The present invention provides a compound of formula (I): [structure] wherein R 1a is optionally substituted C 1-6 alkyl, etc.; R 1m is hydrogen atom, etc.; G 1 , G 2 , G 3 and G 4 are (i), etc. ((i) G 1 is â€”N(R 1b )â€”, G 2 is â€”COâ€”, G 3 is â€”C(R 1c )(R 1d )â€”, and G 4 is oxygen, etc.); R 1b is optionally substituted C 1-6 alkyl, etc.; R 1c and R 1d are each independently optionally substituted C 1-6 alkyl, etc.; R 2 is optionally substituted C 1-6 alkyl, etc.; R 3a , R 3b , R 3c and R 3d are each independently a group: -A-B (A is a single bond, etc., B is hydrogen atom, etc.), etc.; n is 1, etc.; R 5 is C 1-4 alkoxycarbonyl, etc., or a pharmaceutically acceptable salt thereof, which is useful as a renin inhibitor.

Description

63 parts

›CROSS REFERENCE TO RELATED APPLICATION

This application is a National Stage of International Application No. PCT/JP2010/060716 filed Jun. 24, 2010, claiming priority based on Japanese Patent Application No. 2009-150382, filed Jun. 24, 2009, the contents of all of which are incorporated herein by reference in their entirety.

›TECHNICAL FIELD

The present invention relates to N-substituted cyclic amino derivatives which are useful as a medication. Specifically, it relates to N-substituted cyclic amino derivatives which are effective as a renin inhibitor. Further, it relates to a therapeutic agent for hypertension comprising N-substituted cyclic amino derivatives which are effective as a renin inhibitor.

›BACKGROUND ART

A renin-angiotensin (RA) system is a hormone system which is important for maintaining electrolyte balance of blood pressure and within body, and plays an important role for development and progress of circulatory diseases such as hypertension, congestive heart failure, renal disorder.

Renin which is an important component of RA system is an aspartic protease which is secreted mainly from the kidney into the blood, and specifically breaks down angiotensinogen which is generated in the liver to produce angiotensin I. Angiotensin I is converted into angiotensin II by angiotensin converting enzyme (ACE) which exists in lung and vascular endothelial cells. Angiotensin II not only constricts a blood vessel, but also stimulates the adrenal gland to promote secretions of aldosterone. Aldosterone acts on the kidney to conserve sodium and eliminate potassium. These cascades cause increased blood pressure (Nonpatent Document 1).

Recently, it has been indicated that RA system components also exist in local sites including peripheral tissues or central tissues such as heart, blood vessel, kidney, adrenal gland, adipose, and (pro)renin receptor has the possibility to play an important role in activation of local RA system as an additional new component (Nonpatent Document 2), and the importance of local (tissue) RA system has been recognized. It has been indicated that circulating RA system involves in short-term circulation controls, while tissue RA system has the possibility to cause organ damages such as cardiomegaly, arteriosclerosis, renal disorder by inducing long-term various organ remodelings in heart, kidney, blood vessel, etc. (Nonpatent Document 3).

RA system inhibiting agents include ACE inhibitors and angiotensin II receptor antagonists (ARB). It has been shown that these agents (especially, the former) are useful as a therapeutic agent not only for hypertension, but also for cardiovascular diseases and renal diseases such as heart failure and diabetic nephropathy, and these agents have been applied in a wide clinical setting (Nonpatent Document 4, Nonpatent Document 5).

There are multiple RA system inhibiting steps, and among them, renin is located in upstream of RA system and limits the cascade. Thus, to inhibit renin is significantly attractive approach in theory (Nonpatent Document 6, Nonpatent Document 7). Actually, it has been shown that a renin inhibitor aliskiren which has been recently developed significantly inhibits plasma renin activity in clinical trial intended for hypertension patients, and shows excellent hypotensive effects comparable to other RA system inhibiting agents (Nonpatent Document 8, Nonpatent Document 9, Nonpatent Document 10).

As a compound group wherein nitrogen atom in the ring of cyclic amino is substituted, a compound group of the following formula:

wherein R 1 is hydrogen atom, C 1-6 alkyl, —C(A)D, C 3-8 cycloalkyl, aryl, hetero, aryl-C 1-4 alkyl, or hetero-C 1-4 alkyl, R 2 is aryl or heteroaryl, A is S or O, D is hydrogen atom, halogen atom, C 1-6 alkyl, aryl, aryl-C 1-4 alkyl, or hetero-C 1-4 alkyl, n is 0 or 1, provided that if n is 1, m is 0 or 1, provided that if n is 2, m is 0, * is a chiral center, R 3 is hydrogen atom, C 1-6 alkyl, etc. has been known (Patent Document 1). However, this compound group is structurally different from the present compound in view of aryl or heteroaryl skeleton in “R 2 ”.

As a renin inhibitor having cyclic amino, derivatives with a piperidine ring (Patent Documents 2 and 3), derivatives with a pyrrolidine ring (Patent Document 4) have been reported to be effective as a renin inhibitor. The compounds disclosed in these documents are structurally characterized in that they all have a partial structure wherein amino group binds to 3-position of piperidine ring and pyrrolidine ring via carbonyl group or methylene chain, and that nitrogen atom in the ring of piperidine ring and pyrrolidine ring is unsubstituted. It has been reported that a compound group having aminocarbonyl on 3-position of pyrrolidine ring or piperidine ring is effective as a renin inhibitor (Patent Documents 5 to 12). However, all these compound groups are structurally characterized in that nitrogen atom in the ring of cyclic amino (including pyrrolidine ring, piperidine ring) is unsubstituted. Hence, they are different from the present invention described hereinafter in that nitrogen atom in the ring of cyclic amino is unsubstituted or substituted by specific substituents.

[Patent Document 1] WO2006/064336 pamphlet [Patent Document 2] WO2006/069788 pamphlet [Patent Document 3] WO2006/094763 pamphlet [Patent Document 4] WO2006/066896 pamphlet [Patent Document 5] WO2008/093737 pamphlet [Patent Document 6] WO2008/136457 pamphlet [Patent Document 7] WO2008/153135 pamphlet [Patent Document 8] WO2009/005002 pamphlet [Patent Document 9] WO2009/014217 pamphlet [Patent Document 10] WO2009/072649 pamphlet [Patent Document 11] WO2009/078481 pamphlet [Patent Document 12] WO2009/154300 pamphlet [Nonpatent Document 1] Nat Rev Drug Discov. 1(8): p. 621-36 (2002) [Nonpatent Document 2] Curr Hypertens Rep. 6(2): p. 129-32 (2004) [Nonpatent Document 3] Physiol. Rev. 86: p. 747-803, (2006) [Nonpatent Document 4] Curr Diab Rep. 6(1): p. 8-16, (2006) [Nonpatent Document 5] J Hypertens Suppl. 23(1): S9-17, (2005) [Nonpatent Document 6] J Exp Med. 106(3): p. 439-53, (1957) [Nonpatent Document 7] J Am Soc Nephrol 16: p. 592-599 (2005) [Nonpatent Document 8] Hypertension 42(6): p. 1137-43, (2003) [Nonpatent Document 9] Circulation 111(8): p. 1012-8, (2005) [Nonpatent Document 10] J Hypertens. 24(Suppl 4): S82. Abstract P4.269, (2006)

›DISCLOSURE OF INVENTION · 1 of 14

Problems to be Resolved by the Invention

The problem to be resolved by the present invention is to provide novel compounds having an excellent renin inhibitory effect as well as showing few side effects.

Means of Solving the Problems

According to the extensive studies to resolve the problem, the present inventors have found that the following compounds or pharmaceutically acceptable salts thereof wherein nitrogen atom in the ring of cyclic amino has specific substituents (which may be abbreviated as the present compound hereinafter, if needed) surprisingly show excellent renin inhibitory effects, and may reduce adverse effects such as actions or symptoms derived from inflammation-inducing effects, and have achieved the present invention.

The present invention is described as follows.

Item 1: A compound of formula (I):

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

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

G 1 , G 2 , G 3 and G 4 are any of the following (i) to (v) (in which,

(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 —, oxygen, sulfur, or absence,

(ii) G 1 is —N(R 1b )—, G 2 is —CO—, G 3 is —N(R 1b )—, and G 4 is absence (wherein R 1b in G 1 and G 3 are each independent),

(iii) G 1 is oxygen, G 2 is —CH 2 —, G 3 is oxygen, and G 4 is absence,

(iv) G 1 is oxygen, G 2 is —CH 2 —, G 3 is —CH 2 —, and G 4 is oxygen, or

(v) G 1 is —N(R 1b )—, G 2 is —CO—, G 3 and G 4 are —C(R 1d )═C(R 1y )—);

R 1b is optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, or optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl C 1-4 alkyl;

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

(wherein,

R 1e , R 1f , R 1g , R 1h and R 1i are each independently, same or different,

(a) hydrogen atom,

(b) halogen atom,

(d) C 1-4 alkyl (in which the group may be optionally substituted by 5- to 6-membered saturated heterocyclyloxy, C 1-4 alkoxy (in which alkoxy may be optionally substituted by C 1-4 alkoxy or C 3-6 alkoxy), or 1 to 3 fluorine atoms),

(e) C 1-4 alkoxy (in which the group may be optionally substituted by 1 to 3 halogen atoms, C 1-4 alkoxy or C 1-6 alkylaminocarbonyl),

(f) C 3-6 cycloalkoxy (in which the group may be optionally substituted by C 1-4 alkoxy),

(g) 5- to 6-membered saturated heterocyclyloxy,

(h) C 1-6 alkylaminocarbonyl,

(i) hydroxyl, or

(j) C 1-4 alkylsulfonyl, or

R 1e , R 1h and R 1i are each independently hydrogen atom, R 1f and R 1g combine each other to form a condensed ring), or alternatively,

