Bicyclic heterocyclic derivative

This application is a National Stage of International Application No. PCT/JP2008/073184, filed Dec. 19, 2008, claiming priority from Japanese Patent Application Nos. 2007-328087 and 2008-202960, filed Dec. 19, 2007 and Aug. 6, 2008, respectively, the contents of all of which are incorporated herein by reference in their entirety.

The present invention relates to derivatives being useful as a medicament. More particularly, the present invention relates to a bicyclic heterocyclic derivative being effective as a renin inhibitor. Further, the present invention relates to a remedy for treatment of hypertension comprising as the active ingredient bicyclic heterocyclic derivatives being effective as a renin inhibitor.

Renin-angiotensin (RA) system is a hormone system being important to the maintenance of blood pressure or electrocyte balance in the living body, and plays an important role in the onset or exacerbation of circulatory system diseases such as hypertension, congestive heart failure, kidney damage, etc.

Renin, that is an important component of the RA system, is an aspartic protease secreted mainly 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 present at the lung or the vascular endothelial cells. Angiotensin II constricts the blood vessel as well as stimulates the adrenal gland to promote the secretion of aldosteron. Aldosteron acts on the kidney and let it pool sodium and excrete potassium. Such a cascade leads to the elevated blood pressure (Non-patent Document 1).

Recently, it is suggested that a component of the RA system exists locally in peripheral tissues such as heart, blood vessel, kidney, adrenal grand, adipose, etc. or the central tissues, and that a (pro)renin receptor may possibly play an important role as a novel component in the activation of the local RA system (Non-patent Document 2), and hence, the importance of the local (tissue) RA system is being recognized. It is suggested that the tissue RA system may possibly cause organ damages such as heart enlargement, arterioscrelosis, kidney damage, etc. by promoting in the long-term the remodeling of various organs such as heart, kidney, blood vessel, etc., while the circulatory RA system anticipates in the control of the short-term circulation (Non-patent Document 3).

As a medicament inhibiting the RA system, ACE inhibitors and angiotensin II receptor blockers (ARB) may be exemplified, and these medicaments (especially the former ones) have been proved to be useful as a remedy for the treatment of not only hypertension but also cardiovascular diseases and renal diseases such as heart failure, diabetic nephropathy, etc. and have been widely used in the clinical field (Non-patent Document 4, Non-patent Document 5).

Several steps for inhibiting the RA system exist, and among them, since renin is located on the most upper stream of the RA system and controls the rate of this cascade, it is theoretically quite appealing approach to inhibit renin (Non-patent Document 6, Non-patent Document 7). In fact, it has been confirmed that aliskiren, which is a renin inhibitor being developed recently, prominently inhibits the serum renin activity, and exhibits an excellent hypotensive activity as comparable to other RA system inhibitors in the clinical trial of hypertension patients (Non-patent Document 8, Non-patent Document 9, Non-patent Document 10).

Various renin inhibitors have been reported. For example, Patent Document 1 and Patent Document 2 reported that derivatives having a piperidine ring are useful as a renin inhibitor. Patent Document 3 reported that derivatives having a pyrrolidine ring are useful as a renin inhibitor. The compounds disclosed in these literatures are characteristic in that these compounds have a partial structure where a piperidine ring or a pyrrolidine ring binds to an amino group at the 3-position thereof via a carbonyl group or a methylene group. However, it has not been known until now that compounds having a basic structure of 3-(substituted-(benzoxazinon-6-yl)carbonylamino)piperidine, etc. 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

Problems to be Solved by Invention

An object of the present invention is to provide a novel compound having 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, referred to as the present compound(s) when necessary) have an excellent renin inhibitory activity and finally have accomplished the present invention.

Namely, the present invention relates to the following:

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

[wherein R 1a is a halogen atom, a hydroxy group, a formyl group, a carboxyl group, a cyano group, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 2-6 alkynyl group, an optionally substituted C 3-6 cycloalkyl group, an optionally substituted C 5-6 cycloalkenyl group, an optionally substituted C 1-6 alkylthio group, an optionally substituted C 6-10 arylthio group, an optionally substituted C 1-6 alkylsulfonyl group, an optionally substituted C 1-6 alkoxy group, an optionally substituted C 3-6 cycloalkoxy group, an optionally substituted C 5-6 cycloalkenyloxy group, an optionally substituted amino group, an optionally substituted aminocarbonyl group, an optionally substituted C 1-4 alkoxycarbonyl group, an optionally substituted C 1-4 alkylcarbonyl group, an optionally substituted C 6-10 arylcarbonyl group, an optionally substituted C 6-10 aryl group, an optionally substituted C 6-10 aryloxy group, an optionally substituted C 7-14 aralkyloxy group, or an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group;

R 1m is a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a C 3-6 cycloalkyl group, a C 1-6 alkoxy group, or a C 3-6 cycloalkoxy group;

G 1 , G 2 , G 3 and G 4 are one of the following (i) to (iv) (wherein

(i) G 1 is —N(R 1b )—, G 2 is —CO—, G 3 is —C(R 1c )(R 1d )—, and G 4 is —C(R 1x )(R 1y )—, —SO 2 —, an oxygen atom, a sulfur atom, or does not exist at all,

(ii) G 1 is —N(R 1b )—, G 2 is —CO—, G 3 is —N(R 1b )—, and G 4 does not exist at all (R 1b for G 1 and G 3 are independent each other),

(iii) G 1 is an oxygen atom, G 2 is —CH 2 —, G 3 is an oxygen atom, and G 4 does not exist at all, or

(iv) G 1 is an oxygen atom, G 2 is —CH 2 —, G 3 is —CH 2 —, and G 4 is an oxygen atom);

R 1b is an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 2-6 alkynyl group, or an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl-C 1-4 alkyl group; R 1c and R 1d are independently the same or different, and each is a hydrogen atom, a halogen atom, a hydroxy group, a carboxyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 5-6 cycloalkenyl group, an optionally substituted C 2-6 alkynyl group, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-6 cycloalkyl group, an optionally substituted aminocarbonyl group, an optionally substituted saturated heterocyclic group, an optionally substituted C 1-6 alkoxy group, an optionally substituted C 3-6 cycloalkoxy group, an optionally substituted aminocarbonyl group, an optionally substituted C 1-4 alkoxycarbonyl group, an optionally substituted C 1-4 alkylcarbonyl group, an optionally substituted C 6-10 arylcarbonyl group, an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group, a cyano group, an optionally substituted C 6-10 aryloxy group, an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryloxy, an optionally substituted C 7-14 aralkyloxy group, an optionally substituted C 7-14 aralkyl group, an optionally substituted amino group, an optionally substituted saturated heterocyclyl-oxy group, an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl-C 1-4 alkyl group, or a group of the following formula:

(in which

R 1e , R 1f , R 1g , R 1h and R 1i are independently the same or different, and each is a hydrogen atom, a halogen atom, a cyano group, a C 1-4 alkyl group (said group being optionally substituted with a 5- or 6-membered saturated heterocyclyl-oxy, a C 1-4 alkoxy (being optionally substituted with C 1-4 alkoxy or C 3-6 alkoxy), or 1 to 3 fluorine atom(s)), a C 1-4 alkoxy group (said group being optionally substituted with 1 to 3 halogen atom(s), C 1-4 alkoxy or C 1-6 alkylaminocarbonyl), a C 3-6 cycloalkoxy group (being optionally substituted with C 1-4 alkoxy), 5- or 6-membered saturated heterocyclyl-oxy group, a C 1-6 alkylaminocarbonyl group, a hydroxy group, or a C 1-4 alkoxysulfonyl group, or

R 1e , R 1h and R 1i are independently a hydrogen atom, R 1f and R 1g , combine each other to form a condensed ring), or R 1c and R 1d combine each other to form a group of the following formula:

(wherein D is an oxygen atom, a sulfur atom, —SO 2 —, —NR 5 —, —NR 5 CO—, —NR 5 SO 2 —, —NR 5 CONR 5 —, —CH(R 6 )—, or —CH(R 6 )CH 2 —, R 5 is a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 1-4 alkoxycarbonyl group, an optionally substituted C 1-4 alkylsulfonyl group, or an optionally substituted C 6-10 arylsulfonyl group, R 6 is a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkoxy group, an optionally substituted C 3-6 cycloalkoxy group, an optionally substituted C 7-14 aralkyloxy group, or an optionally substituted aminocarbonyloxy group, p and q are independently the same or different and each is 0, 1 or 2);

R 1x and R 1y are independently the same or different and each is a hydrogen atom, a halogen atom, or a C 1-4 alkyl group, or R 1x and R 1y combine each other to form a group of the following formula:

(in which R 1z is a hydrogen atom, a halogen atom, a C 1-4 alkyl group or a C 1-4 alkoxy group, r is 1, 2, 3 or 4);

R 2 is a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 2-6 alkynyl group, an optionally substituted C 3-10 cycloalkyl group, an optionally substituted C 5-6 cycloalkenyl group, an optionally substituted C 6-10 aryl group, an optionally substituted C 7-14 aralkyl group, or an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group;

R 3a , R 3b , R 3c and R 3d are independently the same or different and each is a halogen atom, a hydroxy group, a formyl group, a carboxyl group, a cyano group, or a group: -A-B (in which A is a single bond, —(CH 2 ) s O—, —(CH 2 ) s N(R 4 )—, —(CH 2 ) s SO 2 —, —(CH 2 ) s CO—, —(CH 2 ) s COO—, —(CH 2 ) s N(R 4 )CO—, —(CH 2 ) s N(R 4 )SO 2 —, —(CH 2 ) s N(R 4 )COO—, —(CH 2 ) s OCON(R 4 )—, —(CH 2 ) s OCO—, —(CH 2 ) s CON(R 4 )—, —(CH 2 ) s N(R 4 )CON(R 4 )—, or —(CH 2 ) s SO 2 N(R 4 )—,

B is a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 2-6 alkynyl group, an optionally substituted C 3-10 cycloalkyl group, an optionally substituted C 5-6 cycloalkenyl group, an optionally substituted C 6-10 aryl group, an optionally substituted C 7-14 aralkyl group, an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group, an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl-C 1-4 alkyl group, or an optionally substituted saturated heterocyclic group (when A is —(CH 2 ) s N(R 4 )—, —(CH 2 ) s OCON(R 4 )—, —(CH 2 ) s CON(R 4 )—, —(CH 2 ) s N(R 4 )CON(R 4 )—, or —(CH 2 ) s SO 2 N(R 4 )—, then R 4 and B may combine each other to form a ring)), or two of R 3a , R 3b , R 3c and R 3d are a hydrogen atom, and the remaining 2 groups may combine each other to form a fused ring with a heterocyclic ring;

R 4 is a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-10 cycloalkyl group, an optionally substituted C 6-10 aryl group, an optionally substituted C 7-14 aralkyl group, or an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group;

s is 0, 1 or 2 (when A is —(CH 2 ) s N(R 4 )—, then s is 0 or 2, and when A is —(CH 2 ) s CON(R 4 )—, then s is 1 or 2);

n is 0, 1 or 2]

Item 2: The compound according to Item 1 or a pharmaceutically acceptable salt thereof, wherein G 1 , G 2 , G 3 and G 4 are the following (i) or (ii) (wherein (i) G 1 is —N(R 1b )—, G 2 is —CO—, G 3 is —C(R 1c )(R 1d )—, and G 4 is —C(R 1x )(R 1y )—, —SO 2 —, an oxygen atom, a sulfur atom, or does not exist at all, or (ii) G 1 is —N(R 1b )—, G 2 is —CO—, G 3 is —N(R 1b )—, and G 4 does not exist at all).

Item 3: The compound according to Item 1 or a pharmaceutically acceptable salt thereof, wherein G 1 is —N(R 1b )—, G 2 is —CO—, G 3 is —C(R 1c )(R 1d )—, and G 4 is —CH 2 —, —C(CH 3 )(CH 3 )—, —SO 2 —, an oxygen atom, or a sulfur atom.

Item 4: The compound according to Item 3 or a pharmaceutically acceptable salt thereof, wherein G 4 is an oxygen atom.

Item 5: The compound according to Item 3 or a pharmaceutically acceptable salt thereof, wherein G 4 is a sulfur atom.

Item 6: The compound according to Item 3 or a pharmaceutically acceptable salt thereof, wherein G 4 is —CH 2 —.

Item 7: The compound according to Item 2 or a pharmaceutically acceptable salt thereof, wherein G 4 does not exist at all.

Item 8: The compound according to Item 2 or a pharmaceutically acceptable salt thereof, wherein G 1 is —N(R 1b )—, G 2 is —CO—, G 3 is —N(R 1b )—, and G 4 does not exist at all.

Item 9: The compound according to any one of Items 1 to 8 or a pharmaceutically acceptable salt thereof, wherein R 1a and R 1m are located on any position selected from the following formulae (A) to (C):

Item 10: The compound according to any one of Items 1 to 9 or a pharmaceutically acceptable salt thereof, wherein R 1a is one group selected from a group consisting of

1: a halogen atom;

2: a cyano group;

3: a C 1-6 alkyl group (said group being optionally substituted with (a) 1 to 3 fluorine atom(s), (b) C 1-4 alkoxy, or (c) C 3-6 cycloalkoxy);

4: a C 1-6 alkoxy group (said group being optionally substituted with (a) 1 to 3 fluorine atom(s), or (b) C 3-6 cycloalkoxy);

5: a C 3-6 cycloalkyl group;

6: a C 3-6 cycloalkoxy group (said group being optionally substituted with (a) 1 to 3 fluorine atom(s), or (b) C 1-4 alkoxy); and

7: a 5- or 6-membered heteroaryl group (said group being optionally substituted with C 1-4 alkyl).

Item 11: The compound according to any one of Items 1 to 10 or a pharmaceutically acceptable salt thereof, wherein R 1a is a halogen atom, a cyano group, a C 1-6 alkyl group being optionally substituted with 1 to 3 fluorine atom(s), or a C 1-6 alkoxy group. Item 12: The compound according to Item 11 or a pharmaceutically acceptable salt thereof, wherein R 1a is a C 1-6 alkyl group being optionally substituted with 1 to 3 fluorine atom(s). Item 13: The compound according to one of Items 1 to 12 or a pharmaceutically acceptable salt thereof, wherein R 1m is a hydrogen atom, a halogen atom, or a C 1-6 alkoxy group. Item 14: The compound according to Item 13 or a pharmaceutically acceptable salt thereof, wherein R 1m is a hydrogen atom. Item 15: The compound according to one of Items 1 to 14 or a pharmaceutically acceptable salt thereof, wherein R 1b is

1: a C 1-6 alkyl group (said group being optionally substituted with one group selected from a group consisting of (a) hydroxy, (b) C 1-4 alkoxy (being optionally substituted with 1 to 3 fluorine atom(s) or C 1-4 alkoxy), (c) cyano, (d) trilfluoromethyl, (e) trifluoromethoxy, (f) C 3-6 cycloalkyl (being optionally substituted with 1 to 2 fluorine atom(s), C 1-4 alkyl being optionally substituted with C 1-4 alkoxy, or C 1-4 alkoxy), (g) C 3-6 cycloalkoxy, (h) formylamino, (i) C 1-4 alkylcarbonylamino (being optionally substituted with 1 to 3 fluorine atom(s)), (j) N—(C 1-4 alkylcarbonyl)-N—(C 1-6 alkyl)-amino, (k) C 3-6 cycloalkylcarbonylamino, (l) (C 3-6 cycloalkyl-C 1-4 alkyl)carbonylamino, (m) C 1-4 alkylthiocarbonyl-amino, (n) C 1-4 alkoxycarbonylamino (being optionally substituted with 1 to 3 fluorine atom(s)), (O)N—(C 1-4 alkoxycarbonyl)-N—(C 1-6 alkyl)-amino, (p) mono- or di-(C 1-6 alkyl)aminocarbonyloxy, (q) C 1-6 alkylaminocarbonyl (being optionally substituted with 1 to 3 fluorine atom(s)), (r) di-(C 1-6 alkyl)-aminocarbonyl, (s) C 3-6 cycloalkylaminocarbonyl, (t) C 1-6 alkylaminocarbonylamino, (u) C 1-6 alkyl-aminothiocarbonylamino, (v) C 1-4 alkylcarbonyl (being optionally substituted with C 1-4 alkoxy), (w) C 1-4 alkylcarbonyloxy, (x) C 1-4 alkoxycarbonyl, (y) C 1-6 alkylsulfonyl, (z) C 1-4 alkylsulfonylamino, (aa) 5- or 6-membered saturated heterocyclic group, (ab) carboxyl, and (ac) C 1-6 alkylamino (said alkyl being optionally substituted with 1 to 3 fluorine atom(s)));

2: a C 2-6 alkenyl group (said group being optionally substituted with a halogen atom);

3: a C 2-6 alkynyl group (said group being optionally substituted with C 1-4 alkoxy);

4: a 5- or 6-membered heteroaryl-C 1-4 alkyl group; or

5: a C 3-6 cycloalkyl group.

Item 16: The compound according to one of Items 1 to 15 or a pharmaceutically acceptable salt thereof, wherein R 1b is a C 1-6 alkyl group being optionally substituted with C 1-6 alkoxy, C 1-4 alkylcarbonylamino (being optionally substituted with 1 to 3 fluorine atom(s)), or C 1-4 alkoxycarbonylamino; or 5- or 6-membered heteroaryl-C 1-4 alkyl group. Item 17: The compound according to Item 16 or a pharmaceutically acceptable salt thereof, wherein R 1b is a C 1-6 alkyl group being optionally substituted with C 1-6 alkoxy. Item 18: The compound according to Item 17 or a pharmaceutically acceptable salt thereof, wherein R 1b is a 3-methoxypropoxy group. Item 19: The compound according to Item 17 or a pharmaceutically acceptable salt thereof, wherein R 1b is a 4-methoxybutyl group. Item 20: The compound according to Item 16 or a pharmaceutically acceptable salt thereof, wherein R 1b is a C 1-6 alkyl group being optionally substituted with C 1-4 alkylcarbonylamino (being optionally substituted with 1 to 3 fluorine atom(s)). Item 21: The compound according to Item 20 or a pharmaceutically acceptable salt thereof, wherein R 1b is a 2-(ethylcarbonylamino)ethyl group. Item 22: The compound according to Item 20 or a pharmaceutically acceptable salt thereof, wherein R 1b is a 2-(difluororoacetylamino)ethyl group. Item 23: The compound according to Item 16 or a pharmaceutically acceptable salt thereof, wherein R 1b is a C 1-6 alkyl group being optionally substituted with C 1-4 alkoxycarbonylamino Item 24: The compound according to Item 23 or a pharmaceutically acceptable salt thereof, wherein R 1b is a 2-(methoxycarbonylamino)ethyl group. Item 25: The compound according to any one of Items 1 to 24 or a pharmaceutically acceptable salt thereof, wherein R 1c is a hydrogen atom, a halogen atom, or a C 1-6 alkyl group being optionally substituted with C 1-4 alkoxy. Item 26: The compound according to any one of Items 1 to 25 or a pharmaceutically acceptable salt thereof, wherein R 1c is a hydrogen atom, or a C 1-6 alkyl group. Item 27: The compound according to any one of Items 1 to 26 or a pharmaceutically acceptable salt thereof, wherein R 1c is a C 1-6 alkyl group. Item 28: The compound according to any one of Items 1 to 27 or a pharmaceutically acceptable salt thereof, wherein R 1d is one group selected from a group consisting of 1: a hydrogen atom; 2: a halogen atom; 3: a cyano group; 4: a C 2-6 alkenyl group (being optionally substituted with C 6-10 aryl having optionally C 1-4 alkoxy substituent); 5: alkynyl group (being optionally substituted with C 6-10 aryl having optionally C 1-4 alkoxy a C 2-6 substituent); 6: a C 1-6 alkyl group (said group being optionally substituted with the same or different 1 to 2 group(s) selected from a group consisting of

(a) 1 to 3 halogen atom(s),

(b) cyano,

(c) C 3-6 cycloalkyl (said group being optionally substituted with a halogen atom, C 1-4 alkyl or C 1-4 alkoxy),

(d) hydroxy,

(e) C 1-4 alkoxy (said group being optionally substituted with the same or different 1 to 3 group(s) selected from a group consisting of a halogen atom, cyano, C 3-6 cycloalkoxy (having optionally mono- or di-(C 1-6 alkyl)aminocarbonyl substituent), mono- or di-(C 1-6 alkyl)aminosulfonyl, C 1-6 alkylsulfonyl, aminocarbonyl having optionally mono- or di-(C 1-6 alkyl) substituent, C 1-4 alkylcarbonyl, 5- to 7-membered cyclic aminocarbonyl, hydroxy, C 1-4 alkoxy, 5- or 6-membered saturated heterocyclic group, and C 1-4 alkoxycarbonyl),

(f) C 3-6 cycloalkoxy (said group being optionally substituted with C 1-4 alkyl (having optionally C 1-4 alkoxy substituent)),

(g) C 6-10 aryloxy (said group being optionally substituted with the same or different 1 to 3 group(s) selected from a group consisting of a halogen atom, cyano, and C 1-4 alkoxy),

(h) mono- or di-substituted amino (said group being substituted with 1 to 2 group(s) selected from a group consisting of C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkyl (having optionally aminocarbonyl substituent), C 3-6 cycloalkyl-C 1-4 alkoxycarbonyl, C 1-4 alkylcarbonyl, C 3-6 cycloalkylcarbonyl (having optionally C 1-4 alkylsulfonylamino substituent), 5- or 6-membered saturated heterocyclyl-C 1-4 alkyl (having optionally C 1-4 alkyl substituent), 5- or 6-membered saturated heterocyclyl-carbonyl, 5- or 6-membered saturated heterocyclyl-oxycarbonyl, 5- or 6-membered saturated heterocyclyl-C 1-4 alkylcarbonyl, and C 1-4 alkylsulfonyl),

(i) 5- to 7-membered cyclic amino (being optionally substituted with the same or different 1 to 4 group(s) selected from a group consisting of C 1-4 alkyl, C 7-14 aralkyl, and oxo),

(i) mono- or di-(C 1-6 alkyl)aminocarbonyl,

(k) 4- to 7-membered cyclic aminocarbonyl (being optionally substituted with C 1-4 alkyl),

(l) mono- or di-substituted aminocarbonyloxy (said amino being substituted with the same or different 1 to 2 group(s) selected from a group consisting of C 1-6 alkyl (having optionally 5- or 6-membered saturated heterocyclic substituent), C 3-6 cycloalkyl (having optionally hydroxy substituent), and 5- or 6-membered saturated heterocyclic group),

(m) 5- to 7-membered cyclic aminocarbonyloxy (being optionally substituted with 1 to 2 fluorine atom(s)),

(n) 5- to 7-membered cyclic aminocarbonyl-C 1-4 alkoxy,

(o) mono- or di-(C 1-6 alkyl)aminocarbonyl-C 1-4 alkoxy,

(p) 5- or 6-membered saturated heterocyclic group (being substituted with the same or different group selected from a group consisting of C 1-4 alkyl and oxo),

(q) 5- or 6-membered saturated heterocyclyl-C 1-4 alkoxy (having optionally C 1-4 alkyl substituent),

(r) 5- or 6-membered saturated heterocyclyl-oxy (having optionally the same or different 1 to 2 substituents selected from a group consisting of C 1-4 alkyl and oxo),

(s) mono- or di-C 1-4 alkylaminosulfonyl,

(t) carboxy,

(u) C 1-4 alkoxycarbonyl,

(v) C 6-10 arylcarbonyl (said group having optionally C 1-4 alkoxy substituent),

(w) C 1-4 alkoxycarbonylamino,

(x) C 6-10 aryloxycarbonylamino (having optionally a halogen substituent),

(y) 5- or 6-membered monocyclic aryloxycarbonylamino, and

(z) N—(C 1-4 alkylaminocarbonyl)-N—(C 1-6 alkyl)amino);

7: a C 3-10 cycloalkyl group (said group being optionally substituted with

(a) a halogen atom,

(b) hydroxy, or

(c) C 1-4 alkoxy);

8: a C 7-14 aralkyl group (said group being optionally substituted with the same or different 1 to 3 group(s) selected from a group consisting of

(a) a halogen atom,

(b) cyano,

(c) hydroxy,

(d) C 1-4 alkoxy, and

(e) C 1-4 alkyl having optionally C 1-4 alkoxy substituent);

9: a C 1-6 alkoxy group (said group being optionally substituted with

(a) C 1-4 alkoxycarbonylamino,

(b) N—(C 1-6 alkylsulfonyl)-N—(C 1-6 alkyl)aminocarbonyl,

(c) mono- or di-(C 1-6 alkyl)aminocarbonyl, or

(d) 5- to 7-membered cyclic aminocarbonyl);

10: a C 3-6 cycloalkoxy group; 11: a C 7-14 aralkyloxy group (having optionally C 1-4 alkoxy substituent); 12: mono- or di-substituted aminocarbonyl group (said amino being optionally substituted with C 1-6 alkyl having optionally 5- or 6-membered saturated heterocyclic substituent); 13: 5- to 7-membered cyclic aminocarbonyl group (said group being optionally substituted with a group selected from a group consisting of

(a) a halogen atom,

(b) C 1-4 alkoxy, and

(c) C 6-10 aryl having optionally a halogen substituent);

14: a saturated heterocyclic group (said group being optionally substituted with the same or different 1 to 4 group(s) selected from a group consisting of

(a) C 1-4 alkyl,

(b) C 6-10 aryl having optionally 1 to 3 halogen substituent(s), and

(c) oxo);

15: a saturated heterocyclyl-oxy group (said group being optionally substituted with C 1-4 alkoxycarbonyl or C 1-4 alkylcarbonyl); 16: 5- to 10-membered monocyclic or polycyclic heteroaryl group (said group being optionally substituted with the same or different 1 to 2 group(s) selected from a group consisting of

(a) a halogen atom,

(b) C 1-4 alkyl having optionally 1 to 3 fluorine substituent(s), and

(c) C 1-4 alkoxy (having optionally mono- or di-(C 1-6 alkyl)aminocarbonyl substituent));

17: 5- to 10-membered monocyclic or polycyclic heteroaryl-C 1-4 alkyl group; 18: an amino group (said amino being optionally substituted with

(a) C 3-6 cycloalkyl-C 1-4 alkyl (having optionally aminocarbonyl substituent),

(b) C 1-4 alkylcarbonyl (having optionally C 1-4 alkoxy substituent),

(c) C 3-6 cycloalkylcarbonyl (having optionally C 1-4 alkylsulfonylamino substituent) or

(d) 5- or 6-membered saturated heterocyclyl-oxycarbonyl);

19: a hydroxy group, and 20: a group of the following formula:

Item 29: The compound according to any one of Items 1 to 28 or a pharmaceutically acceptable salt thereof, wherein R 1d is one group selected from a group consisting of

1: a hydrogen atom;

2: a halogen atom;

3: a C 1-6 alkyl group (said group being optionally substituted with

(a) 1 to 3 halogen atom(s),

(b) hydroxy,

(c) a C 1-4 alkoxy (said group having optionally 1 to 2 substituent(s) selected from a group consisting of hydroxy, C 1-4 alkoxy, 5- or 6-membered saturated heterocyclic group, and C 1-4 alkoxycarbonyl),

(d) aryloxy (said group having optionally the same or different 1 to 3 substituent(s) a C 6-10 selected from a group consisting of cyano and C 1-4 alkoxy),

(e) a C 1-6 alkylaminocarbonyloxy,

(f) (5- or 6-membered saturated heterocyclyl-C 1-4 alkyl)aminocarbonyloxy, or

(g) 5- to 7-membered cyclic aminocarbonyloxy);

4: an aminocarbonyl group; 5: a mono- or di-(C 1-6 alkyl)aminocarbonyl group; 6: an N-(5- or 6-membered saturated heterocyclyl-C 1-4 alkyl)-N—(C 1-6 alkyl)-aminocarbonyl group; 7: a 5- to 7-membered cyclic aminocarbonyl group; 8: a C 7-14 aralkyl group being optionally substituted with C 1-4 alkoxy; 9: a 5- or 6-membered saturated heterocyclic group; 10: a C 3-6 cycloalkyl group; 11: a C 3-6 cycloalkoxy group; and 12: a group of the following formula:

Item 30: The compound according to any one of Items 1 to 29 or a pharmaceutically acceptable salt thereof, wherein R 1d is a C 1-6 alkyl group being substituted with one group selected from a group consisting of

1: halogen,

2: hydroxy,

3: C 1-4 alkoxy (said group having optionally 1 to 2 substituent(s) selected from a group consisting of (a) hydroxy,

(b) C 1-4 alkoxy,

(c) 5- or 6-membered saturated heterocyclic group, and

(d) C 1-4 alkoxycarbonyl),

4: C 6-10 aryloxy (said group having optionally the same or different 1 to 3 substituent(s) selected from a group consisting of cyano and C 1-4 alkoxy), 5: C 1-6 alkylaminocarbonyloxy, 6: (5- or 6-membered saturated heterocyclyl-C 1-4 alkyl)aminocarbonyloxy, and 7: 5- to 7-membered cyclic aminocarbonyloxy. Item 31: The compound according to any one of Items 1 to 29 or a pharmaceutically acceptable salt thereof, wherein R 1d is a group of the following formula:

Item 32: The compound according to any one of Items 1 to 31 or a pharmaceutically acceptable salt thereof, wherein R 1e , R 1f , R 1g , R 1h and R 1i are independently the same or different, and each is

1: a hydrogen atom,

2: a halogen atom,

3: a cyano group,

4: a C 1-4 alkyl group (said group being optionally substituted with

(a) 5- or 6-membered saturated heterocyclyl-oxy,

(b) C 1-4 alkoxy (having optionally C 1-4 alkoxy or C 3-6 cycloalkoxy substituent), or

(c) 1 to 3 fluorine atom(s)),

5: a C 1-4 alkoxy group (said group being optionally substituted with

(a) 1 to 3 halogen atom(s),

(b) C 1-4 alkoxy, or

(c) C 1-6 alkylaminocarbonyl),

6: a C 3-6 cycloalkoxy group (said group being optionally substituted with C 1-4 alkoxy), 7: a 5- or 6-membered saturated heterocyclyl-oxy group, 8: a C 1-6 alkylaminocarbonyl group, 9: a hydroxy group, or 10: a C 1-4 alkoxysulfonyl group. Item 33: The compound according to any one of Items 1 to 32 or a pharmaceutically acceptable salt thereof, wherein R 1e , R 1f , R 1g , R 1h and R 1i are independently the same or different, and each is the same or different 1 to 3 group(s) selected from a group consisting of a hydrogen atom, a halogen atom, a cyano group, a C 1-4 alkyl group having optionally 1 to 3 fluorine substituent(s), a C 1-4 alkoxy group, a hydroxy group, and a C 1-4 alkoxysulfonyl group. Item 34: The compound according to any one of Items 1 to 33 or a pharmaceutically acceptable salt thereof, wherein R 1e , R 1f , R 1g , R 1h and R 1i are independently the same or different and each is a hydrogen atom, a halogen atom, or a C 1-4 alkoxy group. Item 35: The compound according to any one of Items 1 to 33 or a pharmaceutically acceptable salt thereof, wherein R 1d is a group selected from the groups of the following formulae:

Item 36: The compound according to any one of Items 1 to 24 or a pharmaceutically acceptable salt thereof, wherein R 1c and R 1d combine each other to form a group of the following formula:

Item 37: The compound according to Item 36 or a pharmaceutically acceptable salt thereof, wherein R 5 is a hydrogen atom, a C 1-6 alkyl group, a C 1-4 alkoxycarbonyl group, a C 1-4 alkylsulfonyl group, or a C 6-10 arylsulfonyl group.

Item 38: The compound according to Item 36 or a pharmaceutically acceptable salt thereof, wherein R 6 is a hydrogen atom, a halogen atom, a C 1-4 alkoxy group being optionally substituted with C 1-4 alkoxy, a C 7-14 aralkyloxy group having optionally 1 to 3 substituent(s) selected from a group consisting of fluorine atom and cyano, or an aminocarbonyloxy group being optionally substituted with mono- or di-(C 1-6 alkyl).

Item 39: The compound according to any one of Items 36 to 38 or a pharmaceutically acceptable salt thereof, wherein D, p and q are one of the following combinations:

(i) D is an oxygen atom, and p and q are the same and each is 2,

(ii) D is —CH 2 —, and p and q are the same and each is 1 or 2, or

(iii) D is —CH 2 CH 2 —, and p and q are the same and each is 0 or 1.

Item 40: The compound according to any one of Items 1 to 39 or a pharmaceutically acceptable salt thereof, wherein R 2 is one group selected from a group consisting of a C 1-6 alkyl group being optionally substituted with C 3-6 cycloalkyl (said C 1-6 alkyl having optionally 1 to 3 halogen substituent(s), and said C 3-6 cycloalkyl having optionally halogen substituent, C 1-4 alkyl substituent or C 1-4 alkoxy substituent); a C 3-6 cycloalkyl group being optionally substituted with halogen atom or C 1-4 alkyl, a C 2-6 alkenyl group, and a C 7-10 aralkyl group having optionally halogen substituent. Item 41: The compound according to Item 40 or a pharmaceutically acceptable salt thereof, wherein R 2 is C 1-6 alkyl. Item 42: The compound according to Item 41 or a pharmaceutically acceptable salt thereof, wherein R 2 is an isopropyl group. Item 43: The compound according to any one of Items 1 to 42 or a pharmaceutically acceptable salt thereof, wherein R 3a , R 3b , R 3c and R 3d are independently a group: -A-B (wherein A is a single bond, —(CH 2 ) s O—, —(CH 2 ) s N(R 4 )—, —(CH 2 ) s COO—, —(CH 2 ) s N(R 4 )CO—, —(CH 2 ) s N(R 4 )SO 2 —, —(CH 2 ) s N(R 4 )COO—, —(CH 2 ) s OCON(R 4 )—, —(CH 2 ) s CON(R 4 )—, or —(CH 2 ) s N(R 4 )CON(R 4 )—,

B is one group selected from a group consisting of

1: a hydrogen atom; 2: a C 1-6 alkyl group (said group being optionally substituted with 1 to 3 group(s) selected from a group consisting of

(a) a halogen atom,

(b) C 3-6 cycloalkyl (said group having optionally the same or different 1 to 2 substituent(s) selected from a group consisting of a halogen atom, hydroxy, C 1-4 alkoxy and C 3-6 cycloalkylcarbonyl-amino),

(c) hydroxy,

(d) C 1-4 alkoxy,

(e) carboxy,

(f) C 1-4 alkoxycarbonyl,

(g) saturated heterocyclic group (said ring having optionally the same or different 1 to 3 substituent(s) selected from a group consisting of C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylcarbonylamino, and oxo),

(h) aminocarbonyl (amino having optionally C 1-4 alkyl, C 3-6 cycloalkyl, or C 3-6 cycloalkyl-C 1-4 alkyl substituent), and

(i) 5- to 7-membered cyclic amino group (said group having optionally the same or different 1 to 3 substituent(s) selected from a group consisting of a halogen atom, C 1-4 alkyl, C 6 aryl having optionally C 1-4 alkoxy substituent, C 6 aryloxy having optionally 1 to 3 halogen substituent(s), and oxo));

3: a C 2-6 alkenyl group (said group being optionally substituted with (a) fluorine substituent, or (b) C 1-6 alkyl substituent); 4: a C 3-10 cycloalkyl group (said group being optionally substituted with (a) a halogen atom, (b) C 1-4 alkyl having optionally C 1-4 alkoxy substituent, (c) hydroxy, or (d) C 1-4 alkoxy); 5: a C 6 aryl group (said group being optionally substituted with the same or different 1 to 4 group(s) selected from a group consisting of

(a) a halogen atom,

(b) C 1-4 alkyl (said C 1-4 alkyl having optionally one substituent selected from a group consisting of 5- to 7-membered cyclic amino (being optionally substituted with a C 6 aryl having optionally 1 to 3 halogen substituent(s)), mono-C 1-6 alkylamino (said C 1-6 alkyl being optionally substituted with a C 6 aryloxy having optionally 1 to 3 halogen substituent(s)), 5- or 6-membered saturated heterocyclic amino (said saturated heterocycle having optionally C 6 aryl substituent), 5- or 6-membered saturated heterocyclyl-oxy (said saturated heterocycle having optionally C 6 aryl or 5- to 10-membered monocyclic or polycyclic heteroaryl substituent), C 6 aryloxy (being optionally substituted with the same or different 1 to 3 group(s) selected from a group consisting of a halogen atom and C 1-4 alkyl), C 1-4 alkoxy, and C 3-6 cycloalkoxy),

(c) C 1-4 alkoxy (said C 1-4 alkoxy being optionally substituted with one group selected from a group consisting of C 1-4 alkoxy, C 6 aryloxy (being optionally substituted with C 1-4 alkyl or 1 to 3 halogen atom(s)), C 3-6 cycloalkyloxy (being optionally substituted with C 1-4 alkyl), phenylamino (said phenyl being optionally substituted with 1 to 3 halogen atom(s)), and C 7-10 aralkyloxy (being optionally substituted with 1 to 3 halogen atom(s))),

(d) C 6 aryloxy (said group being optionally substituted with 1 to 3 group(s) selected from a group consisting of a halogen atom, cyano, C 1-4 alkyl, and C 1-4 alkoxy),

(e) C 7-10 aralkyloxy (being optionally substituted with 1 to 3 group(s) selected from a group consisting of a halogen atom and C 1-4 alkoxy),

(f) 5- to 7-membered cyclic amino (said ring being optionally substituted with (C 1-6 alkyl)(phenylcarbonyl)amino, or C 6 aryloxy (being optionally substituted with the same or different 1 to 3 group(s) selected from a group consisting of a halogen atom and C 1-4 alkyl having optionally hydroxy substituent)),

(g) 5- or 6-membered saturated heterocyclyl-oxy (said ring being optionally substituted with C 6 aryl having optionally 1 to 3 halogen substituent(s), 5- to 10-membered monocyclic or poly cyclic heteroaryl, 5- or 6-membered saturated heterocyclyl-carbonyl, or oxo),

(h) 5- or 6-membered monocyclic heteroaryloxy (being optionally substituted with C 1-4 alkyl),

(i) 5- to 7-membered cyclic aminocarbonyl (being optionally substituted with C 6 aryloxy having optionally 1 to 3 halogen substituent(s)),

(j) 5- to 7-membered cyclic aminocarbonyloxy (being optionally substituted with C 6 aryl), and

(k) C 6 aryl);

6: C 7-14 aralkyl group (said group being optionally substituted with the same or different 1 to 3 group(s) selected from a group consisting of

(a) a halogen atom,

(b) cyano,

(c) C 1-4 alkyl,

(d) hydroxy,

(e) C 1-4 alkoxy (being optionally substituted with 1 to 3 fluorine atom(s)),

(f) C 3-6 cycloalkoxy (being optionally substituted with 1 to 2 halogen atom(s)),

(g) C 1-4 alkoxycarbonyl,

(h) aminocarbonyl,

(i) C 6-10 aryl (being optionally substituted with 1 to 3 halogen atom(s)) and

(i) C 1-4 alkylsulfonyl);

7: 5- to 10-membered monocyclic or polycyclic heteroaryl group (said group being optionally substituted with a halogen atom); 8: 5- to 10-membered monocyclic or polycyclic heteroaryl-C 1-4 alkyl group (said group being optionally substituted with a halogen atom, or C 1-4 alkyl (having optionally 1 to 3 fluorine substituent(s))); and 9: saturated heterocyclic group (said group being optionally substituted with C 1-4 alkyl (having optionally C 1-4 alkoxy substituent)) (provided that when A is —(CH 2 ) s N(R 4 )—, —(CH 2 ) s OCON(R 4 )—, —(CH 2 ) s CON(R 4 )—, or —(CH 2 ) s N(R 4 )CON(R 4 )—, then R 4 and B combine each other to form a ring)). Item 44: The compound according to any one of Items 1 to 42, wherein R 3a , R 3b , R 3c and R 3d attach to the piperidine ring at a substitution position shown in the following formula:

Item 45: The compound according to Item 44 or a pharmaceutically acceptable salt thereof, wherein R 3a , R 3b and R 3d are each a group: -A-B (in which A is a single bond, and B is a hydrogen atom); R 3c is a group: -A-B (in which A is a single bond or —(CH 2 ), O—, and B is a hydrogen atom, an optionally substituted C 6-10 aryl group, an optionally substituted C 7-14 aralkyl group, or an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group).

Item 46: The compound according to Item 45 or a pharmaceutically acceptable salt thereof, wherein R 3c is a group: -A-B (in which A is a single bond, and B is an optionally substituted C 6-10 aryl group).

Item 47: The compound according to Item 46 or a pharmaceutically acceptable salt thereof, wherein B is an optionally substituted C 6-10 aryl group, or an optionally substituted C 7-14 aralkyl group.

Item 48: The compound according to Item 45 or a pharmaceutically acceptable salt thereof, wherein R 3c is a group: -A-B (in which A is —(CH 2 ) s O—, B is a hydrogen atom, an optionally substituted C 6-10 aryl group, or an optionally substituted C 7-14 aralkyl group).

Item 49: The compound according to Item 44 or a pharmaceutically acceptable salt thereof, wherein R 3a , R 3c and R 3d are each a group: -A-B (in which A is a single bond, B is a hydrogen atom); R 3b is a group: -A-B (in which A is a single bond, —(CH 2 ) s O—, —(CH 2 ) s N(R 4 )—, —(CH 2 ) s COO—, —(CH 2 ) s N(R 4 )CO—, —(CH 2 ) s N(R 4 )SO 2 —, —(CH 2 ) s N(R 4 )COO—, —(CH 2 ) s OCON(R 4 )—, —(CH 2 ) s CON(R 4 )—, —(CH 2 ) s N(R 4 )CON(R 4 )—, or —(CH 2 ) s SO 2 N(R 4 )—, B is a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-6 cycloalkyl group, an optionally substituted C 6-10 aryl group, an optionally substituted C 7-14 aralkyl group, an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group, or an optionally substituted 5- or 6-membered saturated heterocyclic group).

Item 50: The compound according to Item 44 or a pharmaceutically acceptable salt thereof, wherein R 3a , R 3b , and R 3c are independently a group: -A-B (in which A is a single bond, B is a hydrogen atom); R 3d is a group: -A-B (in which A is a single bond, —(CH 2 ) s O—, —(CH 2 ) s N(R 4 )—, —(CH 2 ) s COO—, —(CH 2 ) s N(R 4 )CO—, —(CH 2 ) s N(R 4 )SO 2 —, —(CH 2 ) s N(R 4 )COO—, —(CH 2 ) s OCON(R 4 )—, or —(CH 2 ) s N(R 4 )CON(R 4 )—, B is a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 3-10 cycloalkyl group, an optionally substituted C 6-10 aryl group, an optionally substituted C 7-14 aralkyl group, an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group, an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl-C 1-4 alkyl group or an optionally substituted 5- or 6-membered saturated heterocyclic group).

Item 51: The compound according to Item 50 or a pharmaceutically acceptable salt thereof, wherein A for R 3d is —(CH 2 ) s N(R 4 )CO—.

Item 52: The compound according to Item 50 or Item 51 or a pharmaceutically acceptable salt thereof, wherein B for R 3d is an optionally substituted C 1-6 alkyl group.

Item 53: The compound according to Item 51 or a pharmaceutically acceptable salt thereof, wherein B for R 3d is a C 7-14 aralkyl group being optionally substituted with 1 to 3 halogen atom(s).

Item 54: The compound according to any one of Items 50 to 53 or a pharmaceutically acceptable salt thereof, wherein s is 2.

Item 55: The compound according to any one of Items 1 to 54 or a pharmaceutically acceptable salt thereof, wherein R 4 is a hydrogen atom, a C 1-6 alkyl group being substituted with 1 to 3 halogen atom(s) or C 3-6 cycloalkyl, a C 3-6 cycloalkyl group being optionally substituted with 1 to 2 halogen atom(s), or a C 7 aralkyl group.

Item 56: The compound according to Item 55 or a pharmaceutically acceptable salt thereof, wherein R 4 is a C 1-6 alkyl group being substituted with 1 to 3 halogen atom(s), or a C 3-6 cycloalkyl group.

Item 57: The compound according to Item 56 or a pharmaceutically acceptable salt thereof, wherein R 4 is a C 3-6 cycloalkyl group.

Item 58: The compound according to any one of Items 1 to 40 or a pharmaceutically acceptable salt thereof, wherein R 3a , R 3b , R 3c and R 3d are each a group: -A-B (in which A is a single bond, B is a hydrogen atom).

Item 59: The compound according to any one of Items 1 to 43 or a pharmaceutically acceptable salt thereof, wherein n is 1.

Item 60: A pharmaceutical composition, which comprises as the active ingredient a compound as set forth in any one of Items 1 to 59 or a pharmaceutically acceptable salt thereof

Item 61: A renin inhibitor, which comprises as the active ingredient a compound as set forth in any one of Items 1 to 59 or a pharmaceutically acceptable salt thereof

Item 62: A drug for treatment of hypertension, which comprises as the active ingredient a compound as set forth in any one of Items 1 to 59 or a pharmaceutically acceptable salt thereof

Item 63: Use of a compound as set forth in any one of Items 1 to 59 or a pharmaceutically acceptable salt thereof in the preparation of a renin inhibitor.

Item 64: Use of a compound as set forth in any one of Items 1 to 59 or a pharmaceutically acceptable salt thereof in the preparation of a drug for treatment of hypertension.

Item 65: A method for treatment of hypertension, which comprises administering an effective amount of a compound as set forth in any one of Items 1 to 59 or a pharmaceutically acceptable salt thereof to a patient in need.

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

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

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 1-6 alkyl” 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 an “unsubstituted” group. For example, “C 1-6 alkyl” means an “unsubstituted” one.

The term “group” in the present specification means a monovalent group. 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 occasionally 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 1-6 alkyl group” means a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms, and preferable one is a C 1-4 alkyl group. Examples of the C 1-6 alkyl 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 1-6 alkyl group” for “B” includes a group where a C 2-4 ring is formed on one carbon atom of the saturated hydrocarbon group, for example, groups of the following formulae are exemplified. In addition, the alkyl moiety of C 7-14 aralkyl includes likewise.

The “C 2-6 alkenyl group” means a straight or branched chain unsaturated hydrocarbon group having 2 to 10 carbon atoms and one double bond, and includes, for example, vinyl, propenyl, methylpropenyl, butenyl or methylbutenyl, etc.

The “C 2-6 alkenyl group” for “B” includes the groups of the following formula.

The “C 2-6 alkynyl 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 3-10 cycloalkyl group” means a saturated cyclic hydrocarbon group having 3 to 10 carbon atoms, and a preferable one is “C 3-6 cycloalkyl group”, etc. Examples of the “C 3-10 cycloalkyl group” are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl or norbornyl, etc.

The “C 3-10 cycloalkyl group” for “B” also includes a saturated bicyclic group. Examples thereof are the groups of the following formulae:

The “C 3-10 cycloalkyl group” for “B” includes a compound wherein an aromatic ring is condensed, and examples thereof are a group of the following formulae:

The “C 3-6 cycloalkyl-C 1-4 alkyl group” means a group where a “C 3-6 cycloalkyl” is attached to a “C 1-4 alkyl”. Examples thereof are cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, etc.

The “C 5-6 cycloalkenyl group” means a cyclic unsaturated hydrocarbon group having a double bond, and includes, for example, 1-cyclopentenyl, 1-cyclohexenyl, etc.

The “C 6-10 aryl group” means an aromatic hydrocarbon group having 6 to 10 carbon atoms.

Preferable one is a C 6 aryl group (phenyl). Examples of the “C 6-10 aryl group” are phenyl, 1-naphthyl or 2-naphthyl, etc.

The “C 7-14 aralkyl group” means a “C 6-10 aryl-C 1-4 alkyl group”, which is a group where the above-mentioned “alkyl group” is attached to the above-mentioned “aryl group”. Preferable one is a “C 7-10 aralkyl group” (a C 6 aryl-C 1-4 alkyl group). Examples of the “C 7-14 aralkyl group” are benzyl, 2-phenyl, 2-phenylethyl, 1-phenylpropyl or 1-naphthylmethyl, etc.

The C 1-4 alkyl moiety of “C 7-14 aralkyl group” for “B” includes a group which forms a C 2 -C 4 ring on one carbon atom of the C 1-4 alkyl group.

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 1-4 alkyl group” means a group where the above-mentioned “alkyl group” is substituted with the above-mentioned “heteroaryl group”. The heteroaryl moiety of said group includes the same ones as exemplified as the above-mentioned heteroaryl group such as “heteroaryl-C 1-4 alkyl”. Examples thereof are 2-pyridylmethyl, etc.

The “C 1-6 alkyl moiety” of the “C 1-6 alkoxy group” is the same as the above-mentioned “C 1-6 alkyl”. Preferable one is a “C 1-4 alkoxy group”. Examples of the “C 1-6 alkoxy group” are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.

The “C 1-6 alkyl moiety” of the “C 1-6 alkylthio group” is the same as the above-mentioned “C 1-6 alkyl”. Preferable one is a “C 1-4 alkylthio group”. Examples of the “C 1-6 alkylthio group” are methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio or hexylthio, etc.

The “C 1-6 alkyl moiety” of the “C 1-6 alkylsulfonyl group” is the same as the above-mentioned “C 1-6 alkyl”. Preferable one is a “C 1-4 alkylsulfonyl group”. Examples of the “C 1-6 alkylsulfonyl group” are methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, pentylsulfonyl or hexylsulfonyl, etc.

The “C 6-10 aryl moiety” of the “C 6-10 arylthio group” is the same as the above-mentioned “C 6-10 aryl”. Examples of the “C 6-10 arylthio group” are phenylthio, 1-naphthylthio or 2-naphthylthio, etc.

The “C 3-10 cycloalkyl moiety” of the “C 3-10 cycloalkoxy group” is the same as the above-mentioned “C 3-10 cycloalkyl”. Preferable one is a “C 3-6 cycloalkoxy group”, etc. Examples of the “C 3-10 cycloalkoxy group” are cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, adamantyloxy or norbornyloxy, etc.

The “C 5-6 cycloalkenyloxy moiety” of the “C 5-6 cycloalkenyloxy group” is the same as the above-mentioned “C 5-6 cycloalkenyloxy”. Examples thereof are 1-cyclopentenyloxy, etc.

The “C 6-10 aryl moiety” of the “C 6-10 aryloxy group” is the same as the above-mentioned C 6-10 aryl, and the preferable one is a “C 6 aryloxy” (phenyloxy). Example of the “C 6-10 aryloxy group” is phenoxy, 1-naphthyloxy or 2-naphthyloxy, etc.

The “C 7-14 aralkyl moiety” of the “C 7-14 aralkyloxy group” (C 6-10 aryl-C 1-4 alkyloxy group) is the same as the above-mentioned “C 7-14 aralkyl”, and preferable one is a “C 7-10 aralky group” (phenyl-C 1-4 alkyl group), etc. Examples of the “C 7-14 aralkyloxy group” is benzyloxy, phenethyloxy, naphthylmethyloxy, etc.

The “heteroaryloxy group” is a group where the “aralkyl moiety” of the above-mentioned “aralkyloxy group” is replaced by a “heteroaryl”. Examples thereof are a “5- to 10-membered monocyclic or polycyclic heteroaryloxy group”, etc.

The “C 1-4 alkoxy moiety” of the “C 1-4 alkoxysulfonyl group” is the same as the above-mentioned “C 1-4 alkoxy group”. Examples thereof are methoxysulfonyl, etc.

The “C 3-6 cycloalkoxy moiety” of the “C 3-6 cycloalkoxysulfonyl group” is the same as the above-mentioned “C 3-6 cycloalkoxy group”. Examples thereof are cyclopropyloxysulfonyl, etc.

The “C 6-10 aryl moiety” of the “C 6-10 aryloxysulfonyl group” is the same as the above-mentioned “C 6-10 aryl group”. Examples thereof are phenoxysulfonyl, etc.

The “C 1-4 alkoxycarbonyl group” means a group where the above-mentioned “C 1-4 alkoxy group” is attached to a carbonyl group. Examples thereof are methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 2-propoxycarbonyl or tert-butoxycarbonyl, etc.

The “C 3-6 cycloalkoxycarbonyl group” means a group where the above-mentioned “C 3-6 cycloalkoxy group” is attached to a carbonyl group. Examples of the C 3-6 cycloalkoxy moiety are ones as exemplified as the above-mentioned cycloalkoxy group

The “C 1-4 alkylcarbonyl group” means a group where the above-mentioned “C 1-4 alkyl group” is attached to a carbonyl group. Examples thereof are acetyl, propionyl, or butynyl, etc.

