) can be produced from compound (18-3) by the same method as in Process 6 described in Production Method 1.
4) Step 4
The compound (17-8) is produced from the compound (18-4) 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 19
Among the compounds represented by formula (1-2), the compound represented by formula (19-9) or a pharmaceutically acceptable salt is produced, for example, by the method shown below.

[Wherein, R ² , R ^3a , R ^3b , R ^4a , and R ^4b have the same meanings as described above. ]

1) Step 1 to Step 3
Compound (19-5) can be produced from compound (19-1) by a method similar to the production method described in the literature (for example, Organic Letters 7, 4137 (2005), WO08 / 048914, etc.).
2) Step 4 to Step 7
Production of compound (19-9) from compound (19-5) 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.

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

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

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

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

  The compound of the present invention can be converted to a salt by mixing with a pharmaceutically acceptable acid in a solvent such as water, methanol, ethanol, acetone or the like. Examples of pharmaceutically acceptable acids include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfate, phosphoric acid and nitric acid, or acetic acid, propionic acid, oxalic acid, succinic acid, lactic acid, malic acid, tartaric acid and citric acid. And organic acids such as maleic acid, fumaric acid, methanesulfonic acid, p-toluenesulfonic acid, and ascorbic acid.

  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 disease, age, weight, sex, symptom, route of administration, etc. of the patient, but usually the compound of the present invention or a pharmaceutically acceptable salt thereof for an adult (50 kg body weight). 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 synthesized by genetic engineering using Escherichia coli and yeast), insulin resistance improving agents, and the like. (Eg, 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 (Eg, voglibose, acarbose, miglitol, emiglitate, etc.), biguanides (eg, metformin, etc.), insulin secretagogues (eg, tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepipi Sulfonyl urea agents such as repaglinide, repaglinide, senagrinide, nateglinide, mitiglinide, etc.), GLP-1, GLP-1 analogues (exenatide, liraglutide, SUN-E7001, AVE010, BIM-51077, CJC1131, etc.), protein tyrosine phosphatase inhibitors (examples) , 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, tolrestat, 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, 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, medoxotanyl, candesalmil, candesalmil) Silexetil, 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) Terazosin, doxazosin, bunazosin, etc.), αβ blockers (eg, amosulalol, arotinolol, labetalol, carvedilol, etc.).

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

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

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

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

Reference example 1
Methyl 4-bromo-3- (3-methoxypropoxy) benzoate

  To a solution of methyl 4-bromo-3-hydroxybenzoate (14.45 g) in acetonitrile (100 ml) were added potassium carbonate (12.97 g) and 1-bromo-3-methoxypropane (10.53 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 (17.47 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
Methyl 2'-fluoro-2- (3-methoxypropoxy) biphenyl-4-carboxylate

  The compound of Reference Example 1 (12.06 g) was dissolved in 1,2-dimethoxyethane (60 ml) and water (30 ml), sodium carbonate (8.12 g), 2-fluorophenylboronic acid (7.10 g), tetrakistriphenyl Phosphine palladium (8.68 g) was added and heated to reflux. After 5 hours, the reaction solution was cooled to 25 ° C., and the reaction solution was filtered through Celite. A saturated aqueous sodium hydrogen carbonate solution was added to the filtrate, 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 = 5/1) to give the title compound (10.53 g) as a yellow oily compound.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.72-7.69 (m, 1H), 7.66-7.65 (m, 1H), 7.37-7.32 (m, 3H), 7.21-7.17 (m, 1H), 7.15-7.10 (m, 1H), 4.13 (t, J = 6.1 Hz, 2H), 3.94 (s, 3H), 3.41 (t, J = 6.2 Hz, 2H), 3.29 (s, 3H), 1.98-1.92 (m, 2H).

Reference example 3
Methyl 5-bromo-2'-fluoro-2- (3-methoxypropoxy) biphenyl-4-carboxylate

  The compound of Reference Example 2 (9.36 g) was dissolved in dimethylformamide (20 ml), N-bromosuccinimide (7.85 g) was added, and the mixture was stirred at room temperature for 5 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 saturated aqueous ammonium chloride 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 = 5/1) to give the title compound (9.53 g) as a colorless oily compound.

MS (ESI +) 397 (M ⁺ +1, 50%), 399 (M ⁺ +1, 50%).

Reference example 4
Methyl 2'-fluoro-2- (3-methoxypropoxy) -5-[(1E) -prop-1-en-1-yl] biphenyl-4-carboxylate

  The compound of Reference Example 3 (9.53 g) was dissolved in 1,2-dimethoxyethane (40 ml) and water (20 ml), and trans-propenylboronic acid (4.12 g), sodium carbonate (5.09 g), palladium diphenylphosphino Dichloride / dichloromethane complex (3.92 g) was added, and the mixture was heated under reflux for 3 hours. The reaction mixture was filtered through celite, saturated aqueous sodium hydrogen carbonate solution was added to the filtrate, 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 (8.53 g) as a pale yellow oily compound.

MS (ESI +) 359 (M ⁺ +1, 100%).

Reference Example 5
Methyl 2'-fluoro-2- (3-methoxypropoxy) -5-propylbiphenyl-4-carboxylate

  The compound of Reference Example 4 (8.53 g) was dissolved in methanol (120 ml), palladium-carbon (14.3 g) 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 = 5/1) to give the title compound (6.65 g) as a white solid.

MS (ESI +) 361 (M ⁺ +1, 100%).

Reference Example 6
2'-Fluoro-2- (3-methoxypropoxy) -5-propylbiphenyl-4-carboxylic acid

  The compound of Reference Example 5 (6.65 g) was dissolved in methanol (25 ml) and tetrahydrofuran (25 ml), 1N aqueous sodium hydroxide solution (36.9 ml) was added, and the mixture was stirred at 50 ° 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 (6.10 g) as a white solid.

¹ H NMR (400 MHz, MeOD) δ 7.46 (s, 1H), 7.37-7.31 (m, 2H), 7.23-7.19 (m, 1H), 7.16-7.13 (m, 1H), 7.10 (s, 1H) , 4.05 (t, J = 6.1 Hz, 2H), 3.39 (t, J = 6.3 Hz, 2H), 3.26 (s, 3H), 2.92-2.88 (m, 2H), 1.91-1.85 (m, 2H), 1.67-1.57 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H).
MS (ESI +) 347 (M ⁺ +1, 100%).

Reference Example 7
Benzyl [(1R) -2-amino-1-methylethyl] carbamate

  Benzyl [(1R) -2-amino-1-methyl-2-oxoethyl] carbamate (20.0 g) was dissolved in toluene (200 ml), and borane-dimethyl sulfide complex (13.5 ml) was added dropwise under ice cooling. Stir at 0 ° C. for 10 hours. The reaction solution was ice-cooled, 2M aqueous sodium hydroxide solution (200 ml) was added dropwise, and the mixture was stirred at room temperature for 3 hr. The reaction solution was poured into ice water (100 ml) and extracted twice 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 (18.0 g) as a pale yellow oil.

MS (ESI +) 209 (M ⁺ +1, 100%).

Reference Example 8
Benzyl tert-butyl (2R) -propane-1,2-diylbiscarbamate

  The compound of Reference Example 7 (18.0 g) was dissolved in dichloromethane (200 ml), di-tert-butyl dicarbonate (19.8 g) was added at −30 ° C., and the mixture was stirred at room temperature for 5 hours. The reaction solution was poured into ice-saturated aqueous sodium hydrogen carbonate solution (200 ml) and extracted with dichloromethane. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (heptane / tetrahydrofuran = 6/1) to give the title compound (10.74 g) as white crystals.

MS (ESI +) 309 (M ⁺ +1, 100%).

Reference Example 9
tert-Butyl [(2R) -2-aminopropyl] carbamate

  The compound of Reference Example 8 (10.76 g) was dissolved in methanol (120 ml), 20% palladium hydroxide (2.0 g) 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 to give the title compound (6.04 g) as a pale red oil.

MS (ESI +) 175 (M ⁺ +1, 100%).

Reference Example 10
tert-butyl {(2R) -2-[{[2'-fluoro-2- (3-methoxypropoxy) -5-propylbiphenyl-4-yl] carbonyl} (isopropyl) amino] propyl} carbamate

The compound of Reference Example 6 (100 mg) was dissolved in dichloromethane (2 ml), oxalyl chloride (38.7 μl) and dimethylformamide (5.0 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. The compound of Reference Example 9 (93.8 mg) and triethylamine (80.5 μl) were added to the residue and stirred at room temperature for 3 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 (eluent: hexane / ethyl acetate = 2/1) to give the title compound (133 mg) as a colorless oily compound.

MS (ESI +) 545 (M ⁺ +1, 100%).

Reference Example 11
tert-butyl [2- (isopropylamino) ethyl] carbamate

  Tert-butyl (2-aminoethyl) carbamate (409 mg) was dissolved in ethanol (10 ml), acetone (562 μl) and acetic acid (153 μl) were added, and the mixture was stirred at room temperature. After 8 hours, sodium triacetoxyborohydride (1.08 g) was added and stirred at room temperature for 3 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 3 times with chloroform. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (438 mg) as a colorless oily compound.

MS (ESI +) 203 (M ⁺ +1, 100%).

Reference Example 12
tert-butyl {2-[{[2'-fluoro-2- (3-methoxypropoxy) -5-propylbiphenyl-4-yl] carbonyl} (isopropyl) amino] ethyl} carbamate

In the same manner as in Reference Example 10, the title compound (79.1 mg) was synthesized from the corresponding compound.

MS (ESI +) 532 (M ⁺ +1, 100%).

Reference Example 13
tert-butyl N-isopropyl-D-valinate

The title compound (1.89 g) was synthesized from the corresponding compound by a method similar to that in Reference Example 11.

MS (ESI +) 216 (M ⁺ +1, 100%).