R 1c and R 1d combine each other to form a group of the following formula:

(wherein D is oxygen, sulfur, —SO 2 —, —NR 4a —, —NR 4a CO—, NR 4a SO 2 —, —NR 4a CONR 4a —, —CH(R 4b )—, or —CH(R 4b )CH 2 —,

R 4a is hydrogen atom, optionally substituted C 1-6 alkyl, optionally substituted C 1-4 alkoxycarbonyl, optionally substituted C 1-4 alkylsulfonyl, or optionally substituted C 6-10 arylsulfonyl,

R 4b is hydrogen atom, halogen atom, hydroxyl, optionally substituted C 1-6 alkoxy, optionally substituted C 3-6 cycloalkoxy, optionally substituted C 7-14 aralkyloxy, or optionally substituted aminocarbonyloxy,

p and q are each independently, same or different, 0, 1 or 2);

R 1x and R 1y are each independently, same or different, hydrogen atom, halogen atom, or C 1-4 alkyl, or alternatively,

R 1x and R 1y combine each other to form a group of the following formula:

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

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

R 3a , R 3b , R 3a , and R 3d are each independently, same or different, halogen atom, hydroxyl, formyl, carboxy, cyano, or a group: -A-B

›DISCLOSURE OF INVENTION · 2 of 14

(wherein A is a single bond, —(CH 2 ) s O—, —(CH 2 ) s N(R 4c )—, —(CH 2 ) s SO 2 —, —(CH 2 ) s CO—, —(CH 2 ) s COO—, —(CH 2 ) s N(R 4c )CO—, —(CH 2 ) s N(R 4c )SO 2 —, —(CH 2 ) s N(R 4c )COO—, —(CH 2 ) s OCON(R 4c )—, —(CH 2 ) s O—CO—, —(CH 2 ) s CON(R 4c )—, —(CH 2 ) s N(R 4c )CON(R 4c )—, or —(CH 2 ) s SO 2 N(R 4c )—,

B is hydrogen atom, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 3-10 cycloalkyl, optionally substituted C 5-6 cycloalkenyl, optionally substituted C 6-10 aryl, optionally substituted C 7-14 aralkyl, optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl, optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl C 1-4 alkyl, or optionally substituted saturated heterocyclyl,

provided that if A is —(CH 2 ) s N(R 4c )—, —(CH 2 ) s OCON(R 4c )—, —(CH 2 ) s CON(R 4c )—, —(CH 2 ) s N(R 4c )CON(R 4c )— and —(CH 2 ) s SO 2 N(R 4c )—, R 4c and B may combine each other to form a ring,

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

s is 0, 1 or 2,

provided that if A is —(CH 2 ) s N(R 4c )—, s is 0 or 2,

provided that if A is —(CH 2 ) s CON(R 4c )—, s is 1 or 2), or alternatively,

any two of R 3a , R 3b , R 3c and R 3d are hydrogen atom, and the other two combine each other together with the adjacent heterocyclyl to form a bridged ring;

n is 0, 1 or 2;

R 5 is

1: C 1-6 alkyl (in which the group is substituted by

(a) amino,

(b) hydroxy, or

(wherein R 6 is

(i) C 1-4 alkyl (in which the group may be optionally substituted by C 1-4 alkoxy),

(ii) C 3-6 cycloalkyl, or

(iii) C 6-10 aryl (in which the group may be optionally substituted by C 1-4 alkoxy))),

2: C 1-4 alkylcarbonyl (in which the group may be optionally substituted by

(a) amino, or

(b) hydroxy)

3: C 1-4 alkoxycarbonyl (in which the group is substituted by a group of the following formula:

(wherein R 6 has the same meaning as defined above)), or

4: a group of the following formula:

(wherein R 7 and R 8 are each independently, same or different,

(a) hydrogen atom,

(b) C 1-4 alkyl (in which the group may be optionally substituted by C 1-4 alkoxy, C 3-6 cycloalkyl (in which the group may be optionally substituted by C 1-4 alkoxy), 5- to 6-membered saturated heterocyclyl, or 5- to 6-membered saturated heterocyclyloxy),

(d) C 6-10 aryl (in which the group may be optionally substituted by halogen atom, or C 6-10 aryl (in which the aryl may be optionally substituted by halogen atom or C 1-4 alkoxy)),

(e) 5- to 6-membered saturated heterocyclyl, or

(f) 5- to 10-membered monocyclic or polycyclic heteroaryl (in which the group may be optionally substituted by C 1-4 alkyl, or C 1-4 alkoxy),

R 9 is

(a) C 1-6 alkyl (in which the group may be optionally substituted by

1 to 3 fluorine atoms,

hydroxy,

C 1-4 alkoxy,

carboxy,

5- to 6-membered saturated heterocyclyl,

C 3-6 cycloalkyl,

C 1-4 alkoxycarbonyl,

C 1-4 alkoxycarbonylamino,

amino,

mono- or di-(C 1-6 alkyl)amino,

5- to 7-membered cyclic amine,

1 to 2 nitroxy,

aminocarbonyl, or

5- to 7-membered cyclic aminocarbonyl),

(b) C 3-10 cycloalkyl (in which the group may be optionally substituted by hydroxy),

(d) C 1-4 alkylcarbonyl (in which the group may be optionally substituted by hydroxy),

(e) 5- to 10-membered monocyclic or polycyclic heteroaryl,

(f) 5- to 6-membered saturated heterocyclyl (in which the group may be optionally substituted by C 1-4 alkyl optionally substituted by C 1-4 alkoxy),

(g) C 1-6 alkoxy (in which the group may be optionally substituted by C 3-6 cycloalkyl),

(h) C 3-6 cycloalkyloxy (in which the group may be optionally substituted by C 1-4 alkoxy), or

(i) 5- to 6-membered saturated heterocyclyloxy); or a pharmaceutically acceptable salt thereof

Item 2: The compound of Item 1, wherein G 1 , G 2 , G 3 and G 4 are either of the following (i) or (ii) (in which,

(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 —, oxygen, sulfur, or absent, or

(ii) G 1 is —N(R 1b )—, G 2 is —CO—, G 3 is —N(R 1b )—, and G 4 is absent), or a pharmaceutically acceptable salt thereof.

Item 3: The compound of either Item 1 or 2, 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 —, oxygen, or sulfur, or a pharmaceutically acceptable salt thereof.

Item 4: The compound of Item 3, wherein G 4 is oxygen, or a pharmaceutically acceptable salt thereof.

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

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

Item 7: The compound of Item 2, wherein G 4 is absent, or a pharmaceutically acceptable salt thereof.

Item 8: The compound of Item 2, wherein G 1 is —N(R 1b )—, G 2 is —CO—, G 3 is —N(R 1b )—, and G 4 is absent, or a pharmaceutically acceptable salt thereof.

Item 9: The compound of any one of Items 1 to 8, wherein R 1a and R 1m bind to the adjacent ring in any binding positions of the following formulae (A) to (C):

or a pharmaceutically acceptable salt thereof

Item 10: The compound of Item 9, wherein R 1a and R 1m bind to the adjacent ring in either binding position of the following formula (A) or (B):

or a pharmaceutically acceptable salt thereof.

Item 11: The compound of any one of Items 1 to 10, wherein R 1a is one group selected from the group consisting of

1: halogen atom;

2: cyano;

3: C 1-6 alkyl (in which the group may be optionally substituted by

(a) 1 to 3 fluorine atoms,

(b) C 1-4 alkoxy, or

4: C 1-6 alkoxy (in which the group may be optionally substituted by

›DISCLOSURE OF INVENTION · 3 of 14

(a) 1 to 3 fluorine atoms, or

(b) C 3-6 cycloalkyl);

5: C 3-6 cycloalkyl;

6: C 3-6 cycloalkoxy (in which the group may be optionally substituted by

(a) 1 to 3 fluorine atoms, or

(b) C 1-4 alkoxy); and

7: 5- to 6-membered monocyclic heteroaryl (in which the group may be optionally substituted by C 1-4 alkyl); or a pharmaceutically acceptable salt thereof.

Item 12: The compound of any one of Items 1 to 11, wherein R 1a is halogen atom, cyano, C 1-6 alkyl optionally substituted by 1 to 3 fluorine atoms, or C 1-6 alkoxy, or a pharmaceutically acceptable salt thereof.

Item 13: The compound of Item 12, wherein R 1a is C 1-6 alkyl optionally substituted by 1 to 3 fluorine atoms, or a pharmaceutically acceptable salt thereof.

Item 14: The compound of Item 13, wherein R 1a is methyl, or trifluoromethyl, or a pharmaceutically acceptable salt thereof.

Item 15: The compound of any one of Items 1 to 14, wherein R 1m is hydrogen atom, halogen atom, or C 1-6 alkoxy, or a pharmaceutically acceptable salt thereof.

Item 16: The compound of Item 15, wherein R 1m is hydrogen atom, or a pharmaceutically acceptable salt thereof.