The “C 3-10 cycloalkylcarbonyl group” means a group where the above-mentioned “C 3-10 cycloalkyl group” is attached to a carbonyl group. Preferable one includes a C 3-6 cycloalkylcarbonyl group. Examples of the “C 3-10 cycloalkylcarbony group” are cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, adamantylcarbonyl or norbornylcarbonyl, etc.

The “C 3-6 cycloalkyl-C 1-4 alkylcarbonyl group” means a group wherein the above-mentioned “C 3-10 cycloalkyl-C 1-4 alkyl group” is attached to a carbonyl group. Examples thereof are cyclopropylmethylcarbonyl, etc.

The “C 6-10 arylcarbonyl group” means a group where the above-mentioned “C 6-10 aryl group” is attached to a carbonyl group. The “C 6-10 aryl moiety” is the same as the above-mentioned “C 6-10 aryl group”. Preferable one is a “C 6 arylcarbonyl group” (phenylcarbonyl group). Examples of the “C 6-10 arylcarbonyl group” are benzoyl, 1-naphthoyl, or 2-naphthoyl, etc.

The “C 1-4 alkyl moiety” of the “C 1-4 alkylcarbonyloxy group” is the same as the above-mentioned “C 1-4 alkyl group”. Examples thereof are methylcarbonyloxy, ethylcarbonyloxy, isopropylcarbonyloxy, etc.

The “C 3-6 cycloalkyl” moiety of the “C 3-6 cycloalkylcarbonyloxy group” is the same as the above-mentioned “C 3-6 cycloalkyl group”. Examples thereof are cyclopropylcarbonyloxy, cyclobutylcarbonyloxy, cyclopentylcarbonyloxy, etc.

The “C 3-6 cycloalkyl-C 1-4 alkoxy group” means a group where a “C 1-4 alkoxy group” is substituted with the above-mentioned “C 3-6 cycloalkyl group”. Examples thereof are cyclopropylmethoxy, etc.

The “C 3-6 cycloalkyl-C 1-4 alkoxy moiety” of the “C 3-6 cycloalkyl-C 1-4 alkoxycarbonyl group” is the same as mentioned above. Examples thereof are cyclopropylmethoxycarbonyl, etc.

The “C 1-4 alkylcarbonylamino group” means a group where one of the above-mentioned “C 1-4 alkylcarbonyl group”s is attached to an amino group. Examples thereof are methylcarbonylamino, etc. In addition, the “C 1-4 alkyl” may optionally be substituted by 1 to 3 fluorine atom(s).

The “C 1-4 alkylthiocarbonylamino group” means a group where the carbonyl of the above-mentioned “C 1-4 alkylcarbonyl group” is replaced with a thiocarbonyl. Examples thereof are methylthiocarbonylamino, etc.

The “N—(C 1-4 alkylcarbonyl)-N—(C 1-6 alkyl)amino group” means a group where the amino of the above-mentioned “C 1-4 alkyl carbonylamino group” is substituted with the above-mentioned “C 1-6 alkyl group”. Examples thereof are N-methyl-N-ethylcarbonylamino, etc.

The “C 3-6 cycloalkylcarbonylamino group” means a group where one of the above-mentioned

“C 3-6 cycloalkylcarbonyl group” is attached to an amino group. Examples thereof are cyclopropyl-carbonylamino, etc.

The “C 3-6 cycloalkyl-C 1-4 alkylcarbonylamino group” means a group where one of the above-mentioned “C 3-6 cycloalkyl-C 1-4 alkylcarbonyl group” is attached to an amino group. Examples thereof are cyclopropylmethylcarbonylamino, etc.

The “C 1-4 alkoxycarbonylamino group” means a group where one of the above-mentioned “C 1-4 alkoxycarbonyl group” is attached to an amino group. Examples thereof are methoxycarbonylamino, ethoxycarbonylamino, etc. In addition, the “C 1-4 alkyl” may optionally be substituted with 1 to 3 fluorine atom(s).

The “N—(C 1-6 alkyl)-N—(C 1-4 alkoxycarbonyl)-amino group” means a group where a “C 1-6 alkyl group” substitutes to the amino group of the above-mentioned “C 1-4 alkoxycarbonylamino group”, and examples thereof are N-methyl-methoxycarbonylamino, etc.

The “C 1-4 alkylsulfonylamino group” means a group where one of the above-mentioned “C 1-4 alkylsulfonyl group” is attached to an amino group. Examples thereof are methylsulfonylamino, ethylsulfonylamino, etc.

The “C 1-4 alkylsulfonylaminocarbonyl group” means a group where the above-mentioned “C 1-4 alkylsulfonylamino group” is attached to a carbonyl group. Examples thereof are methylsulfonylamino, etc.

The “saturated heterocyclic group” includes, for example, a 5- or 6-membered saturated heterocyclic group having the same or different 1 to 3 heteroatom(s) selected from nitrogen atom, oxygen atom and sulfur atom, where the above-mentioned nitrogen, oxygen and sulfur atom are all a ring-forming atom. Examples thereof are pyranyl, tetrahydrofuryl, pyrrolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, hexamethyleneiminyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, oxoimidazolidinyl, dioxoimidazolidinyl, oxooxazolidinyl, dioxooxazolidinyl, dioxothiazolidinyl, tetrahydrofuranyl, or tetrahydropyridinyl, 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 “5- or 6-membered saturated heterocyclic group” includes a saturated bicyclic group and saturated spirocyclic group having a “5- or 6-membered saturated heterocyclic group” as a basic skeleton. Examples thereof are group of the following group.

The above-mentioned “saturated heterocyclic group” may form a condensed ring with a 6-membered aromatic hydrocarbon or a 6-membered unsaturated heterocycle. For example, said “saturated heterocyclic group” includes a bicyclic 11- or 12-membered “saturated heterocyclic group” wherein the above mentioned 5- or 6-membered 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 “saturated heterocyclic ring moiety” of the “saturated heterocyclyl-oxy group” is the same as the above-mentioned “saturated heterocyclic group”. Examples thereof are 4-pyranyloxy, etc.

The “saturated heterocyclyl-carbonyl group” means a group where the above-mentioned “saturated heterocyclic group” is attached to a carbonyl group. Examples thereof are 4-pyranylcarbonyl, etc.

The “saturated heterocyclyl-C 1-4 alkyl group” means a group where the above-mentioned “saturated heterocyclic group” is attached to a “C 1-4 alkyl group”. Examples thereof are 4-pyranylmethyl, etc.

The “saturated heterocyclyl-C 1-4 alkoxy group” means a group where the above-mentioned “saturated heterocyclic group” is attached to a “C 1-4 alkoxy group”. Examples thereof are 4-pyranylmethoxy, etc.

The “saturated heterocyclyl-oxy moiety” of the “saturated heterocyclyl-oxycarbonyl group” is the same as mentioned above. Examples thereof are 4-pyranyloxycarbonyl, etc.

The “saturated heterocyclyl-C 1-4 alkyl moiety” of the “saturated heterocyclyl-C 1-4 alkylcarbonyl group” is the same. Examples thereof are 4-pyranylmethylcarbonyl, etc.

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

The “mono- or di-substituted amino group” means an amino group which is substituted with the same or different 1 to 2 group(s) selected from “C 1-6 alkyl”, “C 3-6 cycloalkyl”, “C 3-6 cycloalkyl-C 1-4 alkyl”, “C 3-6 cycloalkyl-C 1-4 alkoxycarbonyl”, “C 1-4 alkylcarbonyl”, “saturated heterocycle”, “saturated heterocyclyl-C 1-4 alkyl”, “saturated heterocyclyl-carbonyl”, “saturated heterocyclyl-oxycarbonyl”, “saturated heterocyclyl-C 1-4 alkylcarbonyl”, and “benzyl”.

Examples of the “mono- or di-substituted amino group” are “mono- or di-(C 1-6 alkyl)-substituted amino group” (e.g., methylamino, ethyl amino, dimethylamino, diethylamino, etc.), “mono- or di-(C 3-6 cycloalkyl)-substituted amino group” (e.g., cyclopropylamino, cyclobutylamino, cyclopentylamino, dicyclopropylamino, dicyclobutylamino, cyclodipentylamino, etc.), “mono-(C 3-6 cycloalkyl-C 1-4 alkyl)-substituted amino group” (e.g., cyclopropylmethylamino, cyclobutylmethylamino, cyclopentylmethylamino, etc.), “(C 1-4 alkyl)(benzyl)-substituted amino group” (e.g., N-methyl-N-benzylamino, N-ethyl-N-benzylamino, etc.), “(C 3-6 cycloalkyl)(benzyl)-substituted amino group” (e.g., N-cyclopropyl-N-benzylamino, N-cyclopentyl-N-benzylamino, N-cyclohexyl-N-benzylamino, etc.), “C 3-6 cycloalkyl-C 1-4 alkoxycarbonylamino” (e.g., cyclopropylmethoxycarbonylamino, etc.), “5- or 6-membered saturated heterocyclyl-amino group” (e.g., 3-pyrrolidinylamino, etc.), “saturated heterocyclyl-C 1-4 alkylcarbonylamino group” (e.g., (4-pyranylmethylcarbonyl)amino, etc.), “N—(C 1-6 alkyl)-N-(saturated heterocyclyl-C 1-4 alkyl carbonyl)-amino group” (e.g., N-methyl-N-(4-pyranyl-methylcarbonyl)amino, etc.), “saturated heterocyclyl-carbonylamino group” (e.g., 4-pyranylcarbonyl-amino, etc.), “N—(C 1-6 alkyl)-N-(saturated heterocyclyl-carbonyl)-amino group” (e.g., N-methyl-N-(4-pyranylcarbonyl)amino, etc.), “N—(C 1-4 alkylcarbonyl)-N—(C 1-6 alkyl)-amino group” (e.g., N-methyl-N-methylcarbonylamino, etc.), “(saturated heterocyclyl-oxycarbonyl)amino group” (e.g., 3-tetrahydro-furyloxycarbonylamino, etc.), “N-(saturated heterocyclyl-C 1-4 alkyl)-N—(C 1-6 alkyl)-amino group” (e.g., N-methyl-N-(4-pyranylmethyl)amino, etc.), “N-(saturated heterocyclyl-carbonyl)-N—(C 1-6 alkyl)-amino group” (e.g., N-methyl-N-(4-pyranylcarbonyl)amino, etc.), “N-(saturated heterocyclyl-C 1-4 alkyl-carbonyl)-N—(C 1-6 alkyl)-amino group” (e.g., N-methyl-N-(4-pyranylmethylcarbonyl)amino, etc.), “N-(saturated heterocyclyl-oxycarbonyl)-N—(C 3-6 cycloalkyl)-amino group” (e.g., N-cyclopropyl-N-(4-pyranyloxycarbonyl)amino, etc.), “N-(saturated heterocyclyl-C 1-4 alkylcarbonyl)-N—(C 3-6 cycloalkyl)-amino group” (e.g., N-cyclopropyl-N-(4-pyranylmethylcarbonyl)amino, etc.), etc.

In addition, the “C 1-6 alkyl moiety” of the “mono- or di-(C 1-6 alkyl)-substituted amino group” may optionally be substituted with C 1-6 alkoxy, mono-C 1-6 alkylcarbonylamino (said C 1-6 alkyl being optionally substituted with 1 to 3 fluorine atom(s)), or mono-C 1-6 alkoxycarbonylamino.

The “4- to 7-membered cyclic amino group” means a cyclic amino group having 4 to 7 members, where the nitrogen atom of said ring is a direct bond to said group. Preferable one is 5- to 7-membered ones, and more preferable one is 5- or 6-membered ones. Examples thereof are pyrrolidino, piperidino, morpholino, thiomorpholino, thiomorpholino oxide, thiomorpholino dioxide, piperazino, 2-pyrrolidon-1-yl, etc. Said ring may optionally be substituted with a halogen atom, C 1-4 alkyl, or a C 6 aryl having optionally a C 1-4 alkoxy substituent.

The “5- to 7-membered cyclic amino group” may form a condensed ring with a 6-membered aromatic hydrocarbon or a 6-membered unsaturated heterocycle. Example thereof is a group of the following formula.

The substituent of the “optionally substituted C 1-6 alkyl group” includes, for example,

(a) a halogen atom,

(b) a cyano group,

(c) a C 3-6 cycloalkyl group (said group being optionally substituted by halogen, hydroxy or C 1-4 alkoxy),

(d) a hydroxy group,

(e) a C 1-4 alkoxy group (being optionally substituted by fluorine, C 1-4 alkoxy, or C 3-6 cycloalkyl),

(f) a C 3-6 cycloalkyloxy group,

(g) a C 6 aryloxy group (said group being optionally substituted by the same or different groups selected from a group consisting of halogen, cyano and C 1-4 alkoxy),

(h) a benzyloxy group,

(i) a formyl group,

(j) a C 1-4 alkylcarbonyl group,

(k) a C 3-6 cycloalkylcarbonyl group,

(l) a phenylcarbonyl group,

(m) a benzylcarbonyl group,

(n) a formylcarbonyloxy group,

(o) a C 1-4 alkylcarbonyloxy group,

(p) a C 3-6 cycloalkylcarbonyloxy group,

(q) a carboxyl group,

(r) a C 1-4 alkoxycarbonyl group,

(s) a C 3-6 cycloalkoxycarbonyl group,

(t) an amino group,

(u) a mono-substituted amino group (said group being substituted by (u1) C 1-6 alkyl, (u2) C 3-6 cycloalkyl, (u3) C 3-6 cycloalkyl-C 1-4 alkyl, (u4) benzyl, (u5) C 3-6 cycloalkyl-C 1-4 alkoxycarbonyl, (u6) C 1-4 alkylcarbonyl, (u7) C 3-6 cycloalkylcarbonyl, (u8) saturated heterocyclyl-C 1-4 alkyl, (u9) saturated heterocyclyl-carbonyl, (u10) saturated heterocyclyl-oxycarbonyl, (u11) saturated heterocyclyl-C 1-4 alkylcarbonyl, or (u12) C 1-4 alkyl sulfonyl),

(v) a di-substituted amino group (said group being substituted by the same or different 2 groups selected from the above-mentioned (u1)˜(u12)),

(w) a 5- or 7-membered cyclic amino group,

(x) an optionally substituted aminocarbonyl group,

(y) an optionally substituted aminocarbonyloxy group, or

(z) a saturated heterocyclic group (said ring being optionally substituted with C 1-4 alkyl having optionally C 1-4 alkoxy substituent, C 1-4 alkoxy, or C 1-4 alkylcarbonylamino).

In addition, the substituent of the “optionally substituted C 1-6 alkyl group” should not be limited to those listed above. That is, in addition to the above substituents' list, the groups (f801) to (f826) and (b120) to (b128) as explained below are also included in the substituents' list.

The above-mentioned “optionally substituted aminocarbonyl group” means a group where the “optionally substituted amino” is attached to a carbonyl. The “substituted amino” includes mono-substituted amino group, di-substituted amino group or 5- to 7-membered cyclic amino.

Examples of the “mono- or di-substituted aminocarbonyl group” are ones where the “mono- or di-aminocarbonyl moiety” thereof is the same ones as exemplified as the above-mentioned “mono- or di-substituted amino”

The “5- to 7-membered cyclic aminocarbonyl group” may optionally be substituted with a C 6-10 aryloxy. Examples thereof are 3-phenyloxypyrrolidinocarbonyl, etc.

The “C 1-6 alkyl-aminocarbonylamino group” means an amino group which is substituted with one the above-mentioned “mono-(C 1-6 alkyl)-substituted aminocarbonyl group”, and examples thereof are methylaminocarbonylamino, etc.

The “N—(C 1-6 alkylaminocarbonyl)-N—(C 1-6 alkyl)-amino group” means a group where a “C 1-6 alkyl group” substitutes on the amino group of the above-mentioned “C 1-6 alkylaminocarbonylamino group”, and examples thereof are N-methylaminocarbonyl-N-methylamino, etc.

The “C 1-6 alkylaminothiocarbonylamino group” means a group where the carbonyl of the above-mentioned “C 1-6 alkylaminocarbonylamino group” is replaced with a thiocarbonyl, and examples thereof are methylaminothiocarbonylamino.

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

The“5- to 7-membered cyclic aminocarbonyl moiety” of the “5- to 7-membered cyclic amino-carbonyloxy” is the same as mentioned above. Examples thereof are pyrrolidinocarbonyloxy, etc.

The “5- to 7-membered cyclic aminocarbonyl-C 1-4 alkoxy” means a group where the above-mentioned “5- to 7-membered cyclic aminocarbonyl” is attached to the above-mentioned “C 1-4 alkoxy group”. Examples thereof are 1-morpholinocarbonyl-1,1-dimethylmethoxy, etc.

The substituent of the “optionally substituted C 1-6 alkyl group” for B is preferably the following groups selected from a group consisting of:

(a2) a halogen atom,

(b2) a C 3-6 cycloalkyl (being optionally substituted by the same or different 1 to 2 group(s) selected from a group consisting of (b21) a halogen atom, (b22) hydroxy, (b23) C 1-4 alkoxy, and (b24) C 3-6 cycloalkylcarbonylamino,

(c2) a hydroxy group,

(d2) a C 1-4 alkoxy,

(e2) a C 3-6 cycloalkoxy,

(f2) a C 6 aryloxy (being optionally substituted by C 1-4 alkyl),

(g2) a carboxy,

(h2) a C 1-4 alkoxycarbonyl,

(i2) an amino (being optionally substituted by C 1-6 alkyl or benzyl),

(j2) an aminocarbonyl (the amino moiety being optionally substituted by (j21) C 1-6 alkyl, (j22) C 3-6 cycloalkyl, or (j23) C 3-6 cycloalkyl-C 1-4 alkyl),

(k2) a C 3-6 cycloalkyl carbonylamino,

(l2) a saturated heterocycle (said ring being optionally substituted by the same or different 1 to 2 group(s) selected from a group consisting of (l21) C 1-4 alkyl, (l22) C 1-4 alkoxy, (l23) C 1-4 alkylcarbonylamino, and (l24) oxo), and

(m2) a 5- to 7-membered cyclic amino group (said group being optionally substituted by the same or different 1 to 3 group(s) selected from a group consisting of (m21) a halogen atom, (m22) a C 1-4 alkyl, (m23) C 6 aryl having optionally C 1-4 alkoxy substituent, (m24) a C 6 aryloxy having optionally 1 to 3 halogen substituent(s), and (m25) oxo).

When “B” is a C 1-6 alkyl group being substituted with “mono-(C 1-6 alkyl)-substituted amino”, then the “C 1-6 alkyl” of the amino moiety may be optionally substituted with aminocarbonyl, mono- or di-(C 1-6 alkyl)aminocarbonyl, or 5- or 6-membered cyclic aminocarbonyl (provided that when “A” should be a single bond, and “B” should be an optionally substituted C 1-6 alkyl group. The (C 1-6 alkyl)amino and the cyclic amino moiety are the same as mentioned above). Examples of the “C 1-6 alkyl” of the above-mentioned amino moiety are the following groups.

The substituent of the “optionally substituted C 1-6 alkyl group” for “B” may optionally be substituted with the same or different 1 to 3 group(s) selected from the above-mentioned groups. For example, when “A” is a single bond, then it may be substituted simultaneously with 2 substituents of the above-mentioned (b2) and (j2). In addition, when “A” is a group other than a single bond, said group may be substituted simultaneously with 2 groups of the above-mentioned (b2) and (d2).

Examples of the above-mentioned group include the following “groups”.

The substituent of the “optionally substituted C 1-6 alkoxy group” includes, for example, one group selected from a group consisting of the above-mentioned (a) to (z) (in which the substituent of (u) mono-substituted amino group should be C 1-4 alkyl group or C 3-6 alkyl group, and as for (v), (x) and (y), the same).

The substituent of the “optionally substituted C 2-6 alkenyl group” and the “optionally substituted C 2-6 alkynyl group” includes, for example, one group selected from a group consisting of the above-mentioned (a) to (s) and C 1-4 alkyl (in which the above-mentioned C 1-4 alkyl group being optionally substituted with hydroxy).

The substituent of the “optionally substituted C 3-10 cycloalkyl group” and the “optionally substituted C 3-10 cycloalkyloxy group” includes, for example, one group selected from a group consisting of the above-mentioned (x), a halogen atom, C 1-4 alkyl group being optionally substituted with C 1-4 alkoxy and a C 6-10 aryl group (said aryl group being optionally substituted with a halogen atom, C 1-4 alkyl, a hydroxy group, or C 1-4 alkoxy).

The substituent of the “optionally substituted C 5-6 cycloalkenyl group” and the “optionally substituted C 5-6 cycloalkenyloxy group” includes, for example, one group selected from a group consisting of the above-mentioned (a) to (s) and nitro group.

The substituent of the “optionally substituted C 1-4 alkylcarbonyl” and the “optionally substituted C 3-10 cycloalkylcarbonyl group” includes, for example, one group selected from a group consisting of the above-mentioned (a) to (h), nitro group, C 1-4 alkylcarbonylamino group and C 1-4 alkoxycarbonylamino group.

The substituent of the “optionally substituted C 1-6 alkylthio group”, “optionally substituted C 1-6 alkylsulfonyl group”, and the “optionally substituted C 1-4 alkoxycarbonyl group” includes, for example, one group selected from a group consisting of a halogen atom, a hydroxy group, nitro group, a cyano group, and the above-mentioned (d) to (h).

The substituent of the “optionally substituted C 6-10 aryl group”, the “optionally substituted C 6-10 aryloxy group”, the “optionally substituted C 6-10 arylcarbonyl group”, the “optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group” and the “optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryloxy” includes, for example, the following groups selected from a group consisting of

(a3) a halogen atom,

(b3) a nitro group,

(c3) a cyano group,

(d3) a C 1-4 alkyl group (said group being optionally substituted with a halogen atom, a hydroxy group, or amino),

(e3) a hydroxy group,

(f3) a C 1-4 alkoxy group (said group being optionally substituted with (f31) C 1-4 alkoxy, (f32) C 3-6 cycloalkyl having optionally C 1-4 alkyl substituent, or (f33) a C 6 aryloxy having optionally halogen substituent),

(g3) a C 3-6 cycloalkyloxy group,

(h3) a C 6-10 aryloxy group (said group being optionally substituted with the same or different group selected from a group consisting of a halogen atom, cyano and C 1-4 alkoxy),

(i3) a C 6-10 aryl group (said group being optionally substituted with (i31) a halogen atom, (i32) C 1-4 alkyl having optionally carboxy substituent, (i33) C 1-4 alkoxy having optionally a substituent selected from fluorine atom, a hydroxy group, and carboxy),

(j3) a sulfonyl group,

(k3) a C 1-4 alkoxysulfonyl group,

(l3) a C 3-6 cycloalkoxysulfonyl group,

(m3) a C 6-10 aryloxysulfonyl group (said phenyl being optionally substituted with the same or different group selected from a group consisting of a halogen atom, cyano and a C 1-4 alkoxy),

(n3) benzyloxysulfonyl group,

(o3) 5- or 6-membered monocyclic heteroaryloxy group (said group being optionally substituted with C 1-4 alkyl),

(p3) a saturated heterocyclyl-oxy group (said group being optionally substituted with the same or different 1 to 2 group(s) selected from (p31) a C 6 aryl optionally having a halogen substituent, or (p32) saturated heterocyclyl-carbonyl),

(q3) an amino group (said group being optionally substituted with the same or different 1 to 2 group(s) selected from the above-mentioned u1 to u12),

(r3) 5- to 7-membered cyclic amino group (being optionally substituted with C 6 aryl),

(s3) an optionally substituted aminocarbonyl group, and

(t3) an optionally substituted aminocarbonyloxy group.

In addition, the substituents should not be limited thereto, and may include, in addition to the ones as listed above, the substituents of (e1201) to (e1211) as explained below.

The substituent of the aryl moiety of the “optionally substituted C 7-14 aralkyl group” and the “optionally substituted C 7-14 aralkyloxy group” includes, for example, the following groups selected from a group consisting of

(a4) a halogen atom,

(b4) a cyano group,

(c4) a C 1-4 alkyl group (being optionally substituted with 1 to 3 halogen atom(s)),

(d4) a hydroxy group,

(e4) a C 1-4 alkoxy group (being optionally substituted with 1 to 3 halogen atom(s)),

(f4) a C 3-6 cycloalkoxy group (being optionally substituted with 1 to 2 halogen atom(s)),

(g4) carboxy group,

(h4) a C 1-4 alkoxycarbonyl group,

(i4) a C 6-10 aryl group (being optionally substituted with 1 to 3 halogen atom(s) or C 1-4 alkoxy),

(j4) a C 6-10 aryloxy group,

(k4) a C 7-10 aralkyloxy group,

(l4) an aminocarbonyl group (the amino moiety having optionally a C 1-6 alkyl substituent),

(m4) a C 1-4 alkylsulfonylamino group, and

(n4) a C 1-4 alkylsulfonyl group.

The substituent of the above-mentioned (a4) to (n4) may substitute on the C 1-4 alkyl moiety of the C 7-14 aralkyl group (C 6-10 aryl-C 1-4 alkyl group).

The substituent of the heteroaryl moiety of the “optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl-C 1-4 alkyl group” includes ones as exemplified as a substituent for the “optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group”.

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

(a5) a halogen atom,

(b5) a hydroxy group,

(c5) a nitro group,

(d5) a cyano group,

(e5) a C 1-4 alkyl group (being optionally substituted with 1 to 3 halogen atom(s) or C 1-4 alkoxy),

(f5) a C 1-4 alkoxy group (being optionally substituted with 1 to 3 halogen atom(s)),

(g5) a carboxyl group,

(h5) a C 1-4 alkoxycarbonyl group,

(i5) a C 3-6 cycloalkoxycarbonyl group,

(j5) an amino group (being optionally substituted with C 1-4 alkyl),

(k5) a C 6 aryl group (being optionally substituted with C 1-4 alkoxy),

(l5) an aminocarbonyl group,

(m5) a C 1-4 alkylcarbonylamino group,

(n5) an oxo group, or

(o5) a thioxo group.

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

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

The definitions of “G 1 ”, “G 2 ”, “G 3 ” and “G 4 ” of the compound of the formula (I) are explained below. The compound where G 1 is —N(R 1b )—, G 2 is —CO—, G 3 is —C(R 1c )(R 1d )— and G 4 does not exist at all means a compound of the following formula:

(wherein the definitions are the same as defined in Item 1).

The compound where G 1 is —N(R 1b )—, G 2 is —CO—, G 3 is —N(R 1b )—, and G 4 does not exist at all means a compound of the following formula:

(wherein the definitions are the same as defined in Item 1).

The compound where G 1 is —N(R 1b )—, G 2 is —CO—, G 3 is —C(R 1c )(R 1d )—, and G 4 is —C(R 1x )(R 1y )— means a compound of the following formula:

(wherein the definitions are the same as defined in Item 1). In this case, “R 1c ” and “R 1x ” may combine each other. That is, the compound of the above definition also includes a compound of the following formula:

The definition of a group of the following formula where “R 1x and R 1y combine each other is explained below.

Said definition means a spiro ing of the following formulae (the part expressed with a solid line means a part formed by R 1x and R 1y , and the part expressed with a broken line means a skeleton formed by G 1 to G 4 ).

The binding position of “A” of “a group: -A-B” is explained below. When A is —(CH 2 ) s O— and B is a hydrogen atom, then the “group: -A-B” means a “group: —(CH 2 ) s O—H”.

In case that “A is —(CH 2 ) s N(R 4 )—, —(CH 2 ) s OCON(R 4 )—, —(CH 2 ) s CON(R 4 )—, —(CH 2 ) s N(R 4 )CO—N(R 4 )— or —(CH 2 ) s SO 2 N(R 4 )—, R 4 and B combine each other to form a ring” means that “N(R 4 )—” moiety forms a “5- or 6-membered cyclic amino group”. Examples thereof are groups of the following formulae.

The above-mentioned ring formed by combining R 4 and B includes, for example, a condensed ring with a C 6 aryl, a 5- or 6-membered heteroaryl or a 5- or 6-membered saturated heterocycle. Examples thereof are groups of the following formulae.

The above-mentioned cyclic amino group may optionally be substituted with the same substituents as ones for the above-mentioned “saturated heterocyclic group”. Examples thereof are 4-hydroxypiperidino; 2-methoxymorpholino; 4-formyl-piperidino; 4-methoxycarbonylpiperidino; 4-aminocarbonylpiperidino; 4-N-methylaminopiperidino; 3-phenylpyrrolidino; 4-dimethylaminopiperidino, etc.

In the compounds of the formula (I), when A is —(CH 2 ) s N(R 4 )CON(R 4 )—, then each R 4 may independently be different. Examples thereof are A being “—(CH 2 ) s NHCON(CH 3 )—”, and the like.

The “any two groups of R 3a , R 3b , R 3c and R 3d are a hydrogen atom, and the remaining 2 groups combine each other to form a fused ring with a heterocyclic ring” means that the remaining two groups as defined above form a fused ring with a hetero ring (pyrrolidine ring, piperidine ring, etc.) to which said definition substitutes. Examples of said definition are groups of the following structures.

Preferable embodiments of the compounds of the formula (I) are explained. The definitions for the following partial structure:

(wherein the definitions are the same as defined above) are explained.

The “G 1 ”, “G 2 ”, “G 3 ” and “G 4 ” are preferably, (i) G 1 is —N(R 1b )—, G 2 is —CO—, G 3 is —C(R 1c )(R 1d )—, and G 4 is —C(R 1x )(R 1y )—, —SO 2 —, an oxygen atom, a sulfur atom, or does not exist at all, or (ii) G 1 is —N(R 1b )—, G 2 is —CO—, G 3 is —N(R 1b )—, and G 4 does not exist at all.

The “G 1 ”, “G 2 ”, “G 3 ” and “G 4 ” are preferably, G 1 is —N(R 1b )—, G 2 is —CO—, G 3 is —N(R 1b )—, and G 4 does not exist at all.

The “G 1 ”, “G 2 ”, “G 3 ” and “G 4 ” are more preferably, G 1 is —N(R 1b )—, G 2 is —CO—, G 3 is —C(R 1c )(R 1d )—, and G 4 is —C(R 1x )(R 1y )—, an oxygen atom, or a sulfur atom.

The “G 4 ” is preferably —C(R 1x )(R 1y )—, and R 1x and R 1y are preferably a hydrogen atom or a C 1-4 alkyl group.

The “G 4 ” is preferably an oxygen atom or a sulfur atom.

The “R 1a ” is one group selected from a group consisting of

(a6) a halogen atom,

(b6) a cyano group,

(c6) a C 1-6 alkyl group (being optionally substituted with 1 to 3 fluorine atom(s), C 1-4 alkoxy, or C 3-6 cycloalkoxy),

(d6) a C 1-6 alkoxy group (being optionally substituted with 1 to 3 fluorine atom(s), or C 3-6 cycloalkyl),

(e6) a C 3-6 cycloalkyl group,

(f6) a C 3-6 cycloalkoxy group (being optionally substituted with 1 to 2 fluorine atom(s), or C 1-4 alkoxy), and

(g6) a 5-membered to 6-membered heteroaryl group (being optionally substituted with a halogen atom or C 1-4 alkyl).

The “R 1a ” is preferably a group selected from a group consisting of a halogen atom, a cyano group, a C 1-6 alkyl group having optionally 1 to 3 fluorine substituent(s), and a C 1-6 alkoxy group.

The “R 1a ” preferably substitutes on the following position.

The “R 1b ” is preferably

(a7) a C 1-6 alkyl group (said group being optionally substituted with one group selected from the following groups selected from a group consisting of

(a700) hydroxy, (a702) cyano, (a703) C 1-4 alkoxy (being optionally substituted with 1 to 3 fluorine atom(s) or C 1-4 alkoxy), (a704) trifluoromethyl, (a705) trifluoromethoxy, (a706) C 3-6 cycloalkyl (being optionally substituted with 1 to 2 fluorine atom(s), or C 1-4 alkoxy), (a707) C 3-6 cycloalkoxy, (a708) formylamino, (a709) C 1-4 alkylcarbonylamino (having optionally 1 to 3 fluorine substituent(s)), (a710) N—(C 1-4 alkylcarbonyl)-N—(C 1-6 alkyl)-amino, (a711) C 3-6 cycloalkylcarbonylamino, (a712) (C 3-6 cycloalkyl-C 1-4 alkyl)carbonylamino, (a713) C 1-6 alkylthiocarbonylamino, (a714) C 1-4 alkoxycarbonylamino (having optionally 1 to 3 fluorine substituent(s)), (a715) N—(C 1-4 alkoxycarbonyl)-N—(C 1-6 alkyl)-amino, (a716) mono- or di-(C 1-6 alkyl)aminocarbonyloxy, (a717) C 1-6 alkylaminocarbonyl (having optionally 1 to 3 fluorine atom(s)), (a718) di-(C 1-6 alkyl)aminocarbonyl, (a719) C 3-6 cycloalkylaminocarbonyl, (a720) C 1-6 alkylaminocarbonylamino, (a721) C 1-6 alkylaminothiocarbonylamino, (a722) C 1-4 alkylcarbonyl, (a723) C 1-4 alkyl carbonyloxy, (a724) C 1-4 alkoxycarbonyl, (a725) C 1-6 alkylsulfonyl, (a726) C 1-4 alkylsulfonylamino, (a727) 5- or 6-membered saturated heterocycle, (a728) carboxy, and (a729) C 1-6 alkylamino,

(b7) a C 2-6 alkenyl group (being optionally substituted with a halogen atom),

(c7) a C 2-6 alkynyl group (being optionally substituted with C 1-4 alkoxy), or

(d7) a 5-membered to 6-membered heteroaryl-C 1-4 alkyl group.

The above-mentioned C 1-6 alkyl group(a7) may optionally be substituted with the same or different substituent(s).

The “R 1b ” is preferably a C 1-6 alkyl group substituted with a C 1-4 alkoxy-, and more preferably 3-methoxypropyl group or 4-methoxybutyl group.

The “R 1b ” is preferably a C 1-6 alkyl group substituted with a C 1-6 alkylcarbonylamino, and more preferably 2-(ethylcarbonylamino)ethyl group.

The “R 1b ” is preferably a C 1-6 alkyl group substituted with a C 1-4 alkoxycarbonylamino, and more preferably 2-(methoxycarbonylamino)ethyl group.

The “R 1c ” and “R 1d ” are independently the same or different, and each is a group selected from the following group consisting of

(a8) a hydrogen atom,

(b8) a halogen atom,

(c8) a cyano group,

(d8) a C 2-6 alkenyl group (being optionally substituted with C 6-10 aryl having optionally C 1-4 alkoxy substituent),

(e8) a C 2-6 alkynyl group (being optionally substituted with C 6-10 aryl having optionally C 1-4 alkoxy substituent),

(f8) a C 1-6 alkyl group (said group being optionally substituted with the same or different 1 to 2 group(s) selected from a group consisting of

(f801) 1 to 3 halogen atom(s), (f802) cyano, (f803) C 3-6 cycloalkyl (being optionally substituted with a halogen atom, C 1-4 alkyl, or C 1-4 alkoxy), (f804) hydroxy, (f805) C 1-4 alkoxy (said group being optionally substituted with the same or different 1 to 3 substituent(s) selected from a group consisting of (f80511) a halogen atom, (f80512) cyano, (f80513) C 3-6 cycloalkoxy (being optionally substituted with mono- or di-(C 1-6 alkyl)aminocarbonyl), (f80514) mono- or di-(C 1-6 alkyl)aminosulfonyl, (f80515) C 1-6 alkylsulfonyl, (f80516) aminocarbonyl having optionally mono- or di-(C 1-6 alkyl), (f80517) C 1-4 alkylcarbonyl, and (f80518) 5- to 7-membered cyclic aminocarbonyl, (f806) C 3-6 cycloalkoxy (said group being optionally substituted with (f8061) C 1-4 alkyl (optionally having C 1-4 alkoxy substituent)), (f807) C 6-10 aryloxy (said group being optionally substituted with the same or different 1 to 3 substituents selected from a group consisting of (f8071) a halogen atom, (f8072) cyano, and (f8073) C 1-4 alkoxy) (f808) mono- or di-substituted amino (said group being substituent with the same or different 1 to 2 group(s) selected from a group consisting of (f80811) C 1-6 alkyl, (f80812) C 3-6 cycloalkyl, (f80813) C 3-6 cycloalkyl-C 1-4 alkyl (being optionally substituted with aminocarbonyl), (f80814) C 3-6 cycloalkyl-C 1-4 alkoxycarbonyl, (f80815) C 1-4 alkylcarbonyl, (f80816) C 3-6 cycloalkylcarbonyl (being optionally substituted with C 1-4 alkylsulfonylamino), (f80817) 5- or 6-membered saturated heterocyclyl-C 1-4 alkyl (being optionally substituted with C 1-4 alkyl), (f80818) 5- or 6-membered saturated heterocyclyl-carbonyl, (f80819) 5- or 6-membered saturated heterocyclyl-oxycarbonyl, (f80820) 5- or 6-membered saturated heterocyclyl-C 1-4 alkylcarbonyl, and (f80821) C 1-4 alkylsulfonyl), (f809) 5- to 7-membered cyclic amino (being optionally substituted with 1 to 4 group(s) selected from a group consisting of C 1-4 alkyl, and C 7-14 aralkyl), (f810) mono- or di-(C 1-6 alkyl)aminocarbonyl, (f811) 4- to 7-membered cyclic aminocarbonyl (being optionally substituted with C 1-4 alkyl), (f812) mono- or di-substituted aminocarbonyloxy (said amino being substituted with the same or different 1 to 2 group(s) selected from a group consisting of (f8121) C 1-6 alkyl (being optionally substituted with 5- or 6-membered saturated heterocycle), (f8122) C 3-6 cycloalkyl (being optionally substituted with hydroxy), and (f8123) 5- or 6-membered saturated heterocycle), (f813) 5- to 7-membered cyclic aminocarbonyloxy (being optionally substituted with 1 to 2 fluorine atom(s)), (f814) 5- to 7-membered cyclic aminocarbonyl-C 1-4 alkoxy, (f815) mono- or di-(C 1-6 alkyl)aminocarbonyl-C 1-4 alkoxy, (f816) 5- or 6-membered saturated heterocycle (being optionally substituted with the same or different 1 to 2 group(s) selected from a group consisting of C 1-4 alkyl), (f817) 5- or 6-membered saturated heterocyclyl-C 1-4 alkoxy (being optionally substituted with C 1-4 alkyl), (f818) 5- or 6-membered saturated heterocyclyl-oxy(being optionally substituted with the same or different 1 to 2 group(s) selected from a group consisting of C 1-4 alkyl), (f819) mono- or di-C 1-4 alkylaminosulfonyl, (f820) carboxy, (f821) C 1-4 alkoxycarbonyl, (f822) C 6-10 arylcarbonyl (said group being optionally substituted with C 1-4 alkoxy), (f823) C 1-4 alkoxycarbonylamino, (f824) C 6-10 aryloxycarbonylamino (being optionally substituted with a halogen atom), (f825) 5- or 6-membered monocyclic aryloxycarbonylamino, and (f826) N—(C 1-4 alkylaminocarbonyl)-N—(C 1-6 alkyl)amino),

(g8) a C 3-10 cycloalkyl group (said group being optionally substituted with

(g81) a halogen atom, (g82) hydroxy, or (g83) C 1-4 alkoxy),

(h8) a C 7-14 aralkyl group (said group being optionally substituted with the same or different 1 to 3 group(s) selected from a group consisting of

(h81) a halogen atom, (h82) cyano, (h83) hydroxy, (h84) C 1-4 alkoxy, and (h85) C 1-4 alkyl being optionally substituted with C 1-4 alkoxy),

(i8) a C 1-6 alkoxy group (said group being optionally substituted with C 1-4 alkoxycarbonylamino),

(j8) a C 3-6 cycloalkoxy group,

(k8) a C 7-14 aralkyloxy group (being optionally substituted with C 1-4 alkoxy),

(l8) mono- or di-substituted aminocarbonyl group (said amino being optionally substituted with C 1-6 alkyl having optionally 5- or 6-membered saturated heterocycle substituent),

(m8) 5- to 7-membered cyclic aminocarbonyl group (being optionally substituted with a group selected from a group consisting of a halogen atom, C 1-4 alkoxy and C 6-10 aryl having optionally halogen substituent),

(n8) a saturated heterocyclic group (said group being optionally substituted with the same or different 1 to 4 group(s) selected from a group consisting of

(n81) C 1-4 alkyl, (n82) C 6-10 aryl having optionally 1 to 3 halogen substituent(s)

(o8) a saturated heterocyclyl-oxy group (being optionally substituted with C 1-4 alkoxycarbonyl or C 1-4 alkylcarbonyl)

(p8) a 5- to 10-membered monocyclic or polycyclic heteroaryl group (said group being optionally substituted with the same or different 1 to 2 group(s) selected from a group consisting of

(p81) a halogen atom, (p82) C 1-4 alkyl having optionally 1 to 3 fluorine atom(s), and (p83) C 1-4 alkoxy (being optionally substituted with mono- or di-(C 1-6 alkyl)aminocarbonyl)),

(q8) a 5- to 10-membered monocyclic or polycyclic heteroaryl-C 1-4 alkyl group,

(t8) a group of the following formula:

(wherein R 1e , R 1f , R 1g , R 1h and R 1i are the same as defined above).

The “R 1c ” is preferably a group selected from a group consisting of

(a9) a hydrogen atom,

(b9) a halogen atom,

(c9) a hydroxy group, and

(d9) a C 1-6 alkyl group being optionally substituted with C 1-4 alkoxy.

The “R 1d ” is preferably a group selected from a group consisting of (a8) to (t8).

The R 1d ” is more preferably one group selected a group consisting of

(a10) a hydrogen atom,

(b10) a halogen atom,

(c10) a C 1-6 alkyl group (said group being optionally substituted with a group selected from

(c101) 1 to 3 halogen atom(s), (c102) hydroxy, (c103) C 1-4 alkoxy, (c104) C 6-10 aryloxy (said group being optionally substituted with the same or different 1 to 3 group(s) selected from cyano and C 1-4 alkoxy), (c105) C 1-6 alkylaminocarbonyloxy, (c106) (5- or 6-membered saturated heterocyclyl-C 1-4 alkyl)aminocarbonyloxy, or (c107) 5- to 7-membered cyclic aminocarbonyloxy),

(e10) mono- or di-(C 1-6 alkyl)aminocarbonyl group,

(f10) N-(5- or 6-membered saturated heterocyclyl-C 1-4 alkyl)-N—(C alkyl)-aminocarbonyl group,

(g10) 5- to 7-membered cyclic aminocarbonyl group,

(h10) C 7-14 aralkyl group (being optionally substituted with C 1-4 alkoxy),

(i10) 5- or 6-membered saturated heterocyclic group,

(j10) C 3-6 cycloalkyl group,

(k10) C 3-6 cycloalkoxy group, and

(l10) a group of the following formula:

The “R 1e ”, “R 1f ”, “R 1g ”, “R 1h ” and “R 1i ” are independently the same or different, and each is preferably

(a11) a hydrogen atom,

(b11) a halogen atom,

(c11) a cyano group,

(d11) a C 1 . 4 alkyl group (said group being optionally substituted with

(d111) 5- or 6-membered saturated heterocyclyl-oxy, (d112) C 1-4 alkoxy (said group being optionally substituted with C 1-4 alkoxy or C 3-6 alkoxy)),

(e11) a C 1-4 alkoxy group (said group being optionally substituted with

(e111) 1 to 3 halogen atom(s), (e112) C 1-4 alkoxy, or (e113) C 1-6 alkylaminocarbonyl),

(f11) a C 3-6 cycloalkoxy group (said group being optionally substituted with (f111) C 1-4 alkoxy),

(g11) 5- or 6-membered saturated heterocyclyl-oxy group,

(h11) a C 1-6 alkylaminocarbonyl group.

(R 1e , R 1f , R 1g , R 1h and R 1i are the same as defined above).

The “R 1e ”, “R 1f ”, “R 1g ,”, “R 1h ” and “R 1i ” are independently the same or different, and each is preferably

(a11) a hydrogen atom,

(b11) a halogen atom,

(c11) a cyano group,

(d11) a C 1-4 alkyl group (said group being optionally substituted with

(d111) 5- or 6-membered saturated heterocyclyl-oxy, (d112) C 1-4 alkoxy (said group being optionally substituted with C 1-4 alkoxy or C 3-6 alkoxy) or (d113) 1 to 3 fluorine atom(s)),

(e11) a C 1-4 alkoxy group (said group being optionally substituted with

(e111) 1 to 3 halogen atom(s), (e112) C 1-4 alkoxy, or (e113) C 1-6 alkylaminocarbonyl),

(f11) a C 3-6 cycloalkoxy group (said group being optionally substituted with (f111) C 1-4 alkoxy),

(g11) 5- or 6-membered saturated heterocyclyl-oxy group,

(h11) a C 1-6 alkylaminocarbonyl group,

(h12) a hydroxy group, or

(h13) a C 1-4 alkoxysulfonyl group.

The “R 1e ”, “R 1f ”, “R 1g ”, “R 1h ” and “R 1i ” are independently the same or different, and each is preferably a hydrogen atom, a halogen atom, or a C 1-4 alkoxy group.

The “R 1e , R 1h and R 1i are a hydrogen atom, and R 1f and R 1g combine each other to form a condensed ring” means that forming a bicyclic or tricyclic condensed ring with a phenyl group to which R 1f and R 1g attach. Said condensed ring may be any 5- or 6-membered saturated ring or unsaturated ring, and said ring contains at least one atom selected from nitrogen atom, oxygen atom, and sulfur atom. Said ring may optionally be substituted with C 1-4 alkyl group, a hydroxy group, or oxo group.

Examples of the group where “R 1e , R 1h and R 1i are a hydrogen atom, and R 1f and R 1g combine each other to form a condensed ring” are one group selected from the following formulae.

The group of the following formula is preferable when R 1c and R 1d combine each other.

(the part expressed with a solid line is a moiety formed with R 1c and R 1d , and the part expressed with a broken line is a skeleton formed by G 1 to G 4 ).

When “D” is an oxygen atom or a sulfur atom, and p and q are 0, then R 1c and R 1d combine each other to form an oxo group or a thioxo group.

In “—NR 5 CONR 5 —” for “D”, each R 5 is independent each other.

The “—CH(R 6 )CH 2 —” for “D” may be “—CH 2 CH(R 6 )—”. In addition, when “D” is —SO 2 —, —NR 5 CO—, —NR 5 SO 2 —, —NR 5 CONR 5 —, then “p” and “q” are not simultaneously 0. When “D” is “—CH(R 6 )—”, and “R 6 ” is a halogen atom, then the hydrogen atom of “—CH(R 6 )—” may be replaced with a halogen atom.

Examples of the groups as mentioned above are structures of the following formulae.

Preferable R 5 is a group selected from a group consisting of a hydrogen atom, a C 1-6 alkyl group, a C 1-4 alkoxycarbonyl group, a C 1-4 alkylsulfonyl group, and a C 6-10 arylsulfonyl group.

Preferable R 6 is a group selected from a group consisting of a hydrogen atom; a halogen atom; a C 1-4 alkoxy group being optionally substituted with C 1-4 alkoxy; a C 7-14 aralkyloxy group being optionally substituted with 1 to 3 group(s) selected from a group consisting of a fluorine atom and cyano; and an aminocarbonyloxy group being optionally substituted with mono- or di-(C 1-6 alkyl), and a hydrogen atom is more preferable.

As to “D”, “p” and “q”, preferable combinations are

(i) D is an oxygen atom, “p” and “q” are 2,

(ii) D is —CH 2 —, “p” and “q” are 1 or 2, or

(iii) D is —CH 2 CH 2 —, and “p” and “q” are 0 or 1.

The above-mentioned partial structure of the compound of the formula (I) includes, for example, a partial structure selected from the following group.

The “R 2 ” is one group selected from

(a100) a hydrogen atom,

(b100) a C 1-6 alkyl group (being optionally substituted with a halogen atom; C 3-6 cycloalkyl having optionally a substituent selected from a halogen atom, C 1-4 alkyl and C 1-4 alkoxy),

(c100) a C 3-6 cycloalkyl group (being optionally substituted with a halogen atom or C 1-4 alkyl),

(d100) a C 2-6 alkenyl group, and

(e100) a C 7-10 aralkyl group (being optionally substituted with a halogen atom).

Preferable “R 2 ” is a C 1-6 alkyl group, and more preferable one is isopropyl group.

Preferable “B” is one group selected from

(a12) a hydrogen atom,

(b12) a C 1-6 alkyl group (said group being optionally substituted with 1 to 3 group(s) selected from

(b120) a halogen atom, (b121) a C 3-6 cycloalkyl (said group being optionally substituted with the same or different 1 to 2 group(s) selected from (i) a halogen atom, (ii) hydroxy, (iii) C 1-4 alkoxy, and (iv) C 3-6 cycloalkylcarbonylamino), (b122) a hydroxy group, (b123) C 1-4 alkoxy, (b124) carboxy, (b125) C 1-4 alkoxycarbonyl, (b126) saturated heterocycle (said ring being optionally substituted with the same or different 1 to 3 group(s) selected from (i) C 1-4 alkyl, (ii) C 1-4 alkoxy, (iii) C 1-4 alkylcarbonylamino, and (iv) oxo), (b127) aminocarbonyl (amino being optionally substituted with (i) C 1-4 alkyl, (ii) C 3-6 cycloalkyl, or (iii) C 3-6 cycloalkyl-C 1-4 alkyl), and (b128) 5- to 7-membered cyclic amino group (said group being optionally substituted with the same or different 1 to 3 group(s) selected from (i) a halogen atom, (ii) C 1-4 alkyl, (iii) C 6 aryl having optionally C 1-4 alkoxy substituent, (iv) C 6 aryloxy having optionally 1 to 3 halogen substituent(s), and (iv) oxo)),

(c12) a C 2-6 alkenyl group (being optionally substituted with 1 to 2 group(s) selected from fluorine atom and C 1-6 alkyl),

(d12) a C 3-10 cycloalkyl group (said group being optionally substituted with

(d121) a halogen atom, (d122) C 1-4 alkyl being optionally substituted with C 1-4 alkoxy, (d123) hydroxy, or (d124) C 1-4 alkoxy),

(e12) a C 6 aryl group (said group being optionally substituted with the same or different 1 to 3 group(s) selected from

(e1201) a halogen atom, (e1202) C 1-4 alkyl (said C 1-4 alkyl being optionally substituted with one group selected from (i) 5- to 7-membered cyclic amino (being optionally substituted with C 6 aryl having optionally 1 to 3 halogen substituent(s)), (ii) mono-C 1-6 alkylamino (said C 1-6 alkyl being optionally substituted with C 6 aryloxy having optionally 1 to 3 halogen substituent(s)), (iii) 5- or 6-membered saturated heterocyclyl-amino (said saturated heterocycle being optionally substituted with C 6 aryl), (iv) 5- or 6-membered saturated heterocyclyl-oxy (said saturated heterocycle being optionally substituted with C 6 aryl or 5- to 10-membered monocyclic or polycyclic heteroaryl), (v) C 6 aryloxy (being optionally substituted with the same or different 1 to 3 group(s) selected from a halogen atom and C 1-4 alkyl), (vi) C 1-4 alkoxy, and (vii) C 3-6 cycloalkoxy), (e1203) C 1-4 alkoxy (said C 1-4 alkoxy being optionally substituted with one group selected from (i) C 1-4 alkoxy, (ii) C 6 aryloxy (being optionally substituted with 1 to 3 group(s) selected from C 1-4 alkyl and a halogen atom), (iii) C 3-6 cycloalkyloxy (being optionally substituted with C 1-4 alkyl), (iv) phenylamino (said phenyl being optionally substituted with 1 to 3 halogen atom(s)), and (v) C 7-10 aralkyloxy (being optionally substituted with 1 to 3 halogen atom(s))), (e1204) C 6 aryloxy (said aryl being optionally substituted with 1 to 3 group(s) selected from (i) a halogen atom, (ii) cyano, (iii) C 1-4 alkyl, and (iv) C 1-4 alkoxy), (e1205) C 7-10 aralkyloxy (being optionally substituted with 1 to 3 group(s) selected from a halogen atom and a C 1-4 alkoxy), (e1206) 5- to 7-membered cyclic amino (said ring being optionally substituted with (i) (C 1-6 alkyl)(phenylcarbonyl)amino, or (ii) C 6 aryloxy (being optionally substituted with the same or different 1 to 3 group(s) selected from a halogen atom and C 1-4 alkyl having optionally hydroxy substituent)), (e1207) 5- or 6-membered saturated heterocyclyl-oxy (said ring being optionally substituted with (i) C 6 aryl having optionally 1 to 3 halogen substituent(s), (ii) 5- to 10-membered monocyclic or polycyclic heteroaryl, (iii) 5- or 6-membered saturated heterocyclyl-carbonyl, (iv) oxo), (e1208) 5- or 6-membered monocyclic heteroaryloxy (being optionally substituted with C 1-4 alkyl) (e1209) 5- to 7-membered cyclic aminocarbonyl (being optionally substituted with C 6 aryloxy having optionally 1 to 3 halogen substituent(s)), (e1210) 5- to 7-membered cyclic aminocarbonyloxy (being optionally substituted with C 6 aryl), and (e1211) C 6 aryl),

(f12) a C 7-14 aralkyl group (said group being optionally substituted with the same or different 1 to 3 group(s) selected from

(f120) a halogen atom, (f121) cyano, (f122) C 1-4 alkyl, (f123) hydroxy, (f124) C 1-4 alkoxy (being optionally substituted with 1 to 3 fluorine atom(s)), (f125) C 3-6 cycloalkoxy (being optionally substituted with 1 to 2 halogen atom(s)), (f126) C 1-4 alkoxycarbonyl, (f127) aminocarbonyl, (f128) C 6-10 aryl (being optionally substituted with 1 to 3 halogen atom(s)) and (f129) C 1-4 alkylsulfonyl),

(g12) a 5- to 10-membered monocyclic or polycyclic heteroaryl group (said group being optionally substituted with a halogen atom),

(h12) a 5- to 10-membered monocyclic or polycyclic heteroaryl-C 1-4 alkyl group (said group being optionally substituted with

(h121) a halogen atom, or (h122) C 1-4 alkyl (being optionally substituted with 1 to 3 fluorine atom(s))), and

(i12) a saturated heterocyclic group (said group being optionally substituted with C 1-4 alkyl having optionally C 1-4 alkoxy substituent).