Reference Example 14
tert-butyl N-[(benzyloxy) carbonyl] -N-isopropyl-D-valinate

The compound of Reference Example 13 (1.89 g) was dissolved in 1,4-dioxane (10 ml), saturated aqueous sodium hydrogen carbonate solution (10 ml) and benzyl chloroformate (2.10 g) were added, and the mixture was stirred at room temperature for 16 hours. After stirring at 70 ° C. for 5 hours, a saturated aqueous sodium hydrogen carbonate solution 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. The obtained residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 5/1) to give the title compound (1.55 g) as a white solid.

MS (ESI +) 350 (M ⁺ +1, 100%).

Reference Example 15
N-[(Benzyloxy) carbonyl] -N-isopropyl-D-valine

To a solution of the compound of Reference Example 14 (1.55 g) in dioxane (10 ml) was added 4N hydrochloric acid / dioxane solution (10 ml), stirred at 70 ° C. for 2 hours, and then concentrated under reduced pressure to give the title compound (1.25 g ) Was obtained as a white solid.

MS (ESI +) 294 (M ⁺ +1, 100%).

Reference Example 16
Benzyl [(1R) -1- (aminocarbonyl) -2-methylpropyl] isopropylcarbamate

  The compound of Reference Example 15 (1.25 g) was dissolved in dimethylformamide (15 ml), 1-hydroxybenzotriazole (985 mg), 1-ethyl-3- (dimethylaminopropyl) carbodiimide hydrochloride (1.23 g), triethylamine (897 μl) and ammonium chloride (344 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 ammonium chloride solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (1.26 g) as a pale yellow oil.

MS (ESI +) 293 (M ⁺ +1, 100%).

Reference Example 17
Benzyl [(1R) -1- (aminomethyl) -2-methylpropyl] isopropylcarbamate

  The compound of Reference Example 16 (1.26 g) was dissolved in tetrahydrofuran (10 ml), borane-dimethyl sulfide complex (814 μl) was added, and the mixture was heated to reflux. After 7 hours, a 10% aqueous sodium hydroxide solution was added to the reaction solution at room temperature, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (1.15 g) as a pale yellow oil.

MS (ESI +) 279 (M ⁺ +1, 100%).

Reference Example 18
tert-butyl {(2R) -2-[{(benzyloxy) carbonyl} (isopropyl) amino] -3-methylbutyl} carbamate

  The compound of Reference Example 17 (1.15 g) was dissolved in tetrahydrofuran (7 ml), saturated aqueous sodium hydrogen carbonate solution (7 ml) and di-tert-butyl dicarbonate (1.40 g) were added, and the mixture was stirred at room temperature for 17 hours. 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 5% aqueous potassium hydrogen sulfate 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 (107 mg) as a colorless oil.

MS (ESI +) 379 (M ⁺ +1, 100%).

Reference Example 19
tert-butyl [(2R) -2- (isopropylamino) -3-methylbutyl] carbamate

  The compound of Reference Example 18 (107 mg) was dissolved in methanol (5 ml), 10% palladium-carbon (60 mg) was added, and the mixture was stirred under a hydrogen atmosphere for 2 hr. The reaction solution was filtered through celite, and concentrated under reduced pressure to give the title compound (66.7 mg) as a colorless oil.

MS (ESI +) 245 (M ⁺ +1, 100%).

Reference Example 20
tert-butyl {(2R) -2-[{[2'-fluoro-2- (3-methoxypropoxy) -5-propylbiphenyl-4-yl] carbonyl} (isopropyl) amino] -3-methylbutyl} carbamate

In the same manner as in Reference Example 10, the title compound (10.8 mg) was synthesized from the corresponding compound.

MS (ESI +) 573 (M ⁺ +1, 100%).

Reference Example 21
Benzyl [(1R) -2-amino-1-phenylethyl] carbamate

The title compound (20.6 g) was synthesized from the corresponding compound by a method similar to that in Reference Example 17.

MS (ESI +) 271 (M ⁺ +1, 100%).

Reference Example 22
Benzyl tert-butyl [(1R) -1-phenylethane-1,2-diyl] biscarbamate

The title compound (12.5 g) was synthesized from the corresponding compound by a method similar to that in Reference Example 18.

MS (ESI +) 371 (M ⁺ +1, 100%).

Reference Example 23
tert-Butyl [(2R) -2-amino-2-phenylethyl] carbamate

The title compound (6.79 g) was synthesized from the corresponding compound by a method similar to that in Reference Example 19.

MS (ESI +) 237 (M ⁺ +1, 100%).

Reference Example 24
tert-butyl [(2R) -2- (isopropylamino) -2-phenylethyl] carbamate

The title compound (452 mg) was synthesized from the corresponding compound by a method similar to that in Reference Example 11.

MS (ESI +) 279 (M ⁺ +1, 100%).

Reference Example 25
tert-butyl {(2R) -2-[{[2'-fluoro-2- (3-methoxypropoxy) -5-propylbiphenyl-4-yl] carbonyl} (isopropyl) amino] -2-phenylethyl} carbamate

In the same manner as in Reference Example 10, the title compound (16.5 mg) was synthesized from the corresponding compound.

MS (ESI +) 573 (M ⁺ +1, 100%).

Reference Example 26
Benzyl [(1R) -2-amino-1-benzylethyl] carbamate

The title compound (19.2 g) was synthesized from the corresponding compound by a method similar to that in Reference Example 17.

MS (ESI +) 285 (M ⁺ +1, 100%).

Reference Example 27
Benzyl tert-butyl [(2R) -3-phenylpropane-1,2-diyl] biscarbamate

The title compound (11.84 g) was synthesized from the corresponding compound by a method similar to that in Reference Example 18.

MS (ESI +) 385 (M ⁺ +1, 100%).

Reference Example 28
tert-Butyl [(2R) -2-amino-3-phenylpropyl] carbamate

The title compound (3.61 g) was synthesized from the corresponding compound by a method similar to that in Reference Example 19.

MS (ESI +) 251 (M ⁺ +1, 100%).

Reference Example 29
tert-Butyl [(2R) -2- (isopropylamino) -3-phenylpropyl] carbamate

The title compound (58.0 mg) was synthesized from the corresponding compound by a method similar to that in Reference Example 11.

MS (ESI +) 293 (M ⁺ +1, 100%).

Reference Example 30
tert-butyl {(2R) -2-[{[2'-fluoro-2- (3-methoxypropoxy) -5-propylbiphenyl-4-yl] carbonyl} (isopropyl) amino] -3-phenylpropyl} carbamate

In the same manner as in Reference Example 10, the title compound (46.0 mg) was synthesized from the corresponding compound.

MS (ESI +) 621 (M ⁺ +1, 100%).

Reference Example 31
tert-Butyl [(2R) -2-({[2'-Fluoro-2- (3-methoxypropoxy) -5-propylbiphenyl-4-yl] carbonyl} amino) -3-phenylpropyl] carbamate

In the same manner as in Reference Example 10, the title compound (43.4 mg) was synthesized from the corresponding compound.

MS (ESI +) 579 (M ⁺ +1, 100%).

Reference Example 32
N-[(Benzyloxy) carbonyl] -3-methyl-D-valine

The title compound (1.57 g) was synthesized from the corresponding compound by a method similar to that in Reference Example 14.

MS (ESI +) 266 (M ⁺ +1, 100%).

Reference Example 33
Benzyl [(1R) -1- (aminocarbonyl) -2,2-dimethylpropyl] carbamate

In the same manner as in Reference Example 16, the title compound (1.07 g) was synthesized from the corresponding compound.

MS (ESI +) 265 (M ⁺ +1, 100%).

Reference Example 34
Benzyl [(1R) -1- (aminomethyl) -2,2-dimethylpropyl] carbamate

The title compound (1.13 g) was synthesized from the corresponding compound by a method similar to that in Reference Example 17.

MS (ESI +) 251 (M ⁺ +1, 100%).

Reference Example 35
Benzyl tert-butyl [(2R) -3,3-dimethylbutane-1,2-diyl] biscarbamate

The title compound (816 mg) was synthesized from the corresponding compound by a method similar to that in Reference Example 18.

MS (ESI +) 351 (M ⁺ +1, 100%).

Reference Example 36
tert-Butyl [(2R) -2-amino-3,3-dimethylbutyl] carbamate

The title compound (555 mg) was synthesized from the corresponding compound by a method similar to that in Reference Example 19.

MS (ESI +) 217 (M ⁺ +1, 100%).

Reference Example 37
tert-Butyl [(2R) -2-({[2'-Fluoro-2- (3-methoxypropoxy) -5-propylbiphenyl-4-yl] carbonyl} amino) -3,3-dimethylbutyl] carbamate

The title compound (52.9 mg) was synthesized from the corresponding compound by a method similar to that in Reference Example 10.

MS (ESI +) 545 (M ⁺ +1, 100%).

Reference Example 38
tert-Butyl [(2R) -2- (isopropylamino) -3,3-dimethylbutyl] carbamate

In the same manner as in Reference Example 11, the title compound (126 mg) was synthesized from the corresponding compound.

MS (ESI +) 259 (M ⁺ +1, 100%).

Reference Example 39
tert-butyl {(2R) -2-[{[2'-fluoro-2- (3-methoxypropoxy) -5-propylbiphenyl-4-yl] carbonyl} (isopropyl) amino] -3,3-dimethylbutyl } Carbamate

In the same manner as in Reference Example 10, the title compound (141 mg) was synthesized from the corresponding compound.

MS (ESI +) 587 (M ⁺ +1, 100%).

Reference Example 40
tert-Butyl (2-amino-2-methylpropyl) carbamate

  2-Methylpropane-1,2-diamine (22.1 g) was dissolved in chloroform (1 L), and a solution of di-tert-butyl dicarbonate (10.5 g) in chloroform (100 ml) was added dropwise at 5 ° C. Stir for hours. The reaction solution was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution 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. The obtained residue was washed with hexane to give the title compound (6.20 g) as white crystals.

MS (ESI +) 189 (M ⁺ +1, 100%).

Reference Example 41
tert-Butyl [2-({[2'-Fluoro-2- (3-methoxypropoxy) -5-propylbiphenyl-4-yl] carbonyl} amino) -2-methylpropyl] carbamate

In the same manner as in Reference Example 10, the title compound (109 mg) was synthesized from the corresponding compound.