Item 17: The compound of any one of Items 1 to 16, wherein R 1b is

1: C 1-6 alkyl (in which the group may be optionally substituted by two groups selected from the group consisting of

(a) hydroxy,

(b) C 1-4 alkoxy (in which the group may be optionally substituted by 1 to 3 fluorine atoms, or C 1-4 alkoxy),

(d) trifluoromethyl,

(e) trifluoromethoxy,

(f) C 3-6 cycloalkyl (in which the group may be optionally substituted by 1 to 2 fluorine atoms, C 1-4 alkyl optionally substituted by C 1-4 alkoxy, or C 1-4 alkoxy),

(g) C 3-6 cycloalkoxy,

(h) formylamino,

(i) C 1-4 alkylcarbonylamino (in which the group may be optionally substituted by 1 to 3 fluorine atoms),

(j) N—(C 1-4 alkylcarbonyl)-N—(C 1-6 alkyl)-amino,

(k) C 3-6 cycloalkylcarbonylamino,

(l) (C 3-6 cycloalkylC 1-4 alkyl)carbonylamino,

(m) C 1-4 alkylthiocarbonylamino,

(n) C 1-4 alkoxycarbonylamino (in which the group may be optionally substituted by 1 to 3 fluorine atoms),

(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 (in which the group may be optionally substituted by 1 to 3 fluorine atoms),

(r) di-(C 1-6 alkyl)aminocarbonyl,

(s) C 3-6 cycloalkylaminocarbonyl,

(t) C 1-6 alkylaminocarbonylamino,

(u) C 1-6 alkylaminothiocarbonylamino,

(v) C 1-4 alkylcarbonyl (in which the group may be optionally substituted by 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- to 6-membered saturated heterocyclyl,

(ab) carboxy, and

(ac) C 1-6 alkylamino (in which alkyl may be optionally substituted by 1 to 3 fluorine atoms));

2: C 2-6 alkenyl (in which the group may be optionally substituted by halogen atom);

3: C 2-6 alkynyl (in which the group may be optionally substituted by C 1-4 alkoxy);

4: 5- to 6-membered monocyclic heteroarylC 1-4 alkyl; or

5: C 3-6 cycloalkyl; or a pharmaceutically acceptable salt thereof

Item 18: The compound of any one of Items 1 to 17, wherein R 1b is (a) C 1-6 alkyl, which is optionally substituted by C 1-4 alkoxy, C 1-4 alkylcarbonylamino optionally substituted by 1 to 3 fluorine atoms, or C 1-4 alkoxycarbonylamino; or (b) 5- to 6-membered heteroarylC 1-4 alkyl; or a pharmaceutically acceptable salt thereof.

Item 19: The compound of Item 18, wherein R 1b is C 1-6 alkyl optionally substituted by C 1-4 alkoxy, or a pharmaceutically acceptable salt thereof

Item 20: The compound of Item 19, wherein R 1b is 3-methoxypropyl, or a pharmaceutically acceptable salt thereof.

Item 21: The compound of Item 19, wherein R 1b is 4-methoxybutyl, or a pharmaceutically acceptable salt thereof.

Item 22: The compound of Item 18, wherein R 1b is C 1-6 alkyl which is optionally substituted by C 1-4 alkylcarbonylamino optionally substituted by 1 to 3 fluorine atoms, or a pharmaceutically acceptable salt thereof.

Item 23: The compound of Item 22, wherein R 1b is 2-(ethylcarbonylamino)ethyl, or a pharmaceutically acceptable salt thereof.

Item 24: The compound of Item 22, wherein R 1b is 2-(difluoroacetylamino)ethyl, or a pharmaceutically acceptable salt thereof.

Item 25: The compound of Item 18, wherein R 1b is C 1-6 alkyl optionally substituted by C 1-4 alkoxycarbonylamino, or a pharmaceutically acceptable salt thereof.

Item 26: The compound of Item 25, wherein R 1b is 2-(methoxycarbonylamino)ethyl, or a pharmaceutically acceptable salt thereof.

Item 27: The compound of any one of Items 1 to 26, wherein R 1c is hydrogen atom, halogen atom, or C 1-6 alkyl optionally substituted by C 1-4 alkoxy, or a pharmaceutically acceptable salt thereof.

Item 28: The compound of any one of Items 1 to 27, wherein R 1c is hydrogen atom, or C 1-6 alkyl, or a pharmaceutically acceptable salt thereof.

Item 29: The compound of Item 28, wherein R 1c is C 1-6 alkyl, or a pharmaceutically acceptable salt thereof.

Item 30: The compound of any one of Items 1 to 29, wherein R 1d is one group selected from the group consisting of

1: hydrogen atom;

2: halogen atom;

3: cyano;

4: C 2-6 alkenyl (in which the group may be optionally substituted by C 6-10 aryl optionally substituted by C 1-4 alkoxy);

5: C 2-6 alkynyl (in which the group may be optionally substituted by C 6-10 aryl optionally substituted by C 1-4 alkoxy);

6: C 1-6 alkyl (in which the group may be optionally substituted by same or different 1 to 2 groups selected from the group consisting of

(a) 1 to 3 halogen atoms,

(b) cyano,

(d) hydroxy,

(e) C 1-4 alkoxy (in which the group may be optionally substituted by same or different 1 to 3 groups selected from the group consisting of

halogen atom,

cyano,

C 3-6 cycloalkoxy optionally substituted by mono- or di-(C 1-6 alkyl)aminocarbonyl, mono- or di-(C 1-6 alkyl)aminosulfonyl,

C 1-6 alkylsulfonyl,

aminocarbonyl optionally substituted by mono- or di-(C 1-6 alkyl),

›DISCLOSURE OF INVENTION · 4 of 14

C 1-4 alkylcarbonyl,

5- to 7-membered cyclic aminocarbonyl,

hydroxy,

C 1-4 alkoxy,

5- to 6-membered saturated heterocyclyl, and

C 1-4 alkoxycarbonyl),

(f) C 3-6 cycloalkoxy (in which the group may be optionally substituted by C 1-4 alkyl optionally substituted by C 1-4 alkoxy),

(g) C 6-10 aryloxy (in which the group may be optionally substituted by same or different 1 to 3 groups selected from the group consisting of halogen atom, cyano, and C 1-4 alkoxy),

(h) mono- or di-substituted amino (in which the group is substituted by same or different 1 to 2 groups selected from the group consisting of

C 1-6 alkyl,

C 3-6 cycloalkyl,

C 3-6 cycloalkylC 1-4 alkyl optionally substituted by aminocarbonyl,

C 3-6 cycloalkylC 1-4 alkoxycarbonyl,

C 1-4 alkylcarbonyl,

C 3-6 cycloalkylcarbonyl optionally substituted by C 1-4 alkylsulfonylamino,

5- to 6-membered saturated heterocyclylC 1-4 alkyl optionally substituted by C 1-4 alkyl,

5- to 6-membered saturated heterocyclylcarbonyl,

5- to 6-membered saturated heterocyclyloxycarbonyl,

5- to 6-membered saturated heterocyclylC 1-4 alkylcarbonyl, and

C 1-4 alkylsulfonyl),

(i) 5- to 7-membered cyclic amino (in which the group may be optionally substituted by same or different 1 to 4 groups selected from the group consisting of C 1-4 alkyl, C 7-14 aralkyl, and oxo),

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

(k) 4- to 7-membered cyclic aminocarbonyl (in which cyclic amino may be optionally substituted by C 1-4 alkyl),

(l) aminocarbonyloxy (in which amino is substituted by same or different 1 to 2 groups selected from the group consisting of

C 1-6 alkyl optionally substituted by 5- to 6-membered saturated heterocyclyl,

C 3-6 cycloalkyl optionally substituted by hydroxy, and

5- to 6-membered saturated heterocyclyl),

(m) 5- to 7-membered cyclic aminocarbonyloxy (in which cyclic amino may be optionally substituted by 1 to 2 fluorine atoms),

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

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

(p) 5- to 6-membered saturated heterocyclyl (in which the group may be optionally substituted by same or different groups selected from the group consisting of C 1-4 alkyl and oxo),

(q) 5- to 6-membered saturated heterocyclylC 1-4 alkoxy (in which heterocyclyl may be optionally substituted by C 1-4 alkyl),

(r) 5- to 6-membered saturated heterocyclyloxy (in which heterocyclyl may be optionally substituted by same or different 1 to 2 groups selected from the 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 (in which the group may be optionally substituted by C 1-4 alkoxy),

(w) C 1-4 alkoxycarbonylamino,

(x) C 6-10 aryloxycarbonylamino (in which aryl may be optionally substituted by halogen atom),

(y) 5- to 6-membered monocyclic heteroaryloxycarbonylamino, and

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

7: C 3-10 cycloalkyl (in which the group may be optionally substituted by

(a) halogen atom,

(b) hydroxy, or

8: C 7-14 aralkyl (in which the group may be optionally substituted by same or different 1 to 3 groups selected from the group consisting of

(a) halogen atom,

(b) cyano,

(d) C 1-4 alkoxy, and

(e) C 1-4 alkyl optionally substituted by C 1-4 alkoxy);

9: C 1-6 alkoxy (in which the group may be optionally substituted by

(a) C 1-4 alkoxycarbonylamino,

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

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

10: C 3-6 cycloalkoxy;

11: C 7-14 aralkyloxy optionally substituted by C 1-4 alkoxy;

12: mono- or di-substituted aminocarbonyl (in which amino may be optionally substituted by C 1-6 alkyl optionally substituted by 5- to 6-membered saturated heterocyclyl);

13: 5- to 7-membered cyclic aminocarbonyl (in which the group may be optionally substituted by a group selected from the group consisting of

(a) halogen atom,

(b) C 1-4 alkoxy, and

14: saturated heterocyclyl (in which the group may be optionally substituted by same or different 1 to 4 groups selected from the group consisting of

(a) C 1-4 alkyl,

(b) C 6-10 aryl optionally substituted by 1 to 3 halogen atoms, and

15: saturated heterocyclyloxy (in which the group may be optionally substituted by C 1-4 alkoxycarbonyl, or C 1-4 alkylcarbonyl);

16: 5- to 10-membered monocyclic or polycyclic heteroaryl (in which the group may be optionally substituted by same or different 1 to 2 groups selected from the group consisting of

(a) halogen atom,

(b) C 1-4 alkyl optionally substituted by 1 to 3 fluorine atoms, and

17: 5- to 10-membered monocyclic or polycyclic heteroarylC 1-4 alkyl;