The “C 1-6 alkoxy group substituted with a C 1-4 alkoxy”, which is a substituent (e1203) for “B” includes the following group.

The “R 4 ” is preferably one group selected from a group consisting of a hydrogen atom, 1 to 3 halogen atom(s), a C 1-6 alkyl group substituted with a C 3-6 cycloalkyl, a C 3-6 cycloalkyl group and a C 7 aralkyl group, and a hydrogen atom and a C 3-6 cycloalkyl group are more preferable.

The compound of the present invention in more preferable embodiments includes the compounds of the following formulae.

Namely, the present invention relates to the following.

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

[wherein R 1a , R 1m , G 1 , G 2 , G 3 , G 4 , R 2 , R 3a , R 3b , R 3e , R 3d and n are the same as defined in Item 1, provided that among the compounds of the formula (I), the compound of the following formula:

should be restricted to compounds wherein R 1a , R 1m , G 1 , G 2 , G 3 , G 4 and R 2 are the same as defined above; R 3 is one of the above-mentioned R 3a , R 3b , R 3e , or R 3d (wherein R 3a , R 3b , R 3e and R 3d are the same as defined above, provided that when R 3 is a group: -A-B, then A is a single bond, B is an optionally substituted C 7-14 aralkyl group or an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group, or A is —(CH 2 ) s O—, B is a hydrogen atom, an optionally substituted C 6-10 aryl group, or an optionally substituted C 7-14 aralkyl group)].

The present invention also includes the compound according to any one of Items 2 to Items 65, or a pharmaceutically acceptable salt thereof, wherein the compound of the formula (I) is replaced by the compound of the formula (Ia).

(2) A compound of the formula (Ic), or a pharmaceutically acceptable salt thereof.

[wherein R 1a , R 1m , G 1 , G 2 , G 3 , G 4 , R 2 , R 3a , R 3b , R 3c , R 3d and n are the same as defined above, provided that among the compounds of the formula (I), the compound of the following formula:

should be restricted to compounds wherein R 3 is one of the above-mentioned R 3a , R 3b , R 3c and R 3d (wherein when R 3 is a group: -A-B, then (i) A is —(CH 2 ) s N(R 4 )CO—, or —(CH 2 ) s N(R 4 )COO—; B is the same as defined in Item 1; R 4 is an optionally substituted C 3-10 cycloalkyl group, an optionally substituted C 6-10 aryl group, or an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group, (ii) A is —(CH 2 ) s N(R 4 )—; B is the same as defined in Item 1; R 4 is an optionally substituted C 3-10 cycloalkyl group, or an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group, (iii) A is —(CH 2 ) s N(R 4 )SO 2 —, —(CH 2 ) s OCON(R 4 )—, or —(CH 2 ) s SO 2 N(R 4 )—; B is the same as defined in Item 1; R 4 is an optionally substituted C 3-10 cycloalkyl group, or an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group, (iv) A is -(CH 2 ) s N(R 4 )CON(H)—; B is the same as defined in Item 1; R 4 is an optionally substituted C 3-10 cycloalkyl group, or an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group, (v) A is —(CH 2 ) s CON(R 4 )—; B is the same as defined in Item 1; R 4 is a C 1-6 alkyl group, an optionally substituted C 6-10 aryl group, or an optionally substituted C 7-14 aralkyl group, (vi) A is —(CH 2 ) s SO 2 —, —(CH 2 ) s CO—, or —(CH 2 ) s COO—; B is a hydrogen atom, an optionally substituted C 3-10 cycloalkyl group, an optionally substituted C 5-6 cycloalkenyl group, or an optionally substituted C 6-10 aryl group, or (vii) A is a single bond; B is a hydrogen atom, an optionally substituted C 3-10 cycloalkyl group, an optionally substituted C 5-6 cycloalkenyl group, an optionally substituted C 6-10 aryl group, an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group, or an optionally substituted saturated heterocyclic group)].

The present invention also includes the compound according to any one of Item 2 to Item 65, or a pharmaceutically acceptable salt thereof, wherein the compound of the formula (I) is replaced by the compound of the formula (Ic).

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

[wherein R 1a , R 1m , G 1 , G 2 , G 3 , G 4 , R 2 , R 3a , R 3b , R 3c , R 3d and n are the same as defined in Item 1, provided that the compounds of the formula (Ib) and the compound (Id) in the formula (Ie) should be restricted to ones as mentioned above]

The present invention also includes the compound according to any one of Item 2 to Item 65, or a pharmaceutically acceptable salt thereof, wherein the compound of the formula (I) is replaced by the compound of the formula (Ie).

(4) A compound of the formula (II), or a pharmaceutically acceptable salt thereof.

[wherein R 12a is a halogen atom, a cyano group, or a C 1-6 alkyl group being optionally substituted with a fluorine atom;

G 42 is an oxygen atom, or a sulfur atom;

R 12b is a C 1-6 alkyl group being optionally substituted with C 1-4 alkoxy, C 1-4 alkylcarbonylamino (said alkyl being optionally substituted with 1 to 3 fluorine atom(s)), or a C 1-4 alkoxycarbonylamino; or a 5-membered to 6-membered heteroaryl-C 1-4 alkyl group;

R 12c is a hydrogen atom, a halogen atom, or a C 1-6 alkyl group being optionally substituted with C 1-4 alkoxy;

R 12d is one group selected from a group consisting of a hydrogen atom; a halogen atom; a C 1-6 alkyl group (said group being optionally substituted with 1 to 3 halogen atom(s), hydroxy, C 1-4 alkoxy (said group being optionally substituted with 1 to 2 group(s) selected from hydroxy, C 1-4 alkoxy, 5- or 6-membered saturated heterocycle, and C 1-4 alkoxycarbonyl), C 6-10 aryloxy (said group being optionally substituted with the same or different 1 to 3 group(s) selected from cyano and C 1-4 alkoxy), C 1-6 alkylaminocarbonyloxy (which may optionally be substituted with 5- or 6-membered saturated heterocyclyl-C 1-4 alkyl)aminocarbonyloxy, or a 5- to 7-membered cyclic aminocarbonyloxy); an aminocarbonyl group; a mono- or di-(C 1-6 alkyl)aminocarbonyl group; an N-(5- or 6-membered saturated heterocyclyl-C 1-4 alkyl)-N—(C 1-6 alkyl)-aminocarbonyl group; a 5- to 7-membered cyclic aminocarbonyl group; a C 7-14 aralkyl group being optionally substituted with C 1-4 alkoxy; and a group of the following formula

(wherein R 12e , R 12f , R 12g , R 12h and R 12i are independently the same or different, and each is a hydrogen atom, a halogen atom, a cyano group, a C 1-4 alkyl group being optionally substituted with 1 to 3 fluorine atom(s), a C 1-4 alkoxy group, a hydroxy group, or a C 1-4 alkoxysulfonyl group), or

R 12c and R 12d combine each other to form a group of the following formula:

(D 2 is an oxygen atom, a carbon atom, —CH 2 —, or —CH 2 CH 2 —, p 2 and q 2 are 0, 1 or 2);

R 22 is a hydrogen atom, or a C 1-6 alkyl group]

(5) A compound of the formula (III), or a pharmaceutically acceptable salt thereof.

[wherein R 12a , G 42 , R 12b , R 12c , R 12e , R 12f , R 12g , R 12h , R 12i and R 22 are the same as defined above]

(6) A compound of the formula (IVa), or a pharmaceutically acceptable salt thereof.

[wherein G 42 , R 12a , R 12c , R 12d and R 22 are the same as defined above]

(7) A compound of the formula (IVb), or a pharmaceutically acceptable salt thereof.

[wherein G 42 , R 12a , R 12c , R 12d and R 22 are the same as defined above]

(8) A compound of the formula (Va), or a pharmaceutically acceptable salt thereof.

[wherein G 42 , R 12a , R 12c , R 12d and R 22 are the same as defined above]

(9) A compound of the formula (Vb), or a pharmaceutically acceptable salt thereof.

[wherein G 42 , R 12a , R 12c , R 12d and R 22 are the same as defined above]

(10) A compound of the formula (Vc), or a pharmaceutically acceptable salt thereof.

[wherein G 42 , R 12a , R 12c , R 12d and R 22 are the same as defined above]

The preferable embodiments for the substituents of the compounds of the above-mentioned (1) to (10) (the formula (Ia) to the formula (Vc)) are the same ones as defined in the preferable embodiments for the substituents of the compound of the formula (I).

The “pharmaceutically acceptable salt” includes a salt with an inorganic acid such as hydrochloride, hydrobromide, sulfate, phosphate, or 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:Q144;T2:Q144;T3:Q182;T4:Q263) indicates the following compound.

In the above-mentioned Tables, the mnemonic symbols mean respectively a partial structure of the following partial formulae:

The process for preparing the compound of the formula (I) of the present invention will be illustrated herein below 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 depending on the kinds of the starting compounds.

Method 1

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

[wherein n, G 1 , G 2 , G 3 , G 4 , R 1a , R 1m , R 3a , R 3b , R 3c , R 3d and R 2 are the same as defined in the above-mentioned Item 1, R 300 is a C 1-6 alkyl group, X 1 is a hydroxy group or a chlorine atom, X 2 is an iodine atom, a bromine atom, a chlorine atom, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group or a p-toluenesulfonyloxy group, X 3 is an iodine atom, a methanesulfonyloxy group, a bromine atom or a trifluoromethanesulfonyloxy group, X 4 is a hydroxy group or a chlorine atom, R 120 is a fluorine atom or a C 1-3 alkoxy group, m 104 is an integer of 0, 1, 2, or 3, Y 1 is Cbz, Boc or Alloc]

1) Step 1

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

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.

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 may be selected from the range of about −70° C. to about 80° C.

When X 1 is 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-methyl-morpholine, 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, dimethylamino-pyridine, 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 X 1 is a chlorine atom. The inert solvent includes, for example, halogenated hydrocarbons such as dichloromethane, chloroform, or 1,2-dichloroethane. The reaction temperature may be selected from the range of about −10° C. to about 50° C.

The compound of the formula (1-1) wherein X 1 is a chlorine atom may be synthesized by reacting the compound of the formula (1-1) wherein X 1 is 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 may be 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 X 1 is a hydroxy group.

This Step may also be referred to a method disclosed in a literature (e.g., Tetrahedron 61, 10827 (2005), etc.). The R 3a , R 3b , R 3c , and R 3d , which are the substituent of the compound (1-3), can be converted into substituents disclosed in Method 2 to Method 18 by processes disclosed in Method 2 to Method 18, Method 21, Method 31 and Method 32.

2) Step 2

The compound (1-12) may be synthesized from the compound (1-3) by a similar method to Step 8 of Method 1.

3) Step 3

The compound (1-2) may be synthesized from the compound (1-4) by a similar method to Step 8 of Method 1. In addition, when R 2 of the compound (1-5) is an optionally substituted aryl group or an optionally substituted heteroaryl group, the compound (1-2) may be synthesized from the compound (1-4) by a similar method to ones disclosed in the literature (J. Org. Chem. 71, 6522 (2006), etc.).

4) Step 4

The compound (1-2) may be synthesized from the compound (1-4) by a similar method to ones disclosed in the literature (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.). For instance, the following Methods 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, or 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 may be selected from the range of about −10° C. to about 40° C.

5) Step 5

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

6) Step 6

The compound (1) may be synthesized from the compound (1-12) by a similar method to ones disclosed in the literature (e.g., Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.), etc.).

7) Step 7

The compound (1-1) wherein X 1 is a hydroxy group may be prepared from the compound (1-13) by a similar method to Step 1 of Method 1.

8) Step 8

The compound (1-14) may be prepared by reacting the compound (1-7) with the compound (1-13) 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 X 3 is a chlorine atom or a bromine atom, additives 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 may be selected from the range of about 0° C. to about 150° C.

9) Step 9

The compound (1-15) may be prepared from the compound (1-14) in a similar method to Step 1 of Method 1.

10) Step 10

The compound (1-12) may be prepared from the compound (1-15) in a similar method to Step 1 of Method 1.

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 Y 1 is as defined in the above; Y 2 is Cbz, Boc or Alloc; R 100 is 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 salt thereof may be prepared, for example, by the following method.

[wherein Y 1 and Y 2 are as defined in the above; X 3 is a chlorine atom or a bromine atom; R 101 is a C 1-4 alkyl group; R 102 and R 103 are the same or different, and each is a hydrogen atom, a C 1-4 alkyl, a C 3-6 cycloalkyl, or a C 3-6 cycloalkyl-C 1-4 alkyl]

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 to 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 salt thereof, may be prepared, for example, by the following method.

[wherein Y 1 and Y 2 are as defined in the above; R 104 is the same as defined for B of the above-mentioned Item 1; R 105 is the same as defined for R 4 of the above-mentioned Item 1; or R 104 and R 105 may combine each other to form a ring; X 4 is an iodine atom, a bromine atom, a chlorine atom, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, or a 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 salt thereof may be prepared, for example, by the following method.

[wherein Y 1 and Y 2 are as defined in the above; R 106 is a C 1-4 alkyl group; R 107 is 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 3d in Item 20. The same applies to 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 salt thereof may be prepared, for example, by the following method.

[wherein Y 1 , Y 2 and R 106 are as defined in the above; R 108 is a C 1-4 alkyl group; R 109 is 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. Org. 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 to 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 salt thereof may be prepared, for example, by the following method.

[wherein R 105 , X 4 , Y 1 and Y 2 are as defined in the above; X′ is a hydroxy group or a chlorine atom; and R 110 and R 111 are independent, and they are 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 salt thereof may be prepared, for example, by the following method.

[wherein R 101 , R 102 , R 103 , X 3 , Y 1 and Y 2 are 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 to 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 salt thereof may be prepared, for example by the following method.

[wherein R 101 , R 102 , R 103 , R105, X 4 , Y 1 and Y 2 are as defined in the above]

1) Step 1 to 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 salt thereof may be prepared, for example, by the following method.

[wherein R 102 , R 103 , R105, X 4 , Y 1 and Y 2 are 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 salt thereof may be prepared, for example, by the following method.

[wherein R 104 , R105, X 4 , Y 1 and Y 2 are as defined in the above]

1) Step 1

The compound (11-2) may be prepared by reacting the compound (7-1) and the compound (11-1) by a similar method to ones disclosed in the literatures (e.g., WO01/057044; 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 salt thereof may be prepared, for example, by the following method.

[wherein R 104 , Y 1 and Y 2 are as defined in the above; R 112 is the same as defined for R 4 of the above-mentioned Item 1; R 104 and R 112 may combine each other to form a ring; and m 100a is 0 or 1, m 100b is 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 salt thereof may be prepared, for example, by the following method.

[wherein R 105 , X 4 , Y 1 and Y 2 are as defined in the above; A 100 is —SO 2 —, or —CO—; B 100 is the same as defined in B of the above-mentioned Item 1; m 101 is an integer of 0 or 1]

1) Step 1 to 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 salt thereof may be prepared, for example, by the following method.

[wherein R 104 , R 112 , Y 1 and Y 2 are 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 R 104 , R 112 , R 108 , Y 1 and Y 2 are as defined in the above]

1) Step 1 to 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 Y 1 and Y 2 are as defined in the above; m 100b is an integer of 0 to 4; R 113 is one of the above-mentioned (a) to (z), provided that in the compound (16-4), R 113 is 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. Org. 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) Step 4

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 salt thereof may be prepared, for example, by the following method.

[wherein R 104 , R 105 , X 4 , Y 1 and Y 2 are as defined in the above; m 102 is an integer of 0 or 1]

1) Step 1

The compound (17-2) may be prepared by reacting the compound (17-1) and the compound (11-1) by a similar method to ones disclosed in the literatures (e.g., WO 01/057044, 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 salt thereof may be prepared, for example, by the following method.

[wherein R 105 , X 4 , Y 1 and Y 2 are as defined in the above; m 103 is an integer of 0 or 1; R 114 is 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 salt thereof may be prepared, for example, by the following method.

[wherein R 115 is the same as defined for B of the above-mentioned Item 1]

1) Step 1 to 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 to 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 salt thereof may be prepared, for example, by the following method.

[wherein R 2 is the same as defined in the above Item 1; R 116 is an optionally substituted C 6-10 aryl group, or an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group.]

1) Step 1 to 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 (1-4), the compound of the formula (21-3) or a salt thereof may be prepared, for example, by the following method.

[wherein m 100a , R 112 , A 100 , B 100 , Y 1 and Y 2 are the same as defined in the above.]

1) Step 1

The compound (21-2) may be prepared from the compound (21-1) by a similar method to Step 2 of Method 13. The compound (21-1) may be prepared by a similar method to Steps of Method 12.

2) Step 2

The compound (21-3) may be prepared from the compound (21-2) 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 22

Among the compounds of the formula (1-14), the compound of formula (22-2) or a salt thereof may be prepared, for example, by the following method.

[wherein G 4 , R 1b , R 1c , R 1d and R 300 are the same as defined in the above, and X 6 is a halogen atom]

1) Step 1

The compound (22-2) may be prepared by reacting the compound (22-1) in an inert solvent in the presence of sodium acetate with one compound selected from N-chlorosuccinimide, N-bromosuccinimide, and N-iodosuccinimide. The inert solvent includes, for example, an organic acid such as acetic acid, propionic acid, etc. The reaction temperature is suitably selected from the range of from about 20° C. to about 50° C.

Method 23

Among the compounds of the formula (1-14), the compound of the formula (23-3) and the compound of the formula (23-6) or a salt thereof may be prepared, for example, by the following method.

[wherein G 4 , R 1b , R 1c , R 1d and R 300 are the same as defined in the above; R 208 and R 209 are a hydrogen atom or an alkyl group; R 400 is an alkyl group; and Z 1 is a group of the formula:

(wherein R 200 is a hydrogen atom or a C 1-4 alkyl group, or two R 200 s combine each other to form a 1,2-pheneylene, R 201 , R 202 , R 203 , R 204 , R 205 and R 206 are independent, and each is a hydrogen atom or a C 1-2 alkyl group, m is an integer of 0 or 1, M + is potassium ion, sodium ion or ammonium ion)]

1) Step 1

The compound (23-3) may be prepared by reacting the compound (23-1) and the compound (23-2) in an inert solvent in the presence of a Pd catalyst and an inorganic base. The inorganic base includes, for example, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, or potassium carbonate, etc. The Pd catalyst includes, for example, [1,1′-bis(diphenylphosphino) ferrocene]palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex, etc. The inert solvent includes, for example, water, tetrahydrofuran, or ethers such as 1,4-dioxane, or 1,2-dimethoxyethane, etc. Usually, a mixture of water and an ether solvent is used. The reaction temperature is selected from the range of from about 50° C. to about 120° C.

2) Step 2

The compound (23-5) may be prepared from the compound (23-1) by a similar method to ones disclosed in the literatures (e.g., Eur. J. Org. Chem. EN 5, 1075 (2004), WO 07/39142, J. Org. Chem. 67, 8424 (2002), Organic Letters 4, 107 (2002), Organic Letters 3, 393 (2001), Tetrahedron 58, 465 (2002), etc.). Examples thereof are illustrated below.

The compound (23-5) may be prepared by reacting the compound (23-1) with the compound (23-4) wherein Z 1 is B(OH) 2 in inert solvent in the presence of a Pd catalyst and a base. The inert solvent includes, for example, water, or ether solvents such as tetrahydrofuran, 1,4-dioxane, or 1,2-dimethoxyethane, etc. Usually, a mixture of water and an ether solvent is used. The base includes, for example, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, or potassium hydrogen carbonate, etc. The Pd catalyst includes, for example, palladium diphenylphosphino dichloride, or tetrakis(triphenylphosphine)palladium, etc. The reaction temperature is selected from the range of from about 50° C. to about 150° C.

3) Step 3

The compound (23-6) may be prepared by subjecting the compound (23-5) 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, or 2-propanol, etc. The reaction temperature is selected from the range of from about 0° C. to about 50° C.

Method 24

Among the compounds of the formula (1-14), the compound of the formula (24-1) or a salt thereof may be prepared, for example, by the following method.

[wherein G 4 , R 1b , R 1c , R 1d and R 300 are the same as defined in the above]

1) Step 1

The compound (24-1) may be prepared from the compound (23-1) by a similar method to ones disclosed in the literatures (e.g., Synth. Commun. 24, 887 (1994), Organic Letters 9, 1711 (2007), Tetrahedron Lett. 40, 8193 (1999), Tetrahedron Lett. 45, 1441 (2004), etc.).

Method 25

Among the compounds of the formula (1-13), the compound of the formula (25-4) or a salt thereof may be prepared, for example, by the following method.

[wherein R 1a , R 1c and R 1d are the same as defined in the above, R 401 is a C 1-6 alkyl group, R 402 is a C 1-2 alkyl group]

1) Step 1

The compound (25-3) may be prepared by reacting the compound (25-1) and the compound (25-2) 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 may be selected from the range of from 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 (25-4) may be prepared by reacting an iron and the compound (25-3) 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 may be selected from the range of about 30° C. to about 100° C. ii. The compound (25-4) may be prepared by subjecting the compound (25-3) 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 may be selected from the range of about 0° C. to about 50° C.

Method 26

Among the compounds of the formula (1-14), the compound of the formula (26-5) may be prepared, for example, by the following method.

[wherein X 3 , R 1a , R 1b , R 1c , R 1d , R 401 and R 402 are the same as defined in the above, and X 6 is a bromine atom or an iodine atom]

1) Step 1

The compound (26-2) may be prepared by reacting the compound (26-1) with the compound (25-2) 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, or 1,2-dimethoxyethane, etc. The reaction temperature may be selected from the range of from about 0° C. to about 50° C.

2) Step 2

The compound (26-3) may be prepared from the compound (26-2) by a similar method to Step 2 of Method 25.

3) Step 3

The compound (26-4) may be prepared by reacting the compound (26-3) with the compound (1-7) 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, or 1,2-dimethoxyethane, etc., or nitrile solvents such as acetonitrile, or propionitrile, etc. The reaction temperature may be selected from the range of from about 30° C. to about 100° C.

4) Step 4

The compound (26-5) may be prepared by reacting the compound (26-4) 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 may be selected from the range of from about 70° C. to about 150° C.

Method 27

Among the compounds of the formula (1-3), the compound of the formula (27-7) or a salt thereof may be prepared, for example, by the following method.

[wherein n, R 401 , Y 1 , R 1a , R 1c , R 1d , R 3a , R 3c , R 3d and R 2 are the same as defined in the above.]

1) Step 1

The compound (27-2) may be prepared, for example, by reacting the compound (27-1) with acetic anhydride in a pyridine solvent. The reaction temperature may be selected from the range of from about 10° C. to about 40° C.

2) Step 2

The compound (27-3) may be prepared from the compound (27-2) in a similar manner to Step 1 of Method 1.

3) Step 3

The compound (27-4) may be prepared from the compound (27-3) in a similar manner to Step 1 of Method 1.

4) Step 4

The compound (27-5) may be prepared by reacting the compound (27-4) 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, or sodium hydride, etc. The inert solvent includes, for example, alcohols such as methanol, ethanol, or 2-propanol, etc. The reaction temperature may be selected from the range of from about 10° C. to about 40° C.

5) Step 5

The compound (27-6) may be prepared from the compound (27-5) in a similar manner to Step 1 of Method 1.

6) Step 6

The compound (27-7) may be prepared from the compound (27-6) in a similar manner to Step 6 of Method 1.

Method 28

Among the compounds of the formula (1-13), the compound (28-3) or a salt thereof may be prepared, for example, by the following method.

[wherein R 1a , R 1c , R 1d , R 401 and R 300 are the same as defined in the above, and X 7 is a bromine atom or a chlorine atom]

1) Step 1

The compound (28-3) may be prepared from the compound (28-1) by a similar method to ones disclosed in the literatures (e.g., Chem. Pharm. Bull. 46, 1716 (1998), etc.).

Method 29

Among the compounds of the formula (1-13), the compound of the formula (29-4) or a salt thereof may be prepared, for example, by the following method.

[wherein X 5 , X 7 , R 1a , R 1c , R 1d , R 401 , and R 300 are the same as defined in the above.]

1) Step 1

The compound (29-2) may be prepared from the compound (29-1) 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 to Step 3

The compound (29-4) may be prepared from the compound (29-2) by a similar method to ones disclosed in the literatures (e.g., WO 2005/082872, etc.).

Method 30

Among the compounds of the formula (1-13), the compound of the formula (30-5) or a salt thereof may be prepared, for example, by the following method.

[wherein X 3 , R 1a , R 1b , R 1c , X 1d , and R 300 are the same as defined in the above; R 403 is a C 1-6 alkyl group; X 8 is an iodine atom, a bromine atom, a chlorine atom or a trifluoromethanesulfonyloxy group; X 9 is an iodine atom, a bromine atom, a chlorine atom, a methanesulfonyloxy group, a trifluoromethanesulfonyl-oxy group or a p-toluenesulfonyloxy group.]

1) Step 1

The compound (30-2) may be prepared from the compound (30-1) by a similar method to ones disclosed in the literatures (e.g., J. Am. Chem. Soc. 123, 6989 (2001), J. Org. Chem. 70, 4360 (2005), Synth. Commun. 29, 591 (1999), etc.).

2) Step 2

The compound (30-3) may be prepared from the compound (30-2) by a similar method to Step 8 of Method 1.

3) Step 3

The compound (30-5) may be prepared from the compound (30-3) by a similar method to ones disclosed in the literatures (e.g., WO 2004/096773, etc.).

Method 31

Among the compounds of the formula (1-2), the compound of the formula (31-3) or a salt thereof may be prepared, for example, by the following method.

[wherein R 112 , s, Y 1 and Y 2 are the same as defined in the above; R 506 is the same as B as defined in the above; and R 507 is the same as R 4 as defined in the above.]

1) Step 1

The compound (31-2) may be prepared from the compound (21-1) 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 (31-3) may be prepared from the compound (31-2) 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 32

Among the compounds of the formula (I), the compound of the formula (32-17) or a salt thereof may be prepared, for example, by the following method.

[wherein G 4 , R 1a , R 1b , R 1c , X 1d , and R 2 are the same as defined in the above, and R 600 is the same as B as defined in Item 1.]

1) Step 1

The compound (32-2) may be prepared by reacting the compound (32-1) 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, or sodium hydride, etc. The inert solvent includes, for example, aprotic solvents such as N,N′-dimethylformamide, dimethylsulfoxide, or hexamethylenephosphoamide, etc. The reaction temperature may be selected from the range of from about 10° C. to about 40° C.

2) Step 2

The compound (32-3) may be prepared by reacting the compound (32-2) with trifluoroacetic acid in an inert solvent. The inert solvent includes, for example, halogenated hydrocarbon solvents such as dichloromethane, chloroform, or 1,2-dichloroethane, etc. The reaction temperature may be selected from the range of from about 10° C. to about 40° C.

3) Step 3

The compound (32-4) may be prepared by subjecting the compound (32-3) 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, or ethanol, etc. The reaction temperature may be selected from the range of from about 10° C. to about 40° C.

4) Step 4

The compound (32-5) may be prepared by reacting the compound (32-4) with di-tert-butyl dicarbonate in an inert solvent. The inert solvent includes, for example, ethers such as dioxane, tetrahydrofuran, etc. The reaction temperature may be selected from the range of from about 10° C. to about 40° C.

5) Step 5

The compound (32-6) may be prepared by subjecting the compound (32-5) to reduction under hydrogen atmosphere in the presence of platinum oxide in an inert solvent. The inert solvent includes alcohols such as methanol, or ethanol, etc. The reaction temperature may be selected from the range of from about 10° C. to about 40° C.

6) Step 6

The compound (32-7) may be prepared by reacting the compound (32-6) with p-methoxybenzyl chloride in an inert solvent in the presence of an inorganic base. The inorganic base includes potassium carbonate, or cesium carbonate, etc. The inert solvent includes, for example, aprotic solvents such as N,N′-dimethylformamide, dimethylsulfoxide, or hexamethylenephosphoamide, etc. The reaction temperature may be selected from the range of 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 (32-8) may be prepared from the compound (32-7) by a similar method to Step 6 of Method 1.

8) Step 8

The compound (32-9) may be prepared from the compound (32-8) by a similar method to Step 4 of Method 1.

9) Step 9

The compound (32-10) may be prepared from the compound (32-9) by a similar method to Step 10 of Method 1.

10) Step 10

The compound (32-11) may be prepared by subjecting the compound (32-10) 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, or ethanol, etc. The reaction temperature may be selected from the range of from about 10° C. to about 40° C.

11) Step 11

The compound (32-12) may be prepared from the compound (32-11) by a similar method to Step 4 of Method 32.

12) Step 12

The compound (32-13) may be prepared from the compound (32-12) by a similar method to Step 2 of Method 3.

13) Step 13

The compound (32-14) may be prepared from the compound (32-13) 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, or tetrahydrofuran, etc.

i. the compound (32-13) is reacted with ethyl chloroformate in the presence of triethylamine. The reaction temperature may 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 may be selected from the range of from about 0° C. to about 20° C.

14) Step 14

The compound (32-15) may be prepared by subjecting the compound (32-14) to Swern oxidation. For instance, dimethylsulfoxide was added to oxalyl chloride in a halogenated hydrocarbon solvent such as dichloromethane, chloroform, or 1,2-dichloroethane, etc., and then, the compound (30-14) is added thereto, and further, diisopropylethylamine is added. The reaction temperature may be selected from the range of from about −80° C. to about −30° C.

15) Step 15

The compound (32-16) may be prepared from the compound (32-15) by a similar method to Step 4 of Method 1.

16) Step 16

The compound (32-17) may be prepared from the compound (32-16) by a similar method to Step 6 of Method 1.

Method 33

Among the compounds of the formula (I), the compound of the formula (33-2) or a salt thereof may be prepared, for example, by the following method.

[wherein G 4 , R 1a , R 1b , R 1c , X 1d , R 2 are the same as defined in the above; Z 100 is C(O), S(O) 2 , or C(O)N(R 601 ); R 601 is the same as R 4 as defined in Item 1.]

1) Step 1

The compound (33-1) may be prepared from the compound (33-16) 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 (33-2) may be prepared from the compound (33-1) by a similar method of Step 6 of Method 1.

In the above-mentioned each step, when the starting compounds used in each reaction has reactive groups 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 completed or after some reactions are done, to give the desired compound. The protecting groups for 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 acids 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-butyloxycarbonyl group may be removed, for example, by reacting in the presence of acids 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 solvents 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 therapy, it may be administered orally or parenterally (e.g., intravenously, subcutaneously or intramuscularly, locally, rectally, percutaneously, 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, an agent 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, troglitazone, rosiglitazone or a maleate thereof, GI-262570, JTT-501, CC-555, YM-440, KRP-297, CS-011, etc.), α-glucosidase inhibitors (e.g., voglibose, acarbose, miglitol, emiglitate, etc.), biguanides (e.g., metformine, etc.), insulin secretagogues (e.g., sulfonylureas 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 scavenger (e.g., thioctic acid, etc.), cerebral vasodilators (e.g., tiapride, mexiletine, etc.). A antilipidemic agent includes HMG-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 agonists (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, hydrochlorotiazide, hydroflumethiazide, bentylhydrochlorothiazide, penflutizide, polythiazide, methychlothiazide, etc.), antialdosterone preparations (e.g., spironolactone, 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.

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.

Reference Example 1

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-dimethylformamide (70 ml) were added potassium carbonate (25.1 g) and ethyl 2-bromoisobutyrate (20.0 g), and the mixture was heated at 80° C. with stirring. Ten hours later, 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+) 312 (M + +1, 100%).

Reference Example 2

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 gradually added dropwise a solution of the compound of Reference Example 1 (11.8 g) in acetic acid (50 ml)/ethanol (50 ml) at 80° C., and after the addition, the mixture was heated at 80° C. with stirring. Three hours later, the reaction solution was cooled to 25° C., and the insoluble materials were removed by filtration on celite. 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 by repulping with ethyl acetate, and collected by filtration to give the title compound (6.8 g) as a white solid.

MS (ESI+) 236 (M + +1, 100%).

Reference Example 3

Methyl 4-(3-methoxypropyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

To a solution of the compound of Reference Example 2 (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 at 80° C. with stirring. Six hours later, the reaction solution was cooled to 25° C., and water was added thereto. 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+) 308 (M + +1, 100%).

Reference Example 4

4-(3-Methoxypropyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylic acid

The compound of Reference Example 3 (2.0 g) was dissolved in tetrahydrofuran (5 ml) and methanol (5 ml), and thereto was added a 2N aqueous sodium hydroxide solution (5 ml), and the mixture was heated at 60° C. with stirring 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+) 294 (M + +1, 100%).

Reference Example 5

tert-Butyl (3R)-3-(isopropyl{[4-(3-methoxypropyl)-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 4 (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 residue was added toluene, and the mixture was concentrated under reduced pressure. The obtained residue was dissolved in dichloromethane (10 ml), and thereto was added dropwise a solution of tert-butyl (3R)-3-(isopropylamino)piperidine-1-carboxylate (1.51 g), triethylamine (1.2 ml) in dichloromethane (20 ml), and the mixture was stirred at room temperature for 2 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 magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (the developing solvent: hexane/ethyl acetate=2/1) to give the title compound (2.0 g).

MS (ESI+) 518 (M + +1, 100%).

Reference Example 6

tert-Butyl (3R)-3-[{[7-bromo-4-(3-methoxypropyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

The compound of Reference Example 5 (280 mg) was dissolved in N,N-dimethylformamide (3 ml), and thereto was added N-bromosuccinimide (200 mg), and the mixture was stirred at 70° C. for 3 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 hydrogen carbonate solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to give the title compound (300 mg).

MS (ESI+) 595 (M + +1, 100%), 597 (M + +1, 100%).

Reference Example 7

tert-Butyl (3R)-3-[isopropyl({4-(3-methoxypropyl)-2,2-dimethyl-3-oxo-7-[(1E)-prop-1-en-1-yl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)amino]piperidine-1-carboxylate

The compound of Reference Example 6 (300 mg) was dissolved in dimethoxyethane (3 ml) and water (1.5 ml), and thereto were added trans-propenylboronic acid (170 mg), sodium carbonate (106 mg), palladium diphenylphosphino dichloride.dichloromethane complex (7.8 mg), and the mixture was refluxed for 8 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, and 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 (260 mg).

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

Reference Example 8

tert-Butyl (3R)-3-(isopropyl{[4-(3-methoxypropyl)-2,2-dimethyl-3-oxo-7-propyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl)amino]piperidine-1-carboxylate

The compound of Reference Example 7 (90.1 mg) was dissolved in ethyl acetate (10 ml), and thereto was added palladium-carbon (100 mg), and the mixture was stirred under hydrogen atmosphere for 5 hours. The reaction solution was filtered on celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to give the title compound (60.0 mg).

MS (ESI+) 560 (M + +1, 100%).

Reference Example 9

tert-Butyl (3R)-3-[{[7-ethyl-4-(3-methoxypropyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 6 and vinylboronic acid pinacol ester, the title compound was obtained in a similar manner to Reference Examples 7 and 8.

MS (ESI+) 546 (M + +1, 100%).

Reference Example 10

tert-Butyl (3R)-3-(isopropyl{[4-(3-methoxypropyl)-2,2,7-trimethyl-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 6 (275 mg), bis(tributylphosphine)-palladium (25 mg) in tetrahydrofuran (4 ml) was added a 2.0 M solution of methylzinc chloride in tetrahydrofuran (0.3 ml) at room temperature, and the mixture was stirred at room temperature for 4 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 silica gel column chromatography (hexane/ethyl acetate=2/1) to give the title compound (170 mg).

MS (ESI+) 532 (M + +1, 100%).

Reference Example 11

tert-Butyl (3R)-3-[{[7-cyano-4-(3-methoxypropyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

To a solution of Reference Example 6 (130 mg) in N,N-dimethylformamide (3 ml) were added zinc cyanide (100 mg) and ditributylphosphine palladium (38.2 mg), and the mixture was heated at 100° C. with stirring for 6 hours. The mixture was cooled to room temperature, and then, a saturated aqueous sodium hydrogen carbonate solution 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=1/1) to give the title compound (90.4 mg).

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

Reference Example 12

tert-Butyl (3R)-3-[{[7-chloro-4-(3-methoxypropyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

The compound of Reference Example 5 (200 mg) was dissolved in N,N-dimethylformamide (3 ml), and thereto was added N-chlorosuccinimide (100 mg), and the mixture was stirred at 80° C. for 3 hours. The mixture was cooled to room temperature, and thereto was added water. The mixture was extracted with ethyl acetate, and the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to give the title compound (150 mg).

MS (ESI+) 552 (M + +1, 100%).

Reference Example 13

Methyl 4-{2-[(methoxycarbonyl)amino]ethyl}-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

Using the compound of Reference Example 2 and methyl (2-bromoethyl)carbamate, the title compound was obtained in a similar manner to Reference Example 3.

MS (ESI+) 546 (M + +1, 100%).

Reference Example 14

tert-Butyl (3R)-3-[[(7-bromo-4-{2-[(methoxycarbonyl)amino]ethyl}-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl](isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 13, the title compound was obtained in a similar manner to Reference Example 6.

MS (ESI+) 624 (M + +1, 100%), 626 (M + +1, 100%).

Reference Example 15

tert-Butyl (3R)-3-{isopropyl[(4-{2-[(methoxycarbonyl)amino]ethyl}-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl]amino}piperidine-1-carboxylate

Using the compound of Reference Example 14, the title compound was obtained in a similar manner to Reference Example 10.

MS (ESI+) 561 (M + +1, 100%).

Reference Example 16

tert-Butyl (3R)-3-[[(7-chloro-4-{2-[(methoxycarbonyl)amino]ethyl}-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl](isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 13, the title compound was obtained in a similar manner to Reference Example 12.

MS (ESI+) 581 (M + +1, 100%).

Reference Example 17

Methyl 4-(4-methoxybutyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

Using the compound of Reference Example 2 and 1-chloro-4-methoxybutane, the title compound was obtained in a similar manner to Reference Example 3.

MS (ESI+) 322 (M + +1, 100%).

Reference Example 18

tert-Butyl (3R)-3-[{[7-chloro-4-(4-methoxybutyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 17, the title compound was obtained in a similar manner to Reference Example 12.

MS (ESI+) 566 (M + +1, 100%).

Reference Example 19

Methyl 4-(3-ethoxypropyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

Using the compound of Reference Example 2 and 1-bromo-3-ethoxypropane, the title compound was obtained in a similar manner to Reference Example 3.

MS (ESI+) 322 (M + +1, 100%).

Reference Example 20

tert-Butyl (3R)-3-[{[7-chloro-4-(3-ethoxypropyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 19, the title compound was obtained in a similar manner to Reference Example 12.

MS (ESI+) 566 (M + +1, 100%).

Reference Example 21

tert-Butyl (3R)-3-(isopropyl{[4-(4-methoxybutyl)-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}amino)piperidine-1-carboxylate

Using the compound of Reference Example 17, the title compound was obtained in a similar manner to Reference Example 10.

MS (ESI+) 546 (M + +1, 100%).

Reference Example 22

Ethyl 2-(4-bromo-2-nitrophenoxy)-2-methylbutanoate

To a solution of ethyl 2-hydroxy-2-methylbutyrate (3.5 g) in tetrahydrofuran (80 ml) was added under ice-cooling sodium hydride (1.2 g), and the mixture was stirred at room temperature for 10 minutes. To the mixture was added a drop of 15-crown-5, and further thereto was added dropwise 5-bromo-2-fluoronitrobenzene (2.8 ml), and the mixture was stirred at room temperature for 14 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 (hexane/ethyl acetate=15/1) to give the title compound (5.5 g).

MS (ESI+) 346 (M + +1, 100%), 348 (M + +1, 98%).

Reference Example 23

6-Bromo-2-ethyl-2-methyl-2H-1,4-benzoxazin-3(4H)-one

The title compound was synthesized from the corresponding compound in a similar manner to Reference Example 2.

MS (ESI+) 270 (M + +1, 100%), 272 (M + +1, 100%).

Reference Example 24

6-Bromo-2-ethyl-4-(3-methoxypropyl)-2-methyl-2H-1,4-benzoxazin-3(4H)-one

The title compound was synthesized from the corresponding compound in a similar manner to Reference Example 3.

MS (ESI+) 611 (M + +1, 100%), 613 (M + +1, 100%).

Reference Example 25

Methyl 2-ethyl-4-(3-methoxypropyl)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

To a solution of the compound of Reference Example 24 (4.3 g) in N,N-dimethylacetamide (50 ml)/methanol (20 ml) were added palladium acetate (849 mg), 1,3-bis(diphenylphosphino)propane (1.56 g), and N,N-diisopropylethylamine (4.4 ml), and the mixture was stirred at 100° C. for 4 hours under carbon monoxide atmosphere. The reaction solution was cooled to room temperature, filtered on celite, and water was added to the filtrate. 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 (hexane/ethyl acetate=3/1) to give the title compound (2.4 g).

MS (ESI+) 322 (M + +1, 100%).

Reference Example 26

Methyl 4-[(1R)-2-ethoxy-1-methyl-2-oxoethoxy]-3-nitrobenzoate

To a solution of methyl 4-hydroxy-3-nitrobenzoate (5.0 g) and ethyl L-lactate (2.9 ml) in tetrahydrofuran (120 ml) was added triphenylphosphine (10 g), and the mixture was stirred at room temperature for 10 minutes. To the mixture was added under ice-cooling diisopropyl azodicarboxylate (20 ml), and the mixture was stirred at 60° C. for 4 hours. The reaction solution was cooled to room temperature, and water was added thereto, 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=5/1) to give the title compound (9.5 g).

MS (ESI+) 298 (M + +1, 100%).

Reference Example 27

Methyl (2R)-4-(4-methoxybutyl)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

Using the compound of Reference Example 26, the title compound was synthesized in a similar manner to Reference Example 17.

MS (ESI+) 308 (M + +1, 100%).

Reference Example 28

Methyl 4-[1-(methoxycarbonyl)propoxy]-3-nitrobenzoate

Using methyl 4-hydroxy-3-nitrobenzoate and methyl 2-bromobutyrate, the title compound was synthesized in a similar manner to Reference Example 1.

MS (ESI+) 298 (M + +1, 100%).

Reference Example 29

4-(Acetyloxy)-3-nitrobenzoic acid

To 4-hydroxy-3-nitrobenzoic acid (10 g) were added pyridine (12 ml) and acetic anhydride (55 ml), and the mixture was stirred at room temperature for 65 hours. The reaction solution was concentrated under reduced pressure, and thereto was added a 5% aqueous sodium 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 (11.7 g).

MS (ESI+) 226 (M + +1, 100%).

Reference Example 30

tert-Butyl (3R)-3-[[4-(acetyloxy)-3-nitrobenzoyl](isopropyl)amino]piperidine-1-carboxylate

The title compound was synthesized from the corresponding compound in a similar manner to Reference Example 5.

MS (ESI+) 450 (M + +1, 100%).

Reference Example 31

tert-Butyl (3R)-3-[(4-hydroxy-3-nitrobenzoyl)(isopropyl)amino]piperidine-1-carboxylate

To a solution of the compound of Reference Example 30 (4.4 g) in methanol (60 ml) was added sodium methoxide (1 M methanol solution, 12.7 ml), and the mixture was stirred at room temperature for 2 hours. To the reaction solution was added Amberlite (registered trade mark), and the mixture was stirred at room temperature for 30 minutes, filtered, and washed with methanol. The filtrate was concentrated under reduced pressure to give the title compound (4.1 g).

MS (ESI+) 408 (M + +1, 86%).

Reference Example 32

Diethyl (4-{[[(3R)-1-(tert-butoxycarbonyl)piperidin-3-yl](isopropyl)amino]carbonyl}-2-nitrophenyl-oxy)(methyl)malonate

Using the compound of Reference Example 31 and diethyl 2-bromo-2-methylmalonate, the title compound was synthesized in a similar manner to Reference Example 1.

MS (ESI+) 580 (M + +1, 84%).

Reference Example 33

Ethyl 6-{[[(3R)-1-(tert-butoxycarbonyl)piperidin-3-yl](isopropyl)amino]carbonyl}-4-(4-methoxybutyl)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylate

Using the compound of Reference Example 32, the title compound was obtained in a similar manner to Reference Example 2 and Reference Example 3.

MS (ESI+) 590 (M + +1, 100%).

Reference Example 34

6-{[[(3R)-1-(tert-Butoxycarbonyl)piperidin-3-yl](isopropyl)amino]carbonyl}-4-(4-methoxybutyl)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid

To the compound of Reference Example 33 (1.8 g) were added methanol (20 ml) and a 1N aqueous sodium hydroxide solution (6 ml), and the mixture was stirred at 60° C. for 3 hours. The reaction solution was cooled to room temperature, and thereto was added a 5% aqueous sodium hydrogen sulfate solution. The mixture was extracted with chloroform, and 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 (1.7 g).

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

Reference Example 35

tert-Butyl (3R)-3-[{[2-(hydroxymethyl)-4-(4-methoxybutyl)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

To a solution of the compound of Reference Example 34 (1.68 g) and triethylamine (500 μl) in tetrahydrofuran (10 ml) wad added dropwise isopropyl chloroformate (495 μl) under ice-cooling, and the mixture was stirred in an ice bath for one hour. The precipitates were removed by filtration, and to the filtrate was added dropwise a solution of sodium borohydride (228 mg) in water (2 ml) under ice-cooling. The mixture was stirred in an ice-bath for one hour. 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 (hexane/ethyl acetate=1/5) to give the title compound (510 mg).

MS (ESI+) 548 (M + +1, 100%).

Reference Example 36

tert-Butyl (3R)-3-[{[2-(ethoxymethyl)-4-(4-methoxybutyl)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

To a solution of the compound of Reference Example 35 (20 mg) in N,N-dimethylformamide (1 ml) were added sodium hydride (10 mg) and ethyl iodide (50 μl), the mixture was stirred at room temperature for 2 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 (hexane/ethyl acetate=1/1) to give the title compound (19 mg).

MS (ESI+) 576 (M + +1, 100%).

Reference Example 37

tert-Butyl (3R)-3-[{[7-chloro-2-ethyl-4-(3-methoxypropyl)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 25, the title compound was synthesized in a similar manner to Reference Example 12.

MS (ESI+) 566 (M + +1, 100%).

Reference Example 38

tert-Butyl (3R)-3-[{[7-bromo-2-ethyl-4-(3-methoxypropyl)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 25, the title compound was synthesized in a similar manner to Reference Example 6.

MS (ESI+) 610 (M + +1, 100%) 612 (M + +1, 100%).

Reference Example 39

tert-Butyl (3R)-3-[{[7-cyano-2-ethyl-4-(3-methoxypropyl)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 25, the title compound was synthesized in a similar manner to Reference Example 11.

MS (ESI+) 557 (M + +1, 100%).

Reference Example 40

tert-Butyl (3R)-3-[{[(2R)-7-chloro-4-(3-methoxypropyl)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 26, the title compound was synthesized in a similar manner to Reference Example 12.

MS (ESI+) 538 (M + +1, 100%).

Reference Example 41

tert-Butyl (3R)-3-[{[(2R)-7-bromo-4-(3-methoxypropyl)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 26, the title compound was synthesized in a similar manner to Reference Example 6.

MS (ESI+) 582 (M + +1, 100%) 584 (M + +1, 100%).

Reference Example 42

tert-Butyl (3R)-3-(isopropyl{[(2R)-4-(3-methoxypropyl)-2,7-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}amino)piperidine-1-carboxylate

Using the compound of Reference Example 26, the title compound was synthesized in a similar manner to Reference Example 10.

MS (ESI+) 518 (M + +1, 100%).

Reference Example 43

tert-Butyl (3R)-3-[{[(2R)-7-chloro-4-(4-methoxybutyl)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 27, the title compound was synthesized in a similar manner to Reference Example 18.

MS (ESI+) 552 (M + +1, 100%).

Reference Example 44

tert-Butyl (3R)-3-[{[(2R)-7-bromo-4-(4-methoxybutyl)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 27, the title compound was synthesized in a similar manner to Reference Example 6.

MS (ESI+) 596 (M + +1, 100%) 598 (M + +1, 100%).

Reference Example 45

tert-Butyl (3R)-3-(isopropyl{[(2R)-4-(4-methoxybutyl)-2,7-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}amino)piperidine-1-carboxylate

Using the compound of Reference Example 27, the title compound was synthesized in a similar manner to Reference Example 21.

MS (ESI+) 532 (M + +1, 100%).

Reference Example 46

tert-Butyl (3R)-3-[[((2R)-7-chloro-4-{2-[(methoxycarbonyl)amino]ethyl}-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl](isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 26, the title compound was synthesized in a similar manner to Reference Example 16.

MS (ESI+) 567 (M + +1, 100%).

Reference Example 47

tert-Butyl (3R)-3-[[((2R)-7-bromo-4-{2-[(methoxycarbonyl)amino]ethyl}-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl](isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 26, the title compound was synthesized in a similar manner to Reference Example 14.

MS (ESI+) 611 (M + +1, 100%) 613(M + +1, 100%).

Reference Example 48

tert-Butyl (3R)-3-{isopropyl[((2R)-4-{2-[(methoxycarbonyl)amino]ethyl}-2,7-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl]amino}piperidine-1-carboxylate

Using the compound of Reference Example 26, the title compound was synthesized in a similar manner to Reference Example 15.

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

Reference Example 49

tert-Butyl (3R)-3-[{[7-chloro-2-ethyl-4-(3-methoxypropyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 28, the title compound was synthesized in a similar manner to Reference Example 12.

MS (ESI+) 552 (M + +1, 100%).

Reference Example 50

tert-Butyl (3R)-3-[{[7-chloro-2-(ethoxymethyl)-4-(4-methoxybutyl)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 36, the title compound was synthesized in a similar manner to Reference Example 12.

MS (ESI+) 610 (M + +1, 100%).

Reference Example 51

Methyl 4-hydroxy-2-(trifluoromethyl)benzoate

4-Hydroxy-2-(trifluoromethyl)benzoic acid (30.0 g) was dissolved in methanol (600 ml), thereto was added dropwise conc. sulfuric acid (10 ml). Then, the mixture was refluxed with stirring for 20 hours. The mixture was cooled to room temperature, and to the reaction mixture was added water (200 ml), and methanol was removed by evaporation, and the resultant was extracted twice with ethyl acetate (300 ml). The organic layer was washed with water, a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (32.0 g).

1 H NMR (400 MHz, CDCl 3 ) δ 9.77 (s, 1H), 7.79-7.76 (m, 1H), 7.28-7.22 (m, 1H), 7.03-6.99 (m, 1H), 3.88 (s, 3H).

Reference Example 52

Methyl 4-hydroxy-5-nitro-2-(trifluoromethyl)benzoate

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

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

Reference Example 53

Methyl 5-amino-4-hydroxy-2-(trifluoromethyl)benzoate

Methyl 4-hydroxy-5-nitro-2-(trifluoromethyl)benzoate (58.0 g) was dissolved in methanol (600 ml), and thereto was added 10% palladium carbon (50% wet.: 11.60 g). The mixture was vigorously stirred under hydrogen atmosphere at 25° C. for 8 hours. After the reaction was complete, the mixture was filtered on celite, washed with methanol, and the filtrate was concentrated under reduced pressure to give the title compound (53.0 g).

MS (ESI+) 236 (M + +1, 100%).