MS (ESI +) 517 (M ⁺ +1, 100%).

Reference Example 42
Benzyl N ² -[(benzyloxy) carbonyl] -Da-aspartate

In the same manner as in Reference Example 16, the title compound (2.53 g) was synthesized from the corresponding compound.

MS (ESI +) 357 (M ⁺ +1, 100%).

Reference Example 43
Benzyl [(1R) -1- (aminomethyl) -3-hydroxypropyl] carbamate

The title compound was synthesized from the corresponding compound by a method similar to that in Reference Example 17.

MS (ESI +) 239 (M ⁺ +1, 100%).

Reference Example 44
Benzyl tert-butyl [(2R) -4-hydroxybutane-1,2-diyl] biscarbamate

The title compound (189 mg) was synthesized from the corresponding compound by a method similar to that in Reference Example 18.

MS (ESI +) 339 (M ⁺ +1, 100%).

Reference Example 45
Benzyl tert-butyl ((2R) -4-{[tert-butyl (dimethyl) silyl] oxy} butane-1,2-diyl) biscarbamate

  The compound of Reference Example 44 (189 mg) was dissolved in dimethylformamide (2 ml), imidazole (56.9 mg) and TBSCl (101 mg) were added, and the mixture was stirred for 18 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, 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 = 3/1) to give the title compound (170 mg) as a colorless oil.

MS (ESI +) 453 (M ⁺ +1, 100%).

Reference Example 46
tert-butyl ((2R) -2-amino-4-{[tert-butyl (dimethyl) silyl] oxy} butyl) carbamate

In the same manner as in Reference Example 19, the title compound (109 mg) was synthesized from the corresponding compound.

MS (ESI +) 319 (M ⁺ +1, 100%).

Reference Example 47
tert-butyl [(2R) -4-{[tert-butyl (dimethyl) silyl] oxy} -2- (isopropylamino) butyl] carbamate

The title compound (106 mg) was synthesized from the corresponding compound by a method similar to that in Reference Example 11.

MS (ESI +) 361 (M ⁺ +1, 100%).

Reference Example 48
tert-butyl {(2R) -4-{[tert-butyl (dimethyl) silyl] oxy} -2-[{[2'-fluoro-2- (3-methoxypropoxy) -5-propylbiphenyl-4-yl ] Carbonyl} (isopropyl) amino] butyl} carbamate

In the same manner as in Reference Example 10, the title compound (62.0 mg) was synthesized from the corresponding compound.

MS (ESI +) 689 (M ⁺ +1, 100%).

Reference Example 49
tert-butyl {(2R) -2-[{[2'-fluoro-2- (3-methoxypropoxy) -5-propylbiphenyl-4-yl] carbonyl} (isopropyl) amino] -4-hydroxybutyl} carbamate

  The compound of Reference Example 48 (62.0 mg) was dissolved in tetrahydrofuran (1.0 ml), tetrabutylammonium fluoride (1.0 M THF solution) (0.13 ml) was added, and the mixture was stirred for 3 hours. A saturated aqueous ammonium chloride 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 = 1/3) to give the title compound (40.0 mg) as a colorless oil.

MS (ESI +) 575 (M ⁺ +1, 100%).

Reference Example 50
Benzyl [(1R) -1- (aminomethyl) -3-methylbutyl] carbamate

The title compound (19.2 g) was synthesized from the corresponding compound by a method similar to that in Reference Example 17.

MS (ESI +) 251 (M ⁺ +1, 100%).

Reference Example 51
Benzyl tert-butyl [(2R) -4-methylpentane-1,2-diyl] biscarbamate

The title compound (12.6 g) was synthesized from the corresponding compound by a method similar to that in Reference Example 18.

MS (ESI +) 351 (M ⁺ +1, 100%).

Reference Example 52
tert-Butyl [(2R) -2-amino-4-methylpentyl] carbamate

The title compound (7.43 g) was synthesized from the corresponding compound by a method similar to that in Reference Example 19.

MS (ESI +) 217 (M ⁺ +1, 100%).

Reference Example 53
tert-Butyl [(2R) -2- (isopropylamino) -4-methylpentyl] carbamate

The title compound (399 mg) was synthesized from the corresponding compound by a method similar to that in Reference Example 11.

MS (ESI +) 259 (M ⁺ +1, 100%).

Reference Example 54
tert-butyl {(2R) -2-[{[2'-fluoro-2- (3-methoxypropoxy) -5-propylbiphenyl-4-yl] carbonyl} (isopropyl) amino] -4-methylpentyl} carbamate

The title compound (50.8 mg) was synthesized from the corresponding compound by a method similar to that in Reference Example 10.

MS (ESI +) 587 (M ⁺ +1, 100%).

Reference Example 55
N ² -[(Benzyloxy) carbonyl] -D-alloisoleucinamide

In the same manner as in Reference Example 16, the title compound (42.14 g) was synthesized from the corresponding compound.

MS (ESI +) 265 (M ⁺ +1, 100%).

Reference Example 56
Benzyl [(1R, 2S) -1- (aminomethyl) -2-methylbutyl] carbamate

The title compound (35.6 g) was synthesized from the corresponding compound by a method similar to that in Reference Example 17.

MS (ESI +) 251 (M ⁺ +1, 100%).

Reference Example 57
Benzyl tert-butyl [(2R, 3S) -3-methylpentane-1,2-diyl] biscarbamate

The title compound (33.3 g) was synthesized from the corresponding compound by a method similar to that in Reference Example 18.

MS (ESI +) 351 (M ⁺ +1, 100%).

Reference Example 58
tert-Butyl [(2R, 3S) -2-amino-3-methylpentyl] carbamate

The title compound (17.1 g) was synthesized from the corresponding compound by a method similar to that in Reference Example 19.

MS (ESI +) 217 (M ⁺ +1, 100%).

Reference Example 59
tert-Butyl [(2R, 3S) -2- (isopropylamino) -3-methylpentyl] carbamate

The title compound (309 mg) was synthesized from the corresponding compound by a method similar to that in Reference Example 11.

MS (ESI +) 259 (M ⁺ +1, 100%).

Reference Example 60
tert-butyl {(2R, 3S) -2-[{[2'-fluoro-2- (3-methoxypropoxy) -5-propylbiphenyl-4-yl] carbonyl} (isopropyl) amino] -3-methylpentyl } Carbamate

In the same manner as in Reference Example 10, the title compound (24.5 mg) was synthesized from the corresponding compound.

MS (ESI +) 587 (M ⁺ +1, 100%).

Reference Example 61
Na-[(benzyloxy) carbonyl] -O- (tert-butyl) -D-tyrosine amide

In the same manner as in Reference Example 16, the title compound (4.79 g) was synthesized from the corresponding compound.

MS (ESI +) 371 (M ⁺ +1, 100%).

Reference Example 62
Benzyl [(1R) -2-amino-1- (4-tert-butoxybenzyl) ethyl] carbamate

The title compound (4.25 g) was synthesized from the corresponding compound by a method similar to that in Reference Example 17.

MS (ESI +) 357 (M ⁺ +1, 100%).

Reference Example 63
Benzyl tert-butyl [(2R) -3- (4-tert-butoxyphenyl) propane-1,2-diyl] biscarbamate

The title compound (1.14 g) was synthesized from the corresponding compound by a method similar to that in Reference Example 18.

MS (ESI +) 457 n (M ⁺ +1, 100%).

Reference Example 64
A: tert-butyl [(2R) -2-amino-3- (4-tert-butoxyphenyl) propyl] carbamate
B: tert-butyl [(2R) -3- (4-tert-butoxyphenyl) -2- (methylamino) propyl] carbamate

In the same manner as in Reference Example 19, the title compound (695 mg) was synthesized as a mixture from the corresponding compound.

MS (ESI +) A: 323 (M ⁺ +1, 100%), B: 336 (M ⁺ +1, 100%).

Reference Example 65
A: tert-butyl [(2R) -3- (4-tert-butoxyphenyl) -2- (isopropylamino) propyl] carbamate

In the same manner as in Reference Example 11, the title compound (645 mg) was synthesized as a mixture from the corresponding compound.

MS (ESI +) A: 365 (M ⁺ +1, 100%), B: 336 (M ⁺ +1, 100%).

Reference Example 66
A: tert-butyl {(2R) -3- (4-tert-butoxyphenyl) -2-[{[2'-fluoro-2- (3-methoxypropoxy) -5-propylbiphenyl-4-yl] carbonyl } (Isopropyl) amino] propyl} carbamate
B: tert-butyl {(2R) -3- (4-tert-butoxyphenyl) -2-[{[2'-fluoro-2- (3-methoxypropoxy) -5-propylbiphenyl-4-yl] carbonyl } (Methyl) amino] propyl} carbamate

In the same manner as in Reference Example 10, the title compound (24.5 mg) was synthesized from the corresponding compound.

MS (ESI +) A: 693 (M ⁺ +1, 100%).
B: 665 (M ⁺ +1, 100%).

Reference Example 67
N-[(1R) -2-amino-1- (4-hydroxybenzyl) ethyl] -2'-fluoro-N-isopropyl-2- (3-methoxypropoxy) -5-propylbiphenyl-4-carboxamide Hydrochloric acid salt

To a solution of Reference Example 66 A (201 mg) in dioxane (2 ml) was added 4N hydrochloric acid / dioxane solution (2 ml), stirred for 2 hours, and concentrated under reduced pressure to give the title compound (172 mg) as a white solid. Obtained.

MS (ESI +) 537 (M ⁺ +1, 100%).

Reference Example 68
tert-butyl [(2R) -2-[{[2'-fluoro-2- (3-methoxypropoxy) -5-propylbiphenyl-4-yl] carbonyl} (isopropyl) amino] -3- (4-hydroxy Phenyl) propyl] carbamate

The title compound (147 mg) was synthesized from the corresponding compound by a method similar to that in Reference Example 18.

MS (ESI +) 637 (M ⁺ +1, 100%).

Reference Example 69
tert-butyl {(2R) -3- (4-ethoxyphenyl) -2-[{[2'-fluoro-2- (3-methoxypropoxy) -5-propylbiphenyl-4-yl] carbonyl} (isopropyl) Amino] propyl} carbamate

  The compound of Reference Example 68 (59.0 mg) was dissolved in acetone (2 ml), potassium carbonate (25.6 mg) and iodoethane (14.3 μl) were added, and the mixture was heated to reflux for 18 hours. A saturated aqueous ammonium chloride 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 (56.7 mg) as a colorless oil.

MS (ESI +) 665 (M + +1, 100%).

Reference Example 70
N-[(1R) -2-amino-1- (4-hydroxybenzyl) ethyl] -2'-fluoro-2- (3-methoxypropoxy) -N-methyl-5-propylbiphenyl-4-carboxamide Hydrochloride salt

To a solution of Reference Example 66 B (27.0 mg) in dioxane (2 ml) was added 4N hydrochloric acid / dioxane solution (2 ml), stirred for 2 hours, and concentrated under reduced pressure to give the title compound (16.0 mg) as a white solid. Obtained.

MS (ESI +) 509 (M ⁺ +1, 100%).

Reference Example 71
tert-butyl [(2R) -2-[{[2'-fluoro-2- (3-methoxypropoxy) -5-propylbiphenyl-4-yl] carbonyl} (methyl) amino] -3- (4-hydroxy Phenyl) propyl] carbamate

The title compound (14.1 mg) was synthesized from the corresponding compound by a method similar to that in Reference Example 18.

MS (ESI +) 608 (M ⁺ +1, 100%).

Reference Example 72
tert-butyl [(2R) -2-[{[2'-fluoro-2- (3-methoxypropoxy) -5-propylbiphenyl-4-yl] carbonyl} (methyl) amino] -3- (4- { 3-[(2-Methoxybenzyl) oxy] propoxy} phenyl) propyl] carbamate

  The compound of Reference Example 71 (14.1 mg) was dissolved in acetonitrile (1.5 ml), potassium carbonate (4.8 mg), XXX (7.8 mg) synthesized by the method described in the literature (WO2004089915, WO2004204455) was added, and the mixture was stirred at 60 ° C. for 5 hours. did. A saturated aqueous ammonium chloride 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 (10.2 mg) as a colorless oil.

MS (ESI +) 787 (M ⁺ +1, 100%).

Reference Example 73
Benzyl (2-amino-2-methylpropyl) carbamate

2-Methylpropane-1,2-diamine (4.00 g) was dissolved in toluene (40 ml), and a solution of benzyl chloroformate (3.20 g) in toluene (12 ml) was added under ice cooling. After stirring at room temperature for 12 hours, the mixture was filtered, and dichloromethane (6 ml) was added to the filtrate and filtered. The filtrate was concentrated under reduced pressure to give the title compound (4.12 g) as a white solid.

MS (ESI +) 223 (M ⁺ +1, 100%).

Reference Example 74
Benzyl tert-butyl (2-methylpropane-1,2-diyl) biscarbamate

The title compound (5.36 g) was synthesized from the corresponding compound by a method similar to that in Reference Example 18.

MS (ESI +) 323 (M ⁺ +1, 100%).

Reference Example 75
tert-Butyl (2-amino-1,1-dimethylethyl) carbamate

The title compound (2.46 g) was synthesized from the corresponding compound by a method similar to that in Reference Example 19.

MS (ESI +) 189 (M + +1, 100%).

Reference Example 76
tert-butyl ((2R) -2- (isopropylamino) -1,1-dimethylethyl) carbamate

The title compound (2.96 g) was synthesized from the corresponding compound by a method similar to that in Reference Example 11.

MS (ESI +) 231 (M ⁺ +1, 100%).

Reference Example 77
tert-butyl {2-[{[2'-fluoro-2- (3-methoxypropoxy) -5-propylbiphenyl-4-yl] carbonyl} (isopropyl) amino] -1,1-dimethylethyl} carbamate

In the same manner as in Reference Example 10, the title compound (220 mg) was synthesized from the corresponding compound.

MS (ESI +) 559 (M ⁺ +1, 100%).

Reference Example 78
Methyl 4-hydroxy-2- (trifluoromethyl) benzoate

4-hydroxy-2- (trifluoromethyl) benzoic acid (30.0 g) was dissolved in methanol (600 ml), concentrated sulfuric acid (10 ml) was added dropwise, and the mixture was stirred for 20 hours under reflux. After cooling to room temperature, water (200 ml) was added to the reaction mixture, methanol was distilled off under reduced pressure, and the mixture was extracted twice with ethyl acetate (300 ml). The organic layer was washed with water, saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (32.0 g).

1H NMR (400 MHz, CDCl3) δ9.77 (s, 1H), 7.79-7.76 (m, 1H), 7.28-7.22 (m, 1H), 7.03-6.99 (m, 1H), 3.88 (s, 3H) .

Reference Example 79
Methyl 4-hydroxy-5-nitro-2- (trifluoromethyl) benzoate

Methyl 4-hydroxy-2- (trifluoromethyl) benzoate (32.0 g) was dissolved in acetic acid (180 ml), concentrated sulfuric acid (0.45 ml) was added, and the mixture was heated to 65 ° C. Thereafter, a solution of 70% concentrated nitric acid (12.4 g) in acetic acid (60 ml) was slowly added dropwise and stirred at 65 ° C. for 1 hour. The reaction mixture was cooled to room temperature, poured into ice water (500 ml) and extracted twice with toluene (800 ml). The organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (15.0 g).

1H NMR (400 MHz, CDCl3) δ 10.8 (s, 1H), 8.72 (s, 1H), 7.61 (s, 1H), 3.96 (s, 3H).

Reference Example 80
Methyl 5-amino-4-hydroxy-2- (trifluoromethyl) benzoate

Dissolve methyl 4-hydroxy-5-nitro-2- (trifluoromethyl) benzoate (58.0 g) in methanol (600 ml), add 10% palladium / carbon (50% wet.: 11.60 g), and under hydrogen atmosphere Stir vigorously at 25 ° C. for 8 hours. After completion of the reaction, the mixture was filtered through celite, washed with methanol, and the filtrate was concentrated under reduced pressure to obtain the title compound (53.0 g).

MS (ESI +) 236 (M ⁺ +1, 100%).

Reference Example 81
Methyl 2,2-dimethyl-3-oxo-7- (trifluoromethyl) -3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

Methyl 5-amino-4-hydroxy-2- (trifluoromethyl) benzoate (53.0 g) is dissolved in chloroform (200 ml) and tetrahydrofuran (200 ml), and an aqueous sodium hydrogen carbonate solution (27.60 g / 240 ml) is added. Stir vigorously. After cooling in an ice bath, 2-bromoisobutyryl bromide (65.5 g) was slowly added dropwise and stirred for 30 minutes, warmed to room temperature and stirred for 2.5 hours. After completion of the reaction, the mixture was extracted twice with chloroform (300 ml). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain methyl 5-[(2-bromo-2-methylpropanoyl) amino] -4-hydroxy-2- (trifluoromethyl) benzoate. The crude product was diluted with N, N, -dimethylformamide (500 ml), potassium carbonate (60.53 g) was added, and the mixture was stirred at 50 ° C. for 5 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and the solid was removed by filtration. Ethyl acetate (500 ml) was added to the filtrate and washed with 1N hydrochloric acid (500 ml) and saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. Crystallization from ethyl acetate / hexane (5/1, 200 ml) gave the title compound (48.5 g). .

MS (ESI +) 304 (M ⁺ +1, 31%).

Reference Example 82
Methyl 4- (4-methoxybutyl) -2,2-dimethyl-3-oxo-7- (trifluoromethyl) -3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

  To a solution of the compound of Reference Example 81 (10.04 g) in dimethylformamide (60 ml) was added cesium carbonate (16.18 g), lithium iodide (6.65 g), and 1-chloro-4-methoxybutane (5.68 g) at 80 ° C. And stirred with heating. After 6 hours, the reaction solution was filtered through Celite, water was added, and the mixture was extracted with ethyl acetate. The extract was washed twice with organic layer water and saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 5/1) to give the title compound (9.64 g).

MS (ESI +) 390 (M ⁺ +1, 100%).

Reference Example 83
4- (4-Methoxybutyl) -2,2-dimethyl-3-oxo-7- (trifluoromethyl) -3,4-dihydro-2H-1,4-benzoxazine-6-carboxylic acid

  In the same manner as in Reference Example 6, the title compound (8.99 g) was synthesized from the corresponding compound.

MS (ESI +) 376 (M ⁺ +1, 100%).

Reference Example 84
Methyl 4- (2-{[(benzyloxy) carbonyl] amino} ethyl) -2,2-dimethyl-3-oxo-7- (trifluoromethyl) -3,4-dihydro-2H-1,4-benzo Oxazine-6-carboxylate

  Using the compound of Reference Example 81, the title compound was obtained according to the synthesis method of Reference Example 82.

MS (ESI +) 413 (M ⁺ +1, 100%).

Reference Example 85
4- (2-{[(Benzyloxy) carbonyl] amino} ethyl) -2,2-dimethyl-3-oxo-7- (trifluoromethyl) -3,4-dihydro-2H-1,4-benzoxazine -6-carboxylic acid

  Using the compound of Reference Example 84, the title compound was obtained according to the synthesis method of Reference Example 6.

MS (ESI +) 413 (M ⁺ +1, 100).

Reference Example 86
Benzyl {2- [6-{[{2-[(tert-butoxycarbonyl) amino] ethyl} (isopropyl) amino] carbonyl} -2,2-dimethyl-3-oxo-7- (trifluoromethyl) -2 , 3-Dihydro-4H-1,4-benzoxazin-4-yl] ethyl} carbamate

In the same manner as in Reference Example 10, the title compound (834 mg) was synthesized from the corresponding compound.

MS (ESI +) 651 (M ⁺ +1, 100%).

Reference Example 87
tert-butyl {2-[{[4- (2-aminoethyl) -2,2-dimethyl-3-oxo-7- (trifluoromethyl) -3,4-dihydro-2H-1,4-benzoxazine -6-yl] carbonyl} (isopropyl) amino] ethyl} carbamate

The title compound (681 mg) was synthesized from the corresponding compound by a method similar to that in Reference Example 19.

MS (ESI +) 517 (M ⁺ +1, 100%).

Reference Example 88
tert-butyl {2-[{[2,2-dimethyl-3-oxo-4- [2- (propionylamino) ethyl] -7- (trifluoromethyl) -3,4-dihydro-2H-1,4 -Benzoxazin-6-yl] carbonyl} (isopropyl) amino] ethyl} carbamate

  The compound of Reference Example 87 (681 mg) was dissolved in tetrahydrofuran (5 ml), triethylamine (357 μl) and propionyl chloride (133 μl) were added under ice cooling, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous ammonium chloride 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 = 1/1) to give the title compound (351 mg) as a white solid.

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

Reference Example 89
tert-butyl [(2R) -2- (isopropyl {[4- (4-methoxybutyl) -2,2-dimethyl-3-oxo-7- (trifluoromethyl) -3,4-dihydro-2H-1 , 4-Benzoxazin-6-yl] carbonyl} amino) propyl] carbamate

In the same manner as in Reference Example 10, the title compound (156 mg) was synthesized from the corresponding compound.

MS (ESI +) 574 (M ⁺ +1, 100%).

Reference Example 90
tert-butyl [2- (isopropyl {[4- (4-methoxybutyl) -2,2-dimethyl-3-oxo-7- (trifluoromethyl) -3,4-dihydro-2H-1,4-benzo Oxazin-6-yl] carbonyl} amino) ethyl] carbamate

In the same manner as in Reference Example 10, the title compound (288 mg) was synthesized from the corresponding compound.

MS (ESI +) 560 (M ⁺ +1, 100%).

Reference Example 91
Benzyl tert-butyl (2R) -propane-1,2-diylbiscarbamate

The title compound (901 mg) was synthesized from the corresponding compound by a method similar to that in Reference Example 14.

MS (ESI +) 309 (M ⁺ +1, 100%).

Reference Example 92
Benzyl [(1R) -2-amino-1-methylethyl] carbamate hydrochloride

The title compound (633 mg) was synthesized from the corresponding compound by a method similar to that in Reference Example 67.

MS (ESI +) 245 (M ⁺ +1, 100%).

Reference Example 93
Benzyl [(1R) -2- (isopropylamino) -1-methylethyl] carbamate

The title compound (477 mg) was synthesized from the corresponding compound by a method similar to that in Reference Example 11.

MS (ESI +) 251 (M ⁺ +1, 100%).

Reference Example 94
Benzyl [(1R) -2- (isopropyl {[4- (4-methoxybutyl) -2,2-dimethyl-3-oxo-7- (trifluoromethyl) -3,4-dihydro-2H-1,4 -Benzoxazin-6-yl] carbonyl} amino) -1-methylethyl] carbamate

In the same manner as in Reference Example 10, the title compound (194 mg) was synthesized from the corresponding compound.

MS (ESI +) 608 (M ⁺ +1, 100%).

Example 1
N-[(1R) -2-Amino-1-methylethyl] -2'-fluoro-N-isopropyl-2- (3-methoxypropoxy) -5-propylbiphenyl-4-carboxamide hydrochloride

A 4N hydrochloric acid / dioxane solution (2 ml) was added to a solution of the compound of Reference Example 10 (83.3 mg) in 1,4-dioxane (2 ml), stirred at 25 ° C. for 2 hours, and then concentrated under reduced pressure to give the title. Compound (62.7 mg) was obtained as a white solid.
H-NMR (400MHz, DMSO-d ₆ ) δ 7.78 (brs, 2H), 7.43-7.34 (m, 2H), 7.26-7.22 (m, 2H), 7.15-7.04 (m, 2H), 4.02-3.97 ( m, 2H), 3.69-3.59 (m, 3H), 3.47-3.42 (m, 1H), 3.37-3.27 (m, 3H), 3.15 (s, 3H), 2.44-2.32 (m, 1H), 1.81- 1.76 (m, 2H), 1.60-1.47 (m, 5H), 1.18-1.08 (m, 6H), 0.90-0.85 (m, 3H).
MS (ESI +) 445 (M ⁺ +1, 100%).

Example 2
N-[(1R) -2-amino-1-phenylethyl] -2'-fluoro-N-isopropyl-2- (3-methoxypropoxy) -5-propylbiphenyl-4-carboxamide hydrochloride

In the same manner as in Example 1, the title compound (16.0 mg) was synthesized from the corresponding compound.
¹ H-NMR (400MHz, DMSO-d ₆ ) δ 8.05 (brs, 3H), 7.70-7.68 (m, 1H), 7.44-7.33 (m, 6H), 7.27-7.18 (m, 3H), 7.12 (s , 1H), 4.07-3.96 (m, 3H), 3.78-3.66 (m, 3H), 3.37-3.27 (m, 2H), 3.17 (s, 3H), 2.48-2.31 (m, 2H), 1.90-1.80 (m, 2H), 1.54-1.49 (m, 2H), 1.30 (d, J = 6.6 Hz, 3H), 0.92 (d, J = 6.8 Hz, 3H), 0.80-0.75 (m, 3H).
MS (ESI +) 507 (M ⁺ +1, 100%).

Example 3
N- (2-aminoethyl) -2'-fluoro-N-isopropyl-2- (3-methoxypropoxy) -5-propylbiphenyl-4-carboxamide hydrochloride

The title compound (34.2 mg) was synthesized from the corresponding compound by a method similar to that in Example 1.
¹ H-NMR (400 MHz, MeOD) δ 7.38-7.31 (m, 2H), 7.23-7.19 (m, 2H), 7.16-7.12 (m, 1H), 6.96 (s, 1H), 4.06-4.02 (m, 2H), 3.94-3.90 (m, 1H), 3.76-3.67 (m, 2H), 3.38 (t, J = 6.2 Hz, 2H), 3.31-3.22 (m, 2H), 3.25 (s, 3H), 2.59 -2.45 (m, 2H), 1.88-1.85 (m, 2H), 1.72-1.59 (m, 2H), 1.25-1.21 (m, 6H), 0.96 (t, J = 7.3 Hz, 3H).
MS (ESI +) 431 (M ⁺ +1, 100%).

Example 4
N-[(1R) -2-amino-1-benzylethyl] -2'-fluoro-N-isopropyl-2- (3-methoxypropoxy) -5-propylbiphenyl-4-carboxamide hydrochloride

In the same manner as in Example 1, the title compound (16.0 mg) was synthesized from the corresponding compound.
¹ H-NMR (400MHz, DMSO-d ₆ ) δ 8.05 (brs, 3H), 7.70-7.68 (m, 1H), 7.44-7.33 (m, 6H), 7.27-7.18 (m, 3H), 7.12 (s , 1H), 4.07-3.96 (m, 3H), 3.78-3.66 (m, 3H), 3.37-3.27 (m, 2H), 3.17 (s, 3H), 2.48-2.31 (m, 2H), 1.90-1.80 (m, 2H), 1.54-1.49 (m, 2H), 1.30 (d, J = 6.6 Hz, 3H), 0.92 (d, J = 6.8 Hz, 3H), 0.80-0.75 (m, 3H).
MS (ESI +) 507 (M ⁺ +1, 100%).

Example 5
N-[(1R) -2-amino-1- (4- {3-[(2-methoxybenzyl) oxy] propoxy} benzyl) ethyl] -2'-fluoro-2- (3-methoxypropoxy) -N -Methyl-5-propylbiphenyl-4-carboxamide hydrochloride
The title compound (9.9 mg) was synthesized from the corresponding compound by a method similar to that in Example 1.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.06 (brs, 3H), 7.40-7.19 (m, 9H), 6.95-6.85 (m, 5H), 4.45 (s, 2H), 4.03-4.00 (m , 3H), 3.73 (s, 3H), 3.61-3.58 (m, 3H), 3.30-3.26 (m, 2H), 3.17-3.10 (m, 4H), 3.00 (m, 2H), 2.80 (m, 1H ), 2.64 (m, 3H), 2.01-1.90 (m, 3H), 1.78-1.75 (m, 2H), 1.68-1.43 (m, 2H), 1.29-1.21 (m, 2H), 0.87-0.62 (m , 3H).
MS (ESI +) 687 (M ⁺ +1, 100%).

Example 16
N- (2-aminoethyl) -N-isopropyl-2,2-dimethyl-3-oxo-4- [2- (propionylamino) ethyl] -7- (trifluoromethyl) -3,4-dihydro-2H -1,4-Benzoxazine-6-carboxamide hydrochloride

The title compound (318 mg) was synthesized from the corresponding compound by a method similar to that in Example 1.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.14-8.07 (m, 4H), 7.61 (s, 1H), 7.36 (s, 1H), 3.95-3.91 (m, 2H), 3.66-3.50 (m , 4H), 3.32-3.09 (m, 4H), 3.00-2.95 (m, 1H), 1.48 (s, 3H), 1.40 (s, 3H), 1.17 (d, J = 6.6 Hz, 3H), 1.03 ( d, J = 6.5 Hz, 3H), 0.96-0.91 (m, 3H).
MS (ESI +) 473 (M ⁺ +1, 100%).

Example 17
N-[(1R) -2-amino-1-methylethyl] -N-isopropyl-4- (4-methoxybutyl) -2,2-dimethyl-3-oxo-7- (trifluoromethyl) -3, 4-Dihydro-2H-1,4-benzoxazine-6-carboxamide hydrochloride

In the same manner as in Example 1, the title compound (129 mg) was synthesized from the corresponding compound.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.10 (brs, 3H), 7.58-7.38 (m, 1H), 7.35-7.15 (m, 1H), 4.20-4.17 (m, 1H), 3.93-3.89 (m, 1H), 3.71-3.55 (m, 3H), 3.51-3.46 (m, 1H), 3.31-3.26 (m, 2H), 3.17 (s, 3H), 1.55-1.49 (m, 8H), 1.44 -1.38 (m, 5), 1.20-1.11 (m, 3H), 1.09-1.02 (m, 3H).
MS (ESI +) 474 (M ⁺ +1, 100%).

Example 18
N- (2-aminoethyl) -N-isopropyl-4- (4-methoxybutyl) -2,2-dimethyl-3-oxo-7- (trifluoromethyl) -3,4-dihydro-2H-1, 4-Benzoxazine-6-carboxamide hydrochloride

The title compound (204 mg) was synthesized from the corresponding compound by a method similar to that in Example 1.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.09 (brs, 3H), 7.44 (s, 1H), 7.38 (s, 1H), 4.10-4.07 (m, 1H), 3.91-3.87 (m, 1H ), 3.70-3.47 (m, 3H), 3.30-3.27 (m, 2H), 3.17 (s, 3H), 3.12-3.09 (m, 1H), 2.90 (m, 1H), 1.53-1.52 (m, 4H ), 1.49 (s, 3H), 1.41 (s, 3H), 1.15 (d, J = 6.6 Hz, 3H), 1.05 (d, J = 6.5 Hz, 3H).
MS (ESI +) 460 (M ⁺ +1, 100%).

Example 19
N-[(2R) -2-aminopropyl] -N-isopropyl-4- (4-methoxybutyl) -2,2-dimethyl-3-oxo-7- (trifluoromethyl) -3,4-dihydro- 2H-1,4-Benzoxazine-6-carboxamide hydrochloride

The compound of Reference Example 94 (194 mg) was dissolved in methanol (5 ml), 10% palladium-carbon (260 mg) was added, and the mixture was stirred at room temperature for 3 hours in a hydrogen atmosphere. The reaction mixture was filtered through Celite and the solvent was distilled off. The residue was purified by amino silica gel chromatography (developing solvent: hexane / ethyl acetate = 1/3) to obtain a colorless oily compound (79.3 mg). A 4N hydrochloric acid / dioxane solution (2 ml) was added to a 1,4-dioxane (2 ml) solution of the obtained compound and concentrated under reduced pressure to obtain the title compound (80.8 mg) as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.07 (brs, 3H), 7.59-7.54 (m, 1H), 7.39-7.38 (m, 1H), 4.15-4.10 (m, 1H), 3.97-3.92 (m, 1H), 3.73-3.58 (m, 2H), 3.50-3.38 (m, 2H), 3.31-3.28 (m, 2H), 3.17 (s, 3H), 1.53-1.48 (m, 6H), 1.44 -1.39 (m, 3H), 1.29-1.24 (m, 3H), 1.20-1.17 (m, 3H), 1.05-1.00 (m, 3H).
MS (ESI +) 474 (M ⁺ +1, 100%).

In vitro renin inhibition test
50 ng 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 are primary and secondary pulmonary hypertension, primary and secondary aldosteronemia, renovascular hypertension, primary and secondary renal diseases such as glomerulonephritis, IgA nephropathy, Diabetic nephropathy, hypertensive nephropathy (neurosclerosis), nephrotic syndrome, renal failure, left ventricular hypertrophy, left ventricular fibrosis, left ventricular diastolic failure, left ventricular failure, atrial fibrillation, unstable angina, myocardium Infarct, cardiomyopathy, stroke, restenosis after vascular reconstruction, diabetic retinopathy, cognitive impairment, eg Alzheimer's disease, treatment of cerebrovascular dementia, and vascular disorders, eg migraine, Raynaud's disease, and atheromatous It is also expected to be useful for minimizing the arteriosclerosis process. It is also useful for the treatment of 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 (22)

A compound represented by formula (I) or a pharmaceutically acceptable salt thereof.
[Wherein, R ^1a and R ^1d are the same or different and each independently 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 _2-6 alkenyl group, an optionally substituted C _2-6 alkynyl group, an optionally substituted C _3-10 cycloalkyl group, an _optionally substituted C _5-6 cycloalkenyl group, optionally substituted _{C 1-6} alkylthio group, optionally substituted _{C 1-6} alkylsulfinyl group, optionally substituted _{C 1-6} alkylsulfonyl group, optionally substituted _{C 1-6} alkoxy group, C _3-10 cycloalkoxy group which may be substituted, C _5-6 cycloalkenyloxy group which may be substituted, amino group which may be mono- or di-substituted, which may be substituted There 5- to 7-membered cyclic amino group, an optionally substituted amino group, optionally substituted C _1-4 alkoxycarbonyl group, an optionally substituted C _1-4 alkylcarbonyl group, optionally substituted A good C _6-10 aryl group, an optionally substituted C _6-10 aryloxy group, or an optionally substituted 5-10 membered monocyclic or polycyclic heteroaryl group;
R ^1b is an optionally substituted _{C 1-6} alkyl group, optionally substituted _{C 1-6} alkylsulfinyl group, optionally substituted _{C 1-6} alkylsulfonyl group, an optionally substituted _{C 1- 6} alkoxy group, C _3-6 alkynyloxy group which may be substituted, amino group which may be mono- or di-substituted, aminocarbonyl group which may be substituted, C _1-4 alkoxycarbonyl group which may be substituted Or an optionally substituted C _1-4 alkylcarbonyl group (wherein the optionally substituted C _1-6 alkyl group includes C _1-4 alkoxy, C _3-6 cycloalkoxy, and C _1-6 alkylcarbonylamino (said alkyl may be substituted with 1-3 fluorine atoms.) is one group selected from the group consisting of, optionally substituted Substituents have _{C 1-6} alkoxy groups, one to three fluorine atoms, _{hydroxy, C 1-4 alkoxy, C 3-6} cycloalkoxy, cyano, _{mono--C 1-6} alkylcarbonylamino, mono- -C Substituted with one group selected from the group consisting of _1-6 alkoxycarbonylamino, aminocarbonyl, C _1-6 alkylaminocarbonyloxy, C _1-4 alkoxycarbonyl, and C _1-4 alkylcarbonyl).
R ^1c is 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 _3-6 cycloalkyl group, or optionally substituted. Good C _5-6 cycloalkenyl group, optionally substituted 5- or 6-membered saturated heterocyclic group, optionally substituted C _1-6 alkylthio group, optionally substituted C _1-6 alkylsulfinyl group , optionally substituted _{C 1-6} alkylsulfonyl group, optionally substituted _{C 6-10} arylthio group, optionally substituted _{C 6-10} arylsulfinyl group, optionally substituted _{C 6-10} arylsulfonyl Group, optionally substituted C _1-6 alkoxy group, optionally substituted C _3-6 cycloalkyloxy group, optionally substituted C _6-10 aryloxy group, substituted An optionally substituted amino group, an optionally substituted aminocarbonyl group, an optionally substituted C _1-4 alkoxycarbonyl group, an optionally substituted C _3-6 cycloalkyloxycarbonyl group, an optionally substituted C _1-4 alkylcarbonyl group, optionally substituted C _3-6 cycloalkylcarbonyl group, optionally substituted C _6-10 arylcarbonyl group, _optionally substituted 5 to 10 membered monocyclic or polycyclic A cyclic heteroarylcarbonyl group, an optionally substituted C _7-14 aralkyl group, an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group, or
A group represented by
R ^1e , R ^1f , R ^1g and R ¹ⁱ are each independently the same or different and are each a hydrogen atom, a halogen atom, a carboxy group, a cyano group, an optionally substituted C _1-6 alkyl group, or a substituted group. _May be a C _1-6 alkoxy group, an optionally substituted C _3-10 cycloalkyl group, an optionally substituted C _3-10 cycloalkyloxy group, a saturated heterocyclic oxy group, an optionally substituted aminocarbonyl A group, or an optionally substituted C _1-4 alkoxycarbonyl group;
R ^1h is a cyano group, a halogen atom, or a group: -AB
(Here, A 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 j) CO -, - N (R j) SO 2 -, - N (R j) COO -, - _{^{OCO -, - SO 2 N (}} R j) CO -, - OCH 2 CH 2 SO 2 -, - C (CH 3) (CH 3) CO-, or a _-CH 2 _OCH 2 CO-,
R ^j is a hydrogen atom, a C _1-4 alkylcarbonyl group, or an optionally substituted C _1-6 alkyl group,
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 _3-10 cycloalkyl group, a mono- or di-substituted An optionally substituted amino group, an optionally substituted 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 cyclic group It is a monocyclic or polycyclic heteroaryl group. (However, when A is —O—, —COO— or —N (R ^j ) COO—, B is not the amino group).
Alternatively, R ^1e , R ^1h and R ¹ⁱ are both hydrogen atoms, and R ^1f and R ^1g together form a condensed ring. Or R ^1b and R ^1c are taken together to form
A ring represented by (wherein
G ¹ is —N (R ^1k ) —, an oxygen atom, —CH (R ^1k ) —, or —C (R ^1k ) ^═ ,
G ² is —CH ₂ —, —CO—, —CS—, or —CH═;
G ³ is —C (R ^1m ) (R ¹ⁿ ) —, —N (R ^1k ) —, —CO—, or an oxygen atom,
G ⁴ is —C (R ^1m ) (R ¹ⁿ ) —, —N (R ^1k ) —, ^—SO— , —SO ₂ —, an oxygen atom, a sulfur atom, or an absent atom.
R ^1k is optionally substituted _{C 1-6} alkyl group, optionally substituted _{C 2-6} alkenyl group, an optionally substituted _{C 2-6} alkynyl group or substituted 5-membered to 10, Membered monocyclic or polycyclic heteroaryl C _1-4 alkyl group,
R ^1m and R ¹ⁿ are each independently the same or different and are each a hydrogen atom, a halogen atom, a hydroxyl group, a carboxy group, an optionally substituted C _2-6 alkenyl group, or an optionally substituted C _5-6 cycloalkenyl. Group, optionally substituted C _2-6 alkynyl group, optionally substituted C _1-6 alkyl group, optionally substituted C _3-6 cycloalkyl group, optionally substituted aminocarbonyl group, substituted Saturated heterocyclic group which may be substituted, C _1-6 alkoxy group which may be substituted, C _3-6 cycloalkoxy group which may be substituted, aminocarbonyl group which may be substituted, C ₁ which may be substituted _-4 alkoxycarbonyl group, C _1-4 alkylcarbonyl group which may be substituted, C _6-10 arylcarbonyl group which may be substituted, 5-membered to 10-membered monocycle which may be substituted Formula or polycyclic heteroaryl group, cyano group, optionally substituted C _6-10 aryloxy group, _optionally substituted 5 to 10 membered monocyclic or polycyclic heteroaryloxy group, substituted which may _{C 7-14} aralkyloxy group optionally, an optionally substituted _{C 7-14} aralkyl group or a group represented by formula,
A group represented by
R ^1o , R ^1p , R ^1q , R ^1r and R ^1s are each independently the same or different and are each independently a hydrogen atom, a halogen atom, a cyano group, a C _1-4 alkyl group (the group is a 5-membered or 6- A member of saturated heterocyclic oxy, or C _1-4 alkoxy (which may be substituted with C _1-4 alkoxy or C _3-6 alkoxy), a C _1-4 alkoxy group ( The group may be substituted with a halogen atom, C _1-4 alkoxy or C _1-6 alkylaminocarbonyl.), C _3-6 cycloalkoxy group (may be substituted with C _1-4 alkoxy) , 5-membered or 6-membered heterocyclic oxy group to saturated or a _{C 1-6} alkylaminocarbonyl group, or ^{R 1o,} is ^{R 1r} and ^{R 1s} are each independently a hydrogen ^atom, Oyo ^{R 1p} R ^1q together form a condensed ring. Or R ^1m and R ¹ⁿ together are
In the group represented by (wherein, D represents an oxygen atom, a sulfur _{^{atom, -SO 2 -, - NR 5}} -, - NR 5 CO -, - NR 5 SO 2 -, - NR 5 CONR 5 -, - OCH (R ⁶ ) —, —CH (R ⁶ ) —, or —CH (R ⁶ ) CH ₂ —, wherein R ⁵ is a hydrogen atom, an optionally substituted C _1-6 alkyl group, or optionally substituted. A good C _1-4 alkylcarbonyl group, an optionally substituted C _1-4 alkoxycarbonyl group, an optionally substituted aminocarbonyl group, an optionally substituted C _1-4 alkylsulfonyl group, or an optionally substituted A C _6-10 arylsulfonyl group, R ⁶ is a hydrogen atom, an optionally substituted C _1-6 alkoxy group, an optionally substituted C _3-6 cycloalkoxy group, an optionally substituted C _{7- 14} aralkyloxy group, A conversion to an amino group which may, optionally substituted C _1-4 alkoxycarbonylamino group optionally or an optionally substituted aminocarbonyl group,, p and q are each independently, identical or different, 0, 1 or 2.). );
R 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. A -10} cycloalkyl group, an optionally substituted C _5-6 cycloalkenyl group, an optionally substituted C _6-10 aryl group, an optionally substituted C _7-14 aralkyl group, or an optionally substituted 5 A membered to 10-membered monocyclic or polycyclic heteroaryl group;
R ^3a and R ^3b are each independently the same or different and are each a hydrogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C _2-6 alkenyl group, or an optionally substituted C _2-6 alkynyl group, optionally substituted C _3-6 cycloalkyl group, _optionally substituted C _6-10 aryl group, _optionally substituted C _7-14 aralkyl group, optionally saturated A terocyclic group, or an optionally substituted 5- to 10-membered heteroaryl group;
R ^4a and R ^4b are each independently the same or different and are each a hydrogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C _2-6 alkenyl group, or an optionally substituted C _2-6 alkynyl group, optionally substituted _{C 3-6} cycloalkyl group, optionally substituted _{C 6-10} aryl group, optionally substituted _{C 7-14} aralkyl group, optionally substituted _{C 6 A -10} aryloxy group, an optionally substituted saturated heterocyclic group, or an optionally substituted 5- to 10-membered heteroaryl group, or R ^4a and R ^{4b taken} together
In a group represented by (wherein, M is an oxygen atom, a sulfur _{^{atom, -SO 2 -, - NR 7}} -, - NR 7 CO -, - NR 7 SO 2 -, - NR 7 CONR 7 -, - CH (R ⁸ ) —, or —CH (R ⁸ ) CH ₂ —, wherein R ⁷ is a hydrogen atom, an optionally substituted C _1-6 alkyl group, or an optionally substituted C _1-4 alkoxycarbonyl group. , An optionally substituted C _1-4 alkylsulfonyl group, or an optionally substituted C _6-10 arylsulfonyl group, and R ⁸ is a hydrogen atom, an optionally substituted C _1-6 alkoxy group, a substituted is an optionally C _3-6 cycloalkoxy group, a substituted an optionally C _7-14 aralkyloxy group or an optionally substituted aminocarbonyl group also,, R ⁹ is a hydrogen atom, it may be substituted C _1-6 alkyl Or a C _1-6 alkoxy group which may be substituted, and r and s are each independently the same or different and are 0, 1 or 2. ] The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R ^1a is a C _1-6 alkyl group which may be substituted with a halogen atom. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R ^1d is a hydrogen atom. R ^1a , R ^1b , R ^1c and R ^1d are
The compound or pharmaceutically acceptable salt according to any one of claims 1 to 3, wherein the benzene ring is substituted at a substitution position represented by formula (1). R ^<1b> is _C1-6 alkoxy group substituted by _C1-4 alkoxy, The compound as described in any one of Claims 1-4, or its pharmaceutically acceptable salt. The compound according to claim 5, or a pharmaceutically acceptable salt thereof, wherein R ^1b is a 3-methoxypropyloxy group. R ^1c is a compound represented by the following formula
7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof. R ^1e , R ^1f , R ^1g and R ¹ⁱ are each independently the same or different and each is a hydrogen atom or a halogen atom;
R ^1h is a group: -A-B (wherein, A represents a single _{bond, -O -, - SO 2 -} , - CO -, - N (R 1j) CO- or ^{-N (R} 1j) SO ₂ −
R ^1j is a C _1-6 alkyl group or a C _3-6 cycloalkyl group,
B is a hydrogen atom; a C _1-6 alkyl group (the group includes 1 to 3 fluorine atoms, C _3-6 cycloalkyl, di- (C _1-6 alkyl) aminocarbonyl, 5-membered or 6-membered An aminocarbonyl which may be substituted with a saturated heterocycle, or a C _3-10 cycloalkylamino (which may be substituted with hydroxy); an amino group which may be di-substituted ( The group is C _1-6 alkyl (which may be substituted with 1 to 3 fluorine atoms or C _1-4 alkoxy), a 5- or 6-membered saturated heterocyclic ring, C _3-6 cycloalkyl, And optionally substituted by the same or different 1 or 2 groups selected from the group consisting of C _6-10 aryl); or a 5- to 7-membered cyclic amino group (the group is hydroxy or C _{1 -4} is substituted by alkoxy Is may be substituted with may be _{C 1-4} alkyl.). The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof. R ^1b and ^{R 1c} together, the following formula
The compound as described in any one of Claims 1-4 which forms the ring represented by this, or its pharmaceutically acceptable salt. G ¹ is —N (R ^1k ) —, G ² is —CO—, G ³ is —C (R ^1m ) (R ¹ⁿ ) —, and G ⁴ is —C ( The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein R ^1m ) (R ¹ⁿ )-, -SO _2- , an oxygen atom, or a sulfur atom. The compound according to claim 10, or a pharmaceutically acceptable salt thereof, wherein G ⁴ is an oxygen atom. R ^1k is a C _1-6 alkyl group (the group may be substituted with hydroxy, C _1-4 alkoxy (1 to 3 fluorine atoms, C _1-4 alkoxy, C _1-6 alkylaminocarbonyl) C _3-6 cycloalkyl, or 5 or 6 membered saturated hetero ring optionally substituted with C _1-4 alkyl.), Trifluoromethyl, difluoromethyl, C _3-6 cyclo alkyl (1-2 fluorine _atoms, may be substituted with _{C 1-4} alkoxy which may be substituted with _{C 1-4} alkyl, or _{C 1-4 alkoxy.), C 3-6} cycloalkoxy, carboxyl , C _1-6 alkylcarbonylamino (may be substituted with 1 to 5 fluorine atoms, hydroxy, C _1-4 alkoxy, or C _3-6 cycloalkyl), N- (C _{1 -4 alkylcarbonyl)-N-(C 1-6} alkyl) -. Amino _may be substituted by _{C 3-6} cycloalkylcarbonyl amino _{(C 1-4 alkoxy), C 1-6} alkyl thiocarbonyl amino, C _1-4 alkoxycarbonylamino (which may be substituted with 1 to 3 fluorine atoms), N- (C _1-4 alkoxycarbonyl) -N- (C _1-6 alkyl) -amino, C _3-6 Cycloalkoxycarbonylamino, mono- (C _1-6 alkyl) aminocarbonyloxy, di- (C _1-6 alkyl) aminocarbonyloxy, substituted with 4-7 membered cyclic aminocarbonyloxy (C _1-4 alkoxy) C _1-6 alkylaminocarbonyl (may be substituted with 1 to 3 fluorine atoms or C _3-6 cycloalkyl). , C _3-6 cycloalkylaminocarbonyl, C _1-6 alkylaminocarbonylamino, C _1-4 alkylcarbonyl, C _1-4 alkylcarbonyloxy, C _1-4 alkoxycarbonyl, C _1-6 alkylsulfonyl, C ₁ (It may be substituted with one group selected from the group consisting of _-6 alkylsulfonylamino and 5- or 6-membered saturated heterocyclic ring (which may be substituted with C _1-4 alkyl).) A C _2-6 alkenyl group (which may be substituted with a halogen atom); a C _2-6 alkynyl group (which may be substituted with C _1-4 alkoxy); or a 5- to 6-membered heteroaryl C; _{It is a 1-4} alkyl group, The compound as described in any one of Claims 9-11, or its pharmaceutically acceptable salt. R ^1m and R ¹ⁿ are each independently the same or different and are each a hydrogen atom; a halogen atom; a C _1-6 alkyl group (the group is represented by 1 to 3 fluorine atoms, C _1-4 alkoxy (the alkoxy Is C _6-10 aryl optionally substituted with 1 to 3 groups selected from the group consisting of a halogen atom and cyano, C _1-4 alkoxy optionally substituted with 1 to 3 fluorine atoms, C _3-6 cycloalkyl (C _3-6 cycloalkyl may be substituted with C _6-10 aryl optionally substituted with 1 to 3 groups selected from the group consisting of a halogen atom and cyano. ) 5 or 6 membered saturated heterocycle, 5 or 6 membered saturated heterocyclic oxy, or N- (C _3-10 cycloalkyl optionally substituted with hydroxy) -N- (C _{1- 6} alkyl) Aminoka May be substituted with sulfonyl), C _3-6 cycloalkyl, C _3-6 cycloalkoxy, C _7-14 aralkyloxy (optionally substituted with a halogen atom), saturated heterocyclic oxy, N— (C _3-6 cycloalkyl) -N— (C _1-6 alkyl) amino (C _3-6 cycloalkyl) may be substituted with 1 to 3 groups selected from the group consisting of halogen atoms and cyano. _May be substituted with good C _6-10 aryl.), N- (C _3-6 cycloalkylC _1-4 alkyl) -N- (C _1-6 alkyl) aminocarbonyl, N- (C _1-4 Alkylcarbonyl) -N- (C _1-6 alkyl) amino (wherein the C _1-4 alkylcarbonyl may be substituted with a 5 or 6 membered saturated heterocyclic ring which may be substituted with C _1-4 alkyl). Good), N _{(C 1-4 alkoxycarbonyl)-N-(C 1-6} alkyl) amino, _{N-(C 3-6} cycloalkyl _{sulfonyl)-N-(C 1-6} alkyl) amino, 5-membered to 7-membered cyclic amino, or a 5- to 7-membered cyclic aminocarbonyl (1-3 fluorine atoms or _{C 1-4} alkoxy which may be substituted with _{C 1-4} alkyl, or _{C 1-4} may be substituted with alkoxy ); C _3-6 cycloalkyl group; aminocarbonyl group (which group may be substituted with C _1-6 alkyl); 5-membered to 10-membered monocyclic Or a polycyclic heteroaryl group (the group may be substituted with 1 to 3 fluorine atoms, C _1-4 alkyl, or cyano); a C _7-14 aralkyl group (the group The group may be substituted with a halogen atom There. ); And the following formula
The compound as described in any one of Claims 9-12, or its pharmacologically acceptable salt. R ^1o , R ^1p , R ^1q , R ^1r and R ^1s are each independently the same or different and are each independently a hydrogen atom, a cyano group, a C _1-4 alkyl group, or a C _1-4 alkoxy group (the group a compound or a pharmaceutically acceptable salt thereof, as claimed in claim 13 is C _1-4 may be substituted by alkoxy.). The compound according to claim 14, or a pharmaceutically acceptable salt thereof, wherein R ^1m and R ¹ⁿ are each independently a C _1-6 alkyl group. R ² _{is, C 1-6} alkyl (optionally substituted with halogen atom or _{C 3-6 cycloalkyl.); C 2-6} alkenyl group (optionally substituted with halogen _{atoms.); C 2- 6} alkynyl group (which may be substituted with a halogen atom); C _3-6 cycloalkyl group (which may be substituted with a halogen atom, C _1-4 alkyl, or C _1-4 alkoxy); C ₆ aryl group (a halogen atom, a _{C 6-10} aryl optionally substituted by a halogen atom, or _{C 1-4} may be substituted with optionally _{C 6-10} aryloxy substituted with _{alkoxy.); C 7-10} aralkyl group (which may be substituted with a halogen atom.); and 5-membered or 6-membered heteroaryl group (. which C _1-4 which may be substituted with alkyl) one claim 1 to 15 is Compound or a pharmaceutically acceptable salt thereof, according to. The compound according to claim 16, or a pharmaceutically acceptable salt thereof, wherein R ² is a C _1-6 alkyl group. The compound according to claim 17, or a pharmaceutically acceptable salt thereof, wherein R ² is an isopropyl group. R ^3a and R ^3b are each independently the same or different and are each a hydrogen atom; a C _1-6 alkyl group (the group is a halogen atom, hydroxy, C _3-6 cycloalkyl, C _1-4 alkoxy, N - _{(C 1-4 alkylcarbonyl)-N-(C 1-6} alkyl) amino, N- _{(C 1-6 alkylsulfonyl)-N-(C 1-6} alkyl) amino, _{N- (C 6-10 arylsulfonyl)-N-(C 1-6} alkyl) amino, _{N-(C 1-4 alkoxycarbonyl)-N-(C 1-6} alkyl) amino or _{C 7-14} aralkyloxy (1-3, A fluorine atom or a C _3-6 cycloalkoxy which may be substituted with a C _1-4 alkoxy.) May be substituted.); A C _2-6 alkenyl group; a C _2-6 alkynyl group C _{3 -6} cycloalkyl group (which may be substituted with C _1-4 alkoxy); C _6-10 aryl group (the group may be substituted with halogen atom or C _1-4 alkoxy); C _7-10 aralkyl group (the group is a halogen atom, C _1-4 alkyl (the group is a 5- or 6-membered cyclic amino _optionally substituted with C _6-10 aryloxy (the aryl is 1 to Substituted with 3 fluorine atoms), or substituted with 5- to 7-membered cyclic amino (optionally substituted with C _6-10 aryloxy optionally substituted with fluorine atoms). C _1-4 alkoxy (the group may be C _1-4 alkoxy, C _3-6 cycloalkyl (which may be substituted with C _1-4 alkoxy)), C _3-6 cycloalkyloxy ( Substituted with C _1-4 alkyl C _6-10 aryloxy (the group may be substituted with 1 to 3 fluorine atoms, or cyano), or C _7- optionally substituted with C _1-4 alkoxy. ₁₄ may be substituted with aralkyloxy), C _6-10 aryl (may be substituted with a halogen atom), C _6-10 aryloxy (may be substituted with a halogen atom or cyano), C _7-14 aralkyloxy (optionally substituted with C _1-4 alkoxy), 5 or 6 membered saturated heterocyclic oxy (substituted with 5 or 6 membered saturated heterocyclic carbonyl, or fluorine atom) May be substituted with C _6-10 aryl, which may be substituted), and may be substituted with 5 or 6 membered heteroaryloxy (C _1-4 alkyl). ) May be substituted with a 5- to 7-membered cyclic aminocarbonyl (which may be substituted with a C _6-10 aryloxy which may be substituted with a fluorine atom). ); 5-membered or 6-membered saturated heterocyclic group; 5-membered to 10-membered heteroaryl group (the group may be substituted with 1 to 3 fluorine atoms, C _1-4 alkyl, C _{1- 4} alkoxy optionally substituted _{C 1-4} alkoxy, 5-membered or 6-membered saturated heterocyclic amino _{carbonyl, C 1-4} optionally _{C 6-10} aryl optionally substituted with alkoxy, and _{C 1-6} alkylamino And may be substituted with 1 to 2 groups selected from the group consisting of carbonyl.); And a C _6-10 aryloxy group (which may be substituted with C _6-10 aryloxy). It is one group selected, The compound as described in any one of Claims 1-18, or its pharmaceutically acceptable salt. R ^3a and R ^3b are each independently the same or different, hydrogen atom; C _1-6 alkyl group optionally substituted with hydroxy; C _6-10 aryl group; C _1-4 alkoxy substituted with _20. The compound according to claim 19, which is a C _7-10 aralkyl group (the alkoxy may be substituted with C _7-14 aralkyloxy which may be substituted with C _1-4 alkoxy), or a compound thereof. A pharmaceutically acceptable salt. R ^4a and R ^4b are each independently the same or different from each other; a hydrogen atom; a C _1-6 alkyl group (the group is a halogen atom, C _3-6 cycloalkyl, C _1-4 alkoxy (the group is C _1-4 alkoxy, optionally substituted with a 5- to 7-membered cyclic aminocarbonyl.) 5-membered or 6-membered saturated heterocyclic ring, or N— (C _1-4 alkylcarbonyl) -N— ( C _3-6 cycloalkyl) amino (C _1-4 alkylcarbonyl may be substituted with a 5- or 6-membered saturated heterocyclic ring, or C _6-10 aryl optionally substituted with a halogen atom.) A C _2-6 alkenyl group (the group is C _6-10 aryl optionally substituted with C _1-4 alkoxy, or N- (C _1-4 alkylcarbonyl) -N - _{(C 3-6} cycloalkyl Alkyl) amino (C _1-4 alkylcarbonyl may be substituted with 5-membered may be substituted with C _1-4 alkyl or a 6-membered to saturation may be substituted by hetero ring))..; C _{2-6 (which} may be substituted with _{C 3-6 cycloalkyl.) alkynyl; C 3-6 (which} may be substituted with _{C 1-4 alkoxy.)} cycloalkyl _{group; C 6-10} aryl group (The group may be substituted with di- (C _1-6 alkyl) aminocarbonyl, or C _1-4 alkyl.); C _7-10 aralkyl group (the group is a halogen atom, or cyano. May be substituted);
21. A 5- or 6-membered saturated heterocyclic group; and a 5- to 10-membered heteroaryl group (which may be substituted with _C1-4 alkyl). Or a pharmaceutically acceptable salt thereof. The compound according to claim 21, or a pharmaceutically acceptable salt thereof, wherein either one of R ^4a and R ^4b is a hydrogen atom, and the other is a hydrogen atom or a C _1-6 alkyl group.