18: amino (in which amino may be optionally substituted by

(a) C 3-6 cycloalkylC 1-4 alkyl (in which cycloalkyl may be optionally substituted by aminocarbonyl),

(b) C 1-4 alkylcarbonyl (in which alkyl may be optionally substituted by C 1-4 alkoxy),

(d) 5- to 6-membered saturated heterocyclyloxycarbonyl);

19: hydroxyl, and

20: a group of the following formula:

or a pharmaceutically acceptable salt thereof

Item 31: The compound of any one of Items 1 to 30, wherein R 1d is one group selected from the group consisting of

1: hydrogen atom;

2: halogen atom;

3: C 1-6 alkyl (in which the group may be optionally substituted by

(a) 1 to 3 halogen atoms,

(b) hydroxy,

(c) C 1-4 alkoxy (in which the group may be optionally substituted by 1 to 2 groups selected from the group consisting of hydroxy, C 1-4 alkoxy, 5- to 6-membered saturated heterocyclyl, and C 1-4 alkoxycarbonyl),

(d) C 6-10 aryloxy (in which the group may be optionally substituted by same or different 1 to 3 groups selected from the group consisting of cyano and C 1-4 alkoxy),

(e) C 1-6 alkylaminocarbonyloxy,

(f) (5- to 6-membered saturated heterocyclylC 1-4 alkyl)aminocarbonyloxy, or

›DISCLOSURE OF INVENTION · 5 of 14

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

4: aminocarbonyl;

5: mono- or di-(C 1-6 alkyl)aminocarbonyl;

6: N-(5- to 6-membered saturated heterocyclylC 1-4 alkyl)-N—(C 1-6 alkyl)-aminocarbonyl;

7: 5- to 7-membered cyclic aminocarbonyl;

8: C 7-14 aralkyl optionally substituted by C 1-4 alkoxy;

9: 5- to 6-membered saturated heterocyclyl;

10: C 3-6 cycloalkyl;

11: C 3-6 cycloalkoxy; and

12: a group of the following formula:

or a pharmaceutically acceptable salt thereof

Item 32: The compound of any one of Items 1 to 31, wherein R 1d is C 1-6 alkyl optionally substituted by one group selected from the group consisting of

1: 1 to 3 halogen atoms,

2: hydroxy,

3: C 1-4 alkoxy (in which the group may be optionally substituted by 1 to 2 groups selected from the group consisting of

(a) hydroxy,

(b) C 1-4 alkoxy,

(d) C 1-4 alkoxycarbonyl),

4: C 6-10 aryloxy (in which the group may be optionally substituted by same or different 1 to 3 groups selected from the group consisting of cyano and C 1-4 alkoxy),

5: C 1-6 alkylaminocarbonyloxy,

6: (5- to 6-membered saturated heterocyclylC 1-4 alkyl)aminocarbonyloxy, and

7: 5- to 7-membered cyclic aminocarbonyloxy, or a pharmaceutically acceptable salt thereof.

Item 33: The compound of any one of Items 1 to 32, wherein R 1d is C 1-6 alkyl optionally substituted by C 1-4 alkoxy, or a pharmaceutically acceptable salt thereof.

Item 34: The compound of any one of Items 1 to 31, wherein R 1d is a group of the following formula:

or a pharmaceutically acceptable salt thereof

Item 35: The compound of Item 34, wherein R 1e , R 1f , R 1g , R 1h and R 1i are each independently, same or different, a group selected from the group consisting of

1: hydrogen atom,

2: halogen atom,

3: cyano,

4: C 1-4 alkyl (in which the group may be optionally substituted by

(a) 5- to 6-membered saturated heterocyclyloxy,

(b) C 1-4 alkoxy (in which the group may be optionally substituted by C 1-4 alkoxy or C 3-6 cycloalkoxy), or

5: C 1-4 alkoxy (in which the group may be optionally substituted by

(a) 1 to 3 halogen atoms,

(b) C 1-4 alkoxy, or

6: C 3-6 cycloalkoxy (in which the group may be optionally substituted by C 1-4 alkoxy),

7: 5- to 6-membered saturated heterocyclyloxy,

8: C 1-6 alkylaminocarbonyl,

9: hydroxyl, and

10: C 1-4 alkylsulfonyl, or a pharmaceutically acceptable salt thereof

Item 36: The compound of Item 35, wherein R 1e , R 1f , R 1g , R 1h and R 1i are each independently, same or different, a group selected from the group consisting of hydrogen atom, halogen atom, cyano, C 1-4 alkyl optionally substituted by 1 to 3 fluorine atoms, C 1-4 alkoxy, hydroxyl, and C 1-4 alkylsulfonyl, or a pharmaceutically acceptable salt thereof

Item 37: The compound of Item 36, wherein R 1e , R 1f , R 1g , R 1h and R 1i are each independently, same or different, selected from the group consisting of hydrogen atom, halogen atom, and C 1-4 alkoxy, or a pharmaceutically acceptable salt thereof

Item 38: The compound of Item 36, wherein R 1d is any group selected from the group consisting of

or a pharmaceutically acceptable salt thereof.

Item 39: The compound of any one of Items 1 to 26, wherein R 1c and R 1d combine each other to form a group of the following formula:

or a pharmaceutically acceptable salt thereof

Item 40: The compound of Item 39, wherein R 4a is selected from the group consisting of hydrogen atom, C 1-6 alkyl, C 1-4 alkoxycarbonyl, C 1-4 alkylsulfonyl, and C 6-10 arylsulfonyl, or a pharmaceutically acceptable salt thereof.

Item 41: The compound of Item 39, wherein R 4b is (a) hydrogen atom, (b) halogen atom, (c) C 1-4 alkoxy optionally substituted by C 1-4 alkoxy, (d) C 7-14 aralkyloxy optionally substituted by 1 to 3 groups selected from the group consisting of fluorine atom and cyano, or (e) aminocarbonyloxy optionally substituted by mono- or di-(C 1-6 alkyl), or a pharmaceutically acceptable salt thereof.

Item 42: The compound of any one of Items 39 to 41, wherein D, p and q are any of the following (i) to (iii) (in which

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

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

(iii) D is —CH 2 CH 2 —, and p and q are the same and 0 or 1), or a pharmaceutically acceptable salt thereof

Item 43: The compound of any one of Items 1 to 26, wherein R 1c and R 1d combine each other to form a group of the following formula:

or a pharmaceutically acceptable salt thereof

Item 44: The compound of any one of Items 1 to 43, wherein R 2 is one group selected from the group consisting of (a) C 1-6 alkyl optionally substituted by C 3-6 cycloalkyl (in which C 1-6 alkyl may be optionally substituted by 1 to 3 halogen atoms, and C 3-6 cycloalkyl may be optionally substituted by halogen atom, C 1-4 alkyl or C 1-4 alkoxy); (b) C 3-6 cycloalkyl optionally substituted by halogen atom or C 1-4 alkyl; (c) C 2-6 alkenyl; and (d) C 7-10 aralkyl optionally substituted by halogen atom, or a pharmaceutically acceptable salt thereof.

Item 45: The compound of Item 44, wherein R 2 is C 1-6 alkyl, or a pharmaceutically acceptable salt thereof.

Item 46: The compound of Item 45, wherein R 2 is isopropyl, or a pharmaceutically acceptable salt thereof.

Item 47: The compound of any one of Items 1 to 46, wherein R 3a , R 3b , R 3c and R 3d are each independently a group: -A-B

(wherein A is a single bond, —(CH 2 ) s O—, —(CH 2 ) s N(R 4c )—, —(CH 2 ) s COO—, —(CH 2 ) s N(R 4c )CO—, —(CH 2 ) s N(R 4c )SO 2 —, —(CH 2 ) s N(R 4c )COO—, —(CH 2 ) s OCON(R 4c )—, —(CH 2 ) s CON(R 4c )—, or —(CH 2 ) s N(R 4c )CON(R 4c )—,

B is one group selected from the group consisting of

1: hydrogen atom;

2: C 1-6 alkyl (in which the group may be optionally substituted by same or different 1 to 3 groups selected from the group consisting of

(a) halogen atom,

(b) C 3-6 cycloalkyl (in which the group may be optionally substituted by same or different 1 to 2 groups selected from the group consisting of halogen atom, hydroxy, C 1-4 alkoxy and C 3-6 cycloalkylcarbonylamino),

›DISCLOSURE OF INVENTION · 6 of 14

(d) C 1-4 alkoxy,

(e) carboxy,

(f) C 1-4 alkoxycarbonyl,

(g) saturated heterocyclyl (in which the ring may be optionally substituted by same or different 1 to 3 groups selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylcarbonylamino, and oxo),

(h) aminocarbonyl (in which amino may be optionally substituted by C 1-4 alkyl, C 3-6 cycloalkyl, or C 3-6 cycloalkylC 1-4 alkyl), and

(i) 5- to 7-membered cyclic amino (in which the group may be optionally substituted by same or different 1 to 3 groups selected from the group consisting of halogen atom, C 1-4 alkyl, C 6 aryl optionally substituted by C 1-4 alkoxy, C 6 aryloxy optionally substituted by 1 to 3 halogen atoms and oxo));

3: C 2-6 alkenyl (in which the group may be optionally substituted by

(a) fluorine, or

(b) C 1-6 alkyl);

4: C 3-10 cycloalkyl (in which the group may be optionally substituted by

(a) halogen atom,

(b) C 1-4 alkyl optionally substituted by C 1-4 alkoxy,

(d) C 1-4 alkoxy);

5: C 6 aryl (in which the group may be optionally substituted by same or different 1 to 4 groups selected from the group consisting of

(a) halogen atom,

(b) C 1-4 alkyl (in which C 1-4 alkyl may be optionally substituted by one group selected from the group consisting of

5- to 7-membered cyclic amino (in which the group may be optionally substituted by C 6 aryloxy optionally substituted by 1 to 3 halogen atoms),

mono-C 1-6 alkylamino (in which C 1-6 alkyl may be optionally substituted by C 6 aryloxy optionally substituted by 1 to 3 halogen atoms),

5- to 6-membered saturated heterocyclylamino (in which saturated heterocyclyl may be optionally substituted by C 6 aryl),

5- to 6-membered saturated heterocyclyloxy (in which saturated heterocyclyl may be optionally substituted by C 6 aryl, or 5- to 10-membered monocyclic or polycyclic heteroaryl),

C 6 aryloxy (in which the aryl may be optionally substituted by same or different 1 to 3 groups selected from the group consisting of halogen atom and C 1-4 alkyl),

C 1-4 alkoxy, and

C 3-6 cycloalkoxy),

C 1-4 alkoxy,

C 6 aryloxy (in which the aryl may be optionally substituted by C 1-4 alkyl or 1 to 3 halogen atoms),

C 3-6 cycloalkyl optionally substituted by C 1-4 alkyl or C 1-4 alkoxy,

C 3-6 cycloalkyloxy optionally substituted by C 1-4 alkyl,

phenylamino (in which phenyl may be optionally substituted by 1 to 3 halogen atoms), and

C 7-10 aralkyloxy optionally substituted by 1 to 3 halogen atoms),

(d) C 6 aryloxy (in which the group may be optionally substituted by 1 to 3 groups selected from the group consisting of halogen atom, cyano, C 1-4 alkyl, and C 1-4 alkoxy),

(e) C 7-10 aralkyloxy (in which the group may be optionally substituted by 1 to 3 groups selected from the group consisting of halogen atom and C 1-4 alkoxy),

(f) 5- to 7-membered cyclic amino (in which cyclic amino may be optionally substituted by

(C 1-6 alkyl)(phenylcarbonyl)amino, or

C 6 aryloxy (in which the group may be optionally substituted by same or different 1 to 3 groups selected from the group consisting of halogen atom, and C 1-4 alkyl optionally substituted by hydroxy)),

(g) 5- to 6-membered saturated heterocyclyloxy (in which the ring may be optionally substituted by

C 6 aryl optionally substituted by 1 to 3 halogen atoms,

5- to 10-membered monocyclic or polycyclic heteroaryl,

5- to 6-membered saturated heterocyclylcarbonyl, or oxo),

(h) 5- to 6-membered monocyclic heteroaryloxy (in which heteroaryl may be optionally substituted by C 1-4 alkyl),

(i) 5- to 7-membered cyclic aminocarbonyl (in which cyclic amino may be optionally substituted by C 6 aryloxy optionally substituted by 1 to 3 halogen atoms),

(j) 5- to 7-membered cyclic aminocarbonyloxy (in which cyclic amino may be optionally substituted by C 6 aryl), and

(k) C 6 aryl);

6: C 7-14 aralkyl (in which the group may be optionally substituted by same or different 1 to 3 groups selected from the group consisting of

(a) halogen atom,

(b) cyano,

(d) hydroxy,

(e) C 1-4 alkoxy (in which the group may be optionally substituted by 1 to 3 fluorine atoms),

(f) C 3-6 cycloalkoxy (in which the group may be optionally substituted by 1 to 2 halogen atoms),

(g) C 1-4 alkoxycarbonyl,

(h) aminocarbonyl,

(i) C 6-10 aryl (in which the aryl may be optionally substituted by 1 to 3 halogen atoms) and

(j) C 1-4 alkylsulfonyl);

7: 5- to 10-membered monocyclic or polycyclic heteroaryl (in which the group may be optionally substituted by halogen atom);

8: 5- to 10-membered monocyclic or polycyclic heteroarylC 1-4 alkyl (in which the group may be optionally substituted by halogen atom, or C 1-4 alkyl (in which alkyl may be optionally substituted by 1 to 3 fluorine atoms)); and

9: saturated heterocyclyl (in which the group may be optionally substituted by C 1-4 alkyl optionally substituted by C 1-4 alkoxy),

provided that if A is —(CH 2 ) s N(R 4c )—, —(CH 2 ) s OCON(R 4c )—, —(CH 2 ) s CON(R 4c )—, and —(CH 2 ) s N(R 4c )CON(R 4c )—, R 4c and B may combine each other to form a ring), or a pharmaceutically acceptable salt thereof.

Item 48: The compound of any one of Items 1 to 47, wherein R 3a , R 3b , R 3c and R 3d bind to piperidine ring on substitution positions represented by the following formula:

or a pharmaceutically acceptable salt thereof

Item 49: The compound of Item 48, wherein R 3a , R 3b ) and R 3d are all a group: -A-B (wherein A is a single bond, and B is hydrogen atom);

R 3c is a group: -A-B

(wherein A is a single bond, or —(CH 2 ) s O—, and B is hydrogen atom, optionally substituted C 6-10 aryl, optionally substituted C 7-14 aralkyl, or optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl), or a pharmaceutically acceptable salt thereof.

Item 50: The compound of Item 49, wherein R 3c is a group: -A-B

(wherein A is a single bond, and B is optionally substituted C 6-10 aryl), or a pharmaceutically acceptable salt thereof.

Item 51: The compound of Item 49, wherein B is optionally substituted C 6-10 aryl, or optionally substituted C 7-14 aralkyl, or a pharmaceutically acceptable salt thereof.

›DISCLOSURE OF INVENTION · 7 of 14

Item 52: The compound of Item 49, wherein R 3c is a group: -A-B

(wherein A is —(CH 2 ) s O—, and B is hydrogen atom, optionally substituted C 6-10 aryl, or optionally substituted C 7-14 aralkyl), or a pharmaceutically acceptable salt thereof.

Item 53: The compound of Item 48, wherein R 3a , R 3c and R ad are all a group: -A-B (wherein A is a single bond, and B is hydrogen atom);

R 3b is a group: -A-B

(wherein A is a single bond, —(CH 2 ) s —, —(CH 2 ) s N(R 4c )—, —(CH 2 ) s COO—, —(CH 2 ) s N(R 4c )CO—, —(CH 2 ) s N(R 4c )SO 2 —, —(CH 2 ) s N(R 4c )COO—, —(CH 2 ) s OCON(R 4c )—, —(CH 2 ) s CON(R 4c )—, —(CH 2 ) s N(R 4c )CON(R 4c )—, or —(CH 2 ) s SO 2 N(R 4c )—,

B is hydrogen atom, optionally substituted C 1-6 alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 6-10 aryl, optionally substituted C 7-14 aralkyl, optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl, or optionally substituted 5- to 6-membered saturated heterocyclyl), or a pharmaceutically acceptable salt thereof.

Item 54: The compound of Item 48, wherein R 3a , R 3b , and R 3c are each independently a group: -A-B

(wherein A is a single bond, and B is hydrogen atom);

R 3d is a group: -A-B

(wherein A is a single bond, —(CH 2 ) s O—, —(CH 2 ) s N(R 4c )—, —(CH 2 ) s COO—, —(CH 2 ) s N(R 4c )CO—, —(CH 2 ) s N(R 4c )SO 2 —, —(CH 2 ) s N(R 4c )COO—, —(CH 2 ) s OCON(R 4c )—, or —(CH 2 ) s N(R 4c )CON(R 4c )—,

B is hydrogen atom, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 3-10 cycloalkyl, optionally substituted C 6-10 aryl, optionally substituted C 7-14 aralkyl, optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl, optionally substituted 5- to 10-membered monocyclic or polycyclic heteroarylC 1-4 alkyl or optionally substituted 5- to 6-membered saturated heterocyclyl), or a pharmaceutically acceptable salt thereof.

Item 55: The compound of Item 54, wherein A in R ad is —(CH 2 ) s N(R 4c )CO—, or a pharmaceutically acceptable salt thereof.

Item 56: The compound of either Item 54 or 55, wherein B in R 3d is optionally substituted C 1-6 alkyl, or a pharmaceutically acceptable salt thereof.

Item 57: The compound of Item 55, wherein B in R ad is C 7-14 aralkyl optionally substituted by 1 to 3 halogen atoms, or a pharmaceutically acceptable salt thereof

Item 58: The compound of any one of Items 54 to 57, wherein s is 2, or a pharmaceutically acceptable salt thereof.

Item 59: The compound of any one of Items 1 to 58, wherein R 4c is hydrogen atom, C 1-6 alkyl substituted by 1 to 3 halogen atoms or C 3-6 cycloalkyl, C 3-6 cycloalkyl optionally substituted by 1 to 2 halogen atoms, or C 7 aralkyl, or a pharmaceutically acceptable salt thereof.

Item 60: The compound of Item 59, wherein R 4c is C 1-6 alkyl substituted by 1 to 3 halogen atoms, or C 3-6 cycloalkyl, or a pharmaceutically acceptable salt thereof.

Item 61: The compound of Item 60, wherein R 4c is C 3-6 cycloalkyl, or a pharmaceutically acceptable salt thereof.

Item 62: The compound of any one of Items 1 to 48, wherein R 3a , R 3b , R 3c and R 3d are all a group: -A-B (wherein A is a single bond, and B is hydrogen atom), or a pharmaceutically acceptable salt thereof.

Item 63: The compound of any one of Items 1 to 47, wherein n is 1, or a pharmaceutically acceptable salt thereof.

Item 64: The compound of any one of Items 1 to 63, wherein R 5 is C 1-4 alkoxycarbonyl (in which the group is substituted by a group of the following formula:

wherein R 6 is the same as defined above, or a pharmaceutically acceptable salt thereof

Item 65: The compound of any one of Items 1 to 64, wherein R 5 is a group of the following formula:

wherein R 6 is the same as defined above, or a pharmaceutically acceptable salt thereof

Item 66: The compound of Item 65, wherein R 6 is methyl, or a pharmaceutically acceptable salt thereof.

Item 67: The compound of any one of Items 1 to 63, wherein R 5 is a group of the following formula:

(in which R 7 and R 8 are each independently, same or different, hydrogen atom, or C 1-4 alkyl, and

R 9 is

(a) C 1-6 alkyl (in which the group may be optionally substituted by 1 to 3 fluorine atoms, amino, hydroxy, C 1-4 alkoxy, carboxy, C 1-4 alkoxycarbonyl, C 1-4 alkoxycarbonylamino, or 1 to 2 nitroxy),

(b) C 3-10 cycloalkyl,

(d) C 6-10 aryl (in which the group is substituted by C 1-4 alkyl, or C 1-4 alkylcarbonyloxy),

(e) 5- to 10-membered monocyclic or polycyclic heteroaryl,

(f) 5- to 6-membered saturated heterocyclyl,

(g) C 1-6 alkoxy (in which the group may be optionally substituted by C 3-6 cycloalkyl),

(h) C 3-6 cycloalkyloxy, or

(i) 5- to 6-membered saturated heterocyclyloxy), or a pharmaceutically acceptable salt thereof.

Item 68: The compound of Item 67, wherein R 7 is hydrogen atom, and R 8 is methyl, or a pharmaceutically acceptable salt thereof.

Item 69: The compound of either Item 67 or 68, wherein R 9 is

(a) C 1-4 alkyl (in which the group may be optionally substituted by amino, hydroxy, C 1-4 alkoxy, carboxy, C 1-4 alkoxycarbonyl, or C 1-4 alkoxycarbonylamino),

(b) C 3-10 cycloalkyl,

(d) C 6-10 aryl (in which the group is substituted by C 1-4 alkylcarbonyloxy),

(e) 5- to 10-membered monocyclic or polycyclic heteroaryl,

(f) 5- to 6-membered saturated heterocyclyl,

(g) C 1-6 alkoxy (in which the group may be optionally substituted by C 3-6 cycloalkyl),

(h) C 3-6 cycloalkyloxy, or

(i) 5- to 6-membered saturated heterocyclyloxy, or a pharmaceutically acceptable salt thereof.

Item 70: The compound of Item 69, wherein R 9 is

1: C 1-4 alkyl,

2: C 3-6 cycloalkyl,

3: C 1-6 alkoxy (in which the group may be optionally substituted by C 3-6 cycloalkyl),

4: C 3-6 cycloalkyloxy, or

5: 5- to 6-membered saturated heterocyclyloxy, or a pharmaceutically acceptable salt thereof

Item 71: The compound of Item 70, wherein R 9 is

1: C 1-4 alkyl, or

2: C 1-6 alkoxy, or a pharmaceutically acceptable salt thereof.

›DISCLOSURE OF INVENTION · 8 of 14

Item 72: The compound of Item 1, selected from the group consisting of:

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

(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (3R)-3-[isopropyl({2,2,7-trimethyl-3-oxo-4-[2-(propanoylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)amino]piperidine-1-carboxylate,

1-[(cyclohexylcarbonyl)oxy]ethyl (3R)-3-[propan-2-yl({2,2,7-trimethyl-3-oxo-4-[2-(propanoylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)amino]piperidine-1-carboxylate,

[(2-methylpropanoyl)oxy]methyl (3R)-3-[propan-2-yl({2,2,7-trimethyl-3-oxo-4-[2-(propanoylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)amino]piperazine-1-carboxylate,

{[(propan-2-yloxy)carbonyl]oxy}methyl (3R)-3-[propan-2-yl({2,2,7-trimethyl-3-oxo-4-[2-(propanoylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)amino]piperidine-1-carboxylate,

(acetyloxy)methyl (3R)-3-[propan-2-yl({2,2,7-trimethyl-3-oxo-4-[2-(propanoylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)amino]piperidine-1-carboxylate,

(2-oxo-5-phenyl-1,3-dioxol-4-yl)methyl (3R)-3-[propan-2-yl({2,2,7-trimethyl-3-oxo-4-[2-(propanoylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)amino]piperidine-1-carboxylate,

1-{[(propan-2-yloxy)carbonyl]oxy}ethyl (3R)-3-[propan-2-yl({2,2,7-trimethyl-3-oxo-4-[2-(propanoylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)amino]piperidine-1-carboxylate,

[(methoxycarbonyl)oxy]methyl (3R)-3-[propan-2-yl({2,2,7-trimethyl-3-oxo-4-[2-(propanoylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)amino]piperidine-1-carboxylate,

[(ethoxycarbonyl)oxy]methyl (3R)-3-[propan-2-yl({2,2,7-trimethyl-3-oxo-4-[2-(propanoylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)amino]piperidine-1-carboxylate,

{[(cyclopropylmethoxy)carbonyl]oxy}methyl (3R)-3-[propan-2-yl({2,2,7-trimethyl-3-oxo-4-[2-(propanoylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)amino]piperidine-1-carboxylate,

{[(cyclobutyloxy)carbonyl]oxy}methyl (3R)-3-[propan-2-yl({2,2,7-trimethyl-3-oxo-4-[2-(propanoylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)amino]piperidine-1-carboxylate,

{[(tetrahydro-2H-pyran-4-yloxy)carbonyl]oxy}methyl (3R)-3-[propan-2-yl({2,2,7-trimethyl-3-oxo-4-[2-(propanoylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)amino]-piperidine-1-carboxylate,

{[(pentane-3-yloxy)carbonyl]oxy}methyl (3R)-3-[propan-2-yl({2,2,7-trimethyl-3-oxo-4-[2-(propanoylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)amino]piperidine-1-carboxylate,

{[(cyclopentyloxy)carbonyl]oxy}methyl (3R)-3-[propan-2-yl({2,2,7-trimethyl-3-oxo-4-[2-(propanoylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)amino]piperidine-1-carboxylate,

1-[(ethoxycarbonyl)oxy]ethyl (3R)-3-[propan-2-yl({2,2,7-trimethyl-3-oxo-4-[2-(propanoylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)amino]piperidine-1-carboxylate,

1-(acetyloxy)ethyl (3R)-3-[propan-2-yl({2,2,7-trimethyl-3-oxo-4-[2-(propanoylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)amino]piperidine-1-carboxylate,

1-(propanoyloxy)ethyl (3R)-3-[propan-2-yl({2,2,7-trimethyl-3-oxo-4-[2-(propanoylamino)-ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)amino]piperidine-1-carboxylate,

1-(acetyloxy)-2-methylpropyl (3R)-3-[propan-2-yl({2,2,7-trimethyl-3-oxo-4-[2-(propanoylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)amino]piperidine-1-carboxylate,

2-methyl-1-(propanoyloxy)propyl (3R)-3-[propan-2-yl({2,2,7-trimethyl-3-oxo-4-[2-(propanoylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)amino]piperidine-1-carboxylate,

2-(acetyloxy)propan-2-yl (3R)-3-[propan-2-yl({2,2,7-trimethyl-3-oxo-4-[2-(propanoylamino)-ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)amino]piperidine-1-carboxylate,

2,2-dimethyl-3-oxo-4-[2-(propanoylamino)ethyl]-N-(propan-2-yl)-7-(trifluoromethyl)-N-[(3R)-1-(L-valyl)piperidin-3-yl]-3,4-dihydro-2H-1,4-benzoxazine-6-carboxamide,

N-[(3R)-1-(L-alanyl)piperidin-3-yl]-2,2-dimethyl-3-oxo-4-[2-(propanoylamino)ethyl]-N-(propan-2-yl)-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxamide,

N-{(3R)-1-[(2S)-2-hydroxypropanoyl]piperidin-3-yl}-2,2-dimethyl-3-oxo-4-[2-(propanoylamino)ethyl]-N-(propan-2-yl)-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxamide,

N-[(3R)-1-acetylpiperidine-3-yl]-2,2-dimethyl-3-oxo-4-[2-(propanoylamino)ethyl]-N-(propan-2-yl)-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxamide,

1-[(2-methylpropanoyl)oxy]ethyl (3R)-3-[({2,2-dimethyl-3-oxo-4-[2-(propanoylamino)ethyl]-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)(propan-2-yl)amino]-piperidine-1-carboxylate,

(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (3R)-3-[({2,2-dimethyl-3-oxo-4-[2-(propanoylamino)-ethyl]-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)(propan-2-yl)amino]-piperidine-1-carboxylate,

{[(propan-2-yloxy)carbonyl]oxy}methyl (3R)-3-[({2,2-dimethyl-3-oxo-4-[2-(propanoylamino)ethyl]-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)-(propan-2-yl)amino]piperidine-1-carboxylate,

{[(tetrahydro-2H-pyran-4-yloxy)carbonyl]oxy}methyl (3R)-3-[({2,2-dimethyl-3-oxo-4-[2-(propanoylamino)ethyl]-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)-(propan-2-yl)amino]piperidine-1-carboxylate,

(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (3R)-3-[({2,2-dimethyl-3-oxo-4-[2-(propanoylamino)-ethyl]-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzothiazin-6-yl}carbonyl)(propan-2-yl)-amino]piperidine-1-carboxylate,

2,2-dimethyl-N-{(3R)-1-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl]piperidin-3-yl}-3-oxo-4-[2-(propanoylamino)ethyl]-N-(propan-2-yl)-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxamide,

2,2,7-trimethyl-3-oxo-N-{(3R)-1-[(2-oxo-5-phenyl-1,3-dioxol-4-yl)methyl]piperidin-3-yl}-4-[2-(propanoylamino)ethyl]-N-(propan-2-yl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxamide,

1-(acetyloxy)ethyl (3R)-3-[({7-methyl-3-oxo-4-[2-(propanoylamino)ethyl]-3,4-dihydrospiro-[1,4-benzoxazine-2,1′-cyclobutan]-6-yl}carbonyl)(propan-2-yl)amino]piperidine-1-carboxylate,

›DISCLOSURE OF INVENTION · 9 of 14

1-[(ethoxycarbonyl)oxy]ethyl (3R)-3-[({7-methyl-3-oxo-4-[2-(propanoylamino)ethyl]-3,4-dihydrospiro[1,4-benzoxazine-2,1′-cyclobutan]-6-yl}carbonyl)(propan-2-yl)amino]piperidine-1-carboxylate,

1-(acetyloxy)-2-methylpropyl (3R)-3-[({7-methyl-3-oxo-4-[2-(propanoylamino)ethyl]-3,4-dihydrospiro[1,4-benzoxazine-2,1′-cyclobutan]-6-yl}carbonyl)(propan-2-yl)amino]piperidine-1-carboxylate,

1-(propanoyloxy)ethyl (3R)-3-[({7-methyl-3-oxo-4-[2-(propanoylamino)ethyl]-3,4-dihydrospiro[1,4-benzoxazine-2,1′-cyclobutan]-6-yl}carbonyl)(propan-2-yl)amino]piperidine-1-carboxylate,

1-(propanoyloxy)ethyl (3R)-3-[{[(2S)-2-(methoxymethyl)-2-methyl-3-oxo-4-[2-(propanoylamino)ethyl]-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}-(propan-2-yl)amino]piperidine-1-carboxylate,

1-[(ethoxycarbonyl)oxy]ethyl (3R)-3-[{[(2S)-2-(methoxymethyl)-2-methyl-3-oxo-4-[2-(propanoylamino)ethyl]-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}-(propan-2-yl)amino]piperidine-1-carboxylate,

(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (3R)-3-{[(4-{2-[(difluoroacetyl)amino]ethyl}-7-methyl-3-oxo-3,4-dihydrospiro[1,4-benzoxazine-2,1′-cyclopropan]-6-yl)carbonyl](propan-2-yl)amino}piperidine-1-carboxylate,

(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (3R)-3-[({7-methyl-3-oxo-4-[2-(propanoylamino)-ethyl]-3,4-dihydrospiro[1,4-benzoxazine-2,1′-cyclopropan]-6-yl}carbonyl)(propan-2-yl)-amino]piperidine-1-carboxylate,

1-(propanoyloxy)ethyl (3R)-3-[({7-methyl-3-oxo-4-[2-(propanoylamino)ethyl]-3,4-dihydrospiro[1,4-benzoxazine-2,1′-cyclopropan]-6-yl}carbonyl)(propan-2-yl)amino]-piperidine-1-carboxylate,

1-[(2-methylpropanoyl)oxy]ethyl (3R)-3-[({7-methyl-3-oxo-4-[2-(propanoylamino)ethyl]-3,4-dihydrospiro[1,4-benzoxazine-2,1′-cyclopropan]-6-yl}carbonyl)(propan-2-yl)amino]-piperidine-1-carboxylate,

1-[(tetrahydro-2H-pyran-4-ylcarbonyl)oxy]ethyl (3R)-3-[({7-methyl-3-oxo-4-[2-(propanoylamino)ethyl]-3,4-dihydrospiro[1,4-benzoxazine-2,1′-cyclopropan]-6-yl}carbonyl)-(propan-2-yl)amino]piperidine-1-carboxylate,

(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (3R)-3-{[(4-{2-[(difluoroacetyl)amino]ethyl}-7-methyl-3-oxo-3,4-dihydrospiro[1,4-benzoxazine-2,1′-cyclobutan]-6-yl)carbonyl](propan-2-yl)amino}piperidine-1-carboxylate,

2-methyl-1-[(2-methylpropanoyl)oxy]propyl (3R)-3-[({7-methyl-3-oxo-4-[2-(propanoylamino)ethyl]-3,4-dihydrospiro[1,4-benzoxazine-2,1′-cyclobutan]-6-yl}carbonyl)-(propan-2-yl)amino]piperidine-1-carboxylate,

2-methyl-1-(propanoyloxy)propyl (3R)-3-[({7-methyl-3-oxo-4-[2-(propanoylamino)ethyl]-3,4-dihydrospiro[1,4-benzoxazine-2,1′-cyclobutan]-6-yl}carbonyl)(propan-2-yl)amino]piperidine-1-carboxylate,

1-[(2-methylpropanoyl)oxy]ethyl (3R)-3-[({7-methyl-3-oxo-4-[2-(propanoylamino)ethyl]-3,4-dihydrospiro[1,4-benzoxazine-2,1′-cyclobutan]-6-yl}carbonyl)(propan-2-yl)amino]piperidine-1-carboxylate,

1-[(tetrahydro-2H-pyran-4-ylcarbonyl)oxy]ethyl (3R)-3-[({7-methyl-3-oxo-4-[2-(propanoylamino)ethyl]-3,4-dihydrospiro[1,4-benzoxazine-2,1′-cyclobutan]-6-yl}carbonyl)-(propan-2-yl)amino]piperidine-1-carboxylate,

1-[(methoxyacetyl)oxy]ethyl (3R)-3-[({7-methyl-3-oxo-4-[2-(propanoylamino)ethyl]-3,4-dihydrospiro[1,4-benzoxazine-2,1′-cyclobutan]-6-yl}carbonyl)(propan-2-yl)amino]piperidine-1-carboxylate,

1-[(3-hydroxy-3-methylbutanoyl)oxy]ethyl (3R)-3-[({7-methyl-3-oxo-4-[2-(propanoylamino)-ethyl]-3,4-dihydrospiro[1,4-benzoxazine-2,1′-cyclobutan]-6-yl}carbonyl)(propan-2-yl)amino]-piperidine-1-carboxylate,

2-methyl-1-[(2-methylpropanoyl)oxy]propyl (3R)-3-[propan-2-yl({2,2,7-trimethyl-3-oxo-4-[2-(propanoylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)amino]piperidine-1-carboxylate,

(1S)-1-(propanoyloxy)ethyl (3R)-3-[propan-2-yl({2,2,7-trimethyl-3-oxo-4-[2-(propanoylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)amino]piperidine-1-carboxylate,

(1R)-1-(propanoyloxy)ethyl (3R)-3-[propan-2-yl({2,2,7-trimethyl-3-oxo-4-[2-(propanoylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)amino]piperidine-1-carboxylate,

1-{[(cyclohexyloxy)carbonyl]oxy}ethyl (3R)-3-[propan-2-yl({2,2,7-trimethyl-3-oxo-4-[2-(propanoylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)amino]piperidine-1-carboxylate,

tert-butyl 1-[({(3R)-3-[propan-2-yl({2,2,7-trimethyl-3-oxo-4-[2-(propanoylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)amino]piperidin-1-yl}carbonyl)oxy]ethyl butanedioate,

4-oxo-4-{1-[({(3R)-3-[propan-2-yl({2,2,7-trimethyl-3-oxo-4-[2-(propanoylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)amino]piperidin-1-yl}carbonyl)oxy]ethoxy}-butanoic acid,

1-{[N-(tert-butoxycarbonyl)glycyl]oxy}ethyl (3R)-3-[propan-2-yl({2,2,7-trimethyl-3-oxo-4-[2-(propanoylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)amino]piperidine-1-carboxylate,

1-(glycyloxy)ethyl (3R)-3-[propan-2-yl({2,2,7-trimethyl-3-oxo-4-[2-(propanoylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)amino]piperidine-1-carboxylate,

1-[({(3R)-3-[propan-2-yl({2,2,7-trimethyl-3-oxo-4-[2-(propanoylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)amino]piperidin-1-yl}carbonyl)oxy]ethylpyridine-3-carboxylate,

1-[(tetrahydro-2H-pyran-4-ylcarbonyl)oxy]ethyl (3R)-3-[propan-2-yl({2,2,7-trimethyl-3-oxo-4-[2-(propanoylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)amino]piperidine-1-carboxylate,

1-[(methoxyacetyl)oxy]ethyl (3R)-3-[propan-2-yl({2,2,7-trimethyl-3-oxo-4-[2-(propanoylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)amino]piperidine-1-carboxylate,

1-(L-valyloxy)ethyl (3R)-3-[propan-2-yl({2,2,7-trimethyl-3-oxo-4-[2-(propanoylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)amino]piperidine-1-carboxylate,

1-[(4-hydroxybutanoyl)oxy]ethyl (3R)-3-[propan-2-yl({2,2,7-trimethyl-3-oxo-4-[2-(propanoylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)amino]piperidine-1-carboxylate,

1-({[2-(acetyloxy)phenyl]carbonyl}oxy)ethyl (3R)-3-[propan-2-yl({2,2,7-trimethyl-3-oxo-4-[2-(propanoylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)amino]piperidine-1-carboxylate,

1-[(2-oxopropanoyl)oxy]ethyl (3R)-3-[propan-2-yl({2,2,7-trimethyl-3-oxo-4-[2-(propanoylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)amino]piperidine-1-carboxylate,

›DISCLOSURE OF INVENTION · 10 of 14

(1S)-1-[(2-methylpropanoyl)oxy]ethyl (3R)-3-[propan-2-yl({2,2,7-trimethyl-3-oxo-4-[2-(propanoylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)amino]piperidine-1-carboxylate,

(1R)-1-[(2-methylpropanoyl)oxy]ethyl (3R)-3-[propan-2-yl({2,2,7-trimethyl-3-oxo-4-[2-(propanoylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)amino]piperidine-1-carboxylate,

1-[(3-hydroxy-3-methylbutanoyl)oxy]ethyl (3R)-3-[propan-2-yl({2,2,7-trimethyl-3-oxo-4-[2-(propanoylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)amino]piperidine-1-carboxylate,

(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (3R)-3-[{[2-(hydroxymethyl)-2-methyl-3-oxo-4-[2-(propanoylamino)ethyl]-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}-(propan-2-yl)amino]piperidine-1-carboxylate,

(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (3R)-3-[{[2-(methoxymethyl)-2-methyl-3-oxo-4-[2-(propanoylamino)ethyl]-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}-(propan-2-yl)amino]piperidine-1-carboxylate,

(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (3R)-3-[{[4-{2-[(difluoroacetyl)amino]ethyl}-3-oxo-7-(trifluoromethyl)-3,4-dihydrospiro[1,4-benzoxazine-2,1′-cyclopropan]-6-yl]carbonyl}-(propan-2-yl)amino]piperidine-1-carboxylate,

1-[(2-methylpropanoyl)oxy]ethyl (3R)-3-[{[4-{2-[(difluoroacetyl)amino]ethyl}-3-oxo-7-(trifluoromethyl)-3,4-dihydrospiro[1,4-benzoxazine-2,1′-cyclopropan]-6-yl]carbonyl}(propan-2-yl)amino]piperidine-1-carboxylate,

(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (3R)-3-[{[(2R)-2-methyl-3-oxo-4-[2-(propanoylamino)ethyl]-2,7-bis(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]-carbonyl}(propan-2-yl)amino]piperidine-1-carboxylate,

1-[(2-methylpropanoyl)oxy]ethyl (3R)-3-[{[(2S)-2-(methoxymethyl)-2-methyl-3-oxo-4-[2-(propanoylamino)ethyl]-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}-(propan-2-yl)amino]piperidine-1-carboxylate,

2-methyl-1-(propanoyloxy)propyl (3R)-3-[{[(2S)-2-(methoxymethyl)-2-methyl-3-oxo-4-[2-(propanoylamino)ethyl]-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}-(propan-2-yl)amino]piperidine-1-carboxylate,

2-methyl-1-[(2-methylpropanoyloxy)oxy]propyl (3R)-3-[{[(2S)-2-(methoxymethyl)-2-methyl-3-oxo-4-[2-(propanoylamino)ethyl]-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]-carbonyl}(propan-2-yl)amino]piperidine-1-carboxylate,

(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (3R)-3-{[(4-{2-[(difluoroacetyl)amino]ethyl}-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl)carbonyl](propan-2-yl)amino}-piperidine-1-carboxylate,

(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (3R)-3-[({7-methyl-3-oxo-4-[2-(propanoylamino)-ethyl]-3,4-dihydrospiro[1,4-benzothiazine-2,1′-cyclobutan]-6-yl}carbonyl)(propan-2-yl)-amino]piperidine-1-carboxylate,

1-{[(4-methylphenyl)carbonyl]oxy}ethyl (3R)-3-[({7-methyl-3-oxo-4-[2-(propanoylamino)-ethyl]-3,4-dihydrospiro[1,4-benzoxazine-2,1′-cyclobutan]-6-yl}carbonyl)(propan-2-yl)amino]-piperidine-1-carboxylate,

(1R)-1-[(2-methylpropanoyl)oxy]ethyl (3R)-3-[({2-(methoxymethyl)-2,7-dimethyl-3-oxo-4-[2-(propanoylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)(propan-2-yl)amino]-piperidine-1-carboxylate,

(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (3R)-3-[({7-methyl-3-oxo-4-[2-(propanoylamino)-ethyl]-3,4-dihydrospiro[1,4-benzoxazine-2,1′-cyclobutan]-6-yl}carbonyl)(propan-2-yl)amino]-piperidine-1-carboxylate,

(1R)-1-[(2-methylpropanoyl)oxy]ethyl (3R)-3-[({7-methyl-3-oxo-4-[2-(propanoylamino)-ethyl]-3,4-dihydrospiro[1,4-benzoxazine-2,1′-cyclobutan]-6-yl}carbonyl)(propan-2-yl)amino]-piperidine-1-carboxylate,

(1S)-1-[(2-methylpropanoyl)oxy]ethyl (3R)-3-[({7-methyl-3-oxo-4-[2-(propanoylamino)-ethyl]-3,4-dihydrospiro[1,4-benzoxazine-2,1′-cyclobutan]-6-yl}carbonyl)(propan-2-yl)amino]-piperidine-1-carboxylate,

1-[(4-methoxybutanoyl)oxy]ethyl (3R)-3-[({7-methyl-3-oxo-4-[2-(propanoylamino)ethyl]-3,4-dihydrospiro[1,4-benzoxazine-2,1′-cyclobutan]-6-yl}carbonyl)(propan-2-yl)amino]piperidine-1-carboxylate,

1-[(4-methoxybutanoyl)oxy]ethyl (3R)-3-[propan-2-yl({2,2,7-trimethyl-3-oxo-4-[2-(propanoylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)amino]piperidine-1-carboxylate,

1-(propanoyloxy)ethyl (3R)-3-[({2-(methoxymethyl)-2,7-dimethyl-3-oxo-4-[2-(propanoylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)(propan-2-yl)amino]-piperidine-1-carboxylate,

(1R)-1-[(tetrahydro-2H-pyran-4-ylcarbonyl)oxy]ethyl (3R)-3-[propan-2-yl({2,2,7-trimethyl-3-oxo-4-[2-(propanoylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)amino]-piperidine-1-carboxylate,

(1S)-1-[(tetrahydro-2H-pyran-4-ylcarbonyl)oxy]ethyl (3R)-3-[propan-2-yl({2,2,7-trimethyl-3-oxo-4-[2-(propanoylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)amino]-piperidine-1-carboxylate,

1-[({(3R)-3-[({7-methyl-3-oxo-4-[2-(propanoylamino)ethyl]-3,4-dihydrospiro[1,4-benzoxazine-2,1′-cyclobutan]-6-yl}carbonyl)(propan-2-yl)amino]piperidin-1-yl}carbonyl)-oxy]ethylpyridine-3-carboxylate,

(1S)-1-[(ethoxycarbonyl)oxy]ethyl (3R)-3-[propan-2-yl({2,2,7-trimethyl-3-oxo-4-[2-(propanoylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)amino]piperidine-1-carboxylate,

(1R)-1-[(ethoxycarbonyl)oxy]ethyl (3R)-3-[propan-2-yl({2,2,7-trimethyl-3-oxo-4-[2-(propanoylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)amino]piperidine-1-carboxylate,

1-[(2-methylpropanoyl)oxy]ethyl (3R)-3-[({(2S)-2-(methoxymethyl)-2,7-dimethyl-3-oxo-4-[2-(propanoylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)(propan-2-yl)amino]-piperidine-1-carboxylate,

(1R)-1-[(2-methylpropanoyl)oxy]ethyl (3R)-3-[({(2S)-2-(methoxymethyl)-2,7-dimethyl-3-oxo-4-[2-(propanoylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)(propan-2-yl)-amino]piperidine-1-carboxylate,

(1S)-1-[(2-methylpropanoyl)oxy]ethyl (3R)-3-[({(2S)-2-(methoxymethyl)-2,7-dimethyl-3-oxo-4-[2-(propanoylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)(propan-2-yl)-amino]piperidine-1-carboxylate,

1-[(tetrahydro-2H-pyran-4-ylcarbonyl)oxy]ethyl (3R)-3-[({2-(methoxymethyl)-2,7-dimethyl-3-oxo-4-[2-(propanoylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)(propan-2-yl)amino]piperidine-1-carboxylate,

›DISCLOSURE OF INVENTION · 11 of 14

1-{[(cyclohexyloxy)carbonyl]oxy}ethyl (3R)-3-[({7-methyl-3-oxo-4-[2-(propanoylamino)-ethyl]-3,4-dihydrospiro[1,4-benzoxazine-2,1′-cyclobutan]-6-yl}carbonyl)(propan-2-yl)amino]-piperidine-1-carboxylate,

1-[(difluoroacetyl)oxy]ethyl (3R)-3-[({7-methyl-3-oxo-4-[2-(propanoylamino)ethyl]-3,4-dihydrospiro[1,4-benzoxazine-2,1′-cyclobutan]-6-yl}carbonyl)(propan-2-yl)amino]piperidine-1-carboxylate,

1-[(cyclopropylacetyl)oxy]ethyl (3R)-3-[propan-2-yl({2,2,7-trimethyl-3-oxo-4-[2-(propanoylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)amino]piperidine-1-carboxylate,

1-{[6,7-bis(nitroxy)heptanoyl]oxy}ethyl (3R)-3-[propan-2-yl({2,2,7-trimethyl-3-oxo-4-[2-(propanoylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)amino]piperidine-1-carboxylate, and

1-[(cyclohexylcarbonyl)oxy]ethyl (3R)-3-[({2,2-dimethyl-3-oxo-4-[2-(propanoylamino)ethyl]-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)(propan-2-yl)amino]-piperidine-1-carboxylate, or a pharmaceutically acceptable salt thereof.

Item 73: The compound of Item 1, selected from the group consisting of:

(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (3R)-3-[isopropyl({2,2,7-trimethyl-3-oxo-4-[2-(propanoylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)amino]piperidine-1-carboxylate,

(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (3R)-3-{[(4-{2-[(difluoroacetyl)amino]ethyl}-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl)carbonyl](propan-2-yl)amino}-piperidine-1-carboxylate,

Item 74: The compound of Item 1, selected from the group consisting of: