AMIDE DERIVATIVE

TECHNICAL FIELD

The present invention relates to an amide derivative being useful as a medicament. More particularly, the present invention relates to an amide derivative being efficacious as a renin inhibitor. Further, the present invention relates to a therapeutic agent of hypertension, which comprises as the active ingredient an amide derivative being efficacious as a renin inhibitor.

BACKGROUND ART

Renin-angiotensin (RA) system is a hormone system being important to the maintenance of blood pressure or electrolyte balance within the body, and plays an important role in the onset or development of circulatory system diseases such as hypertension, congestive heart failure, renal disease, etc.

Renin, which is an important component of RA system, is aspartic protease being mainly excreted from the kidney into the blood, and specifically decomposes angiotensinogen produced in the liver to produce angiotensin I. Angiotensin I is converted into angiotensin II by angiotensin-converting enzyme (ACE) being existing in the lung or vascular endothelial cells. Angiotensin II constricts the blood vessel as well as stimulates the adrenal gland to promote the secretion of aldosterone. Aldosterone acts on the kidney to store sodium and to excrete potassium. This cascade will lead to the increase in blood pressure (Non-patent document 1).

Recently, it has been indicated that there are components of RA system in the peripheral tissues or the central tissues such as heart, blood vessel, kidney, adrenal gland, adipose, etc. topically, and further that there is a possibility that a novel component, (pro)renin receptor, plays an important role in the activation of local RA system (Non-patent document 2), by which the importance of topical (tissue) RA system has become recognized. On the contrary to the circulatory RA system which participates in the short-term circulation control, the tissue RA system initiates the remodeling of various organs in the longer term such as heart, kidney, blood vessel, etc. Accordingly, it is suggested that there is a possibility that the tissue RA system may cause the organ damages such as cardiac enlargement, arteriosclerosis, renal disease, etc. (Non-patent document 3).

As a drug suppressing RA system, ACE inhibitors and angiotensin II receptor antagonists (ARB) can be exemplified, but these drugs (especially the former ones) have been proven to be useful as a therapeutic agent not only for hypertension but also for cardiovascular diseases such as heart failure or diabetic nephropathy, and hence, these drugs have widely been used (Non-patent document 4, Non-patent document 5).

There are multiple steps for suppressing RA system, and among them, renin is located at the most upper stream of RA system and controls the rate of this cascade, so that it is quite inviting approach on theory to inhibit renin (Non-patent document 6, Non-patent document 7). In fact, it is confirmed that aliskiren, which is a renin inhibitor and has been developed recently, significantly inhibits plasma renin activity and exhibits excellent hypotensive activity comparable to other RA system inhibitors in the clinical test in patients with hypertension (Non-patent document 8, Non-patent document 9, Non-patent document 10).

At the moment, various renin inhibitors have been reported, for example, Patent document 1 and Patent document 2 disclose that derivatives having a piperidine ring are useful as a renin inhibitor. Patent document 3 discloses that derivatives having a pyrrolidine ring are useful as a renin inhibitor. The compounds disclosed in these literatures are structurally characteristic in that the 3-position of piperidine ring or pyrrolidine ring is attached to an amino group via a carbonyl group or a methylene chain. However, it has not been known until now that compounds having a 3-((3-substituted phenyl)carbonylamino)piperidine as a basic skeleton are useful as a renin inhibitor.

[Non-patent document 1] Nat Rev Drug Discov. 1(8): p. 621-36 (2002)
[Non-patent document 2] Curr Hypertens Rep. 6(2): p. 129-32 (2004)
[Non-patent document 3] Physiol. Rev. 86: p. 747-803, (2006)
[Non-patent document 4] Curr Diab Rep. 6(1): p. 8-16, (2006)
[Non-patent document 5] J Hypertens Suppl. 23(1): S9-17, (2005)
[Non-patent document 6] J Exp Med. 106(3): p. 439-53, (1957)
[Non-patent document 7] J Am Soc Nephrol 16: p. 592-599, (2005)
[Non-patent document 8] Hypertension 42(6): p. 1137-43, (2003)
[Non-patent document 9] Circulation 111(8): p. 1012-8, (2005)
[Non-patent document 10] J Hypertens. 24 (Suppl 4): S82. Abstract P4.269, (2006)
[Patent document 1] WO 06/069788 pamphlet
[Patent document 2] WO 06/094763 pamphlet
[Patent document 3] WO 06/066896 pamphlet

DISCLOSURE OF INVENTION
[Problems to be Solved by Invention]

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

[Means for Solving the Problems]

The present inventors have intensively studied in order to achieve the above object, and have found that the following compounds or a pharmaceutically acceptable salt thereof (hereinafter, occasionally referred to as the present compound(s)) exhibit an excellent renin inhibitory activity, and have accomplished the present invention.

Namely, the present invention is as follows:

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

[wherein R^1ais a hydrogen atom, a halogen atom, a hydroxy group, a formyl group, a carboxyl group, a cyano group, an optionally substituted C_1-6alkyl group, an optionally substituted C_2-6alkenyl group, an optionally substituted C_2-6alkynyl group, an optionally substituted C_3-6cycloalkyl group, a C_1-6alkylthio group, a C_1-6alkylsulfonyl group, a C_1-6alkoxy group optionally substituted by halogen, C_1-4alkoxy or C_3-6cycloalkyl, an optionally substituted C_3-6cycloalkoxy group, an optionally substituted amino group, an aminocarbonyl group, a C_1-4alkoxycarbonyl group, a C_1-4alkyl-carbonyl group, an optionally substituted C_6-10aryl group, an optionally substituted C_6-10aryloxy group, or an optionally substituted C_7-14aralkyloxy group;

R^1bis a C_1-6alkyl group substituted by mono-C_1-6alkoxycarbonylamino, an optionally substituted C_1-6alkylsulfinyl group, an optionally substituted C_1-6alkyl-sulfonyl group, a substituted C_1-6alkoxy group, an optionally substituted amino group, an optionally substituted aminocarbonyl group, an optionally substituted C_1-4alkoxy-carbonyl group, or an optionally substituted C_1-4alkylcarbonyl group (where the substituted C_1-6alkoxy group is substituted by one of the members selected from hydroxy, C_1-4alkoxy, C_3-6cycloalkoxy, trifluoromethyl, trifluoromethoxy, difluoro-methoxy, carboxy, mono-C_1-6alkylcarbonylamino and mono-C_1-6alkoxycarbonyl-amino);

R^1cis a hydrogen atom, a halogen atom, a hydroxy group, a formyl group, a carboxyl group, a cyano group, an optionally substituted C_1-6alkyl group, an optionally substituted C_3-6cycloalkyl group, an optionally substituted C_5-6cycloalkenyl group, an optionally substituted 5- or 6-membered saturated heterocyclic group, an optionally substituted C_1-6alkylthio group, an optionally substituted C_1-6alkylsulfinyl group, an optionally substituted C_1-6alkylsulfonyl group, an optionally substituted C_6-10arylthio group, an optionally substituted C_6-10arylsulfinyl group, an optionally substituted C_6-10arylsulfonyl group, an optionally substituted C_1-6alkoxy group, an optionally substituted C_3-6cycloalkyloxy group, an optionally substituted C_6-10aryloxy group, an optionally substituted C_7-14aralkyloxy group, an optionally substituted amino group, an optionally substituted aminocarbonyl group, an optionally substituted C_1-4alkoxy-carbonyl group, an optionally substituted C_3-6cycloalkyloxycarbonyl group, an optionally substituted C_1-4alkylcarbonyl group, an optionally substituted C_3-6cyclo-alkylcarbonyl group, an optionally substituted C_6-10arylcarbonyl group, an optionally substituted C_7-14aralkyl group, or an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroarylcarbonyl group; or

R^1ais a hydrogen atom; and R^1band R^1cmay combine each other to form a condensed ring with the benzene ring containing at least one heteroatom;

R²is a hydrogen atom, an optionally substituted C_1-6alkyl group, an optionally substituted C_2-6alkenyl group, an optionally substituted C_2-6alkynyl group, an optionally substituted C_3-10cycloalkyl group, an optionally substituted C_5-6cycloalkenyl group, an optionally substituted C_6-10aryl group, an optionally substituted C_7-14aralkyl group, or an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group (provided that when R^1ais a C_1-6alkoxy group having a halogen substituent, then R²is not a hydrogen atom);

R^3a, R^3b, R^3cand R^3dare independently the same or different and each is a halogen atom, a cyano group, or a group of the formula: -A-B (in which A is a single bond, —(CH₂)_sO—, —(CH₂)_sN(R⁴)—, —(CH₂)_sSO₂—, —(CH₂)_sCO—, —(CH₂)_sCOO—, —(CH₂)_sN(R⁴)CO—, —(CH₂)_sN(R⁴)SO₂—, —(CH₂)_sN(R⁴)COO—, —(CH₂)_sOCON(R⁴)—, —(CH₂)_sO—CO—, —(CH₂)_sCON(R⁴)—, —(CH₂)_sN(R⁴)CON(R⁴)—, or —(CH₂)_sSO₂N(R⁴)—,

B is a hydrogen atom, an optionally substituted C_1-6alkyl group, an optionally substituted C_2-6alkenyl group, an optionally substituted C_2-6alkynyl group, an optionally substituted C_3-10cycloalkyl group, an optionally substituted C_5-6cycloalkenyl group, an optionally substituted C_6-10aryl group, an optionally substituted C_7-14aralkyl group, an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group, an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl-C_1-4alkyl group, or an optionally substituted saturated heterocyclic group (provided that when A is —(CH₂)_sN(R⁴)—, —(CH₂)_sOCON(R⁴)—, —(CH₂)_sCON(R⁴)—, —(CH₂)_sN(R⁴)CON(R⁴)—, or —(CH₂)_sSO₂N(R⁴)—, then R⁴and B may combine each other to form a ring), or two of R^3a, R^3b, R^3cand R^3dare a hydrogen atom, and the remaining two groups may combine to form a fused ring with a heterocyclic ring;

R⁴is a hydrogen atom, an optionally substituted C_1-6alkyl group, an optionally substituted C_3-10cycloalkyl group, an optionally substituted C_6-10aryl group, an optionally substituted C_7-14aralkyl group, or an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group;

s is 0, 1 or 2 (provided that when A is —(CH₂)_sN(R⁴)—, then s is 0 or 2, and when A is —(CH₂)_sCON(R⁴)—, then s is 1 or 2);

n is 0, 1,or 2]

Item 2: The compound of Item 1 or a pharmaceutically acceptable salt thereof, wherein R^1ais a hydrogen atom, a halogen atom, a hydroxy group, a cyano group, a C_3-6cycloalkyl group, a C_1-6alkyl group, or a C_3-6cycloalkoxy group;

R^1bis a C_1-6alkyl group substituted by mono-C^1-6alkoxycarbonylamino, a substituted C_1-6alkoxy group, or an optionally substituted amino group (in which the substituted C_1-6alkoxy group is substituted by one group selected from hydroxy, C_1-4alkoxy, trifluoromethyl, trifluoromethoxy, difluoromethoxy, carboxy, mono-C_1-6alkyl-carbonylamino and mono-C_1-6alkoxycarbonylamino),

R^1cis a hydrogen atom; a halogen atom; a C_1-6alkoxy group optionally substituted by 1 to 3 halogens or by one of the members selected from C_3-6cycloalkyl, mono- or di-(C_1-6alkyl)-substituted aminocarbonyl, 5- or 6-membered saturated heterocycle, and C_1-4alkoxycarbonyl; a C_3-6cycloalkyloxy group; or a 5- or 6-membered saturated heterocyclic group, or

R^1ais a hydrogen atom; and R^1band R^1cmay combine each other to form a condensed ring with the benzene ring containing at least one heteroatom.

Item 3: The compound of Item 1, or a pharmaceutically acceptable salt thereof, wherein R^1ais a hydrogen atom, a halogen atom, a hydroxy group, a cyano group, a C_3-6cycloalkyl group, a C_1-6alkyl group, or a C_3-6cycloalkoxy group;

R^1bis a C_1-6alkyl group substituted by mono-C_1-6alkoxycarbonylamino, a substituted C_1-6alkoxy group, or an optionally substituted amino group (in which the substituted C_1-6alkoxy group is substituted by one group selected from hydroxy, C_1-4alkoxy, trifluoromethyl, trifluoromethoxy, difluoromethoxy, carboxy, mono-C_1-6alkyl-carbonylamino and mono-C_1-6alkoxycarbonylamino);

R^1cis a hydrogen atom; a halogen atom; a C_1-6alkoxy group optionally substituted by 1 to 3 halogens, or by one of the members selected from C_3-6cycloalkyl, mono- or di-(C_1-6alkyl)-substituted aminocarbonyl, 5- or 6-membered saturated heterocycle, and C_1-4alkoxycarbonyl; a C_3-6cycloalkyloxy group; a C_7-14aralkyloxy group having optionally a mono- or di-(C_1-6alkyl)aminocarbonyl substituent; or a 5- or 6-membered saturated heterocyclic group.

Item 4: The compound of Item 1 or a pharmaceutically acceptable salt thereof, wherein R^1ais a hydrogen atom, a halogen atom, a cyano group, a C_1-6alkyl group having optionally a halogen substituent, a C_2-6alkenyl group, a C_3-6cycloalkyl group, a C_1-6alkoxy group having optionally a halogen substituent, or a C_3-6cycloalkoxy group.

Item 5: The compound of any one of Items 1 to 4 or a pharmaceutically acceptable salt thereof, wherein R^1a, R^1band R^1cattach to the benzene ring at the substitution positions as shown in the following formula:

Item 6: The compound of Item 5 or a pharmaceutically acceptable salt thereof, wherein R^1ais a hydrogen atom, a halogen atom, a cyano group, a C_1-6alkyl group, a C_3-6cycloalkyl group, or a C_3-6cycloalkoxy group.

Item 7: The compound of Item 6 or a pharmaceutically acceptable salt thereof, wherein R^1ais a hydrogen atom, a halogen atom, a C_1-6alkyl group, a C_3-6cycloalkyl group, or a C_3-6cycloalkoxy group.

Item 8: The compound of Item 7 or a pharmaceutically acceptable salt thereof, wherein R^1ais a hydrogen atom, a C_1-6alkyl group, a C_3-6cycloalkyl group, or a C_3-6cycloalkoxy group.

Item 9: The compound of Item 8 or a pharmaceutically acceptable salt thereof, wherein R^1ais a hydrogen atom.

Item 10: The compound of Item 6 or a pharmaceutically acceptable salt thereof, wherein R^1ais a halogen atom, a cyano group, or a C_1-6alkyl group.

Item 11: The compound of Item 10 or a pharmaceutically acceptable salt thereof, wherein R^1ais a C_1-6alkyl group.

Item 12: The compound of Item 10 or a pharmaceutically acceptable salt thereof, wherein R^1ais a halogen atom.

Item 13: The compound of Item 10 or a pharmaceutically acceptable salt thereof, wherein R^1ais a cyano group.

Item 14: The compound of any one of Items 1 to 4 or a pharmaceutically acceptable salt thereof, wherein R^1a, R^1band R^1cattach to the benzene ring at the substitution positions as shown in the following formula:

Item 15: The compound of Item 14 or a pharmaceutically acceptable salt thereof, wherein R^1ais a hydroxy group or a C_3-6cycloalkoxy group.

Item 16: The compound of any one of Items 1 to 15 or a pharmaceutically acceptable salt thereof, wherein R^1bis a substituted C_1-6alkoxy group (in which the substituted C_1-6alkoxy group is substituted by C_1-4alkoxy, carboxy, mono-C_1-6alkylcarbonylamino or mono-C_1-6alkoxycarbonylamino).

Item 17: The compound of Item 16 or a pharmaceutically acceptable salt thereof, wherein R^1bis a C_1-6alkoxy group substituted by C_1-4alkoxy.

Item 18: The compound of Item 17 or a pharmaceutically acceptable salt thereof, wherein R^1bis a 3-methoxypropyloxy group.

Item 19: The compound of any one of Items 1 to 18 or a pharmaceutically acceptable salt thereof, wherein R^1cis a hydrogen atom or a C_1-6alkoxy group.

Item 20: The compound of Item 19 or a pharmaceutically acceptable salt thereof, wherein R^1cis a C_1-6alkoxy group.

Item 21: The compound of Item 1 or Item 2 or a pharmaceutically acceptable salt thereof, wherein R^1ais a hydrogen atom; R^1band R^1ccombine each other to form a condensed ring with a benzene ring containing at least one heteroatom.

Item 22: The compound of Item 21 or a pharmaceutically acceptable salt thereof, wherein the condensed ring is a condensed ring of a 5- or 6-membered saturated heterocyclic ring and a benzene ring.

Item 23: The compound of Item 22 or a pharmaceutically acceptable salt thereof, wherein the condensed ring is a condensed ring with a ring having a partial structure of the following formula:

[wherein (i) G¹is —N(R^1d)—, G²is —CO—, G³is —C(R^1e)(R^1f)—, and G⁴is —CH₂—, an oxygen atom, a sulfur atom, or does not exist at all,

(ii) G¹is —N(R^1d)—, G²is —CO—, G³is —N(R^1d)—, and G⁴does not exist at all (R^1dfor G¹and G³is independent each other),

(iii) G¹is an oxygen atom, G²is —CH₂—, G³is an oxygen atom, and G⁴does not exist at all, or

(iv) G¹is an oxygen atom, G²is —CH₂—, G³is —CH₂—, and G⁴is an oxygen atom;

R^1dis a hydrogen atom, a C_6-10aryl group, or a C_1-6alkyl group optionally substituted by one group selected from hydroxy, C_3-6cycloalkyl, C_1-6alkoxy, C_3-6cyclo-alkoxy, trifluoromethyl, trifluoromethoxy and mono-C_1-6alkoxycarbonylamino;

R^1eand R^1fare independently the same or different and each is a hydrogen atom, a halogen atom, a hydroxy group, a carboxyl group, a cyano group, an optionally substituted C_1-6alkyl group, an optionally substituted C_2-6alkenyl group, an optionally substituted C_2-6alkynyl group, an optionally substituted C_3-6cycloalkyl group, an optionally substituted C_1-6alkoxy group, an optionally substituted C_3-6cycloalkoxy group, an optionally substituted amino group, an optionally substituted aminocarbonyl group, an optionally substituted C_1-4alkoxycarbonyl group, an optionally substituted C_1-4alkylcarbonyl group, an optionally substituted C_6-10arylcarbonyl group, an optionally substituted C_6-10aryl group, an optionally substituted C_7-14aralkyl group, an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group, an optionally substituted C_6-10aryloxy group, an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryloxy group, or an optionally substituted C_7-14aralkyloxy group, provided that the ring expressed with dashed line(s) in said chemical structure means a benzene ring].

Item 24: The compound of Item 23 or a pharmaceutically acceptable salt thereof, wherein R^1dis a C_1-6alkyl group optionally substituted by C_1-6alkoxy or mono-C_1-6alkoxycarbonylamino.

Item 25: The compound of Item 24 or a pharmaceutically acceptable salt thereof, wherein R^1dis a C_1-6alkyl group optionally substituted by C_1-6alkoxy.

Item 26: The compound of Item 25 or a pharmaceutically acceptable salt thereof, wherein R^1dis a 4-methoxybutyl group.

Item 27: The compound of Item 24 or a pharmaceutically acceptable salt thereof, wherein R^1dis a C_1-6alkyl group optionally substituted by mono-C_1-6alkoxy-carbonylamino.

Item 28: The compound of Item 27 or a pharmaceutically acceptable salt thereof, wherein R^1dis a methoxycarbonylaminoethyl group.

Item 29: The compound of any one of Items 23 to 28 or a pharmaceutically acceptable salt thereof, wherein R^1eand R^1fare independently the same or different and each is a hydrogen atom; a halogen atom; a hydroxy group; a cyano group; a C_3-6cycloalkyl group; a C_1-6alkyl group optionally substituted by C_1-4alkoxy, C_3-6cycloalkyl, C_3-6cycloalkyloxy, C_7-10aralkyloxy, or aminocarbonyl having optionally a mono- or di-(C_1-6alkyl) substituent; a C_6-10aryl group having optionally a halogen substituent; a C_7-14aralkyl group having optionally a halogen substituent; an optionally substituted aminocarbonyl group; or a 5- to 10-membered monocyclic or polycyclic heteroaryl group optionally substituted by C_1-4alkyl.

Item 30: The compound of Item 29 or a pharmaceutically acceptable salt thereof, wherein R^1eand R^1fare independently the same or different and each is a hydrogen atom; a C_1-6alkyl group optionally substituted by C_1-6alkoxy; a C_6-10aryl group having optionally a halogen substituent; or an aminocarbonyl group optionally having a mono- or di-(C_1-6alkyl) substituent.

Item 31: The compound of any one of Items 1 to 30 or a pharmaceutically acceptable salt thereof, wherein R²is a C_1-6alkyl group having optionally a C_3-6cycloalkyl substituent, a C_3-6cycloalkyl group, a C_6-10aryl group having optionally a halogen substituent, or a C_7-14aralkyl group having optionally a halogen substituent.

Item 32: The compound of Item 31 or a pharmaceutically acceptable salt thereof, wherein R²is a C_1-6alkyl group or a C_3-6cycloalkyl group.

Item 33: The compound of Item 32 or a pharmaceutically acceptable salt thereof, wherein R²is isopropyl group.

Item 34: The compound of any one of Items 1 to 33 or a pharmaceutically acceptable salt thereof, wherein R^3a, R^3b, R^3c, and R^3dare independently a group of the formula: -A-B (in which A is a single bond, —(CH₂)_sO—, —(CH₂)_sN(R⁴)—, —(CH₂)_sSO₂—, —(CH₂)_sCO—, —(CH₂)_sCOO—, —(CH₂)_sN(R⁴)CO—, —(CH₂)_sN(R⁴)SO₂—, —(CH₂)_sN(R⁴)COO—, —(CH₂)_sOCON(R⁴)—, —(CH₂)_sO—CO—, —(CH₂)_sCON(R⁴)—, —(CH₂)_sN(R⁴)CON(R⁴)—, or —(CH₂)_sSO₂N(R⁴)—,

B is a hydrogen atom; an optionally substituted C_1-6alkyl group; a C_2-6alkenyl group; a C_3-10cycloalkyl group; a C_6-10aryl group optionally substituted by the same or different 1 to 3 groups selected from halogen, cyano, C_1-4alkyl, C_1-4alkoxy, cyano, carboxy, C_1-4alkyl having optionally carboxy substituent, or C₆aryl having optionally a C_1-4alkoxy substituent (said C_1-4alkoxy being optionally substituted by fluorine, hydroxy, or carboxy), C₆aryloxy, C_7-10aralkyloxy having optionally a C_1-4alkoxy substituent, aminocarbonyl having optionally a mono- or di-(C_1-6alkyl) substituent, and C_1-4alkylsulfonylamino; a C_7-14aralkyl group optionaly substituted by the same or different 1 to 3 groups selected from halogen, cyano, C_1-4alkyl having optionally a halogen substituent, hydroxy, C_1-4alkoxy having optionally a halogen substituent, carboxy, C_1-4alkoxycarbonyl, C₆aryl having optionally a C_1-4alkoxy substituent, C₆aryloxy, C_7-10aralkyloxy, aminocarbonyl having optionally a mono- or di-(C_1-6alkyl) substituent, C_1-4alkylsulfonylamino and C_1-4alkylsulfonyl; a 5- or 6-membered monocyclic heteroaryl group optionally substituted by halogen or C₆aryl; a 5- or 6-membered monocyclic heteroaryl-C_1-4alkyl group having optionally a C_1-4alkyl substituent; or a 5- or 6-membered saturated heterocyclic group (provided that when A is —(CH₂)_sN(R⁴)—, —(CH₂)_sOCON(R⁴)—, —(CH₂)_sCON(R⁴)—, —(CH₂)_sN(R⁴)CON(R⁴)—, or —(CH₂)_sSO₂N(R⁴)—, then R⁴and B combine each other to form a ring)).

Item 35: The compound of Item 34 or a pharmaceutically acceptable salt thereof, wherein B is a hydrogen atom; an optionally substituted C_1-6alkyl group; a C_2-6alkenyl group; a C_3-10cycloalkyl group; a C_6-10aryl group optionally substituted by the same or different 1 to 3 groups selected from halogen, C₆aryl, and C₆aryloxy; a C_7-14aralkyl group optionally substituted by the same or different 1 to 3 groups selected from halogen, cyano, C_1-4alkyl having optionally 1 to 3 halogen substituents, hydroxy, C_1-4alkoxy, carboxy, C_1-4alkoxycarbonyl, aminocarbonyl, and C_1-4alkylsulfonylamino; a 5- or 6-membered monocyclic heteroaryl group optionally substituted by halogen or C₆aryl; a 5- or 6-membered monocyclic heteroaryl-C_1-4alkyl group having optionally a C_1-4alkyl substituent; or a 5- or 6-membered saturated heterocyclic group.

Item 36: The compound of any one of Items 1 to 35 or a pharmaceutically acceptable salt thereof, wherein R^3a, R^3b, R^3cand R^3dattach to the piperidine ring at the substitution positions as shown in the following formula:

Item 37: The compound of Item 36 or a pharmaceutically acceptable salt thereof, wherein R^3ais a group of the formula: -A-B (in which A is a single bond, —(CH₂)_sO—, —(CH₂)_sN(R⁴)CO—, —(CH₂)_sOCON(R⁴)—, or —(CH₂)_sCON(R⁴)—, B is a hydrogen atom, an optionally substituted C_1-6alkyl group, or an optionally substituted C_7-14aralkyl group),

R^3bis a group of the formula: -A-B (in which A is a single bond, —(CH₂)_sO—, —(CH₂)_sN(R⁴)—, —(CH₂)_sCOO—, —(CH₂)_sN(R⁴)CO—, —(CH₂)_sN(R⁴)SO₂—, —(CH₂)_sN(R⁴)COO—, —(CH₂)_sOCON(R⁴)—, —(CH₂)_sCON(R⁴)—, or —(CH₂)_sSO₂N(R⁴)—, B is a hydrogen atom, an optionally substituted C_1-6alkyl group, an optionally substituted C_6-10aryl group, an optionally substituted C_7-14aralkyl group, or an optionally substituted 5- or 6-membered saturated heterocyclic group),

R^3cis a group of the formula: -A-B (in which A is a single bond, —(CH₂)_sO—, or —(CH₂)_sCOO—, B is a hydrogen atom, an optionally substituted C_1-6alkyl group, an optionally substituted C_6-10aryl group, an optionally substituted C_7-14aralkyl group, or an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group),

R^3dis a group of the formula: -A-B (in which A is a single bond, —(CH₂)_sO—, —(CH₂)_sN(R⁴)—, —(CH₂)_sCOO—, —(CH₂)_sN(R⁴)CO—, —(CH₂)_sN(R⁴) SO₂—, —(CH₂)_sN(R⁴)COO—, —(CH₂)_sOCON(R⁴)—, —(CH₂)_sCON(R⁴)—, or —(CH₂)_s2SO₂N(R⁴)—, B is a hydrogen atom, an optionally substituted C_1-6alkyl group, an optionally substituted C_6-10aryl group, an optionally substituted C_7-14aralkyl group, or an optionally substituted 5- or 6-membered saturated heterocyclic group), or

two groups of R^3a, R^3b, R^3cand R^3dare a hydrogen atom, and the remaining two groups combine each other to form a fused ring with a piperidine ring.

Item 38: The compound of Item 36 or a pharmaceutically acceptable salt thereof, wherein R^3ais a group of the formula: -A-B (in which A is a single bond, or —(CH₂)_sCON(R⁴)—, B is a hydrogen atom, an optionally substituted C_1-6alkyl group, or an optionally substituted C_7-14aralkyl group);

R^3bis a group of the formula: -A-B (in which A is a single bond, —(CH₂)_sO—, —(CH₂)_sN(R⁴)—, —(CH₂)_sCOO—, —(CH₂)_sN(R⁴)CO—, —(CH₂)_sN(R⁴)SO₂—, —(CH₂)_sN(R⁴)COO—, —(CH₂)_sOCON(R⁴)—, or —(CH₂)_sCON(R⁴)—, B is a hydrogen atom, an optionally substituted C_1-6alkyl group, an optionally substituted C_6-10aryl group, an optionally substituted C_7-14aralkyl group, or an optionally substituted 5- or 6-membered saturated heterocyclic group);

R^3cis a group of the formula: -A-B (in which A is a single bond, —(CH₂)_sO—, or —(CH₂)_sCOO—, B is a hydrogen atom, an optionally substituted C_6-10aryl group, an optionally substituted C_7-14aralkyl group, or an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group);

R^3dis a group of the formula: -A-B (in which A is a single bond, —(CH₂)_sO—, —(CH₂)_sN(R⁴)—, —(CH₂)_sCOO—, —(CH₂)_sN(R⁴)CO—, —(CH₂)_sN(R⁴)SO₂—, —(CH₂)_sN(R⁴)COO—, —(CH₂)_sOCON(R⁴)—, or —(CH₂)_sCON(R⁴)—, B is a hydrogen atom, an optionally substituted C_1-6alkyl group, an optionally substituted C_6-10aryl group, an optionally substituted C_7-14aralkyl group, or an optionally substituted 5- or 6-membered saturated heterocyclic group).

Item 39: The compound of any one of Items 36 to 38 or a pharmaceutically acceptable salt thereof, wherein R^3a, R^3band R^3dare a group of the formula: -A-B (in which A is a single bond, B is a hydrogen atom);

Item 40: The compound of Item 39 or a pharmaceutically acceptable salt thereof, wherein B for R^3cis an optionally substituted C_6-10aryl group, an optionally substituted C_7-14aralkyl group, or an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group.

Item 41: The compound of Item 39 or a pharmaceutically acceptable salt thereof, wherein for R^3c, A is a single bond, and B is an optionally substituted C_6-10aryl group.

Item 42: The compound of Item 36 or Item 38 or a pharmaceutically acceptable salt thereof, wherein R^3a, R^3cand R^3dare a group of the formula: -A-B (in which A is a single bond, and B is a hydrogen atom);

R^3bis a group of the formula: -A-B (in which A is a single bond, —(CH₂)_sO—, —(CH₂)_sN(R⁴)—, —(CH₂)_sCOO—, —(CH₂)_sN(R⁴)CO—, —(CH₂)_sN(R⁴)SO₂—, —(CH₂)_sN(R⁴)COO—, —(CH₂)_sOCON(R⁴)—, or —(CH₂)_sCON(R⁴)—, B is a hydrogen atom, an optionally substituted C_1-6alkyl group, an optionally substituted C_6-10aryl group, an optionally substituted C_7-14aralkyl group, or an optionally substituted 5- or 6-membered saturated heterocyclic group).

Item 43: The compound of Item 42 or a pharmaceutically acceptable salt thereof, wherein A for R^3bis —(CH₂)_sO—, —(CH₂)_sN(R⁴)CO—, —(CH₂)_sN(R⁴)COO—, —(CH₂)_sOCON(R⁴)—, or —(CH₂)_sCON(R⁴)—.

Item 44: The compound of Item 42 or Item 43 or a pharmaceutically acceptable salt thereof, wherein B for R^3bis an optionally substituted C_1-6alkyl group, an optionally substituted C_6-10aryl group, an optionally substituted C_7-14aralkyl group, or an optionally substituted 5- or 6-membered saturated heterocyclic group.

Item 45: The compound of Item 36 or a pharmaceutically acceptable salt thereof, wherein R^3a, R^3band R^3care a group of the formula: -A-B (in which A is a single bond, B is a hydrogen atom);

R^3dis a group of the formula: -A-B (in which A is a single bond, —(CH₂)_sO—, —(CH₂)_sN(R⁴)—, —(CH₂)_sCOO—, —(CH₂)_sN(R⁴)CO—, —(CH₂)_sN(R⁴)SO₂—, —(CH₂)_sN(R⁴)COO—, —(CH₂)_sOCON(R⁴)—, —(CH₂)_sN(R⁴)CON(R⁴)—, or —(CH₂)_sCON(R⁴)—, B is a hydrogen atom, an optionally substituted C_1-6alkyl group, an optionally substituted C_2-6alkenyl group, an optionally substituted C_6-10aryl group, an optionally substituted C_7-14aralkyl group, an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl-C_1-4alkyl group, or an optionally substituted 5- or 6-membered saturated heterocyclic group).

Item 46: The compound of Item 45 or a pharmaceutically acceptable salt thereof, wherein A for R^3dis —(CH₂)_sO—, —(CH₂)_sCOO—, —(CH₂)_sN(R⁴)CO—, —(CH₂)_sN(R⁴)COO—, —(CH₂)_sOCON(R⁴)—, or —(CH₂)_sCON(R⁴)—.

Item 47: The compound of Item 45 or Item 46 or a pharmaceutically acceptable salt thereof, wherein A is —(CH₂)_sN(R⁴)CO—.

Item 48: The compound of any one of Items 45 to 47 or a pharmaceutically acceptable salt thereof, wherein B for R^3dis a hydrogen atom, an optionally substituted C_1-6alkyl group, an optionally substituted C_6-10aryl group, an optionally substituted C_7-14aralkyl group, or an optionally substituted 5- or 6-membered saturated heterocyclic group.

Item 49: The compound of any one of Items 45 to 47 or a pharmaceutically acceptable salt thereof, wherein B for R^3dis an optionally substituted C_1-6alkyl group, an optionally substituted C_2-6alkenyl group, an optionally substituted C_6-10aryl group, an optionally substituted C_7-14aralkyl group, an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl-C_1-4alkyl group, or an optionally substituted 5- or 6-membered saturated heterocyclic group.

Item 50: The compound of Item 45 or a pharmaceutically acceptable salt thereof, wherein for R^3d, A is —(CH₂)_sN(R⁴)CO—, —(CH₂)_sN(R⁴)SO₂—, or —(CH₂)_sN(R⁴)COO—, and B is an optionally substituted C_1-6alkyl group, an optionally substituted C_2-6alkenyl group, an optionally substituted C_6-10aryl group, an optionally substituted C_7-14aralkyl group, or an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl-C_1-4alkyl group; and R⁴is a C_3-6cycloalkyl group.

Item 51: The compound of Item 49 or Item 50 or a pharmaceutically acceptable salt thereof, wherein B is a C_1-6alkyl group optionally substituted by one group selected from C_3-6cycloalkyl, hydroxy, C_1-4alkoxy, carboxy, C_1-4alkoxycarbonyl, di-(C_1-6alkyl)amino, and aminocarbonyl having optionally a mono- or di-(C_1-6alkyl) substituent; a C_2-6alkenyl group; a C_6-10aryl group optionally substituted by the same or different 1 to 3 groups selected from halogen, C₆aryl and C₆aryloxy; a C_7-14aralkyl group optionally substituted by the same or different 1 to 3 groups selected from halogen, cyano, C_1-4alkyl having optionally 1 to 3 halogen substituents, hydroxy, C_1-4alkoxy, carboxy, C_1-4alkoxycarbonyl, aminocarbonyl, and C_1-4alkylsulfonylamino; or a 5- to 10-membered monocyclic or polycyclic heteroaryl-C_1-4alkyl group.

Item 52: The compound of any one of Items 1 to 51 or a pharmaceutically acceptable salt thereof, wherein s is 2.

Item 53: The compound of any one of Items 1 to 52 or a pharmaceutically acceptable salt thereof, wherein R⁴is a hydrogen atom, an optionally substituted C_1-6alkyl group, an optionally substituted C_3-10cycloalkyl group, an optionally substituted C_6-10aryl group, or an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group.

Item 54: The compound of Item 53 or a pharmaceutically acceptable salt thereof, wherein R⁴is a hydrogen atom, a C_1-6alkyl group, a C_3-6cycloalkyl group, a C_6-10aryl group, a C_7-14aralkyl group, or a 5- to 10-membered monocyclic or polycyclic heteroaryl group.

Item 55: The compound of Item 54 or a pharmaceutically acceptable salt thereof, wherein R⁴is a C_3-6cycloalkyl group.

Item 56: The compound of Item 36 or a pharmaceutically acceptable salt thereof, wherein R^3a, R^3b, R^3cand R^3dare independently a group of the formula: -A-B (in which A is a single bond, B is a hydrogen atom).

Item 57: The compound of any one of Items 1 to 35 or a pharmaceutically acceptable salt thereof, wherein n is 1.

Item 58: A compound of the formula (II) or a pharmaceutically acceptable salt thereof.

[wherein R^12ais a hydrogen atom, a halogen atom, a cyano group, an optionally substituted C_1-6alkyl group, a C_2-6alkenyl group, a C_2-6alkynyl group, a C_3-6cycloalkyl group, a C_1-6alkylthio group, a C_1-6alkylsulfonyl group, a C_1-6alkoxy group optionally substituted by halogen, C_1-4alkoxy or C_3-6cycloalkyl, a C_3-6cycloalkoxy group, an optionally substituted amino group, an aminocarbonyl group, a C_1-4alkoxycarbonyl group, a C_1-4alkylcarbonyl group, an optionally substituted C_6-10aryl group, an optionally substituted C_6-10aryloxy group, or an optionally substituted C_7-14aralkyloxy group;

R^12bis a mono-C_1-6alkoxycarbonylamino-substituted C_1-6alkyl group, a substituted C_1-6alkoxy group, or an optionally substituted amino group (in which the substituted C_1-6alkoxy group is substituted by one group selected from hydroxy, C_1-4alkoxy, C_3-6cycloalkoxy, trifluoromethyl, trifluoromethoxy, difluoromethoxy, carboxy, mono-C_1-6alkylcarbonylamino and mono-C_1-6alkoxycarbonylamino);

R^12cis a hydrogen atom, a halogen atom, an optionally substituted C_1-6alkoxy group, or an optionally substituted C_3-6cycloalkyloxy group;

R²²is a hydrogen atom, an optionally substituted C_1-6alkyl group, an optionally substituted C_3-6cycloalkyl group, or an optionally substituted C_6-10aryl group (when R^12ais a C_1-6alkoxy group having a halogen substituent, then R²²is not a hydrogen atom);

R^32ais a group of the formula: -A²-B²(in which A²is a single bond, and B²is a hydrogen atom);

R^32b, R^32cand R^32dare independently the same or different and each is a group of the formula: -A²-B²(in which A²is a single bond, —(CH₂)_s2O—, —(CH₂)_s2N(R⁴²)—, —(CH₂)_s2COO—, —(CH₂)_s2N(R⁴²)CO—, —(CH₂)_s2N(R⁴²)SO₂—, —(CH₂)_s2N(R⁴²)COO—, —(CH₂)_s2OCON(R⁴²)—, —(CH₂)_s2N(R⁴²)CON(R⁴²)—, or —(CH₂)_s2CON(R⁴²)—,

B²is a hydrogen atom, an optionally substituted C_1-6alkyl group, an optionally substituted C_2-6alkenyl group, an optionally substituted C_6-10aryl group, an optionally substituted C_7-14aralkyl group, an optionally substituted 5- or 6-membered monocyclic or polycyclic heteroaryl-C_1-4alkyl group, or an optionally substituted 5- or 6-membered saturated heterocyclic group), or one of R^32b, R^32cand R^32dis a hydrogen atom, and the remaining two groups combine each other to form a fused ring with a piperidine ring;

R⁴²is a hydrogen atom, an optionally substituted C_1-6alkyl group, an optionally substituted C_3-6cycloalkyl group, or an optionally substituted C_7-14aralkyl group;

s2 is 0, 1 or 2 (provided that when A²is —(CH₂)_s2N(R⁴²)—, then s2 is 0 or 2, when A²is —(CH₂)_s2CON(R⁴²)—, then s2 is 1 or 2)].

Item 59: The compound of Item 58 or a pharmaceutically acceptable salt thereof, wherein R^12ais a hydrogen atom, a halogen atom, a cyano group, an optionally substituted C_1-6alkyl group, a C_3-6cycloalkyl group, or a C_3-6cycloalkoxy group.

Item 60: The compound of Item 58 or Item 59 or a pharmaceutically acceptable salt thereon, wherein R^12a, R^12band R^12cattach to the benzene ring at the substitution positions of the following formula:

Item 61: The compound of Item 60 or a pharmaceutically acceptable salt thereof, wherein R^12ais a hydrogen atom, a halogen atom, a C_1-6alkyl group, a C_3-6cycloalkyl group, or a C_3-6cycloalkoxy group.

Item 62: The compound of Item 61 or a pharmaceutically acceptable salt thereof, wherein R^12ais a hydrogen atom.

Item 63: The compound of Item 61 or a pharmaceutically acceptable salt thereof, wherein R^12ais a halogen atom or a C_1-6alkyl group.

Item 64: The compound of Item 63 or a pharmaceutically acceptable salt thereof, wherein R^12ais a halogen atom.

Item 65: The compound of Item 63 or a pharmaceutically acceptable salt thereof, wherein R^12ais a C_1-6alkyl group.

Item 66: The compound of Item 60 or a pharmaceutically acceptable salt thereof, wherein R^12ais a cyano group.

Item 67: The compound of Item 58 or Item 59 or a pharmaceutically acceptable salt thereof, wherein R^12a, R^12band R^12cattach to the benzene ring at the substitution positions of the following formula:

Item 68: The compound of Item 67 or a pharmaceutically acceptable salt thereof, wherein R^12ais a C_3-6cycloalkoxy group.

Item 69: The compound of any one of Items 58 to 68 or a pharmaceutically acceptable salt thereof, wherein R^12bis a C_1-6alkoxy group substituted by one group selected from C_1-4alkoxy, carboxy, mono-C_1-6alkylcarbonylamino and mono-C_1-6alkoxycarbonylamino.

Item 70: The compound of Item 69 or a pharmaceutically acceptable salt thereof, wherein R^12bis a C_1-6alkoxy group substituted by C_1-4alkoxy.

Item 71: The compound of Item 70 or a pharmaceutically acceptable salt thereof, wherein R^12bis a 3-methoxypropyloxy group.

Item 72: The compound of any one of Items 58 to 71 or a pharmaceutically acceptable salt thereof, wherein R^12cis a C_1-6alkoxy group.

Item 73: The compound of any one of Items 58 to 72 or a pharmaceutically acceptable salt thereof, wherein R²²is a C_1-6alkyl group having optionally a C_3-6cycloalkyl substituent, or a C_3-6cycloalkyl group.

Item 74: The compound of Item 73 or a pharmaceutically acceptable salt thereof, wherein R²²is isopropyl group.

Item 75: The compound of any one of Items 58 to 74 or a pharmaceutically acceptable salt thereof, wherein R^32ais a group of the formula: -A²-B²(in which A²is a single bond, and B²is a hydrogen atom);

R^32bis a group of the formula: -A²-B²(in which A²is a single bond, —(CH₂)_s2O—, —(CH₂)_s2N(R⁴²)—, —(CH₂)_s2COO—, —(CH₂)_s2N(R⁴²)CO—, —(CH₂)_s2N(R⁴²)SO₂—, —(CH₂)_s2N(R⁴²)COO—, —(CH₂)_s2OCON(R⁴²)—, —(CH₂)_s2N(R⁴²)CON(R⁴²)—, or —(CH₂)_s2CON(R⁴²)—, and B²is a hydrogen atom, an optionally substituted C_1-6alkyl group, an optionally substituted C_2-6alkenyl group, an optionally substituted C_6-10aryl group, an optionally substituted C_7-14aralkyl group, an optionally substituted 5- or 6-membered monocyclic or polycyclic heteroaryl-C_1-4alkyl group, or an optionally substituted 5- or 6-membered saturated heterocyclic group),

R^32cis a group of the formula: -A²-B²(in which A²is a single bond, —(CH₂)_s2O—, or —(CH₂)_s2COO—, and B²is a hydrogen atom, an optionally substituted C_1-6alkyl group, an optionally substituted C_6-10aryl group, an optionally substituted C_7-14aralkyl group, or an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group),

R^32dis a group of the formula: -A²-B²(in which A²is a single bond, —(CH₂)_s2O—, —(CH₂)_s2N(R⁴²)—, —(CH₂)_s2COO—, —(CH₂)_s2N(R⁴²)CO—, —(CH₂)_s2N(R⁴²)SO₂—, —(CH₂)_s2N(R⁴²)COO—, —(CH₂)_s2OCON(R⁴²)—, —(CH₂)_s2N(R⁴²)CON(R⁴²)—, or —(CH₂)_s2CON(R⁴²)—, and B²is a hydrogen atom, an optionally substituted C_1-6alkyl group, an optionally substituted C_2-6alkenyl group, an optionally substituted C_6-10aryl group, an optionally substituted C_7-14aralkyl group, an optionally substituted 5- or 6-membered monocyclic or polycyclic heteroaryl-C_1-4alkyl group, or an optionally substituted 5- or 6-membered saturated heterocyclic group), or one of R^32b, R^32cand R^32dis a hydrogen atom, and the remaining two groups combine each other to form a fused ring with a piperidine ring.

Item 76: The compound of any one of Items 58 to 74 or a pharmaceutically acceptable salt thereof, wherein R^32a, R^32cand R^32dare independently a group of the formula: -A²-B²(in which A²is a single bond, and B²is a hydrogen atom);

R^32bis a group of the formula: -A²-B²(in which A is a single bond, —(CH₂)_s2O—, —(CH₂)_s2N(R⁴²)—, —(CH₂)_s2COO—, —(CH₂)_s2N(R⁴²)CO—, —(CH₂)_s2N(R⁴²)SO₂—, —(CH₂)_s2N(R⁴²)COO—, —(CH₂)_s2OCON(R⁴²)—, —(CH₂)_s2N(R⁴²)CON(R⁴²)—, or —(CH₂)_s2CON(R⁴²)—, and B²is a hydrogen atom, an optionally substituted C_1-6alkyl group, an optionally substituted C_6-10aryl group, an optionally substituted C_7-14aralkyl group, or an optionally substituted 5- or 6-membered saturated heterocyclic group).

Item 77: The compound of Item 76 or a pharmaceutically acceptable salt thereof, wherein B for R^32bis an optionally substituted C_1-6alkyl group, an optionally substituted C_6-10aryl group, an optionally substituted C_7-14aralkyl group, or an optionally substituted 5- or 6-membered saturated heterocyclic group.

Item 78: The compound of any one of Items 58 to 74 or a pharmaceutically acceptable salt thereof, wherein R^32a, R^32band R^32dare independently a group of the formula: -A²-B²(in which A²is a single bond, and B²is a hydrogen atom),

R^32cis a group of the formula: -A²-B²(in which when A²is a single bond, then B²is a hydrogen atom, an optionally substituted C_6-10aryl group, or an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group, and when A²is —(CH₂)_s2O— or —(CH₂)_s2COO—, then B²is a hydrogen atom, an optionally substituted C_1-6alkyl group, an optionally substituted C_6-10aryl group, or an optionally substituted C_7-14aralkyl group).

Item 79: The compound of Item 78 or a pharmaceutically acceptable salt thereof, wherein when for R^32c, A²is a single bond, then B²is an optionally substituted C_6-10aryl group, or an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group.

Item 80: The compound of Item 78 or a pharmaceutically acceptable salt thereof, wherein R^32cis a group of the formula: -A²-B²(in which when A²is a single bond, then B²is a hydrogen atom, and when A²is —(CH₂)_s2O— or —(CH₂)_s2COO—, then B²is a hydrogen atom, an optionally substituted C_1-6alkyl group, or an optionally substituted C_7-14aralkyl group).

Item 81: The compound of Item 78 or a pharmaceutically acceptable salt thereof, wherein R^32cis a group of the formula: -A²-B²(in which A²is a single bond, and B²is an optionally substituted C_6-10aryl group).

Item 82: The compound of any one of Items 58 to 74 or a pharmaceutically acceptable salt thereof, wherein R^32a, R^32band R^32care independently a group of the formula: -A²-B²(in which A²is a single bond, and B²is a hydrogen atom);

R^32dis a group of the formula: -A²-B²(in which A²is a single bond, —(CH₂)_s2O—, —(CH₂)_s2N(R⁴²)—, —(CH₂)_s2COO—, —(CH₂)_s2N(R⁴²)CO—, —(CH₂)_s2N(R⁴²)SO₂—, —(CH₂)_s2N(R⁴²)COO—, —(CH₂)_s2OCON(R⁴²)—, —(CH₂)_s2N(R⁴²)CON(R⁴²)—, or —(CH₂)_s2CON(R⁴²)—, B²is a hydrogen atom, an optionally substituted C_1-6alkyl group, an optionally substituted C_2-6alkenyl group, an optionally substituted C_6-10aryl group, an optionally substituted C_7-14aralkyl group, an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl-C_1-4alkyl group, or an optionally substituted 5- or 6-membered saturated heterocyclic group).

Item 83: The compound of Item 82 or a pharmaceutically acceptable salt thereof, wherein A²is —(CH₂)_s2N(R⁴²)CO—.

Item 84: The compound of Item 82 or a pharmaceutically acceptable salt thereof, wherein for R^32d, A is —(CH₂)_s2N(R⁴²)CO—, —(CH₂)_s2N(R⁴²)SO₂—, or —(CH₂)_s2N(R⁴²)COO—; B²is an optionally substituted C_1-6alkyl group, an optionally substituted C_2-6alkenyl group, an optionally substituted C_6-10aryl group, an optionally substituted C_7-14aralkyl group, or an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl-C_1-4alkyl group; and R⁴²is a C_3-6cycloalkyl group.

Item 85: The compound of any one of Items 82 to 84 or a pharmaceutically acceptable salt thereof, wherein B²is a C_1-6alkyl group optionally substituted by one of the members selected from C_3-6cycloalkyl, hydroxy, C_1-4alkoxy, carboxy, C_1-4alkoxycarbonyl, di-(C_1-6alkyl)amino, and aminocarbonyl having optionally a mono- or di-(C_1-6alkyl) substituent; a C_2-6alkenyl group; a C_6-10aryl group optionally substituted by the same or different 1 to 3 groups selected from halogen, C₆aryl and C₆aryloxy; a C_7-14aralkyl group optionally substituted by the same or different 1 to 3 groups selected from halogen, cyano, C_1-4alkyl having optionally 1 to 3 halogen substituents, hydroxy, C_1-4alkoxy, carboxy, C_1-4alkoxycarbonyl, aminocarbonyl, and C_1-4alkylsulfonylamino; or a 5- to 10-membered monocyclic or polycyclic heteroaryl-C_1-4alkyl group.

Item 86: The compound of any of Items 58 to 83 or a pharmaceutically acceptable salt thereof, wherein R⁴²is a hydrogen atom, a C_1-6alkyl group, a C_3-6cycloalkyl group, or a C_7-14aralkyl group.

Item 87: The compound of Item 86 or a pharmaceutically acceptable salt thereof, wherein R⁴²is a C_3-6cycloalkyl group.

Item 88: The compound of any one of Items 58 to 74 or a pharmaceutically acceptable salt thereof, wherein R^32a, R^32b, R^32cand R^32dare independently a group of the formula: -A²-B²(in which A²is a single bond, and B²is a hydrogen atom).

Item 89: A compound of the following formula (III) or a pharmaceutically acceptable salt thereof.

[wherein R^13ais a hydrogen atom, a halogen atom, a cyano group, a C_1-6alkyl group having optionally a halogen substituent, a C_3-6cycloalkyl group, or a C_3-6cycloalkoxy group;

R^13bis a C_1-6alkoxy group substituted by one of the members selected from C_1-4alkoxy, carboxy, mono-C_1-6alkylcarbonylamino and mono-C_1-6alkoxycarbonylamino,

R^13cis a C_1-6alkoxy group, or R^13ais a hydrogen atom; R^13band R^13ccombine each other to form a condensed ring with the benzene ring containing at least one heteroatom;

R^33dis a group of the formula: -A³-B³(in which A³is —(CH₂)_s3N(R⁴³)—, —(CH₂)_s3N(⁴³)CO—, —(CH₂)_s3N(R⁴³)SO₂—, —(CH₂)_s3N(R⁴³)COO—, —(CH₂)_s3OCON(R⁴³)—, —(CH₂)_s3CON(R⁴³)—, —(CH₂)_s3N(R⁴³)CON(H)—, or —(CH₂)_s3SO₂N(R⁴³)—, B³is a hydrogen atom, an optionally substituted C_1-6alkyl group, an optionally substituted C_2-6alkenyl group, an optionally substituted C_2-6alkynyl group, an optionally substituted C_3-10cycloalkyl group, an optionally substituted C_5-6cycloalkenyl group, an optionally substituted C_6-10aryl group, an optionally substituted C_7-14aralkyl group, an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group, an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl-C_1-4alkyl group, or an optionally substituted saturated heterocyclic group (provided that when A³is —(CH₂)_s3N(R⁴³)—, —(CH₂)_s3OCON(R⁴³)—, —(CH₂)_s3CON(R⁴³)—, or —(CH₂)_s3SO₂N(R⁴³)—, then R⁴³and B³combine each other to form a ring)); R⁴³is a C_3-6cycloalkyl group; and s3 is 0, 1 or 2].

Item 90: The compound of Item 89 or a pharmaceutically acceptable salt thereof, wherein R^13ais a hydrogen atom.

Item 91: The compound of Item 89 or a pharmaceutically acceptable salt thereof, wherein R^13ais a halogen atom.

Item 92: The compound of Item 89 or a pharmaceutically acceptable salt thereof, wherein R^13ais a C_1-6alkyl group having optionally a halogen substituent.

Item 93: The compound of Item 89 or a pharmaceutically acceptable salt thereof, wherein R^13ais a cyano group.

Item 94: The compound of any one of Items 89 to 93 or a pharmaceutically acceptable salt thereof, wherein R^13bis a C_1-6alkoxy group having a C_1-4alkoxy substituent.

Item 95: The compound of Item 94 or a pharmaceutically acceptable salt thereof, wherein R^13bis a 3-propylpropyloxy group.

Item 96: The compound of Item 89 or a pharmaceutically acceptable salt thereof, wherein the condensed ring is a condensed ring having a partial structure of the following formula:

[wherein G¹³is —N(R^13d)—, G²³is —CO—, G³³is —C(R^13e)(R^13f)—, and G⁴³is an oxygen atom or a sulfur atom; R^13dis a C_1-6alkyl group optionally substituted by C_1-6alkoxy or mono-C_1-6alkoxycarbonylamino; R^13eand R^13fare independently the same or different and each is a hydrogen atom; a halogen atom; a hydroxy group; a cyano group; a C_3-6cycloalkyl group; a C_1-6alkyl group optionally substituted by C_1-4alkoxy, C_3-6cyclo-alkyl, or C_7-10aralkyloxy; a C_6-10aryl group having optionally a halogen substituent; a C_7-14aralkyl group having optionally a halogen substituent; an aminocarbonyl group having optionally a mono- or di-(C_1-6alkyl) substituent; or a 5- to 10-membered monocyclic or polycyclic heteroaryl group having optionally a C_1-4alkyl substituent, provided that the ring expressed with dashed line(s) in said chemical structure means a benzene ring].

Item 97: The compound of Item 96 or a pharmaceutically acceptable salt thereof, wherein G⁴³is an oxygen atom.

Item 98: The compound of Item 96 or a pharmaceutically acceptable salt thereof, wherein G⁴³is a sulfur atom.

Item 99: The compound of any one of Items 96 to 98 or a pharmaceutically acceptable salt thereof, wherein R^13dis a 4-methoxybutyl group.

Item 100: The compound of any one of Items 96 to 98 or a pharmaceutically acceptable salt thereof, wherein R^13dis a methoxycarbonylaminoethyl group.

Item 101: The compound of any one of Items 89 to 100 or a pharmaceutically acceptable salt thereof, wherein A³is —(CH₂)_s3N(R⁴³)CO—.

Item 102: The compound of any one of Items 89 to 101 or a pharmaceutically acceptable salt thereof, wherein S3 is 2.

Item 103: The compound of any one of Items 89 to 102 or a pharmaceutically acceptable salt thereof, wherein B³is a C_1-6alkyl group optionally substituted by one of the members selected from C_3-6cycloalkyl, hydroxy, C_1-4alkoxy, carboxy, C_1-4alkoxy-carbonyl, di-(C_1-6alkyl)amino, and aminocarbonyl having optionally a mono- or di-(C_1-6alkyl) substituent; a C_2-6alkenyl group; a C_6-10aryl group optionally substituted by the same or different 1 to 3 groups selected from halogen, C₆aryl, and C₆aryloxy; a C_7-14aralkyl group optionally substituted by the same or different 1 to 3 groups selected from halogen, cyano, C_1-4alkyl having optionally 1 to 3 halogen substituents, hydroxy, C_1-4alkoxy, carboxy, C_1-4alkoxycarbonyl, aminocarbonyl, and C_1-4alkylsulfonylamino; or a 5- to 10-membered monocyclic or polycyclic heteroaryl-C_1-4alkyl group.

Item 104: A medicament comprising as the active ingredient the compound as set forth in any one of Items 1 to 103 or a pharmaceutically acceptable salt thereof.

Item 105: A renin inhibitor comprising as the active ingredient the compound as set forth in any one of Items 1 to 103 or a pharmaceutically acceptable salt thereof.

Item 106: A therapeutic agent for hypertension comprising as the active ingredient the compound as set forth in any one of Items 1 to 103 or a pharmaceutically acceptable salt thereof.

Item 107: Use of the compound as set forth in any one of Items 1 to 103 or a pharmaceutically acceptable salt thereof in the preparation of a renin inhibitor.

Item 108: Use of the compound as set forth in any one of Items 1 to 103 or a pharmaceutically acceptable salt thereof in the preparation of a therapeutic agent for hypertension.

Item 109: A method for treatment of hypertension, which comprises administering an effect amount of the compound as set forth in any one of Items 1 to 103 or a pharmaceutically acceptable salt thereof to a patient in need.

Item 110: An intermediate compound of the following formula (VII) or a pharmaceutically acceptable salt thereof.

[wherein R^37a, R^37b, R^37cand R^37dare independently the same or different and each is a halogen atom, a cyano group, or a group of the formula: -A⁷-B⁷(in which A⁷is a single bond, —(CH₂)_s7O—, —(CH₂)_s7N(R⁴⁷)—, —(CH₂)_s7SO₂—, —(CH₂)_s7CO—, —(CH₂)_s7COO—, —(CH₂)_s7N(R⁴⁷)CO—, —(CH₂)_s7N(R⁴⁷)SO₂—, —(CH₂)_s7N(R⁴⁷)COO—, —(CH₂)_s7OCON(R⁴⁷)—, —(CH₂)_s7O—CO—, —(CH₂)_s7CON(R⁴⁷)—, —(CH₂)_s7N(R⁴⁷)CON(R⁴⁷)—, or —(CH₂)_s7SO₂N(R⁴⁷)—, B⁷is a hydrogen atom, an optionally substituted C_1-6alkyl group, an optionally substituted C_2-6alkenyl group, an optionally substituted C_2-6alkynyl group, an optionally substituted C_3-10cycloalkyl group, an optionally substituted C_5-6cycloalkenyl group, an optionally substituted C_6-10aryl group, an optionally substituted C_7-14aralkyl group, an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group, an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl-C_1-4alkyl group, or an optionally substituted saturated heterocyclic group (provided that when A⁷is —(CH₂)_s7N(R⁴⁷)—, —(CH₂)_s7OCON(R⁴⁷)—, —(CH₂)_s7CON(R⁴⁷)—, —(CH₂)_s7N(R⁴⁷)CON(R⁴⁷)—, or —(CH₂)_s7SO₂N(R⁴⁷)—, then R⁴⁷and B⁷combine each other to form a ring));

R⁴⁷is a hydrogen atom, an optionally substituted C_1-6alkyl group, an optionally substituted C_3-10cycloalkyl group, an optionally substituted C_6-10aryl group, an optionally substituted C_7-14aralkyl group, or an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group;

s7 is 0, 1 or 2 (provided that when A⁷is —(CH₂)_s7N(R⁴⁷)—, then s7 is 0 or 2, and when A⁷is —(CH₂)_s7CON(R⁴⁷)—, then s7 is 1 or 2);

R^37eis isopropyl group or cyclopropyl group;

R^37fis a hydrogen atom, a C_1-4alkoxycarbonyl group, a phenyloxycarbonyl group, an allyloxycarbonyl group, a p-toluenesulfonyl group, or a nitrobenzenesulfonyl group (provided that when R^37eis a cyclopropyl group, and R^37fis a t-butoxycarbonyl group, then (i) the compound where R^37a, R^37band R^37dare independently a group of the formula: -A⁷-B⁷(in which A⁷is a single bond, B⁷is a hydrogen atom); R^37cis a group of the formula: -A⁷-B⁷(in which A⁷is a single bond, and B⁷is a C₆aryl group), and (ii) the compound where R^37a, R^37b, R^37c, and R^37dare independently a group of the formula: -A⁷-B⁷(in which A⁷is a single bond, and B⁷is a hydrogen atom) are excluded].

Item 111: The compound of Item 110 or a pharmaceutically acceptable salt thereof, wherein R^37eis an isopropyl group.

Item 112: The compound of Item 110 or a pharmaceutically acceptable salt thereof, wherein R^37eis a cyclopropyl group.

Item 113: The compound of any one of Items 110 to 112 or a pharmaceutically acceptable salt thereof, wherein R^37fis a hydrogen atom.

Item 114: The compound of any one of Items 100 to 112 or a pharmaceutically acceptable salt thereof, wherein R^37fis a C_1-4alkoxycarbonyl group, or a phenyl-oxycarbonyl group.

Item 115: The compound of any one of Items 110 to 114 or a pharmaceutically acceptable salt thereof, wherein R^37a, R^37band R^37dare independently a group of the formula: -A⁷-B⁷(in which A⁷is a single bond, and B⁷is a hydrogen atom); R^37cis a group of the formula: -A⁷-B⁷(in which A⁷is a single bond, —(CH₂)_s7O—, or —(CH₂)_s7COO—, B⁷is a hydrogen atom, an optionally substituted C_6-10aryl group, an optionally substituted C_7-14aralkyl group, or an optionally substituted 5- or 6-membered monocyclic or polycyclic heteroaryl group).

Item 116: The compound of any one of Items 110 to 114, or a pharmaceutically acceptable salt thereof, wherein R^37a, R^37cand R^37dare independently a group of the formula: -A⁷-B⁷(in which A⁷is a single bond, and B⁷is a hydrogen atom); R^37bis a group of the formula: -A⁷-B⁷(in which A⁷is a single bond, —(CH₂)_s7O—, —(CH₂)_s7N(R⁴⁷)—, —(CH₂)_s7COO—, —(CH₂)_s7N(R⁴⁷)CO—, —(CH₂)_s7N(R⁴⁷)SO₂—, —(CH₂)_s7N(R⁴⁷)COO—, —(CH₂)_s7OCON(R⁴⁷)—, or —(CH₂)_s7CON(R⁴⁷)—, B⁷is a hydrogen atom, an optionally substituted C_1-6alkyl group, an optionally substituted C_6-10aryl group, an optionally substituted C_7-14aralkyl group, or an optionally substituted 5- or 6-membered saturated heterocyclic group).

Item 117: The compound of any one of Items 110 to 114, or a pharmaceutically acceptable salt thereof, wherein R^37a, R^37band R^37care independently a group of the formula: -A⁷-B⁷(in which A⁷is a single bond, and B⁷is a hydrogen atom); R^37dis a group of the formula: -A⁷-B⁷(in which A⁷is a single bond, —(CH₂)_s7O—, —(CH₂)_s7N(R⁴⁷)—, —(CH₂)_s7COO—, —(CH₂)_s7N(R⁴⁷)CO—, —(CH₂)_s7N(R⁴⁷)SO₂—, —(CH₂)_s7N(R⁴⁷)COO—, —(CH₂)_s7OCON(R⁴⁷)—, or —(CH₂)_s7CON(R⁴⁷)—, B⁷is a hydrogen atom, an optionally substituted C_1-6alkyl group, an optionally substituted C_2-6alkenyl group, an optionally substituted C_6-10aryl group, an optionally substituted C_7-14aralkyl group, an optionally substituted 5- or 6-membered monocyclic or polycyclic heteroaryl group, an optionally substituted 5- or 6-membered monocyclic or polycyclic heteroaryl-C_1-4alkyl group, or an optionally substituted 5- or 6-membered saturated heterocyclic group).

Item 118: The compound of Item 117 or a pharmaceutically acceptable salt thereof, wherein B⁷for R^37dis a hydrogen atom, an optionally substituted C_1-6alkyl group, an optionally substituted C_2-6alkenyl group, an optionally substituted C_6-10aryl group, an optionally substituted C_7-14aralkyl group, or an optionally substituted 5- or 6-membered saturated heterocyclic group.

Item 119: The compound of any one of Items 110 to 114 or a pharmaceutically acceptable salt thereof, wherein R^37a, R^37b, R^37cand R^37dare independently a group of the formula: -A⁷-B⁷(in which A⁷is a single bond, and B⁷is a hydrogen atom).

Hereinafter, the compound of the formula (I) or a pharmaceutically acceptable salt thereof are occasionally referred to as “the compound of the present invention”.

[Effects of Invention]

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

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be illustrated in more detail. In the present specification, the number of the carbon atom in definitions for substituents may be expressed, for example, as “C_1-6”. For example, the expression of “C_1-6alkyl” is the same as the expression of an alkyl group having 1 to 6 carbon atoms. In addition, in the present specification, any group without a term of “an optionally substituted” or “substituted” means a “unsubstituted” group. For example, “C_1-6alkyl” means a “unsubstituted” one.

The term “group” in the present specification means a monovalent group unless specified otherwise. For example, the “alkyl group” means a monovalent saturated hydrocarbon group. In addition, in the explanation of each group in the present specification, the term “group” may be omitted. Further, the number of the substituents as defined with “an optionally substituted” or “substituted” is not necessarily limited, and it can be either one or more as long as the substitution can be possible. The definition for each group is also applied to cases where said group is a part of other groups, unless indicated specifically.

The “halogen atom” is, for example, fluorine atom, chlorine atom, bromine atom or iodine atom.

The “C_1-6alkyl group” means a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms, and preferable one is a C_1-4alkyl group. Examples of the C_1-6alkyl group are 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, etc.

The “C_1-6alkyl group” for “B” includes a group where a C_2-4ring is formed on the 1-carbon atom of the saturated hydrocarbon group, for example, groups of the following formulae are exemplified:

The “C_2-6alkenyl group” means a straight or branched chain unsaturated hydrocarbon group having 2 to 6 carbon atoms and one double bond, and includes, for example, vinyl, propenyl, methylpropenyl, butenyl or methylbutenyl, etc.

The “C_2-6alkynyl group” means a straight chain or branched chain unsaturated hydrocarbon group having 2 to 6 carbon atoms and one triple bond, and includes, for example, ethynyl, 1-propinyl, 2-propinyl, 2-butynyl, pentynyl or hexynyl, etc.

The “C_3-10cycloalkyl group” means a saturated cyclic hydrocarbon group having 3 to 10 carbon atoms, and a preferable one is a C_3-6cycloalkyl group. Examples of the “C_3-10cycloalkyl group” are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl or norbornyl, etc.

The “C_3-10cycloalkyl group” for “B” also includes a saturated bicyclic group. Examples thereof are the groups of the following formulae:

The “C_3-6cycloalkyl-C_1-4alkyl group” means a group where a C_3-6cycloalkyl is attached to a C_1-4alkyl. Examples thereof are cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, etc.

The “C_5-6cycloalkenyl group” means a cyclic unsaturated hydrocarbon group having a double bond, and includes, for example, 1-cyclopentenyl, 1-cyclohexenyl, etc.

The “C_6-10aryl group” means an aromatic hydrocarbon group having 6 to 10 carbon atoms. Preferable one is a C₆aryl group (phenyl). Examples of the C_6-10aryl group are phenyl, 1-naphthyl or 2-naphthyl, etc.

The “C_7-14aralkyl group” means a C_6-10aryl-C_1-4alkyl group, which is a group where the above-mentioned alkyl group is attached to the above-mentioned aryl group. Preferable one is a C_7-10aralkyl group (a C₆aryl-C_1-4alkyl group). Examples of the C_7-14aralkyl group are benzyl, 2-phenylethyl, 1-phenylpropyl or 1-naphthylmethyl, etc.

The “heteroaryl group” includes, for example, a 5- to 10-membered monocyclic or polycyclic group, etc., and said group contains the same or different one or more heteroatoms (e.g., 1 to 4 heteroatoms) selected from nitrogen atom, sulfur atom and oxygen atom. Preferable one is, for example, a 5- or 6-membered monocyclic group containing one heteroatom selected from nitrogen atom, sulfur atom and oxygen atom. Examples of the heteroaryl group are pyrrolyl, thienyl, benzothienyl, benzofuranyl, benzoxazolyl, benzothiazolyl, furyl, oxazolyl, thiazolyl, isoxazolyl, imidazolyl, pyrazolyl, pyridyl, pyrazyl, pyrimidyl, pyridazinyl, quinolyl, isoquinolyl, triazolyl, triazinyl, tetrazolyl, indolyl, imidazo[1,2-a]pyridyl, dibenzofuranyl, benzimidazolyl, quinoxalyl, cinnolyl, quinazolyl, indazolyl, naphthyridyl, quinolinoly, or isoquinolinolyl, etc.

The “heteroaryl-C_1-4alkyl group” means a group where the above-mentioned alkyl group is substituted to the above-mentioned heteroaryl group. The heteroaryl moiety of said group includes the same ones as exemplified as the above-mentioned heteroaryl group, for example, a 5- or 6-membered monocyclic heteroaryl-C_1-4alkyl, such as 2-pyridylmethyl, etc.

The “C_1-6alkyl moiety” of the “C_1-6alkoxy group” is the same as the above-mentioned C_1-6alkyl. Preferable one is a C_1-4alkoxy group. Examples of the C_1-6alkoxy group are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.

The “C_1-6alkyl moiety” of the “C_1-6alkylthio group” is the same as the above-mentioned C_1-6alkyl. Preferable one is a C_1-4alkylthio group. Examples of the C_1-6alkylthio group are methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio or hexylthio, etc.

The “C_1-6alkyl moiety” of the “C_1-6alkylsulfinyl group” is the same as the above-mentioned C_1-6alkyl. Preferable one is a C_1-4alkylsulfinyl group. Examples of the C_1-6alkylsulfinyl group are methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl, pentylsulfinyl or hexylsulfinyl, etc.

The “C_1-6alkyl moiety” of the “C_1-6alkylsulfonyl group” is the same as the above-mentioned C_1-6alkyl. Preferable one is a C_1-4alkylsulfonyl group. Examples of the C_1-6alkylsulfonyl group are methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, pentylsulfonyl or hexylsulfonyl, etc.

The “C_6-10aryl moiety” of the “C_6-10arylthio group” is the same as the above-mentioned C_6-10aryl. Examples of the C_6-10arylthio group are phenylthio, 1-naphthylthio or 2-naphthylthio, etc.

The “C_6-10aryl moiety” of the “C_6-10arylsulfinyl group” is the same as the above-mentioned C_6-10aryl. Examples of the C_6-10arylsulfinyl group are phenyl-sulfinyl, 1-naphthylsulfinyl or 2-naphthylsulfinyl, etc.

The “C_6-10aryl moiety” of the “C_6-10arylsulfonyl group” is the same as the above-mentioned C_6-10aryl. Examples of the C_6-10arylsulfonyl group are phenyl-sulfonyl, tosyl, 1-naphthylsulfonyl or 2-naphthylsulfonyl.

The “C_3-10cycloalkyl moiety” of the “C_3-10cycloalkoxy group” is the same as the above-mentioned C_3-10cycloalkyl. Preferable one is a C_3-6cycloalkoxy group, etc. Examples of the C_3-10cycloalkoxy group are cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, adamantyloxy or norbornyloxy, etc.

The “C_6-10aryl moiety” of the “C_6-10aryloxy group” is the same as the above-mentioned C_6-10aryl. Preferable one is a C₆aryloxy (phenyloxy). Examples of the C_6-10aryloxy group are phenoxyl, 1-naphthyloxy or 2-naphthyloxy, etc.

The “C_7-14aralkyloxy group” means a C_6-10aryl-C_1-4alkyloxy group. The “C_7-14aralkyl moiety” is the same as the above-mentioned C_7-14aralkyl. Preferable one is a C₆aryl-C_1-4alkyloxy group (phenyl-C_1-4alkyloxy group). Examples of the C_7-14aralkyloxy group are benzyloxy, phenethyloxy, naphthylmethyloxy, etc.

The “C_1-4alkoxycarbonyl group” means a group where the above-mentioned “C_1-4alkoxy group” is attached to a carbonyl group. Examples thereof are methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 2-propoxycarbonyl or tert-butoxycarbonyl, etc.

The “C_3-6cycloalkoxycarbonyl group” is a group where the above-mentioned “C_3-6cycloalkoxy group” is attached to a carbonyl group. Examples of the C_3-6cycloalkoxy moiety are ones as exemplified as the above-mentioned cycloalkoxy group.

The “C_1-4alkylcarbonyl group” means a group where the above-mentioned “C_1-4alkyl group” is attached to a carbonyl group. Examples thereof are acetyl, propionyl or butyryl, etc.

The “C_3-10cycloalkylcarbonyl group” means a group where the above-mentioned “C_3-10cycloalkyl group” is attached to a carbonyl group. Preferable one includes a C_3-6cycloalkylcarbonyl group. Examples thereof are cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, adamantylcarbonyl or norbornylcarbonyl, etc.

The “C_6-10arylcarbonyl group” means a group where the above-mentioned “C_6-10aryl group” is attached to a carbonyl group. The “C_6-10aryl moiety” is the same as the above-mentioned “C_6-10aryl group”. Preferable one is a “C₆arylcarbonyl group” (phenylcarbonyl group). Examples of the “C_6-10arylcarbonyl group” are benzoyl, 1-naphthoyl or 2-naphthoyl, etc.

The “heteroarylcarbonyl group” means a group where the above-mentioned heteroaryl is attached to a carbonyl group. The “heteroaryl moiety” is the same as ones exemplified as the above-mentioned heteroaryl group. Examples thereof are 2-pyridylcarbonyl, etc.

The “C_1-4alkyl moiety” of the “C_1-4alkylcarbonyloxy group” is the same as the above-mentioned C_1-4alkyl group. Examples thereof are methylcarbonyloxy, ethylcarbonyloxy, isopropylcarbonyloxy, etc.

The “C_3-6cycloalkyl moiety” of the “C_3-6cycloalkylcarbonyloxy group” is the same as ones exemplified as the above-mentioned C_3-6cycloalkyl group. Examples thereof are cyclopropylcarbonyloxy, cyclobutylcarbonyloxy, cyclopentylcarbonyloxy, etc.

The “C_1-4alkylcarbonylamino group” means a group where one of the above-mentioned “C_1-4alkylcarbonyl group” is attached to an amino group. Examples thereof are methylcarbonylamino, ethylcarbonylamino, etc.

The “C_1-4alkoxycarbonylamino group” means a group where one of the above-mentioned “C_1-4alkoxycarbonyl group” is attached to an amino group. Examples thereof are methoxycarbonylamino, ethoxycarbonylamino, etc.

The “C_1-4alkylsulfonylamino group” means a group where one of the above-mentioned “C_1-4alkylsulfonyl group” is attached to an amino group. Examples thereof are methylsulfonylamino, ethylsulfonylamino, etc.

The “saturated heterocyclic group” includes a 5- or 6-membered saturated heterocyclic group containing the same or different 1 to 3 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom. Said nitrogen atom, oxygen atom and sulfur atom are ring-forming atoms. Examples thereof are pyranyl, tetrahydrofuryl, pyrrolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, hexamethyleneiminyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, oxoimidazolidinyl, dioxoimidazolidinyl, oxooxazolidinyl, dioxooxazolidinyl, dioxothiazolidinyl, tetrahydrofuranyl, tetrahydropyridinyl, or 1,4-dihydropyrrolidine, etc. Said group does not bind at the ring-forming nitrogen atom. Namely, said group does not include a concept such as pyrrolidino group.

The above-mentioned “saturated heterocyclic group” may form a condensed ring with a 6-membered aromatic hydrocarbon or a 6-membered unsaturated heterocyclic group. For example, said “saturated heterocyclic group” includes a bicyclic 11- or 12-membered “saturated heterocyclic group” wherein the above mentioned 5- or 6-membere saturated heterocyclic group is condensed with a 6-membered aromatic hydrocarbon group or a 6-membered unsaturated heterocyclic group. The 6-membered aromatic hydrocarbon group includes benzene, etc. The 6-membered unsaturated heterocyclic group includes pyridine, pyrimidine, or pyridazine, etc. Examples thereof are dihydroindolyl, dihydroisoindolyl, dihydropurinyl, dihydrothiazolopyrimidinyl, dihydrobenzodioxanyl, isoindolinyl, indazolyl, pyrrolidinyl, tetrahydroquinolinyl, decahydroquinolinyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, tetrahydronaphthyridinyl or tetrahydropyridoazepinyl, etc.

The “optionally substituted amino group” includes an amino group, a mono-substituted amino group, a di-substituted amino group, or a 5- or 6-membered cyclic amino group.

The “mono-substituted amino group” includes an amino group substituted by one group selected from C_1-6alkyl, C_3-6cycloalkyl, C_3-6cycloalkyl-C_1-4alkyl and benzyl. The “C_1-6alkyl”, the “C_3-6cycloalkyl” and the “C_3-6cycloalkyl-C_1-4alkyl” are the same as defined above.

Examples of the “amino group substituted by a mono-(C_1-6alkyl)” are methylamino, ethylamino, etc.

Examples of the “amino group substituted by a mono-(C_3-6cycloalkyl)” are cyclopropylamino, cyclobutylamino, cyclopentylamino, etc.

Examples of the “amino group substituted by a mono-(C_3-6cycloalkyl-C_1-4alkyl)” are cyclopropylmethylamino, cyclobutylmethylamino, cyclopentylmethylamino, etc.

The “di-substituted amino group” means an amino group substituted by the same or different 2 groups selected from C_1-6alkyl, C_3-6cycloalkyl, C_3-6cycloalkyl-C_1-4alkyl and benzyl. The C_1-6alkyl, the C_3-6cycloalkyl, the C_1-4alkylcarbonyl and the C_3-6cycloalkylcarbonyl are the same as defined above.

Examples of the “amino group substituted by di-C_1-6alkyl” are dimethylamino, diethylamino, etc.

Examples of the “amino group substituted by di-(C_3-6cycloalkyl)” are dicyclopropylamino, dicyclobutylamino, cyclodipentylamino, etc.

Examples of the “amino group substituted by a C_1-6alkyl and a benzyl” are N-methyl-N-benzylamino, N-ethyl-N-benzylamino, etc.

Examples of the “amino group substituted by a C_3-6cycloalkyl and a benzyl” are N-cyclopropyl-N-benzylamino, N-cyclopentyl-N-benzylamino, N-cyclohexyl-N-benzylamino, etc.

The “5- or 6-membered cyclic amino group” means a cyclic amino group consisting of 5 members or 6 members. Said group binds at the ring-forming nitrogen atom. Examples thereof are pyrrolidino, piperidino, morpholino, thiomorpholino, thiomorpholino oxide, thimorpholino dioxide, piperazino, etc. Said ring may be optionally substituted by a C_1-4alkyl or hydroxy group.

The substituent of the “optionally substituted C_1-6alkyl group” includes, for example,

(a) a halogen atom,

(b) a cyano group,

(d) a hydroxy group,

(e) a C_1-4alkoxy group (being optionally substituted by fluorine),

(f) a C_3-6cycloalkyloxy group,

(g) a C₆aryloxy group (said group being optionally substituted by the same or different groups selected from halogen, cyano and C_1-4alkoxy),

(h) a benzyloxy group,

(i) a formyl group,

(j) a C_1-4alkylcarbonyl group,

(k) a C_3-6cycloalkylcarbonyl group,

(l) a phenylcarbonyl group,

(m) a benzylcarbonyl group,

(n) a formylcarbonyloxy group,

(o) a C_1-4alkylcarbonyloxy group,

(p) a C_3-6cycloalkylcarbonyloxy group,

(q) a carboxyl group,

(r) a C_1-4alkoxycarbonyl group,

(s) a C_3-6cycloalkoxycarbonyl group,

(t) an amino group,

(u) a mono-substituted amino group (said group being substituted by (u1) C_1-6alkyl, (u2) C_3-6cycloalkyl, (u3) C_3-6cycloalkyl-C_1-4alkyl, or (u4) benzyl

(v) a di-substituted amino group (said group being substituted by the same or different 2 groups selected from the above-mentioned (u1)˜(u4)),

(w) a 5- or 6-membered cyclic amino group,

(x) an optionally substituted aminocarbonyl group, or

(y) an optionally substituted aminocarbonyloxy group.

In addition, the amino for the above-mentioned (x) and (y) is the same as the above-mentioned (u), (v) and (w).

The above-mentioned “optionally substituted aminocarbonyl group” means a group where the “optionally substituted amino” is attached to a carbonyl group. The “substituted amino” includes a mono-substituted amino group, a di-substituted amino group or a 5- or 6-membered cyclic amino. The substituent of the mono- or di-substituted amino includes, for example, a C_1-6alkyl, a C_3-6cycloalkyl, a C_3-6cyclo-alkyl-C_1-4alkyl, or benzyl.

The “mono-substituted aminocarbonyl group” includes, for example, an aminocarbonyl group substituted by the above-mentioned mono-(C_1-6alkyl), or an aminocarbonyl group substituted by mono-(C_3-6cycloalkyl).

Examples of the aminocarbonyl group substituted by mono-(C_1-6alkyl) are methylaminocarbonyl, ethylaminocarbonyl, etc.

Examples of the aminocarbonyl group substituted by mono-(C_3-6cycloalkyl) are cyclopropylaminocarbonyl, cyclobutylaminocarbonyl, cyclopentylaminocarbonyl, etc.

The “di-substituted aminocarbonyl group” includes, for example, an aminocarbonyl group substituted by a C_1-6alkyl and a C_1-6alkyl, an aminocarbonyl group substituted by a C_1-6alkyl and a C_3-6cycloalkyl, or an aminocarbonyl group substituted by a C_1-6alkyl and a benzyl.

Examples of the “aminocarbonyl group substituted by a C_1-6alkyl and a C_1-6alkyl” are N-methyl-N-methylaminocarbonyl, N-methyl-N-ethylaminocarbonyl, etc.

Examples of the “aminocarbonyl group substituted by a C_1-6alkyl and a C_3-6cycloalkyl” are N-methyl-N-cyclopropylcarbonylamino, N-methyl-N-cyclobutylcarbonylamino, N-methyl-N-cyclopentylcarbonylamino, etc.

Examples of the “aminocarbonyl group substituted by a C_1-6alkyl and a benzyl” are N-methyl-N-benzylamino, N-ethyl-N-benzylamino, etc.

The “5- or 6-membered cyclic aminocarbonyl group” may be optionally substituted by a C_6-10aryloxy. Examples thereof are 3-phenyloxypyrrolidinocarbonyl, etc.

The “optionally substituted aminocarbonyl moiety” of the above-mentioned optionally substituted aminocarbonyloxy group is the same as the above-mentioned optionally substituted aminocarbonyl group. Examples thereof are aminocarbonyloxy, etc.

The substituent of the optionally substituted C_1-6alkyl group for R^1ais preferably a halogen atom.

The substituent of the optionally substituted C_1-6alkyl group for R^1cis preferably a C_1-4alkoxycarbonyl.

The substituent of the optionally substituted C_1-6alkyl group for R²is preferably a halogen atom or a C_3-6cycloalkyl group.

The substituent of the optionally substituted C_1-6alkyl group for B is preferably the following groups:

(a2) a halogen atom,

(b2) a C_3-6cycloalkyl (being optionally substituted by halogen, hydroxy or C_1-4alkoxy),

(c2) a hydroxy group,

(d2) a C_1-4alkoxy,

(e2) a C_3-6cycloalkoxy,

(f2) a C₆aryloxy (being optionally substituted by C_1-4alkyl),

(g2) a carboxy,

(h2) a C_1-4alkoxycarbonyl,

(i2) an amino (being optionally substituted by C_1-6alkyl or benzyl), and

(j2) an aminocarbonyl (the amino moiety being optionally substituted by C_1-6alkyl, C_3-6cycloalkyl, or C_3-6cycloalkyl-C_1-4alkyl).

When B is a C_1-6alkyl group substituted by mono-(C_1-6alkyl)-substituted amino, the C_1-6alkyl moiety of the amino moiety may optionally be substituted by a carbamoyl group, a mono- or di-(C_1-6alkyl)aminocarbonyl, or a 5- or 6-membered cyclic aminocarbonyl (provided that A should be a single bond, and B should be an optionally substituted C_1-6alkyl group (in which (C_1-6alkyl)amino and the cyclic amino moiety are the same as defined above)). Examples of the C_1-6alkyl of the above-mentioned amino moiety are the following compounds.

The substituents of the “optionally substituted C_1-6alkyl group” for B may be optionally substituted by the same or different 1 to 3 groups selected from the above-mentioned group. For example, when A is a single bond, then said group may be optionally substituted by two groups of the above-mentioned (b2) and j2). When A is a group other than a single bond, then said groups may be optionally substituted by two groups of the above-mentioned (b2) and (d2).

Examples thereof are the following groups.

The substituents of the “optionally substituted C_1-6alkoxy group” are, for example, a group selected from the above-mentioned (a) to (y) (in which the substituent of the mono-substituted amino group in (u) is restricted to a C_1-6alkyl group and a C_3-6cycloalkyl group, and the same as for (v), (x) and (y)).

The substituent of the “optionally substituted C_1-6alkoxy group” for R^1ais preferably, for example, a halogen atom, a C_1-4alkoxy or a C_3-6cycloalkyl.

The substituent of the “substituted C_1-6alkoxy group” for R^1bis preferably hydroxy, a C_1-4alkoxy, trifluoromethyl, trifluoromethoxy, difluoromethoxy, carboxy, a mono-C_1-6alkylcarbonylamino, or mono-C_1-6alkoxycarbonylamino.

The substituent of the “optionally substituted C_1-6alkoxy group” for R^1cis preferably a halogen atom, a C_3-6cycloalkyl, a C_1-4alkoxycarbonyl, a mono- or di-(C_1-6alkyl)-substituted aminocarbonyl, or a 5- or 6-membered saturated heterocyclic group.

The substituent of the “optionally substituted C_2-6alkenyl group” and the “optionally substituted C_2-6alkynyl group” is, for example, a group selected from the above-mentioned (a) to (s).

The substituent of the “optionally substituted C_3-10cycloalkyl group” and the “optionally substituted C_3-10cycloalkyloxy group” is, for example, a group selected from the above-mentioned (x), a halogen atom, a C_1-4alkyl and a C_6-10aryl group (said aryl group being optionally substituted by a halogen atom, a C_1-4alkyl, a hydroxy group, or a C_1-4alkoxy).

The substituent of the “optionally substituted C_5-6cycloalkenyl group” is, for example, a group selected from the above-mentioned (a) to (s) and a nitro group.

The substituent of the “optionally substituted C_1-4alkylcarbonyl group” and the “optionally substituted C_3-10cycloalkylcarbonyl group” is, for example, a group selected from the above-mentioned (a) to (h) and nitro group.

The substituent of the “optionally substituted C_1-6alkylthio group”, the “optionally substituted C_1-6alkylsulfinyl group”, the “optionally substituted C_1-6alkylsulfonyl group” and the “optionally substituted C_1-4alkoxycarbonyl group” is, for example, a group selected from a halogen atom, a hydroxy group, a nitro group, a cyano group, and the above-mentioned (d) to (h).

The substituent of the “optionally substituted C_6-10aryl group” and the “optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group” is, for example, the same or different 1 to 3 groups selected from the following groups:

(a3) a halogen atom,

(b3) a cyano group,

(c3) a C_1-4alkyl group,

(d3) a C_1-4alkoxy group,

(e3) a C_6-10aryl group (said group being optionally substituted by (e31) cyano, (e32) carboxy, (e33) C_1-4alky optionally substituted by carboxy, or (e34) C_1-4alkoxy optionally substituted by fluorine, hydroxy, or carboxy),

(f3) a C₆aryloxy,

(g3) a C_7-10aralkyloxy (being optionally substituted by C_1-4alkoxy),

(h3) an aminocarbonyl (the amino moiety being optionally substituted by C_1-6alkyl), and

(i3) a C_1-4alkylsulfonylamino.

The substituent of the “optionally substituted C_6-10aryl group” for B is preferably a group selected from the above-mentioned (a3), (b3), (c3), (d3), (e3), (f3), and (g3)

When A is a single bond, then B is preferably a C₆aryl group substituted by a C₆aryl (having optionally the same substituents as defined for the above-mentioned (e3)).

The substituent of the “optionally substituted C_6-10aryloxy group” and the “optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryloxy group” includes, for example, the above-mentioned (a3) to (i3), etc.

The substituent of the aryl moiety of the “optionally substituted C_7-14aralkyl group” is a group selected from the following groups:

(a4) a halogen atom,

(b4) a cyano group,

(c4) a C_1-4alkyl group (being optionally substituted by 1 to 3 halogen atoms),

(d4) a hydroxy group,

(e4) a C_1-4alkoxy group (being optionally substituted by 1 o 3 halogen atoms),

(f4) a carboxyl group,

(g4) a C_1-4alkoxycarbonyl group,

(h4) a C₆aryl group (being optionally substituted by C_1-4alkoxy)

(i4) a C₆aryloxy group,

(j4) a C_7-10aralkyloxy group,

(k4) an aminocarbonyl group (the amino moiety being optionally substituted by C_1-6alkyl),

(l4) a C_1-4alkylsulfonylamino group, and

(m4) a C_1-4alkylsulfonyl group.

The substituent of the above-mentioned (a4) to (m4) may substitute on the C_1-4alkyl moiety of the C_7-14aralkyl group (C_6-10aryl-C_1-4alkyl group).

The substituent of the “optionally substituted C_7-14aralkyl group” for R^1aand R^1cis preferably (a4).

The substituent of the “optionally substituted C_7-14aralkyl group” for B is preferably the same or different 1 to 3 groups selected from (a4), (b4), (c4), (d4), (e4), (f4), (g4), (k4) and (l4).

The substituent of the “optionally substituted C_7-14aralkyloxy group” includes the above-mentioned (a4) to (m4), etc.

The substituent of the “optionally substituted C_7-14aralkyloxy group” for R^1aincludes (a4) and (k4), etc.

The “optionally substituted C_7-14aralkyloxy group” for R^1cis preferably a C_7-10aralkyloxy group.

The substituent of the heteroaryl moiety of the “optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl-C_1-4alkyl group” includes the same ones as exemplified as a substituent of the “optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group”.

The “optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl-C_1-4alkyl group” for B is preferably a 5- or 6-membered monocyclic heteroaryl-C_1-4alkyl group.

The substituent of the “saturated heterocyclic group” and the “saturated heterocycle” includes, for example, the following groups:

(a5) a halogen atom,

(b5) a hydroxy group,

(c5) a nitro group,

(d5) a cyano group,

(e5) a C_1-4alkyl group (being optionally substituted by 1 to 3 halogen atoms),

(f5) a C_1-4alkoxy group (being optionally substituted by 1 to 3 halogen atoms),

(g5) a carboxyl group,

(h5) a C_1-4alkoxycarbonyl group,

(i5) a C_3-6cycloalkoxycarbonyl group,

(j5) an amino group (being optionally substituted by C_1-4alkyl),

(k5) a C₆aryl group,

(l5) an aminocarbonyl group,

(m5) an oxo group, or

(n5) a thioxo group.

Said “saturated heterocyclic group” or “saturated heterocycle” may be optionally substituted by the same or different 2 substituents selected from the above substituents.

The “optionally substituted saturated heterocyclic group” for R^1cis preferably a 5- or 6-membered saturated heterocyclic group.

The “optionally substituted saturated heterocyclic group” for B is preferably, for example, a 5- or 6-membered saturated heterocyclic group containing the same or different 1 to 3 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom.

The phrase that R^1ais a hydrogen atom; R^1band R^1cmay combine each other to form a condensed ring with the benzene ring containing at least one heteroatom means that two of the above-mentioned definitions form a bicyclic condensed ring containing at least one heteroatom with the benzene ring to which said definitions attach. Herein, the “bicyclic condensed ring” includes a condensed ring of a 5-membered ring and a benzene ring, or a 6-membered ring and a benzene ring. The 5-membered ring and the 6-membered ring in the above-mentioned condensed ring are saturated ones, respectively. The heteroatom in said definitions is a nitrogen atom, an oxygen atom or a sulfur atom, and preferable one is a nitrogen atom or an oxygen atom, and may occasionally be the same or different two atoms.

The compounds wherein R^1ais a hydrogen atom; R^1band R^1cmay combine each other to form a condensed ring containing at least one heteroatom with the benzene ring includes compounds having a partial structure of the following formula:

[wherein, (i) G¹is —N(R^1d)—, G²is —CO—, G³is —C(R^1e)(R^1f)—, and G⁴is —CH₂—, an oxygen atom, a sulfur atom, or does not exist at all,

(ii) G¹is —N(R^1d)—, G²is —CO—, G³is —N(R^1d)—, and G⁴does not exist at all (R^1ds for G¹and G³are independent each other),

(iii) G¹is an oxygen atom, G²is —CH₂—, G³is an oxygen atom, and G⁴does not exist at all, or

(iv) G¹is an oxygen atom, G²is —CH₂—, G³is —CH₂—, and G⁴is an oxygen atom;

R^1dis a hydrogen atom, a C_6-10aryl group, or a C_1-6alkyl group optionally substituted by a group selected from hydroxy, C_3-6cycloalkyl, C_1-6alkoxy, C_3-6cycloalkoxy, trifluoromethyl, trifluoromethoxy and mono-C_1-6alkoxycarbonylamino;

Examples of R^1eand R^1fare, for example, one group selected from the following groups:

(a6) a hydrogen atom,

(b6) a halogen atom,

(c6) a hydroxy group,

(d6) a cyano group,

(e6) a C_3-6cycloalkyl group,

(f6) a C_1-6alkyl group (said group being optionally substituted by

- (f61) C_1-6alkoxy,
- (f62) C_3-6cycloalkyl,
- (f63) C_3-6cycloalkyloxy,
- (f64) C_7-10aralkyloxy, or
- (f65) aminocarbonyl (being optionally substituted by C_1-6alkyl)),

(g6) a C_6-10aryl group (being optionally substituted by halogen),

(h6) a C_7-14aralkyl group (being optionally substituted by halogen),

(i6) an aminocarbonyl group (being optionally substituted by C_1-6alkyl), and

(j6) a 5- to 10-membered monocyclic or polycyclic heteroaryl group (being optionally substituted by C_1-4alkyl).

In addition, R^1eand R^1fare independently the above-mentioned groups.

The binding position of A in the “group of the formula: -A-B” is explained below. The “group of the formula: -A-B” means, for example, a group of the formula: —(CH₂)_sO—H when A is —(CH₂)_sO—, and B is a hydrogen atom.

When A is —(CH₂)_sN(R⁴)—, —(CH₂)_sOCON(R⁴)—, —(CH₂)_sCON(R⁴)—, —(CH₂)_sN(R⁴)CON(R⁴)— or —(CH₂)_sSO₂N(R⁴), the phrase that R⁴and B combine each other to form a ring means that the N(R⁴)— moiety forms a 5- or 6-membered cyclic amino group. For example, A includes a group of the following formulae:

The above-mentioned cyclic amino groups are optionally substituted by the same substituents for the above-mentioned saturated heterocyclic group. Examples thereof are 4-hydroxypiperidino; 2-methoxymorpholino; 4-formylpiperidino; 4-methoxycarbonylpiperidino; 4-aminocarbonylpiperidino; 4-N-methylaminopiperidino; 3-phenylpyrrolidino; 4-dimethylaminopiperidino, etc.

The phrase that “two of R^3a, R^3b, R^3cand R^3dare a hydrogen atom, and the remaining two groups combine each other to form a fused ring with a hetero ring” means that the remaining two groups of the above-mentioned definitions form a fused ring with a hetero ring (pyrrolidine ring, piperidine ring, etc.) to which they attach. Said fused ring includes, for example, a bicyclic ring or a tricyclic ring containing one nitrogen atom and 5 to 10 carbon atoms, and preferably a bicyclic ring. Examples thereof are groups of the following structures:

With respect to each substituent of the compound of the formula (I), more preferable other embodiments are illustrated hereinbelow.

Preferable groups for R^1a, R^1b, and R^1cfor the following partial structure are as follows.

R^1ais a group selected from the following groups:

(a7) a hydrogen atom,

(b7) a halogen atom,

(c7) a hydroxy group,

(d7) a cyano group,

(e7) a C_1-6alkyl group (being optionally substituted by halogen),

(f7) a C_2-6alkenyl group,

(g7) a C_3-6cycloalkyl group,

(h7) a C_1-6alkoxy group (said group being optionally substituted by

- (h71) halogen,
- (h72) C_1-4alkoxy, or
- (h73) C_3-6cycloalkyl),

(i7) a C_3-6cycloalkoxy group,

(j7) a C_6-10aryl group,

(k7) a C₆aryloxy group, and

(l7) a C_7-10aralkyloxy group (said group being optionally substituted by

- (l71) halogen, or
- (l72) mono- or di-(C_1-6alkyl)-substituted aminocarbonyl).

More preferable R^1ais a group selected from a hydrogen atom; a halogen atom; a hydroxy group; a cyano group; a C_1-6alkyl group; a C_1-6alkoxy group having optionally substituted by halogen, C_1-4alkoxy or C_3-6cycloalkyl; a C₃-₆cycloalkoxy group; a C₆aryl group; and a C_7-10aralkyloxy group optionally substituted by halogen or aminocarbonyl having a mono- or di-(C_1-6alkyl) substituent.

Further preferable R^1ais a group selected from a hydrogen atom, a halogen atom, a hydroxy group, a cyano group and a C_1-6alkyl group.

Especially preferable R^1ais a group selected from a hydrogen atom, a halogen atom, a cyano group and a C_1-6alkyl group.

R^1bis a group selected from the following groups:

(a8) a C_1-6alkyl group (said group being substituted by mono-C_1-6alkoxycarbonylamino),

(b8) an amino group (said group being optionally substituted by C_1-6alkyl having optionally a C_1-4alkoxy substituent), and

(c8) a C_1-6alkoxy group (said group being substituted by

- (c81) hydroxy,
- (c82) C_1-4alkoxy,
- (c83) C_3-6cycloalkoxy,
- (c84) trifluoromethyl,
- (c85) trifluoromethoxy,
- (c86) difluoromethoxy,
- (c87) carboxyl,
- (c88) C_1-4alkoxycarbonylamino, or
- (c89) C_1-4alkylcarbonylamino).

R^1bis preferably a C_1-6alkoxy group being substituted by one group selected from C_1-4alkoxy, carboxy, C_1-4alkoxycarbonylamino, and C_1-4alkylcarbonylamino.

More preferable R^1bis a C_1-6alkoxy group being substituted by C_1-4alkoxy or C_1-4alkoxycarbonylamino.

Especially preferable R^1bis a C_1-4alkoxy-substituted C_1-6alkoxy group. Further, 3-methoxypropyloxy group is especially preferable.

R^1cis a group selected from the following groups:

(a9) a hydrogen atom,

(b9) a halogen atom,

(c9) a hydroxy group,

(d9) a cyano group,

(e9) a C_1-6alkyl group (being optionally substituted by C_1-4alkoxycarbonyl),

(f9) a C_7-10aralkyl group,

(g9) a C_1-6alkoxy group (said group being optionally substituted by

- (g91) halogen,
- (g92) C_3-6cycloalkyl,
- (g93) mono- or di-(C_1-6alkyl)-substituted aminocarbonyl,
- (g94) 5- or 6-membered saturated heterocycle, or
- (g95) C_1-4alkoxycarbonyl),

(h9) a C_3-6cycloalkoxy group,

(i9) a C₆aryloxy group,

(9) a C_7-10aralkyloxy group (being optionally substituted by mono- or di-(C_1-6alkyl)aminocarbonyl), and

(k9) a 5- or 6-membered saturated heterocyclic group.

Further preferable R^1cis a hydrogen atom; a C_1-6alkoxy group optionally substituted by halogen, C_3-6cycloalkyl, mono- or di-(C_1-6alkyl)-substituted aminocarbonyl, or 5- or 6-membered saturated heterocycle; a C_3-6cycloalkoxy group; a C₆aryloxy group; a C_7-10aralkyloxy group; or a 5- or 6-membered saturated heterocyclic group.

The above-mentioned partial structure is preferably a partial structure selected from the following groups.

Especially preferable R^1cis a C_1-6alkoxy group.

Preferable embodiment for the following partial structure is as follows.

[wherein (i) G¹is —N(R^1d)—, G²is —CO—, G³is —C(R^1e)(R^1f)—, and G⁴is —CH₂—, oxygen atom, sulfur atom, or does not exist at all,

(ii) G¹is —N(R^1d)—, G²is —CO—, G³is —N(R^1d)—, and G⁴does not exist at all (R^1dfor G¹and G³are independent to each other),

(iii) G¹is an oxygen atom, G²is —CH₂—, G³is an oxygen atom, and G⁴does not exist at all, or

(iv) G¹is an oxygen atom, G²is —CH₂—, G³is —CH₂—, and G⁴is an oxygen atom;

R^1eand R^1fare independently the same or different and each is a hydrogen atom; a halogen atom; a hydroxy group; a cyano group; a C_3-6cycloalkyl group; a C_1-6alkyl group optionally substituted by C_1-4alkoxy, C_3-6cycloalkyl, or C_7-10aralkyloxy; a C_6-10aryl group having optionally a halogen substituent; a C_7-14aralkyl group having optionally a halogen substituent; an aminocarbonyl group optionally substituted by mono- or di-(C_1-6alkyl); or a 5- to 10-membered monocyclic or polycyclic heteroaryl group optionally substituted by C_1-4alkyl, provided that the ring expressed with dashed line(s) in said chemical structure means a benzene ring).

Examples of said definitions are groups as indicated by the following chemical structures, provided that the ring expressed with dashed line(s) in said chemical structure means a benzene ring, and the ring expressed with solid line(s) means a condensed ring formed by combining R^1band R^1cwith the above-mentioned benzene ring.

In the above-mentioned partial structure, R^1dis preferably a C_1-6alkyl group optionally substituted by C_1-6alkoxy or mono-C_1-6alkoxycarbonylamino.

R^1dis preferably a C_1-6alkyl group optionally substituted by C_1-6alkoxy, and 4-methoxybutyl group is more preferable.

R^1dis preferably a C_1-6alkyl group optionally substituted by mono-C_1-6alkoxycarbonylamino, and methoxycarbonylaminoethyl group is more preferable.

The compounds having the above-mentioned partial structure wherein G¹is —N(R^1d)—; G²is —CO—; G³is —C(R^1e)(R^1f)—; G⁴is an oxygen atom or a sulfur atom; R^1dis a C_1-6alkyl group substituted by C_1-6alkoxy or mono-C_1-6alkoxycarbonylamino; R^1eand R^1fare independently the same or different and each is a hydrogen atom, a C_1-6alkyl group optionally substituted by C_1-6alkoxy, a C_6-10aryl group having optionally a halogen substituent, or an aminocarbonyl group being substituted by mono- or di-(C_1-6alkyl) are preferable.

Preferable R²in the formula (I) is a group selected from the following groups:

(a10) a C_1-6alkyl group (being optionally substituted by C_3-6cycloalkyl),

(b10) a C_3-6cycloalkyl group,

(c10) a C₆aryl group (being optionally substituted by halogen), and

(d10) a C_7-10aralkyl group (being optionally substituted by halogen).

R²is preferably a C_1-6alkyl group, and isopropyl group is especially preferable.

Preferable B of the group of the formula: -A-B is a group selected from the following groups:

(a11) a hydrogen atom,

(b11) a C_1-6alkyl group (being optionally substituted by a group selected from the above-mentioned (a2) to j2)),

(c11) a C_2-6alkenyl group,

(d11) a C_3-6cycloalkyl group,

(e11) a C₆aryl group (said group being optionally substituted by the same or different 1 to 3 groups selected from the above-mentioned (a3) to (i3)),

(f11) a C_7-14aralkyl group (said group being optionally substituted by the same or different 1 to 3 groups selected from the above-mentioned (a4) to (m4)),

(g11) a 5- or 6-membered monocyclic heteroaryl group (being optionally substituted by halogen or C₆aryl),

(h11) a 5- or 6-membered monocyclic heteroaryl-C_1-4alkyl group (said group being optionally substituted by C_1-4alkyl), and

(i11) a 5- or 6-membered saturated heterocyclic group.

More preferable B is a group selected from a hydrogen atom; a C_1-6alkyl group (said group being optionally substituted by C_3-6cycloalkyl, hydroxy, C_1-4alkoxy, carboxy, C_1-4alkoxycarbonyl, di-(C_1-6alkyl)-substituted amino, or aminocarbonyl optionally substituted by mono- or di-(C_1-6alkyl)); a C_2-6alkenyl group; a C_6-10aryl group (said group being optionally substituted by the same or different 1 to 3 groups selected from halogen, C₆aryl, and C₆aryloxy); a C_7-14aralkyl group (said group being optionally substituted by the same or different 1 to 3 groups selected from halogen, cyano, C_1-4alkyl having optionally 1 to 3 halogen substituents, hydroxy, C_1-4alkoxy, carboxy, C_1-4alkoxycarbonyl, aminocarbonyl, and C_1-4alkylsulfonylamino); and 5- or 6-membered monocyclic heteroaryl-C_1-4alkyl group.

Preferable R⁴in the formula (I) is a group selected from a hydrogen atom, a C_1-6alkyl group, a C_3-6cycloalkyl group and a C₇aralkyl group.

More preferable R⁴is a group selected from a hydrogen atom and a C_3-6cycloalkyl group, and especially preferable one is a C_3-6cycloalkyl group.

The present compounds of the more preferable embodiments of the present invention include the compounds of the following formula.

(1) The compound of the following formula (Ia) or a pharmaceutically acceptable salt thereof.

[wherein R^1a, R^1b, R^1c, R², R^3a, R^3b, R^3c, R^3dand n are as defined in Item 1, provided that in the formula (Ia), the compound of the following formula:

is limited to those wherein R^1a, R^1b, R^1cand R²are as defined in Item 1;

R³is one of the above-mentioned R^3a, R^3b, R^3c, and R^3d(in which R^3a, R^3b, R^3cand R^3dare as defined in Item 1, provided that when R³is a group of the formula: -A-B, then A is a single bond, and B is an optionally substituted C₆aryl group, or an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group. Said C₆aryl group is substituted at the 3-position thereof by cyano, carboxy, C_1-4alkyl having optionally a carboxy substituent, or a C₆aryl group optionally substituted by a C_1-4alkoxy optionally substituted by fluorine, hydroxy, or carboxy)]

The compounds of any one of Items 2 to 57 wherein the formula (I) is replaced by the formula (Ia) and a pharmaceutically acceptable salt thereof are also included in the present invention.

(2) The compound of the following formula (IIa) or a pharmaceutically acceptable salt thereof.

[wherein R^12a, R^12b, R^12c, R²², R^32a, R^32b, R^32cand R^32dare as defined in Item 58, provided that in the formula (IIa), the compound of the following formula:

is limited to those wherein R^12a, R^12b, R^12cand R²²are as defined in Item 58, and R^32cis the same as R³of the formula (Ib)].

The compounds of any one of Items 59 to 88 wherein the formula (II) is replaced by the formula (IIa) and a pharmaceutically acceptable salt thereof are also included in the present invention.

(3) The compound of the following formula (Ic) or a pharmaceutically acceptable salt thereof.

[wherein R^1a, R^1b, R^1c, R², R^3a, R^3b, R^3c, R^3dand n are as defined in Item 1, provided that in the formula (Ic), the compound of the following formula:

is limited to those wherein R^1a, R^1b, R^1cand R²are as defined in Item 1; R³is one of the above-mentioned R^3a, R^3b, R^3c, and R^3d(in which R^3a, R^3b, R^3cand R^3dare as defined in the formula (I)),

provided that when R³is a group of the formula: -A-B, then (i) A is —(CH₂)_sN(R⁴)CO—, or —(CH₂)_sN(R⁴)COO—; B is as defined in Item 1; R⁴is an optionally substituted C_3-10cycloalkyl group, an optionally substituted C_6-10aryl group, or an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group,

(ii) A is —(CH₂)_sN(R⁴)—; B is as defined in Item 1; R⁴is an optionally substituted C_3-10cycloalkyl group, or an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group,

(iii) A is —(CH₂)_sN(R⁴)SO₂—, —(CH₂)_sOCON(R⁴)— or —(CH₂)_sSO₂N(R⁴)—; B is as defined in Item 1; R⁴is an optionally substituted C_3-10cycloalkyl group, or an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group,

(iv) A is —(CH₂)_sN(R⁴)CON(H)—; B is as defined in Item 1; R⁴is an optionally substituted C_3-10cycloalkyl group, or an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group,

(v) A is —(CH₂)_sCON(R⁴)—; B is as defined in Item 1; R⁴is a C_1-6alkyl group, an optionally substituted C_6-10aryl group, or an optionally substituted C_7-14aralkyl group,

(vi) A is —(CH₂)_sSO₂—, —(CH₂)_sCO—, or —(CH₂)_sCOO—; B is a hydrogen atom, an optionally substituted C_3-10cycloalkyl group, an optionally substituted C_5-6cycloalkenyl group, or an optionally substituted C_6-10aryl group, or

(vii) A is a single bond; B is a hydrogen atom, an optionally substituted C_3-10cycloalkyl group, an optionally substituted C_5-6cycloalkenyl group, an optionally substituted C_6-10aryl group, an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group, or an optionally substituted saturated heterocyclic group].

The compounds of any one of Item 2 to 57 wherein the formula (I) is replaced by the formula (Ic) or a pharmaceutically acceptable salt thereof are also included in the present invention.

(4) The compound of the following formula (IIc) or a pharmaceutically acceptable salt thereof.

[Oretinopathy]

[wherein R^12a, R^12b, R^12c, R²², R^32a, R^32b, R^32cand R^32dare as defined in Item 58, provided that in the formula (IIc), the compound of the following formula:

is limited to those wherein R^12a, R^12b, R^12cand R²²are as defined in Item 58; R^32dis as defined in the formula (II), provided that when R^32dis a group of the formula: -A²-B², then (i) A²is —(CH₂)_s2N(R⁴²)CO—, or —(CH₂)_s2N(R⁴²)COO—; B²is as defined in Item 58; R⁴²is an optionally substituted C_3-10cycloalkyl group, an optionally substituted C_6-10aryl group, or an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group,

(ii) A²is —(CH₂)_s2N(R⁴²)—; B²is as defined in Item 58; R⁴²is an optionally substituted C_3-10cycloalkyl group, or an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group,

(iii) A²is —(CH₂)_s2N(R⁴²)SO₂—, —(CH₂)_s2OCON(R⁴²)—, or —(CH₂)_s2SO₂N(R⁴²)—; B²is as defined in Item 58; R⁴²is an optionally substituted C_3-10cycloalkyl group, or an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group,

(iv) A²is —(CH₂)_sN(R⁴²)CON(H)—; B²is as defined in Item 58; R⁴²is an optionally substituted C_3-10cycloalkyl group, or an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group,

(v) A²is —(CH₂)_s2CON(R⁴²)—; B²is as defined in Item 58; R⁴²is a C_1-6alkyl group, an optionally substituted C_6-10aryl group, or an optionally substituted C_7-14aralkyl group,

(vi) A²is —(CH₂)_s2SO₂—, —(CH₂)_s2CO—, or —(CH₂)_s2COO—; B²is a hydrogen atom, an optionally substituted C_3-10cycloalkyl group, an optionally substituted C_5-6cycloalkenyl group, or an optionally substituted C_6-10aryl group, or

(vii) A²is a single bond; B²is a hydrogen atom, an optionally substituted C_3-10cycloalkyl group, an optionally substituted C_5-6cycloalkenyl group, an optionally substituted C_6-10aryl group, an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group, or an optionally substituted saturated heterocyclic group].

The present invention also includes the compounds disclosed in any one of Items 59 to Item 88, wherein the compound of the formula (II) is replaced by the compound of the formula (IIc) or a pharmaceutically acceptable salt thereof.

(5) The compound of the following formula (Ie), or a pharmaceutically acceptable salt thereof.

[wherein R^1a, R^1b, R^1c, R², R^3a, R^3b, R^3c, R^3dand n are defined in Item 1, provided that in the formula (Ie), the compounds of the formulae (Ib) and (Id) are limited to ones as disclosed above]

The present invention also includes the compounds as listed in Items 2 to Items 57, wherein the compound of the formula (I) is replaced by the compound of the formula (Ie).

(6) The compound of the following formula (IIe) or a pharmaceutically acceptable salt thereof.

[wherein R^12a, R^12b, R^12c, R²², R^32a, R^32b, R^32cand R^32dare as defined in Item 58, provided that in the formula (IIe), the compounds of the formulae (IIb) and (IId) are limited to ones as disclosed above]

The present invention also includes the compound as disclosed in any one of Items 59 to 88, where the compound of the formula (II) is replaced by the compound of the formula (IIe), or a pharmaceutically acceptable salt thereof.

(7) The compound of the following formula (III), or a pharmaceutically acceptable salt thereof.

[wherein R^13a, R^13b, R^13cand R^33dare as defined in Item 89]

In the compound of the above-mentioned formula (III), the condensed ring is preferably a condensed ring having a partial structure of the following formula:

[wherein G¹³, G²³, G³³, and G⁴³are as defined in Item 96].

The compound of the following formula (IIIa), or a pharmaceutically acceptable salt thereof.

[wherein R^13ais a hydrogen atom, a halogen atom, a cyano group, a C_1-6alkyl group, a C_3-6cycloalkyl group, or a C_3-6cycloalkoxy group; R^13bis a C_1-6alkoxy group which is substituted by one group selected from C_1-4alkoxy and mono-C_1-6alkoxycarbonylamino; R^13cis a C_1-6alkoxy group; R^33dis a group of the formula: -A³-B³(A³and B³are as defined in Item 89)]

In the compound of the above-mentioned formula (IIIa), the compounds having a stereo structure of the following formula are preferable.

In the compounds of the above-mentioned formula (IIIa′), the compounds having a stereo structure of the following formula are preferable.

In the compounds of the formulae (IIIa), (IIIa′) and (IIIa″), the preferable compounds are ones wherein R^13ais a hydrogen atom; R^13bis a C_1-6alkoxy group substituted by C_1-4alkoxy; R^33dis a group of the formula: -A³-B³(in which A³is —(CH₂)_s3N(R⁴³)CO—, or —(CH₂)_s3N(R⁴³)CON(H)—, B³is an optionally substituted C_1-6alkyl group, an optionally substituted C_2-6alkenyl group, an optionally substituted C_6-10aryl group, an optionally substituted C_7-14aralkyl group, or an optionally substituted 5- or 6-membered monocyclic heteroaryl-C_1-4alkyl group); R⁴³is a C_3-6cycloalkyl group; s3 is 1, or2.

In the compounds of the formulae (IIIa) and (IIIa′), the preferable compounds are ones wherein R^13ais a hydrogen atom; R^13bis a C_1-6alkoxy group substituted by C_1-4alkoxy; when A³for R³³d is —(CH₂)₂N(R⁴³)CO—, then B³is an optionally substituted C_1-6alkyl group, an optionally substituted C_2-6alkenyl group, an optionally substituted C_7-14aralkyl group, or an optionally substituted 5- or 6-membered monocyclic heteroaryl-C_1-4alkyl group, or when A³for R^33dis —(CH₂)₂N(R⁴³)CONH—, then B³is an optionally substituted C_6-10aryl group; R⁴³is a C_3-6cycloalkyl group; s3 is 1 or 2.

(8) The compound of the following formula (IIIb), or a pharmaceutically acceptable salt thereof.

[wherein R^13a, R^13band R^13care as defined in Item 89; R^33bis a group of the formula: -A²-B²(in which A²and B²are as defined in Item 58)]

In the compound of the above-mentioned formula (IIIb), the preferable compounds are ones having a stereo structure of the following formula:

In the compounds of the above-mentioned formula (IIIb′), the preferable compounds are ones having a stereo structure of the following formula:

(9) The compound of the following formula (IIIc), or a pharmaceutically acceptable salt thereof.

[wherein R^13a, R^13band R^13care as defined in Item 89; R^33cis a group of the formula: -A²-B²(in which A²and B²are as defined in Item 58)]

In the compounds of the above-mentioned formula (IIIc), the preferable compounds are ones having a stereo structure of the following formula:

In the compounds of the above-mentioned formula (IIIc′), the preferable compounds are ones having a stereo structure of the following formula:

(10) The compounds of the following formula (IIId), or a pharmaceutically acceptable salt thereof.

[wherein R^13a, R^13band R^13care as defined in Item 89]

(11) The compound of the following formula (IVa), or a pharmaceutically acceptable salt thereof.

The definitions in the above formula are as defined in Item 89, and preferable embodiment for each definition is the same ones as defined in the compounds of the formulae (IIIa) and formula (IIIa′).

(12) The compound of the following formula (IVb), or a pharmaceutically acceptable salt thereof.

[wherein R^13aand R^13care as defined in Item 89]

(13) The compound of the following formula (Va), or a pharmaceutically acceptable salt thereof.

[wherein, G¹, G², G³and G⁴are as defined in Item 23]

(14) The compound of the following formula (Vb), or a pharmaceutically acceptable salt thereof.

[wherein G¹³, G²³, G³³, G⁴³are as defined in Item 96, and R^33dis the same as defined in Item 89]

(15) The compound of the following formula (Vc), or a pharmaceutically acceptable salt thereof.

[wherein G¹³, G²³, G³³, and G⁴³are as defined in Item 96, and B is as defined in Item 35]

In the compounds of the formulae (Vb) and (Vc), the preferable compounds are ones wherein G¹³, G²³, G³³, and G⁴³are as defined above; R^33dis a group of the formula: -A³-B³(in which A³is —(CH₂)_s3N(R⁴³)CO—, or —(CH₂)_s3N(R⁴³)CON(H)—; B3 is an optionally substituted C_1-6alkyl group, an optionally substituted C_2-6alkenyl group, an optionally substituted C_6-10aryl group, an optionally substituted C_7-14aralkyl group, or an optionally substituted 5- or 6-membered monocyclic heteroaryl-C_1-4alkyl group); R⁴³is a C_3-6cycloalkyl group; and s3 is 1, or 2.

(18) The compound of the following formula (Vd), or a pharmaceutically acceptable salt thereof.

[wherein R^1d, R^1eand R^1fare as defined in Item 23]

Preferable embodiment for each definition of the above formula (Vd) is the same as one of the embodiments of Items 24 to 30.

(19) The compound of the following formula (Ve), or a pharmaceutically acceptable salt thereof.

[wherein R^1d, R^1e, and R^1fare as defined in Item 23, and B is the same as defined in Item 35]

In the compounds of the formulae (Vd) and (Ve), the preferable compounds are ones wherein R^1dis a C_1-6alkyl group substituted by C_1-6alkoxy; R^1eand R^1fare independently the same or different and each is selected from a hydrogen atom and a C_1-6alkyl group optionally substituted by C_1-6alkoxy.

In the compounds as defined in the above-mentioned (1) to (19), the preferable embodiment for each substituents for “B”, and the preferable embodiment for each substituent for “B2” and “B³” are the same as defined for the preferable embodiment of each substituent of the above “B”.

The preferable compound of the intermediate of the above-mentioned formula (VII) are the following compounds. In addition, in those formulae, the concrete example of R^37a, R^37b, R^37cand R^37dare the same ones as the concrete examples of R^3a, R^3b, R^3cand R^3din the formula (I). The preferable embodiment for each definition for “B⁷” is the same as the preferable embodiment of each definition for “B” and the preferable embodiment for each definition of “B²” and “B³”.

R^37fof the formula (VII) may be a hydrogen atom, a protecting group being able to be removed by hydrogenation, or a protecting group being able to be removed under acidic conditions. The above-mentioned protecting group includes, for example, protecting groups disclosed in “PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, John Willey and Sons, 4th edition”, as far as said protecting group does not affect any harmful effects on the desired compound.

Concrete examples of said protecting groups are, for example, carbamate protecting groups (e.g., C_1-4alkoxycarbonyl group such as t-butoxycarbonyl, etc., benzyloxycarbonyl group, allyloxycarbonyl group, etc.), amide protecting groups (e.g., trifluoroacetyl group, etc.), imide protecting groups (e.g., phthaloyl group, etc.), or sulfonamide protecting groups (e.g., p-toluenesulfonyl group, or 2-nitrobenzenesulfonyl group).

The protecting groups being able to be removed by hydrogenation or under acidic conditions are, for example, in addition to C_1-4alkoxycarbonyl group, benzyloxycarbonyl group, allyloxycarbonyl group, p-toluenesulfonyl group, or nitrobenzenesulfonyl group, a group selected from the following compounds. In the following compounds, R^5aand R^5bare independently the same or different, and each is a hydrogen atom, a nitro group, a C_1-4alkoxy group, or a C_1-4alkylsulfinyl group.

The preferable compound of the intermediate compound (VII) are listed below.

(1) The compound of the following formula (VIa):

or a pharmaceutically acceptable salt thereof.

(2) The compound of the following formula (VIb):

or a pharmaceutically acceptable salt thereof.

(3) The compound of the following formula (VIIc):

or a pharmaceutically acceptable salt thereof.

(4) The compound of the following formula (VId):

or a pharmaceutically acceptable salt thereof.

In addition, the compound of the above-mentioned formula (VII) is preferably ones having the following stereo structure (wherein the symbols are as defined above).

When the bond is expressed by a wedged solid or wedged broken line in the following disclosure, such as the formulae (F2), (F4), (F6), (F7) and (F8), it indicates the absolution configuration of a substituent, when the bond is expressed by a heavy line such as the formulae (F1), (F3), and (F5), then it indicates the relative configuration of a substituent (e.g., the formula (F1) indicates (±)-cis form).

The pharmaceutically acceptable salt includes a salt with an inorganic acid such as hydrochloride, hydrobromide, sulfate, phosphate, nitrate, or a salt with an organic acid such as acetate, propionate, oxalate, succinate, lactate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, or ascorbate, etc.

In addition, the present invention includes the compound of the formula (I) or a prodrug thereof, or a pharmaceutically acceptable salt thereof. Further, the present invention also includes a hydrate thereof or a solvate thereof such as ethanolate. Further, the present invention includes a crystalline form of every embodiment.

The term “prodrug of the compound of the formula (I)” used in the present specification means a compound which is converted into the compound of the formula (I) in the living body by reaction by an enzyme or gastric acid under physiological conditions, namely, a compound which is converted into the compound of the formula (I) by oxidization, reduction, hydrolysis, etc. enzymatically, or by hydrolysis by gastric acid.

The compound of the formula (I) may exist in the form of a tautomer. Accordingly, the present invention also includes a tautomer of the compound of the formula (I).

The compound of the present invention may contain at least one asymmetric carbon atom. Accordingly, the present invention includes not only the racemic mixture of the present compound but also optically active compounds of the present compound. When the compound of the present invention has two or more asymmetric carbon atoms, then steric isomerism may occasionally occur. Accordingly, the present invention also includes these stereoisomers and a mixture thereof.

The compound of the present invention may have an axial isomerism due to rotational hindrance at a phenyl group and a carbonyl group. Because of this axial isomerism, the present invention includes the stereoisomers of the following formulae.

The present compound can be exemplified by the following compounds. In the following Tables, the compounds as expressed, for example, by No. 1 (T1:H;T2:H;T3:H;T4:H;T5:H;T6:Q65;T7:Q211;T8:H;T9:H;T10:Q64) indicates the following compound (free base of Example 1).

[Chemical formula 61]

No.
T¹
T²
T³
T⁴
T⁵
T⁶
T⁷
T⁸
T⁹
T¹⁰

1
H
H
H
H
H
Q65
Q211
H
H
Q64

2
H
H
Q301
H
H
Q65
Q211
H
H
Q64

3
H
H
Q71
H
H
Q65
Q211
H
H
Q64

4
H
H
Q72
H
H
Q65
Q211
H
H
Q64

5
H
H
Q73
H
H
Q65
Q211
H
H
Q64

6
H
H
Q74
H
H
Q65
Q211
H
H
Q64

7
H
H
H
H
H
Q65
Q211
H
H
Q108

8
Q75
H
H
H
H
Q65
Q211
H
Cl
Q64

9
Q76
H
H
H
H
Q65
Q211
H
Cl
Q64

10
Q77
H
H
H
H
Q65
Q211
H
H
Q64

11
Q78
H
H
H
H
Q65
Q211
H
H
Q64

12
Q79
H
H
H
H
Q65
Q211
H
H
Q64

13
Q80
H
H
H
H
Q65
Q211
H
H
Q64

14
Q81
H
H
H
H
Q65
Q211
H
H
Q64

15
H
H
H
H
H
Q189
Q211
H
H
Q64

16
Q83
H
H
H
H
Q65
Q211
H
H
Q64

17
H
Q73
H
H
H
Q65
Q211
H
H
Q64

18
H
H
H
H
H
Q65
Q211
H
H
Q62

19
H
H
H
H
H
Q65
Q211
H
Q109
Q64

20
H
Q85
H
H
H
Q65
Q211
H
H
Q64

21
H
Q86
H
H
H
Q65
Q211
H
H
Q64

22
H
Q84
H
H
H
Q65
Q211
H
H
Q64

23
H
H
H
H
H
Q65
Q211
H
H
Q109

24
H
H
H
H
H
Q65
Q211
H
H
Q110

25
H
H
H
H
H
Q65
Q211
H
H
Q111

26
H
H
H
H
H
Q65
Q211
H
H
Q112

27
H
H
H
H
H
Q65
Q211
H
H
Q63

28
H
H
H
H
H
Q65
Q211
H
H
Q113

[Chemical formula 62]

No.
T¹
T²
T³
T⁴
T⁵
T⁶
T⁷
T⁸
T⁹
T¹⁰

29
H
H
H
H
H
Q65
Q211
H
H
Q114

30
H
Q88
H
H
H
Q65
Q211
H
H
Q64

31
H
Q190
H
H
H
Q65
Q211
H
H
Q64

32
H
Q90
H
H
H
Q65
Q211
H
H
Q64

33
H
Q91
H
H
H
Q65
Q211
H
H
Q64

34
H
H
Q92
H
H
Q65
Q211
H
H
Q64

35
H
Q93
H
H
H
Q65
Q211
H
H
Q64

36
H
Q94
H
H
H
Q65
Q211
H
H
Q64

37
H
Q95
H
H
H
Q65
Q211
H
H
Q64

38
H
Q96
H
H
H
Q65
Q211
H
H
Q64

39
H
Q97
H
H
H
Q65
Q211
H
H
Q64

40
Q98
H
H
H
H
Q65
Q211
H
H
Q64

41
Q99
H
H
H
H
Q65
Q211
H
H
Q64

42
H
H
H
H
H
Q65
Q211
H
Cl
Q64

43
Q100
H
H
H
H
Q65
Q211
H
H
Q64

44
Q101
H
H
H
H
Q65
Q211
H
H
Q64

45
Q102
H
H
H
H
Q65
Q211
H
H
Q64

46
H
Q103
H
H
H
Q65
Q211
H
H
Q64

47
H
Q104
H
H
H
Q65
Q211
H
H
Q64

48
H
Q105
H
H
H
Q65
Q211
H
H
Q64

49
H
H
H
H
H
Q65
Q211
H
H
Q191

50
H
Q106
H
H
H
Q65
Q211
H
H
Q64

51
H
Q107
H
H
H
Q65
Q211
H
H
Q64

[Chemical formula 63]

No.
T¹
T²
T³
T⁴
T⁵
T⁶
T⁷
T⁸
T⁹
T¹⁰

52
Q157
H
H
H
H
Q65
Q211
H
H
Q64

53
Q240
H
H
H
H
Q65
Q211
H
H
Q64

54
Q241
H
H
H
H
Q65
Q211
H
H
Q64

55
H
H
Q242
H
H
Q65
Q211
H
H
Q109

56
H
H
H
H
H
Q65
Q213
H
H
Q64

57
H
H
H
H
H
Q65
Q212
H
H
Q64

58
H
H
H
H
H
Q65
Q214
H
H
Q64

59
H
H
H
H
H
Q65
Q213
H
Br
Q64

60
H
H
H
H
H
Q65
Q217
H
H
Q64

61
H
H
H
H
H
Q65
Q218
H
H
Q64

62
H
H
H
H
H
Q65
Q219
H
H
Q64

63
H
H
H
H
H
Q175
Q211
H
Cl
Q64

64
Q82
H
H
H
H
Q65
Q211
H
Cl
Q64

65
H
H
H
H
H
Q65
Q213
H
Q113
Q64

66
H
H
H
H
H
Q65
Q220
H
H
Q64

67
Q247
H
H
H
H
Q65
Q211
H
H
Q64

68
Q248
H
H
H
H
Q65
Q211
H
H
Q64

69
Q249
H
H
H
H
Q65
Q211
H
H
Q64

70
Q250
H
H
H
H
Q65
Q211
H
H
Q64

71
H
Q105
H
H
H
Q65
Q211
H
Cl
Q64

72
H
H
H
H
H
Q65
Q211
H
H
Q191

73
H
H
H
H
H
Q57
Q211
H
Cl
Q64

74
Q251
H
H
H
H
Q65
Q211
H
H
Q64

75
Q252
H
H
H
H
Q65
Q211
H
H
Q64

76
H
H
H
H
H
Q57
Br
H
H
Q64

77
H
H
H
H
H
Q222
Q211
Q65
Cl
Q64

78
H
H
H
H
H
Q65
Q223
H
Cl
Q64

[Chemical formula 64]

No.
T¹
T²
T³
T⁴
T⁵
T⁶
T⁷
T⁸
T⁹
T¹⁰

79
Q156
H
H
H
H
Q65
Q211
H
Cl
Q64

80
Q116
H
H
H
H
Q65
Q211
H
Me
Q64

81
H
H
H
H
H
Q65
Q213
H
CN
Q64

82
H
H
H
H
H
Q65
H
Q224
H
Q64

83
H
H
H
H
H
Q65
H
Q174
H
Q64

84
H
H
H
H
H
Q65
H
Q227
H
Q64

85
H
H
H
H
H
Q65
H
Q225
H
Q64

86
H
H
H
H
H
Q65
H
Q226
H
Q64

87
H
H
H
H
H
Q65
Q228
H
H
Q64

88
H
H
H
H
H
Q65
Q228
H
H
Q64

89
Q118
H
H
H
H
Q65
Q211
H
H
Q64

90
Q254
H
H
H
H
Q65
Q211
H
H
Q64

91
Q255
H
H
H
H
Q65
Q211
H
H
Q64

92
Q256
H
H
H
H
Q65
Q211
H
H
Q64

93
Q257
H
H
H
H
Q65
Q211
H
H
Q64

94
Q119
H
H
H
H
Q65
Q211
H
H
Q64

95
H
H
H
H
H
Q65
Q229
H
H
Q64

96
H
H
H
H
H
Q65
Q230
H
H
Q64

97
H
H
H
H
H
Q65
Q231
H
H
Q64

98
Q259
H
H
H
H
Q65
Q211
H
H
Q64

99
Q260
H
H
H
H
Q65
Q211
H
H
Q64

100
Q261
H
H
H
H
Q65
Q211
H
H
Q64

101
Q262
H
H
H
H
Q65
Q211
H
H
Q64

102
Q263
H
H
H
H
Q65
Q211
H
H
Q64

103
H
H
H
H
H
Q65
Q232
H
H
Q64

104
H
H
H
H
H
Q65
Q233
H
H
Q64

105
Q264
H
H
H
H
Q65
Q211
H
H
Q64

106
Q265
H
H
H
H
Q65
Q211
H
H
Q64

[Chemical formula 65]

No.
T¹
T²
T³
T⁴
T⁵
T⁶
T⁷
T⁸
T⁹
T¹⁰

107
Q266
H
H
H
H
Q65
Q211
H
H
Q64

108
Q267
H
H
H
H
Q65
Q211
H
H
Q64

109
Q268
H
H
H
H
Q65
Q211
H
H
Q64

110
Q269
H
H
H
H
Q65
Q211
H
H
Q64

111
H
H
H
H
H
Q65
Q234
H
H
Q64

112
H
H
H
H
H
Q65
Q234
H
H
Q64

113
Q120
H
H
H
H
Q65
Q211
H
H
Q64

114
Q270
H
H
H
H
Q65
Q211
H
H
Q64

115
Q271
H
H
H
H
Q65
Q211
H
H
Q64

116
Q272
H
H
H
H
Q65
Q211
H
H
Q64

117
Q273
H
H
H
H
Q65
Q211
H
H
Q64

118
Q274
H
H
H
H
Q65
Q211
H
H
Q64

119
Q275
H
H
H
H
Q65
Q211
H
H
Q64

120
Q276
H
H
H
H
Q65
Q211
H
H
Q64

121
Q121
H
H
H
H
Q65
Q211
H
H
Q64

122
Q122
H
H
H
H
Q65
Q211
H
H
Q64

123
Q277
H
H
H
H
Q65
Q211
H
H
Q64

124
Q278
H
H
H
H
Q65
Q211
H
H
Q64

125
Q279
H
H
H
H
Q65
Q211
H
H
Q64

126
Q199
H
H
H
H
Q65
Q211
H
Cl
Q64

127
Q197
H
H
H
H
Q65
Q211
H
H
Q64

128
Q123
H
H
H
H
Q65
Q211
H
H
Q64

129
Q124
H
H
H
H
Q65
Q211
H
H
Q64

130
Q125
H
H
H
H
Q65
Q211
H
H
Q64

131
Q126
H
H
H
H
Q65
Q211
H
H
Q64

132
Q127
H
H
H
H
Q65
Q211
H
H
Q64

133
H
H
H
H
H
Q65
H
Q132
H
Q64

134
H
H
H
H
H
Q65
H
Q214
H
Q64

[Chemical formula 66]

No.
T¹
T²
T³
T⁴

135
H
Q40
H
H

136
H
Q235
H
H

137
H
Q192
H
H

138
H
Q236
H
H

139
H
Q237
H
H

140
H
Q159
H
H

141
H
Q239
H
H

142
H
Q238
H
H

143
H
H
Q242
H

144
H
H
Q243
H

145
H
H
Q244
H

146
H
H
Q245
H

147
Q128
H
H
H

148
Q129
H
H
H

149
Q130
H
H
H

150
Q165
H
H
H

151
Q136
H
H
H

152
Q137
H
H
H

153
Q138
H
H
H

154
Q139
H
H
H

155
Q66
H
H
H

156
Q67
H
H
H

157
Q140
H
H
H

158
Q142
H
H
H

159
Q143
H
H
H

160
Q144
H
H
H

161
Q145
H
H
H

162
Q146
H
H
H

163
Q156
H
H
H

164
Q160
H
H
H

165
Q161
H
H
H

166
Q162
H
H
H

167
Q163
H
H
H

168
Q164
H
H
H

169
Q166
H
H
H

170
Q167
H
H
H

171
Q168
H
H
H

172
Q169
H
H
H

173
Q155
H
H
H

174
Q156
H
H
H

175
Q84
H
H
H

176
Q117
H
H
H

177
Q280
H
H
H

178
Q85
H
H
H

179
Q86
H
H
H

180
Q75
H
H
H

181
Q76
H
H
H

182
Q55
H
H
H

183
Q53
H
H
H

184
Q196
H
H
H

185
Q51
H
H
H

186
Q52
H
H
H

187
Q54
H
H
H

188
Q40
H
H
H

189
Q45
H
H
H

190
Q82
H
H
H

191
H
Q89
H
H

192
H
Q241
H
H

193
Q246
H
H
H

194
Q253
H
H
H

[Chemical formula 67]

No.
T¹
T²
T³
T⁴
T⁵
T⁶
T⁷
T⁸
T⁹
T¹⁰

195
H
H
H
H
H
Q65
Q209
H
H
Q64

196
H
H
H
H
H
Q65
Q132
H
H
Q64

197
Q82
H
H
H
H
Q60
Q211
H
H
Q64

198
Q173
H
H
H
H
Q208
Q211
H
H
Q64

199
H
H
H
H
H
Q65
Q215
H
H
Q64

200
H
H
H
H
H
Q65
Q210
H
H
Q64

201
H
H
H
H
H
Q65
Q216
H
H
Q64

202
Q162
H
H
H
H
Q59
Q211
H
H
Q64

203
Q161
H
H
H
H
Q60
Q211
H
H
Q64

204
Q160
H
H
H
H
Q208
Q211
H
H
Q64

205
Q164
H
H
H
H
Q59
Q211
H
H
Q64

206
H
H
H
H
H
Q65
Q213
H
Q92
Q64

207
Q142
H
H
H
H
Q60
Q211
H
H
Q64

208
Q143
H
H
H
H
Q59
Q211
H
H
Q64

209
Q137
H
H
H
H
Q60
Q211
H
H
Q64

210
Q138
H
H
H
H
Q208
Q211
H
H
Q64

211
Q139
H
H
H
H
Q60
Q211
H
H
Q64

212
H
H
H
H
H
Q65
Q213
H
Cl
Q64

213
Q143
H
H
H
H
Q60
Q211
H
H
Q64

214
H
H
H
H
H
Q65
Q213
H
CN
Q64

215
H
H
H
H
H
Q65
Q228
H
H
Q64

216
H
H
H
H
H
Q65
Q229
H
H
Q64

217
H
H
H
H
H
Q65
Q230
H
H
Q64

218
H
H
H
H
H
Q65
Q231
H
H
Q64

219
Q146
H
H
H
H
Q59
Q211
H
H
Q64

220
Q116
H
H
H
H
Q60
Q211
H
H
Q64

221
Q118
H
H
H
H
Q208
Q211
H
H
Q64

222
Q119
H
H
H
H
Q60
Q211
H
H
Q64

223
Q120
H
H
H
H
Q60
Q211
H
H
Q64

224
Q121
H
H
H
H
Q208
Q211
H
H
Q64

225
Q122
H
H
H
H
Q59
Q211
H
H
Q64

226
H
H
H
H
H
Q65
H
Q65
H
Q64

[Chemical formula 68]

No.
T¹
T²
T³
T⁴
T⁵
T⁶
T⁷
T⁸
T⁹
T¹⁰

227
H
H
H
H
H
Q65
H
Q209
H
Q64

228
Q123
H
H
H
H
Q60
H
H
H
Q64

229
H
H
H
H
H
Q65
H
Q210
H
Q64

230
H
H
H
H
H
Q65
H
Q211
H
Q64

231
H
H
H
H
H
Q65
H
Q212
H
Q64

232
H
H
H
H
H
Q65
H
Q213
H
Q64

233
Q124
H
H
H
H
Q59
H
H
H
Q64

234
Q125
H
H
H
H
Q60
H
H
H
Q64

235
Q126
H
H
H
H
Q208
H
H
H
Q64

236
Q127
H
H
H
H
Q59
H
H
H
Q64

237
Q128
H
H
H
H
Q60
H
H
H
Q64

238
Q129
H
H
H
H
Q208
H
H
H
Q64

239
H
H
Q242
H
H
Q65
Q211
H
H
H

240
Q130
H
H
H
H
Q59
H
H
H
Q64

241
H
H
Q242
H
H
Q65
Q211
H
H
Q63

242
H
H
Q242
H
H
Q65
Q211
H
H
Q113

243
Q154
H
H
H
H
Q65
Q213
H
H
Q64

244
Q199
H
H
H
H
Q65
Q213
H
H
Q64

245
Q200
H
H
H
H
Q65
Q213
H
H
Q64

246
H
H
H
H
H
Q65
H
H
H
Q64

247
H
H
H
H
H
Q65
Br
H
H
Q64

248
H
H
H
H
H
Q221
Q213
H
Cl
Q64

249
H
H
H
H
H
Q221
Q213
H
Br
Q64

250
H
H
H
H
H
Q222
Q213
H
Cl
Q64

[Chemical formula 69]

No.
T¹
T²
T³
T⁴
T¹¹

251
H
H
H
H
Q181

252
H
H
H
H
Q198

253
H
H
H
H
Q178

254
Q83
H
H
H
Q180

255
H
H
H
H
Q194

256
H
H
H
H
Q186

257
H
H
H
H
Q195

258
H
H
H
H
Q182

259
H
H
H
H
Q184

260
H
H
H
H
Q177

261
H
H
H
H
Q180

262
H
H
H
H
Q185

263
H
H
H
H
Q183

264
H
H
H
H
Q176

265
H
H
H
H
Q201

266
Q120
H
H
H
Q202

267
Q127
H
H
H
Q203

268
H
H
H
H
Q204

269
H
H
H
H
Q203

270
H
H
H
H
Q205

271
Q120
H
H
H
Q206

272
Q128
H
H
H
Q207

273
Q102
H
H
H
Q180

[Chemical formula 70]

No.
T¹
T²
T³
T⁴

274
H
Q1
H
H

275
H
Q2
H
H

276
H
Q3
H
H

277
H
Q4
H
H

278
H
Q5
H
H

279
H
Q6
H
H

280
H
Q7
H
H

281
H
Q8
H
H

282
H
Q9
H
H

283
H
Q10
H
H

284
H
Q11
H
H

285
H
Q12
H
H

286
H
Q13
H
H

287
H
Q14
H
H

288
H
Q15
H
H

289
H
Q16
H
H

290
H
Q17
H
H

291
H
Q18
H
H

292
H
Q19
H
H

293
H
Q20
H
H

294
H
Q21
H
H

295
H
Q22
H
H

296
H
Q23
H
H

297
H
Q24
H
H

298
H
Q25
H
H

299
H
Q26
H
H

300
H
Q35
H
H

301
H
Q36
H
H

302
H
Q37
H
H

303
H
H
Q27
H

304
H
H
Q28
H

305
H
H
Q29
H

306
H
H
Q30
H

307
H
H
Q31
H

308
H
H
Q32
H

309
H
H
Q33
H

310
H
H
Q34
H

311
H
Q39
H
H

312
H
Q38
H
H

313
H
Q41
H
H

314
H
H
H
Q40

315
H
H
H
Q41

316
H
Q42
H
H

317
H
Q43
H
H

318
H
Q44
H
H

319
H
Q45
H
H

320
H
Q46
H
H

321
H
Q47
H
H

322
H
Q48
H
H

323
H
Q49
H
H

324
H
Q50
H
H

325
H
Q51
H
H

326
Q38
H
H
H

327
Q174
H
H
H

328
Q53
H
H
H

329
Q128
Q109
H
H

330
Q128
Q113
H
H

331
Q45
H
H
H

332
Q46
H
H
H

333
Q47
H
H
H

334
Q48
H
H
H

335
Q35
H
H
H

336
Q17
H
H
H

337
Q15
H
H
H

338
Q2
H
H
H

339
Q43
H
H
H

340
Q44
H
H
H

341
Q35
Q2
H
H

342
Q35
Q6
H
H

343
Q35
Q15
H
H

344
Q15
Q35
H
H

345
Q35
H
Q34
H

346
Q15
H
Q33
H

347
Q54
H
Q33
H

348
Q43
H
Q34
H

[Chemical formula 71]

No.
T¹
T²
T³
T⁴

349
H
H
H
Q40

350
H
H
H
Q41

351
H
H
H
Q45

352
H
H
H
Q13

353
H
H
H
Q51

354
H
H
H
Q46

355
H
H
H
Q35

356
H
Q37
H
H

357
H
H
Q27
H

358
H
H
Q28
H

359
H
H
Q29
H

360
H
Q50
H
H

361
H
Q51
H
H

362
Q51
H
H
H

363
Q52
H
H
H

364
Q53
H
H
H

365
Q54
H
H
H

366
Q42
H
H
H

[Chemical formula 72]

No.
T¹
T²
T³
T⁴
T⁵
T⁶
T⁷
T⁸
T⁹
T¹⁰

367
H
Q1
H
H
H
Q56
Q211
H
H
Q64

368
H
Q15
H
H
H
Q57
Q211
H
H
Q62

369
H
Q35
H
H
H
Q58
Q211
H
H
Q62

370
H
Q45
H
H
H
Q59
Q211
H
H
Q62

371
H
Q35
H
H
H
Q60
Q211
H
H
Q62

372
H
Q1
H
H
H
Q61
Q211
H
H
Q62

373
H
Q15
H
H
H
Q65
Q193
H
H
Q63

374
Q35
Q1
H
H
H
Q57
Q211
H
H
Q62

375
Q15
H
H
H
H
Q57
Q211
H
H
Q62

376
H
H
Q34
H
H
Q57
Q211
H
H
Q62

377
H
H
Q27
H
H
Q65
Q193
H
H
Q64

378
H
H
H
H
H
Q57
Q211
H
Cl
Q64

379
H
Q35
H
H
H
Q65
Q211
H
Cl
Q64

[Chemical formula 73]

No.
T¹
T²
T³
T⁴
T¹¹

380
H
Q35
H
H
Q68

381
H
Q1
H
H
Q68

382
Q35
H
H
H
Q68

383
Q15
H
H
H
Q68

384
H
Q35
H
H
Q69

385
Q45
H
H
H
Q69

386
H
Q15
H
H
Q69

387
H
H
Q34
H
Q68

388
H
H
H
Q40
Q68

No.
T¹²

389
Q187

390
Q188

391
Q115

392
Q70

[Chemical formula 74]

No.
T¹
T²
T³
T⁴
T⁵
T⁶
T⁷
T⁸
T⁹
T¹⁰

393
Q104
H
H
H
H
Q65
Q211
H
H
Q64

394
Q105
H
H
H
H
Q65
Q211
H
H
Q64

395
H
H
H
H
H
Q65
Q211
H
H
Q191

396
Q106
H
H
H
H
Q65
Q211
H
H
Q64

397
Q107
H
H
H
H
Q65
Q211
H
H
Q64

398
Q264
H
H
H
H
Q65
Q211
H
Q113
Q64

399
Q265
H
H
H
H
Q65
Q211
H
Q109
Q64

400
Q266
H
H
H
H
Q65
Q211
H
Q131
Q64

401
Q267
H
H
H
H
Q65
Q211
H
Q132
Q64

402
Q269
H
H
H
H
Q65
Q211
H
Q134
Q64

403
Q272
H
H
H
H
Q65
Q211
H
Q218
Q64

404
Q274
H
H
H
H
Q65
Q211
H
Q62
Q64

405
Q279
H
H
H
H
Q65
Q211
H
Q133
Q64

406
Q199
H
H
H
H
Q65
Q211
H
Cl
Q64

407
Q196
H
H
H
H
Q65
Q211
H
H
Q64

408
Q280
H
H
H
H
Q65
Q211
H
Cl
Q64

409
Q129
H
H
H
H
Q65
Q211
H
Cl
Q64

410
Q246
H
H
H
H
Q65
Q211
H
H
Q64

411
Q173
H
H
H
H
Q65
Q211
H
H
Q64

412
Q254
H
H
H
H
Q65
Q211
H
Cl
Q64

413
Q255
H
H
H
H
Q65
Q211
H
Cl
Q64

414
Q256
H
H
H
H
Q65
Q211
H
Cl
Q64

415
Q257
H
H
H
H
Q65
Q211
H
Cl
Q64

416
Q259
H
H
H
H
Q65
Q211
H
Cl
Q64

417
Q260
H
H
H
H
Q65
Q211
H
Cl
Q64

418
Q261
H
H
H
H
Q65
Q211
H
Cl
Q64

419
Q262
H
H
H
H
Q65
Q211
H
Cl
Q64

420
Q268
H
H
H
H
Q65
Q211
H
H
Q64

[Chemical formula 75]

No.
T¹
T²
T³
T⁴
T⁵
T⁶
T⁷
T⁸
T⁹
T¹⁰

421
Q153
H
H
H
H
Q65
Q211
H
H
Q170

422
Q153
H
H
H
H
Q65
Q211
H
H
Q171

423
Q258
H
H
H
H
Q65
Q211
H
H
Q64

424
Q263
H
H
H
H
Q65
Q211
H
Q134
Q64

425
Q128
H
H
H
H
Q65
Q211
H
H
Q172

426
Q265
H
H
H
H
Q65
Q213
H
H
Q64

427
Q266
H
H
H
H
Q65
Q212
H
H
Q64

428
Q271
H
H
H
H
Q65
Q213
H
H
Q64

429
Q274
H
H
H
H
Q65
Q213
H
H
Q64

430
Q154
H
H
H
H
Q65
Q211
H
H
Q64

431
Q141
H
H
H
H
Q65
Q211
H
H
Q64

432
Q200
H
H
H
H
Q65
Q211
H
H
Q64

433
Q281
H
H
H
H
Q65
Q211
H
H
Q64

434
Q282
H
H
H
H
Q65
Q211
H
H
Q64

435
Q38
H
H
H
H
Q65
Q213
H
H
Q64

436
Q283
H
H
H
H
Q65
Q211
H
H
Q64

437
Q284
H
H
H
H
Q65
Q211
H
H
Q64

438
Q285
H
H
H
H
Q65
Q211
H
H
Q64

439
H
H
H
H
H
Q65
H
H
H
Q64

440
H
H
H
Q109
H
Q65
Q211
H
H
Q64

441
H
H
H
H
H
Q65
Q211
Q65
H
Q64

442
H
H
H
H
H
Q65
Br
H
H
Q64

443
H
H
H
H
H
Q65
H
Q209
H
Q64

444
H
H
H
H
H
Q65
H
Q135
H
Q64

445
H
H
H
H
H
Q65
H
Q228
H
Q64

446
H
H
H
H
H
Q65
H
Q229
H
Q64

447
H
H
H
H
H
Q65
H
Q230
H
Q64

448
H
H
H
H
H
Q65
H
Q231
H
Q64

[Chemical formula 76]

No.
T¹
T²
T³
T⁴
T⁵
T⁶
T⁷
T⁸
T⁹
T¹⁰

449
H
H
H
H
H
Q65
H
Q214
H
Q64

450
H
H
H
H
H
Q65
H
Q92
H
Q64

451
H
H
H
H
H
Q65
Q209
H
H
Q64

452
H
H
H
H
H
Q65
Q135
H
H
Q64

453
H
H
H
H
H
Q65
Q215
H
H
Q64

454
H
H
H
H
H
Q65
Q210
H
H
Q64

455
H
H
H
H
H
Q65
Q216
H
H
Q64

456
H
H
H
H
H
Q65
Q213
H
H
Q64

457
H
H
H
H
H
Q65
Q212
H
H
Q64

458
H
H
H
H
H
Q65
Q214
H
H
Q64

459
H
H
H
H
H
Q65
Q213
H
Br
Q64

460
H
H
H
H
H
Q65
Q213
H
Q65
Q64

461
H
H
H
H
H
Q65
Q218
H
H
Q64

462
H
H
H
H
H
Q65
Q219
H
H
Q64

463
H
H
H
H
H
Q175
Q211
H
Cl
Q64

464
H
H
H
H
H
Q175
Q213
H
Q113
Q64

465
H
H
H
H
H
Q65
Q220
H
H
Q64

466
H
H
H
H
H
Q65
Q286
H
H
Q64

467
H
H
H
H
H
Q65
Q213
H
Cl
Q64

468
H
H
H
H
H
Q221
Q211
H
Cl
Q64

469
H
H
H
H
H
Q221
Br
H
H
Q64

470
H
H
H
H
H
Q222
Q211
H
Cl
Q64

471
H
H
H
H
H
Q65
Q223
H
H
Q64

472
H
H
H
H
H
Q65
Q223
H
H
Q64

473
H
Q147
H
H
H
Q65
Q211
H
H
Q64

474
H
Q148
H
H
H
Q65
Q211
H
H
Q64

475
H
Q149
H
H
H
Q65
Q211
H
H
Q64

476
H
Q150
H
H
H
Q65
Q211
H
H
Q64

477
H
Q151
H
H
H
Q65
Q211
H
H
Q64

478
H
Q152
H
H
H
Q65
Q211
H
H
Q64

479
H
Q153
H
H
H
Q65
Q211
H
H
Q64

480
H
Q87
H
H
H
Q65
Q211
H
H
Q64

481
H
Q158
H
H
H
Q65
Q211
H
H
Q64

[Chemical formula 77]

No.
T¹
T²
T³
T⁴
T¹¹

482
H
H
H
H
Q287

483
H
H
H
H
Q288

484
Q265
H
H
H
Q185

485
Q83
H
H
H
Q183

486
Q271
H
H
H
Q177

487
Q266
H
H
H
Q177

488
Q66
H
H
H
Q201

489
H
H
H
H
Q289

490
H
H
H
H
Q180

491
Q266
H
H
H
Q289

492
H
H
H
H
Q290

493
H
H
H
H
Q291

494
H
H
H
H
Q292

495
H
H
H
H
Q179

496
Q253
H
H
H
Q287

497
Q278
H
H
H
Q287

498
Q265
H
H
H
Q287

499
Q265
H
H
H
Q185

500
Q278
H
H
H
Q294

501
Q265
H
H
H
Q295

502
Q278
H
H
H
Q296

503
Q265
H
H
H
Q297

504
Q265
H
H
H
Q298

505
Q265
H
H
H
Q299

506
Q265
H
H
H
Q300

[Chemical formula 78]

No.
T¹
T⁹

507
Q264
Q293

508
Q266
Q193

509
Q133
Q293

Each abbreviation used in the above-mentioned Tables indicates a partial structure selected from the following partial structures.

The process for preparing the compound of the formula (I) of the present invention will be illustrated hereinbelow by Examples, but the present invention should not be construed to be limited thereto. In addition, in order to simplify the description of the present invention, the following abbreviations may be used in the present specification.

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 of the formula (I) may be synthesized from the well-known compound by a combination of the well-known methods, for example, by the following Methods. In addition, the compound of the formula (I) may be synthesized by suitably combining the following Methods due to the kinds of the starting compounds.

Method 1

The compound of the formula (I) or a pharmaceutically acceptable salt thereof may be prepared, for example, by the following method.

[wherein R^1a, R^1b, R^1c, R^3a, R^3b, R^3c, R^3d, R², and n are as defined in the above-mentioned Item 1; R¹¹⁷is a C_1-3alkyl group optionally substituted by fluorine, C_3-6cycloalkyl or C_1-3alkoxy, or a C_3-6cycloalkyl group optionally substituted by fluorine or C_1-3alkoxy; R¹¹⁸is a C_1-2alkyl group; R¹¹⁹is a C-_1-5alkyl group optionally substituted by fluorine, C_3-6cycloalkyl or C_1-3alkoxy, or a C_3-6cycloalkyl group optionally substituted by fluorine or C_1-3alkoxy; R¹²⁰is a fluorine atom or a C_1-3alkoxy group; m₁₀₄is an integer of 0, 1, 2, or 3; X¹is a hydroxy group or a chlorine atom; X²is iodine atom, bromine atom, chlorine atom, methanesulfonyloxy group, trifluoromethanesulfonyloxy group, or p-toluenesulfonyloxy group; Y¹is Cbz, Boc or Alloc]

1) Step 1

When X¹is a hydroxy group, the compound of the formula (1-3) may be synthesized by reacting the compound of the formula (1-1) with the compound of the formula (1-2) in an inert solvent using a condensing agent, and if necessary, in the presence of a base. A phase-transfer catalyst may be used occasionally.

The base may be any conventional ones which are usually used as a base in conventional reactions and is not necessarily defined, and includes, for example, organic bases such as N-methylmorpholine, triethylamine, diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]nona-5-ene, 1,4-diazabicyclo[5.4.0]undec-7-ene, pyridine, dimethylaminopyridine, or picoline, etc., or inorganic bases such as sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, or sodium hydride, etc. The phase-transfer catalyst includes, for example, quaternary ammonium salts such as tetrabutylammonium bromide or benzyltriethylammonium bromide, etc. or crown ethers such as 18-crown-6-ether, etc. The condensing agent may be ones as described in Jikken-Kagaku-Koza (edited by Chemical Society of Japan, Maruzen), vol. 22. For example, phosphoric esters such as diethyl cyanophosphate or diphenylphosphorylazide, etc., carbodiimides such as 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide•hydrochloride, or dicyclohexylcarbodiimide, a combination of a disulfide such as 2,2′-dipyridylsulfide, etc. and a phospine such as triphenylphosphine, a phosphorus halide such as N,N′-bis(2-oxo-3-oxazolidinyl)phosphinic chloride, etc., a combination of an azodicarboxylic diester such as diethylazodicarboxylate, etc., and a phosphine such as triphenylphosphine, etc. or 2-halo-1-lower alkylpyridinium halide such as 2-chloro-1-methylpyridinium iodide, etc. The inert solvent includes, for example, ethers such as tetrahydrofuran, diethyl ether, 1,4-dioxane, or 1,2-dimethoxyethane, etc., hydrocarbons such as hexane, heptane, toluene, benzene, or xylene, etc., halogenated hydrocarbons such as dichloromethane, chloroform, or 1,2-dichloroethane, etc., ketones such as acetone, etc., aprotic solvents such as acetonitrile, N,N′-dimethylformamide, dimethylsulfoxide, or hexamethylenephosphamide, etc., or a mixture of these solvents. The reaction temperature should be suitably selected from the range of about −70° C. to about 80° C.

When X¹is a chlorine atom, the compound of the formula (1-3) may be synthesized by reacting the compound of the formula (1-2) with the compound of the formula (1-1) in an inert solvent, and if necessary, in the presence of a base. The base includes, for example, organic bases such as N-methylmorpholine, triethylamine, diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[5.4.0]undec-7-ene, pyridine, dimethylaminopyridine, or picoline, etc. The base is usually used in an amount of 1 to 20 equivalents to 1 equivalent of the compound of the formula (1-1) wherein X¹is a chlorine atom. The inert solvent includes, for example, halogenated hydrocarbons such as dichloromethane, chloroform, or 1,2-dichloroethane. The reaction temperature should be suitably selected from the range of about −10° C. to about 50° C.

The compound of the formula (1-1) wherein X¹is a chlorine atom may be synthesized by reacting the compound of the formula (1-1) wherein X¹is a hydroxy group with oxalyl chloride or thionyl chloride in an inert solvent in the presence or absence of an additive. The additive includes, for example, dimethylformamide, diethylformamide, etc. The inert solvent includes, for example, halogenated hydrocarbons such as dichloromethane, dichloroethane, or chloroform, etc. The reaction temperature should be suitably selected from the range of about −10° C. to about 50° C. After the reaction is completed, the reaction solution is concentrated under reduced pressure in the presence of a hydrocarbon solvent such as benzene or toluene to give the compound of the formula (1-1) wherein X¹is a hydroxy group.

The compound (1-1) wherein X¹is a hydroxy group may be prepared by using a commercially available reagent or from a well-known compound by a conventional method. For example, the following compounds (1-1a) to (1-1m) may be synthesized by a similar method to the method disclosed in the literature (e.g., WO 06/100036, etc).

Among the compounds (1-1), the compound as defined as “bicyclic condensed ring” may be prepared, for example, by a similar method to the method disclosed in the literatures (e.g., WO 04/028467, Chemical & Pharmaceutical Bulletin 46, 1716 (1998), WO 04/007491, J. Combinatorial Chemistry 8, 469 (2006), etc.). R^3a, R^3b, R^3cand R^3d, that are substituents of the compound (1-3), may be converted into the substituents disclosed in Methods 2 to 18 by a method disclosed in Methods 2 to 18.

2) Step 2

The compound (I) may be synthesized from the compound (1-3) by a similar method to the method disclosed in the literature (e.g., Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.), etc.).

3) Step 3

The compound (1-2) may be synthesized from the compound (1-4) by a similar method to the method disclosed in Method 1, Step 7. In addition, when R²of the compound (1-5) is an optionally substituted aryl group or an optionally substituted heteroaryl group, the compound (1-2) may be prepared from the compound (1-4) by a similar method to the method disclosed in the literature (J. Org. Chem. 71, 6522 (2006), etc.).

4) Step 4

The compound (1-2) may be prepared from the compound (1-4) by a similar method to the method disclosed in the literatures (e.g., 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.). The following procedures are exemplified.

The compound (1-2) can be prepared by reacting a compound selected from the compound (1-8), the compound (1-9), and the compound (1-10) with the compound (1-4) in an inert solvent in the presence or absence of acetic acid by a reductive amination reaction using a boron hydride compound such as sodium triacetoxyborohydride, sodium cyanoborohydride, etc. The inert solvent includes, for example, halogenated hydrocarbons such as dichloromethane, or dichloroethane, etc.; alcohols such as methanol or ethanol, etc.; ether solvents such as tetrahydrofuran, or 1,4-dioxane, or 1,2-dimethoxyethane, etc. The boron hydride compound may be usually used in an amount of 1 to 3 equivalents to 1 equivalent of the compound (1-4). The reaction temperature should be suitably selected from the range of about −10C. to about 40° C.

5) Step 5

The compound (1-2) may be prepared from the compound (1-6) by a similar method to Step 4 of Method 1.

6) Step 6

By a similar method to Step 1 of Method 1, the compound (1-7) may be prepared from the compound (1-1).

7) Step 7

The compound (1-3) is prepared by reacting the compound (1-7) with the compound (1-5) in an inert solvent in the presence of a base. The base includes, for example, alkali metal salts such as sodium hydrogen carbonate, potassium carbonate, or sodium hydroxide, etc.; organic bases such as triethylamine or 1,8-diazabicyclo[5.4.0]-undec-7-ene (DBU), etc.; alkali metal hydrides such as sodium hydride or potassium hydride, etc.; alkali metal alkoxides such as potassium t-butoxide, etc. When X²is a chlorine atom or a bromine atom, an additive such as sodium iodide or potassium iodide, etc. may be used. The inert solvent includes, for example, ether solvents such as tetrahydrofuran or 1,4-dioxane, etc.; aprotic solvents such as dimethylformamide or dimethylsulfoxide, etc.; halogenated hydrocarbons such as dichloromethane or dichloroethane, etc., or a mixture of these solvents. The reaction temperature should be suitably selected from the range of about 0° C. to about 150° C.

Method 2

Among the compounds of the formula (1-4), the compound of the formula (2-3) or a pharmaceutically acceptable salt thereof may be prepared, for example, by the following method.

[wherein Y¹is as defined in the above; Y²is Cbz, Boc or Alloc; R¹⁰⁰is the same as defined for B of the above-mentioned Item 1]

1) Step 1

The compound (2-2) may be prepared from the compound (2-1) by a similar method to ones disclosed in the literatures (e.g., Comprehensive Organic transformation, R C. Laroque, VCH publisher Inc., 1989, etc.). The compound (2-1) may be prepared by a similar method to ones disclosed in the literatures (e.g., WO 05/028467, etc.).

2) Step 2

The compound (2-3) may be prepared from the compound (2-2) in a similar method to ones disclosed in the literatures (e.g., Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.), etc.).

Method 3

Among the compounds of the formula (1-4), the compound of the formula (3-6) or a pharmaceutically acceptable salt thereof may be prepared, for example, by the following method.

[wherein Y¹and Y²are as defined in the above; X³is a chlorine atom or a bromine atom; R¹⁰¹is a C_1-4alkyl group; R¹⁰²is the same as defined for B of the above-mentioned Item 1; R¹⁰³is as defined in R⁴of the above-mentioned Item 1; or R¹⁰²and R¹⁰³may combine each other to form a ring]

1) Step 1

The compound (3-2) may be prepared from the compound (2-1) in a similar method to ones disclosed in the literatures (e.g., Comprehensive Organic transformation, R. C. Laroque, VCH publisher Inc., 1989, etc.). The compound (2-1) may be prepared by a similar method to ones disclosed in the literatures (e.g., WO 05/028467, etc.).

2) Step 2-Step 3

The compound (3-5) may be prepared from the compound (3-2) by a similar method to ones disclosed in the literatures (e.g., Comprehensive Organic transformation, R. C. Laroque, VCH publisher Inc., 1989, etc.).

3) Step 4

The compound (3-6) may be prepared from the compound (3-5) by a similar method disclosed in the literatures (e.g., Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.), etc.).

Method 4

Among the compounds of the formula (1-4), the compound of the formula (4-3) and the compound of the formula (4-6), or a pharmaceutically acceptable salt thereof may be prepared, for example, by the following method.

[wherein Y¹and Y²are as defined in the above; R¹⁰⁴is the same as defined for B of the above-mentioned Item 1; R¹⁰⁵is the same as defined for R⁴of the above-mentioned Item 1; or R¹⁰⁴and R¹⁰⁵may combine each other to form a ring; X⁴is iodine atom, bromine atom, chlorine atom, methanesulfonyloxy group, trifluoromethanesulfonyloxy group, or p-toluenesulfonyloxy group]

1) Step 1

The compound (4-2) may be prepared from the compound (2-1) by a similar method to ones disclosed in the literatures (e.g., Comprehensive Organic transformation, R. C. Laroque, VCH publisher Inc., 1989, etc.). The compound (2-1) may be prepared by a similar method to ones disclosed in the literatures (e.g., WO 05/028467, etc.).

2) Step 2

The compound (4-3) may be prepared from the compound (4-2) by a similar method to ones disclosed in the literatures (e.g. Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.), etc.).

3) Step 3

The compound (4-5) may be prepared from the compound (4-2) by a similar method to ones disclosed in the literatures (e.g., Comprehensive Organic transformation, R. C. Laroque, VCH publisher Inc., 1989, etc.).

4) Step 4

The compound (4-6) may be prepared from the compound (4-5) by a similar method to ones disclosed in the literatures (e.g., Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.), etc.).

Method 5

Among the compounds of the formula (1-4), the compound of the formula (5-4) or a pharmaceutically acceptable salt thereof may be prepared, for example, by the following method.

[wherein Y¹and Y²are as defined in the above; R¹⁰⁶is a C_1-4alkyl group; R¹⁰⁷is the same as defined for B of the above-mentioned Item 1. In addition, the substituent crossing the bond indicates that such a substituent bonds to one of the positions of R^3a, R^3b, R^3c, R^3din Item 36. The same for the following formulae]

1) Step 1

The compound (5-2) may be prepared from the compound (5-1) by a similar method to ones disclosed in the literatures (e.g., Comprehensive Organic transformation, R. C. Laroque, VCH publisher Inc., 1989, etc.). The compound (5-1) may be prepared by a similar method to ones disclosed in the literatures (e.g., WO 97/18813, WO 02/10172, Tetrahedron Letters 46, 7495 (2005), WO 02/02525, etc.).

2) Step 2

The compound (5-3) may be prepared from the compound (5-2) by a similar method to ones disclosed in the literatures (e.g. Comprehensive Organic transformation, R. C. Laroque, VCH publisher Inc., 1989, etc.).

3) Step 3

The compound (5-4) may be prepared from the compound (5-3) by a similar method to ones disclosed in the literatures (e.g., Protective groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.), etc.).

Method 6

Among the compounds of the formula (1-4), the compound of the formula (6-5) or a pharmaceutically acceptable salt thereof may be prepared, for example, by the following method.

[wherein Y¹, Y²and R¹⁰⁶are as defined in the above; R¹⁰⁸is a C_1-4alkyl group; R¹⁰⁹is the same as defined for B of the above-mentioned Item 1]

1) Step 1

The compound (6-1) may be prepared from the compound (5-1) by a similar method to ones disclosed in the literatures (e.g., Comprehensive Organic transformation, R. C. Laroque, VCH publisher Inc., 1989, etc.). The compound (5-1) may be prepared by a similar method to ones disclosed in the literatures (e.g., WO 97/18813, WO 02/10172, Tetrahedron Letters 46, 7495 (2005), WO02/02525, J. Or g. Chem. 70, 6956 (2005), etc.).

2) Step 2

The compound (6-2) may be prepared from the compound (6-1) by a similar method to ones disclosed in the literatures (e.g., Comprehensive Organic transformation, R. C. Laroque, VCH publisher Inc., 1989, J. Org. Chem. 57, 7194 (1992), etc.).

3) Step 3-Step 4

The compound (6-4) may be prepared from the compound (6-2) by a similar method to ones disclosed in the literatures (e.g., Comprehensive Organic transformation, R. C. Laroque, VCH publisher Inc., 1989, etc.).

4) Step 5

The compound (6-5) may be prepared from the compound (6-4) by a similar method to ones disclosed in the literatures (e.g., Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.), etc.).

Method 7

Among the compounds of the formula (1-4), the compound of the formula (7-4), the compound of the formula (7-6), and the compound of the formula (7-8) or a pharmaceutically acceptable salt thereof may be prepared, for example, by the following method.

[wherein R¹⁰⁵, X⁴, Y¹and Y²are as defined in the above; X⁵is a hydroxy group or a chlorine atom; and R¹¹⁰and R¹¹¹are independently the same as B of the above-mentioned Item 1]

1) Step 1

The compound (7-3) may be prepared from the compound (7-1) by a similar method to ones disclosed in the literatures (e.g., Comprehensive Organic transformation, R. C. Laroque, VCH publisher Inc., 1989; Chem. Pharm. Bull. 40, 102 (1992); J. Med. Chem. 26, 507 (1983), etc.). The compound (7-1) may be prepared by a similar method to ones disclosed in the literatures (e.g., WO 05/028467, etc.).

2) Step 2

The compound (7-4) may be prepared from the compound (7-3) by a similar method to ones disclosed in the literatures (e.g., Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.), etc.).

3) Step 3

The compound (7-5) may be prepared from the compound (7-3) by a similar method to ones disclosed in the literatures (e.g., Comprehensive Organic transformation, R. C. Laroque, VCH publisher Inc., 1989, etc.).

4) Step 4

The compound (7-6) may be prepared from the compound (7-5) by a similar method to ones disclosed in the literatures (e.g., Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.), etc.).

5) Step 5

The compound (7-7) may be prepared from the compound (7-1) by a similar method to ones disclosed in the literatures (e.g., Comprehensive Organic transformation, R. C. Laroque, VCH publisher Inc., 1989; J. Org. Chem. 61, 3849 (1996); J. Org. Chem. 68, 4120 (2003); J. Org. Chem. 63, 370 (1998); J. Org. Chem. 70, 2195 (2005), etc.).

6) Step 6

The compound (7-8) may be prepared from the compound (7-7) by a similar method to ones disclosed in the literatures (e.g., Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.), etc.).

Method 8

Among the compounds of the formula (1-4), the compound of the formula (8-4) or a pharmaceutically acceptable salt thereof may be prepared, for example, by the following method.

[wherein R¹⁰¹, Ru¹⁰², R¹⁰³, X³, Y¹and Y²are as defined in the above]

1) Step 1

The compound (8-1) may be prepared from the compound (7-1) by a similar method to ones disclosed in the literatures (e.g., Comprehensive Organic transformation, R. C. Laroque, VCH publisher Inc., 1989; Synthetic Communications 34, 219 (2004); etc.). The compound (7-1) may be prepared by a similar method to ones disclosed in the literatures (e.g., WO 05/028467, etc.).

2) Step 2-Step 3

The compound (8-3) may be prepared from the compound (8-1) by a similar method to ones disclosed in the literatures (e.g., Comprehensive Organic transformation, R. C. Laroque, VCH publisher Inc., 1989, etc.).

3) Step 4

The compound (8-4) may be prepared from the compound (8-3) by a similar method to ones disclosed in the literatures (e.g., Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.), etc.).

Method 9

Among the compounds of the formula (1-4), the compound of the formula (9-4) or a pharmaceutically acceptable salt thereof may be prepared, for example by the following method.

[wherein R¹⁰¹, R¹⁰², R¹⁰³, R¹⁰⁵, X⁴, Y¹and Y²are as defined in the above]

1) Step 1-Step 3

The compound (9-3) may be prepared from the compound (8-1) by a similar method to ones disclosed in the literatures (e.g., Comprehensive Organic transformation, R. C. Laroque, VCH publisher Inc., 1989, etc.).

2) Step 4

The compound (9-4) may be prepared from the compound (9-3) by a similar method to ones disclosed in the literatures (e.g., Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.), etc.).

Method 10

Among the compounds of the formula (1-4), the compound of the formula (10-4) and the compound of the formula (10-6) or a pharmaceutically acceptable salt thereof may be prepared, for example, by the following method.

[wherein R¹⁰², R¹⁰³, R¹⁰⁵, X⁴, Y¹and Y²are as defined in the above]

1) Step 1

The compound (10-2) may be prepared from the compound (7-1) by a similar method to ones disclosed in the literatures (e.g., Tetrahedron: Asymmetry 16, 2599 (2005), etc.). The compound (7-1) may be prepared by a similar method to ones disclosed in the literatures (e.g., WO 05/028467, etc.)

2) Step 2

The compound (10-3) may be prepared from the compound (10-2) by a similar method to ones disclosed in the literatures (e.g., Tetrahedron: Asymmetry 16, 2599 (2005), etc.).

3) Step 3

The compound (10-4) may be prepared from the compound (10-3) by a similar method to ones disclosed in the literatures (e.g., Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.), etc.).

4) Step 4

The compound (10-5) may be prepared from the compound (10-3) by a similar method to ones disclosed in the literatures (e.g., Comprehensive Organic transformation, R. C. Laroque, VCH publisher Inc., 1989, etc.).

5) Step 5

The compound (10-6) may be prepared from the compound (10-5) by a similar method to ones disclosed in the literatures (e.g., Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.), etc.).

Method 11

Among the compounds of the formula (1-4), the compound of the formula (11-3) and the compound of the formula (11-5) or a pharmaceutically acceptable salt thereof may be prepared, for example, by the following method.

[wherein R¹⁰⁴, R¹⁰⁵, X⁴, Y¹and Y²are as defined in the above]

1) Step 1

The compound (11-2) may be prepared from the compound (7-1) by a similar method to ones disclosed in the literatures (e.g., Comprehensive Organic transformation, R. C. Laroque, VCH publisher Inc., 1989; WO 05/095357; WO 05/085275; etc.). The compound (7-1) may be prepared by a similar method to ones disclosed in the literatures (e.g., WO 05/028467, etc.).

2) Step 2

The compound (11-3) may be prepared from the compound (11-2) by a similar method to ones disclosed in the literatures (e.g., Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.), etc.).

3) Step 3

The compound (11-4) may be prepared from the compound (11-2) by a similar method to ones disclosed in the literatures (e.g., Comprehensive Organic transformation, R. C. Laroque, VCH publisher Inc., 1989, etc.).

4) Step 4

The compound (11-5) may be prepared from the compound (11-4) by a similar method to ones disclosed in the literatures (e.g., Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.), etc.).

Method 12

Among the compounds. of the formula (1-4), the compound of the formula (12-3) or a pharmaceutically acceptable salt thereof may be prepared, for example, by the following method.

[wherein R¹⁰⁴, Y¹and Y²are as defined in the above; R¹¹²is the same as defined for R⁴of the above-mentioned Item 1, R¹⁰⁴and R¹¹²may combine each other to form a ring and m_100ais 1 or 2.]

1) Step 1

The compound (12-2) may be prepared from the compound (12-1) by a similar method to ones disclosed in the literatures (e.g., Comprehensive Organic transformation, R. C. Laroque, VCH publisher Inc., 1989, etc.).

2) Step 2

The compound (12-3) may be prepared from the compound (12-2) by a similar method to ones disclosed in the literatures (e.g., Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.), etc.).

Method 13

Among the compounds of the formula (1-4), the compound of the formula (13-4) and the compound of the formula (13-6) or a pharmaceutically acceptable salt thereof may be prepared, for example, by the following method.

[wherein R¹⁰⁵, X⁴, Y¹and Y²are as defined in the above; A¹⁰⁰is —SO₂—, or —CO—; B¹⁰⁰is the same as defined in B of the above-mentioned Item 1; m₁₀₁is an integer of 0 or 1]

1) Step 1-Step 2

The compound (13-3) may be prepared from the compound (13-1) by a similar method to ones disclosed in the literatures (e.g., Comprehensive Organic transformation, R. C. Laroque, VCH publisher Inc., 1989, etc.).

2) Step 3

The compound (13-4) may be prepared from the compound (13-3) by a similar method to ones disclosed in the literatures (e.g., Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.), etc.).

3) Step 4

The compound (13-5) may be prepared from the compound (13-3) by a similar method to ones disclosed in the literatures (e.g., Comprehensive Organic transformation, R. C. Laroque, VCH publisher Inc., 1989, etc.).

4) Step 5

The compound (13-6) may be prepared from the compound (13-5) by a similar method to ones disclosed in the literatures (e.g., Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.), etc.).

Method 14

Among the compounds of the formula (1-4), the compound of the formula (14-2) or a pharmaceutically acceptable salt thereof may be prepared, for example, by the following method.

[wherein R¹⁰⁴, R¹¹², Y¹and Y²are as defined in the above]

1) Step 1

The compound (14-1) may be prepared from the compound (6-1) by a similar method to ones disclosed in the literatures (e.g., Comprehensive Organic transformation, R. C. Laroque, VCH publisher Inc., 1989, etc.).

2) Step 2

The compound (14-2) may be prepared from the compound (14-1) by a similar method to ones disclosed in the literatures (e.g., Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.), etc.).

Method 15

Among the compounds of the formula (1-4), the compound of the formula (15-3) or a pharmaceutically acceptable salt thereof may be prepared, for example, by the following method.

[wherein R¹⁰⁴, R¹¹², R¹⁰⁸, Y¹and Y²are as defined in the above]

1) Step 1-Step 2

The compound (15-2) may be prepared from the compound (6-2) by a similar method to ones disclosed in the literatures (e.g., Comprehensive Organic transformation, R. C. Laroque, VCH publisher Inc., 1989, etc.).

2) Step 3

The compound (15-3) may be prepared from the compound (15-2) by a similar method to ones disclosed in the literatures (e.g., Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.), etc.).

Method 16

Among the compounds of the formula (1-4), the compound of the formula (16-4) and the compound of the formula (16-6) or a pharmaceutically acceptable salt thereof may be prepared, for example, by the following method.

[wherein Y¹and Y²are as defined in the above; m_100bis an integer of 0 to 4; R¹¹³is one of the above-mentioned (a) to (y), provided that in the compound (16-4), R¹¹³is one of the above-mentioned (a) to (s)]

1) Step 1

The compound (16-2) may be prepared from the compound (16-1) by a similar method to ones disclosed in the literatures (e.g., Tetrahedron: Asymmetry 17, 993 (2006), Comprehensive Organic transformation, R. C. Laroque, VCH publisher Inc., 1989, etc.).

2) Step 2

The compound (16-3) may be prepared from the compound (16-2) by a similar method to ones disclosed in the literatures (e.g., Tetrahedron: Asymmetry 8, 3685 (1997); J. Or g. Chem. 61, 6033 (1996); JP-A-8-12605; Comprehensive Organic transformation, R. C. Laroque, VCH publisher Inc., 1989, etc.).

3) Step 3

The compound (16-4) may be prepared from the compound (16-3) by a similar method to ones disclosed in the literatures (e.g., Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.), etc.).

4) Step4

The compound (16-5) may be prepared from the compound (16-3) by a similar method to ones disclosed in the literatures (e.g., Comprehensive Organic transformation, R. C. Laroque, VCH publisher Inc., 1989, etc.).

5) Step 5

The compound (16-6) may be prepared from the compound (16-5) by a similar method to ones disclosed in the literatures (e.g., Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.), etc.).

Method 17

Among the compounds of the formula (1-4), the compound of the formula (17-3) and the compound of the formula (17-5) or a pharmaceutically acceptable salt thereof may be prepared, for example, by the following method.

[wherein R¹⁰⁴, R¹⁰⁵, X⁴, Y¹and Y²are as defined in the above; m₁₀₂is an integer of 0 or 1]

1) Step 1

The compound (17-2) may be prepared from the compound (17-1) by a similar method to ones disclosed in the literatures (e.g., Comprehensive Organic transformation, R. C. Laroque, VCH publisher Inc., 1989; WO05/085275, etc.).

2) Step 2

The compound (17-3) may be prepared from the compound (17-2) by a similar method to ones disclosed in the literatures (e.g., Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.), etc.).

3) Step 3

The compound (17-4) may be prepared from the compound (17-2) by a similar method to ones disclosed in the literatures (e.g., Comprehensive Organic transformation, R. C. Laroque, VCH publisher Inc., 1989, etc.).

4) Step 4

The compound (17-5) may be prepared from the compound (17-4) by a similar method to ones disclosed in the literatures (e.g., Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.), etc.).

Method 18

Among the compounds of the formula (1-4), the compound of the formula (18-5) and the compound of the formula (18-7) or a pharmaceutically acceptable salt thereof may be prepared, for example, by the following method.

[wherein R¹⁰⁵, X⁴, Y¹and Y²are as defined in the above; m₁₀₃is an integer of 0 or 1; R¹¹⁴is the same as defined for B of the above-mentioned Item 1]

1) Step 1

The compound (18-2) may be prepared from the compound (18-1) by a similar method to ones disclosed in the literatures (e.g., Tetrahedron Letters 43, 4275 (2002), etc.).

2) Step 2

The compound (18-4) may be prepared from the compound (18-2) by a similar method to ones disclosed in the literatures (e.g., Comprehensive Organic transformation, R. C. Laroque, VCH publisher Inc., 1989, etc.).

3) Step 3

The compound (18-5) may be prepared from the compound (18-4) by a similar method to ones disclosed in the literatures (e.g., Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.), etc.).

4) Step 4

The compound (18-6) may be prepared from the compound (18-4) by a similar method to ones disclosed in the literatures (e.g., Comprehensive Organic transformation, R. C. Laroque, VCH publisher Inc., 1989, etc.).

5) Step 5

The compound (18-7) may be prepared from the compound (18-6) by a similar method to ones disclosed in the literatures (e.g., Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.), etc.).

Method 19

Among the compounds of the formula (1-4), the compound of the formula (19-13) or a pharmaceutically acceptable salt thereof may be prepared, for example, by the following method.

[wherein R¹¹⁵is the same as defined for B of the above-mentioned Item 1]

1) Step 1-Step 8

The compound (19-11) may be prepared from the compound (19-1) by a similar method to ones disclosed in the literatures (e.g., WO 06/039325, etc.).

2) Step 9-Step 10

The compound (19-13) may be prepared from the compound (19-11) by a similar method to ones disclosed in the literatures (e.g., Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.), etc.).

Method 20

Among the compounds of the formula (1-4), the compound of the formula (20-8) a pharmaceutically acceptable salt thereof may be prepared, for example, by the following method.

[wherein R²is as defined in the above Item 1; R¹¹⁶is an optionally substituted C_6-10aryl group, or an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group.]

1) Step 1-Step 5

The compound (20-7) may be prepared from the compound (20-1) by a similar method to ones disclosed in the literatures (e.g., Bioorganic & Medicinal Chemistry 13, 59 (2005), etc.).

2) Step 6

The compound (20-8) may be prepared from the compound (20-7) by a similar method to ones disclosed in the literatures (e.g., Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.), etc.).

Method 21

Among the compounds of the formula (1-1), the compound of the formula (21-5) or a pharmaceutically acceptable salt thereof may be prepared, for example, by the following method.

[wherein R¹²¹and R¹²²are independently an optionally substituted C_1-6alkyl group, an optionally substituted C_3-10cycloalkyl group, an optionally substituted C_1-6alkoxy group, an optionally substituted C_3-10cycloalkyloxy group, or a halogen atom; R¹²³is a C_1-4alkyl group; R¹²⁴is a hydroxy group, a C_1-4alkoxy group, a C_3-6cycloalkoxy group, a trifluoromethyl group, a trifluoromethoxy group, a carboxyl group, a mono-C_1-6alkyl-carbonylamino group, or a mono-C_1-6alkoxycarbonylamino group; m₁₀₅is an integer of 0 to 4; X⁶is a iodine atom, a bromine atom, a chlorine atom, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, or a p-toluenesulfonyloxy group]

1) Step 1

The compound (21-2) may be prepared from the compound (21-1) by a similar method to ones disclosed in the literatures (e.g., Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.), etc.). The compound (21-1) may be a commercially available reagent or may be prepared by a conventional method from well-known compounds, and the following compounds and the following methods can be exemplified.

[Chemical formula 109]

Literatures

disclosing

methods

WO 06/117653

J. Org. Chem. 26, 3619 (1961)

J.Org.Chem. 26, 3650 (1961)

Yakugaku Zasshi 87, 1070 (1967) and Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.)

Tetrahedron 59, 6363 (2003) and Comprehensive Organic transformation, R. C. Laroque, VCH publisher Inc., 1989

2) Step 2

The compound (21-4) may be prepared from the compound (21-2) by a similar method to Step 7 of Method 1.

3) Step 3

The compound (21-5) may be prepared from the compound (21-4) by a similar method to ones disclosed in the literatures (e.g., Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.), etc.).

Method 22

Among the compounds of the formula (1-4), the compound of formula (22-3) or a pharmaceutically acceptable salt thereof may be prepared, for example, by the following method.

[wherein m_100a, R¹¹², A¹⁰⁰, B¹⁰⁰, Y¹and Y²are as defined in the above]

1) Step 1

The compound (22-2) may be prepared from the compound (22-1) by a similar method to Step 2 of Method 13. The compound (22-1) may be prepared by a similar method to ones disclosed in Method 12.

2) Step 2

The compound (22-3) may be prepared from the compound (22-2) by a similar method to ones disclosed in the literatures (e.g., Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.), etc.).

Method 23

Among the compounds of the formula (1-1), the compound of the formula (23-7) or a pharmaceutically acceptable salt thereof may be prepared, for example, by the following method.

[wherein X³, R^1d, R^1eand R^1fare as defined in the above; R⁴⁰¹is a C_1-6alkyl group; R⁴⁰²is a C_1-2alkyl group]

1) Step 1

The compound (23-3) may be prepared by reacting the compound (23-1) with the compound (23-2) in the presence of a phosphine and a condensing agent in an inert solvent. The phosphine includes, for example, triphenylphosphine, etc., and the inert solvent includes, for example, ethers such as tetrahydrofuran, diethyl ether, 1,4-dioxane, 1,2-dimethoxyethane, etc. The condensing agent includes, for example, azodicarboxylic acid diisopropyl ester, etc. The reaction temperature should be selected from the range of about 0° C. to about 80° C.

2) Step 2

Step 2 may by carried out, for example, by the following method (i. or ii.).

i. The compound (23-4) may be prepared by reacting iron and the compound (23-3) in an inert solvent. The inert solvent includes, for example, water, acetic acid, or alcohols such as methanol, ethanol, 2-propanol, etc., or a mixture of these solvents. The reaction temperature should be selected from the range of about 30° C. to about 100° C.
ii. The compound (23-4) may be prepared by subjecting the compound (23-3) to hydrogenation in the presence of palladium carbon or palladium hydroxide in an inert solvent. The inert solvent includes, for example, alcohols such as methanol, ethanol, 2-propanol, etc. or ethers such as tetrahydrofuran, diethyl ether, 1,4-dioxane, 1,2-dimethoxyethane, etc. The reaction temperature should be selected from the range of about 0° C. to about 50° C.

3) Step 3

The compound (23-6) may be prepared from the compound (23-4) by a similar method to Step 3 of Method 24.

4) Step 4

The compound (23-7) may be prepared from the compound (23-6) by a similar method to Step 2 of Method 3.

Method 24

Among the compounds of the formula (1-1), the compound of the formula (24-6) or a pharmaceutically acceptable salt thereof may be prepared, for example, by the following method.

[wherein X³, R^1d, R^1e, R^1f, R⁴⁰¹and R⁴⁰²are as defined in the above; X⁶is a bromine atom or a iodine atom]

1) Step 1

The compound (24-2) may be prepared by reacting the compound (24-1) with the compound (23-2) in the presence or absence of a crown ether and in the presence of sodium hydride in an inert solvent. The crown ether includes, for example, 15-crown, etc. The inert solvent includes, for example, ethers such as tetrahydrofuran, diethyl ether, 1,4-dioxane, 1,2-dimethoxyethane, etc. The reaction temperature should be selected from the range from about 0° C. to about 50° C.

2) Step 2

The compound (24-3) may be prepared from the compound (24-2) by a similar method to Step 2 of Method 23.

3) Step 3

The compound (24-4) may be prepared by reacting the compound (24-3) with the compound (24-5) in the presence of an inorganic base in an inert solvent. The inorganic base includes, for example, potassium carbonate, sodium hydride, etc. The inert solvent includes, for example, ethers such as tetrahydrofuran, diethyl ether, 1,4-dioxane, 1,2-dimethoxyethane, etc., nitrile solvents such as acetonitrile, propionitrile, etc. The reaction temperature should be selected from the range from about 30° C. to about 100° C.

4) Step 4

The compound (24-5) may be prepared by reacting the compound (24-4) under carbon oxide atmosphere in the presence of methanol or ethanol, an organic base, an auxiliary ligand and palladium acetate in an inert solvent. The auxiliary ligand includes diphenylphosphinopropane, etc. The organic base includes N,N-diisopropylethylamine, etc. The inert solvent includes, for example, acetamide solvents such as dimethylacetamide, etc. The reaction temperature should be selected from the range from about 70° C. to about 150° C.

5) Step 5

The compound (24-6) may be prepared from the compound (24-5) by a similar method to Step 2 of Method 3.

Method 25

Among the compounds of the formula (1-3), the compound of the formula (25-8) or a pharmaceutically acceptable salt thereof may be prepared, for example, by the following method.

[wherein X³, R^1d, n, R⁴⁰¹, Y¹, R^1e, R^1f, R^3a, R^3b, R^3c, R^3dand R²are as defined in the above]

1) Step 1

The compound (25-2) may be prepared, for example, by reacting the compound (25-1) with acetic anhydride in a pyridine solvent. The reaction temperature should be selected from the range from about 10° C. to about 40° C.

2) Step 2

The compound (25-3) may be prepared from the compound (25-2) in a similar manner to Step 1 of Method 1.

3) Step 3

The compound (25-4) may be prepared from the compound (25-3) in a similar manner to Step 1 of Method 1.

4) Step 4

The compound (25-5) may be prepared by reacting the compound (25-4) with a base in the presence or absence of Amberlite (registered trade name) in an inert solvent. The base includes inorganic bases such as sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, sodium hydride, etc. The inert solvent includes, for example, alcohols such as methanol, ethanol, 2-propanol, etc. The reaction temperature should be selected from the range from about 10° C. to about 40° C.

5) Step 5

The compound (25-6) may be prepared from the compound (25-5) in a similar manner to Step 1 of Method 1.

6) Step 6

The compound (25-7) may be prepared from the compound (25-6) in a similar manner to Step 6 of Method 1.

7) Step 7

The compound (25-8) may be prepared from the compound (25-7) in a similar manner to Step 3 of Method 24.

Method 26

The compound of the formula (24-6) or a pharmaceutically acceptable salt thereof may be prepared, for example, by the following method

[wherein X³, R^1d, R^1e, R^1f, R⁴⁰¹and R³⁰⁰are as defined above; X⁷is a bromine atom or a chlorine atom]

1) Step 1

The compound (26-3) may be prepared from the compound (26-1) by a similar method to ones disclosed in the literatures (e.g., Chem. Pharm. Bull. 46, 1716 (1998), etc.).

2) Step 2

The compound (26-4) may be prepared from the compound (26-3) in a similar manner to Step 3 of Method 24.

3) Step 3

The compound (26-6) may be prepared from the compound (26-4) in a similar manner to Step 2 of Method 3.

Method 27

Among the compounds of the formula (1-1), the compound of the formula (27-6) or a pharmaceutically acceptable salt thereof may be prepared, for example, by the following method.

[wherein X³, R^1d, X⁷, R^1e, R^1f, R⁴⁰¹and R³⁰⁰are as defined in the above]

1) Step 1

The compound (27-2) may be prepared from the compound (27-1) by a similar method to ones disclosed in the literatures (e.g., Synth. Commun. 27, 2943 (1997), J. Chem. Soc. Perkin Trans 2, 691 (1988), etc.).

2) Step 2 and Step 3

The compound (27-4) may be prepared from the compound (27-2) by a similar method to ones disclosed in the literatures (e.g., WO 2005/082872, etc.).

3) Step 4

The compound (27-5) may be prepared from the compound (27-4) by a similar method to Step 3 of Method 24.

4) Step 5

The compound (27-6) may be prepared from the compound (27-5) by a similar method to Step 2 of Method 3.

Method 28

Among the compounds of the formula (1-1), the formula (28-6) or a pharmaceutically acceptable salt thereof may be prepared, for example, by the following method.

[wherein X³, R^1d, R^1e, R^1fand R³⁰⁰are as defined in the above; R⁴⁰³is a C_1-6alkyl group; X⁹is a iodine atom, a bromine atom, a chlorine atom, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group or a p-toluenesulfonyloxy group]

1) Step 1

The compound (28-2) may be prepared from the compound (28-1) by a similar method to ones disclosed in the literatures (e.g., J. Am. Chem. Soc. 123, 6989 (2001), J. Or g. Chem. 70, 4360 (2005), Synth. Commun. 29, 591 (1999), etc.).

2) Step 2

The compound (28-3) may be prepared from the compound (28-2) by a similar method to Step 8 of Method 1.

3) Step 3

The compound (28-5) may be prepared from the compound (28-3) by a similar method to ones disclosed in the literatures (e.g., WO 2004/096773, etc.).

4) Step 4

The compound (28-6) may be prepared from the compound (28-5) by a similar method to Step 2 of Method 3.

Method 29

Among the compounds of the formula (1-2), the compound of the formula (29-3) or a salt thereof may be prepared, for example, by the following method.

[wherein R¹¹², m_100aand Y²are as defined in the above; R⁵⁰⁶is the same as B of the above-mentioned Item 1; R⁵⁰⁷is the same as R⁴of the above-mentioned Item 1]

1) Step 1

The compound (29-2) may be prepared from the compound (22-1) by a similar method to ones disclosed in the literatures (e.g., Bioorganic & Medicinal Chemistry Letters 1621, 16 (2006), WO 99/054321, etc.).

2) Step 2

The compound (29-3) may be prepared from the compound (29-2) by a similar method to ones disclosed in the literatures (e.g., Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.), etc.).

Method 30

Among the compounds of the formula (I), the compound of the formula (30-17) or a salt thereof may be prepared, for example, by the following method.

[wherein R^1d, R^1e, R^1fand R²are as defined in the above; R⁶⁰⁰is the same as B of the above-mentioned Item 1; G⁴is CH₂, an oxygen atom, or a sulfur atom]

1) Step 1

The compound (30-2) may be prepared by reacting the compound (30-1) with a base in an inert solvent, followed by reacting the resultant with tert-butyl ethyl malonate. The base includes inorganic bases such as potassium hydride, sodium hydride, etc. The inert solvent includes, for example, aprotic solvents such as N,N′-dimethylformamide, dimethylsulfoxide, hexamethylenephosphoamide, etc. The reaction temperature should be selected from the range from about 10° C. to about 40° C.

2) Step 2

The compound (30-3) may be prepared by reacting the compound (30-2) with trifluoroacetic acid in an inert solvent. The inert solvent includes, for example, halogenated hydrocarbon solvents such as dichloromethane, chloroform, 1,2-dichloroethane, etc. The reaction temperature should be selected from the range from about 10° C. to about 40° C.

3) Step 3

The compound (30-4) may be prepared by subjecting the compound (30-3) to reduction under hydrogen atmosphere in the presence of palladium carbon in an inert solvent. The inert solvent includes, for example, alcohols such as methanol, ethanol, etc. The reaction temperature should be selected from the range from about 1I0C to about 40° C.

4) Step 4

The compound (30-5) may be prepared by reacting the compound (30-4) with di-tert-butyl dicarbonate in an inert solvent. The inert solvent includes, for example, ethers such as dioxane, tetrahydrofuran, etc. The reaction temperature should be selected from the range from about 10° C. to about 40° C.

5) Step 5

The compound (30-6) may be prepared by subjecting the compound (30-5) to reduction under hydrogen atmosphere in the presence of platinum oxide in an inert solvent. The inert solvent includes alcohols such as methanol, ethanol, etc. The reaction temperature should be selected from the range from about 10° C. to about 40° C.

6) Step 6

The compound (30-7) may be prepared by reacting the compound (30-6) with p-methoxybenzyl chloride in an inert solvent in the presence of an inorganic base. The inorganic base includes potassium carbonate, cesium carbonate, etc. The inert solvent includes, for example, aprotic solvents such as N,N′-dimethylformamide, dimethylsulfoxide, hexamethylenephosphoamide, etc. The reaction temperature should be selected from the range from about 10° C. to about 40° C. In addition, in this Step, sodium iodide or potassium iodide may be added.

7) Step 7

The compound (30-8) may be prepared from the compound (30-7) by a similar method to Step 2 of Method 1.

8) Step 8

The compound (30-9) may be prepared from the compound (30-8) by a similar method to Step 4 of Method 1.

9) Step 9

The compound (30-10) may be prepared from the compound (30-9) by a similar method to Step 1 of Method 1.

10) Step 10

The compound (30-11) may be prepared by subjecting the compound (30-10) under hydrogen atmosphere in the presence of palladium carbon in an inert solvent to reduction. The inert solvent includes, for example, alcohols such as methanol, ethanol, etc. The reaction temperature should be selected from the range from about 10° C. to about 40° C.

11) Step 11

The compound (30-12) may be prepared from the compound (30-11) by a similar method to Step 4 of Method 30.

12) Step 12

The compound (30-13) may be prepared from the compound (30-12) by a similar method to Step 2 of Method 3.

13) Step 13

The compound (30-14) may be prepared from the compound (30-13) by carrying out the following reactions (i. to ii.) continuously in an inert solvent. The inert solvent may be, for example, ethers such as dioxane, tetrahydrofuran, etc.

i. the compound (30-13) is reacted with ethyl chloroformate in the presence of triethylamine. The reaction temperature should be selected from the range from about −10° C. to about 20° C.
ii. sodium borohydride is added to the reaction mixture of the above i., and the mixture is reacted. The reaction temperature should be selected from the range from about 0° C. to about 20° C.

14) Step 14

The compound (30-15) may be prepared by subjecting the compound (30-14) to Swern oxidation. For instance, dimethylsulfoxide was added to oxalyl chloride in a halogenated hydrocarbon solvents such as dichloromethane, chloroform, 1,2-dichloroethane, etc., and then, the compound (30-14) is added thereto, and further, diisopropylethylamine is added. The reaction temperature should be selected from the range from about −80° C. to about −30° C.

15) Step 15

The compound (30-16) may be prepared from the compound (30-15) by a similar method to Step 4 of Method 1.

16) Step 16

The compound (30-17) may be prepared from the compound (30-16) by a similar method to Step 2 of Method 1.

Method 31

Among the compounds of the formula (I), the compound of the formula (31-2) or a salt thereof may be prepared, for example, by the following method.

[wherein R⁶⁰⁰, R^1d, R^1e, R^1fand R²are as defined in the above; Z¹⁰⁰is C(O), S(O)₂, C(O)O, or C(O)N(R⁶⁰²); R⁶⁰¹is the same as B of the above-mentioned Item 1; R⁶⁰²is a C_1-6alkyl group; G⁴is CH₂, an oxygen atom, or a sulfur atom, provided that R⁶⁰⁰is the same as R⁴of Item 1]

1) Step 1

The compound (31-1) may be prepared from the compound (30-16) by a similar method to ones disclosed in the literatures (e.g., Comprehensive Organic transformation, R. C. Laroque, VCH publisher Inc., 1989, etc.).

2) Step 2

The compound (31-2) may be prepared from the compound (31-1) by a similar method of Step 2 of Method 1.

Method 32

Among the compounds of the formula (I), the formula (32-9) or a salt thereof may be prepared, for example, by the following method.

[wherein, X¹, Z¹⁰⁰, R⁶⁰⁰, R⁶⁰¹, R^1a, R^1b, R^1cand R²are as defined in the above]

1) Step 1

The compound (32-1) may be prepared from the compound (30-9) by a similar method to Step 1 of Method 1.

2) Step 2

The compound (32-2) may be prepared from the compound (32-1) by a similar method to Step 10 of Method 30.

3) Step 3

The compound (32-3) may be prepared from the compound (32-2) by a similar method to Step 4 of Method 30.

4) Step 4

The compound (32-4) may be prepared from the compound (32-3) by a similar method to Step 2 of Method 3.

5) Step 5

The compound (32-5) may be prepared from the compound (32-4) by a similar method to Step 13 of Method 30.

6) Step 6

The compound (32-6) may be prepared from the compound (32-5) by a similar method to Step 14 of Method 30.

7) Step 7

The compound (32-7) may be prepared from the compound (32-6) by a similar method to Step 4 of Method 1.

8) Step 8

The compound (32-8) may be prepared from the compound (32-7) by a similar method to Step 1 of Method 31.

9) Step 9

The compound (32-9) may be prepared from the compound (32-8) by a similar method to Step 2 of Method 1.

In the above-mentioned each step, when the starting compounds used in each reaction has a reactive group such as a hydroxy group, an amino group or a carboxyl group, then these groups at sites other than the sites to be reacted can be protected by a suitable protecting group prior to the reaction, if necessary, and such protecting groups can be removed after each reaction is complete or after some reactions are done, to give the desired compound. The protecting groups protecting a hydroxy group, an amino group, a carboxyl group, etc. may be any conventional protecting groups usually used in the organic chemistry field, and the introduction and the removal of these protecting groups may be carried out by a conventional method (e.g., the methods disclosed in Protective Groups in Organic Synthesis, T. W. Greene, co-written by G. M. Wuts, 2nd edition, John Wiley & Sons, Inc. (1991)).

For instance, a protecting group for a hydroxy group may be a tert-butyldimethylsilyl group, a methoxymethyl group, a tetrahydropyranyl group, etc. A protecting group for an amino group may be a tert-butyloxycarbonyl group, a benzyloxycarbonyl group, etc. A protecting group for a hydroxy group may be removed by reacting in the presence of an acid such as hydrochloric acid, sulfuric acid, acetic acid, etc. in a solvent such as aqueous methanol, aqueous ethanol, aqueous tetrahydrofuran, etc. In addition, a tert-butyldimethylsilyl group may be removed, for example, in the presence of tetrabutylammonium fluoride in a solvent such as tetrahydrofuran. As for the protecting group for an amino group, tert-butyloxy-carbonyl group may be removed, for example, by reacting in the presence of an acid such as hydrochloric acid, trifluoroacetic acid, etc. in a solvent such as aqueous tetrahydrofuran, methylene chloride, chloroform, aqueous methanol,. etc. A benzyloxycarbonyl group may be removed, for example, by reacting in the presence of an acid such as hydrobromic acid in a solvent such as acetic acid. tert-Butyl ester, ortho ester, acid amide, etc. may be exemplified as a protecting group for a carboxyl group. These protecting groups may be removed, for example, when such a protecting group is a tert-butyl ester, then it can be removed by reacting in the presence of hydrochloric acid in an aqueous solvent. When an ortho ester is used, it can be removed, for example, by treating with an acid in a solvent such as aqueous methanol, aqueous tetrahydrofuran, aqueous 1,2-dimethoxyethane, followed by treatment with an alkali such as sodium hydroxide, etc. When an acid amide is used, then it may be removed, for example, by reacting in the presence of an acid such as hydrochloric acid, sulfuric acid, etc. in a solvent such as water, aqueous methanol, aqueous tetrahydrofuran, etc.

The compound of the formula (I) includes compounds having an optically-active center, and such compounds may be obtained in a mixture of racemic compounds, or in the form of an optically active compound when an optically active starting compound is used. If necessary, the obtained racemic mixture may be resolved physically or chemically by a conventional method into optical enantiomers thereof, or preferably resolved into diastereomers thereof by a reaction using an optically active resolving agent. Diastereomers in a different form may be resolved by a conventional method such as fractional crystallization.

The compound of the present invention may be converted into a salt thereof, for example, by mixing with a pharmaceutically acceptable acid in a solvent such as water, methanol, ethanol, acetone, etc. The pharmaceutically acceptable acid includes, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc. or organic acids such as acetic acid, propionic acid, oxalic acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, maleic acid, fumaric acid, methanesulfonic. acid, p-toluenesulfonic acid, ascorbic acid, etc.

The compound of the present invention may possibly be applied to the treatment of various diseases because of its renin inhibitory activity. The compounds disclosed in the present specification are useful as a therapeutic agent for hypertension. These compounds are also useful in the control of acute and chronic congestive heart failure. These compounds can be expected to be useful in the treatment of primary or secondary pulmonary hypertension, secondary hyperaldosteronism, primary and secondary pulmonary hyperaldosteronism, kidney failure (such as glomerulonephritis, diabetic nephropathy, glomerulosclerosis, primary renal disease, end-stage renal disease, renovascular hypertension), left ventricular failure, diabetic retinopathy, and for the minimization of vascular diseases such as migraine, Raynaud's disease and atherosclerosis process. In addition, these compounds are also useful in the treatment of diseases relating to elevated intraocular pressure such as glaucoma.

When the present compound is used in the treatment, it may be administered orally or parenterally (e.g., intravenously, subcutaneously or intramuscularly, locally, rectally, precutaneously, or transnasally) in the form of a pharmaceutical composition. The composition for oral administration may be, for example, tablets, capsules, pills, granules, powders, solutions, suspensions, etc. The composition for parenteral administration may be, for example, aqueous solutions for injection, or oils, ointments, creams, lotions, aerosols, suppositories, adhesive preparations, etc. These preparations may be prepared by a conventional method, and may additionally contain a nontoxic and nonactive carrier or excipient, that is usually used in the pharmaceutical field.

The dosage may vary depending on each compound, or diseases, ages, body weights, sexes, conditions of each patient, or administration route, etc., and the present compound or a pharmaceutically acceptable salt thereof may usually be administered at a dose of 0.1 to 1000 mg/day, preferably at a dose of 1 to 300 mg/day in an adult (body weight: 50 kg), which is administered once a day or divided into 2 or 3 dosage forms. In addition, the present compound can be administered once in several days to once in several weeks.

Aiming at the enhancement of the pharmacological activity, the present compound may be used in a combination with a medicament such as an antidiabetic agent, a remedy for antidiabetic complications, an antilipedemic agent, a hypotensive agent, an antiobesity agent, a diuretic agent (hereinafter referred to as combined medicine). The administration timing of the present compound and a combined medicine is not necessarily defined, and they can be administered to a subject simultaneously or administered with time-interval.

In addition, the present compound and a combined medicine may be used in the form of a combination drug. The dosage of a combined medicine may be suitably selected based on the dosage thereof which is clinical used. In addition, the mixing ratio of the present compound and a combined medicine may suitably be determined depending on the subject to be administered, administration route, the disease to be treated, the conditions of a patient, and a kind of combination. For example, when the subject to be administered is human, then a combined medicine is used in an amount of 0.01 to 100 parts by weight to one part by weight of the present compound.

The antidiabetic agent includes insulin preparations (e.g., animal insulin preparations extracted from the bovine pancreas or swine pancreas; genetically-engineered human insulin preparations using Escherichia coli or yeast, etc.), insulin sensitizers (e.g., pioglitazone or hydrochloride thereof, troglitazon, rosiglitazone or a maleate thereof, GI-262570, JTT-501, MCC-555, YM-440, KRP-297, CS-011, etc.), α-glucosidase inhibitors (e.g., voglibose, acarbose, miglitol, emiglitate, etc.), biguanide preparations (e.g., metformine, etc.), insulin secretagogues (e.g., sulfonylurea preparations such as tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride, etc.; repaglinide, senaglinide, nateglinide, mitiglinide, etc.), GLP-1, GLP-1 analogues (exenatide, liraglutide, SUN-E7001, AVE010, BIM-51077, CJC1131, etc.), protein tyrosine phosphatase inhibitors (e.g., vanadic acid, etc.), β3 agonists (e.g., GW-427353B, N-5984, etc.), DPPIV inhibitors (e.g., sitagliptin, vildagliptin, saxagliptin, SYR-322, etc.).

The therapeutic agents for diabetic complications include aldose reductase inhibitors (e.g., tolrestat, epalrestat, zenarestat, zopolrestat, minarestat, fidarestat, SK-860, CT-112, etc.), neurotrophic factors (e.g., NGF, NT-3, BDNF, etc.), PKC inhibitors (e.g., LY-333531, etc.), AGE inhibitors (e.g., ALT946, pimagedine, pyratoxatin, N-phenacylthiazolium bromide(ALT766), etc.), active oxygen erasers (e.g., thioctic acid, etc.), cerebral vasodilators (e.g., tiapride, mexiletine, etc.). A antilipidemic agent includes FMG-CoA reductase inhibitors (e.g., pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, itavastatin or sodium salt thereof, etc.), squalene synthetase inhibitors, ACAT inhibitors, etc. The hypotensive agent includes angiotensin-converting enzyme inhibitors (e.g., captopril, enalapril, alacepril, delapril, lisinopril, imidapril, benazepril, cilazapril, temocapril, trandolapril, etc.), angiotensin II antagonists (e.g., olmesartan medoxomil, candesartan cilexetil, losartan, eprosartan, valsartan, telmisartan, irbesartan, tasosartan, etc.), calcium antagonists (e.g., nicardipine hydrochloride, manidipine hydrochloride, nisoldipine, nitrendipine, nilvadipine, amlodipine, etc.), ACE/NEP inhibitors (e.g., omapatrilat, fasidotril, etc.), beta blockers (e.g., atenolol, bisoprolol, betaxolol, metoprolol, etc.), alpha blockers (e.g., urapidil, terazosin, doxazosin, bunazosin, etc.), alpha beta blockers (e.g., amosulalol, arotinolol, labetalol, carvedilol, etc.).

The antiobesity agent includes, for example, central anti-obesity agents (e.g., phentermine, sibutramine, amfepramone, dexamphetamine, Mazindol, SR-141716A, etc.), pancreatic lipase inhibitors (e.g., Orlistat, etc.), peptidic appetite suppressors (e.g., leptin, CNTF (ciliary neurotrophic factor), etc.), cholecystokinin antagonists (e.g., lintitript, FPL-15849, etc.). The diuretic agent includes, for example, xanthine derivatives (e.g., theobromine sodium salicylate, theobromine calcium salicylate. etc.), thiazide preparations (e.g., Ethiazide, cyclopenthiazide, trichloromethiazide, cyclopenthiazide, trichlormethiazide, hydrochlorotiazide, hydroflumethiazide, bentylhydrochlorothiazide, penflutizide, polythiazide, methychlothiazide, etc.), antialdosterone preparations (e.g., spirolactone, triamterene, etc.), carbonate dehydratase inhibitors (e.g., acetazolamide, etc.), chlorbenzenesulfonamide preparations (e.g., chlorthalidone, mefruside, indapamide, etc.), azosemide, isosorbide, ethacrynic acid, Piretanide, bumetanide, furosemide, etc.

The above mentioned combined medicines may be used in a mixture of two or more of these drugs.

When the present compound is used in a combination of a combined medicine, the dosage of these drugs can be lessened within the safe range, in view of the side effects of the drugs. Accordingly, any possible side effect caused by these drugs may safely be inhibited.

Examples

The present invention is illustrated in more detail by Reference Examples, Examples and Experiments, but the present invention should not be construed to be limited thereto. In addition, the compound names used in the following Reference Examples and Examples are not necessarily based on IUPAC nomenclature. Further, in order to simplify the description, some abbreviations may be used, and these abbreviations are as defined in the above-mentioned definitions.

Reference Example 1
Methyl 3-hydroxy-4-methoxybenzoate

3-Hydroxy-4-methoxybenzoic acid (28.8 g) was dissolved in methanol (300 ml), and thereto was added conc. sulfuric acid (1.0 ml), and the mixture was heated under reflux for 18 hours. The reaction mixture was allowed to cool, and concentrated under reduced pressure. To the residue was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (30.9 g) as a white solid.

Reference Example 2
Methyl 4-methoxy-3-(3-methoxypropoxy)benzoate

The compound of Reference Example 1 (19.7 g) was dissolved in acetonitrile (250 ml), and thereto were added potassium carbonate (22.4 g) and 1-bromo-3-methoxypropane (18.5 g), and the mixture was heated under reflux for 6 hours. The reaction mixture was allowed to cool, and concentrated under reduced pressure. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (29.9 g).

Reference Example 3
4-Methoxy-3-(3-methoxypropoxy)carboxylic acid

The compound of Reference Example 2 (29.9 g) was dissolved in methanol, and thereto was added 1N aqueous sodium hydroxide solution (160 ml), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and thereto was added water, and the mixture was extracted with ethyl acetate. To the aqueous layer was added 2N hydrochloric acid, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was crystallized from ethyl acetate to give the title compound (24.6 g) as a white solid.

¹H-NMR (400 MHz, CDCl₃) 7.76(1H, dd, J=2.0, 8.4 Hz, 1H), 7.63(d, J=2.0 Hz, 1H), 6.91(d, J=8.4 Hz, 1H), 4.18(t, J=6.5 Hz, 2H), 3.94(s, 3H). 3.59(t, J=6.2 Hz, 2H), 3.37(s, 3H), 2.17-2.11(m, 2H).

Reference Example 4
4-Methoxy-3-(3-methoxypropoxy)benzoyl chloride

The compound of Reference Example 3 (2.45 g) was dissolved in dichloromethane (10 ml), and thereto was added oxalyl chloride (1.36 ml), and the mixture was stirred at room temperature for 6 hours. The solvent was removed by evaporation, and toluene was added thereto, and the mixture was concentrated under reduced pressure, and this procedure was repeated twice to give the title compound (2.62 g) as a white solid.

Reference Example 5
Benzyl (3R)-3-[(tert-butoxycarbonyl)amino]piperidine-1-carboxylate

(R)-tert-3-Butyl piperidin-3-ylcarbamate (2.00 g) was dissolved in tetrahydrofuran (10 ml), and thereto were added a saturated aqueous sodium hydrogen carbonate solution (10 ml) and benzyl chloroformate (2.21 g), and the mixture was stirred at room temperature for 4 hours. The solvent was removed by evaporation, and water was added to the residue. The mixture was extracted with ethyl acetate, and the organic layer was washed with 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 (developing solvent: hexane/ethyl acetate=5/1 to 5/2) to give the title compound (3.43 g) as a white solid.

¹H-NMR (400MHz, CDCl₃) 7.38-7.28(m, 5H), 5.15(d, J=12.4 Hz, 1H), 5.11(d, J=12.4 Hz, 1H), 4.59(brs, 1H), 3.69(m, 2H), 3.48(m, 1H), 3.37-3.27(m, 2H), 1.85(m, 1H), 1.73-1.67(m, 1H), 1.54(m, 2H), 1.43(s, 9H).

MS (ESI+) 335(M⁺+1, 100%)

Reference Example 6
Benzyl (3R)-3-aminopiperidine-1-carboxylate

The compound of Reference Example 5 (508 mg) was dissolved in dioxane (5 ml), and thereto was added 4N hydrochloric acid/dioxane (5 ml), and the mixture was stirred at room temperature for 3 hours. The solvent was removed by evaporation, and thereto was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (373 mg) as a colorless oily compound.

MS (ESI+) 235 (M⁺+1, 100%)

Reference Example 7
Benzyl (3R)-3-(isopropylamino)piperidine-1-carboxylate

The compound of Reference Example 6 (373 mg) was dissolved in dimethylformamide (4 ml), and thereto were added potassium carbonate (315 mg) and 2-iodopropane (167 μl), and the mixture was stirred at 90° C. for 4 hours. The reaction mixture was allowed to cool, and thereto was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution 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 (developing solvent: chloroform/methanol=20/1) to give the title compound (144 mg) as a colorless oily compound.

¹H-NMR (400 MHz, CDCl₃) 7.38-7.29(m, 5H), 5.13(s, 2H), 4.13-4.01(m, 1H), 3.91-3.88(m, 1H), 2.95-2.92(m, 2H), 2.68(m, 2H), 1.95-1.92(m, 1H), 1.71-1.51(m, 3H), 1.32-1.26(m, 1H), 1.06(brs, 6H).

MS (ESI+) 277 (M+1, 100%).

Reference Example 8
Benzyl (3R)-3-{isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}piperidine-1-carboxylate

The compound of Reference Example 4 (50.9 mg) and the compound of Reference Example 7 (49.5 mg).were dissolved in dichloromethane (2 ml), and thereto was added triethylamine (32.4 μl), and the mixture was stirred at room temperature. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate twice. The combined organic layers were washed with 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 (developing solvent: hexane/ethyl acetate=1/1) to give the title compound (76.9 mg) as a colorless oily compound.

¹H-NMR (400M , CDCl₃) 7.37-7.31(m, 5H), 6.91-6.85(m, 3H), 5.18(d, J=12.4 Hz, 1H), 5.11(d, J=12.4Hz, 1H), 4.20-4.12(m, 4H), 3.96-3.87(m, 1H), 3.87(s, 3H), 3.56(t, J=6.5 Hz, 2H), 3.35(s, 3H), 3.10(brs, 1H), 2.78(brs, 2H), 2.13-2.05(m, 2H), 1.77-1.74(m, 3H), 1.53(m, 1H), 1.26-1.18(m, 6H).

MS (ESI+) 499(M+1, 100%).

Reference Example 9
Benzyl (3S)-3-[(tert-butoxycarbonyl)amino]piperidine-1-carboxylate

The title compound (936 mg) was synthesized in a similar manner to Reference Example 5.

MS (ESI+) 335 (M+1, 100%).

Reference Example 10
Benzyl (3S)-3-aminopiperidine-1-carboxylate hydrochloride

The compound of Reference Example 9 (936 mg) was dissolved in dioxane (3 ml), and thereto was added 4N hydrochloric acid/dioxane (3 ml), and the mixture was stirred at room temperature for 14 hours. The solvent was removed by evaporation, and to the residue was added toluene, and the mixture was concentrated under reduced pressure to give the title compound (750 mg) as a white solid. MS (ESI+) 235 (M+1, 100%).

Reference Example 11
Benzyl (3S)-3-(isopropylamino)piperidine-1-carboxylate

The title compound (15.1 mg) was synthesized in a similar manner to Reference Example 7 except that the compound of Reference Example 10 was used instead of the compound of Reference Example 6 in Reference Example 7.

MS (ESI+) 277 (M+1, 100%).

Reference Example 12
Benzyl (3S)-3-{isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}piperidine-1-carboxylate

The title compound (10.8 mg) was synthesized in a similar manner to Reference Example 8 except that the compound of Reference Example 11 was used instead of the compound of Reference Example 7 in Reference Example 8.

MS (ESI+) 499 (M+1, 100%).

Reference Example 13
Benzyl 3-[(tert-butoxycarbonyl)amino]pyrrolidine-1-carboxylate

The title compound (1.92 g) was synthesized in a similar manner to Reference Example 5.

MS (ESI+) 321 (M+1, 100%).

Reference Example 14
Benzyl 3-aminopyrrolidine-1-carboxylate

The title compound (982 mg) was synthesized in a similar manner to Reference Example 10 except that the compound of Reference Example 13 was used instead of the compound of Reference Example 9 in Reference Example 10.

MS (ESI+) 221 (M+1, 100%).

Reference Example 15
Benzyl 3-(isopropylamino)pyrrolidine-1-carboxylate

The compound of Reference Example 14 (121.5 mg) was dissolved in dichloromethane (2.8 ml), and thereto were added acetone (122 μl) and acetic acid (31.6 μl), and the mixture was stirred at room temperature. Two and half hours thereafter, to the mixture was added sodium triacetoxy brohydride (292 mg), and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium hydrogen sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: chloroform/methanol=30/1 to 20/1) to give the title compound (87.0 mg) as a colorless oily compound.

¹H-NMR (300 MHz, CDCl₃) 7.37-7.28(m, 5H), 5.13(s, 2H), 3.72-3.63(m, 1H), 3.58-3.50(m, 1H), 3.43-3.36(m, 2H), 3.13-3.04(m, 1H), 2.88-2.84(m, 1H), 2.14-204(m, 1H), 1.72-1.63(m, 1H), 1.18(m, 1H), 1.08-1.04(m, 6H).

MS (ESI+) 263 (M+1, 100%).

Reference Example 16
Benzyl 3-{isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}pyrrolidine-1-carboxylate

The title compound (125 mg) was synthesized in a similar manner to Reference Example 8 except that the compound of Reference Example 15 was used instead of the compound of Reference Example 7 in Reference Example 8.

¹H-NMR (300 MHz, CDCl₃) 7.38-7.31(m, 5H), 6.92-6.83(m, 3H), 5.14(s, 2H), 4.12(t, J=6.3 Hz, 2H), 3.96-3.88(m, 3H), 3.81-3.64(m, 2H), 3.56(t, J=6.0 Hz, 2H), 3.47-3.38(m, 1H), 3.35(s, 3H), 2.15-2.06(m, 21), 2.00(m, 1H), 1.70(m, 1H), 1.24(brs, 6H), MS (ESI+) 485 (+1, 100%).

Reference Example 17
Benzyl (2-oxoazepan-3-yl)carbamate

The title compound (3.76 g) was synthesized in a similar manner to Reference Example 5.

¹H-NMR (400 MHz, CDCl₃) 7.36-7.30(m, 5H), 6.17(m, 2H), 5.12(d, J=12.4 Hz, 1H), 5.09(d, J=12.4 Hz, 1H), 4.36-4.32(m, 1H), 3.28-3.23(m, 2H), 2.13-2.10(m, 1H), 2.04-1.99(m, 1H), 1.86-1.74(m, 2H), 1.59-1.52(m, 1H), 1.44-1.37(m, 1H).

MS (ESI+) 263 (M+1, 100%).

Reference Example 18
Benzyl azepan-3-ylcarbamate

The compound of Reference Example 17 (3.76 g) was dissolved in tetrahydrofuran (28 ml), and thereto was added dropwise a 1.0M solution of boron-tetrahydrofuran complex in tetrahydrofuran (35.8 mL) at 0° C., and the mixture was stirred at room temperature for 4 hours. To the reaction mixture was added 3N hydrochloric acid, and the mixture was heated under reflux for 2 hours. The solvent was removed by evaporation, and thereto was added ethyl acetate, and the mixture was separated. To the organic layer was added 3N hydrochloric acid and the mixture was separated. To the combined aqueous layers were added 2N aqueous sodium hydroxide solution so that the pH value thereof was adjusted to around pH 11. This solution was extracted with chloroform three times, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (2.44 g) as a white solid.

¹H-NMR (400 MHz, CDCl₃) 7.37-7.30(m, 5H), 5.42(m, 1H), 5.09(s, 2H), 3.81(brs, 1H), 2.94-2.87(m, 2H), 2.84-2.81(m, 2H), 1.78-1.53(m, 7H).

MS (ESI+) 249 (M+1, 100%).

Reference Example 19
tert-Butyl 3-{[(benzyloxy)carbonyl]amino}azepane-1-carboxylate

The compound of Reference Example 18 (2.44 g) was dissolved in tetrahydrofuran (20 ml) and a saturated aqueous sodium hydrogen carbonate solution (20 ml), and thereto was added di-tert-butyl dicarbonate (2.36 g). The mixture was stirred at room temperature for 15 hours. The solvent was removed by evaporation, and water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with 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 (developing solvent: hexane/ethyl acetate=5 to 5/2) to give the title compound (2.54 g) as a colorless oily compound.

MS (ESI+) 349 (M+1, 100%).

Reference Example 20
tert-Butyl 3-aminoazepane-1-carboxylate

The compound of Reference Example 19 (2.54 g) was dissolved in methanol (20 ml), and thereto was added 10% palladium carbon (508 mg), and the mixture was stirred at room temperature for 4 hours under hydrogen atmosphere. The mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give the title compound (1.55 g) as a colorless oil.

MS (ESI+) 215 (M+1, 100%).

Reference Example 21
tert-Butyl 3-(isopropylamino)azepane-1-carboxylate

The title compound (384 mg) was synthesized in a similar manner to Reference Example 15 except that the compound of Reference Example 20 was used instead of the compound of Reference Example 14 in Reference Example 15.

MS (ESI+) 215 (M+1, 100%).

Reference Example 22
Benzyl 3-{isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}azepane-1-carboxylate

The title compound (636 mg) was synthesized in a similar manner to Reference Example 8 except that the compound of Reference Example 21 was used instead of the compound of Reference Example 7 in Reference Example 8.

¹H-NMR (400 MHz, CDCl₃) 6.95-6.86(m, 3H), 4.14(t, J=6.7 Hz, 2H), 3.93-3.92(m, 1H), 3.90(s, 3H), 3.87-3.76(m, 2H), 3.59-3.56(t, J=6.2 Hz, 2H), 3.47-3.45(m, 1H), 3.36-3.35(m, 1H), 3.35(s, 3H), 3.02(brs, 1H), 2.31-2.25(m, 1H), 2.16-2.09(m, 5H), 2.01-1.98(m, 1H), 1.85-1.82(m, 1H), 1.60-1.56(m, 1H), 1.25(d, J=6.6 Hz, 1.16(d, J=6.6 Hz, 3H).

MS (ESI+) 479 (M+1, 100%).

Reference Example 23
Ethyl 1-benzyl-3-(isopropylamino)piperidine-4-carboxylate

The title compound (3.39 g) was synthesized as a crude product in a similar manner to Reference Example 15.

MS (ESI+) 305 (M+1, 100%).

Reference Example 24
Ethyl 1-benzyl-3-{isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}-piperidine-4-carboxylate

The title compound (1.10 g) was synthesized as a crude product in a similar manner to Reference Example 8 except that the compound of Reference Example 23 was used instead of the compound of Reference Example 4 in Reference Example 8.

MS (ESI+) 527 (M+1, 100%).

Reference Example 25
Ethyl 3-{isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}piperidine-4-carboxylate

The title compound (1.0 g) was obtained as a crude product in a similar manner to Reference Example 20 except that the compound of Reference Example 24 was used instead of the compound of Reference Example 19 in Reference Example 20.

MS (ESI+) 437 (M+1, 100%).

Reference Example 26
1-tert-Butyl 4-ethyl 3-{isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}-piperidine-1,4-dicarboxylate

The title compound (254 mg) was synthesized in a similar manner to Reference Example 19 except that the compound of Reference Example 25 was used instead of the compound of Reference Example 18 in Reference Example 19.

¹H-NMR (400 MHz, CDCl₃) 6.92-6.83(m, 3H), 4.17-3.84(m, 9H), 3.88(s, 3H), 3.56(t, J=6.1 Hz, 2H), 3.34(s, 3H), 3.17(brs, 1H), 2.85-2.79(m, 1H), 2.14-2.07(m, 2H), 194-1.88(m, 1H), 1.67(brs, 1H), 1.47(s, 9H), 1.28-1.08(m, 9H).

MS (ESI+) 537 (M+1, 100%).

Reference Example 27
1-(tert-Butoxycarbonyl)-3-{isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]-amino}piperidine-4-carboxylic acid

The compound of Reference example 2b (241 mg) was dissolved in tetrahydrofuran (2 ml) and ethanol (1 ml), and thereto was added a 10% aqueous sodium hydroxide solution (1 ml) at room temperature, and the mixture was stirred at 80° C. for 5 hours. The reaction mixture was allowed to cool, and thereto was added a 5% aqueous potassium hydrogen sulfate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (239 mg).

MS (ESI+) 509 (M+1, 100%).

Reference Example 28
tert-Butyl 4-(hydroxymethyl)-3-{isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]-amino}piperidine-1-carboxylate

The compound of Reference Example 27 (211 mg) was dissolved in tetrahydrofuran (2 ml), and thereto were added at 0° C. triethylamine (231 μl) and ethyl chloroformate (119 μl), and the mixture was stirred. One hour thereafter, water (1 ml) and sodium borohydride (82.4 mg) were added to the mixture, and the mixture was stirred at room temperature for 4 hours. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with 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 (developing solvent: hexane/ethyl acetate=1 to 1/3) to give the title compound (135 mg) as a colorless oily compound.

MS (ESI+) 495 (M+1, 100%).

Reference Example 29
tert-Butyl 3-{isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}-4-{[(3-methoxybenzyl)oxy]methyl}piperidine-1-carboxylate

The compound of Reference Example 28 (40.3 mg) was dissolved in dimethylformamide (1.5 ml), and thereto was added sodium hydride (9.8 mg) at 0° C., and the mixture was stirred for 10 minutes. To the mixture were added tetrabutylammonium iodide (3.0 mg) and 3-methoxybenzyl chloride (35.5 μl), and the mixture was stirred at room temperature for 6 hours. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. 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 (developing solvent: hexane/ethyl acetate=1) to give the title compound (14.1 mg) as a colorless oily compound.

¹H-NMR (400 MHz, CDCl₃) 7.25-7.22(m, 1H), 6.89-6.81(m, 6H), 4.49(d, J=12.0 Hz, 1H), 4.42(d, J=12.0 Hz, 1H), 4.13-4.04(m, 5H), 3.88(s, 3F), 3.77(s, 3H), 3.56(t, J=6.1 Hz, 2H), 3.46-3.42(m, 2H), 3.35(s, 3H), 3.25(brs, 1H), 3.03-2.84(m, 2H), 2.13-2.05(m, 2H), 1.85(d, J=13.3 Hz, 1H), 1.66-1.51(m, 2H), 1.46(s, 91), 1.19-1.14(m, 6H).

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

Reference Example 30
Benzyl 1-[(tert-butoxycarbonyl)amino]-5-(fluoromethyl)-3-azabicyclo[3.1.1]heptan-3-carboxylate

The title compound (479 mg) was synthesized in a similar manner to Reference Example 5.

¹H-NMR (400 MHz, CDCl₃) 7.39-7.30(m, 5H), 5.17(s, 2H), 4.70(brs, 1H), 4.37(d, J=2.8 Hz, 1H), 4.25(d, J=2.8 Hz, 1H), 3.64(d, J=5.9 Hz, 2H), 3.46(d, J=2.0 Hz, 2H), 2.21-2.14(m, 2H), 1.87-1.81(m, 2H), 1.42(s, 9H).

MS (ESI+) 379(M+1, 100%).

Reference Example 31
Benzyl 1-amino-5-(fluoromethyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate

The title compound (370 mg) was synthesized in a similar manner to Reference Example 6 except that the compound of Reference Example 30 was used instead of the compound of Reference Example 6.

MS (ESI+) 279 (M+1, 100%).

Reference Example 32
Benzyl 1-(fluoromethyl)-5-(isopropylamino)-3-azabicyclo[3.1.1]heptane-3-carboxylate

The title compound (351 mg) was synthesized in a similar manner to Reference Example 15 except that the compound of Reference Example 31 was used instead of the compound of Reference Example 14 in Reference Example 15.

¹H-NMR (400MHz, CDCl₃) 7.38-7.32(m, 5H), 5.17(s, 2H), 4.34(d, J=6.1 Hz, 1H), 4.22(d, J=6.1 Hz, 1H), 3.55(d, J=10.2 Hz, 2H), 3.45(brs, 2H), 3.06-2.98(m, 1H), 1.85-1.68(m, 4H), 1.25-1.21(m, 1H), 1.05(d, J=6.3 Hz, 3H), 1.04(d, J=6.3 Hz, 3H).

MS (ESI+) 321 (M+1, 100%).

Reference Example 33
Benzyl 1-(fluoromethyl)-5-{isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]-amino}-3-azabicyclo[3.1.1]heptane-3-carboxylate

The title compound (43.0 mg) was synthesized in a similar manner to Reference Example 8 except that the compound of Reference Example 32 was used instead of the compound of Reference Example 7 in Reference Example 8.

¹H-NMR (400MHz, CDCl₃) 7.41-7.34(m, 5H), 6.91(m, 1H), 6.89-6.86(m, 1H), 6.82-6.80(m, 1H), 5.18(d, J=15.2 Hz, 2H), 4.28(d, J=14.6 Hz, 1H), 4.19-4.09(m, 3H), 3.93-3.86(m, 1H), 3.87(s 3H), 3.60-3.53(m, 2H), 3.38-3.34(m, 2H), 3.36(s, 3H), 2.14-2.02(m, 4H), 1.83-1.74(m, 1H), 1.42(d, J=6.8 Hz, 31), 1.38(d, J=6.8 Hz, 3H).

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

Reference Example 34
tert-Butyl (3R)-3-{[(benzyloxy)carbonyl]amino}piperidine-1-carboxylate

The title compound (4.69 g) was synthesized in a similar manner to Reference Example 19.

MS (ESI+) 335 (M⁺+1, 100%).

Reference Example 35
tert-Butyl (3R)-3-aminopiperidine-1-carboxylate

The title compound (2.62 g) was synthesized in a similar manner to Reference Example 20 except that the compound of Reference Example 34 was used instead of the compound of Reference Example 19 in Reference Example 20.

MS (ESI+) 201 (M⁺+1, 100%).

Reference Example 36
tert-Butyl (3R)-3-[(4-chlorophenyl)amino]piperidine-1-carboxylate

The compound of Reference Example 35 (198 mg) was dissolved in toluene (2 ml), and thereto were added 4-bromochlorobenzene (158 mg), tris(dibenzylidene-acetone)dipalladium (90.4 mg), sodium tert-butoxide (133 mg) and 2-dicyclohexyl-phosphino-2′-(N,N-dimethylamino)biphenyl (48.5 mg), and the mixture was stirred at 100° C. for 2 hours. The reaction mixture was allowed to cool, and thereto was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with 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 (developing solvent:hexane/ethyl acetate=6 to 5) to give the title compound (196 mg) as a brown solid.

¹H-NMR (400 MHz, CDCl₃) 7.21-7.18(m, 2H), 6.87-6.84(m, 2H), 4.62(d, J=14.4 Hz, 1H), 4.45(d, J=14.4 Hz, 1H), 3.80(s, 31H), 3.66(s, 3H), 3.44-3.38(m, 2H), 2.83-2.73(m, 1H), 2.62-2.55(m, 1H), 2.50-2.41(m, 1H), 2.16-2.11(m, 1H), 2.04-1.95(m, 6H).

MS (ESI+) 311 (M⁺+1, 100%).

Reference Example 37
tert-Butyl (3R)-3-{(4-chlorophenyl)[4-methoxy-3-(3-methoxypropoxy)benzoyl]-amino}piperidine-1-carboxylate

The title compound (17.0 mg) was synthesized in a similar manner to Reference Example 8 except that the compound of Reference Example 36 was used instead of the compound of Reference Example 7 in Reference Example 8.

¹H-NMR (400 MHz, CDCl₃) 7.12-7.09(m, 2H), 6.57-6.53(m, 2H), 3.94(brs, 1H), 3.71-3.65(m, 2H), 3.36-3.31(m, 1H), 3.10(m, 1H), 2.90(brs, 1H), 1.99-1.96(m, 1H), 1.76-1.70(m, 1H), 1.60-1.49(m, 2H), 1.45(s, 9H).

MS (ESI+) 534(M+1, 100%).

Reference Example 38
Methyl 1-(4-methoxybenzyl)-6-oxo-1,4,5,6-tetrahydropyridine-3-carboxylate

Methyl propiolate (18.6 g) was dissolved in diethyl ether (180 ml), and thereto was added dropwise a solution of 4-methoxybenzylamine (27.0 g) in diethyl ether (50 ml) at 0° C. The mixture was stirred at room temperature for 15.5 hours, and the solvent was removed by evaporation. To the obtained residue was added tetrahydrofuran (1.3 L). To the mixture was added acrylic chloride (19.6 g) at room temperature, and the mixture was heated under refluxe for 12 hours. The solvent was removed by evaporation, and to the resultant was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with diethyl ether three times. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=3) to give the title compound (27.7 g) as yellow oily compound.

¹-NMR (400 MHz, CDCl₃) 7.28(s, 1H), 7.21-7.18(m, 2H), 6.88-6.85(m, 2H), 4.67(s, 2H), 3.79(s, 3H), 3.72(s, 3H), 2.62(s, 4H).

MS (ESI+) 276 (M+1, 100%).

Reference Example 39
Methyl 1-(4-methoxybenzyl)-6-oxopiperidine-3-carboxylate

The compound of Reference Example 38 (27.7 g) was dissolved in ethanol (500 ml), and thereto were added sodium carbonate (32.0 g) and a 10% palladium carbon (13.8 g), and the mixture was stirred at room temperature for 4 hours under hydrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=2 to 1) to give the title compound (23.9 g) as a colorless oily compound.

¹H-NMR (400 MHz, CDCl₃) 7.21-7.18(m, 2H), 6.87-6.84(m, 2H), 4.62(d, J=14.4 Hz, 1H), 4.45(d, J=14.4 Hz, 1H), 3.80(s, 3H), 3.66(s, 3H), 3.44-3.38(m, 2H), 2.83-2.73(m, 1H), 2.62-2.55(m, 1H), 2.50-2.41(m, 1H), 2.16-2.11(m, 1H), 2.04-1.95(m, 6H).

MS (ESI+) 278 (M+1, 100%).

Reference Example 40
1-(4-Methoxybenzyl)-6-oxopiperidine-3-carboxylic acid

The compound of Reference Example 39 (23.9 g) was dissolved in tetrahydrofuran (100 ml) and water (400 ml), and thereto was added sodium hydroxide (6.90 g), and the mixture was stirred at room temperature for 8 hours. To the reaction mixture was added conc. hydrochloric acid, so that the pH value thereof was adjusted to pH 3 or below. The mixture was extracted with cycloform three times. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (21.2 g) as a white solid. MS (ESI+) 264 (M+1, 100%).

Reference Example 41
tert-Butyl [1-(4-methoxybenzyl)-6-oxopiperidin-3-yl]carbamate

The compound of Reference Example 40 (23.9 g) was dissolved in toluene (100 ml), and thereto was added triethylamine (19.6 g), and the mixture was stirred at 80° C. To the mixture was added dropwise a solution of phenyl phosporylazide (26.6 g) in toluene (100 ml), and the mixture was stirred for 3 hours. To the mixture were added tert-butanol (180 ml) and potassium tert-butoxide (13.6 g) at 50° C., and the mixture was stirred for 3 hours. The reaction mixture was allowed to cool, and water was added thereto. The mixture was extracted with ethyl acetate, and 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 (developing solvent: hexane/ethyl acetate=1 to 1/3) to give the title compound (15.4 g) as a white solid.

¹H-NMR (400 MHz, CDCl₃) 6.97-6.94(m, 2H), 6.87-6.85(m, 1H), 4.15-4.10(m, 3H), 3.89(s, 3H), 3.59-3.47(m, 4H), 3.35(s, 3H), 3.35-3.27(m, 2H), 3.08(m, 1H), 2.74(m, 1H), 2.15-2.00(m, 3H), 1.69(m, 2H), 1.46(s, 9H), 1.26-1.17(m, 6H).

MS (ESI+) 335 (M+1, 100%).

Reference Example 42
tert-Butyl [1-(4-methoxybenzyl)-6-thioxopiperidin-3-yl]carbamate

The compound of Reference Example 41 (7.35 g) was dissolved in tetrahydrofuran (55 ml), and thereto was added a Lawesson's reagent (4.45 g) at room temperature, and the mixture was stirred for 4 hours. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate twice. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=4 to 1) to give the title compound (7.25 g) as a white solid.

¹H-NMR (400 MHz, CDCl₃) 7.30-7.28(m, 2H), 6.88-6.85(m, 2H), 5.45(d, J=13.6 Hz, 1H), 4.99(d, J=13.6 Hz, 1H), 4.46(brs, 1H), 3.99-3.97(m, 1H), 3.80(m, 3H), 3.55(dd, J=4.8, 13.5 Hz, 1H), 3.25-3.18(m, 1H), 3.09-3.01(m, 1H), 2.06-1.99(m, 1H), 1.68-1.59(m, 1H), 1.39(s, 9H).

MS (ESI+) 351 (M+1, 100%).

Reference Example 43
Ethyl (2E)-[5-[(tert-butoxycarbonyl)amino]-1-(4-methoxybenzyl)piperidin-2-ylidene]-acetate

The compound of Reference Example 42 (6.40 g) was dissolved in acetonitrile (18 ml), and thereto was added ethyl bromoacetate (2.43 ml) at room temperature and the mixture was stirred for 24 hours. To the reaction mixture were added dichloromethane (36 ml), triphenylphosphine (5.75 g) and triethylamine (3.82 ml), and the mixture was stirred for 24 hours. Water was added to the reaction mixture, and extracted with ethyl acetate three times. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=5 to 3/2) to give the title compound (3.07 g) as a white solid.

¹H-NMR (400 Hz, CDCl₃) 7.10(d, J=8.7 Hz, 1H), 6.88-6.86(m, 1H), 4.79(s, 1H), 4.54(m, 1H), 4.36(d, J=15.8 Hz, 1H), 4.27(d, J=15.8 Hz, 1H), 4.04(q, J=7.1 Hz, 2H), 3.93(brs, 1H), 3.80(s, 3H), 3.58-3.50(m, 1H), 3.47-3.43(m, 1H), 3.08-2.94(m, 2H), 2.07-2.01(m, 1H), 1.58-1.51(m, 1H), 1.41(s, 9H), 1.21(t, J=7.1 Hz, 3H).

MS (ESI+) 405 (M+1, 100%).

Reference Example 44
Ethyl [(rac.)-(2S,5R)-5-[(tert-butoxycarbonyl)amino]-1-(4-methoxybenzyl)piperidin-2-yl]acetate and ethyl [(rac.)-(2R,5R)-5-[(tert-butoxycarbonyl)amino]-1-(4-methoxy-benzyl)piperidin-2-yl]acetate

The compound of Reference Example 43 (3.07 g) was dissolved in dichloromethane (75 ml), and thereto were added trifluoroacetic acid (1.69 ml) and sodium cyanoborohydride (715 mg) at 0° C., and the mixture was stirred for 3 hours. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with 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 (developing solvent: hexane/ethyl acetate=7/2 to 2) to give the title compound A (1.48 g) and B (1.51 g) as a colorless oily compound, respectively.

¹H-NMR (400 MHz, CDCl₃) 7.20(d, J=8.5 Hz, 2H), 6.88-6.85(m, 2H), 4.85(brs, 1H), 4.12(q, J=7.1 Hz, 2H), 3.80(s, 3H), 3.66(brs, 1H), 3.58(d, J=13.1 Hz, 1H), 3.41(d, J=13.1 Hz, 1H), 3.06(brs, 1H), 2.71(brd, J=10.7 Hz, 1H), 2.65(dd, J=3.7, 14.6 Hz, 1H), 2.43(dd, J=8.6, 14.6 Hz, 1H), 2.06(brs, 1H), 1.88-1.78(m, 1H), 1.55-1.48(m, 1H), 1.41(s, 9H), 1.24(t, J=7.1 Hz, 3H).

MS (ESI+) 407 (M+1, 100%).

¹H-NMR (400 MHz, CDCl₃) 7.18(d, J=8.6 Hz, 2H), 6.86-6.84(m, 2H), 4.85(brs, 1H), 4.13(q, J=7.1 Hz, 2H), 3.80(s, 3H), 3.77(d, J=13.2 Hz, 1H), 3.68(brs, 1H), 3.26(d, J=13.2 Hz, 1H), 2.89(brs, 1H), 2.68(dd, J=4.9, 14.7 Hz, 1H), 2.50-2.34(m, 2H), 2.43(dd, J=7.0, 14.7 Hz, 1H), 1.69-1.63(m, 4H), 1.41(s, 9H), 1.25(t, J=7.1 Hz, 3H).

MS (ESI+) 407 (M+1, 100%).

Reference Example 45
Ethyl [(rac.)-(2S,5R)-5-amino-1-(4-methoxybenzyl)piperidin-2-yl]acetate

The title compound (1.23 g) was synthesized in a similar manner to Reference Example 6 except that the compound A of Reference Example 44 was used instead of the compound of Reference Example 5 in Reference Example 6.

MS (ESI+) 307 (M+1, 100%).

Reference Example 46
Ethyl [(rac.)-(2S,5R)-5-(isopropylamino)-1-(4-methoxybenzyl)piperidin-2-yl]acetate

The compound of Reference Example 45 (1.23 g) was dissolved in ethanol (15 ml), and thereto were added acetone (802 μl) and acetic acid (219 μl), and the mixture was stirred at 60° C. Four hours thereafter, to the mixture was added sodium cyanoborohydride (1.14 g), and the mixture was further stirred at room temperature for 12 hours. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with chloroform twice. The combined organic layers were washed with aqueous sodium hydrogen carbonate solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: chloroform/methanol=10/1 to 8/1) to give the title compound (966 mg) as a colorless oily compound.

¹H-NMR (400 MHz, CDCl₃) 7.21-7.19(m, 2H), 6.86-6.83(m, 2H), 4.14(t, J=7.2 Hz, 2H), 3.80(s, 3H), 3.78(d, J=13.2 Hz, 1H), 3.26(d, J=13.2 Hz, 1H), 2.84-2.71(m, 5H), 2.41(dd, J=7.8, 14.7 Hz, 1H), 1.91-1.74(m, 3H), 1.49(m, 1H), 1.25(t, J=7.2 Hz, 3H), 1.21-1.18(m, 1H), 0.99-0.95(m, 6H).

MS (ESI+) 349 (M+1, 100%).

Reference Example 47
Ethyl [(rac.)-(2S,5R)-5-{isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}-1-(4-methoxybenzyl)piperidin-2-yl]acetate

The title compound (921 mg) was synthesized in a similar manner to Reference Example 8 except that the compound of Reference Example 47 was used instead of the compound of Reference Example 7 in Reference Example 8.

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

Reference Example 48
[(rac.)-(2S,5R)-5-{Isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}-1-(4-methoxybenzyl)piperidin-2-yl]acetic acid

The title compound (253 mg) was synthesized in a similar manner to Reference Example 27 except that the compound of Reference Example 47 was used instead of the compound of Reference Example 26 in Reference Example 27.

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

Reference Example 49
Ethyl [(rac.)-(2R,5R)-5-amino-1-(4-methoxybenzyl)piperidin-2-yl]acetate

The title compound (144 g) was synthesized in a similar manner to Reference Example 6 except that the compound B of Reference Example 44 was used instead of the compound of Reference Example 5 in Reference Example 6.

MS (ESI+) 307 (M+1, 100%).

Reference Example 50
tert-Butyl (3R)-3-{[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}piperidine-1-carboxylate

The compound of Reference Example 8 was subjected to reduction in a similar manner to Reference Example 20, and then, the resultant was subjected to Boc-zation in a similar manner to Reference Example 26 to give the title compound (370 mg).

MS (ESI+) 423 (M+1, 100%).

Reference Example 51
tert-Butyl (3R)-3-{[4-methoxy-3-(3-methoxypropoxy)benzoyl](methyl)amino}-piperidine-1-carboxylate

The compound of Reference Example 50 (99.7 mg) was dissolved in dimethylformamide (2 ml), and thereto was added sodium hydride (18.8 mg) at 0° C. and the mixture was stirred. Ten minutes thereafter, to the mixture was added iodomethane (29.4 μl), and the mixture was stirred at room temperature for 4 hours. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water twice, and further washed with a saturated aqueous sodium chloride solution. The organic layer is dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=1/2) to give the title compound (65.5 mg) as a colorless oily compound.

MS (ESI+) 437 (M+1, 100%).

Reference Example 52
tert-Butyl (3R)-3-(cyclohexylamino)piperidine-1-carboxylate

The title compound (232 mg) was synthesized in a similar manner to Reference Example 15 except that the compound of Reference Example 35 and cyclohexanone were used instead of the compound of Reference Example 14 and acetone in Reference Example 15, respectively.

MS (ESI+) 283 (M+1, 100%).

Reference Example 53
tert-Butyl (3R)-3-{cyclohexyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}-piperidine-1-carboxylate

The title compound (85.3 mg) was synthesized in a similar manner to Reference Example 8 except that the compound of Reference Example 52 was used instead of the compound of Reference Example 7 in Reference Example 8.

MS (ESI+) 505 (M+1, 100%).

Reference Example 54
tert-Butyl (3R)-3-[(cyclohexylmethyl)amino]piperidine-1-carboxylate

The compound of Reference Example 35 (191 mg) was dissolved in ethanol (3 ml), and thereto were added cyclohexanecarboxyaldehyde (121 μl) and acetic acid (54.5 μl), and the mixture was stirred at 60° C. Three hours thereafter, sodium triacetoxyborohydride (706 mg) was added to the mixture, and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with chloroform. The organic layer was dried over sodium hydrogen sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: chloroform/methanol=20/1) to give the title compound (246 mg) as a colorless oily compound.

MS (ESI+) 297(M+1, 100%).

Reference Example 55
tert-Butyl (3R)-3-{(cyclohexylmethyl)[4-methoxy-3-(3-methoxypropoxy)benzoyl]-amino}piperidine-1-carboxylate

The title compound (155 mg) was synthesized in a similar manner to Reference Example 8 except that the compound of Reference Example 54 was used instead of the compound of Reference Example 7 in Reference Example 8.

MS (ESI+) 519 (M+1, 100%).

Reference Example 56
tert-Butyl (3R)-3-[(4-chlorobenzyl)amino]piperidine-1-carboxylate

The title compound (182 mg) was synthesized in a similar manner to Reference Example 54.

MS (ESI+) 325 (M+1, 100%).

Reference Example 57
tert-Butyl (3R)-3-{(4-chlorobenzyl)[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}-piperidine-1-carboxylate

The title compound (279 mg) was synthesized in a similar manner to Reference Example 8 except that the compound of Reference Example 56 was used instead of the compound of Reference Example 7 in Reference Example 8.

MS (ESI+) 548 (M+1, 100%).

Reference Example 58
tert-Butyl (3R)-3-{ethyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}piperidine-1-carboxylate

The title compound (45.7 mg) was synthesized in a similar manner to Reference Example 51 except that iodoethane was used instead of iodomethane in Reference Example 51.

MS (ESI+) 451(M+1, 100%).

Reference Examples 59-60

The compounds as listed in the following Table were synthesized in a similar manner to Reference Example 51.

TABLE 1

Ref. Ex.
Structure
MS (ESI+)

59

465 (M + 1, 100%)

60

477 (M + 1, 100%)

Reference Example 61
1-{[(rac.)-(2S,5R)-5-{Isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}-1-(4-methoxybenzyl)piperidin-2-yl]acetyl}piperidine-4-carboxyamide

The compound of Reference Example 48 (51.0 mg) was dissolved in dimethylformamide (1 ml), and thereto were added 1-hydroxybenzotriazole (43.2 mg), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride, (54.0 mg), triethylamine (39.3 μl) and isonipecotic amide (15.7 mg), and the mixture was stirred at room temperature for 21 hours. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, 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 (developing solvent: chloroform/methanol=10) to give the title compound (47.2 mg) as a colorless oily compound.

MS (ESI+) 653 (M+1, 100%).

Reference Example 62
N-[(rac.)-(2S,5R)-6-[2-(Butylamino)-2-oxoethyl]-1-(4-methoxybenzyl)piperidin-3-yl]-N-isopropyl-4-methoxy-3-(3-methoxypropoxy)benzamide

The title compound (14.0 mg) was synthesized in a similar manner to Reference Example 61 except that n-butylamine was used instead of isonipecotic amide in Reference Example 61.

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

Reference Example 63
tert-Butyl (rac.)-(2S, 5R)-2-(2-ethoxy-2-oxoethyl)-5-{isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}piperidine-1-carboxylate

The title compound (442 mg) was synthesized in a similar manner to Reference Example 80 except that the compound of Reference Example 47 was used instead of the compound of Reference Example 79 in Reference Example 80.

MS (ESI+) 551 (M+1, 100%).

Reference Example 64
1-tert-Butyl 3-methyl(rac.)-(3R, 5S)-5-(isopropylamino)piperidine-1,3-dicarboxylate

Using 1-tert-butyl 3-methyl(rac.)-(3R,5S)-5-aminopiperidine-1,3-dicarboxylate (U.S. Pat. No. 5,817,678; 475 mg) as a starting compound, the title compound (341 mg) was obtained as a colorless oily product in a similar manner to Reference Example 15.

¹H-NMR (400 MHz, CDCl₃) δ 5.50-4.50(brs, 1H), 4.45-4.20(m, 2H), 3.69(s, 3H), 3.01-2.95(m, 1H), 2.78-2.60(m, 2H), 2.54-2.49(m, 1H), 2.30-2.23(m, 2H), 1.46(s, 9H), 1.33-1.24(m, 1H), 1.07-1.00(m, 6H).

MS (ESI+) 301 ([M+H]⁺, 100%).

Reference Example 65
1-tert-Butyl 3-methyl(rac.)-(3S, 5R)-5-{isopropyl[4-methoxy-3-(3-methoxypropoxy)-benzoyl]amino}piperidine-1,3-dicarboxylate

Using the compound of Reference Example 64 (259 mg) as a starting compound, the title compound (480 mg) was obtained as white amorphous in a similar manner to Reference Example 8.

¹H-NMR (400 MHz, CDCl₃) δ 6.89-6.84(m, 3H), 4.20-4.17(m, 1H), 4.13-4.10(m, 2H), 4.01-3.95(m, 2H), 3.88(s, 3H), 3.70(s, 3H), 3.59-3.54(m, 2H), 3.35(s, 3H), 3.20-3.02(m, 1H), 2.85-2.80(m, 1H), 2.55-2.50(m, 1H) 2.14-2.04(m, 4H), 1.47(s, 9H), 1.27-1.21(m, 7H).

MS (ESI+) 523 ([M+H]⁺, 95%).

Reference Example 66
tert-Butyl (rac.)-(3S,5R)-3-{[benzyl(methyl)amino]carbonyl}-5-{isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}piperidine-1-carboxylate

To a solution of the compound of Reference Example 65 (408 mg) in methanol (7.0 ml) was added 1N aqueous lithium hydroxide solution (7.8 ml), and the mixture was stirred at room temperature for one hour. To the reaction solution was added a 5% aqueous potassium hydrogen sulfate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a carboxylic acid intermediate (0.42 g). To a solution of the obtained carboxylic acid (50.8 mg) in N,N-dimethylformamide (0.5 ml) were added N-methylbenzylamine (0.0193 ml), 1-hydroxybenzotriazole (16.8 mg), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (23.0 mg), and triethylamine (0.0347 ml) at 0° C., and the mixture was stirred at room temperature for 18 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by preparative thin layer silica gel chromatography (hexane/ethyl acetate=1/1 to 1/6) to give the title compound (39.8 mg) as white amorphous.

¹H-NMR (400 MHz, CDCl₃) δ 7.32-7.21(m, 5H), 6.90-6.85(m, 3H), 4.70-4.50(m, 2H), 4.30-3.90(m, 6H), 3.87-3.85(m, 4H), 3.56(t, J=6.1 Hz, 2H), 3.35(s, 3H), 3.00-2.95(m, 4H), 2.80-2.70(m, 1H), 2.12-2.09(m, 2H), 1.90-1.82(m, 1H) 1.45(s, 9H), 1.38-1.24(m, 7H).

MS (ESI+) 612 ([M+H]⁺, 31%).

Reference Example 67
(rac.)-(3R,5R)-1-(tert-Butoxycarbonyl)-5-(methoxycarbonyl)piperidine-3-carboxylic acid

To a solution of 1-tert-butyl 3,5-dimethyl(rac.)-(3R,5R)-piperidine-1,3,5-tricarboxylate (U.S. Pat. No. 5,817,678; 1.14 g) in ethyleneglycol dimethyl ether (8.0 ml) were added water (8.0 ml) and aqueous lithium hydroxide solution (159 mg), and the mixture was stirred at room temperature for 18 hours. To the reacting solution was added water, and the mixture was washed with toluene. To the aqueous layer was added a 5% aqueous potassium hydrogen sulfate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with 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 (chloroform/methanol=100/1 to 100/3) to give the title compound (798 mg) as a colorless oily product.

¹H-NMR (400 MHz, CDCl₃) δ 3.75-3.51 (m, 4H), 3.70(s, 3H), 2.88-2.78(m, 2H), 2.15-2.05(m, 2H), 1.44(s, 9H).

MS (ESI+) 288 ([M+H]⁺, 35%).

Reference Example 68
1-tert-Butyl 3-methyl(rac.)-(3R,5R)-5-{[(benzoyl)carbonyl]amino}piperidine-1,3-dicarboxylate

To a solution of the compound of Reference Example 67 (679 mg) and triethylamine (0.360 ml) in toluene (11 ml) was added dropwise a solution of diphenyl-phosphoryl azide (682 mg) in toluene (2.0 ml) at 80° C. One hour thereafter, the reaction solution was cooled to 50° C., and thereto was added benzyl alcohol (0.488 ml), and the mixture was stirred at 90° C. for 3 hours. The reaction mixture was cooled to room temperature, and water was added to the reaction solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with a saturated sodium hydrogen carbonate solution, water, a 5% aqueous potassium hydrogen sulfate solution 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=9/1 to 2/1) to give the title compound (703 mg) as a colorless oily product.

¹H-NMR (400 MHz, CDCl₃) δ7.39-7.32(m, 5H), 5.10(s, 2H), 4.98-4.95(m, 1H), 4.14-4.05(m, 1H), 3.98-3.94(m, 2H), 3.68(s, 3H), 3.04-2.97(m, 2H), 2.66-2.60(m, 1H), 2.22-2.20(m, 1H), 1.83-1.80(m, 1H), 1.44(s, 9H).

MS (ESI+) 393 ([M+H]⁺, 26%).

Reference Example 69
1-tert-Butyl 3-methyl (rac.)-(3R,5R)-5-(isopropylamino)piperidine-1,3-dicarboxylate

A suspension of the compound of Reference Example 68 (609 mg) and 10% Pd/C (50% wet, 207 mg) in methanol (9.0 ml) was stirred under hydrogen atmosphere at room temperature for 4 hours. After replacement with nitrogen gas, the reaction solution was filtered through celite, and concentrated under reduced pressure. To a solution of the obtained condensed residue in dichloromethane (10 ml) were added acetone (0.445 ml) and acetic acid (0.116 ml), and the mixture was stirred at room temperature for 2 hours. To the reaction solution was added triacetoxy borohydride (1.07 g), and the mixture was stirred at room temperature for 18 hours. To the reaction solution was added a 5% aqueous potassium carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with 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 (chloroform/methanol=100/1 to 100/3) to give the title compound (289 mg) as a colorless oily product.

¹H-NMR (400 MHz, CDCl₃) δ 4.01-3.90(m, 1H), 3.68(s, 3H), 3.68-3.15(m, 4H), 2.98-2.89(m, 2H), 2.79-2.73(m, 1H), 1.95-1.91(m, 1H), 1.82-1.76(m, 1H), 1.45(s, 9H), 1.05-0.99(m, 6H).

MS (ESI+) 301 ([M+H]⁺, 30%).

Reference Example 70
1-tert-Butyl 3-methyl(rac.)-(3R,5R)-5-{isopropyl[4-methoxy-3-(3-methoxypropoxy)-benzoyl]amino}piperidine-1,3-dicarboxylate

Using the compound of Reference Example 69 (219 mg) as a starting compound, the title compound (61.3 mg) was obtained as white amorphous in a similar manner to Reference Example 8.

¹H-NMR (400 MHz, CDCl₃) δ 6.94-6.84(m, 3H), 4.52-4.49(m, 1H), 4.12(t, J=6.5 Hz, 2H), 4.05-4.00(m, 2H), 3.88(s, 3H), 3.72-3.68(m, 4H), 3.56(t, J=6.0 Hz, 2H), 3.35(s, 3H), 3.19-2.92(m, 2H), 2.83-2.79(m, 1H), 2.14-2.04(m, 4H), 1.45(s, 9H), 1.27-1.22(m, 6H).

MS (ESI+) 523 ([M+H]⁺, 63%).

Reference Example 71
Ethyl (rac.)-(2R,5R)-[5-(isopropylamino)-1-(4-methoxybenzyl)piperidin-2-yl]acetate

The title compound (1.17 g) was synthesized in a similar manner to Reference Example 54 except that acetone was used instead of cyclohexane carboxyaldehyde in Reference Example 54.

MS (ESI+) 349 (M+1, 100%).

Reference Example 72
((rac.)-(2S,5R)-1-(tert-Butoxycarbonyl)-5-{isopropyl[4-methoxy-3-(3-methoxy-propoxy)benzoyl]amino}piperidin-2-yl)acetic acid

The title compound (225 mg) was synthesized in a similar manner to Reference Example 27 except that the compound of Reference Example 63 was used instead of the compound of Reference Example 26 in Reference Example 28.

MS (ESI+) 523 (M+1, 100%).

Reference Example 73
Methyl 3-(benzyloxy)-4-methoxybenzoate

The title compound (2.13 g) was synthesized in a similar manner to Reference Example 29 except that the commercially available methyl 3-(hydroxy)-4-methoxy-benzoate was used instead of the compound of Reference Example 28 in Reference Example 29.

¹H-NMR (400 MHz, CDCl₃) δ 7.69(dd, J=2.0, 8.5 Hz, 1H), 7.61(d, J=2.0 Hz, 1H), 7.48-7.46(m, 2H), 7.40-7.36(m, 2H), 7.33-7.31(m, 1H), 6.90(d, J=8.5 Hz, 1H), 3.93(s, 3H), 3.87(s, 3H).

Reference Example 74
3-(Benzyloxy)-4-methoxybenzoic acid

The title compound (1.91 g) was synthesized in a similar manner to Reference Example 3 except that the compound of Reference Example 73 was used instead of the compound of Reference Example 2 in Reference Example 3.

¹H-NMR (400 MHz, CDCl₃) δ 7.77(dd, J=2.0, 8.4 Hz, 1H), 7.65(d, J=2.0 Hz, 1H), 7.49-7.47(m, 2H), 7.41-7.37(m, 2H), 7.34-7.32(m, 1H), 6.93(d, J=8.4 Hz, 1H), 5.20(s, 2H), 3.95(s, 3H).

Reference Example 75
tert-Butyl (3R)-3-(isopropylamino)piperidine-1-carboxylate

The title compound (1.49 g) was synthesized in a similar manner to Reference Example 15 except that the compound of Reference Example 35 was used instead of the compound of Reference Example 14 in Reference Example 15.

MS (ESI+) 243 (M+1, 100%).

Reference Example 76
tert-Butyl (3R)-3-[[3-(benzyloxy)-4-methoxybenzoyl](isopropyl)amino]piperidine-1-carboxylate

The compound of Reference Example 74 (716 mg) was dissolved in dichloromethane (10 ml), and thereto was added oxalyl chloride (369 μl), and the mixture was stirred at room temperature for 4 hours. To the reaction mixture were added triethylamine (1.16 ml) and the compound of Reference Example 73 (671 mg), and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium carbonate solution 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 (developing solvent: hexane/ethyl acetate=2) to give the title compound (326 mg) as a colorless oily compound.

MS (ESI+) 483 (M+1, 100%).

Reference Example 77
tert-Butyl (3R)-3-[(3-hydroxy-4-methoxybenzoyl)(isopropyl)amino]piperidine-1-carboxylate

The title compound (211 mg) was synthesized in a similar manner to Reference Example 20 except that the compound of Reference Example 76 was used instead of Reference Example 19 in Reference Example 20.

MS (ESI+) 393 (M+1, 100%).

Reference Example 78
tert-Butyl (3R)-3-[{3-[2-(acetylamino)ethoxy]-4-methoxybenzoyl}(isopropyl)-amino]piperidine-1-carboxylate

The compound of Reference Example 77 (60.1 mg) was dissolved in dichloromethane (2 ml), and thereto were added 2-acetamido ethanol (14.8 μl), triphenylphosphine (40.3 mg) and diisopropyl azodicarboxylate (77.3 mg), and the mixture was stirred at room temperature for 12 hours. The solvent was removed by evaporation, and the obtained residue was purified by silica gel column chromatography (developing solvent: chloroform/methanol=10) to give the title compound (9.3 mg) as a colorless oily compound.

MS (ESI+) 478 (M+1, 100%).

Reference Example 79
Ethyl [(rac.)-(2R,5R)-5-{isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}-1-(4-methoxybenzyl)piperidin-2-yl]acetate

The title compound (262 mg) was synthesized in a similar manner to Reference Example 8 except that the compound of Reference Example 71 was used instead of the compound of Reference Example 7 in Reference Example 8.

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

Reference Example 80
tert-Butyl (rac.)-(2R,5R)-2-(2-ethoxy-2-oxoethyl)-5-{isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}piperidine-1-carboxylate

The compound of Reference Example 77 (245 mg) was dissolved in methanol (5 ml), and thereto was added a 10% palladium carbon (304 mg), and the mixture was stirred at room temperature under hydrogen atmosphere for 3 hours. After filtration on celite, the filtrate was concentrated under reduced pressure. To the residue were added tetrahydrofuran (2 ml) and a saturated aqueous sodium hydrogen carbonate solution (2 ml), and further thereto was added di-tert-butyl dicarbonate (188 mg). The mixture was stirred at room temperature for 12 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=1) to give the title compound (206 mg) as a colorless oily compound.

MS (ESI+) 551 (M+1, 100%).

Reference Example 81
((rac.)-(2R,5R)-1-(tert-Butoxycarbonyl)-5-{isopropyl[4-methoxy-3-(3-methoxy-propoxy)benzoyl]amino}piperidin-2-yl)acetic acid

The title compound (145 mg) was synthesized in a similar manner to Reference Example 27 except that the compound of Reference Example 80 was used instead of the compound of Reference Example 26 in Reference Example 27.

MS (ESI+) 523 (M+1, 100%).

Reference Example 82
tert-Butyl (rac.)-(2S,5R)-2-{2-[(2-amino-2-oxoethyl)amino]-2-oxoethyl}-5-{isopropyl-[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}piperidine-1-carboxylate

The title compound (21.7 mg) was synthesized in a similar manner to Reference Example 61.

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

Reference Example 83
tert-Butyl (rac.)-(2S,5R)-2-{2-[[2-(dimethylamino)ethyl](ethyl))amino]-2-oxoethyl}-5-{isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}piperidine-1-carboxylate

The title compound (16.0 mg) was synthesized in a similar manner to Reference Example 61.

MS (ESI+) 621 (M+1, 100%).

Reference Example 84
tert-Butyl (rac.)-(2S,5R)-2-{2-[ethyl(isopropyl)amino]-2-oxoethyl}-5-{isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}piperidine-1-carboxylate

The title compound (17.0 mg) was synthesized in a similar manner to Reference Example 61.

MS (ESI+) 592 (M+1, 100%).

Reference Example 85
tert-Butyl (rac.)-(2R,5R)-2-{2-[ethyl(isopropyl)amino]-2-oxoethyl}-5-{isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}piperidine-1-carboxylate

The title compound (2.3 mg) was synthesized in a similar manner to Reference Example 61.

MS (ESI+) 592 (M+1, 100%).

Reference Example 86
tert-Butyl (rac.)-(2S,5R)-2-{2-[(cyclopropylmethyl)(propyl)amino]-2-oxoethyl}-5-{isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}piperidine-1-carboxylate

The title compound (6.8 mg) was synthesized in a similar manner to Reference Example 61.

MS (ESI+) 618 (M+1, 100%).

Reference Example 87
tert-Butyl (rac.)-(2S,5R)-2-(2-hydroxyethyl)-5-{isopropyl[4-methoxy-3-(3-methoxy-propoxy)benzoyl]amino}piperidine-1-carboxylate

The title compound (120 mg) was synthesized in a similar manner to Reference Example 28 except that the compound of Reference Example 72 was used instead of the compound of Reference Example 27 in Reference Example 28.

MS (ESI+) 509 (M+1, 100%).

Reference Example 88
tert-Butyl (rac.)-(2S,5R)-2-(2-hydroxyethyl)-5-{isopropyl[4-methoxy-3-(3-methoxy-propoxy)benzoyl]amino}piperidine-1-carboxylate

The title compound (91.5 mg) was synthesized in a similar manner to Reference Example 87 except that the compound of Reference Example 81 was used instead of the compound of Reference Example 72 in Reference Example 87.

MS (ESI+) 509 (M+1, 100%).

Reference Example 89
tert-Butyl (rac.)-(2S,5R)-5-{isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]-amino}-2-(2-oxoethyl)piperidine-1-carboxylate

The compound of Reference Example 87 (56.2 mg) was dissolved in dichloromethane (2 ml), and thereto were added Molecular Sieves 4A (70 mg), N-methylmorpholine-N-oxide (19.4 mg) and tetra-n-propylammonium perruthenate (7.5 mg), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered through celite with chloroform, and the organic layer was washed with a saturated aqueous ammonium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: chloroform/methanol=20 to 10) to give the title compound (37.5 mg) as a colorless oily compound.

MS (ESI+) 507 (M+1, 100%).

Reference Example 90
tert-Butyl (rac.)-(2R,5R)-5-{isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]-amino}-2-(2-oxoethyl)piperidine-1-carboxyl ate

The title compound (43.8 mg) was obtained in a similar manner to Reference Example 89 except that the compound of Reference Example 88 was used instead of the compound of Reference Example 87 in Reference Example 89.

MS (ESI+) 507 (M+1, 100%).

Reference Example 91
tert-Butyl (rac.)-(2S,5R)-2-[2-(cyclopropylamino)ethyl]-5-{isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}piperidine-1-carboxylate

The title compound (13.2 mg) was synthesized in a similar manner to Reference Example 46 except that cyclopropylamine and the compound of Reference Example 89 were used instead of the compound of Reference Example 45 and acetone, respectively, in Reference Example 46.

MS (ESI+) 548 (M+1, 100%).

Reference Example 92
tert-Butyl (rac.)-(2R,5R)-2-[2-(cyclopropylamino)ethyl]-5-{isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}piperidine-1-carboxylate

The title compound (25.9 mg) was synthesized in a similar manner to Reference Example 91 except that the compound of Reference Example 90 was used instead of the compound of Reference Example 89 in Reference Example 91.

MS (ESI+) 548 (M+1, 100%).

Reference Example 93
tert-Butyl (rac.)-(2S,5R)-2-{2-[cyclopropyl(2-oxo-2-phenylethyl)amino]ethyl}-5-{isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}piperidine-1-carboxylate

The compound of Reference Example 91 (13.2 mg) was dissolved in dichloromethane (2 ml), and thereto were added triethylamine (16.8 μl) and phenylacetyl chloride (9.6 μl) at room temperature, and the mixture was stirred for 2 hours. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: chloroform/methanol=10) to give the title compound (6.0 mg) as a colorless oily compound.

MS (ESI+) 666 (M+1, 100%).

Reference Example 94
tert-Butyl (rac.)-(2R,5R)-2-{2-[cyclopropyl(2-oxo-2-phenylethyl)amino]ethyl}-5-{isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}piperidine-1-carboxylate

The compound of Reference Example 92 (25.9 mg) was dissolved in dichloromethane (1 ml), and thereto were added triethylamine (32.9 μl) and phenylacetyl chloride (18.7 μl) at room temperature, and the mixture was stirred for 2 hours. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=1/3) to give the title compound (20.1 mg) as a colorless oily compound.

MS (ESI+) 666 (M+1, 100%).

Reference Example 95
tert-Butyl (rac.)-(3S,5R)-3-(hydroxymethyl)-5-{isopropyl[4-methoxy-3-(3-methoxy-propoxy)benzoyl]amino}piperidine-1-carboxylate

The title compound (23.5 mg) was synthesized in a similar manner to Reference Example 28.

¹H-NMR (400 MHz, CDCl₃) δ 6.90-6.84(m, 3H), 4.25-4.18(m, 1H), 4.12(t, J=6.5 Hz, 2H), 4.05-3.90(m, 3H), 3.88(s, 3H), 3.58-3.52(m, 4H), 3.35(s, 3H), 2.55-2.40(m, 2H), 2.14-2.08(m, 2H), 1.82-1.80(m, 4H), 1.46(s, 9H), 1.28-1.21(m, 6H).

MS (ESI+) 495 ([M+H]⁺, 14%).

Reference Example 96
tert-Butyl 3-(cyclopropylamino)piperidine-1-carboxylate

The title compound (234 mg) was synthesized in a similar manner to Reference Example 54.

MS (ESI+) 241 (M+1, 100%).

Reference Example 97
tert-Butyl 3-{cyclopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}piperidine-1-carboxylate

The title compound (112 mg) was synthesized in a similar manner to Reference Example 8 except that the compound of Reference Example 96 was used instead of the compound of Reference Example 7 in Reference Example 8.

MS (ESI+) 463 (M+1, 100%).

Reference Example 98
2-Methoxy-1-(3-methoxypropoxy)-4-methylbenzene

The title compound (2.69 g) was synthesized in a similar manner to Reference Example 2.

¹H-NMR (400 MHz, CDCl₃) 6.80(d, J=7.9 Hz, 1H), 6.70-6.67(m, 2H), 4.08(t, J=6.5 Hz, 2H), 3.85(s, 31), 3.57(t, J=6.2 Hz, 2H), 3.35(s, 3H), 2.30(s, 3H), 2.12-2.05(m, 2H),

Reference Example 99
1-Bromo-4-methoxy-5-(3-methoxypropoxy)-2-methylbenzene

The compound of Reference Example 98 (2.69 g) was dissolved in acetonitrile (40 ml), and thereto was added N-bromosuccinimide (2.50 g), and the mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated, and the obtained residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=6) to give the title compound (3.08 g) as pale brown oily compound.

¹H-NMR (400 MHz, CDCl₃) 7.05(s, 1H), 6.73(s, 1H), 4.07(t. J=6.5 Hz, 2H), 3.83(s, 3H), 3.55(t, J=6.1 Hz, 2H), 3.35(s, 3H), 2.32(s, 3H), 2.12-2.05(m, 2H).

Reference Example 100
3-Methoxy-5-(3-methoxypropoxy)-2-methylbenzaldehyde

The compound of Reference Example 99 (3.08 g) was dissolved in tetrahydrofuran (30 ml), and thereto was added butyllithium (7.3 ml, 1.6M in Hexane) at −78° C. Thirty minutes thereafter, to the mixture was added N,N-dimethylformamide (1.24 ml), and warmed gradually to room temperature, and then stirred for 12 hours. To the reaction mixture was added 1M hydrochloric acid, and the mixture was extracted with diethyl ether. The organic layer was washed with 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 (developing solvent: hexane/ethyl acetate=7/2) to give the title compound (1.91 g) as a colorless oily compound.

¹H-NMR (400 MHz, CDCl₃) 10.19(s, 1H), 7.37(s, 1H), 6.69(s, 1H), 4.15(t. J=6.6 Hz, 2H), 3.93(s, 3H), 3.57(t, J=6.1 Hz, 2H), 3.36(s, 3H), 2.63(s, 3H), 2.13-2.08(m, 2H).

Reference Example 101
4-Methoxy-5-(3-methoxypropoxy)-2-methylbenzoic acid

The compound of Reference Example 100 (1.62 g) was dissolved in t-butanol (60 ml), dichloromethane (20 ml) and water (60 ml), and thereto were added sodium dihydrogen phosphate dihydrate (6.80 g), 2-methyl-2-butene (8.66 ml) and sodium chlorite (6.04 g), and the mixture was stirred at room temperature for 5 hours. To the reaction mixture was added 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with 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 (developing solvent: chloroform/methanol=10/1) to give the title compound (801 mg) as a white solid.

¹H-NMR (400 MHz, CDCl₃) 7.65(s, 1H), 6.71(s, 1H), 4.15(t. J=6.5 Hz, 2H), 3.92(s, 31), 3.58(t, J=6.2 Hz, 2H), 3.37(s, 3H), 2.62(s, 3H), 2.15-2.09(m, 2H).

Reference Example 102
4-Methoxy-5-(3-methoxypropoxy)-2-methylbenzoyl chloride

The title compound (320 mg) was synthesized in a similar manner to Reference Example 4.

Reference Example 103
tert-Butyl (rac.)-(3R,5S)-3-{isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]-amino}-5-(phenoxymethyl)piperidine-1-carboxylate

The compound of Reference Example 95 (49 mg) was dissolved in tetrahydrofuran (2 ml), and thereto were added phenol (19 mg), triphenylphosphine (52 mg) and a 1.9 M solution of diisopropyl azocarboxylate in toluene (105 ul), and the mixture was stirred at room temperature for 24 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium carbonate solution and a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by preparative thin layer silica gel column chromatography (developing solvent: hexane/ethyl acetate=1/1) to give the title compound (47 mg) as a colorless oily compound.

MS (ESI+) 571 (M⁺+1, 45%).

Reference Example 104
tert-Butyl (rac.)-(3S,5R)-3-[(benzyloxy)methyl]-5-{isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}piperidine-1-carboxylate

The compound of Reference Example 95 (49 mg) was dissolved in tetrahydrofuran (2 ml), and thereto was added sodium hydride (13 mg), and the mixture was heated with stirring at 50° C. for 30 minutes. To the mixture was added benzyl chloride (43 mg), and the mixture was stirred at 50° C. for 5 hours. To the reaction mixture was added a 5% aqueous potassium hydrogen sulfate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by preparative thin layer silica gel column chromatography (developing solvent: hexane/ethyl acetate=1/1) to give the title compound (38 mg) as a colorless oily compound.

MS (ESI+) 585 (M⁺+1, 41%).

Reference Example 105
tert-Butyl (rac.)-(3R,5S)-3-{isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]-amino}-5-[({[(2-phenylethyl)amino]carbonyl}oxy)methyl]piperidine-1-carboxylate

The compound of Reference Example 95 (49 mg) was dissolved in dioxane (0.5 ml), and thereto was added phenethyl isocyanate (145 mg), and the mixture was heated with stirring at 80° C. for 15 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by preparative thin layer silica gel column chromatography (developing solvent: hexane/ethyl acetate=1/3) to give the title compound (41.3 mg) as a colorless oily compound.

MS (ESI+) 642 (M⁺+1, 33%).

Reference Example 106
tert-Butyl (rac.)-(3R,5S)-3-{isopropyl[4-methoxy-3-(3-methoxypropoxy)-2-methyl-benzoyl]amino}piperidine-1-carboxylate

The title compound (483 mg) was synthesized in a similar manner to Reference Example 8 except that the compound of Reference Example 102 and the compound of Reference Example 3 5 were used instead of the compound of Reference Example 4 and the compound of Reference Example 7, respectively, in Reference Example 8.

MS (ESI+) 479 (M⁺+1, 100%).

Reference Examples 107-109

The compounds (20.7 mg) as listed in the following Table were synthesized in a similar manner to Reference Example 61.

TABLE 2

Ref.

Yield

Ex.
Structure
(mg)
MS (ESI+)

107

20.7
618 (M + 1, 100%)

108

9.6
646 (M + 1, 100%)

109

35.7
562 (M + 1, 100%)

Reference Example 110
tert-Butyl 3-(cyclopropylamino)piperidine-1-carboxylate

The title compound (73.8 mg) was synthesized in a similar manner to

Reference Example 54.

MS (BSI+) 257 (M+1, 100%).

Reference Example 111
tert-Butyl (3R)-3-{isobutyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}-piperidine-1-carboxylate

The title compound (108 mg) was synthesized in a similar manner to Reference Example 8.

MS (ESI+) 479 (M+1, 100%).

Reference Example 112
2-Chloro-5-hydroxy-4-methoxybenzaldehyde

To 4,5-dimethoxy-2-chlorobenzaldehyde was added conc. sulfuric acid (23 ml), and the mixture was stirred at 65° C. for 6 hours. The reaction mixture was added to an iced-water where sodium hydroxide (38 g) was dissolved, and the aqueous layer was washed twice with ethyl acetate. To the aqueous layer, which was cooled to 0° C., was added conc. hydrochloric acid so that the pH value thereof was adjusted to pH 1, and the mixture was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=2) to give the title compound (2.19 g) as a white solid.

¹H-NMR (400 MHz, CDCl₃) 10.31(s, 1H), 7.47(s, 1H), 6.88(s, 1H), 5.67(brs, 1H), 3.99(s, 3H).

Reference Example 113
2-Chloro-4-methoxy-5-(3-methoxypropoxy)benzaldehyde

The title compound (2.73 g) was synthesized in a similar manner to Reference Example 2.

¹H-NMR (400 MHz, CDCl₃) 10.31(s, 1H), 7.42(s, 1H), 6.87(s, 1H), 4.15(t, J=6.6 Hz, 2H), 3.94(s, 3H), 3.55(t, J=6.1 Hz, 2H), 3.35(s, 3H), 2.14-2.09(m, 2H).

Reference Example 114
2-Chloro-4-methoxy-5-(3-methoxypropoxy)benzoic acid

The title compound (495 mg) was synthesized in a similar manner to Reference Example 103.

¹H-NMR (400 MHz, CDCl₃) 7.58(s, 1H), 6.90(s, 1H), 4.13(t, J=6.4 Hz, 2H), 3.91(s, 3H), 3.57(t, J=6.1 Hz, 2H), 3.36(s, 3H), 2.12-2.09(m, 2H).

Reference Example 115
2-Chloro-4-methoxy-5-(3-methoxypropoxy)benzoyl chloride

The title compound (190 mg) was synthesized in a similar manner to Reference Example 4.

Reference Example 116
tert-Butyl (3R)-3-[[2-chloro-4-methoxy-5-(3-methoxypropoxy)benzoyl](isopropyl)-amino]piperidine-1-carboxylate

The title compound (317 mg) was synthesized in a similar manner to Reference Example 8.

MS (ESI+) 499 (M+1, 100%).

Reference Example 117
tert-Butyl (rac.)-(2R,5R)-2-[2-(isopropylamino)ethyl]-5-{isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}piperidine-1-carboxylate

The title compound (11.7 mg) was synthesized in a similar manner to Reference Example 46.

MS (ESI+) 550 (M+1, 100%).

Reference Examples 118-119

The compounds (3.2 mg) as listed in the following Table were synthesized in a similar manner to Reference Example 88.

TABLE 3

Ref.

Yield

No.
Structure
(mg)
MS (ESI)

118

3.2
668 (M + 1, 100%)

119

4.2
696 (M + 1, 100%)

Reference Examples 120-124

The title compound (24.7 mg) was synthesized in a similar manner to Reference Example 103.

TABLE 4

Ref.

Yield

No.
Structure
(mg)
MS (ESI+)

120

24.7
647 (M⁺ + 1, 45%)

121

42.3
677 (M⁺ + 1, 40%)

122

39.0
647 (M⁺ + 1, 36%)

123

44.5
663 (M⁺ + 1, 29%)

124

58.1
677 (M⁺ + 1, 36%)

Reference Example 125
tert-Butyl (rac.)-(3S,5R)-3-({[(isopropylamino)carbonyl]oxy}methyl)-5-{isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}piperidine-1-carboxylate

The title compound (176.6 mg) was synthesized in a similar manner to Reference Example 105.

MS (ESI+) 580 (M⁺+1, 100%).

Reference Example 126
tert-Butyl (rac.)-(3S,5R)-3-[({[ethyl(2-phenylethyl)amino]carbonyl}oxy)methyl]-5-{isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}piperidine-1-carboxylate

The compound of Reference Example 105 (54 mg) was dissolved in dimethyl-formamide (2 ml), and thereto was added sodium hydroxide (purity: 55%, 11 mg), and the mixture was stirred at 40° C. for 30 minutes. Then, to the mixture was added ethyl iodide (39 mg), and the mixture was stirred at room temperature overnight. To the reaction mixture was added a 5% aqueous potassium hydrogen sulfate solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by preparative thin layer silica gel column chromatography (developing solvent: hexane/ethyl acetate=1/3) to give the title compound (15.1 mg) as a colorless oily compound.

MS (ESI+) 670 (M⁺+1, 25%).

Reference Examples 127-128

The compounds (12.6 mg) as listed in the following Table were synthesized in a similar manner to Reference Example 126.

TABLE 5

Ref

Yield

No.
Structure
(mg)
MS (ESI+)

127

12.6
684 (M⁺ + 1, 25%)

128

11.1
712 (M⁺ + 1, 32%)

Reference Example 129
tert-Butyl (rac.)-(3R,5R)-3-{isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]-amino}-5-{[(3-methylbutanoyl)amino]methyl}piperidine-1-carboxylate

The compound of Reference Example 95 (1.042 g) was dissolved in tetrahydrofuran (20 ml), and thereto were added phthalimide (0.37 g), triphenylphosphine (0.66 g) and a 1.9M solution of diisopropyl azocarboxylate in toluene (1.33 ml), and the mixture was stirred at room temperature for 48 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium carbonate solution 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 (developing solvent: hexane/ethyl acetate=1/2) to give a colorless oily compound (1.269 g).

Subsequently, said colorless oily compound (0.59 g) was dissolved in ethanol (10 ml), and thereto was added hydrazine monohydrate (459 μl), and the mixture was heated with stirring at 50° C. for 3 hours. Ethanol was removed by evaporation, and diluted with diethyl ether. The insoluble white solid was removed by filtration, and the residue was concentrated. To the resultant was added a 10% aqueous potassium carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give a crude amine product (657 mg).

Said crude amine product (90 mg) was dissolved in tetrahydrofuran (2 ml), and thereto was added triethylamine (51 μl), and further thereto was added dropwise isovaleric chloride (33 mg). The mixture was stirred at room temperature overnight. To the reaction mixture was added a 5% aqueous potassium hydrogen sulfate solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by preparative thin layer silica gel column chromatography (developing solvent: ethyl acetate) to give the title compound (54.8 mg) as a colorless oily compound.

MS (ESI+) 578 (M⁺+1, 20%).

Reference Examples 130-131

The compounds (76.5 mg) as listed in the following Table were synthesized in a similar manner to Reference Example 129.

TABLE 6

Ref.

Yield

No.
Structure
(mg)
MS (ESI+)

130

76.5
628 (M⁺ + 1, 100%)

131

43.2
628 (M⁺ + 1, 19%)

Reference Example 132
tert-Butyl [(rac.)-(3R,4R)-1-benzyl-4-phenylpiperidin-3-yl]carbonate

The title compound (170 mg) was synthesized in a similar manner to Reference Example 18.

MS (ESI+) 367 (M+1, 100%).

Reference Example 133
(rac.)-(3R,4R)-1-Benzyl-4-phenylpiperidine-3-amine dihydrochloride

The title compound (156 mg) was synthesized in a similar manner to Reference Example 10.

MS (ESI+) 267 (M+1, 100%).

Reference Example 134
(rac.)-(3R,4R)-1-Benzyl-N-isopropyl-4-phenylpiperidine-3-amine

The title compound (137 mg) was synthesized in a similar manner to Reference Example 15.

MS (ESI+) 309 (M+1, 100%).

Reference Example 135
N-[(rac.)-(3R,4R)-1-Benzyl-4-phenylpiperidin-3-yl]-N-isopropyl-4-methoxy-3-(3-methoxypropoxy)benzamide

The title compound (174 mg) was synthesized in a similar manner to Reference Example 8.

MS (ESI+) 531 (M+1, 100%).

Reference Example 136
tert-Butyl (2R,5R)-2-{2-[cyclopropyl(2-methoxyacetyl)amino]ethyl}-5-{isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}piperidine-1-carboxylate

The title compound (60 mg) was synthesized in a similar manner to Reference Example 61 except that methoxyacetic acid and tert-butyl-(2S,5R)-2-[2-(cyclopropyl-amino)ethyl]-5-{isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}-piperidine-1-carboxylate were used instead of the compound of Reference Example 48 and isopecotic amide, respectively.

MS (ESI+) 620 (M+1, 100%)

Reference Example 137
tert-Butyl (2R,5R)-2-{2-[cyclopropyl(3-methoxypropanoyl)amino]ethyl}-5-{isopropyl-[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}piperidine-1-carboxylate

The title compound (16 mg) was synthesized in a similar manner to Reference Example 61 except that 3-methoxypropionic acid and tert-butyl (2S,5R)-2-[2-(cyclo-propylamino)ethyl]-5-{isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}-piperidine-1-carboxylate were used instead of the compound of Reference Example 48 and isopecotic amide, respectively.

MS (ESI+) 634 (M+1, 100%)

Reference Example 138
tert-Butyl (2R,5R)-2-{2-[cyclopropyl(4-methoxybutanoyl)amino]ethyl}-5-{isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}piperidine-1-carboxylate

The title compound (35 mg) was synthesized in a similar manner to Reference Example 61 except that 3-methoxybutanoic acid and tert-butyl (2S,5R)-2-[2-(cyclo-propylamino)ethyl]-5-{isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}-piperidine-1-carboxylate were used instead of the compound of Reference Example 48 and isopecotic amide, respectively.

MS (ESI+) 648 (M+1, 100%)

Reference Example 139
tert-Butyl (2R,5R)-2-{2-[[4-(benzoyloxy)butanoyl](cyclopropyl)amino]ethyl}-5-{isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}piperidine-1-carboxylate

The title compound (73 mg) was synthesized in a similar manner to Reference Example 61 except that 4-benzyloxybutanoic acid and tert-butyl-(2S,5R)-2-[2-(cyclopropylamino)ethyl]-5-{isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}-piperidine-1-carboxylate were used instead of the compound of Reference Example 48 and isopecotic amide, respectively.

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

Reference Example 140
tert-Butyl (2R,5R)-2-{2-[cyclopropyl(4-hydroxybutanoyl)amino]ethyl}-5-{isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}piperidine-1-carboxylate

The compound obtained in Reference Example 139 (72 mg) was dissolved in methanol (1 ml), and thereto was added a 10% Pd/C (50% wet, 100 mg), and the mixture was stirred at 25° C. under hydrogen atmosphere for 3 hours. After replacement with nitrogen gas, the reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to give the title compound (63 mg) as a colorless oily product.

MS (ESI+) 634 (M+1, 100%)

Reference Example 141
tert-Butyl (2R,5R)-2-{2-[cyclopropyl(3-hydroxy-3-methylbutanoyl)amino]ethyl}-5-{isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}piperidine-1-carboxylate

The title compound (40 mg) was synthesized in a similar manner to Reference Example 61 except that b-hydroxyisovaleric acid and tert-butyl-(2S,5R)-2-[2-(cyclopropylamino)ethyl]-5-{isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}-piperidine-1-carboxylate were used instead of the compound of Reference Example 48 and isopecotic amide, respectively.

MS (ESI+) 648 (M+1, 100%)

Reference Example 142
tert-Butyl (2R,5R)-2-{2-[cyclopropyl(3-methylbut-2-enoyl)amino]ethyl}-5-{isopropyl-[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}piperidine-1-carboxylate

The title compound (18 mg) was synthesized in a similar manner to Reference Example 61 except that 3,3-dimethylacrylic acid and tert-butyl (2S,5R)-2-[2-(cyclo-propylamino)ethyl]-5-{isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}-piperidine-1-carboxylate were used instead of the compound of Reference Example 48 and isopecotic amide, respectively.

MS (ESI+) 630 (M+1, 100%)

Reference Example 143
(2R,5R)-2-{2-[(3-Cyano-3-methylbutanoyl)(cyclopropyl)amino]ethyl}-5-{isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}piperidine-1-carboxylic acid tert-butyl ester

The title compound (50 mg) was synthesized in a similar manner to Reference Example 61 except that 3-cyano-3-methylbutanoic acid and tert-butyl (2S,5R)-2-[2-(cyclopropylamino)ethyl]-5-{isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]-amino}piperidine-1-carboxylate were used instead of the compound of Reference Example 48 and isopecotic amide, respectively.

MS (ESI+) 657 (M+1, 100%)

Reference Example 144
tert-Butyl (2R,5R)-2-{2-[(cyclohexylacetyl)(cyclopropyl)amino]ethyl}-5-{isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}piperidine-1-carboxylate

The title compound (30 mg) was synthesized in a similar manner to Reference Example 61 except that cyclohexylacetic acid and tert-butyl (2S,5R)-2-[2-(cyclopro-pylamino)ethyl]-5-{isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}-piperidine-1-carboxylate were used instead of the compound of Reference Example 48 and isopecotic amide, respectively.

MS (ESI+) 672 (M+1, 100%)

Reference Example 145
tert-Butyl (2R,5R)-2-{2-[cyclopropyl(4-ethoxy-4-oxobutanoyl)amino]ethyl}-5-{isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}piperidine-1-carboxylate

The title compound (25 mg) was synthesized in a similar manner to Reference Example 61 except that monoethylsuccinic acid and tert-butyl (2S,5R)-2-[2-(cyclo-propylamino)ethyl]-5-{isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}-piperidine-1-carboxylate were used instead of the compound of Reference Example 48 and isopecotic acid, respectively.

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

Reference Example 146
4-[[2-((2R,5R)-1-(tert-Butoxycarbonyl)-5-{isopropyl[4-methoxy-3-(3-methoxy-propoxy)benzoyl]amino}piperidin-2-yl)ethyl](cyclopropyl)amino]-4-oxobutanoic acid

The compound obtained in Reference Example 145 (25 mg) was dissolved in ethanol (1 ml), and thereto was added sodium hydroxide (1 ml, 2M aqueous solution), and the mixture was stirred at 25° C. for 10 hours. The reaction solution was washed with diethyl ether, and the aqueous layer was acidified with hydrochloric acid, and the mixture was extracted with diethyl ether. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (22 mg) as colorless liquid.

MS (ESI+) 648 (M+1, 100%)

Reference Example 147
tert-Butyl (2R,5R)-2-{2-[(anilinocarbonyl)(cyclopropyl)amino]ethyl}-5-{isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}piperidine-1-carboxylate

tert-Butyl-(2S,5R)-2-[2-(cyclopropylamino)ethyl]-5-{isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}piperidine-1-carboxylate (68.0 mg) was dissolved in dichloromethane (0.6 ml), and thereto was added phenylisocyanate (0.027 ml). The reaction mixture was stirred at room temperature for 21 hours, and thereto was added aqueous ammonia (1.0 ml), and the mixture was stirred for 20 minutes. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, water and a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by thin layer silica gel chromatography (developing solvent: hexane/ethyl acetate=1/3) to give the title compound (62.7 mg) as a colorless oily compound.

¹H-NMR (400 MHz, CDCl₃) 7.43-7.42(m, 2H), 7.29-7.27(m, 3H), 7.04-6.98(m, 1H), 6.90-6.85(m, 3H), 4.33-4.16(m, 1H), 4.13-4.09(m, 2H), 3.98-3.95(m, 2H), 3.87(s, 3H), 3.75-3.66(m, 1H), 3.56(t, J=6.1 Hz, 2H), 3.42-3.36(m, 1H), 3.34(s, 3H), 3.20-3.00(m, 2H), 2.77-2.66(m, 1H), 2.13-2.04(m, 2H), 1.74-1.55(m, 6H), 1.46(s, 9H), 1.27-1.17(m, 6H), 0.97-0.82(m, 4H).

MS (ESI+) 667 (M+1, 85%).

Reference Example 148
tert-Butyl (2R,5R)-2-{2-[(benzylsulfonyl)(cyclopropyl)amino]ethyl}-5-{isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}piperidine-1-carboxylate

tert-Butyl (2S,5R)-2-[2-(cyclopropylamino)ethyl]-5-{isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}piperidine-1-carboxylate (50.0 mg) was dissolved in dichloromethane (0.5 ml), and thereto were added α-toluenesulfonyl chloride (19.1 mg) and triethylamine (0.025 ml), and the mixture was stirred at room temperature for 3 hours. To the reaction solution was added methanol (0.1 ml), and the mixture was stirred for 20 minutes. To the reaction solution was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, water and a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by thin layer silica gel chromatography (developing solvent: hexane/ethyl acetate=2/3) to give the title compound (33.4 mg) as a colorless oily compound.

¹H-NMR (400 MHz, CDCl₃) 7.38-7.33(m, 5H), 6.87-6.84(m, 3H), 4.25(s, 2H), 4.25-4.15(m, 1H), 4.10(t, J=6.5 Hz, 2H), 3.98-3.95(m, 1H), 3.87(s, 3H), 3.85-3.78(m, 1H), 3.56(t, J=6.1 Hz, 2H), 3.34(s, 3H), 3.20-3.00(m, 2H), 2.80-2.82(m, 1H), 2.49-2.40(m, 1H), 2.25-2.20(m, 1H), 2.11-2.04(m, 2H), 1.65-1.55(m, 6H), 1.46(s, 9H), 1.27-1.17(m, 6H), 0.73-0.70(m, 4H).

MS (ESI+) 702 (M+1, 50%).

Reference Example 149
tert-Butyl (2R,5R)-2-{2-[cyclopropyl(ethoxycarbonyl)amino]ethyl}-5-{isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}piperidine-1-carboxylate

tert-Butyl-(2S,5R)-2-[2-(cyclopropylamino)ethyl]-5-{isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}piperidine-1-carboxylate (50.0 mg) was dissolved in dichloromethane (0.5 ml), and thereto were added ethyl chloroformate (0.009 ml) and triethylamine(0.025 ml), and the mixture was stirred at room temperature for 5 hours. To the reaction solution was added methanol (0.1 ml), and the mixture was stirred for 20 minutes. To the reaction solution was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, water, and a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by thin layer silica gel chromatography (developing solvent: hexane/ethyl acetate=1/4) to give the title compound (33.7 mg) as a colorless oily compound.

¹H-NMR (400 MHz, CDCl₃) 6.89-6.84(m, 3H), 4.25-4.22(m, 1H), 4.14-4.09(m, 4H), 4.00-3.90(m, 2H), 3.87(s, 3H), 3.85-3.78(m, 1H), 3.56(t, J=6.1 Hz, 2H), 3.34(s, 3H), 3.25-3.20(m, 1H), 3.20-3.05(m, 2H), 2.70-2.60(m, 1H), 2.13-2.08(m, 3H), 1.80-1.65(m, 4H), 1.65-1.50(m, 1H), 1.46(s, 9H), 1.27-1.17(m, 9H), 0.75-0.59(m, 4H).

MS (ESI+) 620 (M+1, 45%).

Reference Example 150
tert-Butyl (2R,5R)-2-{2-[{[3-(butoxycarbonyl)phenyl]acetyl}(cyclopropyl)amino]-ethyl}-5-{isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}piperidine-1-carboxylate

The title compound was obtained as a colorless oily compound in a similar manner to Reference Example 136 except that [3-(butoxycarbonyl)phenyl]acetic acid (WO 92/21672) was used.

¹H-NMR (400 MHz, CDCl₃) 7.95-7.90(m, 2H), 7.51-7.47(m, 1H), 7.40-7.38(m, 1H), 6.89-6.85(m, 3H), 4.32-4.28(m, 2H), 4.11(t, J=6.5 Hz, 2H), 3.93-3.90(m, 4H), 3.87(s, 3H), 3.56(t, J=6.1 Hz, 2H), 3.34(s, 3H), 3.20-2.90(m, 3H), 2.75-2.65(m, 1H), 2.12-2.04(m, 4H), 1.75-1.65(m, 7H), 1.51-1.45(m, 12H), 1.25-1.15(m, 6H), 0.98-0.95(m, 7H).

MS (ESI+) 766 (M+1, 100%).

Reference Example 151
tert-Butyl (2R,5R)-2-[2-(cyclopropyl{[3-(carboxyl)phenyl]acetyl}amino)ethyl]-5-{isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}piperidine-1-carboxylate

The compound of Reference Example 150 (265 mg) was dissolved in ethanol (150 ml), and thereto was added a 1N aqueous sodium hydroxide solution (132 ml), and the mixture was stirred at room temperature for 6 hours. Ethanol was removed by evaporation, and to the remaining residue was added a 5% aqueous potassium hydrogen sulfate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (249 mg) as a colorless oily compound.

¹H-NMR (400 MHz, CDCl₃) 7.93-7.90(m, 2H), 7.49-7.47(m, 1H), 7.40-7.36(m, 1H), 6.91-6.82(m, 3H), 4.14-4.08(m, 2H), 4.01-3.90(m, 4H), 3.87(s, 3H), 3.75-3.70(m, 2H), 3.56(t, J=6.1 Hz, 2H), 3.45-3.40(m, 1H), 3.34(s, 3H), 3.20-2.90(m, 3H), 2.75-2.65(m, 1H), 2.15-2.08(m, 3H), 1.85-1.65(m, 4H), 1.45(s, 9H), 1.25-1.15(m, 6H), 0.94-0.90(m, 4H).

MS (ESI+) 710 (M+1, 98%).

Reference Example 152
tert-Butyl (2R,5R)-2-{2-[{[3-(aminocarbonyl)phenyl]acetyl}(cyclopropyl)amino]-ethyl}-5-{isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}piperidine-1-carboxylate

The title compound was obtained as a colorless oily compound in a similar manner to Reference Example 61.

¹H-NMR (400MHz, CDCl₃) 7.80-7.73(m, 2H), 7.54-7.51(m, 1H), 7.39-7.34(m, 2H), 6.87-6.84(m, 3H), 5.38-5.25(m, 1H), 4.19-3.80(m, 12H), 3.56(t, J=6.0 Hz, 2H), 3.45-3.40(m, 1H), 3.34(s, 3H), 3.20-2.80(m, 3H), 2.75-2.65(m, 1H), 2.15-2.08(m, 3H), 1.85-1.70(m, 3H), 1.45(s, 9H), 1.24-1.13(m, 6H), 0.87-0.79(m, 4H).

MS (ESI+) 709 (M+1, 100%).

Reference Example 153
tert-Butyl (2R,5R)-2-[2-(cyclopropyl{[3-(ethoxycarbonyl)phenyl]acetyl) amino)ethyl]-5-{isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino) piperidine-1-carboxylate

The title compound was obtained as a colorless oily compound in a similar manner to Reference Example 61.

¹H-NMR (400 MHz, CDCl₃) 7.92-7.91(m, 2H), 7.51-7.46(m, 1H), 7.39-7.36(m, 1H), 6.89-6.82(m, 3H), 4.35(q, J=7.1 Hz, 2H), 4.30-4.21(m, 1H), 4.11(t, J=6.4 Hz, 2H), 4.02-3.90(m, 4H), 3.87(s, 3H), 3.85-3.65(m, 2H), 3.55(t, J=6.1 Hz, 2H), 3.50-3.45(m, 1H), 3.34(s, 3H), 3.20-2.90(m, 2H), 2.75-2.65(m, 1H), 2.13-2.04(m, 3H), 1.75-1.65(m, 3H), 1.51-1.50(m, 1H), 1.44(s, 9H), 1.37(t, J=7.1 Hz, 3H), 1.22-1.15(m, 6H), 0.95-0.91(m, 4H).

MS (ESI+) 739 (M+1, 100%).

Reference Example 154
tert-Butyl (rac.)-(2R,5R)-2-(2-{cyclopropyl[(4-fluorophenyl)acetyl]amino}ethyl)-5-{isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}piperidine-1-carboxylate

The title compound (15.7 mg) was synthesized in a similar manner to Reference Example 93.

MS (ESI+) 684 (M⁺+1, 100%).

Reference Example 155
tert-Butyl (rac.)-(2R,5R)-2-{2-[benzoyl(cyclopropyl)amino]ethyl}-5-{isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}piperidine-1-carboxylate

The title compound (3.8 mg) was synthesized in a similar manner to Reference Example 93.

MS (ESI+) 652 (M⁺+1, 100%).

Reference Example 156
tert-Butyl (rac. )-(2R,5R)-2-{2-[cyclopropyl(3-phenylpropanoyl)amino]ethyl}-5-{isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}piperidine-1-carboxylate

The title compound (7.7 mg) was synthesized in a similar manner to Reference Example 93.

MS (ESI+) 680 (M⁺+1, 100%).

Reference Example 157
Methyl 3-hydroxybenzoate

The title compound (525 mg) was synthesized in a similar manner to Reference Example 1.

¹H-NMR (400 MHz, CDCl₃) 7.62-7.59(m, 2H), 7.34-7.29(m, 1H), 7.09-7.06(m, 1H), 5.92(brs, 2H), 3.92(s, 3H).

Reference Example 158
Methyl 3-(3-methoxypropoxy)benzoate

The title compound (738 mg) was synthesized in a similar manner to Reference Example 2.

¹H-NMR (400 MHz, CDCl₃) 7.63-7.61(m, 1H), 7.57-7.56(m, 1H), 7.33(t, J=8.0 Hz, 1H), 7.10(m, 1H), 4.10(t, J=6.3 Hz, 2H), 3.91(s, 3H), 3.56(t, J=6.2 Hz, 2H), 3.36(s, 3H), 2.06(m, 2H).

Reference Example 159
3-(3-Methoxypropoxy)benzoic acid

The title compound (618 mg) was synthesized in a similar manner to Reference Example 3.

¹H-NMR (400 MHz, CDCl₃) 7.72-7.69(m, 1H), 7.64-7.63(m, 1H), 7.37(t, J=8.0 Hz, 1H), 7.15(ddd, J=0.9, 2.6, 8.2 Hz, 1H), 4.12(t, J=6.3 Hz, 2H), 3.59(t, J=6.2 Hz, 2H), 3.38(s, 3H), 2.14-2.05(m, 2H).

Reference Example 160
3-(3-Methoxypropoxy)benzoyl chloride

The title compound (85 mg) was synthesized in a similar manner to Reference Example 4.

Reference Example 161
tert-Butyl (3R)-3-{isopropyl[3-(3-methoxypropoxy)benzoyl]amino}piperidine-1-carboxylate

The title compound (218 mg) was synthesized in a similar manner to Reference Example 8.

MS (ESI+) 435 (M⁺+1, 100%).

Reference Example 162
tert-Butyl ((1S)-1-acetyl-4-{[(benzyloxy)carbonyl]amino}butyl)carbamate

N⁵-[(Benzyloxy)carbonyl]-N²-(tert-butoxycarbonyl)-L-ornithine (366 mg) was dissolved in tetrahydrofuran (1.0 ml), and thereto was added methyl lithium (1.6M in ether) (2.7 ml) at 0° C. The mixture was stirred at room temperature for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with 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 (developing solvent: hexane/ethyl acetate=1/1) to give the title compound (51 mg) as a colorless oily compound.

MS (ESI+) 365 (M⁺+1, 100%).

Reference Example 163
tert-Butyl [(3R)-2-methylpiperidin-3-yl]carbamate

tert-Butyl ((1S)-1-acetyl-4-{[(benzyloxy)carbonyl]amino}butyl)carbamate (53 mg) was dissolved in methanol (1.0 ml), and thereto was added a 10% palladium carbon (50 mg), and the mixture was stirred at room temperature for 6 hours under hydrogen atmosphere of 0.45 MPa. The reaction solution was filtered through celite, and the obtained residue was concentrated under reduced pressure to give the title compound (30.0 mg) as a colorless oily diastereomers mixture.

MS (ESI+) 215 (M⁺+1, 100%).

Reference Example 164
Benzyl (2R,3R)-3-[(tert-butoxycarbonyl)amino]-2-methylpiperidine-1-carboxylate
Benzyl (2S,3R)-3-[(tert-butoxycarbonyl)amino]-2-methylpiperidine-1-carboxylate

In a similar manner to Reference Example 5, benzyl (2R,3R)-3-[(tert-butoxy-carbonyl)amino]-2-methylpiperidine-1-carboxylate(148 mg) and benzyl (2S,3R)-3-[(tert-butoxycarbonyl)amino]-2-methylpiperidine-1-carboxylate (343 mg) were synthesized.

MS (ESI+) 349 (M⁺+1, 100%).

Reference Example 165
Benzyl (2R,3R)-3-amino-2-methylpiperidine-1-carboxylate hydrochloride

The title compound (330 mg) was synthesized in a similar manner to Reference Example 6.

MS (ESI+) 249 (M⁺+1, 100%).

Reference Example 166
Benzyl (2R,3R)-3-(isopropylamino)-2-methylpiperidine-1-carboxylate

The title compound (107 mg) was synthesized in a similar manner to Reference Example 54.

MS (ESI+) 291 (M⁺+1, 100%).

Reference Example 167
tert-Butyl (2R,3R)-3-{isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}-2-methylpiperidine-1-carboxylate

The title compound (110 mg) was synthesized in a similar manner to Reference Example 8.

MS (ESI+) 513 (M⁺+1, 100%).

Reference Example 168
(a) Methyl 3,5-bis(3-methoxypropoxy)benzoate
(b) Methyl 3-hydroxy-5-(3-methoxypropoxy)benzoate

The title compounds (a) (2.06 g) and (b) (2.18 g) were synthesized in a similar manner to Reference Example 2.

(a) ¹H-NMR (400 MHz, CDCl₃) 7.15-7.11(m, 2H), 6.79(brs, 1H), 6.62-6.61(m, 1H), 4.05(t, J=6.3 Hz, 2H), 3.89(s, 3H), 3.59(t, J=6.2 Hz, 2H), 3.38(s, 3H), 2.08-2.02(m, 2H).

(b) ¹H-NMR (400 MHz, CDCl₃) 7.22-7.18(d, J=2.3 Hz, 2H), 6.66(t, J=2.3 Hz, 1H), 4.09(t, J=7.1 Hz, 4H), 3.90(s, 3H), 3.54(t, J=6.2 Hz, 4H), 3.36(s, 6H), 2.08-2.02(m, 4H).

Reference Example 169
3,5-Bis(3-methoxypropoxy)benzoic acid

The title compound (2.20 g) was synthesized in a similar manner to Reference Example 3.

¹H-NMR (400 MHz, CDCl₃) 7.24(d, J=2.3 Hz, 2H), 6.70(t, J=2.3 Hz, 1H), 4.09(t, J=6.3 Hz, 4H), 3.57(t, J=6.2 Hz, 4H), 3.37(s, 6H), 2.09-2.03(m, 4H).

Reference Example 170
3,5-Bis(3-methoxypropoxy)benzoyl chloride

The title compound (2.20 g) was synthesized in a similar manner to Reference Example 4.

Reference Example 171
tert-Butyl (3R)-3-[[3,5-bis(3-methoxypropoxy)benzoyl](isopropyl)amino]piperidine-1-carboxylate

The title compound (513 mg) was synthesized in a similar manner to Reference Example 8.

MS (ESI+) 523 (M⁺+1, 100%).

Reference Example 172
Methyl 4-bromo-3-(3-methoxypropoxy)benzoate

The title compound (3.49 g) was synthesized in a similar manner to Reference Example 2.

¹H-NMR (400 MHz, CDCl₃) 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 173
4-Bromo-3-(3-methoxypropoxy)benzoic acid

The title compound (3.10 g) was synthesized in a similar manner to Reference Example 3.

¹H-NMR (400 MHz, CDCl₃) 7.63(d, J=8.2 Hz, 1H), 7.60(d, J=1.7 Hz, 1H), 7.56(dd, J=1.7, 8.2 Hz, 1H), 4.21(t, J=6.2 Hz, 2H), 3.63(t, J=6.1 Hz, 2H), 3.38(s, 3H), 2.17-2.10(m, 2H).

Reference Example 174
4-Bromo-3-(3-methoxypropoxy)benzoyl chloride

The title compound (3.57 g) was synthesized in a similar manner to Reference Example 4.

Reference Example 175
tert-Butyl (3R)-3-[[4-bromo-3-(3-methoxypropoxy)benzoyl](isopropyl)amino]-piperidine-1-carboxylate

The title compound (5.37 g) was synthesized in a similar manner to Reference Example 8.

MS (ESI+) 513 (M⁺+1, 50%), 515 (M⁺+1, 50%).

Reference Example 176
Methyl 3-(benzyloxy)-5-(3-methoxypropoxy)benzoate

The title compound (2.44 g) was synthesized in a similar manner to Reference Example 29.

¹H-NMR (400 MHz, CDCl₃) 7.43-7.32(m, 5H), 7.28-7.27(m, 1H), 7.22-7.21(m, 1H), 6.73(t, J=2.3 Hz, 1H), 5.07(s, 2H), 4.07(t, J=6.3 Hz, 2H), 3.90(s, 3H), 3.54(t, J=6.2 Hz, 2H), 3.36(s, 3H), 2.07-2.01(m, 2H).

Reference Example 177
3-(Benzyloxy)-5-(3-methoxypropoxy)benzoic acid

The title compound (2.34 g) was synthesized in a similar manner to Reference Example 3.

Reference Example 178
3-(Benzyloxy)-5-(3-methoxypropoxy)benzoyl chloride

The title compound (2.40 g) was synthesized in a similar manner to Reference Example 4.

Reference Example 179
tert-Butyl (3R)-3-[[3-(benzyloxy)-5-(3-methoxypropoxy)benzoyl](isopropyl)-amino]piperidine-1-carboxylate

The title compound (3.58 g) was synthesized in a similar manner to Reference Example 8.

MS (ESI+) 541 (M⁺+1, 100%).

Example 180
tert-Butyl (3R)-3-[[3-hydroxy-5-(3-methoxypropoxy)benzoyl](isopropyl)amino]-piperidine-1-carboxylate

The title compound (2.46 g) was synthesized in a similar manner to Reference Example 20.

MS (ESI+) 451 (M⁺+1, 100%).

Reference Example 181
tert-Butyl (3R)-3-{isopropyl[3-(3-methoxypropoxy)-5-phenoxybenzoyl]amino}-piperidine-1-carboxylate

tert-Butyl (3R)-3-[[3-hydroxy-5-(3-methoxypropoxy)benzoyl](isopropyl)-amino]piperidine-1-carboxylate (84.3 mg) was dissolved in dichloromethane (2 ml), and thereto were added triethylamine (52.1 μl), copper acetate (33.9 mg), and phenylboronic acid (45.6 mg). The mixture was stirred at room temperature for 15 hours, and thereto was added a saturated aqueous sodium hydrogen carbonate solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with 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 (developing solvent: hexane/ethyl acetate=3/1) to give the title compound (44.4 mg) as a colorless oily compound.

MS (ESI+) 527 (M⁺+1, 100%).

Reference Example 182
tert-Butyl (3R)-3-{isopropyl[3-methoxy-5-(3-methoxypropoxy)benzoyl]amino}-piperidine-1-carboxylate

The title compound (65.6 mg) was synthesized in a similar manner to Reference Example 51.

MS (ESI+) 465 (M⁺+1, 100%).

Reference Example 183
tert-Butyl (3R)-3-[[3-(cyclopropylmethyl)-5-(3-methoxypropoxy)benzoyl](isopropyl)-amino]piperidine-1-carboxylate

The title compound (86.1 mg) was synthesized in a similar manner to Reference Example 51.

MS (ESI+) 505 (M⁺+1, 100%).

Reference Example 184
tert-Butyl (3R)-3-[[3-isopropoxy-5-(3-methoxypropoxy)benzoyl](isopropyl)amino]-piperidine-1-carboxylate

The title compound (73.5 mg) was synthesized in a similar manner to Reference Example 51.

MS (ESI+) 493 (M⁺+1, 100%).

Reference Example 185
tert-Butyl (3R)-3-[[3-(cyclohexyloxy)-5-(3-methoxypropoxy)benzoyl](isopropyl)-amino]piperidine-1-carboxylate

The title compound (12.1 mg) was synthesized in a similar manner to Reference Example 51.

MS (ESI+) 533 (M⁺+1, 100%).

Reference Example 186
tert-Butyl (3R)-3-[isopropyl(3-(3-methoxypropoxy)-5-{[(trifluoromethyl)sulfonyl]oxy}-benzoyl)amino]piperidine-1-carboxylate

tert-Butyl (3R)-3-[[3-hydroxy-5-(3-methoxypropoxy)benzoyl](isopropyl)-amino]piperidine-1-carboxylate (245 mg) was dissolved in dichloromethane (2 ml), and thereto were added triethylamine (151 μl) and trifluorosulfonic anhydride (110 μl) under ice-cooling. Then, the mixture was stirred at room temperature for 6 hours. To the reaction solution was added a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with 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 (developing solvent: hexane/ethyl acetate=3/1) to give the title compound (266 mg) as a pale yellow oily compound.

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

Reference Example 187
tert-Butyl (3R)-3-(isopropyl{[5-(3-methoxypropoxy)biphenyl-3-yl]carbonyl}amino)-piperidine-1-carboxylate

tert-Butyl (3R)-3-[isopropyl(3-(3-methoxypropoxy)-5-{[(trifluoromethyl)-sulfonyl]oxy}benzoyl)amino]piperidine-1-carboxylate (119 mg) was dissolved in 1,2-dimethoxyethane (2 ml) and water (1 ml), and thereto were added sodium carbonate (64.9 mg), phenylboronic acid (49.7 mg) and tetrakistriphenylphosphine palladium (46.3 mg), and the mixture was heated under reflux. Five hours thereafter, the reaction solution was cooled to 25° C., and thereto was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with 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=2/1) to give the title compound (59.9 mg) as a colorless oily compound.

MS (ESI+) 511 (M+1, 100%).

Reference Example 188
Ethyl 3-hydroxy-4-(phenoxymethyl)benzoate

The title compound (9.88 g) was synthesized in a similar manner to Reference Example 29.

Reference Example 189
Ethyl 3-(3-methoxypropoxy)-4-(phenoxymethyl)benzoate

The title compound (12.06 g) was synthesized in a similar manner to Reference Example 2.

Reference Example 190
3-(3-Methoxypropoxy)-4-(phenoxymethyl)benzoic acid

The title compound (10.38 g) was synthesized in a similar manner to Reference Example 3.

Reference Example 191
3-(3-Methoxypropoxy)-4-(phenoxymethyl)benzoyl chloride

The title compound (10.5 g) was synthesized in a similar manner to Reference Example 4.

Reference Example 192
tert-Butyl (3R)-3-[[4-(benzyloxy)-3-(3-methoxypropoxy)benzoyl](isopropyl)amino]-piperidine-1-carboxylate

The title compound (15.41 g) was synthesized in a similar manner to Reference Example 8.

MS (ESI+) 541 (M⁺+1, 100%).

Reference Example 193
tert-Butyl (3R)-3-[[4-hydroxy-3-(3-methoxypropoxy)benzoyl](isopropyl)amino]-piperidine-1-carboxylate

The title compound (3.35 g) was synthesized in a similar manner to Reference Example 20.

MS (ESI+) 451 (M⁺+1, 100%).

Reference Example 194
tert-Butyl (3R)-3-[[4-butyl-3-(3-methoxypropoxy)benzoyl](isopropyl)amino]piperidine-1-carboxylate

tert-Butyl (3R)-3-[[4-bromo-3-(3-methoxypropoxy)benzoyl](isopropyl)amino]-piperidine-1-carboxylate (274 mg) was dissolved in 1,2-dimethoxyethane (2 ml) and water (1 ml), and thereto were added sodium carbonate (113 mg), butylboronic acid (81.5 mg), tetrakisphenylphosphine palladium (60.4 mg), and the mixture was heated under reflux. Five hours thereafter, the reaction solution was cooled to 25° C., and thereto was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with 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=2/1) to give the title compound (8.1 mg) as a colorless oily compound.

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

Reference Example 195
tert-Butyl (3R)-3-{isopropyl[3-(3-methoxypropoxy)-4-phenoxybenzoyl]amino}-piperidine-1-carboxylate

tert-Butyl (3R)-3-[[4-hydroxy-3-(3-methoxypropoxy)benzoyl](isopropyl)-amino]piperidine-1-carboxylate (84.3 mg) was dissolved in dichloromethane (2 ml), and thereto were added triethylamine (116 μl), copper acetate (75.9 mg) and phenylboronic acid (102 mg). The mixture was stirred at room temperature for 15 hours, and thereto was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with 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 (developing solvent: hexane/ethyl acetate=2/1) to give the title compound (50.7 mg) as a colorless oily compound.

MS (ESI+) 427 (M⁺+1, 100%).

Reference Example 196
tert-Butyl (3R)-3-{isopropyl[3-(3-methoxypropoxy)-4-(2-phenylethyl)-benzoyl]amino}piperidine-1-carboxylate

tert-Butyl (3R)-3-[[4-bromo-3-(3-methoxypropoxy)benzoyl](isopropyl)amino]-piperidine-1-carboxylate (86.0 mg) was dissolved in 1,2-dimethoxyethane (2 ml) and water (1 ml), and thereto were added sodium carbonate (53.1 mg), phenethylboronic acid (50.1 mg) and tetrakistriphenylphosphine palladium (47.4 mg), and the mixture was heated under reflux. Five hours thereafter, the reaction solution was cooled to 25° C., and thereto was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with 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=2/1) to give the title compound (4.8 mg) as a colorless oily compound.

MS (ESI+) 539 (M+1, 100%).

Reference Example 197
tert-Butyl (3R)-3-[[4-isopropoxy-3-(3-methoxypropoxy)benzoyl](isopropyl)amino]-piperidine-1-carboxylate

The title compound (49.2 mg) was synthesized in a similar manner to Reference Example 51.

MS (ESI+) 493 (M⁺+1, 100%).

Reference Example 198
tert-Butyl (3R)-3-[[4-(cyclopropylmethoxy)-3-(3-methoxypropoxy)benzoyl]-(isopropyl)amino]piperidine-1-carboxylate

The title compound (49.6 mg) was synthesized in a similar manner to Reference Example 51.

MS (ESI+) 505 (M⁺+1, 100%).

Reference Example 199
tert-Butyl (3R)-3-[[4-(cyclohexyloxy)-3-(3-methoxypropoxy)benzoyl](isopropyl)-amino]piperidine-1-carboxylate

The title compound (10.2 mg) was synthesized in a similar manner to Reference Example 51.

MS (ESI+) 533 (M⁺+1, 100%).

Reference Example 200
tert-Butyl (3R)-3-[[2-bromo-4-isopropoxy-5-(3-methoxypropoxy)benzoyl](isopropyl)-amino]piperidine-1-carboxylate

tert-Butyl (3R)-3-[[4-isopropoxy-3-(3-methoxypropoxy)benzoyl](isopropyl)-amino]piperidine-1-carboxylate (56.4 mg) was dissolved in acetic acid (2 ml), and thereto were added sodium acetate (39.4 mg) and bromine (5.9 μl) at room temperature. Twelve hours thereafter, a saturated aqueous sodium thiosulfate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a 1M aqueous sodium hydroxide solution 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=3/1) to give the title compound (60.6 mg) as a colorless oily compound.

MS (ESI+) 571 (M⁺+1, 50%), 573(M⁺+1, 50%).

Reference Example 201
tert-Butyl (3R)-3-[{[5-isopropoxy-4-(3-methoxypropoxy)biphenyl-2-yl]carbonyl}-(isopropyl)amino]piperidine-1-carboxylate

tert-Butyl (3R)-3-[[2-bromo-4-isopropoxy-5-(3-methoxypropoxy)benzoyl]-(isopropyl)amino]piperidine-1-carboxylate (33.1 mg) was dissolved in 1,2-dimethoxy-ethane (2 ml) and water (1 ml), and thereto were added sodium carbonate (12.1 mg), phenylboronic acid (14.1 mg), and tetrakistriphenylphosphine palladium (13.1 mg), and the mixture was heated under reflux. Five hours thereafter, the reaction solution was cooled to 25° C., and thereto was added a saturated aqueous sodium hydrogen carbonate solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with 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=2/1) to give the title compound (5.8 mg) as a colorless oily compound.

MS (ESI+) 569 (M⁺+1, 100%).

Reference Example 202
tert-Butyl (3R)-3-[[4-ethoxy-3-(3-methoxypropoxy)benzoyl](isopropyl)amino]-piperidine-1-carboxylate

The title compound (57.3 mg) was synthesized in a similar manner to Reference Example 51.

MS (ESI+) 579 (M⁺+1, 100%).

Reference Example 203
tert-Butyl (3R)-3-{isopropyl[3-(3-methoxypropoxy)-4-propoxybenzoyl]amino}-piperidine-1-carboxylate

The title compound (58.6 mg) was synthesized in a similar manner to Reference Example 51.

MS (ESI+) 493 (M⁺+1, 100%).

Reference Example 204
tert-Butyl (3R)-3-[[4-(2-fluoroethoxy)-3-(3-methoxypropoxy)benzoyl](isopropyl)-amino]piperidine-1-carboxylate

The title compound (58.0 mg) was synthesized in a similar manner to Reference Example 51.

MS (ESI+) 497 (M⁺+1, 100%).

Reference Example 205
tert-Butyl (3R)-3-[[5-(3-tert-butoxy-3-oxopropoxy)-2-chloro-4-methoxybenzoyl]-(isopropyl)amino]piperidine-1-carboxylate

tert-Butyl (3R)-3-[(2-chloro-5-hydroxy-4-methoxybenzoyl)(isopropyl)amino]-piperidine-1-carboxylate (108 mg) was dissolved in dichloromethane (2 ml), and thereto were added under ice-cooling t-butyl 3-hydroxypropiolate (56.0 μl), triphenylphosphine (113 mg) and diisopropyl azodicarboxylate (80.2 μl). The mixture was stirred at room temperature for 14 hours, and the reaction solution was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1) to give the title compound (11.0 mg) as a colorless oily compound.

MS (ESI+) 556 (M⁺+1, 100%).

Reference Example 206
tert-Butyl (3R)-3-[{4-isopropoxy-5-(3-methoxypropoxy)-2-[(1E)-prop-1-en-1-yl]-benzoyl}(isopropyl)amino]piperidine-1-carboxylate

tert-Butyl (3R)-3-[[2-bromo-4-isopropoxy-5-(3-methoxypropoxy)benzoyl]-(isopropyl)amino]piperidine-1-carboxylate (294 mg) was dissolved in dimethoxyethane (2 ml) and water (1 ml), and thereto were added trans-propenylboronic acid (88.5 mg), sodium carbonate (109 mg), and palladium diphenylphosphine dichloride.dichloro-methane complex (84.1 mg), and the mixture was heated under reflux for 3 hours. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with 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=2/1) to give the title compound (195 mg) as a pale yellow oily compound.

MS (ESI+) 533 (M+1, 100%).

Reference Example 207
tert-Butyl (3R)-3-[[4-isopropoxy-5-(3-methoxypropoxy)-2-propylbenzoyl](isopropyl)-amino]piperidine-1-carboxylate

tert-Butyl (3R)-3-[{4-isopropoxy-5-(3-methoxypropoxy)-2-[(1E)-prop-1-en-1-yl]benzoyl}(isopropyl)amino]piperidine-1-carboxylate (195 mg) was dissolved in ethanol (4 ml), and thereto was added palladium carbon (190 mg), and the mixture was stirred under hydrogen atmosphere for 5 hours. The reaction solution was filtered through celite, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to give the title compound (157 mg) as a pale yellow oily compound.

MS (ESI+) 535 (M+1, 100%).

Reference Example 208
tert-Butyl (3R)-3-{isopropyl[3-(3-methoxypropoxy)-4-morpholin-4-ylbenzoyl]amino}-piperidine-1-carboxylate

tert-Butyl (3R)-3-[[4-bromo-3-(3-methoxypropoxy)benzoyl](isopropyl)amino]-piperidine-1-carboxylate (162 mg) was dissolved in toluene (2 ml), and thereto were added sodium t-butoxide (42.5 mg), tris(dibenzylideneacetone)dipalladium (28.9 mg), BINAP (29.5 mg) and morpholine (30.4 μl), and the mixture was heated under reflux. Ten hours thereafter, to the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with chloroform. The organic layer was washed with 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=1/3) to give the title compound (8.7 mg) as a colorless oily compound.

MS (ESI+) 520 (M+1, 100%).

Reference Example 209
3-Methoxypropoxy 4-formyl-3-(3-methoxypropoxy)benzoate

The title compound (191 mg) was synthesized in a similar manner to Reference Example 2.

¹H-NMR (400 MHz, CDCl₃) 10.53(s, 1H), 7.88(d, J=7.9 Hz, 1H), 7.69-7.66(m, 2H), 4.45(t, J=6.5 Hz, 2H), 4.27(t, J=6.3 Hz, 2H), 3.60(t, J=6.0 Hz, 2H), 3.54(t, J=6.2 Hz, 2H), 3.38(s, 3H), 3.37(s, 3H), 2.19-2.12(m, 2H), 2.10-2.03(m, 2H).

Reference Example 210
4-Formyl-3-(3-methoxypropoxy)benzoic acid

The title compound (147 mg) was synthesized in a similar manner to Reference Example 3.

¹H-NMR (400 MHz, CDCl₃) 10.55 (s, 1H), 7.91 (d, J=8.3 Hz, 1H), 7.75-7.73 (m, 2H), 4.28 (t, J=6.2 Hz, 2H), 3.61 (t, J=6.0 Hz, 2H), 3.38 (s, 3H), 2.19-2.13 (m, 2H).

Reference Example 211
4-Formyl-3-(3-methoxypropoxy)benzoyl chloride

The title compound (150 mg) was synthesized in a similar manner to Reference Example 4.

Reference Example 212
tert-Butyl (3R)-3-[[4-formyl-3-(3-methoxypropoxy)benzoyl](isopropyl)amino]-piperidine-1-carboxylate

The title compound (111 mg) was synthesized in a similar manner to Reference Example 8.

MS (ESI+) 463 (M⁺+1, 100%).

Reference Example 213
Diethyl 4-[4-{[[(3R)-1-(tert-butoxycarbonyl)piperidin-3-yl](isopropyl)amino]-carbonyl}-2-(3-methoxypropoxy)phenyl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate

To a solution of thionyl chloride (21.1 μl) in dichloromethane (0.5 ml) was added dropwise pyridine (28.7 μl)/dichloromethane (0.5 ml) under ice-cooling. Then, a solution of tert-butyl (3R)-3-[[4-formyl-3-(3-methoxypropoxy)benzoyl](isopropyl)-amino]piperidine-1-carboxylate (114 mg)/dichloromethane (2.0 ml) was added dropwise to the mixture, and the mixture was stirred at 0° C. for 1 hour. To the mixture was added ethyl 3-aminochrotonate (91.4 μl), and the mixture was stirred at room temperature for 12 hours. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. 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=1/1) to give the title compound (58.5 mg) as a colorless oily compound.

MS (ESI+) 686 (M+1, 100%).

Reference Example 214
tert-Butyl (3R)-3-[[2-chloro-4-isopropoxy-5-(3-methoxypropoxy)benzoyl](isopropyl)-amino]piperidine-1-carboxylate

tert-Butyl (3R)-3-[[4-isopropoxy-3-(3-methoxypropoxy)benzoyl](isopropyl)-amino]piperidine-1-carboxylate (86.1 mg) was dissolved in acetic acid (1 ml), and thereto were added sodium acetate (60.3 mg) and N-chlorosuccinimide (25.7 mg), and the mixture was stirred at room temperature for 18 hours. To the reaction mixture was added a saturated aqueous sodium thiosulfate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N aqueous sodium hydroxide solution twice, washed with a saturated aqueous sodium hydrogen carbonate solution, and further washed with 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=1/1) to give the title compound (73.3 mg) as a colorless oily compound.

MS (ESI+) 527 (M+1, 100%).

Reference Example 215
Methyl(2-bromoethyl)carbamate

2-Bromoethylamine bromate (4.51 g) was dissolved in dichloromethane (15 ml), and thereto were added triethylamine (7.67 ml) and methyl chloroformate (1.87 ml) at 0° C. The mixture was stirred at room temperature for 12 hours, and thereto was added a saturated aqueous sodium hydrogen carbonate solution. The mixture was extracted with chloroform three times. The organic layer was 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 (478 mg) as a colorless oily compound.

H-NMR (400 MHz, CDCl₃) 5.09(brs, 1H), 3.69(s, 3H), 3.63-3.57(m, 2H), 3.55-3.46(m, 2H).

Reference Example 216
tert-Butyl (3R)-3-[(2-chloro-4-methoxy-5-{2-[(methoxycarbonyl)amino]ethoxy}-benzoyl)(isopropyl)amino]piperidine-1-carboxylate

tert-Butyl (3R)-3-[(2-chloro-5-hydroxy-4-methoxybenzoyl)(isopropyl)-amino]piperidine-1-carboxylate (55.0 mg) was dissolved in dimethylformamide (1 ml), and thereto was added sodium hydride (12.9 mg) at 0° C. The mixture was stirred for 15 minutes, and thereto was added methyl(2-bromoethyl)carbamate (70.4 mg), and the mixture was stirred for 12 hours. To the reaction solution was added a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. 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=1/1) to give the title compound (54.4 mg) as a colorless oily compound.

MS (ESI+) 528 (M⁺+1, 100%).

Reference Example 217
Methyl 4-bromo-3-{2-[(methoxycarbonyl)amino]ethoxy}benzoate

Methyl 4-bromo-3-hydroxybenzoate (600 mg) was dissolved in acetonitrile (7.0 ml), and thereto were added potassium carbonate (719 mg) and methyl(2-bromo-ethyl)carbamate (473 mg), and the mixture was heated under reflux for 6 hours. The reaction mixture was allowed to cool, and water was added thereto, and the mixture was extracted with ethyl acetate. 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=2/1) to give the title compound (754 mg) as a white solid.

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

Reference Example 218
4-Bromo-3-{2-[(methoxycarbonyl)amino]ethoxy}benzoic acid

The title compound (658 mg) was synthesized in a similar manner to Reference Example 3.

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

Reference Example 219
Methyl{2-[2-bromo-5-(chlorocarbonyl)phenoxy]ethyl}carbamate

The title compound (764 mg) was synthesized in a similar manner to Reference Example 4.

Reference Example 220
tert-Butyl (3R)-3-[(4-bromo-3-{2-[(methoxycarbonyl)amino]ethoxy}benzoyl)-(isopropyl)amino]piperidine-1-carboxylate

The title compound (542 mg) was synthesized in a similar manner to Reference Example 8.

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

Reference Example 221
Methyl(3-bromopropyl)carbamate

3-Bromopropylamine bromate (5.00 g) was dissolved in chloroform (80 ml), and thereto were added triethylamine (5.80 g) and methyl chloroformate (2.40 g) at 0° C. The mixture was stirred at room temperature for 12 hours, and to the reaction solution was added water, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1 to 3/1) to give the title compound (3.6 g) as a colorless oily compound.

MS (ESI+) 196 (M⁺+1, 50%), 198 (M⁺+1, 50%).

Reference Example 222
tert-Butyl (3R)-3-[(2-chloro-4-methoxy-5-{3-[(methoxycarbonyl)amino]propoxy}-benzoyl)(isopropyl)amino]piperidine-1-carboxylate

tert-Butyl (3R)-3-[(2-chloro-5-hydroxy-4-methoxybenzoyl)(isopropyl)-amino]piperidine-1-carboxylate (134 mg) was dissolved in dimethylformamide (2 ml), and thereto was added sodium hydride (43.8 mg) at 0° C. The mixture was stirred for 10 minutes, and then, thereto was added methyl(3-bromopropyl)carbamate (307 mg), and the mixture was stirred for 6 hours. To the reaction solution was added a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water twice, washed with 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=1/1) to give the title compound (124 mg) as a white solid.

MS (ESI+) 542 (M⁺+1, 100%).

Reference Example 223
tert-Butyl (3R)-3-[[4-(cyclopentyloxy)-3-(3-methoxypropoxy)benzoyl](isopropyl)-amino]piperidine-1-carboxylate

The title compound (201 mg) was synthesized in a similar manner to Reference Example 51.

MS (ESI+) 519 (M⁺+1, 100%).

Reference Example 224
Methyl 4-(2-ethoxy-1,1-dimethyl-2-oxoethoxy)-3-nitrobenzoate

To a solution of methyl 4-hydroxy-3-nitrobenzoate (18.0 g) in N,N-dimethyl-formamide (70 ml) were added potassium carbonate (25.1 g) and ethyl 2-bromo-isobutylate (20.0 g), and the mixture was heated with stirring at 80° C. Ten hours thereafter, the reaction solution was cooled to 25° C., and water was added to the reaction solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with a saturated aqueous sodium chloride solution, 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 (11.8 g).

MS (ESI+) (M⁺+1, 100%).

Reference Example 225
Methyl 2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

To a suspension of iron (12.0 g) in acetic acid (30 ml) was slowly added dropwise a solution of the compound of Reference Example 224 (11.8 g) in acetic acid (50 ml)/ethanol (50 ml) at 80° C., and after the addition, the mixture was heated with stirring at 80° C. Three hours thereafter, the reaction solution was cooled to 25° C., and the insoluble materials were removed by filtration through celite, and the filtrate was concentrated under reduced pressure. To the obtained residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was washed with ethyl acetate to give the title compound (6.8 g) as a white solid.

MS (ESI+) (M⁺+1, 100%).

Reference Example 226
Methyl 4-(4-methoxybutyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

To a solution of the compound of Reference Example 225 (1.80 g) in N,N-dimethylformamide (20 ml) were added sodium hydride (55% wg, 0.40 g) and 1-bromo-3-methoxypropane (1.40 g), and the mixture was heated with stirring at 80° C. Six hours thereafter, the reaction solution was cooled to 25° C., and thereto was added water. The mixture was extracted with ethyl acetate, and the organic layer was washed with a saturated aqueous sodium chloride solution, 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 (1.85 g).

MS (ESI+) (M⁺+1, 100%).

Reference Example 227
4-(4-Methoxybutyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylic acid

The compound of Reference Example 226 (2.0 g) was dissolved in tetrahydro-furan (5 ml) and methanol (5 ml), and thereto was added 2N aqueous sodium hydroxide solution (5 ml), and the mixture was stirred at 60° C. for 5 hours. The reaction solution was concentrated under reduced pressure, and thereto was added a 5% potassium hydrogen sulfate, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (1.81 g).

MS (ESI+) (M⁺+1, 100%).

Reference Example 228
tert-Butyl (3R)-3-(isopropyl{[4-(4-methoxybutyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}amino)piperidine-1-carboxylate

To a solution of the compound of Reference Example 227 (1.47 g) in dichloromethane (20 ml) were added oxalyl chloride (0.66 ml) and dimethylformamide (10 μl), and the mixture was stirred at room temperature for one hour. The solvent was removed by evaporation, and to the resultant was added toluene, and the mixture was concentrated under reduced pressure. The obtained residue was dissolved in dichloromethane (10 ml), and the mixture was added dropwise to a solution of tert-butyl (3R)-3-(isopropylamino)piperidine-1-carboxylate (1.51 g) and triethylamine (1.2 ml) in dichloromethane (20 ml), and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=2/1) to give the title compound (2.0 g).

MS (ESI+) (M⁺+1, 100%).

Example 1
N-Isopropyl-4-methoxy-3-(3-methoxypropoxy)-N-[(3R)-piperidin-3-yl]benzamide hydrochloride

The compound of Reference Example 8 (79.6 mg) was dissolved in methanol (4 ml), and thereto was added a 10% palladium carbon (80 mg), and the mixture was stirred at room temperature under hydrogen atmosphere for 3 hours. The mixture was filtered through celite, and chloroform was added thereto. The mixture was washed with a saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was dissolved in THF (2 ml), and thereto was added a 4N hydrochloric acid-dioxane (2 ml). The mixture was concentrated to give the title compound (60.0 mg) as a colorless oily product.

¹H-NMR (400 MHz, MeOD) 6.93(d, J=8.3 Hz, 1H), 6.85-6.83(m, 2H), 3.99(t, J=6.3 Hz, 2H), 3.92(brs, 1H), 3.77(s, 3H), 3.66-3.60(m, 1H), 3.58-3.55(m, 2H), 3.49-3.47(m, 3H), 3.29(m, 1H), 3.24(s, 3H), 2.87-2.81(m, 1H), 2.60(m, 1H), 2.03-1.91(m, 3H), 1.83-1.80(m, 2H), 1.16-1.15(m, 6H).

MS (ESI+) 365 (M⁺+1, 100%)

Example 2
N-Isopropyl-4-methoxy-3-(3-methoxypropoxy)-N-[(3S)-piperidin-3-yl]benzamide

The compound of Reference Example 12 (10.8 mg) was dissolved in methanol (2 ml), and thereto was added a 10% palladium carbon (8.4 mg), and the mixture was stirred at room temperature under hydrogen atmosphere for 2 hours. The mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give the title compound (9.3 mg) as a colorless oily product.

¹H-NMR (400 MHz, CDCl₃) 6.90-6.83(m, 3H), 4.12(t, J=6.5 Hz, 2H), 3.91-3.86(m, 1H), 3.87(s, 3H), 3.58-3.52(m, 3H), 3.35(s, 3H), 3.10-2.87(m, 3H), 2.40(brs, 2H), 2.13-2.07(m, 3H), 1.79-1.70(m, 3H), 1.26-1.19(m, 6H).

MS (ESI+) 365 (M⁺+1, 100%)

Example 3
N-Isopropyl-4-methoxy-3-(3-methoxypropoxy)-N-pyrrolidin-3-ylbenzamide

The compound of Reference Example 16 (124 mg) was dissolved in methanol (4 ml), and thereto was added a 10% palladium carbon (18 mg), and the mixture was stirred at room temperature for 4 hours under hydrogen atmosphere. The mixture was filtered through celite, and the solvent was removed by evaporation. The residue was purified by preparative thin layer silica gel chromatography (developing solvent:chloroform/methanol=10/1) to give the title compound (50.4 mg) as a colorless oily product.

¹H-NMR (300 MHz, CDCl₃) 6.93-6.86(m, 3H), 4.27-4.11(m, 2H), 4.12(t, J=6.6 Hz, 2H), 3.90(s, 3H), 3.81-3.75(m, 1H), 3.68-3.39(m, 3H), 3.57(t, J=6.0 Hz, (2H), 3.35(s, 3H), 2.88(brs, 1H), 2.56-2.30(m, 2H), 2.16-2.07(m, 2H), 1.24-1.17(m, 6H).

MS (ESI+) 351 (M⁺+1, 100%).

Example 4
N-Azepan-3-yl-N-isopropyl-4-methoxy-3-(3-methoxypropoxy)benzamide hydrochloride

The compound of Reference Example 22 (378 mg) was dissolved in dioxane (4 ml), and thereto was added a 4N hydrochloric acid/dioxane (4 ml), and the mixture was stirred at 25° C. for 2 hours. The reaction solution was concentrated under reduced pressure, and thereto was added toluene, and dioxane was completely removed by azeotropic distillation to give the title compound (164 mg) as a colorless oily product.

MS (ESI+) 379 (M⁺+1, 100%).

Example 5
Ethyl 3-{isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}piperidine-4-carboxylate hydrochloride

The title compound (13.3 mg) was synthesized in a similar manner to Example 4 except that the compound of Reference Example 26 was used instead of the compound of Reference Example 22 in Example 4.

¹H-NMR (400 MHz, CDCl₃) 6.92-6.87(m, 3H), 4.19-4.12(m, 5H), 3.88(s, 3H), 3.79-3.76(m, 3H), 3.67-3.63(m, 3H), 3.58-3.52(m, 2H), 3.35(s, 3H), 3.00(m, 1H), 2.17-2.05(m, 2H), 1.69(m, 2H), 1.35-1.08(m, 9H).

MS (ESI+) 437 (M⁺+1, 100%).

Example 6
3-{Isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}piperidine-4-carboxylic acid hydrochloride

The title compound (19.5 mg) was synthesized in a similar manner to Example 4 except that the compound of Reference Example 27 was used instead of the compound of Reference Example 22 in Example 4.

¹H-NMR (400 MHz, CDCl₃) 7.18-6.89(m, 3H), 4.42-4.15(m, 4H), 3.93-3.87(m, 2H), 3.87(s, 3H), 3.81-3.75(m, 2H), 3.71-3.62(m, 3H), 3.60-3.48(m, 1H), 3.48-3.36(m, 1H), 3.48(s, 3H), 2.38-2.02(m, 5H), 1.03(s, 6H).

MS (ESI+) 409 (M⁺+1, 100%).

Example 7
N-[5-(Fluoromethyl)-3-azabicyclo[3.1.1]hept-1-yl]-N-isopropyl-4-methoxy-3-(3-methoxypropoxy)benzamide

The title compound (9.1 mg) was synthesized in a similar manner to Example 3 except that the compound of Reference Example 33 was used instead of the compound of Reference Example 16 in Example 3.

¹H-NMR (400 MHz, CDCl₃) 6.92(d, J=1.8 Hz, 1H), 6.88(dd, J=1.8, 8.1 Hz, 1H), 6.81(d, J=8.1 Hz, 1H), 4.19(s, 1H), 4.12(t, J=6.6 Hz, 1H), 4.07(s, 1H), 3.88(s, 3H), 3.68-3.65(m, 1H), 3.57(t, J=6.1 Hz, 2H), 3.35(s, 3H), 3.28(s, 2H), 2.78(s, 2H), 2.14-2.02(m, 2H), 2.04-2.02 (m, 1H), 1.88(m, 3H), 1.39(d, J=6.8 Hz, 6H).

MS (ESI+) 409 (M⁺+1, 100%).

Example 8
N-[4-(Hydroxymethyl)piperidin-3-yl]-N-isopropyl-4-methoxy-3-(3-methoxypropoxy)-benzamide hydrochloride

The title compound (21.5 mg) was synthesized in a similar manner to Example 4 except that the compound of Reference Example 28 was used instead of the compound of Reference Example 22 in Example 4.

¹H-NMR (400 MHz, MeOD) 7.05-6.98(m, 3H), 4.12-3.98(m, 4H), 3.88(s, 3H), 3.76-3.65(m, 2H), 3.60-3.59(m, 2H), 3.49-3.40(m, 2H), 3.35(s, 3H), 3.06-3.03(m, 2H), 2.16(d, J=14.6 Hz, 1H), 2.08-2.02(m, 2H), 1.76-1.72(m, 1H), 1.59-1.37(m, 1H), 1.29-1.19(m, 6H).

MS (ESI+) 395 (M⁺+1, 100%).

Example 9
N-Isopropyl-4-methoxy-N-(4-{[(3-methoxybenzyl)oxy]methyl}piperidin-3-yl)-3-(3-methoxypropoxy)benzamide hydrochloride

The title compound (13.7 mg) was synthesized in a similar manner to Example 4 except that the compound of Reference Example 29 was used instead of the compound of Reference Example 22 in Example 4.

¹H-NMR (400 MHz, MeOD) 7.16-7.12(m, 1H), 6.87-6.76(m, 6H), 4.45(d, J=11.8 Hz, 1H), 4.36(d, J=11.8 Hz, 1H), 3.97-3.90(m, 4H), 3.77(s, 3H), 3.65(s, 3H), 3.58-3.55(m, 2H), 3.49-3.44(m, 2H), 3.41-3.35(m, 2H), 3.24(s, 3H), 3.11(m, 1H), 2.99-2.93(m, 1H), 2.06-2.03(m, 1H), 1.95-1.89(m, 2H), 1.76-1.74(m, 1H), 1.42-1.40(m, 1H), 1.12(d, J=6.6 Hz, 3H), 1.07(d, J=6.7 Hz, 3H).

MS (ESI+) 515 (M⁺+1, 100%).

Example 10
N-(4-Chlorophenyl)-4-methoxy-3-(3-methoxypropoxy)-N-[3R-piperidin-3-yl]-benzamide

The compound of Reference Example 37 (17 mg) was dissolved in dioxane (2 ml), and thereto was added a 4N hydrochloric acid/dioxane (2 ml), and the mixture was stirred at 25° C. for 2 hours. The reaction solution was concentrated under reduced pressure, and thereto was added a saturated aqueous sodium hydrogen carbonate solution. The mixture was extracted with chloroform, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative thin layer silica gel chromatography (developing solvent: chloroform/methanol=10/1) to give the title compound (2.7 mg) as a colorless oily product.

¹H-NMR (300 MHz, CDCl₃) 7.22(d, J=8.7 Hz, 2H), 6.95(d, J=8.7 Hz, 2H), 6.85-6.81(m, 2H), 6.62(d, J=8.1 Hz, 1H), 4.65(m, 1H), 3.90(t, J=6.3 Hz, 2H), 3.79(s, 3H), 3.51(t, J=6.2 Hz, 2H), 3.36(m, 1H), 3.35(s, 3H), 3.03(brd, J=12.9 Hz, 1H), 2.68-2.60(m, 1H), 2.45-2.37(m, 1H), 2.05-1.96(m, 3H), 1.96-1.41(m, 4H).

MS (ESI+) 434 (M⁺+1, 100%).

Example 11
N-((rac.)-(3R,6S)-6-{2-[(2-Amino-2-oxoethyl)amino]-2-oxoethyl}piperidin-3-yl)-N-isopropyl-4-methoxy-3-(3-methoxypropoxy)benzamide hydrochloride

The title compound (18.9 mg) was synthesized in a similar manner to Example 4 except that the compound of Reference Example 82 was used instead of the compound of Reference Example 22 in Example 4.

¹H NMR (400 MHz, DMSO-d₆) δ 9.61-9.58(m, 1H), 8.93-8.90(m, 1H), 7.00-6.98(m, 1H), 6.92-6.86(m, 2H), 4.01(t, J=6.6 Hz, 2H), 3.84-3.73(m, 7H), 3.58-3.55(m, 1H), 3.46(t, J=6.2 Hz, 2H), 3.34(s, 3H), 3.24(s, 3H), 3.11-3.08(m, 2H), 2.90-2.80(m, 1H), 2.16-2.13(m, 1H), 1.97-1.93(m, 2H), 1.04-1.01(m, 6H).

MS (ESI+) 479 (M⁺+1, 100%).

Example 12
N-((rac.)-(3R,6S)-6-{2-[[2-(Dimethylamino)ethyl](ethyl)amino]-2-oxoethyl}piperidin-3-yl)-N-isopropyl-4-methoxy-3-(3-methoxypropoxy)benzamide dihydrochloride

The title compound (16.7 mg) was synthesized in a similar manner to Example 4 except that the compound of Reference Example 83 was used instead of the compound of Reference Example 22 in Example 4.

MS (ESI+) 521 (M⁺+1, 100%).

Example 13
3-Hydroxy-N-isopropyl-4-methoxy-N-[(3R)-piperidin-3-yl]benzamide hydrochloride

The title compound (15.0 mg) was synthesized in a similar manner to Example 4 except that the compound of Reference Example 77 was used instead of the compound of Reference Example 22 in Example 4.

MS (ESI+) 293 (M⁺+1, 100%).

Example 14
Ethyl ((rac.)-(2R,5R)-5-{isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]-amino}piperidin-2-yl)acetate

The title compound (7.5 mg) was synthesized in a similar manner to Example 10 except that the compound of Reference Example 80 was used instead of the compound of Reference Example 37 in Example 10.

MS (ESI+) 451(M⁺+1, 100%).

Example 15
((rac.)-(2R,5R)-5-{Isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}-piperidin-2-yl)acetic acid hydrochloride

The title compound (5.0 mg) was synthesized in a similar manner to Example 4 except that the compound of Reference Example 81 was used instead of the compound of Reference Example 22 in Example 4.

MS (ESI+) 423 (M⁺+1, 100%).

Example 16
((rac.)-(2S,5R)-5-{Isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}-piperidin-2-yl)acetic acid hydrochloride

The title compound (5.0 mg) was synthesized in a similar manner to Example 4 except that the compound of Reference Example 72 was used instead of the compound of Reference Example 22 in Example 4.

MS (ESI+) 423 (M⁺+1, 100%).

Example 17
N-[(rac.)-(3R,6S)-6-(2-Hydroxyethyl)piperidin-3-yl]-N-isopropyl-4-methoxy-3-(3-methoxypropoxy)benzamide hydrochloride

The title compound (2.5 mg) was synthesized in a similar manner to Example 4 except that the compound of Reference Example 87 was used instead of the compound of Reference Example 22 in Example 4.

MS (ESI+) 409 (M⁺+1, 100%).

Example 18
N-((rac.)-(3R,6S)-6-{2-[Ethyl(isopropyl)amino]-2-oxoethyl}piperidin-3-yl)-N-isopropyl-4-methoxy-3-(3-methoxypropoxy)benzamide hydrochloride

The title compound (14.8 mg) was synthesized in a similar manner to Example 4 except that the compound of Reference Example 84 was used instead of the compound of Reference Example 22 in Example 4.

MS (ESI+) 492 (M⁺+1, 100%).

Example 19
N-((rac.)-(3R,6S)-6-{2-[(Cyclopropylmethyl)(propyl)amino]-2-oxoethyl}piperidin-3-yl)-N-isopropyl-4-methoxy-3-(3-methoxypropoxy)benzamide hydrochloride

The title compound (4.5 mg) was synthesized in a similar manner to Example 4 except that the compound of Reference Example 86 was used instead of the compound of Reference Example 22 in Example 4.

MS (ESI+) 518 (M⁺+1, 100%).

Example 20
N-((rac.)-(3R,6R)-6-{2-[(Cyclopropylmethyl)(propyl)amino]-2-oxoethyl}piperidin-3-yl)-N-isopropyl-4-methoxy-3-(3-methoxypropoxy)benzamide hydrochloride

The title compound (15.7 mg) was synthesized in a similar manner to Example 4 except that the compound of Reference Example 107 was used instead of the compound of Reference Example 22 in Example 4.

Example 21
3-[2-(Acetylamino)ethoxy]-N-isopropyl-4-methoxy-N-[(3R)-piperidin-3-yl]benzamide hydrochloride

The title compound (11.7 mg) was synthesized in a similar manner to Example 4 except that the compound of Reference Example 78 was used instead of the compound of Reference Example 22 in Example 4.

MS (ESI+) 378 (M⁺+1, 100%).

Example 22
N-((rac.)-(3R,6R)-6-{2-[Ethyl(isopropyl)amino]-2-oxoethyl}piperidin-3-yl)-N-isopropyl-4-methoxy-3-(3-methoxypropoxy)benzamide hydrochloride

The title compound (3.7 mg) was synthesized in a similar manner to Example 4 except that the compound of Reference Example 85 was used instead of the compound of Reference Example 22 in Example 4.

MS (ESI+) 492(M⁺+1, 100%).

Example 23
N-((rac.)-(3R,6S)-6-{2-[Cyclopropyl(phenylacetyl)amino]ethyl}piperidin-3-yl)-N-isopropyl-4-methoxy-3-(3-methoxypropoxy)benzamide hydrochloride

The title compound (3.7 mg) was synthesized in a similar manner to Example 4 except that the compound of Reference Example 93 was used instead of the compound of Reference Example 22 in Example 4.

MS (ESI+) 492 (M⁺+1, 100%). cl Example 24

N-((rac.)-(3R,6R)-6-{2-[Cyclopropyl(phenylacetyl)amino]ethyl}piperidin-3-yl)-N-isopropyl-4-methoxy-3-(3-methoxypropoxy)benzamide hydrochloride

The title compound (19.4 mg) was synthesized in a similar manner to Example 4 except that the compound of Reference Example 94 was used instead of the compound of Reference Example 22 in Example 4.

¹H-NMR (400 MHz, MeOD) 7.22-7.14(m, 5H), 6.94(d, J=8.1 Hz, 1H), 6.88-6.86(m, 2H), 4.00(t, J=6.3 Hz, 2H), 3.90(s, 2H), 3.78(s, 3H), 3.67-3.53(m, 5H), 3.51-3.40(m, 3H), 3.25(s, 3H), 3.09-3.04(m, 1H), 2.73-2.71(m, 1H), 2.59(brs, 1H), 2.00-1.89(m, 6H), 1.72-1.69(m, 1H), 1.20-1.10(m, 6H), 0.93(d, J=6.8 Hz, 2H), 0.83(brs, 2H).

MS (ESI+) 566 (M⁺+1, 100%).

Example 25
N-[(rac.)-(3R,5S)-5-(Hydroxymethyl)piperidin-3-yl]-N-isopropyl-4-methoxy-3-(3-methoxypropoxy)benzamide hydrochloride

The title compound (3.7 mg) was synthesized in a similar manner to Example 4 except that that the compound of Reference Example 95 was used instead of the compound of Reference Example 22 in except that.

MS (ESI+) 492(M⁺+1, 100%).

Example 26
N-Cyclopropyl-4-methoxy-3-(3-methoxypropoxy)-N-[(3R)-piperidin-3-yl]benzamide hydrochloride

The title compound (101 mg) was synthesized in a similar manner to Example 4 except that the compound of Reference Example 97 was used instead of the compound of Reference Example 22 in Example 4.

¹H-NMR(400 MHz, MeOD) 7.10-7.01(m, 2H), 6.90(d, J=8.3 Hz, 1H), 4.17-4.11(m, 1H), 3.99(t, J=6.3 Hz, 2H), 3.78(s, 3H), 3.48(t, J=6.2 Hz, 2H), 3.44-3.41(m, 1H), 3.37-3.24(m, 2H), 3.24(s, 3H), 2.92-2.88(m, 1H), 2.85-2.80(m, 1H), 2.26-2.19(m, 1H), 2.09-1.90(m, 4H), 1.78-1.75(m, 1H), 0.64-0.35(m, 2H), 0.45-0.35(m, 2H).

MS (ESI+) 363(M⁺+1, 100%).

Example 27
N-Isopropyl-4-methoxy-5-(3-methoxypropoxy)-2-methyl-N-[(3R)-piperidin-3-yl]-benzamide

The title compound (254 mg) was synthesized in a similar manner to Example 10 except that the compound of Reference Example 106 was used instead of the compound of Reference Example 37 in Example 10.

¹H-NMR (400 MHz, CDCl₃) 6.68(s, 1H), 6.63(s, 1H), 4.11-4.04(m, 2H), 3.93-3.83(m, 1H), 3.85(s, 3H), 3.75-3.70(m, 1H), 3.57-3.49(m, 2H), 3.34(s, 3H), 3.13(m, 1H), 2.99-2.85(m, 2H), 2.70-2.64(m, 1H), 2.23(s, 3H), 2.09-2.05(m, 2H), 1.80-1.54(m, 4H), 1.28-1.07(m, 6H).

MS (ESI+) 379(M⁺+1, 100%).

Example 28
N-[(rac.)-(3R,6R)-6-(2-Hydroxyethyl)piperidin-3-yl]-N-isopropyl-4-methoxy-3-(3-methoxypropoxy)benzamide hydrochloride

The title compound (17.3 mg) was synthesized in a similar manner to Example 4 except that the compound of Reference Example 88 was used instead of the compound of Reference Example 22 in Example 4.

¹H-NMR (400 MHz, MeOD) 6.93(d, J=8.0 Hz, 1H), 6.88-6.85(m, 2H), 4.01-3.95(m, 4H), 3.77(s, 3H), 3.75-3.71(m, 1H), 3.67-3.55(m 3H), 3.48(t, J=6.1 Hz, 2H), 3.24(s, 3H), 3.13(dd, J=5.2, 12.8 Hz, 1H), 2.60(brs, 1H), 2.08-2.02(m, 1H), 1.97-1.91(m, 4H), 1.87-1.73(m, 2H), 1.19-1.11(m, 6H).

MS (ESI+) 409(M⁺+1, 100%).

Example 29
N-Isopropyl-4-methoxy-3-(3-methoxypropoxy)-N-[(rac.)-(3R,5S)-5-(phenoxymethyl)-piperidin-3-yl]benzamide hydrochloride

The title compound (41.8 mg) was synthesized in a similar manner to Example 4 except that the compound of Reference Example 103 was used instead of the compound of Reference Example 22 in Example 4.

¹H-NMR (300 MHz, CDCl₃) 7.29-7.27(m, 3H), 6.98-6.84(m, 6H), 4.13-4.11(m, 2H), 4.04-3.43(m, 7H), 3.87(s, 3H), 3.58-3.54(m, 2H), 3.34(s, 3H), 2.88-2.84(m, 3H), 2.14-2.08(m, 2H), 1.93-1.90(m, 1H), 1.32-1.22(m, 6H).

MS (ESI+) 471(M⁺+1, 100%).

Example 30
N-{(rac.)-(3R,5S)-5-[(Benzyloxy)methyl]piperidin-3-yl}-N-isopropyl-4-methoxy-3-(3-methoxypropoxy)benzamide hydrochloride

The title compound (34.5 mg) was synthesized in a similar manner to Example 4 except that the compound of Reference Example 104 was used instead of the compound of Reference Example 22 in Example 4.

¹H-NMR (300 MHz, CDCl₃) 7.37-7.27(m, 5H), 6.88-6.85(m, 3H), 4.47(s, 2H), 4.13-4.09(m, 2H), 4.02-3.34(m, 7H), 3.87(s, 3H), 3.58-3.54(m, 2H), 3.34(s, 3H), 2.71-2.50(m, 3H), 2.14-2.06(m, 2H), 1.81-1.78(m, 1H), 1.27-1.17(m, 6H).

MS (ESI+) 485(M⁺+1, 100%).

Example 31
((rac.)-(3S,5R)-5-{Isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}-piperidin-3-yl)methyl(2-phenylethyl)carbamate hydrochloride

The title compound (41.0 mg) was synthesized in a similar manner to Example 4 except that the compound of Reference Example 105 was used instead of the compound of Reference Example 22 in Example 4.

¹H-NMR (300 MHz, CDCl₃) 7.32-7.16(m, 5H), 6.89-6.86(m, 3H), 5.61(bs, 1H), 4.13-4.08(m, 4H), 3.93-3.37(m, 7H), 3.87(s, 3H), 3.58-3.53(m, 2H), 3.34(s, 3H), 2.80-2.78(m, 2H), 2.70-2.60(m, 3H), 2.12-2.08(m, 2H), 1.78-1.76(m, 1H), 1.26-1.19(m, 6H).

MS (ESI+) 542(M⁺+1, 100%).

Examples 32-38

The compounds as listed in the following Table were obtained in a similar manner to Example 4 except that the compounds of Reference Example 51, Reference Example 53, Reference Example 55, Reference Example 57, and Reference Examples 58-60 were used instead of the compound of Reference Example 22 in Example 4 respectively.

TABLE 7

Ex.

No.
Structure

¹H-NMR (400 MHz, solvent)/MS(ESI+)

32

¹H-NMR (400 MHz, MeOD) 7.05 (m, 3 H), 4.12-4.06 (m, 2 H), 3.89 (s, 3 H), 3.61- 3.58 (m, 2 H), 3.40 (m, 1 H), 3.35-3.31 (m, 5 H), 3.26-3.21 (m, 1 H), 2.99 (m, 4 H), 2.08-2.02 (m, 6 H). MS (ESI+) 33 (M⁺ + 1, 100%).

33

¹H-NMR (400 MHz, CDCl₃) 6.90-6.83 (m, 3 H). 4.11 (t, J = 6.5 Hz, 2 H), 3.89 (s, 3 H), 3.56 (t, J = 6.1 Hz, 2 H), 3.49-3.40 (m, 2 H), 3.35 (s, 3 H), 3.11-3.00 (m, 3 H), 2.66 (m, 2 H), 2. 14-2.07 (m, 2 H), 1.84- 1.56 (m, 10 H), 1.33-1.10 (m, 2 H), 0.90- 0.84 (m, 2 H). MS (ESI+) 405 (M⁺ + 1, 100%).

34

¹H-NMR (400 MHz, CDCl₃) 6.95-6.92 (m, 2 H), 6.84 (d, J = 8.1 Hz, 1 H), 4.12 (t, J = 6.5 Hz, 2 H), 3.88 (s, 3 H), 3.81-3.74 (m, 1 H), 3.56 (t, J = 6.1 Hz, 2 H), 3.50 (s, 3 H), 3.21-2.71 (m, 5 H), 2.47 (m, 2 H), 2.13- 2.07 (m, 2 H), 1.93-1.69 (m, 9 H), 1.41- 1.16 (m, 4 H), 0.88 (m, 2 H). MS (ESI+) 419 (M⁺ + 1, 100%).

35

¹H-NMR (400 MHz, DMSO-d₆) 9.34- 9.32 (m, 1 H), 7.41-7.39 (m, 2 H), 7.33- 7.31 (m, 2 H), 7.00 (m, 3 H), 4.59 (brs, 2 H), 4.18 (brs, 1 H), 3.95-3.83 (m, 2 H), 3.78 (s, 3 H), 3.49-3.44 (m, 2 H), 3.24 (s, 3 H), 3.22- 3.16 (m, 1 H), 3.07-3.06 (m, 2 H), 2.71- 2.68 (m, 1 H), 1.97-1.79 (m, 5 H), 1.53- 1.52 (m, 1 H). MS (ESI+) 447 (M⁺ + 1, 100%).

36

¹H-NMR (400 MHz, DMSO-d₆) 7.01- 6.98 (m, 1 H), 6.93-6.89 (m, 2 H), 4.05- 3.99 (m, 3 H), 3.79 (s, 3 H), 3.49-3.45 (m, 2 H), 3.33-3.25 (m, 2 H), 3.24 (s, 3 H), 3.19- 3.16 (m, 3 H), 2.80-2.77 (m, 1 H), 2.12- 1.90 (m, 2 H), 1.84 (m, 3) H), 1.60-1.56 (m, 1 H), 1.07-1.05 (m, 3 H). MS (ESI+) 451 (M⁺ + 1, 100%).

37

¹H-NMR (400 MHz, CDCl₃) 7.04-7.02 (m, 1 H), 6.98-6.96 (m, 2 H), 4.09 (t, J = 6.3 Hz, 2 H), 3.87 (s, 3 H), 3.75-3.64 (m, 5 H), 3.58 (t, J = 6.2 Hz, 2 H), 3.40 (brs, 1 H), 3.34 (s, 3 H), 2.97-2.90 (m, 1 H), 2.19- 2.01 (m, 4 H), 1.63-1.61 (m, 3 H), 1.33- 1.29 (m, 1 H), 0.90-0.83 (m, 3 H)

38

¹H-NMR (400 MHz, CDCl₃) 6.95-6.88 (m, 3 H), 4.00-3.98 (m, 3 H), 3.77 (s, 3 H), 3.65- 3.54 (m, 3 H), 3.48 (t, J = 6.1 Hz, 2 H), 3.39 (brs, 1 H), 3.24 (s, 3 H), 3.24 (m, 1 H), 1.99-1.91 (m, 4 H), 1.69 (brs, 1 H), 1.23- 1.19 (m, 1 H), 0.93 (brs, 1 H), 0.45 (d, J = 7.6 Hz, 2 H), 0.08 (brs, 2 H).

Example 39
N-((rac.)-(3R,6S)-6-{2-[Butylamino]-2-oxoethyl}piperidin-3-yl)-N-isopropyl-4-methoxy-3-(3-methoxypropoxy)benzamide hydrochloride

The title compound (14.8 mg) was synthesized in a similar manner to Example 4 except that the compound of Reference Example 62 was used instead of the compound of Reference Example 22 in Example 4.

¹H-NMR (400 MHz, CDCl₃) 7.00-6.84(m, 3H), 4.13-4.06(m, 3H), 3.93-3.91(m, 1H), 3.88(s, 3H), 3.70-3.61(m, 1H), 3.56(t, J=6.1 Hz, 2H), 3.35(s, 3H), 3.29-3.12(m, 4H), 2.63-2.50(m, 4H), 2.14-2.08(m, 2H), 1.88-1.79(m, 2H), 1.51-1.44(m, 2H), 1.38-1.26(m, 8H), 0.94-0.84(m, 4H).

MS (ESI+) 478(M⁺+1, 100%).

Example 40
Methyl (rac.)-(3R,5R)-5-{isopropyl[4-methoxy-3-(methoxypropoxy)benzoyl]-amino}piperidine-3-carboxylate hydrochloride

The title compound (17.9 mg) was synthesized in a similar manner to Example 4 except that the compound of Reference Example 70 was used instead of the compound of Reference Example 22 in Example 4.

MS (ESI+) 423([M+H]⁺, 69%).

Example 41
(rac.)-(3S,5R)-N-Benzyl-5-{isopropy[4-methoxy-3-(3-methoxyproroxy)benzoyl]-amino}-N-methylpiperidine-3-carboxamide hydrochloride

The title compound (30.0 mg) was synthesized in a similar manner to Example 4 except that the compound of Reference Example 66 was used instead of the compound of Reference Example 22 in Example 4.

¹H NMR (400 MHz, DMSO-d₆) δ 9.35-9.30(m, 2H), 7.42-7.22(m, 5H), 7.00-6.87(m, 3H), 4.67-4.63(m, 1H), 4.52-4.49(m, 1H), 4.02-3.98(m, 2H), 3.82-3.77(m, 6H), 3.46(t, J=6.3 Hz, 2H), 3.34(s, 3H), 3.23(s, 3H), 3.19-3.17(m, 1H), 3.05-2.95(m, 2H), 2.90-2.87(m, 2H), 2.80-2.75(m, 1H), 1.97-1.91(m, 2H), 1.23-0.93(m, 6H).

MS (ESI+) 512([M+H]⁺, 100%).

Example 42
N-Isopropyl-4-methoxy-N-((rac.)-(3R,5S)-5-{[(3-methoxybenzoyl)amino]methyl}-piperidin-3-yl)-3-(methoxypropoxy)benzamide hydrochloride

The title compound (61.5 mg) was synthesized in a similar manner to Example 4 except that the compound of Reference Example 130 was used instead of the compound of Reference Example 22 in Example 4.

¹H-NMR (300 MHz, CDCl₃) δ 7.49-7.44(m, 3H), 6.99-6.96(m, 1H), 6.86-6.82(m, 3H), 4.07-3.97(m, 2H), 3.86(s, 3H), 3.81(s, 3H), 3.81-3.61(m, 6H), 3.57-3.52(m, 2H), 3.33(s, 3H), 2.60-2.54(m, 4H), 2.09-2.07(m, 2H), 1.83-1.81(m, 1H), 1.23-1.12(m, 6H).

MS (ESI+) 528(M⁺+1, 100%).

Example 43
Benzyl [((rac.)-(3S,5R)-5-{isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]-amino}piperidin-3-yl)methyl]carbamate hydrochloride

The title compound (40.8 mg) was synthesized in a similar manner to Example 4 except that the compound of Reference Example 131 was used instead of the compound of Reference Example 22 in Example 4.

¹H-NMR (300 MHz, CDCl₃) δ 7.34-7.32(m, 5H), 6.89-6.85(m, 3H), 5.09(s, 2H), 4.10-4.02(m, 2H), 3.87(s, 3H), 3.79-3.62(m, 4H), 3.58-3.53(m, 2H), 3.34(s, 3H), 3.20-3.10(m, 2H), 2.58-2.17(m, 4H), 2.10-2.07(m, 2H), 1.78-1.76(m, 1H), 1.26-1.16(m, 6H).

MS (ESI+) 528(M⁺+1, 100%).

Example 44
N-Isopropyl-4-methoxy-3-(3-methoxypropoxy)-N-((rac.)-(3R,5S)-5-{[(3-methyl-butanoyl)amino]methyl}piperidin-3-yl)benzamide hydrochloride

The title compound (28.3 mg) was synthesized in a similar manner to Example 4 except that the compound of Reference Example 129 was used instead of the compound of Reference Example 22 in Example 4.

¹H NMR (300 MHz, CDCl₃) δ 6.88-6.85(m, 3H), 4.11-4.02(m, 2H), 3.87(s, 3H), 3.80-3.62(m, 6H), 3.58-3.54(m, 2H), 3.34(s, 3H), 2.59-2.55(m, 3H), 2.20-2.10(m, 6H), 1.86-1.83(m, 1H), 1.26-1.18(m, 6H), 0.96-0.92(m, 6H).

MS (ESI+) 478(M⁺+1, 100%).

Example 45
N-Isopropyl-4-methoxy-3-(3-methoxypropoxy)-N-[(rac.)-(3R,4R)-4-phenylpiperidin-3-yl]benzamide hydrochloride

The title compound (108 mg) was synthesized in a similar manner to Example 1 except that the compound of Reference Example 129 was used instead of the compound of Reference Example 22 in Example 1.

MS (ESI+) 441(M⁺+1, 100%).

Example 46
N-{(rac.)-(3R,5S)-5-[(Biphenyl-2-yloxy)methyl]piperidin-3-yl}-N-isopropyl-4-methoxy-3-(3-methoxypropoxy)benzamide hydrochloride

The title compound (28.3 mg) was synthesized in a similar manner to Example 4 except that the compound of Reference Example 120 was used instead of the compound of Reference Example 22 in Example 4.

¹H NMR (300 MHz, CDCl₃) δ 7.50-7.39(m, 4H), 7.35-7.26(m, 3H), 7.09-7.03(m, 1H), 6.91-6.85(m, 4H), 4.13-4.09(m, 2H), 4.01(s, 3H), 3.87-3.54(m, 8H), 3.34(s, 3H), 2.65-2.60(m, 3H), 2.15-2.08(m, 2H), 1.87-1.84(m, 2H), 1.24-1.12(m, 6H).

MS (ESI+) 547(M⁺+1, 100%).

Example 47
N-((rac.)-(3R,5S)-5-{[2-(Benzoyloxy)phenoxy]methyl}piperidin-3-yl)-N-isopropyl-4-methoxy-3-(3-methoxypropoxy)benzamide hydrochloride

The title compound (42.4 mg) was synthesized in a similar manner to Example 4 except that the compound of Reference Example 121 was used instead of the compound of Reference Example 22 in Example 4.

¹H NMR (300 MHz, CDCl₃) δ 7.42-7.37(m, 3H), 7.31-7.29(m, 2H), 6.91-6.84(m, 7H), 5.08(s, 2H), 4.10-4.08(m, 2H), 3.87(s, 3H), 3.79-3.62(m, 6H), 3.57-3.53(m, 2H), 3.34(s, 3H), 2.78-2.74(m, 3H), 2.12-2.07(m, 2H), 1.74-1.70(m, 2H), 1.28-1.16(m, 6H).

MS (ESI+) 577(M⁺+1, 100%).

Example 48
N-{(rac.)-(3R,5S)-5-[(Biphenyl-3-yloxy)methyl]piperidin-3-yl}-N-isopropyl-4-methoxy-3-(3-methoxypropoxy)benzamide hydrochloride

The title compound (34.8 mg) was synthesized in a similar manner to Example 4 except that the compound of Reference Example 122 was used instead of the compound of Reference Example 22 in Example 4.

¹H NMR (300 MHz, CDCl₃) δ 7.61-7.55(m, 2H), 7.45-7.26(m, 4H), 7.20-7.09(m, 2H), 6.89-6.84(m, 4H), 4.23-4.11(m, 2H), 3.91(s, 3H), 3.86-3.62(m, 6H), 3.57-3.53(m, 2H), 3.33(s, 3H), 2.93-2.87(m, 2H), 2.11-2.09(m, 2H), 1.96-1.90(m, 2H), 1.32-1.22(m, 6H).

MS (ESI+) 547(M⁺+1, 100%).

Example 49
N-Isopropyl-4-methoxy-3-(3-methoxypropoxy)-N-{(rac.)-(3R,5S)-5-[(3-phenoxy-phenoxy)methyl]piperidin-3-yl}benzamide hydrochloride

The title compound (44.5 mg) was synthesized in a similar manner to Example 4 except that the compound of Reference Example 123 was used instead of the compound of Reference Example 22 in Example 4.

¹H NMR (300 MHz, CDCl₃) δ 7.36-7.00(m, 6H), 6.89-6.85(m, 3H), 6.61-6.50(m, 3H), 4.13-4.09(m, 2H), 3.87(s, 3H), 3.80-3.62(m, 6H), 3.58-3.53(m, 2H), 3.34(s, 3H), 2.85-2.81(m, 3H), 2.12-2.08(m, 2H), 1.88-1.86(m, 2H), 1.30-1.20(m, 6H).

MS (ESI+) 563(M⁺+1, 100%).

Example 50
N-((rac.)-(3R,5S)-5-{[3-(Benzoyloxy)phenoxy]methyl}piperidin-3-yl)-N-isopropyl-4-methoxy-3-(3-methoxypropoxy)benzamide hydrochloride

The title compound (54.3 mg) was synthesized in a similar manner to Example 4 except that the compound of Reference Example 124 was used instead of the compound of Reference Example 22 in Example 4.

¹H NMR (300 MHz, CDCl₃) δ 7.44-7.29(m, 5H), 7.18-7.12(m, 1H), 6.89-6.84(m, 3H), 6.59-6.45(m, 3H), 5.03(s, 2H), 4.13-4.09(m, 2H), 3.86(s, 3H), 3.79-3.61(m, 6H), 3.57-3.53(m, 2H), 3.34(s, 3H), 2.89-2.82(m, 3H), 2.12-2.08(m, 2H), 1.94-1.90(m, 2H), 1.31-1.21(m, 6H).

MS (ESI+) 577(M⁺+1, 100%).

Example 51
N-((rac.)-(3R,6R)-6-{2-[Cyclohexyl(isopropyl)amino]-2-oxoethyl}piperidin-3-yl)-N-isopropyl-4-methoxy-3-(3-methoxypropoxy)benzamide hydrochloride

The title compound (9.0 mg) was synthesized in a similar manner to Example 4 except that the compound of Reference Example 108 was used instead of the compound of Reference Example 22 in Example 4.

¹H-NMR (400 MHz, MeOD) 6.94(d, J=8.2 Hz, 1H), 6.88-6.86(m, 2H), 4.00(m,2H), 3.88(m, 1H), 3.78(s, 3H), 3.74-3.71(m, 1H), 3.66-3.55(m, 4H), 3.49(d, J=6.1 Hz, 2H), 3.25(s, 3H), 3.16-3.12(m, 1H), 2.96-2.87(m, 1H), 2.83-2.78(m, 1H), 2.60(brs, 1H), 2.32(brs, 1H), 1.98-1.92(m, 4H), 1.76-1.70(m, 4H), 1.54-1.36(m, 4H), 1.31-1.26(m, 4H), 1.23-1.05(m, 10H).

MS (ESI+) 546(M⁺+1, 100%).

Example 52
N-{ (rac.)-(3R,6R)-6-[2-(Cyclopropylamino)-2-oxoethyl]piperidin-3-yl)-N-isopropyl-4-methoxy-3-(3-methoxypropoxy)benzamide hydrochloride

The title compound (30.8 mg) was synthesized in a similar manner to Example 4 except that the compound of Reference Example 109 was used instead of the compound of Reference Example 22 in Example 4.

¹H-NMR (400 MHz, MeOD) 6.94(d, J=7.9 Hz, 1H), 6.89-6.86(m, 2H), 4.00(d,J=6.3 Hz, 2H), 3.96(m, 1H), 3.78(s, 3H), 3.66-3.55(m, 3H), 3.49(d, J=6.1 Hz, 2H), 3.25(s, 3H), 3.16(dd, J=5.2, 13.0 Hz, 1H), 2.78-2.72(m, 1H), 2.63-2.53(m, 3H), 1.93-1.75(m, 5H), 1.20-1.11(m, 6H), 0.66-0.62(m, 2H), 0.44-0.40(m, 2H).

MS (ESI+) 462(M⁺+1, 100%).

Example 53
2-Chloro-N-isopropyl-methoxy-5-(3-methoxypropoxy)-N-[(3R)-piperidin-3-yl]-benzamide hydrochloride

The title compound (274 mg) was synthesized in a similar manner to Example 4 except that the compound of Reference Example 116 was used instead of the compound of Reference Example 22 in Example 4.

¹H-NMR (400 MHz, MeOD) 6.96-6.78(m, 2H), 4.03-3.96(m, 3H), 3.76(s, 3H), 3.68-3.57(m, 2H), 3.47(d, J=6.0 Hz, 2H), 3.33-3.29(m, 1H), 3.24(s, 3H), 2.89-2.83(m, 1H), 2.78-2.68(m, 1H), 2.03-1.81(m, 5H), 1.48-1.43(m, 1H), 1.20-1.06(m, 6H).

MS (ESI+) 399(M⁺+1, 100%).

Example 54
N-{(rac.)-(3R,6R)-6-[2-(Cyclohexylamino)ethyl]piperidin-3-yl}-N-isopropyl-4-methoxy-3-(3-methoxypropoxy)benzamide dihydrochloride

The title compound (6.8 mg) was synthesized in a similar manner to Example 4 except that the compound of Reference Example 92 was used instead of the compound of Reference Example 22 in Example 4.

¹H-NMR (400 MHz, MeOD) 6.94(d, J=8.6 Hz, 1H), 6.88-6.87(m, 2H), 4.01-3.95(m, 3H), 3.78(s, 3H), 3.70-3.54(m, 5H), 3.48(d, J=6.1 Hz, 2H), 3.24(s, 3H), 2.73-2.69(m, 1H), 2.60(brs, 1H), 2.22-2.17(m, 1H), 1.97-1.91(m, 4H), 1.79-1.77(m, 1H), 1.19-1.11(m, 7H), 0.86-0.84(m, 4H).

MS (ESI+) 448(M⁺+1, 100%).

Example 55
N-Isopropyl-N-((rac.)-(3R,6R)-6-{2-[isopropyl(phenylacetyl)amino]ethyl}piperidin-3-yl)-4-methoxy-3-(3-methoxypropoxy)benzamide hydrochloride

The title compound (3.5 mg) was synthesized in a similar manner to Example 4 except that the compound of Reference Example 118 was used instead of the compound of Reference Example 22 in Example 4.

¹H-NMR (400 MHz, MeOD) 7.21-7.13(m, 5H), 6.93(d, J=8.1 Hz, 1H), 6.87-6.85(m, 2H), 4.01-3.98(m, 3H), 3.77(s, 3H), 3.75(s, 2H), 3.65-3.54(m, 5H), 3.48(t, J=6.0 Hz, 2H), 3.24(s, 3H), 3.12-3.07(m, 1H), 2.59(brs, 1H), 2.00-1.90(m, 6H), 1.75-1.71(m, 1H), 1.22-1.09(m, 7H), 1.05-1.01(m, 6H).

MS (ESI+) 568(M⁺+1, 100%).

Example 56
N-[(rac.)-(3R,6R)-6-(2-{cyclopropyl[(4-methoxyphenyl)acetyl]amino}ethyl)piperidin-3-yl)-N-isopropyl-4-methoxy-3-(3-methoxypropoxy)benzamide hydrochloride

The title compound (4.7 mg) was synthesized in a similar manner to Example 4 except that the compound of Reference Example 119 was used instead of the compound of Reference Example 22 in Example 4.

¹H-NMR (400 MHz, MeOD) 7.13-7.08(m, 2H), 6.93(d, J=8.1 Hz, 1H), 6.87-6.85(m, 2H), 6.80-6.75(m, 2H), 4.01-3.98(m, 3H), 3.82(s, 2H), 3.77(s, 3H), 3.67(s, 3H), 3.64-3.43(m, 6H), 3.24(s, 3H), 3.06-3.02(m, 1H), 2.72-2.67(m, 1H), 2.56(brs, 1H), 1.98-1.86(m, 6H), 1.71-1.66(m, 1H), 1.21-1.09(m, 7H), 0.93-0.79(m, 4H).

MS (ESI+) 596(M⁺+1, 100%).

Example 57
((rac.)-(3R,5R)-5-{Isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}-piperidin-3-yl)methyl isopropylcarbamate hydrochloride

The title compound (32.1 mg) was synthesized in a similar manner to Example 4 except that the compound of Reference Example 125 was used instead of the compound of Reference Example 22.

¹H-NMR (300 MHz, CDCl₃) 6.89-6.87(m, 3H), 5.50-5.48(m, 1H), 4.14-4.09(m, 2H), 3.83(s, 3H), 3.80-3.62(m, 6H), 3.59-3.54(m, 2H), 3.35(s, 3H), 2.70-2.63(m, 3H), 2.15-2.09(m, 3H), 1.78-1.60(m, 2H), 1.29-1.14(m, 12H).

MS (ESI+) 480(M⁺+1, 100%).

Examples 58-59

The compounds as listed in the following Table were synthesized in a similar manner to Example 53 except that the compounds of Reference Example 126 and Reference Example 127 were used instead of the compound of Reference Example 119 in Example 53, respectively.

TABLE 8

Ex. No.
Structure
MS (ESI⁺)

58

570 (M⁺ + 1, 100%).

59

584 (M⁺ + 1, 100%)

Example 60
N-Isobutyl-4-methoxy-3-(3-methoxypropoxy)-N-[(3R)-piperidin-3-yl]benzamide hydrochloride

The title compound (92.0 mg) was synthesized in a similar manner to Example 4 except that the compound of Reference Example 111 was used instead of the compound of Reference Example 22 in Example 4.

¹H-NMR (400 MHz, MeOD) 6.95-6.89(m, 3H), 3.99(d,J=6.2 Hz, 2H), 3.90(brs, 1H), 3.78(s, 3H), 3.66-3.55(m, 2H), 3.49(d, J=6.0 Hz, 2H), 3.35(brs, 1H), 3.25(s, 3H), 3.19-3.09(m, 2H), 2.88-2.82(m, 1H), 2.17(brs, 1H), 1.96-1.93(m, 5H), 1.65(brs, 1H), 0.76(brs, 1H).

MS (ESI+) 379(M⁺+1, 100%).

Example 61
((rac.)-(3 S,5R)-5-{Isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}-piperidin-3-yl)methyl(3-methylbutyl)(2-phenylethyl)carbamate hydrochloride

The title compound (13.6 mg) was synthesized in a similar manner to Example 4 except that the compound of Reference Example 128 was used instead of the compound of Reference Example 22 in Example 4.

MS (ESI+) 612(M⁺+1, 100%).

Example 62
Benzyl [((rac.)-(3S,5R)-5-{isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]-amino}piperidin-3-yl)methyl]carbamate hydrochloride

The title compound (40.8 mg) was synthesized in a similar manner to Example 4 except that the compound of Reference Example 131 was used instead of the compound of Reference Example 22 in Example 4.

¹H-NMR (300 MHz, CDCl₃) 7.34-7.32(m, 5H), 6.89-6.85(m, 3H), 5.09(s, 2H), 4.10-4.02(m, 2H), 3.87(s, 3H), 3.79-3.62(m, 4H), 3.58-3.53(m, 2H), 3.34(s, 3H), 3.20-3.10(m, 2H), 2.58-2.17(m, 4H), 2.10-2.07(m, 2H), 1.78-1.76(m, 1H), 1.26-1.16(m, 6H).

MS (ESI+) 528(M⁺+1, 100%).

Example 63
N-((3R,6R)-6-{2-[Cyclopropyl(methoxyacetyl)amino]ethyl}piperidin-3-yl)-N-isopropyl-4-methoxy-3-(3-methoxypropoxy)benzamide hydrochloride

The title compound (60 mg) was synthesized in a similar manner to Example 4.

¹H NMR (400 MHz, DMSO-d₆) 9.76(m, 1H), 8.99-8.97(m, 1H), 6.99-6.97(m, 1H), 6.90-6.85(m, 2H), 4.30-4.22(m, 2H), 4.01(t, J=6.7 Hz, 2H), 3.92-3.59(m, 3H), 3.77(s, 3H), 3.53-3.40(m, 5H), 3.28(s, 3H), 3.22(s, 3H), 2.94-2.91(m, 1H), 2.73-2.63(m, 2H), 2.00-1.84(m, 6H), 1.58-1.55(m, 1H), 1.15-1.10(m, 6H), 0.78(m, 4H)

MS (ESI+) 520(M⁺+1, 100%).

Example 64
N-((3R,6R)-6-{2-[Cyclopropyl(3-methoxypropanoyl)amino]ethyl}piperidin-3-yl)-N-isopropyl-4-methoxy-3-(3-methoxypropoxy)benzamide hydrochloride

The title compound (14 mg) was synthesized in a similar manner to Example 4.

¹H NMR (400 MHz, DMSO-d₆) 9.2(m, 1H), 8.6(m, 1H), 7.00-6.97(m, 1H), 6.89-6.85(m, 2H), 4.01(t, J=6.7 Hz, 2H), 3.83-3.80(m, 2H), 3.78(s, 3H), 3.58-3.33(m, 9H), 3.23(s, 3H), 3.22(s, 3H), 2.96-2.95(m, 1H), 2.82-2.66(m, 3H), 1.98-1.86(m, 6H), 1.58-1.56(m, 1H), 1.23-1.12(m, 6H), 0.88-0.76(m, 4H).

MS (ESI+) 534(M⁺+1, 100%)

Example 65
N-((3R,6R)-6-{2-[Cyclopropyl(4-methoxybutanoyl)amino]ethyl}piperidin-3-yl)-N-isopropyl-4-methoxy-3-(3-methoxypropoxy)benzamide hydrochloride

The title compound (34 mg) was synthesized in a similar manner to Example 4.

¹H NMR (400 MHz, DMSO-d₆) 9.5(m, 1H), 8.8(m, 1H), 6.99-6.97(m, 1H), 6.90-6.85(m, 2H), 4.00(t, J=6.7 Hz, 2H), 3.98-3.48(m, 2H), 3.78(s, 3H), 3.48-3.24(m, 5H), 3.21(s, 3H), 3.19(s, 3H), 2.95-2.93(m, 1H), 2.76-2.66(m, 3H), 2.55(m, 2H), 1.98-1.82(m, 8H), 1.78-1.71(m, 2H), 1.58-1.55(m, 1H), 1.18-1.11(m, 6H), 0.86-0.74(m, 4H).

MS (ESI+) 548(M⁺+1, 100%)

Example 66
N-((3R,6R)-6-{2-[Cyclopropyl(4-hydroxybutanoyl)amino]ethyl}piperidin-3-yl)-N-isopropyl-4-methoxy-3-(3-methoxypropoxy)benzamide hydrochloride

The title compound (63 mg) was synthesized in a similar manner to Example 4.

¹H NMR (400 MHz, DMSO-d₆) 6.99-6.97(m, 1H), 6.91-6.87(m, 2H), 4.46(m, 1H), 4.23-4.00(t, J=6.7 Hz, 2H), 3.83-3.47(m, 3H), 3.78(s, 3H), 3.47-3.38(m, 6H), 3.23(s, 3H), 2.93(m, 1H), 2.74-2.52(m, 3H), 1.98-1.86(m, 7H), 1.68-1.55(m, 3H), 1.16-1.10(m, 6H), 0.85-0.83(m, 2H), 0.77-0.76(m, 2H).

MS (ESI+) 534(M⁺+1, 100%)

Example 67
N-((3R,6R)-6-{2-[Cyclopropyl(3-hydroxy-3-methylbutanoyl)amino]ethyl}piperidin-3-yl)-N-isopropyl-4-methoxy-3-(3-methoxypropoxy)benzamide hydrochloride

The title compound (30 mg) was synthesized in a similar manner to Example 4.

¹H-NMR (400 MHz, CD₃OD) 7.05-7.03(m, 1H), 6.98-6.95(m, 2H), 4.11-4.06(m, 4H), 3.94-3.91(m, 2H), 3.88(s, 3H), 3.67-3.59(m, 4H), 3.57-3.20(m, 3H), 3.32(s, 3H), 2.85-2.82(m, 1H), 2.60(m, 2H), 2.13-2.01(m, 7H), 1.86-1.83(m, 1H), 1.71-1.68(m, 2H), 1.40-1.21(m, 8H), 1.00-0.98(m, 2H), 0.88-0.85(m, 2H).

MS (ESI+) 548(M⁺+1, 100%)

Example 68
N-((3R,6R-6-{2-[Cyclopropyl(3-methyl-2-butenoyl)amino]ethyl}piperidin-3-yl)-N-isopropyl-4-methoxy-3-(3-methoxypropoxy)benzamide hydrochloride

The title compound (15 mg) was synthesized in a similar manner to Example 4.

¹H-NMR (400 MHz, CD₃OD) 7.05-7.03(m, 1H), 6.98-6.96(m, 2H), 6.35(s, 1H), 4.11-4.06(m, 4H), 3.88(s, 3H), 3.76-3.22(m, 8H), 3.32(s, 3H), 2.13-2.00(m, 8H), 1.93(s, 3H), 1.87-1.79(m, 2H), 1.32-1.13(m, 7H), 0.96-0.90(m, 3H), 0.80(m, 2H).

MS (ESI+) 530(M⁺+1, 100%)

Example 69
N⁴-Cyclopropyl-N⁴-[2-((2R,5R)-5-{isopropyl[4-methoxy-3-(3-methoxypropoxy)-benzoyl]amino}piperidin-2-yl)ethyl]-2,2-dimethylsuccinamide trifluoroacetate

The compound obtained in Reference Example 143 (32 mg) was dissolved in trifluoroacetic acid (3 ml), and the mixture was stirred at 25° C. for 5 hours. The reaction solution was concentrated under reduced pressure to give the title compound (30 mg) as a colorless oily compound.

¹H NMR (400 MHz, DMSO-d₆) 6.99-6.98(m, 1H), 6.90-6.85(m, 2H), 4.00(t, J=6.7 Hz, 2H), 3.84(m, 1H), 3.78(s, 3H), 3.65-3.33(m, 6H), 3.23(s, 3H), 3.05-2.71(m, 5H), 1.96-1.85(m, 6H), 1.60(m, 1H), 1.38-1.06(m, 7H), 1.18(s, 6H), 0.86-0.84(m, 2H), 0.77-0.76(m, 2H).

MS (ESI+) 557(M⁺+1, 100%)

Example 70
N-((3R,6R)-6-{2-[(Cyclohexylacetyl)(cyclopropyl)amino]ethyl}piperidin-3-yl)-N-isopropyl-4-methoxy-3-(3-methoxypropoxy)benzamide hydrochloride

The title compound (13 mg) was synthesized in a similar manner to Example 4.

¹H-NMR (400 MHz, CD₃OD) 7.03(m, 1H), 6.98-6.96(m, 2H), 4.11-4.06(m, 4H), 3.88(s, 3H), 3.70-3.40(m, 6H), 3.35(s, 3H), 3.27-3.22(m, 1H), 2.91-2.68(m, 4H), 2.16-2.00(m, 6H), 1.87-1.83(m, 1H), 1.33-1.20(m, 14H), 1.03-1.01(m, 2H), 0.90-0.89(m, 2H).

MS (ESI+) 572(M⁺+1, 100%)

Example 71
4-{Cyclopropyl[2-((2R,5R)-5-{isopropyl[4-methoxy-3-(3-methoxypropoxy)-benzoyl]amino}piperidin-2-yl)ethyl]amino}-4-oxobutanoic acid hydrochloride

The title compound (15 mg) was synthesized in a similar manner to Example 4.

¹H NMR (400 MHz, DMSO-d₆) 9.2(m, 1H), 8.6(m, 1H), 7.00-6.97(m, 1H), 6.89-6.85(m, 2H), 4.01(t, J=6.7 Hz, 2H), 3.83-3.80(m, 2H), 3.78(s, 3H), 3.58-3.33(m, 9H), 3.23(s, 3H), 2.96-2.95(m, 1H), 2.82-2.66(m, 3H), 1.98-1.86(m, 6H), 1.58-1.56(m, 1H), 1.23-1.12(m, 6H), 0.88-0.76(m, 4H).

MS (ESI+) 548(M⁺+1, 100%)

Example 72
N-((3R,6R)-6-{2-[[(2-chlorophenyl)acetyl](cyclopropyl)amino]ethyl}piperidin-3-yl)-N-isopropyl-4-methoxy-3-(3-methoxypropoxy)benzamide trifluoroacetate

tert-Butyl-(2S,5R)-2-[2-(cyclopropylamino)ethyl]-5-{isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]amino}piperidine-1-carboxylate (50.0 mg) was dissolved in dimethylformamide (0.5 ml), and thereto were added o-chlorophenylacetic acid (23.4 mg), 1-hydroxybenzotriazole (19.7 mg), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (29.8 mg) and triethylamine (37.9 μl), and the mixture was stirred at room temperature for 21 hours. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, water, and a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was dissolved in methanol (0.5 ml), and thereto was added a 4N solution of hydrochloric acid in 1,4-dioxane (0.5 ml), and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, purified by reverse phase silica gel column chromatography (developing solvent: acetonitrile/aqueous trifluoroacetic acid solution) to give the title compound (58.3 mg) as a colorless oily compound.

¹H-NMR (400 MHz, CD₃OD) 7.41-7.26(m, 4H), 7.04-6.95(m, 3H), 4.12-4.07(m, 5H), 3.98(s, 2H), 3.87(s, 3H), 3.59-3.55(m, 5H), 3.42-3.38(m, 2H), 3.34(s, 3H), 3.19-3.14(m, 1H), 3.01-2.96(m, 1H), 2.65-2.58(m, 1H), 2.12-1.98(m, 7H), 1.23-1.01(m, 6H), 1.01-0.98(m, 4H).

MS (ESI+) 600(M⁺+1, 100%)

Example 73
N-[(3R,6R)-6-(2-{Cyclopropyl[(2-methoxyphenyl)acetyl]amino}ethyl)piperidin-3-yl]-N-isopropyl-4-methoxy-3-(3-methoxypropoxy)benzamide trifluoroacetate

The title compound was synthesized in a similar manner to Example 72 as a colorless oily compound.

¹H-NMR (400 MHz, CD₃OD) 7.26-7.23(m, 2H), 7.18-7.16(m, 5H), 4.09-4.02(m, 5H), 3.98-3.3.89(m, 5H), 3.50(s, 3H), 3.72-3.48(m, 5H), 3.35-3.39(m, 2H), 3.35(s, 3H), 3.15-3.10(m, 1H), 2.95-2.81(m, 1H), 2.75-2.62(m, 1H), 2.12-1.99(m, 7H), 1.23-1.12(m, 6H), 1.02-0.94(m, 4H).

MS (ESI+) 596(M+1, 100%).

Example 74
N-{(3R,6R)-6-[2-(Cyclopropyl{[2-(trifluoromethyl)phenyl]acetyl}amino)ethyl]-piperidin-3-yl}-N-isopropyl-4-methoxy-3-(3-methoxypropoxy)benzamide trifluoroacetate

The title compound was synthesized in a similar manner to Example 72 as a colorless oily compound.

¹H-NMR (400 MHz, CD₃OD) 7.69-7.67(m, 1H), 7.59-7.56(m, 1H), 7.46-7.39(m, 2H), 7.03-6.93(m, 3H), 4.20(s, 2H), 4.09-4.04(m, 5H), 3.97(s, 3H), 3.63-3.50(m, 5H), 3.42-3.38(m, 2H), 3.35(s, 3H), 3.19-3.11(m, 1H), 2.95-2.89(m, 1H), 2.70-2.62(m, 1H), 2.12-1.80(m, 7H), 1.28-1.17(m, 6H), 1.05-0.94(m, 4H).

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

Example 75
N-((3R,6R)-6-{2-[Cyclopropyl(pyridin-2-ylacetyl)amino]ethyl}piperidin-3-yl)-N-isopropyl-4-methoxy-3-(3-methoxypropoxy)benzamide trifluoroacetate

The title compound was synthesized in a similar manner to Example 72 as a colorless oily compound.

¹H-NMR (400 MHz, CD₃OD) 8.77-8.72(m, 1H), 8.46-8.40(m, 1H), 7.92-7.86(m, 2H), 7.04-6.94(m, 3H), 4.11-4.01(m, 4H), 3.87(s, 3H), 3.70-3.49(m, 7H), 3.42-3.38(m, 3H), 3.35(s, 3H), 3.21-3.11(m, 1H), 2.99-2.89(m, 1H), 2.75-2.62(m, 1H), 2.18-1.80(m, 7H), 1.25-1.17(m, 6H), 1.10-0.98(m, 4H).

MS (ESI+) 567(M+1, 100%).

Example 76
N-[(3R,6R)-6-(2-{Cyclopropyl[(2R)-2-hydroxy-2-phenylacetyl]amino}ethyl)piperidin-3-yl]-N-isopropyl-4-methoxy-3-(3-methoxypropoxy)benzamide trifluoroacetate

The title compound was synthesized in a similar manner to Example 72 as a colorless oily compound.

¹H-NMR (400 MHz, CD₃OD) 7.49-7.47(m, 2H), 7.41-7.33(m, 3H), 7.03-6.94(m, 3H), 5.78(s, 1H), 4.10-3.97(m, 5H), 3.86(s, 3H), 3.85-3.76(m, 1H), 3.59-3.55(m, 4H), 3.42-3.38(m, 2H), 3.33(s, 3H), 3.19-3.15(m, 2H), 2.68-2.58(m, 1H), 2.44-2.37(m, 1H), 2.06-1.86(m, 7H), 1.23-1.11(m, 6H), 1.01-0.81(m, 4H).

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

Example 77
N-((3R,6R)-6-{2-[Cyclopropyl(3-hydroxy-2-phenylpropanoyl)amino]ethyl}piperidin-3-yl)-N-isopropyl-4-methoxy-3-(3-methoxypropoxy)benzamide trifluoroacetate

The title compound was synthesized in a similar manner to Example 72 as a colorless oily compound.

¹H-NMR (400 MHz, CD₃OD) 7.39-7.26(m, 5H), 7.03-6.94(m, 3H), 4.95-4.92(m, 1H), 4.67-4.63(m, 1H), 4.14-4.06(m, 5H), 3.86(s, 3H), 3.67-3.55(m, 6H), 3.59-3.55(m, 2H), 3.33(s, 3H), 3.19-3.15(m, 2H), 2.69-2.64(m, 2H), 2.06-1.92(m, 7H), 1.23-1.18(m, 6H), 0.94-0.72(m, 4H).

MS (ESI+) 596(M+1, 100%).

Example 78
N-((3R,6R)-6-{2-[Cyclopropyl(pyridin-3-ylacetyl)amino]ethyl}piperidin-3-yl)-N-isopropyl-4-methoxy-3-(3-methoxypropoxy)benzamide trifluoroacetate

The title compound was synthesized in a similar manner to Example 72 as a colorless oily product.

¹H-NMR (400 MHz, CD₃OD) 8.77-8.71(m, 2H), 8.46-8.40(m, 1H), 7.96-7.94(m, 1H), 7.03-6.93(m, 3H), 4.28-4.26(m, 2H), 4.09-4.07(m, 2H), 3.86(s, 3H), 3.70-3.49(m, 7H), 3.42-3.38(m, 3H), 3.35(s, 3H), 3.21-3.11(m, 1H), 2.99-2.89(m, 1H), 2.75-2.62(m, 1H), 2.18-1.80(m, 7H), 1.22-1.17(m, 6H), 1.10-0.99(m, 4H).

MS (ESI+) 567(M+1, 100%).

Example 79
N-((3R,6R)-6-{2-[Cyclopropyl(1H-imidazol-5-ylacetyl)amino]ethyl}piperidin-3-yl)-N-isopropyl-4-methoxy-3-(3-methoxypropoxy)benzamide trifluoroacetate

The title compound was synthesized in a similar manner to Example 72 as a colorless oily compound.

¹H-NMR (400 MHz, CD₃OD) 8.79(s, 1H), 7.41(s, 1H), 7.04-6.93(m, 3H), 4.17(s, 2H), 4.09-4.06(m, 5H), 3.86(s, 3H), 3.70-3.49(m, 8H), 3.35(s, 3H), 3.12-3.12(m, 1H), 2.89-2.81(m, 1H), 2.85-2.74(m, 1H), 2.13-1.98(m, 7H), 1.23-1.17(m, 6H), 1.09-0.95(m, 4H).

MS (ESI+) 556(M+1, 100%).

Example 80
N-((3R,6R)-6-{2-[Cyclopropyl(pyridin-4-ylacetyl)amino]ethyl}piperidin-3-yl)-N-isopropyl-4-methoxy-3-(3-methoxypropoxy)benzamide trifluoroacetate

The title compound was synthesized in a similar manner to Example 72 as a colorless oily product.

¹H-NMR (400 MHz, CD₃OD) 8.75-8.73(m, 2H), 8.00-7.98(m, 2H), 7.04-6.94(m, 3H), 4.37-4.35(m, 2H), 4.09-3.97(m, 4H), 3.87(s, 3H), 3.62-3.55(m, 6H), 3.42-3.38(m, 2H), 3.35(s, 3H), 3.21-3.10(m, 1H), 2.95-2.80(m, 1H), 2.70-2.62(m, 1H), 2.12-1.98(m, 7H), 1.23-1.17(m, 6H), 1.06-0.98(m, 4H).

MS (ESI+) 567(M+1, 100%).

Example 81
N-((3R,6R)-6-{2-[Cyclopropyl({3-[(methylsulfonyl)amino]phenyl}acetyl)amino]-ethyl}piperidin-3-yl)-N-isopropyl-4-methoxy-3-(3-methoxypropoxy)benzamide trifluoroacetate

Using 3-(methanesulfonylamino)phenylacetic acid (WO 2005/105780), the title compound was synthesized in a similar manner to Example 72 as a colorless oily compound.

¹H-NMR (400 MHz, CD₃OD) 7.32-7.26(m, 2H), 7.10-6.95(m, 5H), 4.10-3.97(m, 6H), 3.86(s, 3H), 3.64-3.57(m, 6H), 3.35(s, 3H), 3.28-3.15(m, 4H), 2.95(s, 3H), 2.82-2.76(m, 1H), 2.75-2.64(m, 1H), 2.06-2.02(m, 7H), 1.24-1.17(m, 6H), 1.02-0.90(m, 4H),

MS (ESI+) 659(M+1, 100%).

Example 82
N-((3R,6R)-6-{2-[[(3-Cyanophenyl)acetyl](cyclopropyl)amino]ethyl}piperidin-3-yl)-N-isopropyl-4-methoxy-3-(3-methoxypropoxy)benzamide trifluoroacetate

The title compound was synthesized in a similar manner to Example 72 as a colorless oily compound.

¹H-NMR (400 MHz, CD₃OD) 7.66-7.60(m, 3H), 7.51-7.48(m, 1H), 7.04-6.94(m, 3H), 4.09-4.07(m, 6H), 3.86(s, 3H), 3.62-3.50(m, 6H), 3.42-3.38(m, 2H), 3.33(s, 3H), 3.21-3.11(m, 1H), 2.95-2.88(m, 1H), 2.75-2.67(m, 1H), 2.08-1.80(m, 7H), 1.25-1.17(m, 6H), 1.04-0.94(m, 4H).

MS (ESI+) 591(M+1, 100%).

Example 83
N-((3R,6R)-6-{2-[(Anilinocarbonyl)(cyclopropyl)amino]ethyl}piperidin-3-yl)-N-isopropyl-4-methoxy-3-(3-methoxypropoxy)benzamide hydrochloride

The compound of Reference Example 147 was dissolved in methanol (0.5 ml), and thereto was added a 4N solution of hydrochloric acid in 1,4-dioxane (0.5 ml), and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure to give the title compound (53.7 mg) as a colorless oily compound.

¹H-NMR (400 MHz, CD₃OD) 7.46-7.42(m, 2H), 7.30-7.26(m, 2H), 7.08-6.94(m, 4H), 6.88-6.75(m, 2H), 4.10-4.07(m, 3H), 3.86(s, 3H), 3.68-3.65(m, 4H), 3.59-3.51(m, 4H), 3.33(s, 3H), 3.21-3.11(m, 1H), 2.95-2.88(m, 1H), 2.75-2.67(m, 1H), 2.08-1.80(m, 7H), 1.24-1.18(m, 6H), 1.05-0.89(m, 4H).

MS (ESI+) 567(M+1, 100%).

Example 84
N-((3R,6R)-6-{2-[(Benzylsulfonyl)(cyclopropyl)amino]ethyl}piperidin-3-yl)-N-isopropyl-4-methoxy-3-(3-methoxypropoxy)benzamide hydrochloride

The title compound was synthesized in a similar manner to Example 83 as a colorless oily compound.

¹H (400 MHz, CD₃OD) 7.43-7.36(m, 5H), 7.03-6.94(m, 3H), 4.88(m, 2H), 4.42(s, 2H), 4.09-3.93(m, 4H), 3.86(s, 3H), 3.68-3.64(m, 1H), 3.57(t, J=6.1 Hz, 2H), 3.51-3.47(m, 1H), 3.34(s, 3H), 3.27-3.18(m, 2H), 2.75-2.65(m, 1H), 2.66-2.55(m, 1H), 2.11-1.85(m, 7H), 1.23-1.18(m, 6H), 0.75-0.70(m, 4H).

MS (ESI+) 620(M+1, 50%).

Example 85
Ethyl cyclopropyl[2-((2R,5R)-5-{isopropyl[4-methoxy-3-(3-methoxypropoxy)benzoyl]-amino}piperidin-2-yl)ethyl]carbamate hydrochloride

The title compound was synthesized in a similar manner to Example 83 as a colorless oily compound.

¹H-NMR (400 MHz, CD₃OD) 7.04-7.01(m, 1H), 6.97-6.94(m, 2H), 4.88(m, 2H), 4.18-4.12(m, 2H), 4.10-4.07(m, 4H), 3.86(s, 3H), 3.71-3.64(m, 1H), 3.57(t, J=6.1 Hz, 2H), 3.54-3.48(m, 2H), 3.34(s, 3H), 3.27-3.20(m, 2H), 2.75-2.65(m, 2H), 2.10-2.00(m, 6H), 1.90-1.82(m, 1H), 1.28(t, J=7.1 Hz, 3H), 1.24-1.21(m, 6H), 0.82-0.68(m, 4H).

MS (ESI+) 520(M+1, 100%).

Example 86
3-(2-{Cyclopropyl[2-((2R,5R)-5-{isopropyl[4-methoxy-3-(3-methoxypropoxy)-benzoyl]amino}piperidin-2-yl)ethyl]amino}-2-oxoethyl)benzoic acid hydrochloride

The title compound was synthesized in a similar manner to Example 83 as a colorless oily compound.

¹H-NMR (400 MHz, CD₃OD) 7.96-7.91(m, 2H), 7.55-7.42(m, 2H), 7.03-6.91(m, 3H), 4.08-4.06(m, 4H), 4.01-3.89(m, 1H), 3.86(s, 3H), 3.75-3.51(m, 8H), 3.33(s, 3H), 3.29-3.18(m, 1H), 2.85-2.80(m, 1H), 2.66-2.54(m, 1H), 2.20-1.95(m, 4H) 1.87-1.80(m, 4H), 1.23-1.18(m, 6H), 1.10-1.02(m, 4H).

MS (ESI+) 610(M+1, 100%).

Example 87
N-((3R,6R)-6-{2-[{[3-(Aminocarbonyl)phenyl]acetyl}(cyclopropyl)amino]ethyl}-piperidin-3-yl)-N-isopropyl-4-methoxy-3-(3-methoxypropoxy)benzamide hydrochloride

The title compound was synthesized in a similar manner to Example 83 as a colorless oily compound.

¹H-NMR (400 MHz, CD₃OD) 7.81-7.75(m, 2H), 7.50-7.41(m, 2H), 7.03-6.91(m, 3H), 4.90-4.88(m, 4H), 4.09-3.91(m, 6H), 3.86(s, 3H), 3.70-3.55(m, 6H), 3.34(s, 3H), 3.27-3.18(m, 1H), 2.85-2.80(m, 1H), 2.70-2.60(m, 1H), 2.15-1.90(m, 6H), 1.87-1.80(m, 1H), 1.23-1.18(m, 6H), 1.04-0.93(m, 4H).

MS (ESI+) 609(M+1, 100%).

Example 88
Ethyl 3-(2-{cyclopropyl[2-((2R,5R)-5-{isopropyl[4-methoxy-3-(3-methoxypropoxy)-benzoyl]amino}piperidin-2-yl)ethyl]amino}-2-oxoethyl)benzoate hydrochloride

The title compound was synthesized in a similar manner to Example 83 as a colorless oily compound.

¹H-NMR (400 MHz, CD₃OD) 7.94-7.90(m, 2H), 7.55-7.42(m, 2H), 7.03-6.91(m, 3H), 4.33(q, J=7.1 Hz, 2H), 4.15-3.90(m, 6H), 3.86(s, 3H), 3.75-3.55(m, 7H), 3.33(s, 3H), 3.20-3.15(m, 1H), 2.85-2.80(m, 1H), 2.70-2.60(m, 1H), 2.15-1.90(m, 6H), 1.87-1.75(m, 2H), 1.37(t, J=7.1 Hz, 3H), 1.23-1.17(m, 6H), 1.02-0.93(m, 4H).

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

Example 89
N-[(rac.)-(3R,6R)-6-(2-{Cyclopropyl[(4-fluorophenyl)acetyl]amino}ethyl)piperidin-3-yl]-N-isopropyl-4-methoxy-3-(3-methoxypropoxy)benzamide hydrochloride

The title compound (3.8 mg) was synthesized in a similar manner to Example 4.

¹H-NMR (400 MHz, MeOD) 7.22-7.19(m, 2H), 6.97-6.92(m, 3H), 6.87-6.85(m, 2H), 4.00-3.95(m, 3H), 3.88(s, 2H), 3.77(s, 3H), 3.68-3.41(m, 7H), 3.24(s, 3H), 3.08-3.06(m, 1H), 2.73(brs, 1H), 2.59(brs, 1H), 1.97-1.88(m, 6H), 1.71-1.69(m, 1H), 1.20-1.09(m, 6H), 0.92-0.83(m, 4H).

MS (ESI+) 584(M⁺+1, 100%).

Example 90
N-((rac.)-(3R,6R)-6-{2-[Benzoyl(cyclopropyl)amino]ethyl}piperidin-3-yl)-N-isopropyl-4-methoxy-3-(3-methoxypropoxy)benzamide hydrochloride

The title compound (3.8 mg) was synthesized in a similar manner to Example 4.

¹H-NMR (400 MHz, MeOD) 7.46-7.42(m, 5H), 6.95-6.86(m, 3H), 4.01-3.95(m, 3H), 3.77(s, 3H), 3.67-3.54(m, 5H), 3.49-3.41(m, 3H), 3.24(s, 3H), 2.86(brs, 1H), 2.64(brs, 1H), 2.22-2.16(m, 1H), 1.97-1.91(m, 3H), 1.78(m, 1H), 1.51(m, 1H), 1.24-1.10(m, 7H), 0.54(brs, 2H), 0.42(brs, 2H).

MS (ESI+) 552(M⁺+1, 100%).

Example 91
N-((rac.)-(3R,6R)-6-{2-[Cyclopropyl(3-phenylpropanoyl)amino]ethyl}piperidin-3-yl)-N-isopropyl-4-methoxy-3-(3-methoxypropoxy)benzamide hydrochloride

The title compound (9.7 mg) was synthesized in a similar manner to Example 4.

¹H-NMR (400 MHz, MeOD) 7.20-7.10(m, 5H), 6.94(d, J=8.4 Hz, 1H), 6.89-6.86(m, 2H), 4.01-3.98(m, 3H), 3.90-3.82(m, 1H), 3.78(s, 3H), 3.65-3.47(m, 7H), 3.37-3.30(m, 1H), 3.25(s, 3H), 3.07(m, 2H), 2.62-2.50(m, 3H), 1.98-1.85(m, 7H), 1.21-1.11(m, 6H), 0.87-0.79(m, 2H), 0.74-0.68(m, 2H).

MS (ESI+) 580(M⁺+1, 100%).

Example 92
N-Isopropyl-3-(3-methoxypropoxy)-N-[(3R)-piperidin-3-yl]benzamide hydrochloride

The title compound (193 mg) was synthesized in a similar manner to Example 4.

¹H-NMR (400 MHz, MeOD) 7.33-7.29(m, 1H), 6.97-6.94(m, 1H), 6.84-6.83(m, 2H), 4.03-4.00(m, 3H), 3.84(brs, 1H), 3.68-3.59(m, 1H), 3.53-3.48(m, 2H), 3.27-3.24(m, 5H), 2.90-2.87(m, 1H), 2.69(brs, 1H), 2.06-1.83(m, 5H), 1.16(brs, 6H).

MS (ESI+) 335(M⁺+1, 100%).

Example 93
N-Isopropyl-4-methoxy-3-(3-methoxypropoxy)-N-[(2R,3R)-2-methylpiperidin-3-yl]benzamide

The title compound (1.6 mg) was synthesized in a similar manner to Example 2.

¹H-NMR (400 MHz, CDCl₃) 6.91-6.82(m, 3H), 4.24-4.19(m, 1H), 4.15-4.10(m, 3H), 3.90(s, 3H), 3.65-3.55(m, 2H), 3.36-3.34(m, 5H), 3.14(brs, 1H), 3.03-2.95(m, 1H), 2.24(m, 1H), 2.15-2.00(m, 5H), 1.44-1.33(m, 3H), 1.27-1.18(m, 6H).

MS (ESI+) 379(M⁺+1, 100%).

Example 94
N-Isopropyl-3,5-bis(3-methoxypropoxy)-N-[(3R)-piperidin-3-yl]benzamide hydrochloride

The title compound (338 mg) was synthesized in a similar manner to Example 4.

¹H NMR (400 MHz, DMSO-d₆) 9.27-9.16(m, 2H), 6.5 1(t, J=2.2 Hz, 1H), 6.42(d, J=2.2 Hz, 2H), 4.01(t, J=6.4 Hz, 4H), 3.73-3.59(m, 2H), 3.49-3.40(m, 7H), 3.24(s, 6H), 3.14-3.12(m, 1H), 2.76-2.73(m, 1H), 2.55-2.52(m, 1H), 2.02-1.71(m, 6H),1.14-1.08(m, 6H).

MS (ESI+) 423(M⁺+1, 100%).

Example 95
4-Bromo-N-isopropyl-3-(3-methoxypropoxy)-N-[(3R)-piperidin-3-yl]benzamide hydrochloride

The title compound (83.5 mg) was synthesized in a similar manner to Example 4.

¹H-NMR (300 MHz, MeOD) 7.63(d, J=7.8 Hz, 1H), 7.02(d, J=1.8 Hz, 1H), 6.83(dd, J=1.8, 7.8 Hz, 2H), 4.16(t, J=6.3 Hz, 2H), 4.04-3.90(m, 2H), 3.74-3.56(m, 4H), 3.35(m, 4H), 2.98-2.90(m, 1H), 2.75(brs, 1H), 2.11-2.03(m, 3H), 1.94-1.90(m, 2H), 1.24(brs, 6H).

MS (ESI+) 413(M⁺+1, 50%), 415(M⁺+1, 50%).

Example 96
3-(Benzyloxy)-N-isopropyl-5-(3-methoxypropoxy)-N-[(3R)-piperidin-3-yl]benzamide hydrochloride

The title compound (50.6 mg) was synthesized in a similar manner to Example 4.

¹H-NMR (300 MHz, MeOD) 7.43-7.32(m, 5H), 6.66-6.64(m, 1H), 6.52-6.47(m, 2H), 5.10(s, 2H), 4.05(m, 3H), 3.88(brs, 1H), 3.75-3.53(m, 6H), 2.96-2.87(m, 1H), 2.74(m, 1H), 2.04-1.96(m, 3H), 1.89-1.86(m, 2H), 1.17(brs, 6H).

MS (ESI+) 441(M⁺+1, 100%).

Example 97
3-Hydroxy-N-isopropyl-5-(3-methoxypropoxy)-N-[(3R)-piperidin-3-yl]benzamide hydrochloride

The title compound (30.2 mg) was synthesized in a similar manner to Example 4.

¹H-NMR(300 MHz, MeOD) 6.44-6.42(m, 1H), 6.36-6.31(m, 2H), 4.04-4.00(m, 4H), 3.74-3.63(m, 2H), 3.59-3.53(m, 3H), 3.35(s, 3H), 2.97-2.90(m, 1H), 2.73(brs, 1H), 2.09-1.96(m, 3H), 1.91-1.87(m, 2H), 1.22(brs, 6H).

MS (ESI+) 351(M⁺+1, 100%).

Example 98
N-Isopropyl-3-(3-methoxypropoxy)-5-phenoxy-N-[(3R)-piperidin-3-yl]benzamide hydrochloride

The title compound (42.7 mg) was synthesized in a similar manner to Example 4.

¹H-NMR (400 MHz, MeOD) 7.41-7.37(m, 2H), 7.19-7.15(m, 1H), 7.05-7.03(m, 2H), 6.63-6.62(m, 2H), 6.43(m, 1H), 4.06-3.94(m, 4H), 3.75-3.66(m, 1H), 3.59-3.48(m, 3H), 3.37-3.32(m, 4H), 2.95-2.89(m, 1H), 2.70(brs, 1H), 2.07-1.97(m, 3H), 1.87-1.84(m, 2H), 1.19(brs, 6H).

MS (ESI+) 427(M⁺+1, 100%).

Example 99
N-Isopropyl-3-methoxy-5-(3-methoxypropoxy)-N-[(3R)-piperidin-3-yl]benzamide hydrochloride

The title compound (63.0 mg) was synthesized in a similar manner to Example 4.

¹H-NMR (400 MHz, MeOD) 6.57-6.56(m, 1H), 6.46(brs, 2H), 4.07-4.04(m, 3H), 3.93-3.85(m, 1H), 3.80(s, 3H), 3.75-3.66(m, 2H), 3.59-3.54(m, 2H), 3.39(m, 1H), 3.34(s, 3H), 2.96-2.93(m, 1H), 2.74(brs, 1H), 2.04-1.98(m, 3H), 1.91-1.89(m, 2H), 1.22(brs, 6H).

MS (ESI+) 365(M⁺+1, 100%).

Example 100
3-(Cyclopropylmethoxy)-N-isopropyl-5-(3-methoxypropoxy)-N-[(3R)-piperidin-3-yl]-benzamide hydrochloride

The title compound (77.0 mg) was synthesized in a similar manner to Example 4.

¹H-NMR (400 MHz, MeOD) 6.55(m, 1H), 6.45(m, 2H), 4.07-4.04(m, 3H), 3.93(brs, 1H), 3.83-3.81(m, 2H), 3.74-3.66(m, 2H), 3.59-3.54(m, 2H), 3.39(m, 1H), 3.34(s, 3H), 2.93(m, 1H), 2.74(brs, 1H), 2.04-1.99(m, 3H), 1.91-1.89(m, 2H), 1.22(brs, 6H), 0.62-0.60(m, 2H), 0.35-0.34(m, 2H).

MS (ESI+) 405(M⁺+1, 100%).

Example 101
3-Isopropyl-N-isopropyl-5-(3-methoxypropoxy)-N-[(3R)-piperidin-3-yl]benzamide hydrochloride

The title compound (68.0 mg) was synthesized in a similar manner to Example 4.

¹H-NMR (400 MHz, MeOD) 6.54-6.53(m, 1H), 6.44-6.43(m, 2H), 4.64-4.57(m, 1H), 4.06-4.03(m, 3H), 3.95(brs, 1H), 3.75-3.66(m, 1H), 3.59-3.52(m, 3H), 3.39(m, 1H), 3.34(s, 3H), 2.97-2.91(m, 1H), 2.74(brs, 1H), 2.08-1.98(m, 3H), 1.92-1.89(m, 2H), 1.30(d, J=6.0 Hz, 6H), 1.22(brs, 6H).

MS (ESI+) 393(M⁺+1, 100%).

Example 102
3-(Cyclohexyloxy)-N-isopropyl-5-(3-methoxypropoxy)-N-[(3R)-piperidin-3-yl]-benzamide hydrochloride

The title compound (68.0 mg) was synthesized in a similar manner to Example 4.

¹H-NMR (400 MHz, MeOD) 6.54-6.53(m, 1H), 6.44(m, 2H), 4.32-4.30(m, 2H), 4.06-3.95(m, 4H), 3.57-3.54(m, 3H), 3.39(m, 1H), 3.34(s, 3H), 2.94(m, 1H), 2.74(brs, 1H), 2.05-1.89(m, 3H), 1.78(m, 2H), 1.59-1.22(m, 16H).

MS (ESI+) 433(M⁺+1, 100%).

Example 103
N-Isopropyl-5-(3-methoxypropoxy)-N-[(3R)-piperidin-3-yl]biphenyl-3-carboxyamide hydrochloride

The title compound (59.0 mg) was synthesized in a similar manner to Example 4.

¹H-NMR(300 MHz, MeOD) 7.63-7.60(m, 2H), 7.48-7.37(m, 3H), 7.26-7.24(m, 1H), 7.14-7.13(m, 1H), 6.89-6.88(m, 1H), 4.18-4.03(m, 4H), 3.74-3.57(m, 4H), 3.39(m, 1H), 3.35(s, 3H), 2.96(m, 1H), 2.79(m, 1H), 2.10-2.02(m, 3H), 1.93(m, 2H), 1.25(brs, 6H).

MS (ESI+) 411(M⁺+1, 100%).

Example 104
4-(Benzyloxy)-N-isopropyl-3-(3-methoxypropoxy)-N-[(3R)-piperidin-3-yl]benzamide hydrochloride

The title compound (38.0 mg) was synthesized in a similar manner to Example 4.

¹H-NMR (400 MHz, MeOD) 7.46(m, 2H), 7.38-7.34(m, 2H), 7.32-7.28(m, 1H), 7.07(d, J=8.2 Hz, 1H), 6.98(d, J=1.8 Hz, 1H), 6.89(dd, J=1.8, 8.2 Hz, 1H), 5.14(s, 2H),4.11(t, J=6.2 Hz, 2H), 4.00(brs, 1H), 3.75-3.56(m, 5H), 3.39(m, 1H), 3.30(s, 3H), 2.97-2.90(m, 1H), 2.69(brs, 1H), 2.07-2.01(m, 3H), 1.91-1.88(m, 2H), 1.24(brs, 6H).

MS (ESI+) 441(M⁺+1, 100%).

Example 105
4-Hydroxy-N-isopropyl-3-(3-methoxypropoxy)-N-[(3R)-piperidin-3-yl]benzamide hydrochloride

The title compound (65.0 mg) was synthesized in a similar manner to Example 4.

¹H-NMR (400 MHz, MeOD) 6.93(d, J=1.7 Hz, 1H), 6.86(d, J=8.1 Hz, 1H), 6.82(dd, J=1.7, 8.1 Hz, 1H), 4.14-4.11(m, 3H), 4.04(brs, 1H), 3.61-3.52(m, 3H), 3.39-3.35(m, 5H), 2.98-2.90(m, 1H), 2.78(brs, 1H), 2.09-2.03(m, 3H), 1.92-1.82(m, 2H), 1.26(brs, 6H).

MS (ESI+) 351(M⁺+1, 100%).

Example 106
4-Butyl-N-isopropyl-3-(3-methoxypropoxy)-N-[(3R)-piperidin-3-yl]benzamide hydrochloride

The title compound (8.0 mg) was synthesized in a similar manner to Example 4.

¹H-NMR (400 MHz, MeOD) 7.21-7.19(m, 1H), 6.87-6.83(m, 2H), 4.35-4.29(m, 2H), 4.22-4.16(m, 1H), 4.10-4.06(m, 2H), 3.74-3.65(m, 3H), 3.35-3.32(m, 4H), 2.95(m, 1H), 2.78-2.62(m, 3H), 2.08-2.01(m, 3H), 1.90(m, 2H), 1.59-1.54(m, 2H), 1.41-1.24(m, 8H), 0.94(t, J=7.2 Hz, 3H).

MS (ESI+) 391(M⁺+1, 100%).

Example 107
N-Isopropyl-3-(3-methoxypropoxy)-4-phenoxyN-[(3R)-piperidin-3-yl]benzamide hydrochloride

The title compound (48.8 mg) was synthesized in a similar manner to Example 4.

¹H-NMR (400 MHz, MeOD) 7.32-7.28(m, 2H), 7.11-7.02(m, 3H), 6.97-6.95(m, 1H), 6.89-6.87(m, 2H), 4.06-4.03(m, 4H), 3.75-3.65(m, 1H), 3.40-3.35(m, 2H), 3.23(t, J=6.2 Hz, 2H), 3.19(s, 3H), 2.98-2.92(m, 1H), 2.76(brs, 1H), 2.09-2.04(m, 1H), 1.94-1.81(m, 4H), 1.27(brs, 6H).

MS (ESI+) 427(M⁺+1, 100%).

Example 108
N-Isopropyl-3-(3-methoxypropoxy)-4-(2-phenylethyl)-N-[(3R)-piperidin-3-yl]-benzamide hydrochloride

The title compound (9.4 mg) was synthesized in a similar manner to Example 4.

¹H-NMR (400 MHz, MeOD) 7.24-7.20(m, 2H), 7.14-7.13(m, 4H), 6.89-6.88(m, 1H), 6.81-6.79(m, 1H), 4.32-4.30(m, 6H), 4.10-4.07(m, 3H), 3.79-3.61(m, 1H), 3.35(s, 3H), 2.95-2.87(m, 5H), 2.11-2.05(m, 3H), 1.93-1.90(m, 2H), 1.23(brs, 6H).

MS (ESI+) 439(M⁺+1, 100%).

Example 109
4-Isopropoxy-N-isopropyl-3-(3-methoxypropoxy)-N-[(3R)-piperidin-3-yl]benzamide hydrochloride

The title compound (49.8 mg) was synthesized in a similar manner to Example 4.

¹H-NMR (400 MHz, MeOD) 7.02(d, J=8.2 Hz, 1H), 6.96(d, J=1.8 Hz, 1H), 6.90(dd, J=1.8, 8.2 Hz, 1H), 4.62-4.56(m, 1H), 4.17-4.02(m, 4H), 3.77-3.63(m, 4H), 3.39(m, 1H), 3.34(s, 3H), 2.97-2.91(m, 1H), 2.70(brs, 1H), 2.07-2.00(m, 3H), 1.92-1.89(m, 2H), 1.32(d, J=6.1 Hz, 6H), 1.25(m, 6H).

MS (ESI+) 393(M⁺+1, 100%).

Example 110
4-(Cyclopropylmethoxy)-N-isopropyl-3-(3-methoxypropoxy)-N-[(3R)-piperidin-3-yl]benzamide hydrochloride

The title compound (48.2 mg) was synthesized in a similar manner to Example 4.

¹H-NMR (400 MHz, MeOD) 6.99-6.90(m, 3H), 4.14-4.09(m, 2H), 4.00(m, 2H), 3.87(m, 2H), 3.72-3.59(m, 4H), 3.39(m, 1H), 3.34(s, 3H), 2.92(m, 1H), 2.69(brs, 1H), 2.04(m, 3H), 1.88(m, 2H), 1.24(m, 7H), 0.60(m, 2H), 0.35(m, 2H).

MS (ESI+) 405(M⁺+1, 100%).

Example 111
4-(Cyclohexyloxy)-N-isopropyl-3-(3-methoxypropoxy)-N-[(3R)-piperidin-3-yl]-benzamide hydrochloride

The title compound (10.0 mg) was synthesized in a similar manner to Example 4.

¹H-NMR (400 MHz, MeOD) 7.03-7.01(m, 1H), 6.96-6.95(m, 1H), 6.89(m, 1H), 4.34-4.30(m, 2H), 4.11-3.98(m, 4H), 3.80-3.58(m, 3H), 3.39(m, 1H), 3.34(s, 3H), 2.92(m, 1H), 2.69(brs, 1H), 2.09-2.01(m, 3H), 1.92-1.80(m, 6H), 1.58-1.53(m, 3H), 1.44-1.35(m, 3H), 1.25(brs, 6H).

MS (ESI+) 433(M⁺+1, 100%).

Example 112
2-Bromo-4-isopropoxy-N-isopropyl-5-(3-methoxypropoxy)-N-[(3R)-piperidin-3-yl]-benzamide hydrochloride

The title compound (27.5 mg) was synthesized in a similar manner to Example 4.

¹H-NMR (400 MHz, MeOD) 7.18(m, 1H), 6.93-6.89(m, 1H), 4.59-4.56(m, 1H), 4.09-4.05(m, 3H), 3.79-3.56(m, 4H), 3.39-3.36(m, 2H), 3.34(s, 3H), 2.97(m, 1H), 2.80(m, 1H), 2.11-1.99(m, 3H), 1.95-1.86(m, 2H), 1.35-1.28(m, 9H), 1.19-1.16(m, 3H).

MS (ESI+) 471(M⁺+1, 50%), 473(M⁺+1, 50%).

Example 113
5-Isopropoxy-N-isopropyl-4-(3-methoxypropoxy)-N-[(3R)-piperidin-3-yl]biphenyl-2-carboxamide hydrochloride

The title compound (6.0 mg) was synthesized in a similar manner to Example 4.

¹H-NMR (400 MHz, MeOD) 7.48-7.35(m, 5H), 7.01(s, 1H), 6.93-6.89(m, 1H), 4.67-4.61(m, 1H), 4.31-4.30(m, 2H), 4.13(m, 2H), 3.78-3.36(m, 6H), 3.31(s, 3H), 2.99-2.85(m, 1H), 2.09-2.03(m, 3H), 1.82-1.73(m, 2H), 1.38-1.26(m, 9H), 1.00(d, J=6.6 Hz, 3H).

MS (ESI+) 469(M⁺+1, 100%).

Example 114
4-Ethoxy-N-isopropyl-3-(3-methoxypropoxy)-N-[(3R)-piperidin-3-yl]benzamide hydrochloride

The title compound (59.5 mg) was synthesized in a similar manner to Example 4.

¹H-NMR (400 MHz, MeOD) 7.00(d, J=8.2 Hz, 1H), 6.95(d, J=1.8 Hz, 1H), 6.91(dd, J=1.8, 8.2 Hz, 1H), 4.12-4.02(m, 6H), 3.74-3.57(m, 4H), 3.39(m, 1H), 3.34(s, 3H), 2.97-2.91(m, 1H), 2.70(brs, 1H), 2.08-2.00(m, 3H), 1.92-1.89(m, 2H), 1.41(t, J=7.0 Hz, 3H), 1.25(brs, 6H).

MS (ESI+) 379(M⁺+1, 100%).

Example 115
N-Isopropyl-3-(3-methoxypropoxy)-N-[(3R)-piperidin-3-yl]-4-propoxybenzamide hydrochloride

The title compound (59.1 mg) was synthesized in a similar manner to Example 4.

¹H-NMR (400 MHz, MeOD) 7.00(d, J=8.2 Hz, 1H), 6.95(d, J=1.8 Hz, 1H), 6.91(dd, J=1.8, 8.2 Hz, 1H), 4.09(t, J=6.3 Hz, 2H), 4.01-3.98(m, 3H), 3.75-3.58(m, 5H), 3.39(m, 1H), 3.34(s, 3H), 2.98-2.91(m, 1H), 2.70(brs, 1H), 2.05-2.00(m, 3H), 1.93-1.78(m, 4H), 1.26-1.24(m, 6H), 1.06(t, J=7.4 Hz, 3H).

MS (ESI+) 393(M⁺+1, 100%).

Example 116
4-(2-Fluoroethoxy)-N-isopropyl-3-(3-methoxypropoxy)-N-[(3R)-piperidin-3-yl]-benzamide hydrochloride

The title compound (60.0 mg) was synthesized in a similar manner to Example 4.

¹H-NMR (400 MHz, MeOD) 7.05(d, J=8.2 Hz, 1H), 6.98(d, J=1.8 Hz, 1H), 6.92(dd, J=1.8, 8.2 Hz, 1H), 4.83-4.78(m, 1H), 4.68-4.66(m, 1H), 4.35-4.30(m, 1H), 4.25-4.23(m, 1H), 4.11(t, J=6.2 Hz, 2H), 4.00(m, 2H), 3.87-3.55(m, 4H), 3.39(m, 1H), 3.34(s, 3H), 2.97-2.91(m, 1H), 2.69(brs, 1H), 2.09-2.01(m, 3H), 1.93-1.90(m, 2H), 1.25(m, 6H).

MS (ESI+) 397(M⁺+1, 100%).

Example 117
3-[4-Chloro-5-({isopropyl[(3R)-piperidin-3-yl]amino}carbonyl)-2-methoxyphenoxy]-propanoic acid hydrochloride

The title compound (7.0 mg) was synthesized in a similar manner to Example 4.

MS (ESI+) 399(M⁺+1, 100%).

Example 118
4-Isopropoxy-N-isopropyl-5-(3-methoxypropoxy)-N-[(3R)-piperidin-3-yl]-2-propyl-benzamide hydrochloride

The title compound (12.7 mg) was synthesized in a similar manner to Example 4.

¹H-NMR (400 MHz, MeOD) 6.88(m, 1H), 6.77-6.73(m, 1H), 4.57-4.54(m, 1H), 4.12-4.03(m, 3H), 3.84-3.56(m, 5H), 3.41-3.39(m, 1H), 3.34(s, 3H), 2.96(m, 1H), 2.80(m, 1H), 2.51-2.44(m, 2H), 2.10-1.98(m, 3H), 1.91-1.89(m, 2H), 1.67-1.56(m, 2H), 1.31(t, J=6.0 Hz, 6H), 1.21-1.17(m, 6H), 0.95(t, J=7.3 Hz, 3H).

MS (ESI+) 435(M⁺+1, 100%).

Example 119
N-Isopropyl-3-(3-methoxypropoxy)-4-morpholin-4-yl-N-[(3R)-piperidin-3-yl]-benzamide hydrochloride

The title compound (12.7 mg) was synthesized in a similar manner to Example 4.

¹H-NMR (400 MHz, MeOD) 7.62(d, J=8.2 Hz, 1H), 7.24(s, 1H), 7.10(d, J=8.2 Hz, 1H), 4.31(t, J=6.2 Hz, 2H), 4.08-4.06(m, 5H), 3.89-3.87(m, 1H), 3.75-3.58(m, 7H), 3.39-3.36(m, 5H), 2.95(m, 1H), 2.78(brs, 1H), 2.19-2.13(m, 2H), 2.09-2.05(m, 1H), 1.95-1.89(m, 2H), 1.24(brs, 6H).

MS (ESI+) 420(M⁺+1, 100%).

Example 120
Diethyl 4-[4-({isopropyl[(3R)-piperidin-3-yl]amino}carbonyl)-2-(3-methoxypropoxy)-phenyl-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate

The title compound (17.3 mg) was synthesized in a similar manner to Example 10.

¹H-NMR (400 MHz, MeOD) 7.21(d, J=7.6 Hz, 1H), 6.72-6.69(m, 2H), 5.75(s,1H), 5.19(s, 1H), 4.05-3.95(m, 8H), 3.52(t, J=6.6 Hz, 2H), 3.38-3.33(m, 1H), 3.36(s, 3H), 3.00-2.98(m, 2H), 2.70-2.56(m, 3H), 2.26(s, 6H), 2.06-1.99(m, 2H), 1.77(m, 2H), 1.34-1.13(m, 12H).

MS (ESI+) 586(M⁺+1, 100%).

Example 121
2-Chloro-4-isopropoxy-N-isopropyl-5-(3-methoxypropoxy)-N-[(3R)-piperidin-3-yl]-benzamide hydrochloride

The title compound (69.7 mg) was synthesized in a similar manner to Example 4.

¹H-NMR (400 MHz, MeOD) 7.05-7.04(m, 1H), 6.93-6.89(m, 1H), 4.62-4.56(m, 1H), 4.12-4.05(m, 3H), 3.79-3.72(m, 1H), 3.67-3.56(m, 4H), 3.41-3.38(m, 1H), 3.35(s, 3H), 2.97(m, 1H), 2.81(m, 1H), 2.11-1.97(m, 3H), 1.94-1.85(m, 2H), 1.38-1.16(m, 12H).

MS (ESI+) 427(M⁺+1, 100%).

Example 122
Methyl{2-[4-chloro-5-({isopropyl[(3R)-piperidin-3-yl]amino}carbonyl-2-methoxy-phenoxy]ethyl}carbamate hydrochloride

The title compound (50.0 mg) was synthesized in a similar manner to Example 4.

¹H-NMR (400 MHz, MeOD) 7.08-7.07(m, 1H), 6.97-6.93(m, 1H), 4.12-4.02(m, 3H), 3.87(s, 3H), 3.77-3.72(m, 1H), 3.68-3.63(m, 4H), 3.59-3.52(m, 1H), 3.48-3.45(m, 2H), 3.40-3.37(m, 1H), 2.11-2.07(m, 1H), 1.94-1.82(m, 2H), 1.27-1.16(m, 6H).

MS (ESI+) 428(M⁺+1, 100%).

Example 123
Methyl{2-[2-bromo-5-({isopropyl[(3R)-piperidin-3-yl]amino}carbonyl)phenoxy]-ethyl}carbamate hydrochloride

The title compound (24.9 mg) was synthesized in a similar manner to Example 4.

¹H-NMR (400 MHz, MeOD) 7.63(d, J=8.0 Hz, 1H), 7.05(d, J=1.7 Hz, 1H), 6.86(dd, J=1.7, 8.0 Hz, 1H), 4.12(t, J=5.7 Hz, 1H), 4.05(brs, 1H), 3.90-3.88(m, 1H), 3.64(s, 3H), 3.59-3.48(m, 3H), 3.35(m, 2H), 2.94-2.91(m, 1H), 2.76(brs, 1H), 2.12-2.06(m, 1H), 1.97-1.84(m, 2H), 1.23(brs, 6H).

MS (ESI+) 442(M⁺+1, 50%), 444(M⁺+1, 50%).

Example 124
Methyl{3-[5-({isopropyl[(3R)-piperidin-3-yl]amino}carbonyl)-2-methoxyphenoxy]-propyl}carbamate hydrochloride

The title compound (114 mg) was synthesized in a similar manner to Example 4.

¹H-NMR (400 MHz, MeOD) 7.06-7.05(m, 1H), 6.92-6.88(m, 1H), 4.13-4.03(m, 3H), 3.86(s, 3H), 3.77-3.72(m, 1H), 3.67-3.57(m, 5H), 3.41-3.28(m, 3H), 2.98-2.91(m, 1H), 2.85-2.77(m, 1H), 2.11-2.07(m, 1H), 1.99-1.84(m, 4H), 1.28-1.16(m, 6H).

MS (ESI+) 442(M⁺+1, 100%).

Example 125
4-(Cyclopentyloxy)-N-isopropyl-3-(3-methoxypropoxy)-N-[(3R)-piperidin-3-yl]-benzamide hydrochloride

The title compound (144 mg) was synthesized in a similar manner to Example 4.

¹H-NMR (400 MHz, MeOD) 7.00(d, J=8.2 Hz, 1H), 6.94(d, J=1.9 Hz, 1H), 6.91(dd, J=1.9, 8.2 Hz, 1H), 4.09-4.04(m, 4H), 3.60-3.57(m, 3H), 3.39-3.30(m, 6H), 2.97-2.90(m, 1H), 2.69(brs, 1H), 2.08-1.99(m, 3H), 1.94-1.79(m, 8H), 1.69-1.64(m, 2H), 1.26(brs, 6H).

MS (ESI+) 419(M⁺+1, 100%).

Example 126
N-Isopropyl-4-(4-methoxybutyl)-2,2-dimethyl-3-oxo-N-[(3R)-piperidin-3-yl]-3,4-dihydro-2H-1,4-benzoxazine-6-carboxyamide hydrochloride

The title compound (20 mg) was synthesized in a similar manner to Example 4.

MS (ESI+) 432(M⁺+1, 100%).

Examples 127 to 135

The compounds of Examples 127-135 are listed in the following Table, said compounds being synthesized as an analog compounds of Example 126.

[Chemical formula 450]

Ex. No.
R^1d
R^1e
R^1f

127
MeO₂CNH(CH₂)₂
Me
Me

128
MeO(CH₂)₃
(S)-Ph(2,5-F)
(R)-Me

129
MeO(CH₂)₃
Me
Et

130
MeO(CH₂)₃
H
(R)-Me

131
MeO(CH₂)₃
H
Et

132
MeO(CH₂)₃
CONMe₂
Me

133
MeO₂CNH(CH₂)₂
(S)-Ph(2,5-F)
(R)-Me

134
MeO(CH₂)₃
Me
Me

135
MeO(CH₂)₄
CH2OMe
Me

The physiochemical properties of the above compounds are shown below.

The compound of Example 127: MS (ESI+) 447(M⁺+1, 100%).
The compound of Example 128: MS (ESI+) 516(M⁺+1, 100%).
The compound of Example 129: MS (ESI+) 432(M⁺+1, 100%).
The compound of Example 130: MS (ESI+) 404(M⁺+1, 100%).
The compound of Example 131: MS (ESI+) 418(M⁺+1, 100%).
The compound of Example 132: MS (ESI+) 475(M⁺+1, 100%).
The compound of Example 133: MS (ESI+) 545(M⁺+1, 100%).
The compound of Example 134: MS (ESI+) 418(M⁺+1, 100%).
The compound of Example 135: MS (ESI+) 448(M⁺+1, 100%).

Examples 136-169

The compounds of Examples 136-169 are listed in the following Tables, said compounds being synthesized as an analog compound of Example 1.

TABLE 9

Ex. No.
Structure
MS (ESI+)

136

455 (M⁺ + 1, 100%).

137

498 (M⁺ + 1, 100%).

138

584 (M⁺ + 1, 100%).

139

464 (M⁺ + 1, 100%).

140

463 (M⁺ + 1, 100%).

141

449 (M⁺ + 1, 100%).

142

407 (M⁺ + 1, 100%).

143

407 (M⁺ + 1, 100%).

144

576 (M⁺ + 1, 100%).

145

455 (M⁺ + 1, 100%).

146

534 (M⁺ + 1, 100%).

147

528 (M⁺ + 1, 100%).

148

618 (M⁺ + 1, 100%).

149

598 (M⁺ + 1, 100%).

150

584 (M⁺ + 1, 100%).

151

582 (M⁺ + 1, 100%).

152

596 (M⁺ + 1, 100%).

153

556 (M⁺ + 1, 100%).

154

610 (M⁺ + 1, 100%).

155

517 (M⁺ + 1, 100%).

156

503 (M⁺ + 1, 100%).

157

517 (M⁺ + 1, 100%).

158

593 (M⁺ + 1, 100%).

159

508 (M⁺ + 1, 100%).

160

574 ((M⁺ + 1, 100%).

161

576 (M⁺ + 1, 100%)

162

562 (M⁺ + 1, 100%)

163

561 (M⁺ + 1, 100%).

164

589 (M⁺ + 1, 100%).

165

418 (M⁺ + 1, 100%).

166

512 (M⁺ + 1, 100%).

167

459 (M⁺ + 1, 100%).

168

459 (M⁺ + 1, 100%).

169

459 (M⁺ + 1, 100%).

Examples 170-172

The compounds of Examples 170-172 are listed in the following Table, said compound being synthesized as an analog compound of Example 126.

[Chemical formula 451]

Ex. No.
R^1d
R^1e
R^1f

170
MeO(CH₂)₄
H
(R)-Me

171
MeO(CH₂)₄
Me
Me

172
MeO(CH₂)₄
(S)-CH₂OMe
(R)-Me

(2R)-N-Isopropyl-4-(4-methoxybutyl)-2-methyl-3-oxo-N-[(3R)-piperidin-3-yl]-3,4-dihydro-2H-1,4-benzothiazine-6-carboxyamide hydrochloride, that is the compound of Example 170, was synthesized by the following method.

The compound of Example 170 (140 mg) was synthesized from tert-butyl (3R)-3-(isopropyl{[(2R)-4-(4-methoxybutyl)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl]carbonyl}amino)piperidine-1-carboxylate in a similar manner to Example 4.

¹H-NMR (400 MHz, CDCl₃) 9.90-9.59 (brs, 2H), 7.30 (d, 1H, J=7.6 Hz),7.01 (brs, 1H), 6.87 (d, 1H, J=7.6 Hz), 4.16-3.70 (m, 4H), 3.48-3.26 (m, 4H), 3.23 (s, 3H), 2.90-2.65 (m, 2H), 2.12-1.45 (m, 8H), 1.38 (d, 3H, J=7.0 Hz), 1.32-1.06 (m, 6H).

MS (ESI+) 434(M⁺+1, 100%).

tert-Butyl (3R)-3-(isopropyl{[(2R)-4-(4-methoxybutyl)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl]carbonyl}amino)piperidine-1-carboxylate was synthesized by the following Method.

tert-Butyl (3R)-3-(isopropyl{[(2R)-4-(4-methoxybutyl)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl]carbonyl}amino)piperidine-1-carboxylate (149.7 mg) was synthesized from (2R)-4-(4-methoxybutyl)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboxylic acid in a similar manner to Reference Example 228.

¹H-NMR (400 MHz, CDCl₃) 7.38-7.36(m, 1H), 7.09 (brs, 1H), 6.97-6.95 (m, 1H), 4.14-3.74 (m, 5H), 3.49-3.45 (m, 1H), 3.39 (t, 1H, J=6.3 Hz), 3.31 (s, 3H), 3.15-2.96 (m, 1H), 2.88-2.65 (m, 2H), 1.82-1.55 (m, 7H), 1.54-1.39 (m, 12H), 1.34-1.08 (m, 6H).

MS (ESI+) 534(M⁺+1, 100%).

(2R)-4-(4-Methoxybutyl)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboxylic acid was synthesized by the following method

(2R)-4-(4-Methoxybutyl)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboxylic acid was synthesized from ethyl (2R)-4-(4-methoxybutyl)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboxylate (178.3 mg) in a similar manner to Reference Example 3.

MS (ESI+) 310(M⁺+1, 100%).

Ethyl (2R)-4-(4-methoxybutyl)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboxylate was synthesized by the following method.

To a solution of ethyl (2R)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboxylate (164.7 mg) in N,N-dimethylformamide (5 ml) were added 1-chloro-4-methoxybutane (121 mg), potassium carbonate (181 mg), and a catalytic amount of potassium iodide, and the mixture was stirred at 90° C. After cooling, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography to give ethyl (2R)-4-(4-methoxybutyl)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboxylate (178.3 mg).

MS (ESI+) 338 (M⁺+1, 100%).

Ethyl (2R)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboxylate was synthesized by the following method.

Ethyl (2R)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboxylate (164.7 mg) was synthesized from ethyl 4-{[(1R)-2-ethoxy-1-methyl-2-oxoethyl]thio}-3-nitrobenzoate (308.8 mg) in a similar manner to Reference Example 225.

MS (ESI+) 252 (M⁺+1, 100%).

In Vitro Renin Inhibitory Activity Assay

Recombinant human renin (50 ng) was reacted in 0.1M BEPES buffer (pH 7.4) containing 0.1M NaCl, 1 mM EDTA and 0.1 mg/mL BSA together with a substrate and a test compound at 37° C. for one hour. As the substrate, 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 in such an amount so that the final concentration thereof became 4 μM. The elevated fluorescence intensity at the exciting wavelength 340 nm and the fluorescence wavelength 500 nm was measured by a fluorescence plate reader. The concentration of a test compound to be needed to inhibit an enzyme activity in the presence of a test compound in plural concentrations by 50% was calculated as an IC₅₀value.

TABLE 10

Human renin

Test
inhibitory activity

Compound
IC₅₀(μM)

Example 1
0.33

Example 14
0.93

Example 20
0.42

Example 22
0.48

Example 23
0.33

Example 27
0.19

Example 31
0.24

Example 41
0.43

Example 43
0.77

Example 45
0.41

Example 46
0.79

Example 48
0.62

Example 49
0.74

Example 50
0.54

Example 51
0.50

Example 52
0.59

Example 53
0.22

Example 55
0.69

Example 57
0.83

Example 58
0.15

Example 59
0.11

Example 64
0.0168

Example 66
0.061

Example 67
0.0129

Example 68
0.0067

Example 69
0.0279

Example 72
0.0037

Example 73
0.0046

Example 74
0.0051

Example 75
0.0047

Example 78
0.00079

Example 81
0.0013

Example 86
0.004

Example 126
0.0217

Example 135
0.0353

Compound A
1.6

Compound B
2.3

The chemical structures of Compound A and Compound B are shown as follows. Compound A and Compound B are disclosed in Examples of the literature WO 06/066896.

INDUSTRIAL APPLICABILITY

The compounds of the present invention are useful as a therapeutic agent for treatment of hypertension. These compounds are also useful in the control of acute and chronic congestive heart failure. These compounds can also be expected to be useful in the treatment of primary and secondary pulmonary hypertension, secondary hyperaldosteronism, primary and secondary pulmonary hyperaldosteronism, kidney failure, such as glomerulonephritis, diabetic nephropathy, glomerulosclerosis, primary kidney disease, end stage kidney disease, renovascular hypertension, left ventricular failure, diabetic retinopathy, and also useful in inhibition of angiopathy such as migraine, Raynaud's disease, and atherosclerosis process as much as possible. In addition, these compounds are useful in the treatment of diseases relating to elevated intraocular pressure such as glaucoma.

[Sequence Listing Free Text]

The amino acid sequence disclosed in Seq ID:1 is an amino acid sequence used in the renin inhibitory activity assay.

The amino acid sequence disclosed in Seq ID:2 is an amino acid sequence used in the renin inhibitory activity assay.

Number	Date	Country	Kind
2007-022513	Jan 2007	JP	national
2007-050871	Feb 2007	JP	national
2007-338384	Dec 2007	JP	national

AMIDE DERIVATIVE

Information

Publication Number

Date Filed

Date Published

Inventors

Original Assignees

CPC

US Classifications

International Classifications

Abstract

Description

Claims

Priority Claims (3)

PCT Information