Reference Example 54

Methyl 5-amino-4-hydroxy-2-methylbenzoate

Using 4-hydroxy-2-methylbenzoic acid, the title compound was obtained in a similar manner to Reference Example 53.

MS (ESI+) 182 (M + +1, 100%).

Reference Example 55

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

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

MS (ESI+) 304 (M + +1, 31%).

Reference Example 56

Methyl 2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

Using methyl 5-amino-4-hydroxy-2-methylbenzoate, the title compound was obtained in a similar manner to Reference Example 55.

MS (ESI+) 250 (M + +1, 35%).

Reference Example 57

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

Using the compound of Reference Example 55, the title compound was obtained in a similar manner to Reference Example 3.

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

Reference Example 58

tert-Butyl (3R)-3-(isopropyl{[4-(4-methoxybutyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}amino)piperidine-1-carboxylate

Using the compound of Reference Example 57, the title compound was obtained in a similar manner to Reference Example 5.

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

Reference Example 59

tert-Butyl (3R)-3-(isopropyl{[4-(3-methoxypropyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}amino)piperidine-1-carboxylate

Using the compound of Reference Example 55, the title compound was obtained in a similar manner to Reference Example 3 and Reference Example 5.

MS (ESI+) 586 (M + +1, 100%).

Reference Example 60

tert-Butyl (3R)-3-(isopropyl{[4-{2-[(methoxycarbonyl)amino]ethyl}-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}amino)piperidine-1-carboxylate

Using the compound of Reference Example 55, the title compound was obtained in a similar manner to Reference Example 13 and Reference Example 5.

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

Reference Example 61

tert-Butyl (3R)-3-[{[7-bromo-4-(4-methoxybutyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 17, the title compound was obtained in a similar manner to Reference Example 6.

MS (ESI+) 610 (M + +1, 100%).

Reference Example 62

tert-Butyl (3R)-3-[{[7-cyano-4-(4-methoxybutyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 61, the title compound was obtained in a similar manner to Reference Example 11.

MS (ESI+) 557 (M + +1, 100%).

Reference Example 63

Methyl (2R)-4-(4-methoxybutyl)-2-methyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

Using the compound of Reference Example 52, the title compound was obtained in a similar manner to Reference Example 27.

MS (ESI+) 376 (M + +1, 100%).

Reference Example 64

tert-Butyl (3R)-3-(isopropyl{[(2R)-4-(4-methoxybutyl)-2-methyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}amino)piperidine-1-carboxylate

Using the compound of Reference Example 63, the title compound was obtained in a similar manner to Reference Example 5.

MS (ESI+) 586 (M + +1, 100%).

Reference Example 65

2,2-Dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylic acid

Using the compound of Reference Example 55, the title compound was obtained in a similar manner to Reference Example 4.

MS (ESI+) 289 (M + +1, 13%).

Reference Example 66

tert-Butyl (3R)-3-[{[2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 65, the title compound was obtained in a similar manner to Reference Example 5.

MS (ESI+) 514 (M + +1, 27%).

Reference Example 67

tert-Butyl (3R)-3-(isopropyl{[7-methoxy-4-(4-methoxybutyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}amino)piperidine-1-carboxylate

To tert-Butyl (3R)-3-[{[7-bromo-4-(4-methoxybutyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate (500 mg) were added CuBr (59 mg), NaOMe (1M methanol solution) (16.4 ml) and DMF (5.5 ml), and the mixture was stirred at 100° C. for 15 hours. After the reaction was complete, water was added to the reaction solution, and the mixture was extracted with ethyl acetate solution. The obtained ethyl acetate solution was washed with water and a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/2) to give the title compound (240 mg) as a colorless liquid.

MS (ESI+) 562 (M + +1, 30%).

Reference Example 68

Methyl 4-(4-cyanobutyl)-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

To the compound of Reference Example 56 (700 mg) were added sodium hydride (155 mg), 5-chloropentanenitrile (1.0 ml), potassium iodide (100 mg) and N,N-dimethylformamide (9 ml), and the mixture was stirred at 100° C. for 5 hours. After the reaction was complete, water was added to the reaction solution, and the mixture was extracted with ethyl acetate solution. The obtained ethyl acetate solution was washed with water and an aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to give the title compound (250 mg) as a colorless liquid.

MS (ESI+) 331 (M + +1, 72%).

Reference Example 69

Methyl 4-(2-{[(dimethylamino)carbonyl]oxy}ethyl)-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

Using the compound of Reference Example 56, the title compound was obtained in a similar manner to Reference Example 3.

MS (ESI+) 365 (M + +1, 26%).

Reference Example 70

Methyl 4-hex-5-en-1-yl-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

Using the compound of Reference Example 56, the title compound was obtained in a similar manner to Reference Example 3.

MS (ESI+) 332 (M + +1, 81%).

Reference Example 71

Methyl 4-(4-{[tert-butyl(dimethyl)silyl]oxy}butyl)-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

Using the compound of Reference Example 56, the title compound was obtained in a similar manner to Reference Example 3.

MS (ESI+) 436 (M + +1, 51%).

Reference Example 72

Methyl 4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

Using the compound of Reference Example 56, the title compound was obtained in a similar manner to Reference Example 3.

MS (ESI+) 413 (M + +1, 30%).

Reference Example 73

Methyl 4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

Using the compound of Reference Example 56, the title compound was obtained in a similar manner to Reference Example 3.

MS (ESI+) 427 (M + +1, 37%).

Reference Example 74

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

Using the compound of Reference Example 55, the title compound was obtained in a similar manner to Reference Example 3.

MS (ESI+) 427 (M + +1, 42%).

Reference Example 75

Methyl 4-(3-{[(benzyloxy)carbonyl]amino}propyl)-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

Using the compound of Reference Example 56, the title compound was obtained in a similar manner to Reference Example 3.

MS (ESI+) 441 (M + +1, 24%).

Reference Example 76

Methyl 2-ethyl 4-{2-[(methoxycarbonyl)amino]ethyl}-2-methyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

Using methyl 2-ethyl-2-methyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate, the title compound was obtained in a similar manner to Reference Example 13.

MS (ESI+) 419 (M + +1, 20%).

Reference Example 77

Methyl 2,2,7-trimethyl-3-oxo-4-(tetrahydro-2H-pyran-4-ylmethyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

Using the compound of Reference Example 56, the title compound was obtained in a similar manner to Reference Example 3.

MS (ESI+) 348 (M + +1, 26%).

Reference Example 78

Methyl 4-[3-(2-ethyl-1,3-dioxolan-2-yl)propyl]-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

Using the compound of Reference Example 56, the title compound was obtained in a similar manner to Reference Example 3.

MS (ESI+) 392 (M + +1, 30%).

Reference Example 79

Methyl 4-[4-(benzyloxy)butyl]-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

Using the compound of Reference Example 56, the title compound was obtained in a similar manner to Reference Example 3.

MS (ESI+) 412 (M + +1, 35%).

Reference Example 80

Methyl 4-[2-(benzyloxy)ethyl]-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

Using the compound of Reference Example 56, the title compound was obtained in a similar manner to Reference Example 3.

MS (ESI+) 384 (M + +1, 24%).

Reference Example 81

Methyl 2,2,7-trimethyl-3-oxo-4-(4,4,4-trifluorobutyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

Using the compound of Reference Example 56, the title compound was obtained in a similar manner to Reference Example 3.

MS (ESI+) 360 (M + +1, 23%).

Reference Example 82

Methyl 2,2,7-trimethyl-3-oxo-4-(5,5,5-trifluoropentyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

Using the compound of Reference Example 56, the title compound was obtained in a similar manner to Reference Example 3.

MS (ESI+) 374 (M + +1, 26%).

Reference Example 83

Methyl 4-(4-tert-butoxy-4-oxobutyl)-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

Using the compound of Reference Example 56, the title compound was obtained in a similar manner to Reference Example 3.

MS (ESI+) 392 (M + +1, 22%).

Reference Example 84

Methyl 4-(2-tert-butoxy-2-oxoethyl)-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

Using the compound of Reference Example 56, the title compound was obtained in a similar manner to Reference Example 3.

MS (ESI+) 364 (M + +1, 21%).

Reference Example 85

tert-Butyl (3R)-3-[{[4-((2S)-2-{[(benzyloxy)carbonyl]amino}propyl)-2,2-dimethyl-3-oxo-7-(trifluoro-methyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

To tert-butyl (3R)-3-[{[2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate (100 mg) were added 2-hydroxycarbamic acid benzyl ester (49 mg), diisopropyl azodicarboxylate (0.26 ml), triphenylphosphine (122 mg) and tetrahydrofuran (3 ml), and the mixture was stirred at room temperature overnight. After the reaction was complete, the mixture was concentrated, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) to give the title compound (120 mg).

MS (ESI+) 705 (M + +1, 39%).

Reference Example 86

tert-Butyl (3R)-3-[{[4-(3-ethoxy-3-oxopropyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

To tert-Butyl (3R)-3-[{[2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate (460 mg) were added 3-bromopropionic acid ethyl ester (0.19 ml), potassium carbonate (298 mg) and acetonitrile (5 ml), and the mixture was refluxed for 5 hours. After the reaction was complete, water was added to the reaction solution, and the mixture was extracted with ethyl acetate solution. The obtained ethyl acetate solution was washed with water and an aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) to give the title compound (350 mg) as a colorless liquid.

MS (ESI+) 614 (M + +1, 32%).

Reference Example 87

tert-Butyl (3R)-3-(isopropyl{[4-[(2S)-3-methoxy-2-methyl-3-oxopropyl]-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}amino)piperidine-1-carboxylate

Using the compound of Reference Example 66, the title compound was obtained in a similar manner to Reference Example 3.

MS (ESI+) 614 (M + +1, 32%).

Reference Example 88

tert-Butyl (3R)-3-[{[4-(1H-imidazol-5-ylmethyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 66, the title compound was obtained in a similar manner to Reference Example 3.

MS (ESI+) 594 (M + +1, 31%).

Reference Example 89

tert-Butyl (3R)-3-[{[4-(2-{[(dimethylamino)carbonyl]oxy}ethyl)-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 69, the title compound was obtained in a similar manner to Reference Example 5.

MS (ESI+) 575 (M + +1, 32%).

Reference Example 90

tert-Butyl (3R)-3-[{[4-(4-cyanobutyl)-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]-carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 68, the title compound was obtained in a similar manner to Reference Example 5.

MS (ESI+) 541 (M + +1, 32%).

Reference Example 91

tert-Butyl (3R)-3-[[(4-hex-5-en-1-yl-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)-carbonyl](isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 70, the title compound was obtained in a similar manner to Reference Example 5.

MS (ESI+) 542 (M + +1, 34%).

Reference Example 92

tert-Butyl (3R)-3-[{[4-(4-{[tert-butyl(dimethyl)silyl]oxy}butyl)-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 71, the title compound was obtained in a similar manner to Reference Example 5.

MS (ESI+) 646 (M + +1, 38%).

Reference Example 93

tert-Butyl (3R)-3-[{[4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 72, the title compound was obtained in a similar manner to Reference Example 5.

MS (ESI+) 623 (M + +1, 37%).

Reference Example 94

tert-Butyl (3R)-3-[{[4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 73, the title compound was obtained in a similar manner to Reference Example 5.

MS (ESI+) 637 (M + +1, 38%).

Reference Example 95

tert-Butyl (3R)-3-[{[4-(3-{[(benzyloxy)carbonyl]amino}propyl)-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 75, the title compound was obtained in a similar manner to Reference Example 5.

MS (ESI+) 651 (M + +1, 39%).

Reference Example 96

tert-Butyl (3R)-3-(isopropyl{[2,2,7-trimethyl-3-oxo-4-(tetrahydro-2H-pyran-4-ylmethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}amino)piperidine-1-carboxylate

Using the compound of Reference Example 77, the title compound was obtained in a similar manner to Reference Example 5.

MS (ESI+) 558 (M + +1, 34%).

Reference Example 97

tert-Butyl (3R)-3-(isopropyl{[2,2,7-trimethyl-3-oxo-4-(4-oxohexyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}amino)piperidine-1-carboxylate

Using the compound of Reference Example 78, the title compound was obtained in a similar manner to Reference Example 5.

MS (ESI+) 558 (M + +1, 34%).

Reference Example 98

tert-Butyl (3R)-3-[({4-[4-(benzyloxy)butyl]-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 79, the title compound was obtained in a similar manner to Reference Example 5.

MS (ESI+) 622 (M + +1, 39%).

Reference Example 99

tert-Butyl (3R)-3-[({442-(benzyloxy)ethyl]-2,2,7-trimethyl-3-oxy-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 80, the title compound was obtained in a similar manner to Reference Example 5.

MS (ESI+) 594 (M + +1, 37%).

Reference Example 100

tert-Butyl (3R)-3-(isopropyl{[2,2,7-trimethyl-3-oxo-4-(4,4,4-trifluorobutyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}amino)piperidine-1-carboxylate

Using the compound of Reference Example 81, the title compound was obtained in a similar manner to Reference Example 5.

MS (ESI+) 570 (M + +1, 31%).

Reference Example 101

tert-Butyl (3R)-3-(isopropyl{[2,2,7-trimethyl-3-oxo-4-(5,5,5-trifluoropentyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}amino)piperidine-1-carboxylate

Using the compound of Reference Example 82, the title compound was obtained in a similar manner to Reference Example 5.

MS (ESI+) 584 (M + +1, 32%).

Reference Example 102

tert-Butyl (3R)-3-[{[2-ethyl-4-{3-[(methoxycarbonyl)amino]propyl}-2-methyl-3-oxo-7-(trifluoro-methyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 76, the title compound was obtained in a similar manner to Reference Example 5.

MS (ESI+) 629 (M + +1, 32%).

Reference Example 103

tert-Butyl (3R)-3-[isopropyl({2,2,7-trimethyl-4-[4-(methylamino)-4-oxobutyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 112, the title compound was obtained in a similar manner to Reference Example 5.

MS (ESI+) 559 (M + +1, 32%).

Reference Example 104

tert-Butyl (3R)-3-[({4-[4-(ethylamino)-4-oxobutyl]-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 113, the title compound was obtained in a similar manner to Reference Example 5.

MS (ESI+) 573 (M + +1, 34%).

Reference Example 105

tert-Butyl (3R)-3-[[(4-{2-[(2,2-difluoroethyl)amino]-2-oxoethyl}-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl](isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 128, the title compound was obtained in a similar manner to Reference Example 5.

MS (ESI+) 581 (M + +1, 31%).

Reference Example 106

tert-Butyl (3R)-3-[{[4-(4-tert-butoxy-4-oxobutyl)-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 83, the title compound was obtained in a similar manner to Reference Example 5.

MS (ESI+) 602 (M + +1, 36%).

Reference Example 107

3-[6-{[[(3R)-1-(tert-Butoxycarbonyl)piperidin-3-yl](isopropyl)amino]carbonyl}-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-2,3-dihydro-4H-1,4-benzoxazin-4-yl]propanoic acid

To tert-butyl (3R)-3-[{[4-(3-ethoxy-3-oxopropyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate (350 mg) were added a 2N NaOH aqueous solution (5 ml), MeOH (5 ml) and THF (5 ml), and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the solvent was concentrated, and thereto was added dropwise a 2N aqueous hydrochloric acid solution. The precipitated crystals were extracted with ethyl acetate. The obtained ethyl acetate solution was washed with water and an aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The obtained residue (260 mg) was used in the subsequent reaction without a further treatment.

MS (ESI+) 586 (M + +1, 30%).

Reference Example 108

(2S)-3-[6-{[[(3R)-1-(tert-Butoxycarbonyl)piperidine-3-yl](isopropyl)amino]carbonyl}-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-2,3-dihydro-4H-1,4-benzoxazin-4-yl]-2-methylpropionic acid

Using the compound of Reference Example 87, the title compound was obtained in a similar manner to Reference Example 107.

MS (ESI+) 600 (M + +1, 31%).

Reference Example 109

4-[6-(Methoxycarbonyl)-2,2,7-trimethyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl]butanoic acid

To methyl 4-(4-tert-butoxy-4-oxobutyl)-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate (2.7 g) was added TFA (5 ml), and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was neutralized with a saturated aqueous sodium hydrogen carbonate solution, and the precipitated compound was extracted with ethyl acetate. The obtained ethyl acetate solution was washed with water and an aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The obtained residue (950 mg) was used in the subsequent reaction without further treatment.

MS (ESI+) 336 (M + +1, 18%).

Reference Example 110

[6-(Methoxycarbonyl)-2,2,7-trimethyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl]acetic acid

Using the compound of Reference Example 84, the title compound was obtained in a similar manner to Reference Example 109.

MS (ESI+) 308 (M + +1, 16%).

Reference Example 111

tert-Butyl (3R)-3-[{[4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 74, the title compound was obtained in a similar manner to Reference Example 5.

MS (ESI+) 691 (M + +1, 38%).

Reference Example 112

tert-Butyl (3R)-3-[isopropyl({2,2,7-trimethyl-4-[4-(methylamino)-4-oxobutyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)amino]piperidine-1-carboxylate

To 4-[6-(methoxycarbonyl)-2,2,7-trimethyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl]-butanoic acid (500 mg) were added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (372 mg), 1-hydroxybenzotriazole (262 mg), triethylamine (0.27 ml), chloroform (10 ml), methylamine (0.20 ml), and the mixture was stirred at room temperature overnight. After the reaction was complete, the mixture was concentrated, and the obtained residue was purified by silica gel column chromatography (chloroform/methanol=9/1) to give the title compound (420 mg) as colorless amorphous.

MS (ESI+) 349 (M + +1, 20%).

Reference Example 113

tert-Butyl (3R)-3-[({4-[4-(ethylamino)-4-oxobutyl]-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 109, the title compound was obtained in a similar manner to Reference Example 112.

MS (ESI+) 363 (M + +1, 21%).

Reference Example 114

tert-Butyl (3R)-3-[{[2,2-dimethyl-4-[3-(methylamino)-3-oxopropyl]-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 107, the title compound was obtained in a similar manner to Reference Example 112.

MS (ESI+) 599 (M + +1, 31%).

Reference Example 115

tert-Butyl (3R)-3-[{[4-[3-(ethylamino)-3-oxopropyl]-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 107, the title compound was obtained in a similar manner to Reference Example 112.

MS (ESI+) 613 (M + +1, 32%).

Reference Example 116

tert-Butyl (3R)-3-[{[4-{3-[(2-fluoroethyl)amino]-3-oxopropyl}-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 107, the title compound was obtained in a similar manner to Reference Example 112.

MS (ESI+) 631 (M + +1, 32%).

Reference Example 117

tert-Butyl (3R)-3-[{[4-{3-[(2,2-difluoroethyl)amino]-3-oxopropyl}-2,2-dimethyl-3-oxo-7-(trifluoro-methyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 107, the title compound was obtained in a similar manner to Reference Example 112.

MS (ESI+) 649 (M + +1, 32%).

Reference Example 118

tert-Butyl (3R)-3-[{[4-[3-(cyclopropylamino)-3-oxopropyl]-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 107, the title compound was obtained in a similar manner to Reference Example 112.

MS (ESI+) 625 (M + +1, 34%).

Reference Example 119

tert-Butyl (3R)-3-[{[4-[(2S)-3-(ethylamino)-2-methyl-3-oxopropyl]-2,2-dimethyl-3-oxo-7-(trifluoro-methyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 108, the title compound was obtained in a similar manner to Reference Example 112.

MS (ESI+) 627 (M + +1, 34%).

Reference Example 120

tert-Butyl (3R)-3-[[(4-{2-[(cyclopropylcarbonyl)amino]ethyl}-2,2,7-trimethyl)-3-oxy-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl](isopropyl)]piperidine-1-carboxylate

Using the compound of Reference Example 139, the title compound was obtained in a similar manner to Reference Example 112.

MS (ESI+) 571 (M + +1, 34%).

Reference Example 121

tert-Butyl (3R)-3-[[(4-{2-[(difluoroacetyl)amino]ethyl}-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl](isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 139, the title compound was obtained in a similar manner to Reference Example 120.

MS (ESI+) 581 (M + +1, 31%).

Reference Example 122

tert-Butyl (3R)-3-[[(4-{2-[(difluoroacetyl)amino]ethyl}-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl](isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 141, the title compound was obtained in a similar manner to Reference Example 120.

MS (ESI+) 567 (M + +1, 30%).

Reference Example 123

tert-Butyl (3R)-3-[[(2,2-dimethyl-3-oxo-4-{2-[(3,3,3-trifluoropropanyl)amino]ethyl}-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl](isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 141, the title compound was obtained in a similar manner to Reference Example 120

MS (ESI+) 599 (M + +1, 31%).

Reference Example 124

tert-Butyl (3R)-3-[{[4-{2-[(difluoroacetyl)amino]ethyl}-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 142, the title compound was obtained in a similar manner to Reference Example 120.

MS (ESI+) 599 (M + +1, 31%).

Reference Example 125

tert-Butyl (3R)-3-[[(4-{2-[(cyclopropylacetyl)amino]ethyl}-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl](isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 139, the title compound was obtained in a similar manner to Reference Example 120.

MS (ESI+) 599 (M + +1, 31%).

Reference Example 126

tert-Butyl (3R)-3-[({4-[2-(butyrylamino)ethyl]-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 139, the title compound was obtained in a similar manner to Reference Example 120.

MS (ESI+) 573 (M + +1, 34%).

Reference Example 127

tert-Butyl (3R)-3-[[(4-{2-[(2,2-difluoropropanoyl)amino]ethyl}-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl](isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 139, the title compound was obtained in a similar manner to Reference Example 120.

MS (ESI+) 595 (M + +1, 32%).

Reference Example 128

Methyl 4-{2-[(2,2-difluoroethyl)amino]-2-oxoethyl}-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

Using the compound of Reference Example 110, the title compound was obtained in a similar manner to Reference Example 112.

MS (ESI+) 371 (M + +1, 18%).

Reference Example 129

tert-Butyl (3R)-3-[{[2,2-dimethyl-3-oxo-4-{2-[(trifluoroacetyl)amino]ethyl}-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 142, the title compound was obtained in a similar manner to Reference Example 120.

MS (ESI+) 653 (M + +1, 31%).

Reference Example 130

tert-Butyl (3R)-3-[[(4-{3-[(difluoroacetyl)amino]propyl}-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl](isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 145, the title compound was obtained in a similar manner to Reference Example 120.

MS (ESI+) 595 (M + +1, 32%).

Reference Example 131

tert-Butyl (3R)-3-[({4-[3-(acetylamino)propyl]-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 145, the title compound was obtained in a similar manner to Reference Example 120.

MS (ESI+) 559 (M + +1, 32%).

Reference Example 132

tert-Butyl (3R)-3-[({4-[2-(acetylamino)ethyl]-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)(isopropyl)amino]piperidine-1-carboxylate

To tert-butyl (3R)-3-[{[4-(2-aminoethyl)-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate (200 mg) were added triethyl-amine (0.040 ml), tetrahydrofuran (3 ml), acetyl chloride (0.04 ml) under ice-cooling, and the mixture was stirred at room temperature for one hour. After the reaction was complete, the mixture was concentrated, and the obtained residue was purified by silica gel column chromatography (chloroform/methanol=9/1) to give the title compound (80 mg) as colorless amorphous.

MS (ESI+) 545 (M + +1, 31%).

Reference Example 133

tert-Butyl (3R)-3-[{[2,2-dimethyl-3-oxo-4-[(2S)-2-(propionylamino)propyl]-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 146, the title compound was obtained in a similar manner to Reference Example 132.

MS (ESI+) 627 (M + +1, 34%).

Reference Example 134

tert-Butyl (3R)-3-{isopropyl[(2,2,7-trimethyl-4-{2-[(methylsulfonyl)amino]ethyl}-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl]amino}piperidine-1-carboxylate

Using the compound of Reference Example 139, the title compound was obtained in a similar manner to Reference Example 132.

MS (ESI+) 581 (M + +1, 30%).

Reference Example 135

tert-Butyl (3R)-3-[isopropyl({2,2,7-trimethyl-3-oxo-4-[2-(propionylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 139, the title compound was obtained in a similar manner to Reference Example 132.

MS (ESI+) 559 (M + +1, 32%).

Reference Example 136

tert-Butyl (3R)-3-[({2,2-dimethyl-3-oxo-4-[2-(propionylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 141, the title compound was obtained in a similar manner to Reference Example 132.

MS (ESI+) 545 (M + +1, 31%).

Reference Example 137

tert-Butyl (3R)-3-[{[2,2-dimethyl-3-oxo-4-[2-(propionylamino)ethyl]-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 142, the title compound was obtained in a similar manner to Reference Example 132.

MS (ESI+) 613 (M + +1, 32%).

Reference Example 138

tert-Butyl (3R)-3-[{[4-{2-[(fluoroacetyl)amino]ethyl}-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 142, the title compound was obtained in a similar manner to Reference Example 132.

MS (ESI+) 617 (M + +1, 31%).

Reference Example 139

tert-Butyl (3R)-3-[{[4-(2-aminoethyl)-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]-carbonyl}(isopropyl)amino]piperidine-1-carboxylate

To tert-butyl (3R)-3-[{[4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate (1.14 g) were added a 10% palladium carbon (500 mg) and methanol (30 ml), and the mixture was stirred at room temperature under hydrogen atmosphere for 2 hours. After the reaction was complete, the mixture was filtered and concentrated. The obtained residue (900 mg) was used in the subsequent reaction without further treatment.

MS (ESI+) 503 (M + +1, 29%).

Reference Example 140

tert-Butyl (3R)-3-[[(4-hexyl-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl](isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 91, the title compound was obtained in a similar manner to Reference Example 139.

MS (ESI+) 544 (M + +1, 34%).

Reference Example 141

tert-Butyl (3R)-3-[{[4-(2-aminoethyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]-carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 93, the title compound was obtained in a similar manner to Reference Example 139.

MS (ESI+) 489 (M + +1, 28%).

Reference Example 142

tert-Butyl (3R)-3-[{[4-(2-aminoethyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 111, the title compound was obtained in a similar manner to Reference Example 139.

MS (ESI+) 557 (M + +1, 29%).

Reference Example 143

tert-Butyl (3R)-3-[{[4-(4-hydroxybutyl)-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]-carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 98, the title compound was obtained in a similar manner to Reference Example 139.

MS (ESI+) 532 (M + +1, 31%).

Reference Example 144

tert-Butyl (3R)-3-[{[4-(2-hydroxyethyl)-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]-carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 98, the title compound was obtained in a similar manner to Reference Example 139.

MS (ESI+) 504 (M + +1, 29%).

Reference Example 145

tert-Butyl (3R)-3-[{[4-(3-amino)-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]-carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 95, the title compound was obtained in a similar manner to Reference Example 139.

MS (ESI+) 517 (M + +1, 30%).

Reference Example 146

tert-Butyl (3R)-3-[{[4-[(2S)-2-aminopropyl]-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 85, the title compound was obtained in a similar manner to Reference Example 139.

MS (ESI+) 571 (M + +1, 30%).

Reference Example 147

tert-Butyl (3R)-3-[({7-chloro-2,2-dimethyl-3-oxo-4-[2-(propionylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 136, the title compound was obtained in a similar manner to Reference Example 12.

MS (ESI+) 580 (M + +1, 32%).

Reference Example 148

tert-Butyl (3R)-3-[[(7-chloro-4-{2-[(difluoroacetyl)amino]ethyl}-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl](isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 122, the title compound was obtained in a similar manner to Reference Example 12.

MS (ESI+) 602 (M + +1, 32%).

Reference Example 149

tert-Butyl (3R)-3-[[(7-chloro-2,2-dimethyl-3-oxo-4-{2-[(3,3,3-trifluoropropanoyl)amino]ethyl}-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl](isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 123, the title compound was obtained in a similar manner to Reference Example 12.

MS (ESI+) 634 (M + +1, 32%).

Reference Example 150

tert-Butyl (3R)-3-[{[4-(4-cyclopropylbutyl)-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

N-Nitroso-N-methylurea (2.62 g) was dissolved in diethyl ether (34 ml), and the mixture was added dropwise into a solution of potassium hydroxide (1.53 g) in water (9 ml) under ice-cooling, and the mixture was stirred at 0° C. for 15 minutes. Then, the obtained supernatant was added dropwise to a solution of tert-butyl (3R)-3-[[(4-hex-5-en-1-yl-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl](isopropyl)amino]piperidine-1-carboxylate (300 mg) with palladium acetate (15 mg) in a mixed solvent of chloroform/diethyl ether. The mixture was stirred at room temperature for one hour. After the reaction was complete, the mixture was filtered and concentrated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to give the title compound (250 mg) as a colorless liquid.

MS (ESI+) 556 (M + +1, 35%).

Reference Example 151

tert-Butyl (3R)-3-(isopropyl{[4-{2-[(methoxycarbonyl)(methyl)amino]ethyl}-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}amino)piperidine-1-carboxylate

To tert-butyl (3R)-3-(isopropyl{[4-{2-[(methoxycarbonyl)amino]ethyl}-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}amino)piperidine-1-carboxylate (110 mg) were added sodium hydride (9.3 mg) and N,N-dimethylformamide (9 ml) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Then, to the mixture was added methyl iodide (0.02 ml), and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, water was added to the reaction solution, and the mixture was extracted with ethyl acetate solution. The obtained ethyl acetate solution was washed with water and an aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/2) to give the title compound (110 mg) as a colorless liquid.

MS (ESI+) 629 (M + +1, 32%).

Reference Example 152

tert-Butyl (3R)-3-{isopropyl[(2,2,7-trimethyl-4-{2-[methyl(propionyl)amino]ethyl}-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl]amino}piperidine-1-carboxylate

Using the compound of Reference Example 135, the title compound was obtained in a similar manner to Reference Example 151.

MS (ESI+) 573 (M + +1, 34%).

Reference Example 153

tert-Butyl (3R)-3-[isopropyl({2,2,7-trimethyl-3-oxo-4-[2-(propionyloxy)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)amino]piperidine-1-carboxylate

To tert-butyl (3R)-3-[{[4-(2-hydroxyethyl)-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate (150 mg) were added sodium hydride (16 mg) and N,N-dimethylformamide (9 ml) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Then, to the mixture was added propionic chloride (0.03 ml), and the mixture was further stirred at room temperature for 2 hours. After the reaction was complete, water was added to the reaction solution, and the mixture was extracted with ethyl acetate solution. The obtained ethyl acetate solution was washed with water and an aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/2) to give the title compound (110 mg) as a colorless liquid.

MS (ESI+) 560 (M + +1, 32%).

Reference Example 154

tert-Butyl (3R)-3-[({4-[4-(cyclopropyloxy)butyl]-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)(isopropyl)amino]piperidine-1-carboxylate

To tert-butyl (3R)-3-[{[4-(4-hydroxybutyl)-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate (200 mg) were added sodium hydride (60 mg) and N,N-dimethylformamide (3 ml) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Then, to the mixture was added bromocyclopropane (0.30 ml), and the mixture was stirred at 150° C. for 6 hours. After the reaction was complete, water was added to the reaction solution, and the mixture was extracted with ethyl acetate solution. The obtained ethyl acetate solution was washed with water and an aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/2) to give the title compound (30 mg) as a colorless liquid.

MS (ESI+) 572 (M + +1, 32%).

Reference Example 155

tert-Butyl (3R)-3-(isopropyl{[2,2,7-trimethyl-3-oxo-4-(2-propoxyethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}amino)piperidine-1-carboxylate

Using the compound of Reference Example 144, the title compound was obtained in a similar manner to Reference Example 154.

MS (ESI+) 546 (M + +1, 31%).

Reference Example 156

tert-Butyl (3R)-3-[{[2,2-dimethyl-3-oxo-4-[2-(propanethioylamino)ethyl]-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

To tert-butyl (3R)-3-[{[4-(2-aminoethyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate (100 mg) were added methylpropane dithionate (23 mg), triethylamine (0.050 ml) and MeOH (3 ml), and the mixture was stirred at room temperature for 3 hours. After the reaction was complete, water was added to the reaction solution, and the mixture was extracted with ethyl acetate solution. The obtained ethyl acetate solution was washed with water and an aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/2) to give the title compound (90 mg) as a colorless liquid.

MS (ESI+) 629 (M + +1, 32%).

Reference Example 157

tert-Butyl (3R)-3-(isopropyl{[2,2,7-trimethyl-4-(2-{[(methylamino)carbonyl]amino}ethyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}amino)piperidine-1-carboxylate

To tert-butyl (3R)-3-[{[4-(2-aminoethyl)-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate (200 mg) were added triphosgene (47 mg), triethylamine (0.12 ml) and chloroform (5 ml) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated, and thereto were added methylamine (0.17 ml) and chloroform (5 ml) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, water was added to the reaction solution, and the mixture was extracted with ethyl acetate solution. The obtained ethyl acetate solution was washed with water and an aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (chloroform /methanol=9/1) to give the title compound (70 mg) as colorless amorphous.

MS (ESI+) 560 (M + +1, 31%).

Reference Example 158

Methyl 7-iodo-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

The compound of Reference Example 2 (1.2 g) was dissolved in chloroform (25 ml), and thereto were added silver trifluoromethanesulfonate (1.38 g) and iodine (1.36 g) under ice-cooling, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was filtered on celite, and the organic layer was washed twice with an aqueous sodium thiosulfate solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (1.2 g) as a pale yellow solid.

MS (ESI+) 362 (M + +1, 100%).

Reference Example 159

Methyl (2R)-7-iodo-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

Using methyl (2R)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate, the title compound (1.3 g) was obtained in a similar manner to Reference Example 158.

MS (ESI+) 348 (M + +1, 100%).

Reference Example 160

Methyl 7-Iodo-4-(4-methoxybutyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

The compound of Reference Example 158 (1.2 g) was dissolved in N,N-dimethylformamide (20 ml), and thereto were added 1-chloro-4-methoxybutane (815 mg), potassium carbonate (919 mg), cesium carbonate (218 mg) and potassium iodide (111 mg), and the mixture was stirred at 90° C. for 8 hours. The reaction mixture was cooled, and water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure.

The obtained residue was purified by silica gel column chromatography (the developing solvent: hexane/ethyl acetate =5:1→4:1) to give the title compound (1.1 g) as a colorless clear oil.

MS (ESI+) 448 (M + +1, 83%).

Reference Example 161

Methyl (2R)-7-Iodo-4-(4-methoxybutyl)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

Using the compound of Reference Example 159, the title compound (1.2 g) was obtained in a similar manner to Reference Example 160.

MS (ESI+) 434 (M + +1, 40%).

Reference Example 162

Methyl 7-Iodo-4- { 2- [(methoxycarbonyl)amino]ethyl}-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

The compound of Reference Example 158 (1.1 g) was dissolved in N,N-dimethylformamide (20 ml), and thereto were added methyl (2-bromoethyl)carbamate (1.1 g) and potassium carbonate (1.05 g), and the mixture was stirred at 90° C. for 8 hours. The reaction mixture was cooled, and water was added thereto. The mixture was extracted with ethyl acetate, and the organic layer was washed twice with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (the developing solvent: hexane/acetone =4:1→3:1) to give the title compound (1.1 g) as a pale yellow oil.

MS (ESI+) 463 (M + +1, 51%).

Reference Example 163

Methyl (2R)-7-Iodo-4-{2-[(methoxycarbonyl)amino]ethyl}-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

Using the compound of Reference Example 159, the title compound (1.2 g) was obtained in a similar manner to Reference Example 162.

MS (ESI+) 449 (M + +1, 33%).

Reference Example 164

Methyl 4-{2-{[(benzyloxy)carbonyl]amino}ethyl}-7-iodo-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

Using the compound of Reference Example 158, the title compound (1.4 g) was obtained in a similar manner to Reference Example 3.

MS (ESI+) 539 (M + +1, 100%).

Reference Example 165

Methyl (2R)-4- { 2- { [(Benzyloxy)carbonyl]amino}ethyl}-7-iodo-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

Using the compound of Reference Example 159, the title compound (1.7 g) was obtained in a similar manner to Reference Example 3.

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

Reference Example 166

Methyl 4-(4-methoxybutyl)-2,2-dimethyl-3-oxo-7-[(trimethylsilyl)ethynyl-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

The compound of Reference Example 160 (1.1 g) was dissolved in triethylamine (20 ml), and thereto were added dichlorobis(triphenylphosphine)palladium (II) (86 mg), copper iodide (23 mg) and trimethylsilylacetylene (1.2 g) under ice-cooling. Then, the mixture was stirred at room temperature for 6 hours. The reaction solvent was evaporated under reduced pressure to some extent, and the resulting residue was diluted with ethyl acetate. The mixture was filtered on celite, and the organic layer was washed twice with a 10% aqueous citric acid solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (the developing solvent: hexane/acetone=5:1→4:1) to give the title compound (730 mg) as a colorless clear oil.

MS (ESI+) 418 (M + +1, 100%).

Reference Example 167

Methyl (2R)-4-(4-methoxybutyl)-2-methyl-3-oxo-7-[(trimethylsilyl)ethynyl-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

Using the compound of Reference Example 161, the title compound (850 mg) was obtained in a similar manner to Reference Example 166.

MS (ESI+) 404 (M + +1, 100%).

Reference Example 168

Methyl 4-{2-[(methoxycarbonyl)amino]ethyl}-2,2-dimethyl-3-oxo-7-[(trimethylsilyl)ethynyl-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

Using the compound of Reference Example 162, the title compound (800 mg) was obtained in a similar manner to Reference Example 166.

MS (ESI+) 433 (M + +1, 100%).

Reference Example 169

Methyl (2R)-4-{2-[(methoxycarbonyl)amino]ethyl}-2-methyl-3-oxo-7-[(trimethylsilyl)ethynyl-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

Using the compound of Reference Example 163, the title compound (850 mg) was obtained in a similar manner to Reference Example 166.

MS (ESI+) 419 (M + +1, 65%).

Reference Example 170

Methyl 4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2,2-dimethyl-3-oxo-7-[(trimethylsilyl)ethynyl-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

Using the compound of Reference Example 164, the title compound (1.9 g) was obtained in a similar manner to Reference Example 166.

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

Reference Example 171

Methyl (2R)-4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2-methyl-3-oxo-7-[(trimethylsilyl)ethynyl-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

Using the compound of Reference Example 165, the title compound (1.2 g) was obtained in a similar manner to Reference Example 166.

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

Reference Example 172

Methyl 7-ethynyl-4-(4-methoxybutyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

The compound of Reference Example 166 (730 mg) was dissolved in tetrahydrofuran (10 ml), and thereto was slowly added a 1 mol/L solution of tetrabutylammonium fluoride in tetrahydrofuran (1.8 ml) dropwise under ice-cooling. Then, the mixture was stirred under ice-cooling for one hour. The reaction solvent was evaporated under reduced pressure to some extent, and the resulting residue was diluted with ethyl acetate. The organic layer was washed twice with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (the developing solvent: hexane/acetone=4:1→3:1) to give the title compound (430 mg) as a colorless clear oil.

MS (ESI+) 346 (M + +1, 90%).

Reference Example 173

Methyl (2R)-7-ethynyl-4-(4-methoxybutyl)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

Using the compound of Reference Example 167, the title compound (530 mg) was obtained in a similar manner to Reference Example 172.

MS (ESI+) 332 (M + +1, 66%).

Reference Example 174

Methyl 7-ethynyl-4-{2-[(methoxycarbonyl)amino]ethyl}-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

Using the compound of Reference Example 168, the title compound (530 mg) was obtained in a similar manner to Reference Example 172.

MS (ESI+) 361 (M + +1, 50%).

Reference Example 175

Methyl (2R)-7-ethynyl-4-{2-[(methoxycarbonyl)amino]ethyl}-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

Using the compound of Reference Example 169, the title compound (530 mg) was obtained in a similar manner to Reference Example 172.

MS (ESI+) 347 (M + +1, 37%).

Reference Example 176

Methyl 4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-7-ethynyl-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

Using the compound of Reference Example 170, the title compound (700 mg) was obtained in a similar manner to Reference Example 172.

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

Reference Example 177

Methyl (2R)-4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-7-ethynyl-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

Using the compound of Reference Example 171, the title compound (750 mg) was obtained in a similar manner to Reference Example 172.

MS (ESI+) 423 (M + +1, 100%).

Reference Example 178

Methyl 7-ethyl-4-(4-methoxybutyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

The compound of Reference Example 172 (500 mg) was dissolved in methanol (15 ml), and to the mixture was added a 20% palladium hydroxide carbon (150 mg) under ice-cooling. Then, the mixture was stirred at room temperature for 6 hours under hydrogen atmosphere. The reaction mixture was filtered on celite, and the reaction solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (the developing solvent: hexane/acetone=5:1→4:1) to give the title compound (400 mg) as a colorless clear oil.

MS (ESI+) 350 (M + +1, 78%).

Reference Example 179

Methyl (2R)-7-ethyl-4-(4-methoxybutyl)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

Using the compound of Reference Example 173, the title compound (450 mg) was obtained in a similar manner to Reference Example 178.

MS (ESI+) 336 (M + +1, 38%).

Reference Example 180

Methyl 7-ethyl-4-{2-[(methoxycarbonyl)amino]ethyl}-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

Using the compound of Reference Example 174, the title compound (520 mg) was obtained in a similar manner to Reference Example 178.

MS (ESI+) 365 (M + +1, 36%).

Reference Example 181

Methyl (2R)-7-ethyl-4-{2-[(methoxycarbonyl)amino]ethyl}-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

Using the compound of Reference Example 175, the title compound (480 mg) was obtained in a similar manner to Reference Example 178.

MS (ESI+) 351 (M + +1, 36%).

Reference Example 182

tert-Butyl (3R)-3-[{[7-ethyl-4-(4-methoxybutyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 178, the title compound (450 mg) was obtained in a similar manner to Reference Example 5.

MS (ESI+) 560 (M + +1, 56%).

Reference Example 183

tert-Butyl (3R)-3-[{[(2R)-7-ethyl-4-(4-methoxybutyl)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 179, the title compound (410 mg) was obtained in a similar manner to Reference Example 5.

MS (ESI+) 546 (M + +1, 50%).

Reference Example 184

tert-Butyl (3R)-3-[[(7-ethyl-4-{2-[(methoxycarbonyl)amino]ethyl}-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl](isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 180, the title compound (460 mg) was obtained in a similar manner to Reference Example 5.

MS (ESI+) 575 (M + +1, 46%).

Reference Example 185

tert-Butyl (3R)-3-[[((2R)-7-ethyl-4-{2-[(methoxycarbonyl)amino]ethyl}-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl](isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 181, the title compound (440 mg) was obtained in a similar manner to Reference Example 5.

MS (ESI+) 561 (M + +1, 26%).

Reference Example 186

tert-Butyl (3R)-3-[{[4-(2-{[(benzyloxy)carbonyl]amino}ethyl}-7-ethynyl-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl](isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 176, the title compound was obtained in a similar manner to Reference Example 5.

MS (ESI+) 647 (M + +1, 22%).

Reference Example 187

tert-Butyl (3R)-3-[{[(2R)-4-(2-{[(benzyloxy)carbonyl]amino}ethyl}-7-ethynyl-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl](isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 177, the title compound (610 mg) was obtained in a similar manner to Reference Example 5.

MS (ESI+) 633 (M + +1, 19%).

Reference Example 188

tert-Butyl (3R)-3-[{[4-(2-aminoethyl)-7-ethyl-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 186, the title compound (430 mg) was obtained in a similar manner to Reference Example 139.

MS (ESI+) 517 (M + +1, 97%).

Reference Example 189

tert-Butyl (3R)-3-[{[(2R)-4-(2-aminoethyl)-7-ethyl-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 187, the title compound (485 mg) was obtained in a similar manner to Reference Example 139.

MS (ESI+) 503 (M + +1, 73%).

Reference Example 190

tert-Butyl (3R)-3-[({7-ethyl-2,2-dimethyl-3-oxo-4-[2-(propylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 188, the title compound (180 mg) was obtained in a similar manner to Reference Example 132.

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

Reference Example 191

tert-Butyl (3R)-3-[[(4-{2-[(difluoroacetyl)amino]ethyl}-7-ethyl-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl](isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 188, the title compound (180 mg) was obtained in a similar manner to Reference Example 120.

MS (ESI+) 595 (M + +1, 39%).

Reference Example 192

tert-Butyl (3R)-3-[[(4-{2-[(ethoxycarbonyl)amino]ethyl}-7-ethyl-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl](isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 188, the title compound (210 mg) was obtained in a similar manner to Reference Example 132.

MS (ESI+) 589 (M + +1, 41%).

Reference Example 193

tert-Butyl (3R)-3-[({4-[2-(butyrylamino)ethyl]-7-ethyl-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 188, the title compound (210 mg) was obtained in a similar manner to Reference Example 132.

MS (ESI+) 587 (M + +1, 40%).

Reference Example 194

tert-Butyl (3R)-3-[({(2R)-7-ethyl-2-methyl-3-oxo-4-[2-(propylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 189, the title compound (120 mg) was obtained in a similar manner to Reference Example 132.

MS (ESI+) 559 (M + +1, 21%).

Reference Example 195

tert-Butyl (3R)-3-[({(2R)-4-[2-(acetylamino)ethyl]-7-ethyl-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 189, the title compound (120 mg) was obtained in a similar manner to Reference Example 132.

MS (ESI+) 545 (M + +1, 16%).

Reference Example 196

tert-Butyl (3R)-3-[({(2R)-7-ethyl-4-[2-(formylamino)ethyl]-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)(isopropyl)amino]piperidine-1-carboxylate

The compound of Reference Example 189 (150 mg) was dissolved in dichloromethane (5 ml), and thereto was added under ice-cooling a solution which had been previously prepared by stirring acetic anhydride (91 mg) and formic acid (82 mg) at 45° C. for one hour. Then, the mixture was stirred at room temperature for 6 hours. To the reaction mixture was added an aqueous sodium hydrogen carbonate solution, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (the developing solvent: chloroform /methanol=30:1→15:1) to give the title compound (110 mg) as amorphous.

MS (ESI+) 531 (M + +1, 22%).

Reference Example 197

tert-Butyl (3R)-3-({[4-(4-methoxybutyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}amino)piperidine-1-carboxylate

4-(4-Methoxybutyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylic acid (100 mg) was dissolved in dimethylformamide (2 ml), and thereto were added 1-hydroxybenzotriazole (61.1 mg), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (76.5 mg), triethylamine (55.6 μl) and tert-butyl (3R)-3-aminopiperidine-1-carboxylate (64.0 mg), and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added a 5% aqueous sodium hydrogen sulfate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a 5% aqueous sodium hydrogen sulfate solution, 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 (hexane/ethyl acetate=1/1) to give the title compound (1136 mg) as a white solid.

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

Reference Example 198

tert-Butyl (rac.)-(3R,4R)-4-benzyl-3-({[4-(4-methoxybutyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}amino)piperidine-1-carboxylate

Using 4-(4-methoxybutyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylic acid and tert-butyl (rac.)-(3R,4R)-3-amino-4-benzylpiperidine-1-carboxylate (US 2005/182095), the title compound was obtained in a similar manner to Reference Example 197.

MS (ESI+) 648 (M + +1, 100%).

Reference Example 199

tert-Butyl (rac.)-(3R,4S)-4-benzyl-3-({[4-(4-methoxybutyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}amino)piperidine-1-carboxylate

Using 4-(4-methoxybutyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylic acid, tert-butyl (rac.)-(3R,4S)-3-amino-4-benzylpiperidine-1-carboxylate (US 2005/182095), the title compound was obtained in a similar manner to Reference Example 197.

MS (ESI+) 648 (M + +1, 100%).

Reference Example 200

tert-Butyl (3R)-3-[{[4-(4-methoxybutyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(methyl)amino]piperidine-1-carboxylate

The compound of Reference Example 197 (71.6 mg) was dissolved in dimethylformamide (2 ml), and thereto was added at 0° C. sodium hydride (15.4 mg), and the mixture was stirred. Five minutes later, to the mixture was added methyl iodide (23.9 μl), and the mixture was stirred at room temperature for 4 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 twice with a saturated aqueous ammonium chloride solution, and washed with a saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (the developing solvent: hexane/ethyl acetate=1/1) to give the title compound (53.9 mg) as a colorless oil.

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

Reference Example 201

tert-Butyl (rac.)-(3R,4R)-4-benzyl-3-[{[4-(4-methoxybutyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(methyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 198, the title compound was obtained in a similar manner to Reference Example 200.

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

Reference Example 202

tert-Butyl (rac.)-(3R,4S)-4-benzyl-3-[{[4-(4-methoxybutyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(methyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 199, the title compound was obtained in a similar manner to Reference Example 200.

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

Reference Example 203

tert-Butyl 3-(isopropyl{[4-(4-methoxybutyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}amino)azepane-1-carboxylate

Using 4-(4-methoxybutyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylic acid and tert-butyl 3-(isopropylamino)azepane-1-carboxylate, the title compound was obtained in a similar manner to Reference Example 5.

MS (ESI+) 614 (M + +1, 100%).

Reference Example 204

Benzyl 3-(isopropyl{[4-(4-methoxybutyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}amino)pyrrolidine-1-carboxylate

Using 4-(4-methoxybutyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylic acid and benzyl 3-(isopropylamino)pyrrolidine-1-carboxylate, the title compound was obtained in a similar manner to Reference Example 5.

MS (ESI+) 620 (M + +1, 100%).

Reference Example 205

Methyl 4-{[(1R)-1-(methoxycarbonyl)-2-methylpropyl]oxy}-2-methyl-5-nitrobenzoate

Using methyl 4-hydroxy-2-methyl-5-nitrobenzoate, the title compound was obtained in a similar manner to Reference Example 26.

MS (ESI+) 326 (M + +1, 65%).

Reference Example 206

Methyl (2R)-2-isopropyl-4-(4-methoxybutyl)-7-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

Using the compound of Reference Example 205, the title compound was obtained in a similar manner to Reference Example 17.

MS (ESI+) 350 (M + +1, 100%).

Reference Example 207

tert-Butyl (3R)-3-(isobutyl {[(2R)-2-isopropyl-4-(4-methoxybutyl)-7-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}amino)piperidine-1-carboxylate

Using the compound of Reference Example 206, the title compound was obtained in a similar manner to Reference Example 5.

MS (ESI+) 560 (M + +1, 30%).

Reference Example 208

Methyl 2,2-difluoro-7-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

Using the compound of Reference Example 54 and bromodifluoroacetyl bromide, the title compound was obtained in a similar manner to Reference Example 55.

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

Reference Example 209

Methyl 4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2,2-difluoro-7-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

Using the compound of Reference Example 208, the title compound was obtained in a similar manner to Reference Example 3.

MS (ESI+) 435 (M + +1, 26%).

Reference Example 210

tert-Butyl 3-[{[4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2,2-difluoro-7-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 209, the title compound was obtained in a similar manner to Reference Example 5.

MS (ESI+) 645 (M + +1, 28%).

Reference Example 211

tert-Butyl 3-[{[4-(2-aminoethyl)-2,2-difluoro-7-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 210, the title compound was obtained in a similar manner to Reference Example 139.

MS (ESI+) 511 (M + +1, 34%).

Reference Example 212

tert-Butyl 3-[({2,2-difluoro-7-methyl-3-oxo-4-[2-(propionylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 211, the title compound was obtained in a similar manner to Reference Example 132.

MS (ESI+) 567 (M + +1, 13%).

Reference Example 213

Methyl 4-fluoro-2-(trifluoromethyl)benzoate

Using the compound of 4-fluoro-2-(trifluoromethyl)benzoic acid, the title compound was obtained in a similar manner to Reference Example 51.

MS (ESI+) 223 (M + +1, 100%).

Reference Example 214

Methyl 4-fluoro-5-nitro-2-(trifluoromethyl)benzoate

Methyl 4-fluoro-5-nitro-2-(trifluoromethyl)benzoate (8.31 g) was dissolved in con. sulfuric acid (8.5 ml), and thereto was added dropwise fuming nitric acid (15.7 ml) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Then, the mixture was warmed to 45° C., and stirred with heating. Ten hours later, the reaction solution was slowly added dropwise into ice-water (50 ml), and thereto was added ethyl acetate (50 ml), and stirred for 30 minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed successively with water, a saturated aqueous sodium hydrogen carbonate solution, 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 (the developing solvent: hexane/ethyl acetate=6/1, 4/1) to give the title compound (1.98 g) as a colorless liquid.

MS (ESI+) 268 (M + +1, 100%).

Reference Example 215

Benzyl (2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoate

(S)-3,3,3-Trifluoro-2-hydroxy-2-methylpropionic acid (1.00 g) was dissolved in tetrahydro-furan (10.0 ml), and thereto were added successively benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (3.64 g) and triethylamine (1.80 ml) under ice-cooling, and the mixture was stirred at room temperature. Ten hours later, to the reaction solution was added a 1N aqueous hydrochloric acid solution under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed successively 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 (the developing solvent: hexane/ethyl acetate=10/1, 5/1) to give the title compound (1.10 g) as a colorless liquid.

1 H NMR (400 MHz, CDCl 3 ) δ 7.43-7.27 (m, 5H), 5.32 (s, 2H), 3.82 (s, 1H), 1.61 (s, 3H).

Reference Example 216

Methyl 4-{(1R)-1-[(benzyloxy)carbonyl]-2,2,2-trifluoro-1-methylethoxy}-5-nitro-2-(trifluoromethyl)benzoate

Using the compounds of Reference Example 214 and Reference Example 215, the title compound was obtained in a similar manner to Reference Example 22.

MS (ESI+) 496 (M + +1, 8%).

Reference Example 217

Methyl (2R)-2-methyl-3-oxo-2,7-bis(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

Using the compound of Reference Example 216, the title compound was obtained in a similar manner to Reference Example 2.

MS (ESI−) 356 (M + −1, 100%).

Reference Example 218

Methyl (2R)-4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2-methyl-3-oxo-2,7-bis(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

Using the compound of Reference Example 217, the title compound was obtained in a similar manner to Reference Example 3.

MS (ESI+) 535 (M + +1, 60%).

Reference Example 219

tert-Butyl 3-[{[(2R)-4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2-methyl-3-oxo-2,7-bis(trifluoro-methyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 218, the title compound was obtained in a similar manner to Reference Example 5.

MS (ESI+) 745 (M + +1, 22%).

Reference Example 220

tert-Butyl 3-[{[(2R)-4-(2-aminoethyl)-2-methyl-3-oxo-2,7-bis(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 219, the title compound was obtained in a similar manner to Reference Example 139.

MS (ESI+) 611 (M + +1, 100%).

Reference Example 221

tert-Butyl 3-(isopropyl{[(2R)-2-methyl-3-oxo-4-[2-(propionylamino)ethyl]-2,7-bis(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}amino)piperidine-1-carboxylate

Using the compound of Reference Example 220, the title compound was obtained in a similar manner to Reference Example 132.

MS (ESI+) 667 (M + +1, 68%).

Reference Example 222

Ethyl (2R)-2-hydroxy-3-(4-methoxyphenyl)propanoate

Commercially available O-methyl-D-tyrosine (5.00 g) was dissolved in 1,4-dioxane (62.5 ml), and thereto were added successively dropwise an aqueous sulfuric acid solution (5.4 g/17.5 ml of water) and an aqueous sodium nitrite solution (6.3 g/15.0 ml of water) under ice-cooling, and the mixture was stirred at room temperature. Ten hours later, 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 chloride solution, dried over sodium hydrogen sulfate, filtered, and concentrated under reduced pressure. The resultant was duly dried, and then, the obtained residue was dissolved in ethanol (50 ml), and further thereto was added conc. sulfuric acid (200 μL). The mixture was refluxed for 15 hours, and the reaction solution was added dropwise into ice-water (50 ml), and the mixture was extracted with ethyl acetate (50 ml). The organic layer was washed successively 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 (the developing solvent: hexane/ethyl acetate=5/1) to give the title compound (3.40 g) as a colorless liquid.

MS (ESI+) 225 (M + +1, 33%).

Reference Example 223

Methyl 4-[(1S)-2-(benzyloxy)-1-(4-methoxybenzyl)-2-oxoethoxy]-5-nitro-2-(trifluoromethyl)benzoate

Using the compound of Reference Example 52, the title compound was obtained in a similar manner to Reference Example 26.

MS (ESI+) 472 (M + +1, 47%).

Reference Example 224

Methyl (2S)-2-(4-methoxybenzyl)-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

Using the compound of Reference Example 223, the title compound was obtained in a similar manner to Reference Example 2.

MS (ESI+) 396 (M + +1, 100%).

Reference Example 225

tert-Butyl 3-(isopropyl{[(2S)-2-(4-methoxybenzyl)-3-oxo-4-[2-(propionylamino)ethyl]-7-(trifluoro-methyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}amino)piperidine-1-carboxylate

Using the compound of Reference Example 224, the title compound was obtained in a similar manner to Reference Example 137.

MS (ESI+) 705 (M + +1, 15%).

Reference Example 226

Methyl 3-amino-5-chloro-4-hydroxybenzoate

Using methyl 3-chloro-4-hydroxybenzoate, the title compound was obtained in a similar manner to Reference Example 53.

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

Reference Example 227

Methyl 8-chloro-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

Using the compound of Reference Example 226, the title compound was obtained in a similar manner to Reference Example 55.

MS (ESI+) 270 (M + +1, 100%).

Reference Example 228

Methyl 8-chloro-4-(4-methoxybutyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

Using the compound of Reference Example 227, the title compound was obtained in a similar manner to Reference Example 3.

MS (ESI+) 356 (M + +1, 100%).

Reference Example 229

tert-Butyl (3R)-3-[{[8-chloro-4-(4-methoxybutyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 228, the title compound was obtained in a similar manner to Reference Example 5.

MS (ESI+) 566 (M + +1, 100%).

Reference Example 230

tert-Butyl (3R)-3-[{[7,8-dichloro-4-(4-methoxybutyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 229, the title compound was obtained in a similar manner to Reference Example 12.

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

Reference Example 231

tert-Butyl (3R)-3-[{[7-bromo-8-chloro-4-(4-methoxybutyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 230, the title compound was obtained in a similar manner to Reference Example 6.

MS (ESI+) 644 (M + +1, 100%).

Reference Example 232

2-Amino-4-bromo-6-fluorophenol

Using the compound of 4-bromo-2-fluoro-6-nitrophenol, the title compound was obtained in a similar manner to Reference Example 53.

MS (ESI+) 205 (M + +1, 100%).

Reference Example 233

6-Bromo-8-fluoro-2,2-dimethyl-2H-1,4-benzoxazin-3(4H)-one

Using the compound of Reference Example 232, the title compound was obtained in a similar manner to Reference Example 55.

MS (ESI+) 273 (M + +1, 100%).

Reference Example 234

6-Bromo-8-fluoro-4-(4-methoxybutyl)-2,2-dimethyl-2H-1,4-benzoxazin-3(4H)-one

Using the compound of Reference Example 233, the title compound was obtained in a similar manner to Reference Example 3.

MS (ESI+) 360 (M + +1, 100%).

Reference Example 235

Methyl 8-fluoro-4-(4-methoxybutyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

Using the compound of Reference Example 234, the title compound was obtained in a similar manner to Reference Example 25.

MS (ESI+) 340 (M + +1, 100%).

Reference Example 236

tert-Butyl (3R)-3-[{[8-fluoro-4-(4-methoxybutyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 235, the title compound was obtained in a similar manner to Reference Example 5.

MS (ESI+) 550 (M + +1, 100%).

Reference Example 237

Methyl 2-(4-bromo-3-methyl-2-nitrophenoxy)-2-methylpropanoate

Using the compound of 3-methyl-2-nitrophenol, the title compound was obtained in a similar manner to Reference Example 1 and Reference Example 6.

MS (ESI+) 332 (M + +1, 100%).

Reference Example 238

tert-Butyl (3R)-3-[{[2-[(dimethylamino)carbonyl]-4-(4-methoxybutyl)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 34, the title compound was obtained in a similar manner to Reference Example 197.

MS (ESI+) 589 (M + +1, 34%).

Reference Example 239

tert-Butyl (3R)-3-(isopropyl{[4-(4-methoxybutyl)-2-methyl-2-(morpholin-4-ylcarbonyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}amino)piperidine-1-carboxylate

Using the compound of Reference Example 34, the title compound was obtained in a similar manner to Reference Example 197.

MS (ESI+) 631 (M + +1, 32%).

Reference Example 240

tert-Butyl (3R)-3-{isopropyl[(4-(4-methoxybutyl)-2-methyl-2-{[methyl(tetrahydro-2H-pyran-4-ylmethyl)amino]carbonyl}-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl]amino}piperidine-1-carboxylate

Using the compound of Reference Example 34, the title compound was obtained in a similar manner to Reference Example 197 and Reference Example 200.

MS (ESI+) 673 (M + +1, 32%).

Reference Example 241

tert-Butyl (3R)-3-[{[7-chloro-2-[(dimethylamino)carbonyl]-4-(4-methoxybutyl)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 238, the title compound was obtained in a similar manner to Reference Example 12.

MS (ESI+) 623 (M + +1, 35%).

Reference Example 242

tert-Butyl (3R)-3-[{[7-chloro-4-(4-methoxybutyl)-2-methyl-2-(morpholin-4-ylcarbonyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 239, the title compound was obtained in a similar manner to Reference Example 12.

MS (ESI+) 665 (M + +1, 40%).

Reference Example 243

tert-Butyl (3R)-3-[[(7-chloro-4-(4-methoxybutyl)-2-methyl-2-{[methyl (tetrahydro-2H-pyran-4-ylmethyl)amino]carbonyl}-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl](isopropyl)amino]-piperidine-1-carboxylate

Using the compound of Reference Example 240, the title compound was obtained in a similar manner to Reference Example 12.

MS (ESI+) 707 (M + +1, 39%).

Reference Example 244

tert-Butyl (3R)-3-[{[7-chloro-4-(4-methoxybutyl)-2-(methoxymethyl)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 245, the title compound was obtained in a similar manner to Reference Example 12.

MS (ESI+) 596 (M + +1, 33%).

Reference Example 245

tert-Butyl (3R)-3-(isopropyl{[4-(4-methoxybutyl)-2-(methoxymethyl)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}amino)piperidine-1-carboxylate

Using the compound of Reference Example 35, the title compound was obtained in a similar manner to Reference Example 36.

MS (ESI+) 562 (M + +1, 42%).

Reference Example 246

tert-Butyl (3R)-3-[{[7-bromo-2-(ethoxymethyl)-4-(4-methoxybutyl)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 36, the title compound was obtained in a similar manner to Reference Example 6.

MS (ESI+) 654 (M + +1, 43%).

Reference Example 247

tert-Butyl (3R)-3-[{[2-(ethoxymethyl)-4-(4-methoxybutyl)-2,7-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 246, the title compound was obtained in a similar manner to Reference Example 10.

MS (ESI+) 590 (M + +1, 43%).

Reference Example 248

Ethyl 6-bromo-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylate

Using 4-bromo-2-nitrophenol, the title compound was obtained in a similar manner to Reference Example 33.

MS (ESI+) 313 (M + +1, 76%).

Reference Example 249

Ethyl 6-bromo-4-(3-methoxyl)propyl)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylate

Using the compound of Reference Example 248, the title compound was obtained in a similar manner to Reference Example 5.

MS (ESI+) 386 (M + +1, 87%).

Reference Example 250

6-Bromo-4-(3-methoxypropyl)-N,N,2-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxamide

Using the compound of Reference Example 249, the title compound was obtained in a similar manner to Reference Example 34 and Reference Example 197.

MS (ESI+) 385 (M + +1, 72%).

Reference Example 251

Methyl 2-[(dimethylamino)carbonyl]-4-(3-methoxypropyl)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

Using the compound of Reference Example 250, the title compound was obtained in a similar manner to Reference Example 25.

MS (ESI+) 365 (M + +1, 76%).

Reference Example 252

tert-Butyl (3R)-3-[{[2-[(dimethylamino)carbonyl]-4-(3-methoxypropyl)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 251, the title compound was obtained in a similar manner to Reference Example 5.

MS (ESI+) 575 (M + +1, 38%).

Reference Example 253

6-Bromo-2′,3′,5′,6′-tetrahydrospiro[1,4-benzoxazine-2,4′-pyran]-3(4H)-one

To a solution of 4-bromo-2-nitrophenol (5.0 g) in tetrahydrofuran (80 ml) was added sodium hydroxide powder (7.8 g), and the mixture was stirred at room temperature for 15 minutes, and further thereto was added tetrahydro-4H-pyran-4-one (180 ml). Under ice-cooling, chloroform (7.3 ml) was added thereto dropwise, and the mixture was stirred for one hour. Then, the mixture was further stirred at room temperature overnight. To the reaction mixture was added 2N hydrochloric acid, 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. Using the obtained residue, the title compound (1.6 g) was obtained in a similar manner to Reference Example 2.

MS (ESI+) 298 (M + +1, 85%).

Reference Example 254

Methyl 4-(4-methoxybutyl)-3-oxo-2′,3,3′,4,5′,6′-hexahydrospiro[1,4-benzoxazine-2,4′-pyran]-6-carboxylate

Using the compound of Reference Example 253, the title compound was obtained in a similar manner to Reference Example 25.

MS (ESI+) 364 (M + +1, 86%).

Reference Example 255

tert-Butyl (3R)-3-(isopropyl{[4-(4-methoxybutyl)-3-oxo-2′,3,3′,4,5′,6′-hexahydrospiro[1,4-benzoxazine-2,4′-pyran]-6-yl]carbonyl}amino)piperidine-1-carboxylate

Using the compound of Reference Example 254, the title compound was obtained in a similar manner to Reference Example 5.

MS (ESI+) 574 (M + +1, 34%).

Reference Example 256

tert-Butyl (3R)-3-[{[7-bromo-4-(4-methoxybutyl)-3-oxo-2′,3,3′,4,5′,6′-hexahydrospiro[1,4-benzoxazine-2,4′-pyran]-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 255, the title compound was obtained in a similar manner to Reference Example 6.

MS (ESI+) 652 (M + +1, 33%).

Reference Example 257

tert-Butyl (3R)-3-(isopropyl{[4-(4-methoxybutyl)-7-methyl-3-oxo-2′,3,3′,4,5′,6′-hexahydrospiro[1,4-benzoxazine-2,4′-pyran]-6-yl]carbonyl}amino)piperidine-1-carboxylate

Using the compound of Reference Example 256, the title compound was obtained in a similar manner to Reference Example 10.

MS (ESI+) 588 (M + +1, 100%).

Reference Example 258

tert-Butyl (3R)-3-[{[7-chloro-4-(4-methoxybutyl)-3-oxo-2′,3,3′,4,5′,6′-hexahydrospiro[1,4-benzoxazine-2,4′-pyran]-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 255, the title compound was obtained in a similar manner to Reference Example 12.

MS (ESI+) 608 (M + +1, 100%).

Reference Example 259

Methyl [2-(6-bromo-3-oxo-2′,3′,5′,6′-tetrahydrospiro[1,4-benzoxazine-2,4′-pyran]-4(3H)-yl)ethyl]-carbamate

Using the compound of Reference Example 253, the title compound was obtained in a similar manner to Reference Example 162.

MS (ESI+) 399 (M + +1, 65%).

Reference Example 260

Methyl 4-{2-[(methoxycarbonyl)amino]ethyl}-3-oxo-2′,3,3′,4,5′,6′-hexahydrospiro[1,4-benzoxazine-2,4′-pyran]-6-carboxylate

Using the compound of Reference Example 259, the title compound was obtained in a similar manner to Reference Example 25.

MS (ESI+) 379 (M + +1, 67%).

Reference Example 261

tert-Butyl (3R)-3-{isopropyl[(4-{2-[(methoxycarbonyl)amino]ethyl}-3-oxo-2′,3,3′,4,5′,6′-hexahydro-spiro[1,4-benzoxazine-2,4′-pyran]-6-yl)carbonyl]amino}piperidine-1-carboxylate

Using the compound of Reference Example 260, the title compound was obtained in a similar manner to Reference Example 5.

MS (ESI+) 589 (M + +1, 33%).

Reference Example 262

tert-Butyl (3R)-3-[[(7-bromo-4-{2-[(methoxycarbonyl)amino]ethyl}-3-oxo-2′,3,3′,4,5′,6′-hexahydro-spiro[1,4-benzoxazine-2,4′-pyran]-6-yl)carbonyl](isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 261, the title compound was obtained in a similar manner to Reference Example 6.

MS (ESI+) 667 (M + +1, 42%).

Reference Example 263

tert-Butyl (3R)-3-{isopropyl[(4-{2-[(methoxycarbonyl)amino]ethyl}-7-methyl-3-oxo-2′,3,3′,4,5′,6′-hexahydrospiro[1,4-benzoxazine-2,4′-pyran]-6-yl)carbonyl]amino}piperidine-1-carboxylate

Using the compound of Reference Example 262, the title compound was obtained in a similar manner to Reference Example 10.

MS (ESI+) 603 (M + +1, 46%).

Reference Example 264

tert-Butyl (3R)-3-[(4-acetoxy-2-methyl-5-nitrobenzoyl)(isopropyl)amino]piperidine-1-carboxylate

Using 4-hydroxy-2-methyl-5-nitrobenzoic acid, the title compound was obtained in a similar manner to Reference Example 31.

MS (ESI+) 422 (M + +1, 12%).

Reference Example 265

Diethyl (4-{[[(3R)-1-(tert-butoxycarbonyl)piperidin-3-yl](isopropyl)amino]carbonyl}-5-methyl-2-nitrophenoxy)(methyl)malonate

Using the compound of Reference Example 264, the title compound was obtained in a similar manner to Reference Example 32.

MS (ESI+) 594 (M + +1, 25%).

Reference Example 266

Ethyl 6-{[[(3R)-1-(tert-butoxycarbonyl)piperidin-3-yl](isopropyl)amino]carbonyl}-4-(4-methoxybutyl)-2,7-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylate

Using the compound of Reference Example 265, the title compound was obtained in a similar manner to Reference Example 33.

MS (ESI+) 604 (M + +1, 32%).

Reference Example 267

6-{[[(3R)-1-(tert-Butoxycarbonyl)piperidin-3-yl](isopropyl)amino]carbonyl}-4-(4-methoxybutyl)-2,7-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid

Using the compound of Reference Example 266, the title compound was obtained in a similar manner to Reference Example 34.

MS (ESI+) 576 (M + +1, 46%).

Reference Example 268

tert-Butyl (3R)-3-[{[2-(hydroxymethyl)-4-(4-methoxybutyl)-2,7-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 267, the title compound was obtained in a similar manner to Reference Example 35.

MS (ESI+) 562 (M + +1, 43%).

Reference Example 269

tert-Butyl (3R)-3-(isopropyl{[4-(4-methoxybutyl)-2-(methoxymethyl)-2,7-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}amino)piperidine-1-carboxylate

Using the compound of Reference Example 268, the title compound was obtained in a similar manner to Reference Example 36.

MS (ESI+) 576 (M + +1, 28%).

Reference Example 270

tert-Butyl (3R)-3-[{[2-({[(ethylamino)carbonyl]oxy}methyl)-4-(4-methoxybutyl)-2,7-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

To a solution of tert-butyl (3R)-3-[{[2-(hydroxymethyl)-4-(4-methoxybutyl)-2,7-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate (66 mg) in tetrahydrofuran (1 ml) was added ethyl isocyanate (83 mg), and the mixture was stirred at 60° C. for 4 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (65 mg).

MS (ESI+) 633 (M + +1, 29%).

Reference Example 271

tert-Butyl (3R)-3-{isopropyl[(4-(4-methoxybutyl)-2,7-dimethyl-3-oxo-2-{[(pyrrolidin-1-ylcarbonyl)oxy]methyl}-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl]amino}piperidine-1-carboxylate

To a solution of tert-butyl (3R)-3-[{[2-(hydroxymethyl)-4-(4-methoxybutyl)-2,7-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate (60 mg), N,N′-carbonyldiimidazole (20 mg) in tetrahydrofuran (1 ml) was added diisopropylethylamine (95 μl), and the mixture was stirred at room temperature for one hour. To the reaction mixture was added pyrrolidine (10 μl), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and 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) to give the title compound (59 mg).

MS (ESI+) 659 (M + +1, 31%).

Reference Example 272

tert-Butyl (3R)-3-[isopropyl({4-(4-methoxybutyl)-2,7-dimethyl-3-oxo-2-[({[(tetrahydro-2H-pyran-4-ylmethyl)amino]carbonyl}oxy)methyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)amino]-piperidine-1-carboxylate

Using the compound of Reference Example 268, the title compound was obtained in a similar manner to Reference Example 271.

MS (ESI+) 703 (M + +1, 28%).

Reference Example 273

tert-Butyl (3R)-3-(isopropyl{[4-(4-methoxybutyl)-2-(methoxymethyl)-2-methyl-3-oxo-7-(trifluoro-methyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}amino)piperidine-1-carboxylate

Using the compound of Reference Example 52, the title compound was obtained in a similar manner to Reference Example 36.

MS (ESI+) 630 (M + +1, 30%).

Reference Example 274

2-Bromo-5-(methoxymethoxy)benzaldehyde

To a solution of 2-bromo-5-hydroxybenzaldehyde (4.4 g) in tetrahydrofuran (100 ml) were added sodium hydride (1.2 g) and chloromethyl methyl ether (2.1 ml), and the mixture was stirred at room temperature overnight. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and 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) to give the title compound (1.84 g).

MS (ESI+) 265 (M + +1, 31%).

Reference Example 275

6-Bromo-2-fluoro-3-(methoxymethoxy)benzaldehyde

A solution of diisopropylamine (364 μl) in tetrahydrofuran (1 ml) was cooled to −78° C., and thereto was added dropwise n-butyl lithium (0.86 ml, 2.77M hexane solution), and the mixture was stirred at 0° C. for 10 minutes. The reaction mixture was cooled to −78° C., and thereto was added dropwise a solution of 1-bromo-3-fluoro-4-(methoxymethoxy)benzene (470 mg) in tetrahydrofuran (1 ml), and the mixture was stirred for 30 minutes. To the mixture was added dropwise N,N-dimethyl-formamide (210 μl), and the mixture was stirred at room temperature for one hour. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate, 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) to give the title compound (48 mg).

MS (ESI+) 265 (M + +1, 35%).

Reference Example 276

1-Bromo-2-(difluoromethyl)-4-(methoxymethoxy)benzene

To a solution of 2-bromo-5-(methoxymethoxy)benzaldehyde (450 mg) in dichloromethane (5 ml) was added under ice-cooling diethylaminosulfur trifluoride (485 μl), and the mixture was stirred at room temperature overnight. 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) to give the title compound (370 mg).

MS (ESI+) 265 (M + +1, 78%).

Reference Example 277

1-Bromo-2-(difluoromethyl)-3-fluoro-4-(methoxymethoxy)benzene

Using the compound of Reference Example 275, the title compound was obtained in a similar manner to Reference Example 276.

MS (ESI+) 265 (M + +1, 89%).

Reference Example 278

Methyl 2-(difluoromethyl)-4-(methoxymethoxy)benzoate

Using the compound of Reference Example 276, the title compound was obtained in a similar manner to Reference Example 25.

MS (ESI+) 247 (M + +1, 79%).

Reference Example 279

Methyl 2-(difluoromethyl)-3-fluoro-4-(methoxymethoxy)benzoate

Using the compound of Reference Example 277, the title compound was obtained in a similar manner to Reference Example 25.

MS (ESI+) 265 (M + +1, 78%).

Reference Example 280

Methyl 2-(difluoromethyl)-4-hydroxybenzoate

To methyl 2-(difluoromethyl)-4-(methoxymethoxy)benzoate (720 mg) were added 2N hydrochloric acid (6 ml) and ethanol (6 ml), and the mixture was stirred at 80° C. for 3 hours. The mixture was cooled to room temperature, and water was added thereto, and extracted with ethyl acetate. To the extract was added a saturated aqueous sodium chloride solution, and the mixture was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (500 mg).

MS (ESI+) 203 (M + +1, 22%).

Reference Example 281

Methyl 2-(difluoromethyl)-3-fluoro-4-hydroxybenzoate

Using the compound of Reference Example 279, the title compound was obtained in a similar manner to Reference Example 280.

MS (ESI+) 221 (M + +1, 18%).

Reference Example 282

tert-Butyl (3R)-3-[{[7-(difluoromethyl)-4-(4-methoxybutyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 280, the title compound was obtained in a similar manner to Reference Example 55, Reference Example 3 and Reference Example 5.

MS (ESI+) 582 (M + +1, 35%).

Reference Example 283

tert-Butyl (3R)-3-[{[7-(difluoromethyl)-8-fluoro-4-(4-methoxybutyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 281, the title compound was obtained in a similar manner to Reference Example 55, Reference Example 3 and Reference Example 5.

MS (ESI+) 600 (M + +1, 34%).

Reference Example 284

tert-Butyl (3R)-3-[[4-(benzyloxy)-5-nitro-2-(trifluoromethyl)benzoyl](isopropyl)amino]piperidine-1-carboxylate

Methyl 4-hydroxy-5-nitro-2-(trifluoromethyl)benzoate (3.0 g) was dissolved in N,N-dimethyl-formamide (50 ml), and thereto were added benzyl bromide (2.3 g) and potassium carbonate (2.3 g), and the mixture was stirred at 80° C. for 6 hours. The reaction mixture was cooled, and water was added thereto. The mixture was extracted with ethyl acetate, and the organic layer was washed twice with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (the developing solvent: hexane/ethyl acetate=8:1→5:1→3:1) to give methyl 4-(benzyloxy)-5-nitro-2-(trifluoromethyl)benzoate (2.1 g), which was treated in a similar manner to Reference Example 5 to give the title compound (1.9 g).

MS (ESI+) 566 (M + +1, 37%).

Reference Example 285

tert-Butyl (3R)-3-[[5-amino-4-hydroxy-2-(trifluoromethyl)benzoyl](isopropyl)amino]piperidine-1-carboxylate

The compound of Reference Example 284 (1.9 g) was dissolved in methanol (30 ml), and thereto was added a 20% palladium hydroxide carbon (600 mg) under ice-cooling. Then, the mixture was stirred at room temperature for 8 hours under hydrogen atmosphere. The reaction mixture was filtered on celite, and the filtrate was concentrated under reduced pressure to give the title compound (1.3 g) as amorphous.

MS (ESI+) 446 (M + +1, 34%).

Reference Example 286

tert-Butyl (3R)-3-[(5-amino-4-hydroxy-2-methylbenzoyl)(isopropyl)amino]piperidine-1-carboxylate

Using methyl 4-hydroxy-2-methyl-5-nitrobenzoate, the title compound was obtained in a similar manner to Reference Example 284.

MS (ESI+) 392 (M + +1, 93%).

Reference Example 287

Methyl 7-methyl-3-oxo-3,4-dihydrospiro[1,4-benzoxazine-2,1′-cyclohexane]-6-carboxylate

Using the compound of Reference Example 54 and 1-bromocyclohexanecarbonyl chloride, the title compound was obtained in a similar manner to Reference Example 55.

MS (ESI+) 290 (M + +1, 100%).

Reference Example 288

Methyl 4-(2-{[(benzoyloxy)carbonyl]amino}ethyl)-7-methyl-3-oxo-3,4-dihydrospiro[1,4-benzoxazine-2,1′-cyclohexane]-6-carboxylate

Using the compound of Reference Example 287, the title compound was obtained in a similar manner to Reference Example 3.

MS (ESI+) 467 (M + +1, 100%).

Reference Example 289

tert-Butyl (3R)-3-[{[4-(2-{[(benzoyloxy)carbonyl]amino}ethyl)-7-methyl-3-oxo-3,4-dihydrospiro[1,4-benzoxazine-2,1′-cyclohexan]-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 288, the title compound was obtained in a similar manner to Reference Example 5.

MS (ESI+) 677 (M + +1, 43%).

Reference Example 290

tert-Butyl (3R)-3-[isopropyl({7-methyl-3-oxo-4-[2-(propionylamino)ethyl]-3,4-dihydrospiro[1,4-benzoxazine-2,1′-cyclohexan]-6-yl}carbonyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 289, the title compound was obtained in a similar manner to Reference Example 132.

MS (ESI+) 599 (M + +1, 30%).

Reference Example 291

tert-Butyl (3R)-3-{isopropyl[(7-methyl-3-oxo-3,4-dihydrospiro[1,4-benzoxazine-2,1′-cyclobutan]-6-yl)carbonyl]amino}piperidine-1-carboxylate

Using the compound of Reference Example 286 and 1-bromocyclobutanecarbonyl chloride, the title compound was obtained in a similar manner to Reference Example 55.

MS (ESI+) 472 (M + +1, 30%).

Reference Example 292

tert-Butyl (3R)-3-(isopropyl{[3-oxo-7-(trifluoromethyl)-3,4-dihydrospiro[1,4-benzoxazine-2,1′-cyclobutan]-6-yl]carbonyl}amino)piperidine-1-carboxylate

Using the compound of Reference Example 285 and 1-bromocyclobutanecarbonyl chloride, the title compound was obtained in a similar manner to Reference Example 55.

MS (ESI+) 526 (M + +1, 31%).

Reference Example 293

tert-Butyl (3R)-3-(isopropyl{[3-oxo-7-(trifluoromethyl)-3,4-dihydrospiro[1,4-benzoxazine-2,1′-cyclopentan]-6-yl]carbonyl}amino)piperidine-1-carboxylate

Using the compound of Reference Example 285 and 1-bromocyclopentanecarbonyl chloride, the title compound was obtained in a similar manner to Reference Example 55.

MS (ESI+) 540 (M + +1, 31%).

Reference Example 294

tert-Butyl (3R)-3-[{[4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-7-methyl-3-oxo-3,4-dihydrospiro[1,4-benzoxazine-2,1′-cyclobutan]-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 291, the title compound was obtained in a similar manner to Reference Example 3.

MS (ESI+) 649 (M + +1, 40%).

Reference Example 295

tert-Butyl (3R)-3-[{[4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-3-oxo-7-(trifluoromethyl)-3,4-dihydrospiro[1,4-benzoxazine-2,1′-cyclobutan]-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 292, the title compound was obtained in a similar manner to Reference Example 3.

MS (ESI+) 703 (M + +1, 39%).

Reference Example 296

tert-Butyl (3R)-3-[{[4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-7-methyl-3-oxo-3,4-dihydrospiro[1,4-benzoxazine-2,1′-cyclopentan]-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 293, the title compound was obtained in a similar manner to Reference Example 3.

MS (ESI+) 717 (M + +1, 30%).

Reference Example 297

tert-Butyl (3R)-3-(isopropyl{[4-{2-[(methoxycarbonyl)amino]ethyl}-3-oxo-7-(trifluoromethyl)-3,4-dihydrospiro[1,4-benzoxazine-2,1′-cyclobutan]-6-yl]carbonyl}amino)piperidine-1-carboxylate

Using the compound of Reference Example 292, the title compound was obtained in a similar manner to Reference Example 162.

MS (ESI+) 627 (M + +1, 30%).

Reference Example 298

tert-Butyl (3R)-3-[isopropyl({7-methyl-3-oxo-4-[2-(propionylamino)ethyl]-3,4-dihydrospiro[1,4-benzoxazine-2,1′-cyclobutan]-6-yl}carbonyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 294, the title compound was obtained in a similar manner to Reference Example 132.

MS (ESI+) 571 (M + +1, 31%).

Reference Example 299

tert-Butyl (3R)-3-(isopropyl{[3-oxo-4-[2-(propionylamino)ethyl]-7-(trifluoromethyl)-3,4-dihydro-spiro[1,4-benzoxazine-2,1′-cyclobutan]-6-yl]carbonyl}amino)piperidine-1-carboxylate

Using the compound of Reference Example 295, the title compound was obtained in a similar manner to Reference Example 132.

MS (ESI+) 625 (M + +1, 32%).

Reference Example 300

tert-Butyl (3R)-3-(isopropyl{[3-oxo-4-[2-(propionylamino)ethyl]-7-(trifluoromethyl)-3,4-dihydro-spiro[1,4-benzoxazine-2,1′-cyclopentan]-6-yl]carbonyl}amino)piperidine-1-carboxylate

Using the compound of Reference Example 296, the title compound was obtained in a similar manner to Reference Example 132.

MS (ESI+) 639 (M + +1, 43%).

Reference Example 301

tert-Butyl (3R)-3-({[2,2-dimethyl-3-oxo-4-[2-(propionylamino)ethyl]-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}amino)piperidine-1-carboxylate

Using the compound of Reference Example 74, the title compound was obtained in a similar manner to Reference Example 5 and Reference Example 132.

MS (ESI+) 571 (M + +1, 38%).

Reference Example 302

tert-Butyl (3R)-3-[{[2,2-dimethyl-3-oxo-4-[2-(propionylamino)ethyl]-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(ethyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 74, the title compound was obtained in a similar manner to Reference Example 5 and Reference Example 132.

MS (ESI+) 599 (M + +1, 38%).

Reference Example 303

tert-Butyl (3R)-3-(sec-butyl {[2,2-dimethyl-3-oxo-4-[2-(propionylamino)ethyl]-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}amino)piperidine-1-carboxylate

Using the compound of Reference Example 74, the title compound was obtained in a similar manner to Reference Example 5 and Reference Example 132.

MS (ESI+) 627 (M + +1, 40%).

Reference Example 304

tert-Butyl (3R)-3-(benzyl{[2,2-dimethyl-3-oxo-4-[2-(propionylamino)ethyl]-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}amino)piperidine-1-carboxylate

Using the compound of Reference Example 74, the title compound was obtained in a similar manner to Reference Example 5 and Reference Example 132.

MS (ESI+) 661 (M + +1, 31%).

Reference Example 305

Ethyl [(2R,5R)-5-(isopropylamino)-1-(4-methoxybenzyl)piperidin-2-yl]acetate

Ethyl [(2R,5R)-5-(tert-butoxycarbonyl)amino]-1-(4-methoxybenzyl)piperidin-2-yl]acetate (20.0 g) and 4N hydrochloric acid-dioxane solution (200 ml) were mixed, and the mixture was stirred at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure, and to the obtained residue was poured diluted aqueous sodium hydroxide solution in order to adjust the pH value to pH 10, and then the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure to give ethyl [(2R,5R)-5-amino]-(4-methoxybenzyl)piperidin-2-yl]acetate (16.3 g) as a pale brown oil. This compound was dissolved in chloroform (100 ml), and thereto were added acetone (14.4 mL), acetic acid (8.5 mL) and molecular sieve 4 Å (16 g), and the mixture was stirred at room temperature for one hour. To this reaction mixture was added sodium triacetoxyborohydride (20.9 g), and the mixture was stirred at room temperature for 14 hours. To this reaction mixture was added ice-cold diluted aqueous sodium hydroxide solution, and the insoluble materials were removed by filtration, and the filtrate was extracted with chloroform. The organic layer was dried over magnesium sulfate, and the solvent was concentrated under reduced pressure to give the title compound (16.2 g) as a pale yellow oil.

MS (ESI+) 349(M + +1, 85%).

Reference Example 306

tert-Butyl (2R,5R)-2-(2-ethoxy-2-oxoethyl)-5-(isopropylamino)piperidine-1-carboxylate

To a solution of ethyl [(2R,5R)-5-(isopropylamino)-1-(4-methoxybenzyl)piperidin-2-yl]acetate (10.0 g) in ethanol (200 mL) were added Boc 2 O (14.2 g) and 10% palladium carbon (20 g), and the mixture was stirred at room temperature for 3 hours under hydrogen atmosphere. Boc 2 O (7.1 g) was added thereto, and the mixture was further stirred for 3 hours. The insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography to give the title compound (6.4 g) as a colorless oil.

MS (ESI+) 329(M + +1, 40%).

Reference Example 307

tert-Butyl (2R,5R)-5-[[(benzyloxy)carbonyl](isopropyl)amino]-2-(2-ethoxy-2-oxoethyl)piperidine-1-carboxylate

To a solution of tert-butyl (2R,5R)-2-(2-ethoxy-2-oxoethyl)-5-(isopropylamino)piperidine-1-carboxylate (6.0 g) in dichloromethane (200 mL) was added diisopropylethylamine (19.1 mL), and thereto was further added dropwise under ice-cooling Z—Cl (13.0 mL) over a period of one hour. The mixture was stirred at room temperature for one hour, and then, the reaction solution was diluted with chloroform. The mixture was washed successively with an ice-cold aqueous potassium hydrogen sulfate solution and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography to give the title compound (8.9 g) as a pale brown oil.

MS (ESI+) 463 (M + +1, 50%).

Reference Example 308

[(2R,5R)-5-[[(Benzyloxy)carbonyl](isopropyl)amino]-1-(tert-butoxycarbonyl)piperidin-2-yl]acetic acid

To a solution of tert-butyl (2R,5R)-5-[[(benzyloxy)carbonyl](isopropyl)amino]-2-(2-ethoxy-2-oxoethyl)piperidine-1-carboxylate (8.5 g) in ethanol (100 mL) was added a 2N aqueous sodium hydroxide solution (50 mL), and the mixture was stirred at 50° C. for one hour. The reaction solution was cooled with ice, and thereto was added an aqueous potassium hydrogen sulfate solution in order to adjust the pH value to pH 3. The mixture was extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (6.0 g) as a colorless solid.

MS (ESI+) 435 (M + +1, 7%).

Reference Example 309

tert-Butyl (2R,5R)-5-[[(benzyloxy)carbonyl](isopropyl)amino]-2-(hydroxyethyl)piperidine-1-carboxylate

To a solution of [(2R,5R)-5-[[(benzyloxy)carbonyl](isopropyl)amino]-1-(tert-butoxycarbonyl)-piperidin-2-yl]acetic acid (8.0 g) in tetrahydrofuran (100 mL) was added triethylamine (7.7 mL), and thereto was added ethyl chloroformate (3.5 mL) under ice-cooling. After the mixture was stirred under ice-cooling for one hour, the insoluble materials were removed by filtration. To the filtrate was added dropwise a solution of sodium borohydride (3.5 g) in water (30 mL) under ice-cooling with stirring. Then, the mixture was stirred at room temperature for one hour. To the mixture was added an aqueous potassium hydrogen sulfate solution under ice-cooling, the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography to give the title compound (6.7 g) as a colorless oil.

MS (ESI+) 421 (M + +1, 32%).

Reference Example 310

tert-Butyl (2R,5R)-5-[[(benzyloxy)carbonyl](isopropyl)amino]-2-(methoxyethyl)piperidine-1-carboxylate

To a solution of tert-butyl (2R,5R)-5-[[(benzyloxy)carbonyl](isopropyl)amino]-2-(hydroxy-ethyl)piperidine-1-carboxylate (2.10 g) in tetrahydrofuran (10 mL) was added methyl iodide (1.42 g), and the mixture was stirred. To the mixture was added 55% sodium hydride (300 mg) under ice-cooling, and the mixture was stirred at room temperature for 19 hours. To the reaction solution was added a saturated aqueous ammonium chloride solution (5 ml), and the mixture was extracted with ethyl acetate (50 ml). The organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (the developing solvent: hexane/ethyl acetate=4/1) to give the title compound (2.15 g).

MS (ESI+) 435 (M + +1, 100%).

Reference Example 311

tert-Butyl (2R,5R)-5-[[(benzyloxy)carbonyl](isopropyl)amino]-2-(2-{[tert-butyl(diphenyl)silyl]oxy}-ethyl)piperidine-1-carboxylate

To a solution of tert-butyl (2R,5R)-5-[[(benzyloxy)carbonyl](isopropyl)amino]-2-(hydroxy-ethyl)piperidine-1-carboxylate (2.93 g) in methylene chloride (35 ml) were added tert-butyl diphenyl-chlorosilane (2.30 g) and imidazole (569 mg), and the mixture was stirred at room temperature for 4 hours. To the mixture was added a saturated aqueous sodium hydrogen carbonate solution (10 ml), and the mixture was extracted with chloroform (100 ml). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (the developing solvent: hexane/ethyl acetate=12/1) to give the title compound (4.42 g).

MS (ESI+) 659 (M + +1, 100%).

Reference Example 312

tert-Butyl (2R,5R)-5-[[(benzyloxy)carbonyl](isopropyl)amino]-2-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)piperidine-1-carboxylate

To a solution of tert-butyl (2R,5R)-5-[[(benzyloxy)carbonyl](isopropyl)amino]-2-(methoxy-ethyl)piperidine-1-carboxylate (2.15 g) in methanol (25 ml) was added 10% palladium carbon (1.05 g), and the mixture was stirred at room temperature for 3 hours under hydrogen atmosphere. The insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (1.35 g) as a pale yellow oil.

MS (ESI+) 301 (M + +1, 100%).

Reference Example 313

tert-Butyl (2R,5R)-2-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-(isopropylamino)piperidine-1-carboxylate

Using the compound of Reference Example 311, the title compound was obtained in a similar manner to Reference Example 312.

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

Reference Example 314

tert-Butyl (2R,5R)-5-[{[4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2,2-dimethyl-3-oxo-7-(trifluoro-methyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropylamino)-2-(2-methoxyethyl)-piperidine-1-carboxylate

Using the compound of Reference Example 74, the title compound was obtained in a similar manner to Reference Example 5.

MS (ESI+) 749 (M + +1, 100%).

Reference Example 315

tert-Butyl (2R,5R)-5-[{[4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2,2-dimethyl-3-oxo-7-(trifluoro-methyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropylamino)-2-(2-{[tert-butyl(diphenyl)-silyl]oxy}ethyl)-piperidine-1-carboxylate

Using the compound of Reference Example 74, the title compound was obtained in a similar manner to Reference Example 5.

MS (ESI+) 974 (M + +1, 100%).

Reference Example 316

tert-Butyl (2R,5R)-5-[{[4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropylamino)-2-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-piperidine-1-carboxylate

Using the compound of Reference Example 73, the title compound was obtained in a similar manner to Reference Example 5.

MS (ESI+) 920 (M + +1, 61%).

Reference Example 317

tert-Butyl (2R,5R)-5-[{[4-(2-aminoethyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropylamino)-2-(2-methoxyethyl)-piperidine-1-carboxylate

Using the compound of Reference Example 314, the title compound was obtained in a similar manner to Reference Example 139.

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

Reference Example 318

tert-Butyl (2R,5R)-5-[{[4-(2-aminoethyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropylamino)-2-(2-{[tert-butyl (diphenyl)silyl]oxy}ethyl)-piperidine-1-carboxylate

Using the compound of Reference Example 315, the title compound was obtained in a similar manner to Reference Example 139.

MS (ESI+) 840 (M + +1, 100%).

Reference Example 319

tert-Butyl (2R,5R)-5-[{[(4-(2-aminoethyl)-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropylamino)-2-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-piperidine-1-carboxylate

Using the compound of Reference Example 316, the title compound was obtained in a similar manner to Reference Example 139.

MS (ESI+) 786 (M + +1, 100%).

Reference Example 320

tert-Butyl (2R,5R)-5-[{[4-{2-[(difluoroacetyl)amino]ethyl}-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropylamino)-2-(2-methoxyethyl)-piperidine-1-carboxylate

Using the compound of Reference Example 317, the title compound was obtained in a similar manner to Reference Example 120.

MS (ESI+) 693 (M + +1, 100%).

Reference Example 321

tert-Butyl (2R,5R)-2-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-[{[4-{2-[(difluoroacetyl)amino]ethyl}-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl-amino)-piperidine-1-carboxylate

Using the compound of Reference Example 318, the title compound was obtained in a similar manner to Reference Example 120.

MS (ESI+) 918 (M + +1, 68%).

Reference Example 322

tert-Butyl (2R,5R)-2-(2-{[tert-butyl (diphenyl)silyl]oxy}ethyl)-5-[[(4-{2-[(difluoroacetyl)amino]ethyl}-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl](isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 319, the title compound was obtained in a similar manner to Reference Example 120.

MS (ESI+) 864 (M + +1, 43%).

Reference Example 323

tert-Butyl (2R,5R)-5-[{[4-{2-[(difluoroacetyl)amino]ethyl}-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]-2-(2-hydroxyethyl)piperidine-1-carboxylate

To a solution of tert-butyl (2R,5R)-2-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-[{[4-{2-[(difluoroacetyl)amino]ethyl}-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropylamino)-piperidine-1-carboxylate (1.48 g) in tetrahydrofuran (10 ml) was added a solution of 1N tetrabutylammonium fluoride in tetrahydrofuran (3.55 ml), and the mixture was stirred at room temperature for 2 hours. To the mixture was added a saturated aqueous sodium chloride solution (5 ml), and the mixture was extracted with ethyl acetate (50 ml). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (the developing solvent: hexane/acetone=2/1) to give the title compound (1.1 g).

MS (ESI+) 679 (M + +1, 100%).

Reference Example 324

tert-Butyl (2R,5R)-5-[[(4-{2-[(difluoroacetyl)amino]ethyl}-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl](isopropyl)amino]-2-(2-hydroxyethyl)piperidine-1-carboxylate

Using the compound of Reference Example 322, the title compound was obtained in a similar manner to Reference Example 323.

MS (ESI+) 626 (M + +1, 48%).

Reference Example 325

tert-Butyl (2R,5R)-5-[{[4-{2-[(difluoroacetyl)amino]ethyl}-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]-2-(2-oxoethyl)piperidine-1-carboxylate

Under the nitrogen atmosphere, to a solution of tert-butyl (2R,5R)-5-[{[4-{2-[(difluoroacetyl)-amino]ethyl}-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}-(isopropyl)amino]-2-(2-hydroxyethyl)piperidine-1-carboxylate (1.1 g) in methylene chloride -acetonitrile (5 ml, 5 ml) were added N-methylmorpholine oxide (283 mg) and molecular sieve 4 Å (750 mg), and the mixture was stirred at room temperature for a while. Then, tetrapropylammonium perruthenate (56 mg) was added thereto, and the mixture was stirred at room temperature for 3 hours. Then, the insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (the developing solvent: hexane/acetone=2/1) to give the title compound (757 mg).

MS (ESI+) 677 (M + +1, 100%).

Reference Example 326

tert-Butyl (2R,5R)-5-[[(4-{2-[(difluoroacetyl)amino]ethyl}-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl](isopropyl)amino]-2-(2-oxoethyl)piperidine-1-carboxylate

Using the compound of Reference Example 324, the title compound was obtained in a similar manner to Reference Example 325.

MS (ESI+) 624 (M + +1, 11%).

Reference Example 327

tert-Butyl (2R,5R)-5-[{[4-{2-[(difluoroacetyl)amino]ethyl}-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]-2-{2-[(2,2,2-trifluoroethyl)-amino]ethyl}piperidine-1-carboxylate

To a solution of tert-butyl (2R,5R)-5-[{[4-{2-[(difluoroacetyl)amino]ethyl}-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]-2-(2-oxoethyl)piperidine-1-carboxylate (377 mg) in ethanol (3 ml) were added 2,2,2-trifluoroethylamine hydrochloride (227 mg), acetic acid (128 μl), sodium triacetoxyborohydride (367 mg), and the mixture was stirred at room temperature for 19 hours. To the reaction solution was added a saturated aqueous sodium hydrogen carbonate solution (2 ml), and the mixture was extracted with ethyl acetate (50 ml). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (the developing solvent: chloroform/methanol=99/1) to give the title compound (425 mg).

MS (ESI+) 761 (M + +1, 100%).

Reference Example 328

tert-Butyl (2R,5R)-5-[[(4-{2-[(difluoroacetyl)amino]ethyl}-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl](isopropyl)amino]-2-{2-[(2,2,2-trifluoroethyl)amino]ethyl}piperidine-1-carboxylate

Using the compound of Reference Example 326, the title compound was obtained in a similar manner to Reference Example 327.

MS (ESI+) 707 (M + +1, 100%).

Reference Example 329

tert-Butyl (2R,5R)-2-[2-(cyclopropylamino)ethyl]-5-[{[4-{2-[(difluoroacetyl)amino]ethyl}-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)-amino]piperidine-1-carboxylate

Using the compound of Reference Example 325, the title compound was obtained in a similar manner to Reference Example 327.

MS (ESI+) 719 (M + +1, 100%).

Reference Example 330

tert-Butyl (2R,5R)-2-[2-(cyclopropylamino)ethyl]-5-[[(4-{2-[(difluoroacetyl)amino]ethyl}-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl](isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 326, the title compound was obtained in a similar manner to Reference Example 327.

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

Reference Example 331

tert-Butyl (2R,5R)-2-{2-[[(4-chlorophenyl)acetyl](cyclopropyl)amino]ethyl}-5-[{[4-{2-[(difluoroacetyl)amino]ethyl}-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl](isopropyl)amino]piperidine-1-carboxylate

To a solution of tert-butyl (2R,5R)-2-[2-(cyclopropylamino)ethyl]-5-[{[4-{2-[(difluoroacetyl)-amino]ethyl}-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}-(isopropyl)amino]piperidine-1-carboxylate (86 mg) in N,N-dimethylformamide (1 ml) were added 4-chlorophenylacetic acid (22 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (34 mg), 1-hydroxybenzotriazole monohydrate (24 mg) and triethylamine (50 μl), and the mixture was stirred at room temperature overnight. To the reaction solution was added water, and the mixture was extracted with ethyl acetate (50 ml). The organic layer was washed with water and a saturated aqueous sodium chloride solution. Then, the mixture was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (the developing solvent: hexane/acetone=2/1) to give the title compound (90 mg).

MS (ESI+) 870 (M + +1, 100%).

Reference Example 332

tert-Butyl (2R,5R)-2-{2-[[(4-chlorophenyl)acetyl](cyclopropyl)amino]ethyl}-5-[[(4-{2-[(difluoroacetyl)amino]ethyl}-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl](isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 330, the title compound was obtained in a similar manner to Reference Example 331.

MS (ESI+) 817 (M + +2, 42%).

Reference Example 333

tert-Butyl (2R,5R)-2-{2-[[(4-chlorophenyl)acetyl](2,2,2-trifluoroethyl)amino]ethyl}-5-[{[4-{2-[(difluoroacetyl)amino]ethyl}-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 327, the title compound was obtained in a similar manner to Reference Example 331.

MS (ESI+) 913 (M + +1, 50%).

Reference Example 334

tert-Butyl (2R,5R)-2-{2-[[(4-chlorophenyl)acetyl](2,2,2-trifluoroethyl)amino]ethyl}-5-[[(4-{2-[(difluoroacetyl)amino]ethyl}-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl]-(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 328, the title compound was obtained in a similar manner to Reference Example 331.

MS (ESI+) 859 (M + +2, 11%).

Reference Example 335

tert-Butyl (2R,5R)-2-(2-{cyclopropyl[(3,4-dichlorophenyl)acetyl]amino}ethyl)-5-[{[4-{2-[(difluoroacetyl)amino]ethyl}-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]-carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 329, the title compound was obtained in a similar manner to Reference Example 331.

MS (ESI+) 904 (M + +1, 100%).

Reference Example 336

tert-Butyl (2R,5R)-2-(2-{cyclopropyl[(3,4-dichlorophenyl)acetyl]amino}ethyl)-5-[[(4-{2-[(difluoro-acetyl)amino]ethyl}-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl](isopropyl)-amino]piperidine-1-carboxylate

Using the compound of Reference Example 330, the title compound was obtained in a similar manner to Reference Example 331.

MS (ESI+) 851 (M + +2, 22%).

Reference Example 337

tert-Butyl (2R,5R)-2-{2-[[(3,4-dichlorophenyl)acetyl](2,2,2-trifluoroethyl)amino]ethyl}-5-[{[4-{2-[(difluoroacetyl)amino]ethyl}-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 327, the title compound was obtained in a similar manner to Reference Example 331.

MS (ESI+) 946 (M + +1, 100%).

Reference Example 338

tert-Butyl (2R,5R)-2-{2-[[2-(4-chlorophenyl)-2-methyl propanoyl](cyclopropyl)amino]ethyl}-5-[{[4-{2-[(difluoroacetyl)amino]ethyl}-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 329, the title compound was obtained in a similar manner to Reference Example 331.

MS (ESI+) 898 (M + +1, 100%).

Reference Example 339

tert-Butyl (2R,5R)-2-{2-[{[1-(4-chlorophenyl)cyclopropyl]carbonyl}(cyclopropyl)amino]ethyl}-5-[{[4-{2-[(difluoroacetyl)amino]ethyl}-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 329, the title compound was obtained in a similar manner to Reference Example 331.

MS (ESI+) 896 (M + +1, 100%).

Reference Example 340

tert-Butyl (2R,5R)-5-[{[2,2-dimethyl-4-(2-{[(methylamino)carbonothioyl]amino}ethyl)-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]-2-(2-methoxyethyl)piperidine-1-carboxylate

Under ice-cooling, to a solution of tert-butyl (2R,5R)-5-[{[4-(2-aminoethyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropylamino)-2-(2-methoxyethyl)-piperidine-1-carboxylate (246 mg) in tetrahydrofuran (3 ml) were added triethylamine (169 μl) and thiophosgene (32 μl), and the mixture was stirred for one hour. Then, to the mixture was added a 40% aqueous methylamine solution (200 μl), and the mixture was stirred overnight. Water was added thereto, and the mixture was extracted with ethyl acetate (50 ml). The organic layer was washed with water and a saturated aqueous sodium chloride solution. Then, the mixture was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (the developing solvent: hexane/acetone=2/1) to give the title compound (90 mg).

MS (ESI+) 688 (M + +1, 100%).

Reference Example 341

(rac)-tert-Butyl (2S,5R)-5-[{[4-{2-[(difluoroacetyl)amino]ethyl}-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]-2-methylpiperidine-1-carboxylate

Using the compound of Reference Example 343, the title compound was obtained in a similar manner to Reference Example 120.

MS (ESI+) 649 (M + +1, 29%).

Reference Example 342

tert-Butyl (2S ,5R)-5- [{[4- {2- [(difluoroacetyl)amino]ethyl }-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino] -2-(2-methoxyethyl)piperidine-1-carboxylate

Using the compound of Reference Example 344, the title compound was obtained in a similar manner to Reference Example 120.

MS (ESI+) 693 (M + +1, 11%).

Reference Example 343

(rac)-tert-Butyl (2S,5R)-5-[{[4-(2-aminoethyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]-2-methylpiperidine-1-carboxylate

Using the compound of Reference Example 345, the title compound was obtained in a similar manner to Reference Example 139.

MS (ESI+) 571 (M + +1, 77%).

Reference Example 344

tert-Butyl (2S,5R)-5-[{[4-(2-aminoethyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]-2-(2-methoxyethyl)piperidine-1-carboxylate

Using the compound of Reference Example 346, the title compound was obtained in a similar manner to Reference Example 139.

MS (ESI+) 615 (M + +1, 27%).

Reference Example 345

(rac)-tert-Butyl (2S ,5R)-5- [{[4-(2-{[(benzyloxy)carbonyl]amino{ethyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl }(isopropyl)amino]-2-methylpiperidine-1-carboxylate

Using the compound of Reference Example 74, the title compound was obtained in a similar manner to Reference Example 5.

MS (ESI+) 705 (M + +1, 31%).

Reference Example 346

tert-Butyl (2S,5R)-5-[{[4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]-2-(2-methoxyethyl)piperidine-1-carboxylate

Using the compound of Reference Example 74, the title compound was obtained in a similar manner to Reference Example 5.

MS (ESI+) 749 (M + +1, 10%).

Reference Example 347

tert-Butyl (2S,5R)-5-(isopropylamino)-2-(2-methoxyethyl)piperidine-1-carboxylate

Using the compound of Reference Example 348, the title compound was obtained in a similar manner to Reference Example 312.

MS (ESI+) 301 (M + +1, 52%).

Reference Example 348

tert-Butyl (2S,5R)-5-[[(benzyloxy)carbonyl](isopropyl)amino]-2-(2-methoxyethyl)piperidine-1-carboxylate

Using the compound of Reference Example 349, the title compound was obtained in a similar manner to Reference Example 310.

MS (ESI+) 435 (M + +1, 11%).

Reference Example 349

tert-Butyl (2S,5R)-5-[[(benzyloxy)carbonyl](isopropyl)amino]-2-(2-hydroxyethyl)piperidine-1-carboxylate

Using the compound of Reference Example 350, the title compound was obtained in a similar manner to Reference Example 309.

MS (ESI+) 421 (M + +1, 15%).

Reference Example 350

tert-Butyl (2S,5R)-5-[[(benzyloxy)carbonyl](isopropyl)amino]-2-(2-ethoxy-2-oxoethyl)piperidine-1-carboxylate

Using the compound of Reference Example 351, the title compound was obtained in a similar manner to Reference Example 307.

MS (ESI+) 463 (M + +1, 11%).

Reference Example 351

tert-Butyl (2S,5R)-2-(2-ethoxy-2-oxoethyl)-5-(isopropylamino)piperidine-1-carboxylate

Using the compound of Reference Example 353, the title compound was obtained in a similar manner to Reference Example 306.

MS (ESI+) 329 (M + +1, 71%).

Reference Example 352

(rac)-tert-Butyl (2S,5R)-5-(isopropylamino)-2-methylpiperidine-1-carboxylate

Using the compound of Reference Example 354, the title compound was obtained in a similar manner to Reference Example 306.

MS (ESI+) 257 (M + +1, 38%).

Reference Example 353

Ethyl [(2S,5R)-5-(isopropylamino)-1-(4-methoxybenzyl)piperidin-2-yl]acetate

To a solution of ethyl [(2S,5R)-5-[(tert-butoxycarbonyl)amino]-1-(4-methoxybenzyl)piperidin-2-yl]acetate (25.0 g) in 1,4-dioxane (90 ml) was added a 4N solution of hydrochloric acid in 1,4-dioxane (92.2 ml), and the mixture was stirred at room temperature for 3 hours. 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 chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a crude intermediate amine compound. To a solution of the obtained intermediate in ethanol (125 ml) were added acetic acid (7.39 g) and acetone (13.5 ml), and the mixture was stirred at 60° C. for one hour. The reaction solution was cooled to room temperature, and thereto was added sodium triacetoxyborohydride (32.6 g), and the mixture was stirred for 16 hours. To the reaction solution was added a 10% 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 (the developing solvent: chloroform/ethanol=20/1) to give the title compound (15.5 g) as a colorless oil.

MS (ESI+) 349 (M + +1, 33%).

Reference Example 354

(rac)-(3R,6S)—N-Isopropyl-1-(4-methoxybenzyl)-6-methylpiperidine-3-amine

Using the compound of Reference Example 355, the title compound was obtained in a similar manner to Reference Example 353.

MS (ESI+) 277 (M + +1, 59%).

Reference Example 355

(rac)-tert-Butyl [(3R,6S)-1-(4-methoxybenzyl)-6-methylpiperidin-3-yl]carbamate

To a solution of tert-butyl (6-methylpiperidin-3-yl)carbamate (8.03 g) in dimethylformamide (90 ml) were added potassium carbonate (10.4 g) and 4-methoxybenzyl chloride (5.34 ml), and the mixture was stirred at room temperature for 6 hours. 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 chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (the developing solvent: chloroform/methanol=100/3) to give the title compound (8.87 g) as a colorless oil.

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

Reference Example 356

tert-Butyl (6-methylpiperidin-3-yl)carbamate

To a solution of tert-butyl (6-methylpyridin-3-yl)carbamate (9.00 g) in a mixture of acetic acid-ethanol (1:1, 100 ml) was added platinum (IV) oxide (900 mg), and the mixture was stirred under hydrogen pressure (0.4 MPa) at room temperature for 9 hours. To the mixture was further added platinum (IV) oxide (2.0 g), and the mixture was stirred for 10 hours. The reaction mixture was filtered on celite, and thereto was added toluene. The mixture was concentrated under reduced pressure, and to the residue was added a 5% aqueous potassium carbonates solution. The mixture was extracted with chloroform, and 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 crude product (8.03 g) of the title compound as a colorless oil.

MS (ESI+) 215 (M + +1, 9%).

Reference Example 357

tert-Butyl (6-methylpyridin-3-yl)carbamate

To a solution of 2-methyl-5-nitropyridine (13.5 g) (Synth. Commun. 1990, 20(19), 2965) in methanol (200 ml) was added 10% palladium-C (50% wet) (2.7 g), and the mixture was stirred at room temperature under hydrogen atmosphere for 4 hours. The reaction mixture was filtered on celite, and concentrated under reduced pressure. To a solution of the obtained residue in 1,4-dioxane (135 ml) was added di-tert-butyl dicarbonate (23.3 g), and the mixture was refluxed for one hour. The reaction solution was cooled to room temperature, and thereto 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 (the developing solvent: hexane/ethyl acetate=1/1) to give the title compound (9.06 g) as a colorless oil.

MS (ESI+) 209 (M + +1, 4%).

Reference Example 358

Methyl 4-mercapto-2-methyl-5-nitrobenzoate

To a solution of methyl 4-chloro-2-methyl-5-nitrobenzoate (1.21 g) in methanol (20 ml) was added sodium hydrosulfide (561 mg), and the mixture was refluxed with stirring for 2 hours. After the reaction was complete, the reaction solution was concentrated, and methanol was concentrated under reduced pressure. Then, to the resultant were added water and 2N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, concentrated under reduced pressure. The obtained residue was purified by column chromatography to give the title compound (1.17 g).

MS (ESI+) 228 (M + +1, 100%).

Reference Example 359

Methyl 4-[(2-ethoxy-1,1-dimethyl-2-oxoethyl)thio]-2-methyl-5-nitrobenzoate

To a solution of methyl 4-mercapto-2-methyl-5-nitrobenzoate (1.17 g) in N,N-dimethyl-formamide (20 ml) were added potassium carbonate (1.42 g), ethyl 2-bromoisobutyrate, and the mixture was stirred at 80° C. for 4 hours. After the reaction was complete, water and 2N hydrochloric acid were added thereto, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, concentrated under reduced pressure. The obtained residue was purified by column chromatography to give a crude product of the title compound (3.56 g).

MS (ESI+) 342 (M + +1, 100%).

Reference Example 360

Methyl 2,7-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboxylate

Iron powder (1.4 g) was suspended in acetic acid (5 ml) and warmed to 100° C., and thereto was added dropwise a solution of the above crude product (methyl 4-[(2-ethoxy-1,1-dimethyl-2-oxoethyl)-thio]-2-methyl-5-nitrobenzoate) in acetic acid (20 ml), and the mixture was heated with stirring for 4 hours. After the reaction was complete, the mixture was cooled to room temperature, and filtered on celite to remove the iron powder. Acetic acid was evaporated under reduced pressure, and water was added to the residue. The mixture was extracted with ethyl acetate, and the organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product of the title compound. The obtained residue was purified by silica gel column chromatography to give the title compound (410 mg).

MS (ESI+) 266 (M + +1, 100%).

Reference Example 361

Methyl 4-{2-[(methoxycarbonyl)amino]ethyl}-2,7-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzothiadine-6-carboxylate

To a solution of methyl 2,7-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboxylate (410 mg) in N,N-dimethylformamide (10 ml) solution were added potassium carbonate (590 mg, 4.3 mmol), methyl (2-bromoethyl)carbamate (422 mg), and the mixture was warmed to 80° C., and heated with stirring for 5 hours. Methyl (2-bromoethyl)carbamate (422 mg) was added thereto, and the mixture was stirred for 4 hours. Then, methyl (2-bromoethyl)carbamate (422 mg) was additionally added again, and the mixture was stirred for 6 hours. The reaction solution was cooled to room temperature, and the reaction solvent was evaporated under reduced pressure. 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 to give the title compound (200 mg).

MS (ESI+) 366 (M + +1, 13%).

Reference Example 362

tert-Butyl (3R)-3-{isopropyl[(4-{2-[(methoxycarbonyl)amino]ethyl}-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl)carbonyl]amino}piperidine-1-carboxylate

Methyl 4-{2-[(methoxycarbonyl)amino]ethyl}-2,7-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboxylate (210 mg) was dissolved in 1M aqueous sodium hydroxide solution/tetrahydrofuran/ethanol=(2:1:1), and the mixture was stirred at 80° C. for one hour. The reaction solution was concentrated under reduced pressure to remove ethanol. To the concentrated residue was added 2N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 4-{2-[(methoxycarbonyl)amino]-ethyl}-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboxylic acid (200 mg).

4-{2-[(Methoxycarbonyl)amino]ethyl}-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzo-thiazine-6-carboxylic acid (200 mg) was dissolved in dichloromethane (4 ml), and thereto were slowly added dropwise DMF (1 drop) and oxalyl chloride (74 μl), and the mixture was stirred at 25° C. for one hour. The solvent was evaporated under reduced pressure, and thereto was added toluene, and the mixture was concentrated under reduced pressure. This procedure was repeated twice so that the resultant was duly dried under reduced pressure.

The above crude product was dissolved in dichloromethane (4 ml), and thereto was slowly added dropwise triethylamine (158 μl), and further thereto was slowly added a solution of tert-butyl (3R)-3-(isopropylamino)piperidine-1-carboxylate (151 mg) in dichloromethane (1 ml) over a period of one hour. Then, the mixture was warmed to room temperature and stirred overnight. After the reaction was complete, to the 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, concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (56 mg).

MS (ESI+) 577 (M + +1, 16%).

Reference Example 363

Methyl 2,7-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboxylate

To a solution of methyl 4-chloro-2-methyl-5-nitrobenzoate (2.52 g) in N,N-dimethylformamide (20 ml) were added potassium carbonate (3.04 g) and ethyl 2-mercaptopropionate (2.2 g), and the mixture was stirred at 80° C. for 4 hours. After the reaction was complete, to the mixture was added a saturated aqueous sodium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, concentrated under reduced pressure to give methyl 4-[(2-ethoxy-1-methyl-2-oxoethyl)thio]-2-methyl-5-nitrobenzoate (4.0 g). Subsequently, the title compound was obtained in a similar manner to Reference Example 2.

MS (ESI+) 252 (M + +1, 100%).

Reference Example 364

Methyl 4-{2-[(methoxycarbonyl)amino]ethyl}-2,7-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboxylate

Using the compound of Reference Example 363, the title compound was obtained in a similar manner to Reference Example 361.

MS (ESI+) 353 (M + +1, 100%).

Reference Example 365

tert-Butyl (3R)-3-{isopropyl[(4-{2-[(methoxycarbonyl)amino]ethyl}-2,7-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl)carbonyl]amino}piperidine-1-carboxylate

Using methyl 4-{2-[(methoxycarbonyl)amino]ethyl}-2,7-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboxylate, 4-{2-[(methoxycarbonyl)amino]ethyl}-2,7-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboxylic acid was obtained in a similar manner to Reference Example 4.

To a solution of 4-{2-[(methoxycarbonyl)amino]ethyl}-2,7-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboxylic acid (460 mg) in N,N-dimethylformamide (4 ml) were added CIP reagent, N-ethyldiisopropylamine, tert-butyl (3R)-3-(isopropylamino)piperidine-1-carboxylate, and the mixture was stirred overnight. After the reaction was complete, to the mixture was added a saturated aqueous sodium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (284 mg).

MS (ESI+) 563 (M + +1, 41%).

Reference Example 366

tert-Butyl (3R)-3-[(4-chloro-2-methyl-5-nitrobenzoyl)(isopropyl)amino]piperidine-1-carboxylate

Using methyl 4-chloro-2-methyl-5-nitrobenzoate, the title compound was obtained in a similar manner to Reference Example 5.

MS (ESI+) 440 (M + +1, 100%).

Reference Example 367

tert-Butyl (3R)-3-[[(2,7-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl)carbonyl](isopropyl)-amino]piperidine-1-carboxylate

Using the compound of Reference Example 366, the title compound was obtained in a similar manner to Reference Example 363

MS (ESI+) 462 (M + +1, 61%).

Reference Example 368

tert-Butyl (3R)-3-(isopropyl{[4-(4-methoxybutyl)-2,7-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl]carbonyl}amino)piperidine-1-carboxylate

Using the compound of Reference Example 367, the title compound was obtained in a similar manner to Reference Example 3.

MS (ESI+) 548 (M + +1, 32%).

Reference Example 369

Methyl 2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboxylate 1,1-dioxide

To a solution of methyl 2,7-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboxylate (1.1 g) in acetic acid (10 ml) was added a 35% aqueous hydrogen peroxide solution (1.4 ml), and the mixture was stirred at 60° C. for 4 hours. Then, to the mixture was added aqueous hydrogen peroxide solution (1.4 ml) again, and the mixture was stirred for 4 hours. After the reaction was complete, to the mixture was added a saturated aqueous sodium chloride 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 silica gel column chromatography to give the title compound (238 mg).

MS (ESI+) 298 (M + +1, 100%).

Reference Example 370

Methyl 4-(4-methoxybutyl)-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboxylate 1,1-dioxide

Using the compound of Reference Example 369, the title compound was obtained in a similar manner to Reference Example 3.

MS (ESI+) 384 (M + +1, 100%).

Reference Example 371

tert-Butyl (3R)-3-(isopropyl{[4-(4-methoxybutyl)-2,2,7-trimethyl-1,1-dioxide-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl]carbonyl}amino)piperidine-1-carboxylate

Using the compound of Reference Example 370, the title compound was obtained in a similar manner to Reference Example 5.

MS (ESI+) 594 (M + +1, 41%).

Reference Example 372

tert-Butyl (3R)-3-[{[4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2,7-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 367, the title compound was obtained in a similar manner to Reference Example 378.

MS (ESI+) 638 (M + +1, 65%).

Reference Example 373

tert-Butyl (3R)-3-[{[4-(2-aminoethyl)-2,7-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 372, the title compound was obtained in a similar manner to Reference Example 139.

MS (ESI+) 505 (M + +1, 100%).

Reference Example 374

tert-Butyl (3R)-3-[({2,7-dimethyl-3-oxo-4-[2-(propionylamide)ethyl]-3,4-dihydro-2H-1,4-benzothiazin-6-yl}carbonyl)(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 373, the title compound was obtained in a similar manner to Reference Example 132.

MS (ESI+) 561 (M + +1, 15%).

Reference Example 375

tert-Butyl (3R)-3-[[4-chloro-5-nitro-2-(trifluoromethyl)benzoyl](isopropyl)amino]piperidine-1-carboxylate

To a solution of methyl 4-hydroxy-5-nitro-2-(trifluoromethyl)benzoate (15 g) in dimethyl-formamide (170 ml) was added dropwise phosphorus oxychloride (7.4 ml) under ice-cooling. The reaction solution was heated at 100° C., and stirred for 2 hours. After the reaction was complete, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give methyl 4-chloro-5-nitro-2-(trifluoromethyl)benzoate (14.78 g).

Using methyl 4-chloro-5-nitro-2-(trifluoromethyl)benzoate, 4-chloro-5-nitro-2-(trifluoromethyl)benzoic acid was obtained in a similar manner to Reference Example 4.

Using 4-chloro-5-nitro-2-(trifluoromethyl)benzoic acid, the title compound was obtained in a similar manner to Reference Example 5.

MS (ESI+) 494 (M + +1, 17%).

Reference Example 376

tert-Butyl (3R)-3-[[4-[(2-ethoxy-1,1-dimethyl-2-oxoethyl)thio]-5-nitro-2-(trifluoromethyl)benzoyl](isopropyl)amino]piperidine-1-carboxylate

The compound of Reference Example 375 (2.20 g) was dissolved in dimethylsulfoxide (45 ml), and thereto was added sodium sulfide 9 hydrate (1.28 g), and the mixture was stirred at room temperature for 2 hours. Then, potassium carbonate (1.80 g) and ethyl 2-bromoisobutyrate (1.33 ml) were added to the mixture, and the mixture was warmed to 50° C., and stirred for 2 hours. After the reaction was complete, water was added to the mixture, 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 product of the title compound. The obtained residue was purified by silica gel column chromatography to give the crude title compound.

MS (ESI+) 606 (M + +1, 74%).

Reference Example 377

tert-Butyl (3R)-3-[{[2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzothiazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 376, the title compound was obtained in a similar manner to Reference Example 2.

MS (ESI+) 530 (M + +1, 20%).

Reference Example 378

tert-Butyl (3R)-3-[{[4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzothiazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

To a solution of BR-3925 (1.51 g) in acetonitrile (20 ml) were added potassium carbonate (590 mg), 18-crown-6 (75 mg), BR-3519 (883 mg), and the mixture was warmed to 80° C., and the mixture was heated with stirring for 7 hours. The reaction solution was cooled to room temperature, and the reaction solvent was evaporated under reduced pressure. 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, concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (2.11 g).

MS (ESI+) 707 (M + +1, 76%).

Reference Example 379

tert-Butyl (3R)-3-[{[2,2-dimethyl-3-oxo-4-[2-(propionylamino)ethyl]-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzothiazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

The compound of Reference Example 378 (2.07 g) was dissolved in methanol (100 ml), and thereto were added 20% palladium hydroxide/carbon (50% wet.), propionic anhydride (0.42 ml, 5.86 mmol), and the mixture was vigorously stirred under hydrogen atmosphere at room temperature for 12 hours. Further, 20% palladium hydroxide/carbon (50% wet.: 1.0 g), propionic anhydride (0.21 ml, 2.93 mmol) were added again, and the mixture was vigorously stirred under hydrogen atmosphere at room temperature for 10 hours.

After the reaction was complete, the mixture was filtered on celite, and washed with methanol, and the filtrate was concentrated under reduced pressure. The crude product was dissolved in tetrahydrofuran (200 ml), dried over sodium sulfate, filtered, concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (the developing solvent: hexane/acetone=20/1-2/1) to give the title compound (1.06 g).

MS (ESI+) 629 (M + +1, 100%).

Reference Example 380

tert-Butyl (3R)-3-[[(7-chloro-4-{2-[(methoxycarbonyl)amino]ethyl}-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl](isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 375, the title compound was obtained in a similar manner to Reference Example 363.

MS (ESI+) 592 (M + +1, 74%).

Reference Example 381

tert-Butyl (3R)-3-[[(7-chloro-4-{2-[(methoxycarbonyl)amino]ethyl}-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl](isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 380, the title compound was obtained in a similar manner to Reference Example 2.

MS (ESI+) 516 (M + +1, 22%).

Reference Example 382

tert-Butyl (3R)-3-[[(7-chloro-4-{2-[(methoxycarbonyl)amino]ethyl}-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl](isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 381, the title compound was obtained in a similar manner to Reference Example 378.

MS (ESI+) 693 (M + +1, 96%).

Reference Example 383

tert-Butyl (3R)-3-(isopropyl{[2-methyl-3-oxo-4-[2-(propionylamine)ethyl]-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzothiazin-6-yl]carbonyl}amino)piperidine-1-carboxylate

Using the compound of Reference Example 382, the title compound was obtained in a similar manner to Reference Example 379.

MS (ESI+) 629 (M + +1, 100%).

Reference Example 384

tert-Butyl (3R)-3-[{[7-ethyl-4-(4-methoxybutyl)-3-oxo-2′,3,3′,4,5′,6′-hexahydrospiro[1,4-benzoxazine-2,4′-pyran]-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 256, the title compound was obtained in a similar manner to Reference Example 9.

MS (ESI+) 602 (M + +1, 45%).

Reference Example 385

Methyl 4-{[1-(methoxycarbonyl)cyclopropyl]oxy}-5-nitro-2-(trifluoromethyl)benzoate

Using methyl 4-chloro-5-nitro-2-(trifluoromethyl)benzoate, the title compound was obtained in a similar manner to Reference Example 22.

MS (ESI+) 364 (M + +1, 100%).

Reference Example 386

tert-Butyl (3R)-3-[[4-{[1-(ethoxycarbonyl)cyclobutyl]thio}-5-nitro-2-(trifluoromethyl)benzoyl]-(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 375, the title compound was obtained in a similar manner to Reference Example 376.

MS (ESI+) 618 (M + +1, 100%).

Reference Example 387

tert-Butyl (3R)-3-{isopropyl[4-{[1-(methoxycarbonyl)cyclopentyl]thio}-5-nitro-2-(trifluoromethyl)benzoyl]amino}piperidine-1-carboxylate

Using the compound of Reference Example 375, the title compound was obtained in a similar manner to Reference Example 376.

MS (ESI+) 618 (M + +1, 15%).

Reference Example 388

Diethyl {[4-{[[(3R)-1-(tert-butoxycarbonyl)piperidin-3-yl](isopropyl)amino]carbonyl}-2-nitro-5-(trifluoromethyl)phenyl]thio}(methyl)malonate

Using the compound of Reference Example 375, the title compound was obtained in a similar manner to Reference Example 376.

MS (ESI+) 664 (M + +1, 20%).

Reference Example 389

Methyl 4-{[1-(methoxycarbonyl)cyclopentyl]thio}-2-methyl-5-nitrobenzoate

Using the compound of Reference Example 358, the title compound was obtained in a similar manner to Reference Example 359.

MS (ESI+) 354 (M + +1, 30%).

Reference Example 390

Methyl 3-oxo-7-(trifluoromethyl)-3,4-dihydrospiro[1,4-benzoxazine-2,1′-cyclopropane]-6-carboxylate

Using the compound of Reference Example 385, the title compound was obtained in a similar manner to Reference Example 2.

MS (ESI+) 302 (M + +1, 100%).

Reference Example 391

Methyl 7-methyl-3-oxo-3,4-dihydrospiro[1,4-benzothiazine-2,1′-cyclopentane]-6-carboxylate

Using the compound of Reference Example 389, the title compound was obtained in a similar manner to Reference Example 2.

MS (ESI+) 292 (M + +1, 100%).

Reference Example 392

tert-Butyl (3R)-3-(isopropyl{[3-oxo-7-(trifluoromethyl)-3,4-dihydrospiro[1,4-benzothiazine-2,1′-cyclobutan]-6-yl]carbonyl}amino)piperidine-1-carboxylate

Using the compound of Reference Example 386, the title compound was obtained in a similar manner to Reference Example 2.

MS (ESI+) 542 (M + +1, 20%).

Reference Example 393

tert-Butyl (3R)-3-(isopropyl{[3-oxo-7-(trifluoromethyl)-3,4-dihydrospiro[1,4-benzothiazine-2,1′-cyclopentan]-6-yl]carbonyl}amino)piperidine-1-carboxylate

Using the compound of Reference Example 387, the title compound was obtained in a similar manner to Reference Example 2.

MS (ESI+) 556 (M + +1, 20%).

Reference Example 394

Ethyl 6-{[[(3R)-1-(tert-butoxycarbonyl)piperidin-3-yl](isopropyl)amino]carbonyl}-2-methyl-3-oxo-7-[(trifluoromethyl)-3,4-dihydro-2H-1,4-benzothiazine-2-carboxylate

Using the compound of Reference Example 388, the title compound was obtained in a similar manner to Reference Example 2.

MS (ESI+) 588 (M + +1, 30%).

Reference Example 395

Methyl 4-(4-methoxybutyl)-3-oxo-7-(trifluoromethyl)-3,4-dihydrospiro[1,4-benzoxazine-2,1′-cyclopropane]-6-carboxylate

Using the compound of Reference Example 390, the title compound was obtained in a similar manner to Reference Example 3.

MS (ESI+) 388 (M + +1, 100%).

Reference Example 396

Methyl 4-{2-[(methoxycarbonyl)amino]ethyl}-3-oxo-7-(trifluoromethyl)-3,4-dihydrospiro[1,4-benzoxazine-2,1′-cyclopropane]-6-carboxylate

Using the compound of Reference Example 390, the title compound was obtained in a similar manner to Reference Example 361.

MS (ESI+) 403 (M + +1, 36%).

Reference Example 397

Methyl 4-{2-[(methoxycarbonyl)amino]ethyl}-7-methyl-3-oxo-3,4-dihydrospiro[1,4-benzothiazine-2,1′-cyclopentane]-6-carboxylate

Using the compound of Reference Example 391, the title compound was obtained in a similar manner to Reference Example 361.

MS (ESI+) 393 (M + +1, 30%).

Reference Example 398

tert-Butyl (3R)-3-(isopropyl{[4-{2-[(methoxycarbonyl)amino]ethyl}-3-oxo-7-(trifluoromethyl)-3,4-dihydrospiro[1,4-benzothiazine-2,1′-cyclobutan]-6-yl]carbonyl}amino)piperidine-1-carboxylate

Using the compound of Reference Example 392, the title compound was obtained in a similar manner to Reference Example 361.

MS (ESI+) 643 (M + +1, 100%).

Reference Example 399

tert-Butyl (3R)-3-(isopropyl{[4-{2-[(methoxycarbonyl)amino]ethyl}-3-oxo-7-(trifluoromethyl)-3,4-dihydrospiro[1,4-benzothiazine-2,1′-cyclopentan]-6-yl]carbonyl}amino)piperidine-1-carboxylate

Using the compound of Reference Example 393, the title compound was obtained in a similar manner to Reference Example 361.

MS (ESI+) 657 (M + +1, 100%).

Reference Example 400

tert-Butyl (3R)-3-(isopropyl{[4-{2-[(methoxycarbonyl)amino]ethyl}-3-oxo-7-(trifluoromethyl)-3,4-dihydrospiro[1,4-benzothiazine-2,1′-cyclopentan]-6-yl]carbonyl}amino)piperidine-1-carboxylate

Using the compound of Reference Example 293, the title compound was obtained in a similar manner to Reference Example 13.

MS (ESI+) 641 (M + +1, 20%).

Reference Example 401

Ethyl 6-{[[(3R)-1-(tert-butoxycarbonyl)piperidin-3-yl](isopropyl)amino]carbonyl}-4-(4-methoxybutyl)-2-methyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzothiazine-2-carboxylate

Using the compound of Reference Example 394, the title compound was obtained in a similar manner to Reference Example 3.

MS (ESI+) 674 (M + +1, 20%).

Reference Example 402

6-{[[(3R)-1-(tert-Butoxycarbonyl)piperidin-3-yl](isopropyl)amino]carbonyl}-4-(4-methoxybutyl)-2-methyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzothiazine-2-carboxylic acid

Using the compound of Reference Example 394, the title compound was obtained in a similar manner to Reference Example 34.

MS (ESI+) 646 (M + +1, 30%).

Reference Example 403

A: tert-Butyl (3R)-3-[{[2-(hydroxymethyl)-4-(4-methoxybutyl)-2-methyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzothiazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

B: tert-Butyl (3R)-3-(isopropyl{[4-(4-methoxybutyl)-2-methyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzothiazin-6-yl]carbonyl}amino)piperidine-1-carboxylate

Using the compound of Reference Example 402, the title compound was obtained in a similar manner to Reference Example 35.

MS (ESI+) A: 632 (M + +1, 11%), B: 602 (M + +1, 17%).

Reference Example 404

tert-Butyl (3R)-3-(isopropyl{[4-(4-methoxybutyl)-2-(methoxymethyl)-2-methyl-3-oxo-7-(trifluoro-methyl)-3,4-dihydro-2H-1,4-benzothiazin-6-yl]carbonyl}amino)piperidine-1-carboxylate

Using the compound A of Reference Example 403A, the title compound was obtained in a similar manner to Reference Example 36.

MS (ESI+) 646 (M + +1, 30%).

Reference Example 405

Methyl 4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-3-oxo-7-(trifluoromethyl)-3,4-dihydrospiro[1,4-benzoxazine-2,1′-cyclopropane]-6-carboxylate

Using the compound of Reference Example 390, the title compound was obtained in a similar manner to Reference Example 378.

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

Reference Example 406

tert-Butyl (3R)-3-[{[4-(2-{[benzyloxy)carbonyl]amino}ethyl)-3-oxo-7-(trifluoromethyl)-3,4-dihydrospiro[1,4-benzothiazine-2,1′-cyclobutan]-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 392, the title compound was obtained in a similar manner to Reference Example 378.

MS (ESI+) 719 (M + +1, 19%).

Reference Example 407

tert-Butyl (3R)-3-[{[4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-3-oxo-7-(trifluoromethyl)-3,4-dihydrospiro[1,4-benzothiazine-2,1′-cyclopentan]-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 393, the title compound was obtained in a similar manner to Reference Example 378.

MS (ESI+) 733 (M + +1, 100%).

Reference Example 408

tert-Butyl (3R)-3-(isopropyl{[4-(4-methoxybutyl)-3-oxo-7-(trifluoromethyl)-3,4-dihydrospiro[1,4-benzoxazine-2,1′-cyclopropan]-6-yl]carbonyl}amino)piperidine-1-carboxylate

Using the compound of Reference Example 395, the title compound was obtained in a similar manner to Reference Example 5.

MS (ESI+) 598 (M + +1, 20%).

Reference Example 409

tert-Butyl (3R)-3-(isopropyl{[4-{2-[(methoxycarbonyl)amino]ethyl}-3-oxo-7-(trifluoromethyl)-3,4-dihydrospiro[1,4-benzoxazine-2,1′-cyclopropan]-6-yl]carbonyl}amino)piperidine-1-carboxylate

Using the compound of Reference Example 396, the title compound was obtained in a similar manner to Reference Example 5.

MS (ESI+) 613 (M + +1, 20%).

Reference Example 410

tert-Butyl (3R)-3-{isopropyl[(4-{2-[(methoxycarbonyl)amino]ethyl}-7-methyl-3-oxo-3,4-dihydrospiro[1,4-benzothiazine-2,1′-cyclopentan]-6-yl)carbonyl]amino}piperidine-1-carboxylate

Using the compound of Reference Example 397, the title compound was obtained in a similar manner to Reference Example 5.

MS (ESI+) 603 (M + +1, 12%).

Reference Example 411

tert-Butyl (3R)-3-[{[4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-3-oxo-7-(trifluoromethyl)-3,4-dihydrospiro[1,4-benzoxazine-2,1′-cyclopropan]-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 405, the title compound was obtained in a similar manner to Reference Example 5.

MS (ESI+) 689 (M + +1, 20%).

Reference Example 412

tert-Butyl (3R)-3-[{[4-(2-aminoethyl)-3-oxo-7-(trifluoromethyl)-3,4-dihydrospiro[1,4-benzoxazine-2,1′-cyclopropan]-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 411, the title compound was obtained in a similar manner to Reference Example 139.

MS (ESI+) 555 (M + +1, 85%).

Reference Example 413

tert-Butyl (3R)-3-[{[4-(2-aminoethyl)-3-oxo-7-(trifluoromethyl)-3,4-dihydrospiro[1,4-benzothiazine-2,1′-cyclobutan]-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 406, the title compound was obtained in a similar manner to Reference Example 139.

MS (ESI+) 585 (M + +1, 100%).

Reference Example 414

tert-Butyl (3R)-3-[{[4-(2-aminoethyl)-3-oxo-7-(trifluoromethyl)-3,4-dihydrospiro[1,4-benzothiazine-2,1′-cyclopentan]-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 407, the title compound was obtained in a similar manner to Reference Example 139.

MS (ESI+) 599 (M + +1, 100%).

Reference Example 415

tert-Butyl (3R)-3-(isopropyl{[3-oxo-4-[2-(propionylamino)ethyl]-7-(trifluoromethyl)-3,4-dihydrospiro[1,4-benzoxazine-2,1′-cyclopropan]-6-yl]carbonyl}amino)piperidine-1-carboxylate

Using the compound of Reference Example 412, the title compound was obtained in a similar manner to Reference Example 132.

MS (ESI+) 611 (M + +1, 7%).

Reference Example 416

tert-Butyl (3R)-3-(isopropyl{[3-oxo-4-[2-(propionylamino)ethyl]-7-(trifluoromethyl)-3,4-dihydrospiro[1,4-benzothiazine-2,1′-cyclobutan]-6-yl]carbonyl}amino)piperidine-1-carboxylate

Using the compound of Reference Example 413, the title compound was obtained in a similar manner to Reference Example 132.

MS (ESI+) 641 (M + +1, 100%).

Reference Example 417

tert-Butyl (3R)-3-(isopropyl{[3-oxo-4-[2-(propionylamino)ethyl]-7-(trifluoromethyl)-3,4-dihydrospiro[1,4-benzothiazine-2,1′-cyclopentan]-6-yl]carbonyl}amino)piperidine-1-carboxylate

Using the compound of Reference Example 414, the title compound was obtained in a similar manner to Reference Example 132.

MS (ESI+) 655 (M + +1, 17%).

Reference Example 418

tert-Butyl (3R)-3-[{[4-{2-[(difluoroacetyl)amino]ethyl}-3-oxo-7-(trifluoromethyl)-3,4-dihydrospiro-[1,4-benzoxazine-2,1′-cyclopropan]-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 415, the title compound was obtained in a similar manner to Reference Example 132.

MS (ESI+) 633 (M + +1, 20%).

Reference Example 419

Methyl 3,3-dimethyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-carboxylate

A solution of diisopropylamine (4.59 g) in THF (25 ml) was cooled to 0° C., and thereto was added dropwise a solution of n-butyl lithium (2.63 M hexane solution, 17 ml). After the addition was complete, the mixture was stirred in an ice-bath for one hour. The mixture was cooled to −78° C., and a solution of methyl 2-methylpropanoate (5.05 g) in THF (5 ml) was added dropwise thereto, and the mixture was stirred for 30 minutes as it stands. This solution was added dropwise into a solution of methyl p-(bromomethyl)benzoate (9.86 g) in THF (10 ml), which was cooled at 0° C., and the mixture was stirred at 0° C. for 2 hours, and then stirred at room temperature overnight.

After the reaction was complete, the reaction was quenched by addition of a saturated aqueous ammonium chloride solution, and the mixture was extracted with water and ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated to give a crude product, which was purified by column chromatography to give methyl 4-(3-methoxy-2,2-dimethyl-3-oxopropyl)benzoate (10.15 g).

Then, to this product was added sulfuric acid (45 ml), and the mixture was cooled to 0° C., and thereto was slowly added dropwise fuming nitric acid (20 ml). The mixture was stirred at 0° C. for 1.5 hours. After the reaction was complete, the reaction solution was poured into ice-water, and the mixture was stirred until the temperature thereof was raised to room temperature. To the mixture was added ethyl acetate, and the mixture was extracted. The organic layer was washed with a water, an aqueous sodium hydrogen carbonate solution, and a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered to give a crude product (11.13 g) containing methyl 4-(3-methoxy-2,2-dimethyl-3-oxopropyl)-3-nitrobenzoate.

To a mixed solvent of acetic acid (50 ml) and ethanol (50 ml) was added reduced iron, and the mixture was stirred at 70° C. for 30 minutes. Then, thereto was added dropwise a solution of the above-obtained crude product in acetic acid (50 ml) and ethanol (50 ml). After the addition was complete, the mixture was stirred at 70° C. for 2 hours. After the reaction was complete, the mixture was cooled to room temperature, and filtered on celite. The filtrate was separated and extracted with ethyl acetate, and the organic layer was washed with water and a saturated aqueous sodium hydrogen carbonate solution, dried over sodium sulfate, filtered to give a crude product. This crude product was subjected to trituration with chloroform/hexane (1/9), and collected by filtration to give the title compound (7.39 g).

MS (ESI+) 234 (M + +1, 100%).

Reference Example 420

Methyl 2′-oxo-1′,4′-dihydro-2′H-spiro[cyclopentane-1,3′-quinoline]-7′-carboxylate

Using methyl cyclopentanecarboxylate, the title compound was obtained in a similar manner to Reference Example 419.

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

Reference Example 421

Methyl 1-(4-methoxybutyl)-3,3-dimethyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-carboxylate

Using the compound of Reference Example 419, the title compound was obtained in a similar manner to Reference Example 3.

MS (ESI+) 320 (M + +1, 75%).

Reference Example 422

Methyl 1-{2-[(methoxycarbonyl)amino]ethyl}-3,3-dimethyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-carboxylate

Using the compound of Reference Example 419, the title compound was obtained in a similar manner to Reference Example 162.

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

Reference Example 423

Methyl 1-(2-{[(benzyloxy)carbonyl]amino}ethyl)-3,3-dimethyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-carboxylate

Using the compound of Reference Example 419, the title compound was obtained in a similar manner to Reference Example 164.

MS (ESI+) 411 (M + +1, 72%).

Reference Example 424

Methyl 1-(2-{[(benzyloxy)carbonyl]amino}ethyl)-6-iodo-3,3-dimethyl-2-oxo-1,2,3,4-tetrahydro-quinoline-7-carboxylate

Using the compound of Reference Example 449, the title compound was obtained in a similar manner to Reference Example 164.

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

Reference Example 425

Methyl 1′-(2-{[(benzyloxy)carbonyl]amino}ethyl)-6′-iodo-2′-oxo-1′,4′-dihydro-2′H-spiro-[cyclopentane-1,3′-quinoline]-7′-carboxylate

Using the compound of Reference Example 450, the title compound was obtained in a similar manner to Reference Example 164.

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

Reference Example 426

Methyl 1-(2-{[(benzyloxy)carbonyl]amino}ethyl)-3,3-dimethyl-2-oxo-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-7-carboxylate

To a solution of methyl 1-(2-{[(benzyloxy)carbonyl]amino}ethyl)-6-iodo-3,3-dimethyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-carboxylate (4.87 g) in NMP (10 ml) were added copper (I) bromide (0.28 g) and FSO 2 CF 2 CO 2 Me (17.43 g), and the mixture was stirred at 120˜130° C. under nitrogen atmosphere for 3 hours. After the reaction was complete, the mixture was cooled to room temperature, and thereto were added water and ethyl acetate. The insoluble materials were removed by filtration on celite, and the filtrate was separated. The organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated to give a crude product. This product was purified by silica gel column chromatography to give the title compound (2.50 g).

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

Reference Example 427

Methyl 1′-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2′-oxo-6′-(trifluoromethyl)-1′,4′-dihydro-2′H-spiro[cyclopentane-1,3′-quinoline]-7′-carboxylate

Using the compound of Reference Example 425, the title compound was obtained in a similar manner to Reference Example 426.

MS (ESI+) 505 (M + +1, 100%).

Reference Example 428

1-(4-Methoxybutyl)-3,3-dimethyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-carboxylic acid

Using the compound of Reference Example 421, the title compound was obtained in a similar manner to Reference Example 4.

MS (ESI+) 306 (M + +1, 100%).

Reference Example 429

1-{2-[(Methoxycarbonyl)amino]ethyl}-3,3-dimethyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-carboxylic acid

Using the compound of Reference Example 422, the title compound was obtained in a similar manner to Reference Example 4.

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

Reference Example 430

1-(2-{[(Benzyloxy)carbonyl]amino}ethyl)-3,3-dimethyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-carboxylic acid

Using the compound of Reference Example 423, the title compound was obtained in a similar manner to Reference Example 4.

MS (ESI+) 397 (M + +1, 100%).

Reference Example 431

1-(2-{[(Benzyloxy)carbonyl]amino}ethyl)-3,3-dimethyl-2-oxo-6-(trifluoromethyl)-1,2,3,4-tetrahydro-quinoline-7-carboxylic acid

Using the compound of Reference Example 426, the title compound was obtained in a similar manner to Reference Example 4.

MS (ESI+) 465 (M + +1, 70%).

Reference Example 432

1′-(2-{[(Benzyloxy)carbonyl]amino}ethyl)-2′-oxo-6′-(trifluoromethyl)-1′,4′-dihydro-2′H-spiro[cyclopentane-1,3′-quinoline]-7′-carboxylic acid

Using the compound of Reference Example 427, the title compound was obtained in a similar manner to Reference Example 4.

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

Reference Example 433

tert-Butyl (3R)-3-(isopropyl{[1-(4-methoxybutyl)-3,3-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl]carbonyl}amino)piperidine-1-carboxylate

Using the compound of Reference Example 428, the title compound was obtained in a similar manner to Reference Example 5.

MS (ESI+) 530 (M + +1, 36%).

Reference Example 434

tert-Butyl (3R)-3-{isopropyl[(1-{2-[(methoxycarbonyl)amino]ethyl}-3,3-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)carbonyl]amino}piperidine-1-carboxylate

Using the compound of Reference Example 429, the title compound was obtained in a similar manner to Reference Example 5.

MS (ESI+) 545 (M + +1, 63%).

Reference Example 435

tert-Butyl (3R)-3-[{[1-(2-{[(benzyloxy)carbonyl]amino}ethyl)-3,3-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 430, the title compound was obtained in a similar manner to Reference Example 5.

MS (ESI+) 621 (M + +1, 35%).

Reference Example 436

tert-Butyl (3R)-3-[{[1-(2-{[(benzyloxy)carbonyl]amino}ethyl)-3,3-dimethyl-2-oxo-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-7-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 431, the title compound was obtained in a similar manner to Reference Example 5.

MS (ESI+) 689 (M + +1, 20%).

Reference Example 437

tert-Butyl (3R)-3-[{[1′-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2′-oxo-6′-(trifluoromethyl)-1′,4′-dihydro-2′H-spiro[cyclopentane-1,3′-quinolin]-7′-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 432, the title compound was obtained in a similar manner to Reference Example 5.

MS (ESI+) 715 (M + +1, 25%).

Reference Example 438

tert-Butyl (3R)-3-[({3,3-dimethyl-2-oxo-1-[2-(propionylamino)ethyl]-1,2,3,4-tetrahydroquinolin-7-yl}carbonyl)(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 435, the title compound was obtained in a similar manner to Reference Example 132.

MS (ESI+) 543 (M + +1, 11%).

Reference Example 439

tert-Butyl (3R)-3-[{[3,3-dimethyl-2-oxo-1-[2-(propionylamino)ethyl]-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-7-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 436, the title compound was obtained in a similar manner to Reference Example 132.

MS (ESI+) 611 (M + +1, 20%).

Reference Example 440

tert-Butyl (3R)-3-(isopropyl{[2′-oxo-1′-[2-(propionylamino)ethyl]-6′-(trifluoromethyl)-1′,4′-dihydro-2′H-spiro[cyclopentane-1,3′-quinolin]-7′-yl]carbonyl}amino)piperidine-1-carboxylate

Using the compound of Reference Example 437, the title compound was obtained in a similar manner to Reference Example 132.

MS (ESI+) 637 (M + +1, 10%).

Reference Example 441

tert-Butyl (3R)-3-[{[6-chloro-1-(4-methoxybutyl)-3,3-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 433, the title compound was obtained in a similar manner to Reference Example 12.

MS (ESI+) 564 (M + +, 21%).

Reference Example 442

tert-Butyl (3R)-3-(isopropyl{[1-(4-methoxybutyl)-3,3,6-trimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl]carbonyl}amino)piperidine-1-carboxylate

Using the compound of Reference Example 433, the title compound was obtained in a similar manner to Reference Example 10.

MS (ESI+) 544 (M + +1, 21%).

Reference Example 443

tert-Butyl (3R)-3-[[(6-bromo-1-{2-[(methoxycarbonyl)amino]ethyl}-3,3-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)carbonyl](isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 434, the title compound was obtained in a similar manner to Reference Example 6.

MS (ESI+) 625 (M + +2, 10%).

Reference Example 444

tert-Butyl (3R)-3-{isopropyl [(1-{2-[(methoxycarbonyl)amino]ethyl}-3,3,6-trimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)carbonyl]amino}piperidine-1-carboxylate

Using the compound of Reference Example 434, the title compound was obtained in a similar manner to Reference Example 10.

MS (ESI+) 559 (M + +1, 14%).

Reference Example 445

tert-Butyl (3R)-3-[isopropyl({3,3,6-trimethyl-2-oxo-1-[2-(propionylamino)ethyl]-1,2,3,4-tetrahydroquinolin-7-yl}carbonyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 439, the title compound was obtained in a similar manner to Reference Example 10.

MS (ESI+) 557 (M + +1, 38%).

Reference Example 446

tert-Butyl (3R)-3-[[(6-chloro-1-{2-[(methoxycarbonyl)amino]ethyl}-3,3-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)carbonyl](isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 434, the title compound was obtained in a similar manner to Reference Example 12.

MS (ESI+) 579 (M + +, 10%).

Reference Example 447

tert-Butyl (3R)-3-[({6-chloro-3,3-dimethyl-2-oxo-1-[2-(propionylamino)ethyl]-1,2,3,4-tetrahydroquinolin-7-yl}carbonyl)(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 439, the title compound was obtained in a similar manner to Reference Example 12.

MS (ESI+) 577 (M + +, 60%).

Reference Example 448

tert-Butyl (3R)-3-[[(6-ethyl-1-{2-[(methoxycarbonyl)amino]ethyl}-3,3-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)carbonyl](isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 443, the title compound was obtained in a similar manner to Reference Example 9.

MS (ESI+) 573 (M + +1, 26%).

Reference Example 449

Methyl 6-iodo-3,3-dimethyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-carboxylate

Using the compound of Reference Example 419, the title compound was obtained in a similar manner to Reference Example 158.

MS (ESI+) 360 (M + +1, 100%).

Reference Example 450

Methyl 6′-iodo-2′-oxo-1′,4′-dihydro-2′H-spiro[cyclopentane-1,3′-quinoline]-7′-carboxylate

Using the compound of Reference Example 420, the title compound was obtained in a similar manner to Reference Example 158.

MS (ESI+) 386 (M + +1, 100%).

Reference Example 451

tert-Butyl (3R)-3-{isopropyl[(2-methyl-3-oxo-2-phenyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl]-amino}piperidine-1-carboxylate

Using the compound of Reference Example 488, the title compound was obtained in a similar manner to Reference Example 22 and Reference Example 2.

MS (ESI+) 508 (M + +1, 21%).

Reference Example 452

Methyl 2-methyl-3-oxo-2-phenyl-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

Using the compound of Reference Example 214, the title compound was obtained in a similar manner to Reference Example 22 and Reference Example 2.

MS (ESI+) 366 (M + +1, 100%).

Reference Example 453

Methyl 2-(3-methoxyphenyl)-2-methyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

Using the compound of Reference Example 214, the title compound was obtained in a similar manner to Reference Example 22 and Reference Example 2.

MS (ESI+) 396 (M + +1, 100%).

Reference Example 454

tert-Butyl (3R)-3-[{[4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2-methyl-3-oxo-2-phenyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 451, the title compound was obtained in a similar manner to Reference Example 164.

MS (ESI+) 685 (M + +1, 46%).

Reference Example 455

tert-Butyl (3R)-3-[isopropyl({2-methyl-3-oxo-2-phenyl-4-[2-(propionylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 454, the title compound was obtained in a similar manner to Reference Example 132.

MS (ESI+) 607 (M + +1, 22%).

Reference Example 456

tert-Butyl (3R)-3-[{[4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2,7-dimethyl-3-oxo-2-phenyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 454, the title compound was obtained in a similar manner to Reference Example 10.

MS (ESI+) 699 (M + +1, 10%).

Reference Example 457

tert-Butyl (3R)-3-[({2,7-dimethyl-3-oxo-2-phenyl-4-[2-(propionylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 456, the title compound was obtained in a similar manner to Reference Example 132.

MS (ESI+) 621 (M + +1, 33%).

Reference Example 458

tert-Butyl (3R)-3-[({7-chloro-2-methyl-3-oxo-2-phenyl-4-[2-(propionylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 455, the title compound was obtained in a similar manner to Reference Example 12.

MS (ESI+) 641 (M + +, 10%).

Reference Example 459

Methyl 4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2-methyl-3-oxo-2-phenyl-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

Using the compound of Reference Example 452, the title compound was obtained in a similar manner to Reference Example 164.

MS (ESI+) 543 (M + +1, 7 0%).

Reference Example 460

Methyl 4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2-(3-methoxyphenyl)-2-methyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

Using the compound of Reference Example 453, the title compound was obtained in a similar manner to Reference Example 164.

MS (ESI+) 573 (M + +1, 36%).

Reference Example 461

tert-Butyl (3R)-3-[{[4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2-methyl-3-oxo-2-phenyl-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 459, the title compound was obtained in a similar manner to Reference Example 5.

MS (ESI+) 753 (M + +1, 22%).

Reference Example 462

tert-Butyl (3R)-3-[{[4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2-(3-methoxyphenyl)-2-methyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 460, the title compound was obtained in a similar manner to Reference Example 5.

MS (ESI+) 783 (M + +1, 19%).

Reference Example 463

tert-Butyl (3R)-3-(isopropyl{[2-methyl-3-oxo-2-phenyl-4-[2-(propionylamino)ethyl]-7-(trifluoro-methyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}amino)piperidine-1-carboxylate

Using the compound of Reference Example 461, the title compound was obtained in a similar manner to Reference Example 132.

MS (ESI+) 675 (M + +1, 31%).

Reference Example 464

tert-Butyl (3R)-3-(isopropyl{[2-(3-methoxyphenyl)-2-methyl-3-oxo-4-[2-(propionylamino)ethyl]-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}amino)piperidine-1-carboxylate

Using the compound of Reference Example 462, the title compound was obtained in a similar manner to Reference Example 132.

MS (ESI+) 705 (M + +1, 14%).

Reference Example 465

4,4,6-Trimethyl-3,4-dihydroquinolin-2(1H)-one

In an ice-bath, to a solution of p-toluidine (3.78 g) and triethylamine (5.5 ml) in chloroform (70 ml) was added dropwise 3,3-dimethylacryloyl chloride (3.76 g). The mixture was stirred at room temperature overnight. Water was added to the reaction solution for separation. The organic layer was dried over sodium sulfate, filtered and concentrated to give a crude product. This product was purified by silica gel column chromatography to give an intermediate (6.11 g), which was dissolved in toluene (120 ml), and thereto was added aluminum chloride (6.50 g), and the mixture was stirred at 100° C. for 5 hours. To the mixture was added aluminum chloride (2.11 g) again, and stirred again at 100° C. for 4 hours. The mixture was cooled to room temperature, and slowly poured into ice-water. The mixture was stirred for 30 minutes, and extracted with ethyl acetate. The organic layer was washed with water, a saturated aqueous sodium hydrogen carbonate solution, a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated to give a crude product, which was purified by silica gel column chromatography to give the title compound (4.20 g).

MS (ESI+) 190 (M + +1, 100%).

Reference Example 466

7-Bromo-4,4,6-trimethyl-3,4-dihydroquinolin-2(1H)-one

Using the compound of Reference Example 465, the title compound was obtained in a similar manner to Reference Example 6.

MS (ESI+) 270 (M + +2, 100%).

Reference Example 467

7-Bromo-1-(4-methoxybutyl)-4,4,6-trimethyl-3,4-dihydroquinolin-2(1H)-one

Using the compound of Reference Example 466, the title compound was obtained in a similar manner to Reference Example 3.

MS (ESI+) 356 (M + +2, 90%).

Reference Example 468

Methyl 1-(4-methoxybutyl)-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-carboxylate

Using the compound of Reference Example 467, the title compound was obtained in a similar manner to Reference Example 25.

MS (ESI+) 334 (M + +1, 100%).

Reference Example 469

tert-Butyl (3R)-3-(isopropyl{[1-(4-methoxybutyl)-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl]carbonyl}amino)piperidine-1-carboxylate

Using the compound of Reference Example 468, the title compound was obtained in a similar manner to Reference Example 5.

MS (ESI+) 544 (M + +1, 46%).

Reference Example 470

Methyl 4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboxylate

Using the compound of Reference Example 360, the title compound was obtained in a similar manner to Reference Example 378.

MS (ESI+) 443 (M + +1, 100%).

Reference Example 471

tert-Butyl (3R)-3-[{[4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 470, the title compound was obtained in a similar manner to Reference Example 5.

MS (ESI+) 653 (M + +1, 53%).

Reference Example 472

tert-Butyl (3R)-3-[isopropyl({2,2,7-trimethyl-3-oxo-4-[2-(propionylamino)ethyl]-3,4-dihydro-2H-1,4-benzothiazin-6-yl}carbonyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 471, the title compound was obtained in a similar manner to Reference Example 132.

MS (ESI+) 575 (M + +1, 13%).

Reference Example 473

tert-Butyl (3R)-3-[{[2-(3,5-difluorophenyl)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 488, the title compound was obtained in a similar manner to Reference Example 22 and Reference Example 2.

MS (ESI+) 544 (M + +1).

Reference Example 474

tert-Butyl (3R)-3-[[(2-(3,5-difluorophenyl)-4-{2-[(methoxycarbonyl)amino]ethyl}-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl](isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 473, the title compound was obtained in a similar manner to Reference Example 13.

MS (ESI+) 645 (M + +1).

Reference Example 475

tert-Butyl (3R)-3-[[(7-chloro-2-(3,5-difluorophenyl)-4-{2-[(methoxycarbonyl)amino]ethyl}-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl](isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 474, the title compound was obtained in a similar manner to Reference Example 12.

MS (ESI+) 679 (M + +1).

Reference Example 476

tert-Butyl (3R)-3-[[(7-bromo-2-(3,5-difluorophenyl)-4-{2-[(methoxycarbonyl)amino]ethyl}-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl](isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 474, the title compound was obtained in a similar manner to Reference Example 6.

MS (ESI+) 723 (M + +1).

Reference Example 477

tert-Butyl (3R)-3-[[(2-(3,5-difluorophenyl)-4-{2-[(methoxycarbonyl)amino]ethyl}-2,7-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl](isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 476, the title compound was obtained in a similar manner to Reference Example 10.

MS (ESI+) 659 (M + +1).

Reference Example 478

tert-Butyl (3R)-3-[({(2S)-2-(3,5-difluorophenyl)-2-methyl-3-oxo-4-[2-(propionylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 473, the title compound was obtained in a similar manner to Reference Examples 164 and 132.

MS (ESI+) 643 (M + +1, 53%).

Reference Example 479

tert-Butyl (3R)-3-[({(2S)-2-(3,5-difluorophenyl)-2,7-dimethyl-3-oxo-4-[2-(propionylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl)(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 473, the title compound was obtained in a similar manner to Reference Example 164, Reference Example 10 and Reference Example 132.

MS (ESI+) 657 (M + +1, 100%).

Reference Example 480

tert-Butyl (3R)-3-(isopropyl{[(2S)-4-(4-methoxybutyl)-2-methyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}amino)piperidine-1-carboxylate

Using the compound of Reference Example 52, the title compound was obtained in a similar manner to Reference Example 64.

MS (ESI+) 586 (M + +1, 40%).

Reference Example 481

tert-Butyl (3R)-3-(isopropyl{[(2S)-2-methyl-3-oxo-4-[2-(propionylamino)ethyl]-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}amino)piperidine-1-carboxylate

Using the compound of Reference Example 52, the title compound was obtained in a similar manner to Reference Example 26, Reference Example 2, Reference Example 164, Reference Example 132.

MS (ESI+) 599 (M + +1, 33%).

Reference Example 482

tert-Butyl (3R)-3-(isopropylamino)piperidine-1-carboxylate

Commercially available tert-butyl (3R)-3-aminopiperidine-1-carboxylate (6.67 g) was dissolved in ethanol (100 ml), and thereto were added acetone (12.2 ml) and acetic acid (2.0 ml), and the mixture was heated at 60° C. with stirring. Seven hours later, to the mixture was added sodium triacetoxyborohydride (9.67 g), and the mixture was stirred at room temperature for 14 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 (the developing solvent: chloroform/methanol=30/1, 15/1, 10) to give the title compound (7.78 g) as a white solid.

MS (ESI+) 243 (M+1, 100%).

Reference Example 483

tert-Butyl 3-(isopropylamino)azepane-1-carboxylate

Using tert-butyl 3-aminoazepane-1-carboxylate, the title compound was obtained in a similar manner to Reference Example 482.

MS (ESI+) 257 (M++1, 100%).

Reference Example 484

Benzyl 3-(isopropylamino)pyrrolidine-1-carboxylate

Using benzyl 3-aminopyrrolidine-1-carboxylate, the title compound was obtained in a similar manner to Reference Example 482.

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

Reference Example 485

tert-Butyl (3R)-3-(ethylamino)piperidine-1-carboxylate

Using tert-butyl (3R)-3-aminopiperidine-1-carboxylate, the title compound was obtained in a similar manner to Reference Example 482.

MS (ESI+) 229 (M + +1, 67%).

Reference Example 486

tert-Butyl (3R)-3-(sec-butylamino)piperidine-1-carboxylate

Using tert-butyl (3R)-3-aminopiperidine-1-carboxylate, the title compound was obtained in a similar manner to Reference Example 482.

MS (ESI+) 257 (M + +1, 100%).

Reference Example 487

tert-Butyl (3R)-3-(benzylamino)piperidine-1-carboxylate

Using tert-butyl (3R)-3-aminopiperidine-1-carboxylate, the title compound was obtained in a similar manner to Reference Example 482.

MS (ESI+) 291 (M + +1, 100%).

Reference Example 488

tert-Butyl (3R)-3-[(4-fluoro-3-nitrobenzoyl)(isopropyl)amino]piperidine-1-carboxylate

Using 4-fluoro-3-nitrobenzoic acid, the title compound was obtained in a similar manner to Reference Example 5.

MS (ESI+) 410 (M + +1, 78%)

Reference Example 489

(2R)-2-(3,5-Difluorophenyl)-2-fluoro-N-isopropyl-3-oxo-N-[(3R)-piperidin-3-yl]-4-[2-(propionyl-amino)ethyl]-3,4-dihydro-2H-1,4-benzoxazine-6-carboxamide hydrochloride

1 H NMR (400 MHz, CDCl 3 ) δ 9.91-9.39 (br, 2H), 7.12-6.55 (m, 6H), 6.79 (br, 0.5H), 6.28 (br, 0.5H), 4.21-3.24 (m, 9H), 2.87-2.49 (m, 2H), 2.22-1.80 (m, 8H), 1.37-0.97 (m, 9H).

Reference Example 490

Methyl {2-[7-({isopropyl[(3R)-piperidin-3-yl]amino}carbonyl)-3,3-dimethyl-2-oxo-3,4-dihydroquinolin-1(2H)-yl]ethyl}carbamate hydrochloride

1 H NMR (400 MHz, CDCl 3 ) δ 9.75-9.65 (m, 2H), 7.17-7.15 (m, 2H), 6.95 (brs, 1H), 4.15-3.82 (m, 4H), 3.66-3.58 (m, 1H), 3.57 (s, 3H), 3.51-3.27 (m, 4H), 2.94-2.81 (m, 1H), 2.81-2.75 (m, 3H), 2.12-1.76 (m, 4H), 1.34-1.08 (m, 12H)

Reference Example 491

N 6 -Isopropyl-4-(3-methoxypropyl)-N 2 ,N 2 ,2-trimethyl-3-oxo-N 6 -[(3R)-piperidin-3-yl]-3,4-dihydro-2H-1,4-benzoxazine-2,6-dicarboxamide hydrochloride

1 H NMR (400 MHz, CDCl 3 ) δ 9.89-9.51 (br, 2H), 7.12-6.83 (m, 3H), 4.18-3.60 (m, 5H), 3.45-3.28 (m, 4H), 3.39-3.27 (m, 3H), 3.18-3.03 (m, 3H), 2.91-2.65 (m, 5H), 2.15-1.53 (m, 8H), 1.40-1.08 (m, 6H).

Reference Example 492

N-Isopropyl-4-(4-methoxybutyl)-2-(methoxymethyl)-2-methyl-3-oxo-N-[(3R)-piperidin-3-yl]-3,4-dihydro-2H-1,4-benzoxazine-6-carboxamide hydrochloride

1 H NMR (400 MHz, CDCl 3 ) δ 9.91-9.55 (br, 2H), 6.93-6.78 (m, 3H), 4.15-3.87 (m, 4H), 3.83-3.72 (m, 2H), 3.51-3.43 (m, 2H), 3.38-3.27 (m, 2H), 3.32 (s, 3H), 3.24 (s, 3H), 2.93-2.78 (m, 2H), 2.08-1.87 (m, 2H), 1.77-1.53 (m, 6H), 1.31 (s, 3H), 1.28-1.07 (m, 6H).

Reference Example 493

N-Isopropyl-4-(4-methoxybutyl)-3-oxo-N-[(3R)-piperidin-3-yl]-2′,3,3′,4,5′,6′-hexahydrospiro[1,4-benzoxazine-2,4′-pyran]-6-carboxamide hydrochloride

RT 2.531 min (Shim-pack XR-ODS, 0.1% trifluoroacetic acid in water/acetonitrile, acetonitrile 30-90%, 5.7 min, 1.0 ml/min).

MS (ESI+) 474 (M + +1, 100%).

Reference Example 494

(2S)-2-Hydroxy-2-phenylpropanoic acid

(2S)-2-Hydroxy-2-phenylpropanoic acid-(1S)-1-(1-naphthyl)ethanamine (1:1) (1.54 g) was dissolved in methanol (50 ml), and thereto was slowly added dropwise conc. sulfuric acid (5 ml). After the addition was complete, the mixture was refluxed for 10 hours. The reaction solution was cooled to room temperature, and concentrated under reduced pressure to remove methanol. The residue was dissolved in ethyl acetate, washed with water, a saturated aqueous sodium hydrogen carbonate solution, and a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (0.83 g).

1 H NMR (400 MHz, CDCl 3 ) δ 7.47-7.44 (m, 2H), 7.36-7.29 (m, 2H), 7.29-7.23 (m, 1H), 6.00 (s, 1H), 3.60 (s, 1H), 1.62 (s, 3H).

Reference Example 495

Methyl (2S)-2-methyl-3-oxo-2-phenyl-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

Using (2S)-2-hydroxy-2-phenylpropanoic acid and methyl 4-fluoro-5-nitro-2-(trifluoromethyl)-benzoate, the title compound was obtained in a similar manner to Reference Example 22 and Reference Example 2.

MS (ESI+) 366 (M + +1, 100%).

Reference Example 496

Methyl (2S)-4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2-methyl-3-oxo-2-phenyl-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

Using methyl (2S)-2-methyl-3-oxo-2-phenyl-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate, the title compound was obtained in a similar manner to Reference Example 164.

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

Reference Example 497

tert-Butyl (3R)-3-[{[(2S)-4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2-methyl-3-oxo-2-phenyl-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Methyl (2S)-4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2-methyl-3-oxo-2-phenyl-7-(trifluoro-methyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate (1.1117 g) was dissolved in 1,4-dioxane (20 ml), and thereto was added 4N-aqueous sodium hydroxide solution (20 ml), and the mixture was stirred at 50° C. for 6 hours. The mixture was cooled to room temperature, and concentrated under reduced pressure to remove 1,4-dioxane. The residue was diluted with water, and the pH value thereof was adjusted to pH 1 with 3N-hydrochloric acid. The precipitated white solid was collected by filtration to give (2S)-4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2-methyl-3-oxo-2-phenyl-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylic acid (1.016 2 g). Thus obtained carboxylic acid (717.7 mg) was dissolved in DMF (6 ml), and thereto were added triethylamine (0.75 ml), dimethylaminopyridine (82.0 mg), tert-butyl (3R)-3-(isopropylamino)piperidine-1-carboxylate (1.3400 g), CIP reagent (1.1922 g), and the mixture was stirred at 60° C. under nitrogen atmosphere for 7 hours. To the mixture were additionally added triethylamine (0.57 ml) and CIP reagent (747.7 mg), and the mixture was further stirred at 60° C. for 4 hours. The reaction solution was cooled to room temperature, diluted with water, and 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 to give a crude product, which was purified by silica gel chromatography to give the title compound (588.4 mg).

MS (ESI+) 753 (M + +1, 26%).

Reference Example 497

tert-Butyl (3R)-3-(isopropyl{[(2S)-2-methyl-3-oxo-2-phenyl-4-[2-(propionylamino)ethyl]-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}amino)piperidine-1-carboxylate

Using tert-butyl (3R)-3-[{[(2S)-4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2-methyl-3-oxo-2-phenyl-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate, the title compound was obtained in a similar manner to Reference Example 132.

MS (ESI+) 675 (M + +1, 40%).

Reference Example 498

Methyl 2-(5-bromo-2-fluorophenyl)-2-methyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

Using methyl 2-(5-bromo-2-fluorophenyl)-2-hydroxypropanoate and methyl 4-fluoro-5-nitro-2-(trifluoromethyl)benzoate, the title compound was obtained in a similar manner to Reference Example 22 and Reference Example 2.

MS (ESI+) 463 (M + +2, 100%).

Reference Example 500

Methyl 4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2-(5-bromo-2-fluorophenyl)-2-methyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

Using methyl 2-(5-bromo-2-fluorophenyl)-2-methyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate, the title compound was obtained in a similar manner to Reference Example 164.

MS (ESI+) 641 (M + +2, 100%).

Reference Example 499

tert-Butyl (3R)-3-[{[4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2-(5-bromo-2-fluorophenyl)-2-methyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using methyl 4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2-(5-bromo-2-fluorophenyl)-2-methyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate, the title compound was obtained in a similar manner to Reference Example 497.

MS (ESI+) 851 (M + +2, 25%).

Reference Example 500

tert-Butyl (3R)-3-[{[4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2-(5-cyano-2-fluorophenyl)-2-methyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using tert-butyl (3R)-3-[{[4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2-(5-bromo-2-fluoro-phenyl)-2-methyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)-amino]piperidine-1-carboxylate, the title compound was obtained in a similar manner to Reference Example 11.

MS (ESI+) 796 (M + +1, 23%).

Reference Example 501

tert-Butyl (3R)-3-[{[2-(5-cyano-2-fluorophenyl)-2-methyl-3-oxo-4-[2-(propionylamino)ethyl]-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using tert-butyl (3R)-3-[{[4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2-(5-cyano-2-fluoro-phenyl)-2-methyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)-amino]piperidine-1-carboxylate, the title compound was obtained in a similar manner to Reference Example 132.

MS (ESI+) 718 (M + +1, 28%).

Reference Example 502

tert-Butyl (3R)-3-[{[2-(2-fluorophenyl)-2-methyl-3-oxo-4-[2-(propionylamino)ethyl]-7-(trifluoro-methyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using tert-butyl (3R)-3-[{[4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2-(5-bromo-2-fluorophenyl)-2-methyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate, the title compound was obtained in a similar manner to Reference Example 132.

MS (ESI+) 693 (M + +1, 44%).

Reference Example 503

Methyl 243-(benzyloxy)phenyl]-2-methyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

Using methyl 2-[3-(benzyloxy)phenyl]-2-hydroxypropanoate and methyl 4-fluoro-5-nitro-2-(trifluoromethyl)benzoate, the title compound was obtained in a similar manner to Reference Example 22 and Reference Example 2.

MS (ESI+) 472 (M + +1, 100%).

Reference Example 504

Methyl 4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2-[3-(benzyloxy)phenyl]-2-methyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

Using methyl 2-[3-(benzyloxy)phenyl]-2-methyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxyalte, the title compound was obtained in a similar manner to Reference Example 164.

MS (ESI+) 635 (M + +1, 18%).

Reference Example 505

tert-Butyl (3R)-3-[{[4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2-[3-(benzyloxy)phenyl]-2-methyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using methyl 4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2-[3-(benzyloxy)phenyl]-2-methyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate, the title compound was obtained in a similar manner to Reference Example 497.

MS (ESI+) 859 (M + +1, 31%).

Reference Example 506

tert-Butyl (3R)-3-[{[2-(3-hydroxyphenyl)-2-methyl-3-oxo-4-[2-(propionylamino)ethyl]-7-(trifluoromethyl)-3,4-hydroxy-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

tert-Butyl (3R)-3-[{[4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2-[3-(benzyloxy)phenyl]-2-methyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]-piperidine-1-carboxylate (279.7 mg) was dissolved in ethyl acetate (4 ml), and thereto were added triethylamine (0.10 ml), propionic anhydride (97.9 mg) and 10% palladium carbon (287.4 mg), and the mixture was stirred at room temperature for 6 hours under hydrogen atmosphere. The reaction solution was filtered on celite to remove palladium carbon, and the filtrate was concentrated under reduced pressure. The residue was dissolved in methanol (3 ml), and thereto was added potassium carbonate (142.6 mg), and the mixture was vigorously stirred at room temperature for 2 hours. To the reaction solution was added water, and the mixture was acidified with a saturated aqueous citric acid solution. The precipitated white solid was collected by filtration to give the title compound (196.8 mg).

MS (ESI+) 691 (M + +1, 21%).

Reference Example 507

tert-Butyl (3R)-3-(isopropyl{[2-methyl-2-{3-[(methylsulfonyl)oxy]phenyl}-3-oxo-4-[2-(propionyl-amino)ethyl]-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}amino)piperidine-1-carboxylate

tert-Butyl (3R)-3-[{[2-(3-hydroxyphenyl)-2-methyl-3-oxo-4-[2-(propionylamino)ethyl]-7-(trifluoromethyl)-3,4-hydroxy-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidin-1-carboxylate (123.0 mg) was dissolved in chloroform (2 ml), and thereto was added triethylamine (0.05 ml), and thereto was further added dropwise a solution of methanesulfonyl chloride (34.2 mg) in chloroform (2 ml). The mixture was stirred at room temperature for 1.5 hours. The reaction solution was washed with water, dried over sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by silica gel chromatography to give the title compound (154.7 mg).

MS (ESI+) 769 (M + +1, 63%).

Reference Example 508

Methyl 2,7-dimethyl-3-oxo-2-[3-(trifluoromethyl)phenyl]-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

Using methyl 2-hydroxy-2-[3-(trifluoromethyl)phenyl]propanoate and methyl 4-fluoro-5-nitro-2-(trifluoromethyl)benzoate, the title compound was obtained in a similar manner to Reference Example 22 and Reference Example 2.

MS (ESI+) 380 (M + +1, 100%).

Reference Example 509

Methyl 4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2,7-dimethyl-3-oxo-2-[3-(trifluoromethyl)phenyl]-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

Using methyl 2,7-dimethyl-3-oxo-2-[3-(trifluoromethyl)phenyl]-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate, the title compound was obtained in a similar manner to Reference Example 164.

MS (ESI+) 557 (M + +1, 61%).

Reference Example 510

tert-Butyl (3R)-3-[({2,7-dimethyl-3-oxo-4-[2-(propionylamino)ethyl]-2-[3-(trifluoromethyl)phenyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)(isopropyl)amino]piperidine-1-carboxylate

Methyl 4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2,7-dimethyl-3-oxo-2-[3-(trifluoromethyl)-phenyl]-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate (368.0 mg) was dissolved in 1,4-dioxane (5 ml), and thereto was added a 4N-aqueous sodium hydroxide solution (5 ml). The mixture was stirred at 60° C. for 2.5 hours, and cooled to room temperature. The mixture was concentrated under reduced pressure to remove 1,4-dioxane, and the residue was diluted with water, and the pH value thereof was adjusted to pH 1 with 3N-hydrochloric acid. The precipitated white solid was collected by filtration to give 4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2,7-dimethyl-3-oxo-2-[3-(trifluoromethyl)phenyl]-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylic acid (340.0 mg). This carboxylic acid was dissolved in DMF (5 ml), and thereto were added triethylamine (0.35 ml), dimethylaminopyridine (45.2 mg), tert-butyl (3R)-3-(isopropylamino)piperidine-1-carboxylate (665.1 mg), CIP reagent (583.6 mg), and the mixture was stirred at 60° C. under nitrogen atmosphere for 4 hours. To the mixture were added again triethylamine (0.26 ml), CIP reagent (351.0 mg), and the mixture was further stirred at 60° C. for 5 hours. The reaction solution was cooled to room temperature, diluted with water, 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 to give a crude product, which was purified by silica gel chromatography to give tert-butyl (3R)-3-[({4-(2-{[(benzyloxy)-carbonyl]amino}ethyl)-2,7-dimethyl-3-oxo-2-[3-(trifluoromethyl)phenyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)(isopropyl)amino]piperidine-1-carboxylate (314.5 mg). Subsequently, this product was dissolved in ethyl acetate (10 ml), and thereto were added 10% palladium carbon (362.7 mg) and propionic anhydride (116.1 mg), and the mixture was vigorously stirred under hydrogen atmosphere for 4 hours. The mixture was filtered on celite to remove palladium carbon, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (259.6 mg).

MS (ESI+) 689 (M+1, 6%).

Reference Example 511

tert-Butyl (3R)-3-(isopropyl{[(2S)-2-methyl-3-oxo-2-phenyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl]-carbonyl}amino)piperidine-1-carboxylate

Using tert-butyl (3R)-3-[(4-fluoro-3-nitrobenzoyl)(isopropyl)amino]piperidine-1-carboxylate and (2S)-2-hydroxy-2-phenylpropanoic acid, the title compound was obtained in a similar manner to Reference Example 22 and Reference Example 2.

MS (ESI+) 508 (M + +1, 38%).

Reference Example 512

tert-Butyl (3R)-3-[{[(2S)-4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2-methyl-3-oxo-2-phenyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using tert-butyl (3R)-3-(isopropyl{[(2S)-2-methyl-3-oxo-2-phenyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}amino)piperidine-1-carboxylate, the title compound was obtained in a similar manner to Reference Example 164.

MS (ESI+) 685 (M + +1, 38%).

Reference Example 513

tert-Butyl (3R)-3-[({(2S)-7-chloro-2-methyl-3-oxo-2-phenyl-4-[2-(propionylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)(isopropyl)amino]piperidine-1-carboxylate

Using tert-butyl (3R)-3-[{[(2S)-4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2-methyl-3-oxo-2-phenyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate, the title compound was obtained in a similar manner to Reference Example 132 and Reference Example 12.

MS (ESI+) 641 (M+, 7%).

Reference Example 514

tert-Butyl (3R)-3-[{[(2S)-4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-7-bromo-2-methyl-3-oxo-2-phenyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using tert-butyl (3R)-3-[{[(2S)-4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2-methyl-3-oxo-2-phenyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate, the title compound was obtained in a similar manner to Reference Example 6.

MS (ESI+) 763 (M+, 15%).

Reference Example 515

tert-Butyl (3R)-3-[{[(2S)-4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2,7-dimethyl-3-oxo-2-phenyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using tert-butyl (3R)-3-[{[(2S)-4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-7-bromo-2-methyl-3-oxo-2-phenyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate, the title compound was obtained in a similar manner to Reference Example 10.

MS (ESI+) 699 (M + +1, 72%).

Reference Example 516

tert-Butyl (3R)-3-[({(2S)-2,7-dimethyl-3-oxo-2-phenyl-4-[2-(propionylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)(isopropyl)amino]piperidine-1-carboxylate

Using tert-butyl (3R)-3-[{[(2S)-4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2,7-dimethyl-3-oxo-2-phenyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate, the title compound was obtained in a similar manner to Reference Example 132.

MS (ESI+) 621 (M + +1, 14%).

Reference Example 517

1-tert-Butyl 3-ethyl 4-oxopiperidine-1,3-dicarboxylate

Ethyl 4-piperidone-3-carboxylate hydrochloride (5.0 g) was dissolved in tetrahydrofuran (30 ml), and thereto were added 10% aqueous potassium carbonate solution (30 ml) and di-tert-butyl dicarbonate (5.8 g) under ice-cooling. Then, the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. The organic layer was washed with a 10% aqueous citric acid solution and an aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound (5.0 g) as a white solid.

1 H-NMR (300 MHz, CDCl 3 ) δ 12.03 (br, 1H), 4.25-4.18 (m, 2H), 4.04 (brs, 2H), 3.56-3.53 (m, 2H), 2.37-2.33 (m, 2H), 1.67 (brs, 2H), 1.46 (s, 9H), 1.31-1.26 (m, 3H).

Reference Example 518

1-tert-Butyl 3-ethyl 4-{[(trifluoromethyl)sulfonyl]oxy}-5,6-dihydropyridin-1,3(2H)-dicarboxylate

1-tert-Butyl 3-ethyl 4-oxopiperidine-1,3-dicarboxylate (7.0 g) was dissolved in methylene chloride (100 ml), and the mixture was cooled to −78° C. To the mixture were added diisopropylethylamine (6.7 ml) and trifluoromethanesulfonic anhydride (5.6 ml). Then, the mixture was stirred at room temperature for 3 days. To the reaction mixture was added an aqueous sodium hydrogen carbonate solution, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=15:1→10:1) to give the title compound (7.0 g) as a pale yellow oil.

MS (ESI+) 404 (M+1, 10%).

Reference Example 519

1-tert-Butyl 3-ethyl 4-biphenyl-3-yl-5,6-dihydropyridine-1,3(2H)-dicarboxylate

1-tert-Butyl-3-ethyl-4-{[(trifluoromethyl)sulfonyl]oxy}-5,6-dihydropyridin-1,3(2H)-dicarboxylate (500 mg) was dissolved in dimethoxyethane (10 ml), and thereto were added at room temperature 3-(N,N-dimethylaminocarbonyl)phenylboronic acid (262 mg), tetrakis(triphenylphosphine) palladium (72 mg), potassium carbonate (514 mg), and the mixture was stirred at 80° C. for 6 hours. The reaction mixture was cooled, and water was added thereto. The mixture was extracted with ethyl acetate, and the organic layer was washed with water, dried over magnesium sulfate, filtered, concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=3:1→2:1) to give the title compound (370 mg) as a colorless clear oil.

MS (ESI+) 408 (M + +1, 100%).

Reference Example 520

(3R,4S)-4-Biphenyl-3-yl-1-(tert-butoxycarbonyl)piperidine 3-carboxylic acid and (3S,4R)-4-biphenyl-3-yl-1-(tert-butoxycarbonyl)piperidine 3-carboxylic acid

1-tert-Butyl 3-ethyl 4-biphenyl-3-yl-5,6-dihydropyridin-1,3(2H)-dicarboxylate (820 mg) was dissolved in methanol (10 ml), and thereto was added magnesium (490 mg) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered on celite, and concentrated under reduced pressure. The residue was diluted with ethyl acetate, and the organic layer was washed with an aqueous ammonium chloride solution and a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was dissolved in ethanol (10 ml), and thereto was added sodium ethoxide (20% ethanol solution, 1.2 ml) at room temperature, and the mixture was stirred at 60° C. for 4 hours. The reaction mixture was cooled, and concentrated under reduced pressure. To the residue was added a 5% aqueous sodium hydrogen sulfate solution, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran-ethanol-water (5 ml-3 ml-1.5 ml), and thereto was added sodium hydroxide (276 mg) at room temperature. The mixture was stirred at room temperature for 16 hours. To the reaction mixture was added a 5% aqueous sodium hydrogen sulfate solution, and extracted with chloroform. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound (344 mg) as amorphous.

MS (ESI+) 410 (M + +1, 100%).

Reference Example 521

tert-Butyl (3R,4R)-3-{[(benzyloxy)carbonyl]amino}-4-biphenyl-3-ylpiperidine-1-carboxylate and tert-butyl (3S,4S)-3-{[(benzyloxy)carbonyl]amino}-4-biphenyl-3-ylpiperidine-1-carboxylate

(3R,4S)-4-Biphenyl-3-yl-1-(tert-butoxycarbonyl)piperidine 3-carboxylic acid and (3S,4R)-4-biphenyl-3-yl-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (320 mg) was dissolved in toluene (9 ml), and thereto were added triethylamine (102 mg) and diphenylphosphoryl azide (254 mg) at room temperature, and the mixture was stirred at 80° C. for one hour. The reaction mixture was cooled to 50° C., and thereto was added benzyl alcohol (273 mg), and the mixture was stirred at 80° C. for 10 hours. The reaction mixture was cooled, and water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1:1→1:2) to give the title compound (400 mg) as amorphous.

MS (ESI+) 487 (M + +1, 100%).

Reference Example 522

tert-Butyl (3R,4R)-3-amino-4-biphenyl-3-ylpiperidine-1-carboxylate and tert-butyl (3S,4S)-3-amino-4-biphenyl-3-ylpiperidine-1-carboxylate

To a solution of tert-butyl (3R,4R)-3-{[(benzyloxy)carbonyl]amino}-4-biphenyl-3-ylpiperidine-1-carboxylate and tert-butyl (3S,4S)-3-{[(benzyloxy)carbonyl]amino}-4-biphenyl-3-ylpiperidine-1-carboxylate (400 mg) in methanol (10 ml) was added 10% palladium carbon (180 mg), and the mixture was stirred at room temperature under hydrogen atmosphere for 3 hours. The insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (296 mg) as pale yellow oil.

MS (ESI+) 353 (M + +1, 100%).

Reference Example 523

tert-Butyl (3R,4R)-4-biphenyl-3-yl-3-(isopropylamino)piperidine-1-carboxylate and tert-butyl (3S,4S)-4-biphenyl-3-yl-3-(isopropylamino)piperidine-1-carboxylate

tert-Butyl (3R,4R)-3-amino-4-biphenyl-3-ylpiperidine-1-carboxylate and tert-butyl (3S,4S)-3-amino-4-biphenyl-3-ylpiperidine-1-carboxylate (296 mg) were dissolved in methanol (5 ml), and thereto were added acetone (244 mg) and acetic acid (0.048 mL), and the mixture was stirred at room temperature for one hour. To this reaction mixture was added sodium triacetoxyborohydride (534 mg), and the mixture was stirred at room temperature for 14 hours. To this reaction mixture was added ice-cooled diluted aqueous sodium hydroxide solution, and the insoluble materials were moved by filtration, and the filtrate was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (194 mg) as pale brown oil.

MS (ESI+) 396 (M + +1, 100%).

Reference Example 524

tert-Butyl (3R,4R)-3-[{[4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]-4-biphenyl-3-ylpiperidine-1-carboxylate and tert-butyl (3S,4S)-3-[{[4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]-4-biphenyl-3-ylpiperidine-1-carboxylate

Using methyl 4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2,2-dimethyl-3-oxo-7-(trifluoro-methyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate and tert-butyl (3R,4R)-4-biphenyl-3-yl-3-(isopropylamino)piperidine-1-carboxylate, and tert-butyl (3S,4S)-4-biphenyl-3-yl-3-(isopropylamino)piperidine-1-carboxylate, the title compound (98 mg) was obtained in a similar manner to Reference Example 5.

MS (ESI+) 844 (M + +1, 21%).

Reference Example 525

tert-Butyl (3R,4R)-3-[{[4-(2-aminoethyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]-4-biphenyl-3-ylpiperidine-1-carboxylate and tert-butyl (3S,4S)-3-[{[4-(2-aminoethyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]-4-biphenyl-3-ylpiperidine-1-carboxylate

Using tert-butyl (3R,4R)-3-[{[4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]-4-biphenyl-3-ylpiperidine-1-carboxylate and tert-butyl (3S,4S)-3-[{[4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]-4-biphenyl-3-ylpiperidine-1-carboxylate, the title compound (74 mg) was obtained in a similar manner to Reference Example 139.

MS (ESI+) 710 (M + +1, 46%).

Reference Example 526

tert-Butyl (3R,4R)-4-biphenyl-3-yl-3-[{[2,2-dimethyl-3-oxo-4-[2-(propionylamino)ethyl]-7-(trifluoro-methyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate and tert-butyl (3S,4S)-4-biphenyl-3-yl-3-[{[2,2-dimethyl-3-oxo-4-[2-(propionylamino)ethyl]-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using tert-butyl (3R,4R)-3-[{[4-(2-aminoethyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]-4-biphenyl-3-ylpiperidine-1-carboxylate and tert-butyl (3S,4S)-3-[{[4-(2-aminoethyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]-4-biphenyl-3-ylpiperidine-1-carboxylate, the title compound (50 mg) was obtained in a similar manner to Reference Example 132.

MS (ESI+) 766 (M + +1, 16%).

Reference Example 527

tert-Butyl (3R)-3-[{[2,2-dimethyl-3-oxo-7-(trifluoromethyl)-4-(2-{[1-(trifluoromethyl)propyl]amino}-ethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

To a solution of tert-butyl (3R)-3-[{[4-(2-aminoethyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate (278 mg) in methylene chloride (2 ml) were added 1,1,1-trifluoro-2-butanone (0.1 ml), diisopropylethylamine (0.34 ml), and titanium tetrachloride (0.05 ml), and the mixture was stirred at room temperature for 3 hours. Then, to the reaction solution were added sodium cyanoborohydride (110 mg) and methanol (10 ml), and the mixture was stirred at room temperature for one hour. To the reaction solution was added a saturated aqueous sodium hydrogen carbonate solution (10 ml), and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=3:1) to give the title compound (100 mg) as amorphous.

MS (ESI+) 667 (M + +1, 100%).

Reference Example 528

Ethyl 4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-6-{[[(3R)-1-(tert-butoxycarbonyl)piperidin-3-yl](isopropyl)amino]carbonyl}-2-methyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylate

Using ethyl 6-{[[(3R)-1-(tert-butoxycarbonyl)piperidin-3-yl](isopropyl)amino]carbonyl}-2-methyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylate, the title compound was obtained in a similar manner to Reference Example 164.

MS (ESI+) 749 (M + +1, 30%).

Reference Example 529

4-(2-{Benzyl[(benzyloxy)carbonyl]amino}ethyl)-6-{[[(3R)-1-(tert-butoxycarbonyl)piperidin-3-yl](isopropyl)amino]carbonyl}-2-methyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid

To a solution of ethyl 4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-6-{[[(3R)-1-(tert-butoxycarbonyl)piperidin-3-yl](isopropyl)amino]carbonyl}-2-methyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylate (1.00 g) in N,N-dimethylacetamide (2.7 ml) was added at 0° C. benzyl bromide (0.794 ml), and sodium hydride (193 mg), and the mixture was stirred for one hour. To the reaction solution were added 2N-aqueous sodium hydroxide solution (5.36 ml) and tetrahydrofuran (5.0 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. The obtained residue was purified by silica gel column chromatography (chloroform /methanol=100/3, containing 5% acetic acid) to give the title compound (0.800 g).

MS (ESI+) 811 (M + +1, 44%).

Reference Example 530

tert-Butyl (3R)-3-[{[4-(2-{benzyl[(benzyloxy)carbonyl]amino}ethyl)-2-(hydroxymethyl)-2-methyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using 4-(2-{benzyl[(benzyloxy)carbonyl]amino}ethyl)-6-{[[(3R)-1-(tert-butoxycarbonyl)-piperidin-3-yl](isopropyl)amino]carbonyl}-2-methyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid, the title compound was synthesized in a similar manner to Reference Example 35.

MS (ESI+) 797 (M + +1, 32%).

Reference Example 531

tert-Butyl (3R)-3-[{[4-(2-{benzyl[(benzyloxy)carbonyl]amino}ethyl)-2-(methoxymethyl)-2-methyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using tert-butyl (3R)-3-[{[4-(2-{benzyl[(benzyloxy)carbonyl]amino}ethyl)-2-(hydroxy-methyl)-2-methyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)-amino]piperidine-1-carboxylate, the title compound was synthesized in a similar manner to Reference Example 36.

MS (ESI+) 811 (M + +1, 44%).

Reference Example 532

tert-Butyl (3R)-3-(isopropyl{[4-{2-[(methoxycarbonyl)amino]ethyl}-2-(methoxymethyl)-2-methyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}amino)piperidine-1-carboxylate

Using tert-butyl (3R)-3-[{[4-(2-{benzyl[(benzyloxy)carbonyl]amino}ethyl)-2-(methoxy-methyl)-2-methyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}-(isopropyl)amino]piperidine-1-carboxylate, the title compound was synthesized in a similar manner to Reference Example 139, Reference Example 162.

MS (ESI+) 645 (M + +1, 69%).

Reference Example 533

tert-Butyl (3R)-3-(isopropyl{[2-(methoxymethyl)-2-methyl-3-oxo-4-[2-(propionylamino)ethyl]-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}amino)piperidine-1-carboxylate

Using tert-butyl (3R)-3-[{[4-(2-{benzyl[(benzyloxy)carbonyl]amino}ethyl)-2-(methoxy-methyl)-2-methyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}-(isopropyl)amino]piperidine-1-carboxylate, the title compound was synthesized in a similar manner to Reference Example 132.

MS (ESI+) 643 (M + +1, 74%).

Reference Example 534

Methyl {2-[(2S)-6-({isopropyl[(3R)-piperidin-3-yl]amino}carbonyl)-2-(methoxymethyl)-2-methyl-3-oxo-7-(trifluoromethyl)-2,3-dihydro-4H-1,4-benzoxazin-4-yl]ethyl}carbamate hydrochloride

Methyl {2-[(2R)-6-({isopropyl[(3R)-piperidin-3-yl]amino}carbonyl)-2-(methoxymethyl)-2-methyl-3-oxo-7-(trifluoromethyl)-2,3-dihydro-4H-1,4-benzoxazin-4-yl]ethyl}carbamate hydrochloride

Methyl {2-[6-({isopropyl[(3R)-piperidin-3-yl]amino}carbonyl)-2-(methoxymethyl)-2-methyl-3-oxo-7-(trifluoromethyl)-2,3-dihydro-4H-1,4-benzoxazin-4-yl]ethyl}carbamate hydrochloride (10 mg) was separated by optically active column chromatography (CHIRALCEL OD-H, 2 cmφ×25 cm, hexane:ethanol:diethylamine=80:20:0.3˜50:50:0.3) to give the title compounds.

Methyl {2-[(2S)-6-({isopropyl[(3R)-piperidin-3-yl]amino}carbonyl)-2-(methoxymethyl)-2-methyl-3-oxo-7-(trifluoromethyl)-2,3-dihydro-4H-1,4-benzoxazin-4-yl]ethyl}carbamate hydrochloride

Chiral column retention time: 7.26 minutes (CHIRALCEL OD-H, 0.46 cmφ×25 cm, hexane:ethanol:diethylamine=80:20:0.3, flow rate: 1.00 ml/minute)

Methyl {2-[(2R)-6-({isopropyl[(3R)-piperidin-3-yl]amino}carbonyl)-2-(methoxymethyl)-2-methyl-3-oxo-7-(trifluoromethyl)-2,3-dihydro-4H-1,4-benzoxazin-4-yl]ethyl}carbamate hydrochloride

Chiral column retention time: 27.78 minutes (CHIRALCEL OD-H, 0.46 cmφ×25 cm, hexane:ethanol:diethylamine=80:20:0.3, flow rate: 1.00 ml/minute).

Reference Example 535

tert-Butyl 4-phenyl-3,6-dihydropyridin-1(2H)-carboxylate

To a solution of 4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (354.6 g) in acetonitrile (12 L) was added triethylamine (366.9 g) at 20° C. in a water-bath, and the mixture was stirred for 15 minutes. To the reaction solution was added dropwise a solution of di-t-butyl carbonate (474.5 g) in acetonitrile (700 ml) at 15˜19° C. in a water-bath, and further thereto was added N,N-dimethylamino-pyridine (11.06 g). The mixture was stirred at room temperature for 12 hours, and the solvent was removed by evaporation under reduced pressure. The obtained residue was diluted with methylene chloride (10 L), and washed with 1M hydrochloric acid (×3) and 5% saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium hydrogen sulfate, and the solvent was evaporated under reduced pressure to give a crude product (470.6 g). The obtained crude product was purified by silica gel column chromatography (methylene chloride/methanol=1/0→50/1) to give the title compound (456.8 g).

1 H NMR (400 MHz, CDCl 3 ) δ 9.77 (s, 1H), 7.79-7.76 (m, 1H), 7.28-7.22 (m, 1H), 7.03-6.99 (m, 1H), 3.88 (s, 3H).

Reference Example 536

tert-Butyl (3R,4R)-3,4-dihydroxy-4-phenylpiperidine-1-carboxylate

To a solution of potassium osmate (VI) 2 hydrate (8.0 g), (DHQD) 2 PHAL (14.2 g), potassium carbonate (379 g), potassium hexacyanoferrate (III) (903 g) in t-butanol (4.8 L) and water (4.8 L) was added methenesulfonamide (73.4 g) at room temperature. Then, tert-butyl 4-phenyl-3,6-dihydropyridine-1(2H)-carboxylate (200 g) was added thereto in an ice-bath, and the mixture was stirred for 2 hours. The mixture was further stirred at room temperature for 12 hours, and thereto was added methylene chloride (7.0 L) for separation to give the organic layer. The aqueous layer was washed twice with methylene chloride, and the obtained organic layers were combined, washed with 2M aqueous potassium hydroxide solution, dried over anhydrous sodium sulfate, and the solvent was removed by evaporation under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to give the title compound (215.5 g).

1 H NMR (300 MHz, CD 3 OD) δ 7.42-7.39 (m, 2H), 7.26-7.21 (m, 2H), 7.15-7.09 (m, 1H), 4.01-3.92 (m, 3H), 3.81-3.76 (m, 2H), 1.85-1.76 (m, 1H), 1.63-1.58 (m, 1H), 1.39 (s, 9H).

Reference Example 537

tert-Butyl (3S,4S)-3-hydroxy-4-phenylpiperidine-1-carboxylate

To a solution of tert-butyl (3R,4R)-3,4-dihydroxy-4-phenylpiperidine-1-carboxylate (120 g) in ethanol (4.3 L) was added Raney nickel (240 g), and the mixture was refluxed for 48 hours with bubbling of hydrogen gas. The reaction solution was cooled, and filtered on celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to give the title compound (105.1 g, 99.4% ee).

1 H NMR (300 MHz, CDCl 3 ) δ 7.39-7.24 (m, 5H), 4.40 (m, 1H), 4.15-4.08 (m, 1H), 3.69 (m, 1H), 2.76-2.48 (m, 3H), 1.84-1.53 (m, 2H), 1.49 (s, 9H).

Reference Example 538

tert-Butyl (3R,4S)-3-amino-4-phenylpiperidine-1-carboxylate

To a solution of tert-butyl (3S,4S)-3-hydroxy-4-phenylpiperidine-1-carboxylate (105.1 g), triphenylphosphine (198.8 g) and phthalimide (111.5 g) in tetrahydrofuran (2.6 L) was added dropwise a solution of diethyl azodicarboxylate (2.2M toluene solution, 345 ml) at 0° C. The reaction solution was stirred at 0° C. for 2 hours, and the temperature thereof was raised slowly, and the mixture was stirred at room temperature for 12 hours. The reaction solution was evaporated under reduced pressure to remove the solvent, and the obtained residue was separated with methylene chloride and water to give the organic layer. The aqueous layer was extracted twice with methylene chloride. The obtained organic layers were combined, and washed twice with water (×2) 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=6/1→4/1) to give a crude product (549.5 g).

The obtained crude product was suspended in toluene (1.4 L), and thereto were added hydrazine monohydrate (83.6 ml), and the mixture was refluxed for 12 hours. The reaction solution was cooled, filtered, and the filtrate was washed with water (×2) and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was removed by evaporation under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/ethyl acetate=6/1→2/1) to give the title compound (32.4 g).

1 H NMR (300 MHz, CDCl 3 ) δ 7.37-7.20 (m, 5H), 4.32-4.19 (m, 2H), 3.18-3.05 (m, 2H), 2.92-2.80 (m, 2H), 2.23-2.18 (m, 1H), 1.64-1.61 (m, 1H), 1.48 (s, 9H).

Reference Example 539

tert-Butyl (3R,4S)-3-({[4-(4-methoxybutyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}amino)-4-phenylpiperidine-1-carboxylate

To a solution of 4-(4-methoxybutyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylic acid (739 mg) in DMF (5 ml) were added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (755 mg), 1-hydroxybenzotriazole (532 mg), triethylamine (549 μl), tert-butyl (3R,4S)-3-amino-4-phenylpiperidine-1-carboxylate (653 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 ammonium chloride solution, a saturated aqueous sodium hydrogen carbonate solution and 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 (the developing solvent: hexane/ethyl acetate=3/1) to give the title compound (1.25 g).

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

Reference Example 540

tert-Butyl (3R,4S)-3-(ethyl{[4-(4-methoxybutyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}amino)-4-phenylpiperidine-1-carboxylate

To a solution of tert-butyl (3R,4S)-3-({[4-(4-methoxybutyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}amino)-4-phenylpiperidine-1-carboxylate (386 mg) in DMF (1 ml) was added sodium hydride (48.7 mg) at 0° C., and the mixture was stirred for 10 minutes. To the mixture was added ethyl iodide (126 μl), and the mixture was stirred at room temperature for 5 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 (×2) 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 (the developing solvent: hexane/ethyl acetate=3/1) to give the title compound (128 g).

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

Reference Example 541

tert-Butyl (3S,4S)-3,4-dihydroxy-4-phenylpiperidine-1-carboxylate

Using tert-butyl 4-phenyl-3,6-dihydropyridin-1(2H)-carboxylate and AD-mix-α, the title compound was obtained in a similar manner to Reference Example 538.

1 H NMR (300 MHz, CD 3 OD) δ 7.42-7.39 (m, 2H), 7.26-7.21 (m, 2H), 7.15-7.09 (m, 1H), 4.01-3.92 (m, 3H), 3.81-3.76 (m, 2H), 1.85-1.76 (m, 1H), 1.63-1.58 (m, 1H), 1.39 (s, 9H).

Reference Example 542

tert-Butyl (3R,4R)-3-hydroxy-4-phenylpiperidine-1-carboxylate

Using tert-butyl (3S,4S)-3,4-dihydroxy-4-phenylpiperidine-1-carboxylate, the title compound was obtained in a similar manner to Reference Example 539.

1 H NMR (300 MHz, CDCl 3 ) δ 7.39-7.24 (m, 5H), 4.40 (m, 1H), 4.15-4.08 (m, 1H), 3.69 (m, 1H), 2.76-2.48 (m, 3H), 1.84-1.53 (m, 2H), 1.49 (s, 9H).

Reference Example 543

tert-Butyl (3S,4R)-3-amino-4-phenylpiperidine-1-carboxylate

Using tert-butyl (3R,4R)-3-hydroxy-4-phenylpiperidine-1-carboxylate, the title compound was obtained in a similar manner to Reference Example 540.

1 H NMR (300 MHz, CDCl 3 ) δ 7.37-7.20 (m, 5H), 4.32-4.19 (m, 2H), 3.18-3.05 (m, 2H), 2.92-2.80 (m, 2H), 2.23-2.18 (m, 1H), 1.64-1.61 (m, 1H), 1.48 (s, 9H).

Reference Example 544

tert-Butyl (3S,4R)-3-({[4-(4-methoxybutyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}amino)-4-phenylpiperidine-1-carboxylate

Using 4-(4-methoxybutyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylic acid and tert-butyl (3S,4R)-3-amino-4-phenylpiperidine-1-carboxylate, the title compound was obtained in a similar manner to Reference Example 541.

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

Reference Example 547

tert-Butyl (3S,4R)-3-(ethyl {[4-(4-methoxybutyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}amino)-4-phenylpiperidine-1-carboxylate

Using tert-butyl (3S,4R)-3-({[4-(4-methoxybutyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}amino)-4-phenylpiperidine-1-carboxylate, the title compound was obtained in a similar manner to Reference Example 542.

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

Reference Example 545

tert-Butyl (3S)-3-(isopropylamino)piperidine-1-carboxylate

Using tert-butyl (3S)-3-aminopiperidine-1-carboxylate, the title compound was obtained in a similar manner to Reference Example 482.

MS (ESI+) 243 (M+1, 100%).

Reference Example 546

tert-Butyl (3S)-3-(isopropyl{[4-(4-methoxybutyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}amino)piperidine-1-carboxylate

Using methyl 4-(4-methoxybutyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate and tert-butyl (3S)-3-(isopropylamino)piperidine-1-carboxylate, the title compound was obtained in a similar manner to Reference Example 5.

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

Reference Example 547

1-tert-Butyl 3-ethyl 4-phenyl-5,6-dihydropyridin-1,3(2H)-dicarboxylate

1-tert-Butyl-3-ethyl-4-{[(trifluoromethyl)sulfonyl]oxy}-5,6-dihydropyridin-1,3(2H)-dicarboxylate (8.97 g) was dissolved in dimethoxyethane (30 ml) and water (30 ml), and thereto were added phenylboronic acid (4.07 g), tetrakis(triphenylphosphine) palladium (2.57 g), and sodium carbonate (4.71 g) at room temperature, and the mixture was stirred at 80° C. for 2 hours. The reaction mixture was cooled, filtered on celite, and 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 (the developing solvent: hexane/ethyl acetate=5/1) to give the title compound (7.07 g) as pale yellow clear oil.

MS (ESI+) 332 (M + +1, 100%).

Reference Example 548

1-(tert-Butoxycarbonyl)-4-phenyl-1,2,5,6-tetrahydropyridin-3-carboxylic acid

1-tert-Butyl 3-ethyl 4-phenyl-5,6-dihydropyridin-1,3(2H)-dicarboxylate (7.07 g) was dissolved in ethanol (50 ml), and thereto was added 1M aqueous sodium hydroxide solution (50 ml), and the mixture was refluxed for 2 hours. The reaction solution was concentrated under reduced pressure, and thereto was added 1M aqueous sodium hydroxide solution and ethyl acetate for separation. To the organic layer was added 1M aqueous sodium hydroxide solution for separation, and the aqueous layers were combined, and the pH value thereof was adjusted to pH<2 by the addition of 2M hydrochloric acid. The mixture was extracted with chloroform, and the organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (5.63 g).

MS (ESI+) 304 (M + +1, 100%).

Reference Example 549

(rac.)-(3S,4S)-1-(tert-Butoxycarbonyl)-4-phenylpiperidine 3-carboxylic acid

1-(tert-Butoxycarbonyl)-4-phenyl-1,2,5,6-tetrahydropyridin-3-carboxylic acid (5.63 g) was dissolved in methanol (60 ml), and thereto was added palladium-carbon (4.06 g), and the mixture was stirred under hydrogen atmosphere for 2 hours. The reaction solution was filtered on celite, and concentrated under reduced pressure to give the title compound (4.76 g).

MS (ESI+) 306 (M + +1, 100%).

Reference Example 550

(3S,4S)-1-(tert-Butoxycarbonyl)-4-phenylpiperidine 3-carboxylic acid

(rac.)-(3S,4S)-1-(tert-Butoxycarbonyl)-4-phenylpiperidine 3-carboxylic acid (4.76 g) was dissolved in methanol (90 ml), and thereto was added (S)-(−)-phenylethylamine (1.59 g), and the mixture was refluxed for 2 hours. The mixture was slowly cooled to room temperature, and the mixture was allowed to stand at 0° C. for 12 hours. The precipitates were collected by filtration, and recrystallized from ethyl acetate and methanol to give the crystals (1.51 g). To the obtained crystals 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 to give the title compound (1.12 g, >99% ee).

MS (ESI+) 306 (M + +1, 100%).

Reference Example 551

1-tert-Butyl 3-methyl (3S,4S)-4-phenylpiperidine-1,3-dicarboxylate

To a solution of (3S,4S)-1-(tert-butoxycarbonyl)-4-phenylpiperidine-3-carboxylic acid (1.12 g) in DMF (12 ml) were added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.41 g), N,N-dimethylaminopyridine (992 mg), triethylamine (1.02 ml) and methanol (595 μl), 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 ammonium chloride solution, 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 (the developing solvent: hexane/ethyl acetate=5/1) to give the title compound (1.00 g).

MS (ESI+) 320 (M + +1, 100%).

Reference Example 552

1-tert-Butyl 3-methyl (3R,4S)-4-phenylpiperidine-1,3-dicarboxylate

1-tert-Butyl 3-methyl (3S,4S)-4-phenylpiperidine-1,3-dicarboxylate (1.00 g) was dissolved in methanol (40 ml), and thereto was added sodium methoxide (1.0 M methanol solution, 4.70 ml), and the mixture was refluxed for 9 hours. The reaction mixture was cooled, and concentrated under reduced pressure. To the residue 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 (the developing solvent: hexane/ethyl acetate=5/1) to give the title compound (585 mg).

MS (ESI+) 320 (M + +1, 100%).

Reference Example 553

(3R,4S)-1-(tert-Butoxycarbonyl)-4-phenylpiperidine 3-carboxylic acid

1-tert-Butyl 3-methyl (3R,4S)-4-phenylpiperidine-1,3-dicarboxylate (585 mg) was dissolved in tetrahydrofuran (5 ml) and methanol (5 ml), and thereto was added 1M aqueous sodium hydroxide solution (5.5 ml), and the mixture was stirred at room temperature 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 sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (546 mg).

MS (ESI+) 306 (M + +1, 100%).

Reference Example 554

tert-Butyl (3R,4R)-3-amino-4-phenylpiperidine-1-carboxylate

(3R,4S)-1-(tert-Butoxycarbonyl)-4-phenylpiperidine-3-carboxylic acid (546 mg) was dissolved in toluene (5 ml), and thereto were added triethylamine (374 μl) and diphenylphosphoryl azide (591 mg) at room temperature, and the mixture was stirred at 110° C. for 3 hours. The reaction mixture was cooled to 80° C., and thereto was added benzyl alcohol (556 μl), and the mixture was stirred for 3 hours. The reaction mixture was cooled, and water was added thereto. 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 (the developing solvent: hexane/ethyl acetate=2/1) to give the crude product (1.92 g).

The obtained residue was dissolved in tetrahydrofuran (8 ml), and thereto was added 10% palladium carbon (910 mg) at room temperature, and the mixture was stirred at room temperature under hydrogen atmosphere for 5 hours. The reaction mixture was filtered on celite, 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 (270 mg).

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

Reference Example 555

tert-Butyl (3R,4R)-3-({[4-(4-methoxybutyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}amino)-4-phenylpiperidine-1-carboxylate

Using 4-(4-methoxybutyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylic acid and tert-butyl (3R,4R)-3-amino-4-phenylpiperidine-1-carboxylate, the title compound was obtained in a similar manner to Reference Example 541.

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

Reference Example 556

tert-Butyl (3R,4R)-3-(ethyl {[4-(4-methoxybutyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}amino)-4-phenylpiperidine-1-carboxylate

Using tert-butyl (3R,4R)-3-({[4-(4-methoxybutyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}amino)-4-phenylpiperidine-1-carboxylate, the title compound was obtained in a similar manner to Reference Example 542.

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

Reference Example 557

(3R,4R)-1-(tert-Butoxycarbonyl)-4-phenylpiperidine-3-carboxylic acid

Using (rac.)-(3S,4S)-1-(tert-butoxycarbonyl)-4-phenylpiperidine-3-carboxylic acid, (R)-(+)-phenylethylamine, the title compound was obtained in a similar manner to Reference Example 553.

MS (ESI+) 306 (M + +1, 100%).

Reference Example 558

1-tert-Butyl 3-methyl (3R,4R)-4-phenylpiperidine-1,3-dicarboxylate

Using (3R,4R)-1-(tert-butoxycarbonyl)-4-phenylpiperidine 3-carboxylic acid, the title compound was obtained in a similar manner to Reference Example 554.

MS (ESI+) 320 (M + +1, 100%).

Reference Example 559

1-tert-Butyl 3-methyl (3S,4R)-4-phenylpiperidine-1,3-dicarboxylate

Using 1-tert-butyl 3-methyl (3R,4R)-4-phenylpiperidine-1,3-dicarboxylate, the title compound was obtained in a similar manner to Reference Example 555.

MS (ESI+) 320 (M + +1, 100%).

Reference Example 560

(3S,4R)-1-(tert-Butoxycarbonyl)-4-phenylpiperidine-3-carboxylic acid

Using 1-tert-butyl 3-methyl (3S,4R)-4-phenylpiperidine 1,3-dicarboxylate, the title compound was obtained in a similar manner to Reference Example 556.

MS (ESI+) 306 (M + +1, 100%).

Reference Example 561

tert-Butyl (3S,4S)-3-amino-4-phenylpiperidine-1-carboxylate

Using (3S,4R)-1-(tert-butoxycarbonyl)-4-phenylpiperidine-3-carboxylic acid, the title compound was obtained in a similar manner to Reference Example 557.

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

Reference Example 562

tert-Butyl (3S,4S)-3-({[4-(4-methoxybutyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]-carbonyl]amino)-4-phenylpiperidine-1-carboxylate

Using 4-(4-methoxybutyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylic acid and tert-butyl (3S,4S)-3-amino-4-phenylpiperidine-1-carboxylate, the title compound was obtained in a similar manner to Reference Example 541.

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

Reference Example 563

tert-Butyl (3S,4S)-3-(ethyl{[4-(4-methoxybutyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}amino)-4-phenylpiperidine-1-carboxylate

Using tert-butyl (3S,4S)-3-({[4-(4-methoxybutyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}amino)-4-phenylpiperidine-1-carboxylate, the title compound was obtained in a similar manner to Reference Example 542.

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

Reference Example 564

tert-Butyl (3R,4R)-3-{[(2-nitrophenyl)sulfonyl]amino}-4-phenylpiperidine-1-carboxylate

tert-Butyl (3R,4R)-3-amino-4-phenylpiperidine-1-carboxylate (124 mg) was dissolved in methylene chloride (2 ml), and thereto were added triethylamine (125 μl) and 2-nitrobenzene sulfonyl chloride (109 mg) at 0° C., and the mixture was stirred at room temperature for 3 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 (the developing solvent: hexane/ethyl acetate=1/1) to give the title compound (202 mg).

MS (ESI+) 462 (M + +1, 100%).

Reference Example 565

tert-Butyl (3R,4R)-3-{ethyl(2-nitrophenyl)sulfonyl]amino}-4-phenylpiperidine-1-carboxylate

tert-Butyl (3R,4R)-3-{[(2-nitrophenyl)sulfonyl]amino}-4-phenylpiperidine-1-carboxylate (202 mg) was dissolved in N,N-dimethylformamide (2 ml), and thereto were added potassium carbonate (182 mg) and ethyl iodide (136 μl), and the mixture was stirred at 60° C. for 1.5 hour. The reaction solution was cooled, and thereto 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 ammonium chloride 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 (the developing solvent: hexane/ethyl acetate=2/1) to give the title compound (209 mg).

MS (ESI+) 490 (M + +1, 100%).

Reference Example 566

tert-Butyl (3R,4R)-3-(ethylamino)-4-phenylpiperidine-1-carboxylate

tert-Butyl (3R,4R)-3-{ethyl(2-nitrophenyl)sulfonyl]amino}-4-phenylpiperidine-1-carboxylate (209 mg) was dissolved in N,N-dimethylformamide (2 ml), and thereto were added lithium hydroxide (95.6 mg) and mercaptoacetic acid (59.0 μl), and the mixture was stirred at 45° C. for 5 hours. The reaction solution was cooled, 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 water (×2) 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 (the developing solvent: hexane/ethyl acetate=1/1) to give the title compound (55.5 mg).

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

Reference Example 567

tert-Butyl (3R,4R)-3-[{[4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2,2-dimethyl-3-oxo-7-(trifluoro-methyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(ethyl)amino]-4-phenylpiperidine-1-carboxylate

Using methyl 4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2,2-dimethyl-3-oxo-7-(trifluoro-methyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate and tert-butyl (3R,4R)-3-(ethylamino)-4-phenylpiperidine-1-carboxylate, the title compound (60.4 mg) was obtained in a similar manner to Reference Example 5.

MS (ESI+) 753 (M + +1, 100%).

Reference Example 568

tert-Butyl (3R,4R)-3-[{[4-(2-aminoethyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(ethyl)amino]-4-phenylpiperidine-1-carboxylate

Using tert-butyl (3R,4R)-3-[{[4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(ethyl)amino]-4-phenylpiperidine-1-carboxylate, the title compound (51.3 mg) was obtained in a similar manner to Reference Example 139.

MS (ESI+) 620 (M + +1, 100%).

Reference Example 569

tert-Butyl (3R,4R)-3-[{[2,2-dimethyl-3-oxo-4-[2-(propionylamino)ethyl]-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(ethyl)amino]-4-phenylpiperidine-1-carboxylate

Using tert-butyl (3R,4R)-3-[{[4-(2-aminoethyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(ethyl)amino]-4-phenylpiperidine-1-carboxylate, the title compound (41.9 mg) was obtained in a similar manner to Reference Example 132.

MS (ESI+) 675 (M + +1, 100%).

Reference Example 570

N,N-Dibenzyl-2-bromoethaneamine

To N,N-dibenzyl-2-aminoethanol (18.47 g) was added hexane (150 ml) and DMF (0.3 ml), and thereto was added dropwise thionyl bromide (15.91 g) at 0° C. The mixture was stirred for 15 hours, and to the reaction solution was added a saturated aqueous sodium hydrogen carbonate solution in an ice-bath, and the mixture was extracted with ethyl acetate. The organic layer was washed with water (×2) 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 (the developing solvent: hexane) to give the title compound (12.80 g).

1 H NMR (400 MHz, CDCl 3 ) δ 7.48-7.39 (m, 8H), 7.36-7.33 (m, 2H), 3.74 (s, 4H), 3.43 (m, 2H), 2.97 (m, 2H).

Reference Example 571

2-Fluoro-4-hydroxy-5-nitrobenzonitrile

Using 2-fluoro-4-hydroxybenzonitrile, the title compound was obtained in a similar manner to Reference Example 52.

1 H NMR (400 MHz, CDCl 3 ) δ 11.11 (brs, 1H), 8.53 (d, J=6.5 Hz, 1H), 7.04 (d, J=9.5 Hz, 1H).

Reference Example 572

5-Amino-2-fluoro-4-hydroxybenzonitrile

Using 2-fluoro-4-hydroxy-5-nitrobenzonitrile, the title compound was obtained in a similar manner to Reference Example 53.

MS (ESI+) 153 (M + +1, 100%).

Reference Example 573

7-Fluoro-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile

Using 5-amino-2-fluoro-4-hydroxybenzonitrile, the title compound was obtained in a similar manner to Reference Example 55.

1 H NMR (400 MHz, CDCl 3 ) δ 9.11 (brs, 1H), 7.06 (d, J=5.9 Hz, 1H), 6.83 (d, J=9.2 Hz, 1H), 1.60 (s, 6H).

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

Reference Example 574

4-[2-(Dibenzylamino)ethyl]-7-fluoro-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile

Using 7-fluoro-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile and N,N-dibenzyl-2-bromoethanamine, the title compound was obtained in a similar manner to Reference Example 3.

MS (ESI+) 444 (M + +1, 100%).

Reference Example 575

4-[2-(Dibenzylamino)ethyl]-7-fluoro-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylic acid

4-[2-(Dibenzylamino)ethyl]-7-fluoro-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile (588 mg) was dissolved in acetic acid (5 ml), and thereto was added conc. hydrochloric acid (5 ml), and the mixture was refluxed for 75 hours. The reaction solution was cooled, and thereto was added water, and filtered. The solid collected by filtration was washed with water and dried at 70° C. for 18 hours to give the title compound (406 mg).

MS (ESI+) 463 (M + +1, 100%).

Reference Example 576

1-tert-Butyl 3-ethyl 4-(2,4,5-trifluorophenyl)-5,6-dihydropyridine-1,3(2H)-dicarboxylate

Using 1-tert-butyl-3-ethyl-4-{[(trifluoromethyl)sulfonyl]oxy}-5,6-dihydropyridin-1,3(2H)-dicarboxylate, the title compound was obtained in a similar manner to Reference Example 550.

MS (ESI+) 386 (M + +1, 100%).

Reference Example 577

(3R,4S)-1-(tert-Butoxycarbonyl)-4-(2,4,5-trifluorophenyl)piperidine-3-carboxylic acid

1-tert-Butyl 3-ethyl 4-(2,4,5-trifluorophenyl)-5,6-dihydropyridine-1,3(2H)-dicarboxylate (9.98 g) was dissolved in methanol (100 ml), and thereto was added magnesium (6.29 g) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. In an ice-bath, to the reaction mixture was added a saturated aqueous ammonium chloride solution, and the mixture was stirred for 30 minutes. The reaction 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 dissolved in ethanol (80 ml), and thereto was added sodium ethoxide (20% ethanol solution, 10.62 g) at room temperature, and the mixture was refluxed for 4 hours. The reaction mixture was cooled, and concentrated under reduced pressure. To the residue was added a 5% aqueous sodium 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 residue was dissolved in tetrahydrofuran (40 ml) and ethanol (40 ml), and thereto was added 1M aqueous sodium hydroxide solution (41.6 ml) at room temperature, and the mixture was stirred at 60° C. for 3 hours. The mixture was cooled, and the reaction mixture was concentrated under reduced pressure. To the residue was added a 5% aqueous sodium 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 (7.89 g).

MS (ESI+) 360 (M + +1, 100%).

Reference Example 578

tert-Butyl (3R,4R)-3-amino-4-(2,4,5-trifluorophenyl)piperidine-1-carboxylate

Using ((3R,4S)-1-(tert-butoxycarbonyl)-4-(2,4,5-trifluorophenyl)piperidine-3-carboxylic acid, the title compound was obtained in a similar manner to Reference Example 557.

MS (ESI+) 331 (M + +1, 100%).

Reference Example 579

tert-Butyl (3R,4R)-3-[({4-[2-(dibenzylamino)ethyl]-7-fluoro-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)amino]-4-(2,4,5-trifluorophenyl)piperidine-1-carboxylate

Using 4-[2-(dibenzylamino)ethyl]-7-fluoro-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylic acid and tert-butyl (3R,4R)-3-amino-4-(2,4,5-trifluorophenyl)piperidine-1-carboxylate, the title compound was obtained in a similar manner to Reference Example 541.

MS (ESI+) 775 (M + +1, 100%).

Reference Example 580

tert-Butyl (3R,4R)-3-[({4-[2-(dibenzylamino)ethyl]-7-fluoro-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)(ethyl)amino]-4-(2,4,5-trifluorophenyl)piperidine-1-carboxylate

Using tert-butyl (3R,4R)-3-[({4-[2-(dibenzylamino)ethyl]-7-fluoro-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)amino]-4-(2,4,5-trifluorophenyl)piperidine-1-carboxylate, the title compound was obtained in a similar manner to Reference Example 542.

MS (ESI+) 803 (M + +1, 100%).

Reference Example 581

tert-Butyl (3R,4R)-3-[{[4-(2-aminoethyl)-7-fluoro-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(ethyl)amino]-4-(2,4,5-trifluorophenyl)piperidine-1-carboxylate

Using tert-butyl (3R,4R)-3-[({4-[2-(dibenzylamino)ethyl]-7-fluoro-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)(ethyl)amino]-4-(2,4,5-trifluorophenyl)piperidine-1-carboxylate, the title compound was obtained in a similar manner to Reference Example 139.

MS (ESI+) 623 (M + +1, 100%).

Reference Example 582

tert-Butyl (3R,4R)-3-[ethyl({7-fluoro-2,2-dimethyl-3-oxo-4-[2-(propionylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)amino]-4-(2,4,5-trifluorophenyl)piperidine-1-carboxylate

Using tert-butyl (3R,4R)-3-[{[4-(2-aminoethyl)-7-fluoro-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(ethyl)amino]-4-(2,4,5-trifluorophenyl)piperidine-1-carboxylate, the title compound was obtained in a similar manner to Reference Example 132.

MS (ESI+) 679 (M + +1, 100%).

Reference Example 583

tert-Butyl (3R)-3-[isopropyl({7-methyl-3-oxo-4-[2-(difluoroacetylamino)ethyl]-3,4-dihydrospiro[1,4-benzoxazine-2,1′-cyclobutan]-6-yl}carbonyl)amino]piperidine-1-carboxylate

Using tert-butyl (3R)-3-[{[4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-7-methyl-3-oxo-3,4-dihydrospiro[1,4-benzoxazine-2,1′-cyclobutan]-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate, the title compound was obtained in a similar manner to Reference Example 139 and Reference Example 112.

MS (ESI+) 649 (M + +1, 100%)

Reference Example 584

tert-Butyl (3R)-3-[(4-{[1,1-dimethyl-2-(octyloxy)-2-oxoethyl]thio}-2-methyl-5-nitrobenzoyl)(isopropyl)amino]piperidine-1-carboxylate

To a solution of tert-butyl (3R)-3-[(4-chloro-2-methyl-5-nitrobenzoyl)(isopropyl)amino]-piperidine-1-carboxylate (5 g) in dimethylsulfoxide (55 ml) were added potassium carbonate (4.7 g), magnesium bromide.diethyl etherate (3.5 g), lithium sulfide (0.78 g), and the mixture was stirred at room temperature. Two hours later, to the reaction solution was added octyl 2-bromoisobutyrate (4.7 g), and the mixture was stirred at 60° C. for one hour. The reaction mixture was cooled to room temperature, and filtered on celite. To the filtrate was added a saturated aqueous sodium hydrogen carbonate solution (150 ml), and the mixture was extracted twice with ethyl acetate (100 ml). The combined 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 (the developing solvent: hexane/ethyl acetate=3/1) to give the title compound (4.9 g).

MS (ESI+) 636 (M + +1, 28%).

Reference Example 585

tert-Butyl (3R)-3-[(4-{[1-(ethoxycarbonyl)cyclobutyl]thio}-2-methyl-5-nitrobenzoyl)(isopropyl)-amino]piperidine-1-carboxylate

Using tert-butyl (3R)-3-[(4-chloro-2-methyl-5-nitrobenzoyl)(isopropyl)amino]piperidine-1-carboxylate, the title compound was obtained in a similar manner to Reference Example 587.

MS (ESI+) 564 (M + +1, 80%).

Reference Example 586

tert-Butyl (3R)-3-{isopropyl[(2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl)carbonyl]-amino}piperidine-1-carboxylate

Using tert-butyl (3R)-3-[(4-{[1,1-dimethyl-2-(octyloxy)-2-oxoethyl]thio}-2-methyl-5-nitrobenzoyl)(isopropyl)amino]piperidine-1-carboxylate, the title compound was obtained in a similar manner to Reference Example 2.

MS (ESI+) 476 (M + +1, 36%).

Reference Example 587

tert-Butyl (3R)-3-{isopropyl[(7-methyl-3-oxo-3,4-dihydrospiro[1,4-benzothiazine-2,1′-cyclobutan]-6-yl)carbonyl]amino}piperidine-1-carboxylate

Using tert-butyl (3R)-3-[(4-{[1-(ethoxycarbonyl)cyclobutyl]thio}-2-methyl-5-nitrobenzoyl)-(isopropyl)amino]piperidine-1-carboxylate, the title compound was obtained in a similar manner to Reference Example 2.

MS (ESI+) 488 (M + +1, 100%).

Reference Example 588

tert-Butyl (3R)-3-[{[4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using tert-butyl (3R)-3-{isopropyl[(2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl)carbonyl]amino}piperidine-1-carboxylate, the title compound was obtained in a similar manner to Reference Example 378.

MS (ESI+) 653 (M + +1, 60%).

Reference Example 589

tert-Butyl (3R)-3-[{[4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-7-methyl-3-oxo-3,4-dihydrospiro[1,4-benzothiazine-2,1′-cyclobutan]-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using tert-butyl (3R)-3-{isopropyl[(7-methyl-3-oxo-3,4-dihydrospiro[1,4-benzothiazine-2,1′-cyclobutan]-6-yl)carbonyl]amino}piperidine-1-carboxylate, the title compound was obtained in a similar manner to Reference Example 3.

MS (ESI+) 665 (M + +1, 57%).

Reference Example 590

tert-Butyl (3R)-3-[{[4-(2-aminoethyl)-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

tert-Butyl (3R)-3-[{[4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate (1.4 g) was dissolved in methanol (11 ml), and thereto was added a 20% palladium hydroxide/carbon (50% wet.) (0.7 g) under hydrogen atmosphere, and the mixture was vigorously stirred at room temperature for 3 hours. After the reaction was complete, the reaction mixture was filtered on celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (the developing solvent: chloroform/methanol=98/2˜92/8) to give the title compound (1.3 g).

MS (ESI+) 519 (M + +1, 100%).

Reference Example 591

tert-Butyl (3R)-3-[[(4-{2-[(difluoroacetyl)amino]ethyl}-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl)carbonyl](isopropyl)amino]piperidine-1-carboxylate

To a solution of tert-butyl (3R)-3-[{[4-(2-aminoethyl)-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate (1.3 g) in chloroform (11 ml) were added WSC (0.86 g), HOBt (0.6 g), triethylamine (0.9 mL), and the mixture was stirred at room temperature. One hour later, to the reaction solution was added a 10% aqueous potassium hydrogen sulfate solution (10 ml), and the mixture was extracted twice with ethyl acetate (10 ml). The combined 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 (the developing solvent: hexane/ethyl acetate=1/2˜1/3) to give the title compound (1 g).

MS (ESI+) 597 (M + +1, 71%).

Reference Example 592

tert-Butyl (3R)-3-[isopropyl({7-methyl-3-oxo-4-[2-(propionylamino)ethyl]-3,4-dihydrospiro[1,4-benzothiazine-2,1′-cyclobutan]-6-yl}carbonyl)amino]piperidine-1-carboxylate

Using tert-butyl (3R)-3-[{[4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-7-methyl-3-oxo-3,4-dihydrospiro[1,4-benzothiazine-2,1′-cyclobutan]-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate, the title compound was obtained in a similar manner to Reference Example 379.

MS (ESI+) 587 (M + +1, 29%).

Reference Example 593

2,6-Dibromo-3-methyl-1H-indole

To 3-methyl-1H-indole (10 g) were added NBS (27.2 g) and CHCl 3 (200 ml), and the mixture was stirred at room temperature for 35 minutes. After the reaction was complete, water was added to the reaction solution, and the mixture was extracted with ethyl acetate solution. This ethyl acetate solution was washed with water and an aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1) to give the title compound (15.7 g) as a brown solid.

MS (ESI+) 287 (M + +1, 10%).

Reference Example 594

6-Bromo-1,3-dihydro-2H-indol-2-one

To 6-bromo-1H-indole-2,3-dione (15 g) was added hydrazine (66 ml), and the mixture was stirred at 125° C. for 2 hours. After the reaction was complete, to the mixture was added 6N aqueous HCl solution (60 ml), and the mixture was stirred at 60° C. for 2 hours. After the reaction was complete, the mixture was neutralized with 3N aqueous NaOH solution, and the mixture was extracted with ethyl acetate. This ethyl acetate solution was washed with water and an aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated to give the title compound (9.1 g) as a red crystal.

MS (ESI+) 213 (M + +1, 16%).

Reference Example 595

6-Bromo-3-methyl-1,3-dihydro-2H-indol-2-one

To 2,6-dibromo-3-methyl-1H-indole (15.7 g) were added 3N aqueous sulfuric acid solution (100 ml) and dioxane (100 ml), and the mixture was refluxed for 5 hours. After the reaction was complete, water was added to the reaction solution, and the mixture was extracted with ethyl acetate solution. This ethyl acetate solution was washed with water and an aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to give the title compound (11.2 g) as a brown crystal.

MS (ESI+) 226 (M + +1, 48%).

Reference Example 596

1-Acetyl-6-bromo-3-methyl-1,3-dihydro-2H-indol-2-one

To 6-bromo-3-methyl-1,3-dihydro-2H-indol-2-one (11.2 g) were added acetic anhydride (12 ml) and xylene (120 ml), and the mixture was refluxed for 5 hours. After the reaction was complete, water was added to the reaction solution, and the mixture was extracted with ethyl acetate solution. This ethyl acetate solution was washed successively with water, a saturated aqueous sodium hydrogen carbonate solution and an aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to give the title compound (9.5 g) as a red solid.

MS (ESI+) 228 (M + +1, 94%).

Reference Example 597

1-Acetyl-6-bromo-1,3-dihydro-2H-indol-2-one

Using 6-bromo-1,3-dihydro-2H-indol-2-one, the title compound was obtained in a similar manner to Reference Example 596.

MS (ESI+) 254 (M + +1, 27%).

Reference Example 598

1-Acetyl-6-bromo-3,3-dimethyl-1,3-dihydro-2H-indol-2-one

To 1-acetyl-6-bromo-3-methyl-1,3-dihydro-2H-indol-2-one (9.5 g) were added NaH (1.57 g), methyl iodide (2.45 ml) and THF (70 ml) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, water was added to the reaction solution, and the mixture was extracted with ethyl acetate solution. This ethyl acetate solution was washed with water and an aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to give the title compound (5.2 g) as a colorless crystal.

MS (ESI+) 282 (M + +1, 34%).

Reference Example 599

1-Acetyl-6-bromo-3,3-diethyl-1,3-dihydro-2H-indol-2-one

Using 1-acetyl-6-bromo-1,3-dihydro-2H-indol-2-one, the title compound was obtained in a similar manner to Reference Example 598.

MS (ESI+) 311 (M + +1, 35%).

Reference Example 600

6-Bromo-3,3-dimethyl-1,3-dihydro-2H-indol-2-one

To 1-acetyl-6-bromo-3,3-dimethyl-1,3-dihydro-2H-indol-2-one (5.2 g) were added 1N aqueous NaOH solution (11 ml) and EtOH (44 ml), and the mixture was stirred at room temperature for one hour. After the reaction was complete, the solvent was concentrated, and thereto was added dropwise a 2N aqueous hydrochloric acid solution. The precipitated crystals were extracted with ethyl acetate, and this ethyl acetate solution was washed with water and an aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated. The obtained residue (4.1 g) was used in the subsequent reaction without further treatment.

MS (ESI+) 326 (M + +1, 62%).

Reference Example 601

6-Bromo-3,3-diethyl-1,3-dihydro-2H-indol-2-one

Using 1-acetyl-6-bromo-3,3-diethyl-1,3-dihydro-2H-indol-2-one, the title compound was obtained in a similar manner to Reference Example 600.

MS (ESI+) 269 (M + +1, 35%).

Reference Example 602

6-Bromo-1-(4-methoxybutyl)-3,3-dimethyl-1,3-dihydro-2H-indol-2-one

To 6-bromo-3,3-dimethyl-1,3-dihydro-2H-indol-2-one (1.5 g) were added DMF (24 mL) and NaH (326 mg) under ice-cooling, and the mixture was stirred at room temperature 15 minutes. Then, to the mixture were added 4-chloromethyl butyl ether (1.54 g) and potassium iodide (208 mg), and the mixture was stirred at 100° C. for 7 hours. After the reaction was complete, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. This ethyl acetate solution was washed with water and an aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to give the title compound (1.87 g) as a colorless liquid.

MS (ESI+) 325 (M + +1, 63%).

Reference Example 603

Benzyl [2-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indole-1-yl)ethyl]carbamate

Using 6-bromo-3,3-dimethyl-1,3-dihydro-2H-indol-2-one, the title compound was obtained in a similar manner to Reference Example 602.

MS (ESI+) 417 (M + +1, 24%).

Reference Example 604

Benzyl [2-(6-bromo-3,3-diethyl-2-oxo-2,3-dihydro-1H-indole-1-yl)ethyl]carbamate

Using 6-bromo-3,3-diethyl-1,3-dihydro-2H-indol-2-one, the title compound was obtained in a similar manner to Reference Example 602.

MS (ESI+) 445 (M + +1, 27%).

Reference Example 605

Methyl 1-(4-methoxybutyl)-3,3-dimethyl-2-oxoindoline-6-carboxylate

To 6-bromo-1-(4-methoxybutyl)-3,3-dimethyl-1,3-dihydro-2H-indol-2-one (1.0 g) were added palladium acetate (207 mg), triphenylphosphine (484 mg), triethylamine (0.86 ml), methanol (0.62 ml), and DMF (10 ml), and the mixture was stirred at 100° C. under carbon monoxide atmosphere for 4 hours. After the reaction was complete, water was added to the reaction solution, and the mixture was extracted with ethyl acetate solution. This ethyl acetate solution was washed with water and an aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1) to give the title compound (480 mg) as a pale yellow liquid.

MS (ESI+) 307 (M + +1, 46%).

Reference Example 606

Methyl 1-(2-{[(benzyloxy)carbonyl]amino}ethyl)-3,3-dimethyl-2-oxoindoline-6-carboxylate

Using the compound of Reference Example 603, the title compound was obtained in a similar manner to Reference Example 605.

MS (ESI+) 397 (M + +1, 41%).

Reference Example 607

Methyl 1-(2-{[(benzyloxy)carbonyl]amino}ethyl)-3,3-diethyl-2-oxoindoline-6-carboxylate

Using the compound of Reference Example 604, the title compound was obtained in a similar manner to Reference Example 605.

MS (ESI+) 425 (M + +1, 33%).

Reference Example 608

1-(4-Methoxybutyl)-3,3-dimethyl-2-oxoindoline-6-carboxylic acid

To methyl 1-(4-methoxybutyl)-3,3-dimethyl-2-oxoindoline-6-carboxylate (480 mg) were added 2N aqueous NaOH solution (5 ml), MeOH (5 ml), and THF (5 ml), and the mixture was stirred at 65° C. for one hour. After the reaction was complete, the solvent was concentrated, and to the resultant was added dropwise 2N aqueous hydrochloric acid solution. The precipitated crystals were extracted with ethyl acetate, and this ethyl acetate solution was washed with water and an aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated. The obtained residue (400 mg) was used in the subsequent reaction without further treatment.

MS (ESI+) 292 (M + +1, 47%).

Reference Example 609

1-(2-{[(Benzyloxy)carbonyl]amino}ethyl)-3,3-dimethyl-2-oxoindoline-6-carboxylic acid

Using the compound of Reference Example 606, the title compound was obtained in a similar manner to Reference Example 608.

MS (ESI+) 383 (M + +1, 22%).

Reference Example 610

1-(2-{[(Benzyloxy)carbonyl]amino}ethyl)-3,3-diethyl-2-oxoindoline-6-carboxylic acid

Using the compound of Reference Example 607, the title compound was obtained in a similar manner to Reference Example 608.

MS (ESI+) 411 (M + +1, 21%).

Reference Example 611

tert-Butyl (3R)-3-(isopropyl{[1-(4-methoxybutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl]carbonyl}amino)piperidine-1-carboxylate

To 1-(4-methoxybutyl)-3,3-dimethyl-2-oxoindoline-6-carboxylic acid (480 mg) were added oxalyl chloride (0.28 ml), DMF (2 drops), chloroform (10 ml), and the mixture was stirred at room temperature for one hour. After the reaction was complete, the solvent was concentrated, and to the obtained residue were added 1-Boc-3R—(N-isopropyl)aminopiperidine (570 mg), triethylamine (0.44 ml), and CHCl 3 (10 ml), and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was concentrated, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) to give the title compound (630 mg) as a colorless liquid.

MS (ESI+) 517 (M + +1, 21%).

Reference Example 612

tert-Butyl (3R)-3-[{[1-(2-{[(benzyloxy)carbonyl]amino}ethyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 609, the title compound was obtained in a similar manner to Reference Example 611.

MS (ESI+) 607 (M + +1, 56%).

Reference Example 613

tert-Butyl (3R)-3-[{[1-(2-{[(benzyloxy)carbonyl]amino}ethyl)-3,3-diethyl-2-oxo-2,3-dihydro-1H-indol-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 610, the title compound was obtained in a similar manner to Reference Example 611.

MS (ESI+) 635 (M + +1, 19%).

Reference Example 614

tert-Butyl (3R)-3-[{[5-chloro-1-(4-methoxybutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

To tert-butyl (3R)-3-(isopropyl{[1-(4-methoxybutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl]carbonyl}amino)piperidine-1-carboxylate (220 mg) were added NCS (86 mg) and DMF (5 ml), and the mixture was stirred at 65° C. for one hour. After the reaction was complete, water was added to the reaction solution, and the mixture was extracted with ethyl acetate solution. This ethyl acetate was washed with water and an aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) to give the title compound (200 mg) as a colorless liquid.

MS (ESI+) 551 (M + +1, 18%).

Reference Example 615

tert-Butyl (3R)-3-[{[1-(2-aminoethyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl]carbonyl}-(isopropyl)amino]piperidine-1-carboxylate

To tert-butyl (3R)-3-[{[1-(2-{[(benzyloxy)carbonyl]amino}ethyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate (800 mg) were added 10% Pd/C (400 mg) and methanol (30 ml), and the mixture was stirred at room temperature under hydrogen atmosphere for 2 hours. After the reaction was complete, the mixture was filtered and concentrated. The obtained residue (600 mg) was used in the subsequent reaction without further treatment.

MS (ESI+) 473 (M + +1, 29%).

Reference Example 616

tert-Butyl (3R)-3-[{[1-(2-aminoethyl)-3,3-diethyl-2-oxo-2,3-dihydro-1H-indol-6-yl]carbonyl}-(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 613, the title compound was obtained in a similar manner to Reference Example 615.

MS (ESI+) 501 (M + +1, 27%).

Reference Example 617

tert-Butyl (3R)-3-[({3,3-dimethyl-2-oxo-1-[2-(propionylamino)ethyl]-2,3-dihydro-1H-indol-6-yl}carbonyl)(isopropyl)amino]piperidine-1-carboxylate

To tert-butyl (3R)-3-[{[1-(2-aminoethyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate (300 mg) were added triethylamine (0.14 ml), THF (3 ml) and acetyl chloride (0.07 ml) under ice-cooling, and the mixture was stirred at room temperature for one hour. After the reaction was complete, the mixture was concentrated, and the obtained residue was purified by silica gel column chromatography (chloroform/methanol=9/1) to give the title compound (190 mg) as colorless amorphous.

MS (ESI+) 529 (M + +1, 39%).

Reference Example 618

tert-Butyl (3R)-3-[({3,3-diethyl-2-oxo-1-[2-(propionylamino)ethyl]-2,3-dihydro-1H-indol-6-yl}-carbonyl)(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 616, the title compound was obtained in a similar manner to Reference Example 617.

MS (ESI+) 557 (M + +1, 34%).

Reference Example 619

tert-Butyl (3R)-3-[[(1-{2-[(difluoroacetyl)amino]ethyl}-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)carbonyl](isopropyl)amino]piperidine-1-carboxylate

To tert-butyl (3R)-3-[{[1-(2-aminoethyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl]-carbonyl}(isopropyl)amino]piperidine-1-carboxylate (300 mg) were added WSC (210 mg), HOBt (150 mg), triethylamine (0.30 ml), chloroform (5 ml), and difluoroacetic acid (79 mg), and the mixture was stirred at room temperature overnight. After the reaction was complete, the mixture was concentrated, and the obtained residue was purified by silica gel column chromatography (chloroform/methanol=9/1) to give the title compound (170 mg) as colorless amorphous.

MS (ESI+) 551 (M + +1, 35%).

Reference Example 620

tert-Butyl (3R)-3-[({5-chloro-3,3-dimethyl-2-oxo-1-[2-(propionylamino)ethyl]-2,3-dihydro-1H-indol-6-yl}carbonyl)(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 617, the title compound was obtained in a similar manner to Reference Example 614.

MS (ESI+) 563 (M + +1, 30%).

Reference Example 621

tert-Butyl (3R)-3-[[(5-chloro-1-{2-[(difluoroacetyl)amino]ethyl}-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)carbonyl](isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 619, the title compound was obtained in a similar manner to Reference Example 614.

MS (ESI+) 585 (M + +1, 23%).

Reference Example 622

tert-Butyl (3R)-3-[({5-chloro-3,3-diethyl-2-oxo-1-[2-(propionylamino)ethyl]-2,3-dihydro-1H-indol-6-yl]carbonyl)(isopropyl)amino]piperidine-1-carboxylate

Using the compound of Reference Example 618, the title compound was obtained in a similar manner to Reference Example 614.

MS (ESI+) 591 (M + +1, 13%).

Reference Example 623

4-Fluoro-2-methyl-5-nitrobenzoic acid

To a suspension of 4-fluoro-2-methylbenzoic acid (32.5 g) in conc. sulfuric acid (50 ml) was added dropwise conc. nitric acid (8.4 ml) at 0° C., and the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into ice-water (500 ml), and the mixture was extracted with diisopropyl ether (300 ml), and the organic layer was washed with water, and a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, concentrated under reduced pressure to give the title compound (40.0 g).

MS (ESI+) 200 (M + +1, 100%).

Reference Example 624

Methyl 4-fluoro-2-methyl-5-nitrobenzoate

Using 4-fluoro-2-methyl-5-nitrobenzoic acid, the title compound was obtained in a similar manner to Reference Example 51.

MS (ESI+) 214 (M + +1, 100%).

Reference Example 625

Methyl 4-{[1-(methoxycarbonyl)cyclopropyl]oxy}-2-methyl-5-nitrobenzoate

Methyl 4-fluoro-2-methyl-5-nitrobenzoate (43.0 g) was dissolved in tetrahydrofuran (300 ml), and thereto was added sodium hydride (55%, 9.60 g) at 0° C., and the mixture was stirred for 30 minutes. To the mixture was added dropwise a solution of methyl 1-hydroxy-1-cyclopropanecarboxylate (22.0 g) in tetrahydrofuran (300 ml) at 0° C., and the mixture was further stirred at room temperature for 3 hours. The mixture was cooled to room temperature, and water (100 ml) was added to the reaction mixture. The mixture was neutralized by addition of 1N aqueous hydrochloric acid solution, and extracted twice with ethyl acetate (300 ml). The organic layer was washed with water, 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 resultant was purified by silica gel column (hexane/ethyl acetate=3:1) to give the title compound (58.0 g).

MS (ESI+) 310 (M + +1, 100%).

Reference Example 626

Methyl 7-methyl-3-oxo-3,4-dihydrospiro[1,4-benzoxazine-2,1′-cyclopropane]-6-carboxylate

Using methyl 4-{[1-(methoxycarbonyl)cyclopropyl]oxy}-2-methyl-5-nitrobenzoate, the title compound was obtained in a similar manner to Reference Example 2.

MS (ESI+) 248 (M + +1, 100%).

Reference Example 627

Methyl 4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-7-methyl-3-oxo-3,4-dihydrospiro[1,4-benzoxazine-2,1′-cyclopropane]-6-carboxylate

Using methyl 7-methyl-3-oxo-3,4-dihydrospiro[1,4-benzoxazine-2,1′-cyclopropane]-6-carboxylate, the title compound was obtained in a similar manner to Reference Example 3.

MS (ESI+) 425 (M + +1, 100%).

Reference Example 628

4-(2-{[(Benzyloxy)carbonyl]amino}ethyl)-7-methyl-3-oxo-3,4-dihydrospiro[1,4-benzoxazine-2,1′-cyclopropane]-6-carboxylic acid

Using methyl 4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-7-methyl-3-oxo-3,4-dihydrospiro[1,4-benzoxazine-2,1′-cyclopropane]-6-carboxylate, the title compound was obtained in a similar manner to Reference Example 4.

MS (ESI+) 411 (M + +1, 100%).

Reference Example 629

tert-Butyl (3R)-3-[{[4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-7-methyl-3-oxo-3,4-dihydrospiro[1,4-benzoxazine-2,1′-cyclopropan]-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using methyl 4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-7-methyl-3-oxo-3,4-dihydrospiro[1,4-benzoxazine-2,1′-cyclopropane]-6-carboxylic acid, the title compound was obtained in a similar manner to Reference Example 5.

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

Reference Example 630

tert-Butyl (3R)-3-[{[4-(2-aminoethyl)-7-methyl-3-oxo-3,4-dihydrospiro[1,4-benzoxazine-2,1′-cyclopropan]-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using tert-butyl (3R)-3-[{[4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-7-methyl-3-oxo-3,4-dihydrospiro[1,4-benzoxazine-2,1′-cyclopropan]-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate, the title compound was obtained in a similar manner to Reference Example 139.

MS (ESI+) 501 (M + +1, 100%).

Reference Example 631

N-Isopropyl-7-methyl-3-oxo-N-[(3R)-piperidin-3-yl]-4-[2-(propionylamino)ethyl]-3,4-dihydrospiro[1,4-benzoxazine-2,1′-cyclopropane]-6-carboxamide hydrochloride

Using tert-butyl (3R)-3-[{[4-(2-aminoethyl)-7-methyl-3-oxo-3,4-dihydrospiro[1,4-benzoxazine-2,1′-cyclopropan]-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate, the title compound was obtained in a similar manner to Reference Example 120.

MS (ESI+) 557 (M + +1, 100%).

Reference Example 632

4-{2-[(Difluoroacetyl)amino]ethyl}-N-isopropyl-7-methyl-3-oxo-N-[(3R)-piperidin-3-yl]-3,4-dihydrospiro[1,4-benzoxazine-2,1′-cyclopropane]-6-carboxamide hydrochloride

Using tert-butyl (3R)-3-[{[4-(2-aminoethyl)-7-methyl-3-oxo-3,4-dihydrospiro[1,4-benzoxazine-2,1′-cyclopropan]-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate, the title compound was obtained in a similar manner to Reference Example 120.

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

Reference Example 636

tert-Butyl (3R)-3-[[4-hydroxy-5-nitro-2-(trifluoromethyl)benzoyl](isopropyl)amino]piperidine-1-carboxylate

Using methyl 4-hydroxy-5-nitro-2-(trifluoromethyl)benzoate, the title compound was obtained in a similar manner to Reference Example 31.

MS (ESI+) 476 (M + +1, 100%).

Reference Example 637

Diethyl [4-{[[(3R)-1-(tert-butoxycarbonyl)piperidin-3-yl](isopropyl)amino]carbonyl}-2-nitro-5-(trifluoromethyl)phenoxy](methyl)malonate

Using tert-butyl (3R)-3-[[4-hydroxy-5-nitro-2-(trifluoromethyl)benzoyl](isopropyl)amino]-piperidine-1-carboxylate, the title compound was obtained in a similar manner to Reference Example 32.

MS (ESI+) 648 (M + +1, 100%).

Reference Example 638

Ethyl 4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-6-{[[(3R)-1-(tert-butoxycarbonyl)piperidin-3-yl]-(isopropyl)amino]carbonyl}-2-methyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylate

Using diethyl [4-{[[(3R)-1-(tert-butoxycarbonyl)piperidin-3-yl](isopropyl)amino]carbonyl}-2-nitro-5-(trifluoromethyl)phenoxy](methyl)malonate, the title compound was obtained in a similar manner to Reference Example 33.

MS (ESI+) 749 (M + +1, 100%).

Reference Example 639

Ethyl 4-(2-{benzyl[(benzyloxy)carbonyl]amino}ethyl)-6-{[[(3R)-1-(tert-butoxycarbonyl)piperidin-3-yl](isopropyl)amino]carbonyl}-2-methyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylate

Using ethyl 4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-6-{[[(3R)-1-(tert-butoxycarbonyl)-piperidin-3-yl](isopropyl)amino]carbonyl}-2-methyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylate, the title compound was obtained in a similar manner to Reference Example 34.

MS (ESI+) 839 (M + +1, 100%).

Reference Example 640

4-(2-{Benzyl[(benzyloxy)carbonyl]amino}ethyl)-6-{[[(3R)-1-(tert-butoxycarbonyl)piperidin-3-yl](isopropyl)amino]carbonyl}-2-methyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid

Using ethyl 4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-6-{[[(3R)-1-(tert-butoxycarbonyl)-piperidin-3-yl](isopropyl)amino]carbonyl}-2-methyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylate, the title compound was obtained in a similar manner to Reference Example 34.

MS (ESI+) 811 (M + +1, 100%).

Reference Example 641

tert-Butyl (3R)-3-[{[4-(2-{benzyl[(benzyloxy)carbonyl]amino}ethyl)-2-(hydroxymethyl)-2-methyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using 4-(2-{benzyl[(benzyloxy)carbonyl]amino}ethyl)-6-{[[(3R)-1-(tert-butoxycarbonyl)-piperidin-3-yl](isopropyl)amino]carbonyl}-2-methyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid, the title compound was obtained in a similar manner to Reference Example 35.

MS (ESI+) 797 (M + +1, 100%).

Reference Example 642

tert-Butyl (3R)-3-[{[4-(2-{benzyl[(benzyloxy)carbonyl]amino}ethyl)-2-(methoxymethyl)-2-methyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using tert-butyl (3R)-3-[{[4-(2-{benzyl[(benzyloxy)carbonyl]amino}ethyl)-2-(hydroxy-methyl)-2-methyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)-amino]piperidine-1-carboxylate, the title compound was obtained in a similar manner to Reference Example 36.

MS (ESI+) 811 (M + +1, 100%).

Reference Example 643

tert-Butyl (3R)-3-[{[4-(2-{benzyl[(benzyloxy)carbonyl]amino}ethyl)-2-methyl-3-oxo-2-[(tetrahydro-2H-pyran-2-yloxy)methyl]-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}-(isopropyl)amino]piperidine-1-carboxylate

To a solution of tert-butyl (3R)-3-[{[4-(2-{benzyl[(benzyloxy)carbonyl]amino}ethyl)-2-(hydroxymethyl)-2-methyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate in methylene chloride (4.0 ml) were added 3,4-dihydro-2H-pyran (86 μl) and pyridinium p-toluenesulfonate (6.3 mg), and the mixture was stirred at room temperature for 12 hours. To the reaction mixture was added water (3 ml), and the mixture was extracted with methylene chloride (5 ml). The organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, concentrated under reduced pressure to give the title compound (440 mg).

MS (ESI+) 881 (M + +1, 100%).

Reference Example 644

tert-Butyl (3R)-3-[{[4-(2-aminoethyl)-2-(methoxymethyl)-2-methyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using tert-butyl (3R)-3-[{[4-(2-{benzyl[(benzyloxy)carbonyl]amino}ethyl)-2-(methoxy-methyl)-2-methyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}-(isopropyl)amino]piperidine-1-carboxylate, the title compound was obtained in a similar manner to Reference Example 139.

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

Reference Example 645

tert-Butyl (3R)-3-[{[4-(2-aminoethyl)-2-methyl-3-oxo-2-[(tetrahydro-2H-pyran-2-yloxy)methyl]-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using tert-butyl (3R)-3-[{[4-(2-{benzyl[(benzyloxy)carbonyl]amino}ethyl)-2-methyl-3-oxo-2-[(tetrahydro-2H-pyran-2-yloxy)methyl]-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate, the title compound was obtained in a similar manner to Reference Example 139.

MS (ESI+) 657 (M + +1, 100%).

Reference Example 646

tert-Butyl (3R)-3-[{[4-{2-[(difluoroacetyl)amino]ethyl}-2-(methoxymethyl)-2-methyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate

Using tert-butyl (3R)-3-[{[4-(2-aminoethyl)-2-(methoxymethyl)-2-methyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate, the title compound was obtained in a similar manner to Reference Example 112.

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

Reference Example 647

tert-Butyl (3R)-3-[{[4-{2-[(difluoroacetyl)amino]ethyl}-2-methyl-3-oxo-2-[(tetrahydro-2H-pyran-2-yloxy)methyl]-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]-piperidine-1-carboxylate

Using tert-butyl (3R)-3-[{[4-(2-aminoethyl)-2-methyl-3-oxo-2-[(tetrahydro-2H-pyran-2-yloxy)-methyl]-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]-piperidine-1-carboxylate, the title compound was obtained in a similar manner to Reference Example 112.

MS (ESI+) 735 (M + +1, 100%).

Reference Example 648

tert-Butyl (3R)-3-(cyclobutyl {[2,2-dimethyl-3-oxo-4-[2-(propionylamino)ethyl]-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}amino)piperidine-1-carboxylate

Using methyl 4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate, the title compound was obtained in a similar manner to Reference Examples 4, 5.

MS (ESI+) 625 (M+1, 67%).

Reference Example 649

tert-Butyl (3R)-3-((cyclopropylmethyl) {[2,2-dimethyl-3-oxo-4-[2-(propionylamino)ethyl]-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}amino)piperidine-1-carboxylate

Using methyl 4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2,2-dimethyl-3-oxo-7-(trifluoro-methyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate, the title compound was obtained in a similar manner to Reference Examples 4, 5.

MS (ESI+) 625 (M+1, 60%).

Reference Example 650

tert-Butyl (3R)-3-[{[2,2-dimethyl-3-oxo-4-[2-(propionylamino)ethyl]-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(2,2,2-trifluoroethyl)amino]piperidine-1-carboxylate

Using methyl 4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2,2-dimethyl-3-oxo-7-(trifluoro-methyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate, the title compound was obtained in a similar manner to Reference Examples 4, 5.

MS (ESI+) 653 (M+1, 44%).

Reference Example 651

tert-Butyl (3R)-3-[{[4-(2-{benzyl[(benzyloxy)carbonyl]amino}ethyl)-2-methyl-2-{[(methyl-sulfonyl)oxy]methyl}-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]-carbonyl}(isopropyl)amino]piperidine-1-carboxylate

To a solution of tert-butyl (3R)-3-[{[4-(2-{benzyl[(benzyloxy)carbonyl]amino}ethyl)-2-(hydroxymethyl)-2-methyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}-(isopropyl)amino]piperidine-1-carboxylate (700 mg) and triethylamine (0.25 ml) in tetrahydrofuran (8 ml) was added dropwise methanesulfonyl chloride (0.11 ml), and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract 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) to give the title compound (793 mg).

MS (ESI+) 875 (M+1, 66%).

Reference Example 652

tert-Butyl (3R)-3-[{[4-(2-{benzyl[(benzyloxy)carbonyl]amino}ethyl)-2-methyl-3-oxo-2-(phenoxy-methyl)-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]-piperidine-1-carboxylate

A solution of tert-butyl (3R)-3-[{[4-(2-{benzyl[(benzyloxy)carbonyl]amino}ethyl)-2-methyl-2-{[(methylsulfonyl)oxy]methyl}-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]-carbonyl}(isopropyl)amino]piperidine-1-carboxylate (170 mg), phenol (18 mg) and cesium carbonate (186 mg) in N,N-dimethylformamide (2 ml) was stirred at 80° C. for 5 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract 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) to give the title compound (49 mg).

MS (ESI+) 873 (M+1, 89%).

Reference Example 653

tert-Butyl (3R)-3-(isopropyl{[4-{2-[(methoxycarbonyl)amino]ethyl}-2-methyl-3-oxo-2-(phenoxy-methyl)-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}amino)piperidine-1-carboxylate

Using tert-butyl (3R)-3-[{[4-(2-{benzyl[(benzyloxy)carbonyl]amino}ethyl)-2-methyl-3-oxo-2-(phenoxymethyl)-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]-piperidine-1-carboxylate, the title compound was obtained in a similar manner to Reference Example 139, Reference Example 162.

MS (ESI+) 705 (M+1, 75%).

Reference Example 654

tert-Butyl (3R)-3-(isopropyl{[4-{2-[(methoxycarbonyl)amino]ethyl}-2-[(3-methoxyphenoxy)methyl]-2-methyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}amino)piperidine-1-carboxylate

Using tert-butyl (3R)-3-[{[4-(2-{benzyl[(benzyloxy)carbonyl]amino}ethyl)-2-methyl-2-{[(methylsulfonyl)oxy]methyl}-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]-carbonyl}(isopropyl)amino]piperidine-1-carboxylate, the title compound was obtained in a similar manner to Reference Example 652, Reference Example 139, Reference Example 162.

MS (ESI+) 737 (M+1, 72%).

Reference Example 655

tert-Butyl (3R)-3-(isopropyl{[4-{2-[(methoxycarbonyl)amino]ethyl}-2-[(4-methoxyphenoxy)methyl]-2-methyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}amino)piperidine-1-carboxylate

Using tert-butyl (3R)-3-[{[4-(2-{benzyl[(benzyloxy)carbonyl]amino}ethyl)-2-methyl-2-{[(methylsulfonyl)oxy]methyl}-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate, the title compound was obtained in a similar manner to Reference Example 652, Reference Example 139, Reference Example 162.

MS (ESI+) 737 (M+1, 68%).

Reference Example 656

tert-Butyl (3R)-3-(isopropyl{[4-(4-methoxybutyl)-2-[(2-methoxyethoxy)methyl]-2-methyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}amino)piperidine-1-carboxylate

To a solution of tert-butyl (3R)-3-[{[2-(hydroxymethyl)-4-(4-methoxybutyl)-2-methyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate (230 mg) in N,N-dimethylformamide (3 ml) were added sodium hydride (50 mg, 55% by weight) and 2-bromoethyl methyl ether (0.11 ml), and the mixture was stirred at 80° C. for 3 hours. To the reaction solution was added a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The mixture was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfa