Pyridine compound substituted with azole

This application is a national stage filing under 35 U.S.C. § 371 of International Application No. PCT/JP2018/030456, filed on Aug. 10, 2018, which claims priority of Japanese Patent Application No. JP 2017-171584, filed on Aug. 10, 2017. The contents of each of these applications are incorporated herein by reference.

The present invention relates to an inhibitor of enzymes that produce 20-hydroxyeicosatetraenoic acid (hereinafter also referred to as “20-HETE”). More specifically, the present invention relates to an azole-substituted pyridine compound which is an inhibitor of 20-HETE producing enzymes.

Physiologically active substances produced from arachidonic acid conventionally include prostaglandins produced by cyclooxygenase and leukotrienes produced by lipoxygenase; in addition to these, 20-HETE produced from arachidonic acid by enzymes belonging to cytochrome P450 have recently been shown to display diverse functions in a living body. So far, 20-HETE has been demonstrated to control vascular tone or evoke cell growth in cerebral blood vessels and key organs such as kidney, suggesting that 20-HETE plays an important physiological role in a living body while being deeply involved in the pathology of various cerebro-vascular diseases, kidney diseases, cardiovascular diseases, and others (Non Patent Literatures 1 to 3). Furthermore, it has been proven in recent years that 20-HETE is involved in the onset of polycystic kidney disease. Polycystic kidney disease is a hereditary cystic kidney disease, which is classified into autosomal dominant polycystic kidney disease and autosomal recessive polycystic kidney disease, in which a great number of cysts are formed in the kidney to cause impaired renal function. It is suggested that when administered to pathologic animals developing polycystic kidney disease, 20-HETE inhibitors not only block intracellular growth signals but also exhibit an ameliorating effect on renal cysts (Non Patent Literature 4). Moreover, increased renal volume and decreased renal function are shown to correlate with increased plasma 20-HETE levels in patients with autosomal dominant polycystic kidney disease, suggesting that 20-HETE is associated with the progression of polycystic kidney disease (Non Patent Literature 5).

Previously reported inhibitors of 20-HETE producing enzymes include, for example, a hydroxyformamidine derivative (Patent Literature 1), a heterocycle derivative as a compound having the phenylazoleskeleton (Patent Literature 2), and a phenylazole compound (Patent Literature 3). Patent Literature 2 discloses a heteroaryl-substituted pyridine compound that is substituted with heteroaryl such as pyrazolyl at the 3-position of pyridine. However, the compound of the present invention or an azole-substituted pyridine compound that is a compound substituted with azole such as pyrazolyl at the 2-position of pyridine is yet to be disclosed.

Patent Literature

PTL 1: WO01/032164

PTL 2: WO03/022821

PTL 3: WO2004/092163

Non Patent Literature

NPL 1: Journal of Vascular Research, Vol. 32, p. 79, 1995

NPL 2: The American Journal of Physiology, Vol. 277, p. R607, 1999

NPL 3: Physiological Reviews, Vol. 82, p. 131, 2002

NPL 4: American Journal of Physiology Renal Physiology, Vol. 296, p. F575, 2009

NPL 5: Journal of Lipid Research, Vol. 55, p. 1139, 2013

Technical Problem

An object of the present invention is to provide a novel compound that inhibits 20-HETE producing enzymes.

Solution to Problem

As a result of intensive studies to solve the above problem, the present inventors found that a compound represented by formula [I] shown below (hereinafter also referred to as the compound [I]) has an inhibitory effect on 20-HETE producing enzymes.

The present invention will be described in detail below.

Briefly, the following are embodiments of the present invention.

(1) In one embodiment, the present invention provides

a compound represented by formula [I] shown below:

wherein

the structure represented by formula [II] shown below:

represents any of the structures represented by formula group [III] shown below:

R 1 represents a hydrogen atom, a fluorine atom, a chlorine atom, methyl, or difluoromethyl;

R 2 , R 3 , and R 4 each independently represent a hydrogen atom, a fluorine atom, or methyl;

R 5 represents any of the structures represented by formula group [IV] shown below:

(A)

when R 5 represents the structure represented by formula [IV-1],

R 51 represents any of the structures represented by formula group [V] shown below:

W 1 represents C 4-10 alkanediyl;

(B)

when R 5 represents the structure represented by formula [IV-2],

R 52 represents carboxy;

L represents any of the structures represented by formula group [VI] shown below:

wherein

ring D represents

(i) C 3-6 cycloalkane,

(ii) 4- to 6-membered saturated oxygen-containing hetero ring,

(iii) 4- to 6-membered saturated sulfur-containing hetero ring (the sulfur atom of the 4- to 6-membered saturated sulfur-containing hetero ring may be substituted with one or two oxo),

(iv) 4- to 6-membered saturated nitrogen-containing hetero ring (the nitrogen atom of the 4- to 6-membered nitrogen-containing hetero ring may be substituted with one C 1-4 alkylcarbonyl);

Y represents the formula —CH 2 —, the formula —CMe 2 -, the formula —O—, the formula —NHCO—, the formula —NMeCO—, the formula —CONH—, or the formula —CONMe-;

W 2 represents C 2-10 alkanediyl, wherein one of the carbon atoms that constitute the C 2-10 alkanediyl represented by W 2 may be replaced with an oxygen atom;

(C)

when R 5 represents the structure represented by formula [IV-3] above,

R 53 represents carboxy, carboxymethyl, or carboxymethoxy, wherein the methylene moiety of the carboxymethyl or carboxymethoxy that is represented by R 53 may be replaced with a structure selected from structure group α below,

structure group α represents any of the structures represented by formula group [VII] below:

wherein

ring D′ represents

(i) C 3-6 cycloalkane,

(ii) 4- to 6-membered saturated oxygen-containing hetero ring,

(iii) 4- to 6-membered saturated sulfur-containing hetero ring (the sulfur atom of the 4- to 6-membered saturated sulfur-containing hetero ring may be substituted with one or two oxo),

(iv) 4- to 6-membered saturated nitrogen-containing hetero ring (the nitrogen atom of the 4- to 6-membered saturated nitrogen-containing hetero ring may be substituted with one C 1-4 alkylcarbonyl);

ring B represents any of the structures represented by formula group [VIII] below:

W 3 represents C 4-8 alkanediyl, the formula —O—W 31 —, or the formula —SO 2 —W 33 —, wherein W 31 represents C 3-7 alkanediyl, W 33 represents C 3-7 alkanediyl;

(D)

when R 5 represents the structure represented by formula [IV-4] above,

ring C represents

(a) C 3-6 cycloalkyl,

(b) 4- to 6-membered saturated nitrogen-containing heterocyclyl,

(c) phenyl,

(d) pyridyl,

(e) pyrazolyl,

(l) triazolyl,

(g) tetrahydronaphthyl,

(h) chromanyl,

(j) indazolyl,

(k) tetrahydroisoquinolyl,

(m) 2-oxotetrahydroisoquinolyl,

(n) the structure represented by formula [IX-1] below,

(p) the structure represented by formula [IX-2] below,

(q) the structure represented by formula [IX-3] below, or

(r) the structure represented by formula [IX-4] below:

(a) when ring C represents C 3-6 cycloalkyl,

R 54 is selected from the group consisting of:

(i) carboxy,

(ii) C 1-4 alkylsulfonylamino,

(iii) C 1-4 alkylsulfonyl(C 1-4 alkyl)amino, and

(iv) C 1-4 alkyl substituted with carboxy;

R 61 and R 62 represent a hydrogen atom;

(b) when ring C represents 4- to 6-membered saturated nitrogen-containing heterocyclyl,

R 54 is selected from the group consisting of:

(i) C 1-4 alkylcarbonyl substituted with carboxy,

(ii) C 1-4 alkylcarbonyl substituted with sulfamoyl,

(iii) C 1-4 alkylcarbonyl substituted with C 1-4 alkylsulfonylamino,

(iv) phenylmethylcarbonyl substituted with carboxy,

(v) phenylcarbonyl substituted with sulfamoyl,

(vi) dihydopyridinylcarbonyl substituted with oxo,

(vii) phenylsulfonyl substituted with carboxy,

(viii) monoC 1-4 alkylaminocarbonyl substituted with carboxy,

(ix) the structure represented by formula [X-1] below, which is substituted with carboxy,

(x) the structure represented by formula [X-2] below, which is substituted with carboxy,

(xi) the structure represented by formula [X-3] below, which is substituted with carboxy,

when position α of the carboxy of the C 1-4 alkylcarbonyl substituted with carboxy, the C 1-4 alkylsulfonyl substituted with carboxy, or the monoC 1-4 alkylaminocarbonyl substituted with carboxy is a methylene moiety, said methylene moiety may be replaced with a structure selected from structure group α above;

wherein R 61 and R 62 represent a hydrogen atom;

(c) when ring C is phenyl,

R 54 is selected from the group consisting of:

(i) carboxy,

(ii) carbamoyl,

(iii) monoC 1-4 alkylaminocarbonyl (the C 1-4 alkyl of the monoC 1-4 alkylaminocarbonyl may be substituted with one hydroxy),

(iv) monoC 1-4 alkylaminosulfonyl (the C 1-4 alkyl of the monoC 1-4 alkylaminosulfonyl may be substituted with one indolyl),

(v) di(C 1-4 alkyl)aminosulfonyl (one C 1-4 alkyl of the di(C 1-4 alkyl)aminosulfonyl may be substituted with one phenyl, and the phenyl may be substituted with one monoC 1-4 alkylaminosulfonyl),

(vi) phenylaminosulfonyl (the phenyl of the phenylaminosulfonyl may be substituted with one fluorine atom),

(vii) C 1-4 alkylsulfonylamino,

(viii) C 1-4 alkylsulfonylaminocarbonyl,

(ix) C 1-4 alkylsulfonyl(C 1-4 alkyl)aminocarbonyl,

(x) C 1-4 alkyl substituted with carboxy (when position α of the carboxy of the C 1-4 alkyl substituted with carboxy is a methylene moiety, said methylene moiety may be replaced with a structure selected from structure group α above),

(xi) C 1-4 alkyl substituted with methylsulfonylaminocarbonyl,

(xii) C 1-4 alkyl substituted with trifluoromethylsulfonylamino,

(xiii) C 1-4 alkyl substituted with methylsulfonyl(methyl)aminocarbonyl,

(xiv) C 1-4 alkyl substituted with monoC 1-4 alkylaminocarbonyl (the C 1-4 alkyl of the monoC 1-4 alkylaminocarbonyl of the C 1-4 alkyl substituted with monoC 1-4 alkylaminocarbonyl may be substituted with one group selected from the group consisting of hydroxy, C 1-4 alkoxy, 4- to 6-membered saturated oxygen-containing heterocyclyl, di(C 1-4 alkyl)amino, and 4- to 6-membered saturated nitrogen-containing heterocyclylcarbonyl),

(xv) C 1-4 alkyl substituted with di(C 1-4 alkyl)aminocarbonyl (one C 1-4 alkyl of the di(C 1-4 alkyl)aminocarbonyl of the C 1-4 alkyl substituted with di(C 1-4 alkyl)aminocarbonyl may be substituted with one hydroxy),

(xvi) C 1-4 alkyl substituted with 4- to 6-membered saturated oxygen-containing heterocyclylaminocarbonyl,

(xvii) C 1-4 alkyl substituted with 4- to 6-membered saturated nitrogen-containing heterocyclylcarbonyl (the 4- to 6-membered saturated nitrogen-containing heterocyclyl of the C 1-4 alkyl substituted with 4- to 6-membered saturated nitrogen-containing heterocyclylcarbonyl may be substituted with one to two groups selected from the group consisting of hydroxy and a fluorine atom),

(xviii) halo-C 1-4 alkyl substituted with carboxy,

(xix) C 2-4 alkenyl substituted with carboxy,

(xx) C 2-4 alkenyl substituted with di(C 1-4 alkyl)aminocarbonyl,

(xxi) C 3-6 cycloalkyl substituted with carboxy,

(xxii) C 3-6 cycloalkyl substituted with di(C 1-4 alkyl)aminocarbonyl,

(xxiii) 4- to 6-membered saturated nitrogen-containing heterocyclyl substituted with carboxy,

(xxiv) phenyl substituted with carboxy,

(xxv) pyridyl substituted with carboxy,

(xxvi) pyrazolyl substituted with carboxy,

(xxvii) pyrazolyl substituted with carboxymethyl (the methylene moiety at position α of the carboxy of the pyrazolyl substituted with carboxymethyl may be replaced with a structure selected from structure group c above),

(xxviii) pyrimidinyl substituted with carboxy,

(xxix) pyrazinyl substituted with carboxy,

(xxx) 2-oxodihydropyridinyl substituted with carboxymethyl (the methylene moiety at position α of the carboxy of the 2-oxodihydropyridinyl substituted with carboxymethyl may be replaced with a structure selected from structure group c above),

(xxxi) monoC 1-4 alkylaminocarbonyl substituted with carboxy (the C 1-4 alkyl of the monoC 1-4 alkylaminocarbonyl substituted with carboxy may be substituted with one group selected from the group consisting of phenyl and benzyl, and when position α of the carboxy of the monoC 1-4 alkylaminocarbonyl substituted with carboxy is a methylene moiety, said methylene moiety may be replaced with a structure selected from formula group α above),

(xxxii) phenylC 1-4 alkylaminocarbonyl substituted with carboxy,

(xxxiii) monoC 1-4 alkylaminocarbonyl substituted with the structure represented by formula [V-6] below,

(xxxiv) di(C 1-4 alkyl)aminocarbonyl substituted with carboxy (when position α of the carboxy of the di(C 1-4 alkyl)aminocarbonyl substituted with carboxy is a methylene moiety, said methylene moiety may be replaced with a structure selected from formula group α above),

(xxxv) C 3-6 cycloalkylaminocarbonyl substituted with carboxy,

(xxxvi) 4- to 6-membered saturated nitrogen-containing heterocyclylcarbonyl substituted with carboxy (the 4- to 6-membered saturated nitrogen-containing heterocyclyl of the 4- to 6-membered nitrogen-containing heterocyclylcarbonyl substituted with carboxy may be substituted with one fluorine atom),

(xxxvii) 4- to 6-membered saturated nitrogen-containing heterocyclylcarbonyl substituted with carboxymethyl (the methylene moiety at position α of the carboxy of the 4- to 6-membered saturated nitrogen-containing heterocyclylcarbonyl substituted with carboxymethyl may be replaced with a structure selected from structure group α above),

(xxxviii) the structure represented by formula [XI-1] below, which is substituted with carboxy,

(xxxix) the structure represented by formula [XI-2] below, which is substituted with carboxy,

(xxxx) the structure represented by formula [XI-3] below, which is substituted with carboxy,

(xxxxi) the structure represented by formula [XI-4] below, which is substituted with carboxy,

(xxxxii) the structure represented by formula [XI-5] below, which is substituted with carboxy,

(xxxxiii) the structure represented by formula [XI-6] below, which is substituted with carboxy,

(xxxxiv) C 1-4 alkylsulfonyl substituted with carboxy (when position α of the carboxy of the C 1-4 alkylsulfonyl substituted with carboxy is a methylene moiety, said methylene moiety may be replaced with a structure selected from structure group c above),

(xxxxv) monoC 1-4 alkylaminosulfonyl substituted with carboxy (when position α of the carboxy of the monoC 1-4 alkylaminosulfonyl substituted with carboxy is a methylene moiety, said methylene moiety may be replaced with a structure selected from structure group c above),

(xxxxvi) di(C 1-4 alkyl)aminosulfonyl substituted with carboxy (when position α of the carboxy of the di(C 1-4 alkyl)aminosulfonyl substituted with carboxy is a methylene moiety, said methylene moiety may be replaced with the structure selected from structure group c above),

(xxxxvii) 4- to 6-membered saturated nitrogen-containing heterocyclylsulfonyl substituted with carboxy (the 4- to 6-membered saturated nitrogen-containing heterocyclyl of the 4- to 6-membered saturated nitrogen-containing heterocyclylsulfonyl substituted with carboxy may be substituted with one fluorine atom),

(xxxxviii) C 1-4 alkoxy substituted with carboxy (when position α of the carboxy of the C 1-4 alkoxy substituted with carboxy is a methylene moiety, said methylene moiety may be replaced with a structure selected from structure group α above),

(xxxxix) hydroxy,

(xxxxx) C 1-4 alkylsulfonyloxy,

(xxxxxi) C 1-4 alkyl substituted with hydroxy,

(xxxxxii) halo-C 1-4 alkyl substituted with hydroxy,

(xxxxxiii) C 1-4 alkylsulfonyl substituted with hydroxy,

(xxxxxiv) C 3-6 cycloalkyl substituted with hydroxy (the C 3-6 cycloalkyl of the C 3-6 cycloalkyl substituted with hydroxy may be substituted with one group selected from the group consisting of carboxy and di(C 1-4 alkyl)aminocarbonyl), or

(xxxxxv) 4- to 6-membered saturated nitrogen-containing heterocyclyl substituted with hydroxy (the nitrogen atom of the 4- to 6-membered saturated nitrogen-containing heterocyclyl substituted with hydroxy may be substituted with one group selected from the group consisting of C 1-4 alkylcarbonyl, C 1-4 alkoxycarbonyl, and di(C 1-4 alkyl)aminocarbonyl), wherein R 61 and R 62 each independently represent a hydrogen atom, a fluorine atom, a chlorine atom, methyl, methoxy, or methylsulfonyl;

(d) when ring C is pyridyl,

R 54 is selected from the group consisting of:

(i) carboxy,

(ii) carbamoyl,

(iii) C 1-4 alkyl substituted with carboxy,

(iv) C 1-4 alkoxy substituted with carboxy,

(v) monoC 1-4 alkylaminocarbonyl substituted with carboxy, and

(vi) 4- to 6-membered saturated nitrogen-containing heterocyclylcarbonyl substituted with carboxy (the 4- to 6-membered saturated nitrogen-containing heterocyclyl of the 4- to 6-membered saturated nitrogen-containing heterocyclylcarbonyl substituted with carboxy may be substituted with one fluorine atom),

wherein when position α of the carboxy of the C 1-4 alkyl substituted with carboxy, the C 1-4 alkoxy substituted with carboxy, or the monoC 1-4 alkylaminocarbonyl substituted with carboxy is a methylene moiety, said methylene moiety may be replaced with a structure selected from structure group α above);

and wherein R 61 and R 62 represent a hydrogen atom;

(e) when ring C is pyrazolyl,

R 54 represents carboxy;

wherein R 61 and R 62 represent a hydrogen atom;

(f) when ring C is triazolyl,

R 54 represents C 1-4 alkyl substituted with carboxy,

wherein when position α of the carboxy of the C 1-4 alkyl substituted with carboxy is a methylene moiety, said methylene moiety may be replaced with a structure selected from structure group α above;

wherein R 61 and R 62 represent a hydrogen atom;

(g) when ring C is tetrahydronaphthyl,

R 54 is carboxy;

wherein R 61 and R 62 represent a hydrogen atom;

(h) when ring C is chromanyl,

R 54 is carboxy;

wherein R 61 and R 62 represent a hydrogen atom;

(j) when ring C is indazolyl,

R 54 represents C 1-4 alkyl substituted with carboxy,

wherein when position α of the carboxy of the C 1-4 alkyl substituted with carboxy is a methylene moiety, said methylene moiety may be replaced with a structure selected from structure group α above;

wherein R 61 and R 62 represent a hydrogen atom;

(k) when ring C is tetrahydroisoquinolyl,

R 54 represents C 1-4 alkylcarbonyl substituted with carboxy,

wherein position α of the carboxy of the C 1-4 alkylcarbonyl substituted with carboxy is a methylene moiety, said methylene moiety may be replaced with a structure selected from structure group α above;

wherein R 61 and R 62 represent a hydrogen atom;

(m) when ring C is 2-oxotetrahydroisoquinolyl,

R 54 represents C 1-4 alkyl substituted with carboxy,

wherein position α of the carboxy of the C 1-4 alkyl substituted with carboxy is a methylene moiety, said methylene moiety may be replaced with a structure selected from structure group α above;

wherein R 61 and R 62 represent a hydrogen atom;

(n) when ring C is the structure represented by formula [IX-1] above, R 54 is selected from the group consisting of:

(i) carboxy,

(ii) C 1-4 alkyl substituted with C 1-4 alkylsulfonylamino, and

(iii) C 1-4 alkyl substituted with C 1-4 alkylsulfonyl(C 1-4 alkyl)amino

wherein when R 54 represents (ii) C 1-4 alkyl substituted with C 1-4 alkylsulfonylamino and the C 1-4 alkyl of the C 1-4 alkylsulfonylamino of the C 1-4 alkyl substituted with C 1-4 alkylsulfonylamino is substituted with one carboxy and if position α of the carboxy of the C 1-4 alkylsulfonylamino substituted with carboxy is a methylene moiety, said methylene moiety may be replaced with a structure selected from structure group α above;

wherein R 61 and R 62 represent a hydrogen atom;

(p) when ring C is the structure represented by formula [IX-2] above,

R 54 is selected from the group consisting of:

(i) carboxy, and

(ii) C 1-4 alkyl substituted with carboxy,

wherein when position α of the carboxy of the C 1-4 alkyl substituted with carboxy is a methylene moiety, said methylene moiety may be replaced with a structure selected from structure group α above;

and wherein R 61 and R 62 represent a hydrogen atom;

(q) when ring C is the structure represented by formula [IX-3] above,

R 54 represents carboxy;

wherein R 61 and R 62 represent a hydrogen atom;

(r) when ring C is the structure represented by formula [IX-4] above,

R 54 represents carboxy;

wherein R 61 and R 62 represent a hydrogen atom;

W 4 represents a single bond, C 1-3 alkanediyl, or the formula —O—CH 2 CH 2 —; or a pharmaceutically acceptable salt thereof.

(2) In another embodiment, the present invention provides the compound according to (1), wherein as regards R 5 of formula [I] above,

(A)

when R 5 is the structure represented by formula [IV-1] above,

R 51 represents any of the structures represented by formula group [V″] below:

W 1 represents C 4-10 alkanediyl;

(B)

when R 5 represents the structure represented by formula [IV-2] above,

R 52 represents carboxy,

L represents any of the structures represented by formula group [VI′] below:

wherein ring D is C 3-6 cycloalkane, 4- to 6-membered saturated oxygen-containing hetero ring, or 4- to 6-membered saturated nitrogen-containing hetero ring (the nitrogen atom of the 4- to 6-membered saturated nitrogen-containing hetero ring may be substituted with C 1-4 alkylcarbonyl);

Y represents the formula —CH 2 —, the formula —CMe 2 -, the formula —O—, the formula —NHCO—, the formula —CONH—, or the formula —CONMe-,

W 2 represents C 2-8 alkanediyl, wherein one of the carbon atoms that constitute the C 2-8 alkanediyl represented by W 2 may be replaced with an oxygen atom;

(C)

when R 5 represents the structure represented by formula [IV-3] above,

R 53 represents carboxy, carboxymethyl, or carboxymethoxy,

wherein the methylene moiety of the carboxymethyl and carboxymethoxy represented by R 53 may be replaced with propane-2,2-diyl;

ring B represents any of the structures represented by formula group [VIII] below:

W 3 represents C 4-8 alkanediyl, or the formula —SO 2 —W 33 —,

W 33 represents C 3-7 alkanediyl;

(D)

when R 5 is the structure represented by formula [IV-4] above,

ring C represents:

(a) C 3-6 cycloalkyl,

(b) 4- to 6-memred saturated nitrogen-containing heterocyclyl,

(c) phenyl,

(d) pyridyl,

(e) pyrazolyl,

(g) tetrahydronaphthyl,

(h) chromanyl,

(j) indazolyl,

(n) the structure represented by formula [IX-1] below,

(p) the structure represented by formula [IX-2] below,

(q) the structure represented by formula [IX-3] below, or

(r) the structure represented by formula [IX-4] below,

wherein

(a) when ring C represents C 3-6 cycloalkyl,

R 54 represents

(i) carboxy or

(iv) C 1-4 alkyl substituted with carboxy,

wherein R 61 and R 62 represent a hydrogen atom;

(b) when ring C represents 4- to 6-membered saturated nitrogen-containing heterocyclyl,

R 54 represents:

(i) C 1-4 alkylcarbonyl substituted with carboxy (when position α of the carboxy of the C 1-4 alkylcarbonyl substituted with carboxy is a methylene moiety, said methylene moiety may be replaced with C 5 cycloalkanediyl),

(ii) C 1-4 alkylcarbonyl substituted with sulfamoyl,

(iv) phenylmethylcarbonyl substituted with carboxy,

(v) phenylcarbonyl substituted with sulfamoyl,

(vi) dihydropyridinylcarbonyl substituted with oxo,

(vii) phenylsulfonyl substituted with carboxy,

(viii) mono-C 1-4 alkylaminocarbonyl substituted with carboxy (when position α of the carboxy of mono-C 1-4 alkylaminocarbonyl substituted with carboxy is a methylene moiety, said methylene moiety may be replaced with propane-2,2-diyl), and

(x) the structure represented by formula [X-2] below, which is substituted with carboxy:

wherein R 61 and R 62 represent a hydrogen atom;

(c) when ring C is phenyl,

R 54 represents:

(i) carboxy,

(ii) carbamoyl,

(iii) mono-C 1-4 alkylaminocarbonyl (the C 1-4 alkyl of the mono-C 1-4 alkylaminocarbonyl may be substituted with one hydroxy),

(iv) mono-C 1-4 alkylaminosulfonyl,

(v) di(C 1-4 alkyl)aminosulfonyl (one C 1-4 alkyl of the di(C 1-4 alkyl)aminosulfonyl is substituted with one phenyl, wherein said phenyl may be substituted with one mono-C 1-4 alkylaminosulfonyl),

(vi) phenylaminosulfonyl (the phenyl of the phenylaminosulfonyl may be substituted with one fluorine atom),

(vii) C 1-4 alkylsulfonylamino,

(viii) C 1-4 alkylsulfonylaminocarbonyl,

(ix) C 1-4 alkylsulfonyl(C 1-4 alkyl)aminocarbonyl,

(x) C 1-4 alkyl substituted with carboxy (when position α of the carboxy of the C 1-4 alkyl substituted with carboxy is a methylene moiety, said methylene moiety may be replaced with a structure selected from the group consisting of ethane-1,1-diyl, propane-2,2-diyl, cyclopropane-1,1-diyl, tetrahydropyran-4,4-diyl, and piperidine-4,4-diyl (the nitrogen atom of the piperidine-4,4-diyl is substituted with methylcarbonyl)),

(xi) C 1-4 alkyl substituted with methylsulfonylaminocarbonyl,

(xii) C 1-4 alkyl substituted with trifluoromethylsulfonylamino,

(xiii) C 1-4 alkyl substituted with methylsulfonyl(methyl)aminocarbonyl,

(xiv) C 1-4 alkyl substituted with mono-C 1-4 alkylaminocarbonyl (the C 1-4 alkyl of the mono-C 1-4 alkylaminocarbonyl of the C 1-4 alkyl substituted with mono-C 1-4 alkylaminocarbonyl may be substituted with one group selected from the group consisting of hydroxy, C 1-4 alkoxy, 4- to 6-membered saturated oxygen-containing heterocyclyl, di(C 1-4 alkyl)amino, and 4- to 6-membered saturated nitrogen-containing heterocyclylcarbonyl),

(xv) C 1-4 alkyl substituted with di(C 1-4 alkyl)aminocarbonyl (one C 1-4 alkyl of the di(C 1-4 alkyl)aminocarbonyl of the C 1-4 alkyl substituted with di(C 1-4 alkyl)aminocarbonyl may be substituted with one hydroxy),

(xvi) C 1-4 alkyl substituted with 4- to 6-membered saturated oxygen-containing heterocyclylaminocarbonyl,

(xvii) C 1-4 alkyl substituted with 4- to 6-membered saturated nitrogen-containing heterocyclylcarbonyl (the 4- to 6-membered saturated nitrogen-containing heterocyclyl of the C 1-4 alkyl substituted with 4- to 6-membered saturated nitrogen-containing heterocyclylcarbonyl may be substituted with one to two groups selected from the group consisting of hydroxy and a fluorine atom),

(xviii) halo-C 1-4 alkyl substituted with carboxy,

(xix) C 2-4 alkenyl substituted with carboxy,

(xx) C 2-4 alkenyl substituted with di(C 1-4 alkyl)aminocarbonyl,

(xxi) C 3-6 cycloalkyl substituted with carboxy,

(xxii) C 3-6 cycloalkyl substituted with di(C 1-4 alkyl)aminocarbonyl,

(xxiii) 4- to 6-membered saturated nitrogen-containing heterocyclyl substituted with carboxy,

(xxiv) phenyl substituted with carboxy,

(xxv) pyridyl substituted with carboxy,

(xxvi) pyrazolyl substituted with carboxy,

(xxvii) pyrazolyl substituted with carboxymethyl,

(xxviii) pyrimidinyl substituted with carboxy,

(xxix) pyrazinyl substituted with carboxy,

(xxx) 2-oxodihydropyridinyl substituted with carboxymethyl,

(xxxi) mono-C 1-4 alkylaminocarbonyl substituted with carboxy (the C 1-4 alkyl of the mono-C 1-4 alkylaminocarbonyl substituted with carboxy may be substituted with one group selected from the group consisting of phenyl and benzyl, wherein when position α of the carboxy of the mono-C 1-4 alkylaminocarbonyl substituted with carboxy is a methylene moiety, said methylene moiety may be replaced with a structure selected from the group consisting of ethane-1,1-diyl, propane-2,2-diyl, cyclopropane-1,1-diyl, cyclopentane-1,1-diyl, and tetrahydropyran-4,4-diyl),

(xxxii) phenylC 1-4 alkylaminocarbonyl substituted with carboxy,

(xxxiii) mono-C 1-4 alkylaminocarbonyl substituted with the structure represented by formula [V-6] below:

(xxxiv) di(C 1-4 alkyl)aminocarbonyl substituted with carboxy (when position α of the carboxy of the di(C 1-4 alkyl)aminocarbonyl substituted with carboxy is a methylene moiety, said methylene moiety may be replaced with propane-2,2-diyl),

(xxxv) C 3-6 cycloalkylaminocarbonyl substituted with carboxy,

(xxxvi) 4- to 6-membered saturated nitrogen-containing heterocyclylcarbonyl substituted with carboxy (the 4- to 6-membered saturated nitrogen-containing heterocyclyl of the 4- to 6-membered saturated nitrogen-containing heterocyclylcarbonyl substituted with carboxy may be substituted with one fluorine atom),

(xxxvii) 4- to 6-membered saturated nitrogen-containing heterocyclylcarbonyl substituted with carboxymethyl,

(xxxviii) the structure represented by formula [XI-1] below, which is substituted with carboxy,

(xxxix) the structure represented by formula [XI-2] below, which is substituted with carboxy,

(xxxx) the structure represented by formula [XI-3] below, which is substituted with carboxy,

(xxxxiii) the structure represented by formula [XI-6] below, which is substituted with carboxy,

(xxxxiv) C 1-4 alkylsulfonyl substituted with carboxy (when position α of the carboxy of the C 1-4 alkylsulfonyl substituted with carboxy is a methylene moiety, said methylene moiety may be replaced with propane-2,2-diyl),

(xxxxv) mono-C 1-4 alkylaminosulfonyl substituted with carboxy (when position α of the carboxy of the mono-C 1-4 alkylaminosulfonyl substituted with carboxy is a methylene moiety, said methylene moiety may be replaced with propane-2,2-diyl),

(xxxxvi) di(C 1-4 alkyl)aminosulfonyl substituted with carboxy (when position α of the carboxy of the di(C 1-4 alkyl)aminosulfonyl substituted with carboxy is a methylene moiety, said methylene moiety may be replaced with propane-2,2-diyl),

(xxxxvii) 4- to 6-membered saturated nitrogen-containing heterocyclylsulfonyl substituted with carboxy (the 4- to 6-membered saturated nitrogen-containing heterocyclyl of the 4- to 6-membered saturated nitrogen-containing heterocyclylsulfonyl substituted with carboxy may be substituted with one fluorine atom),

(xxxxviii) C 1-4 alkoxy substituted with carboxy (when position α of the carboxy of the C 1-4 alkoxy substituted with carboxy is a methylene moiety, said methylene moiety may be replaced with propane-2,2-diyl),

(xxxxix) hydroxy,

(xxxxx) C 1-4 alkylsulfonyloxy,

(xxxxxi) C 1-4 alkyl substituted with hydroxy,

(xxxxxii) halo-C 1-4 alkyl substituted with hydroxy,

(xxxxxiii) C 1-4 alkylsulfonyl substituted with hydroxy,

(xxxxxiv) C 3-6 cycloalkyl substituted with hydroxy (the C 3-6 cycloalkyl of the C 3-6 cycloalkyl substituted with hydroxy may be substituted with one group selected from the group consisting of carboxy and di(C 1-4 alkyl)aminocarbonyl), or

(xxxxxv) 4- to 6-membered saturated nitrogen-containing heterocyclyl substituted with hydroxy (the nitrogen atom of the 4- to 6-membered saturated nitrogen-containing heterocyclyl substituted with hydroxy may be substituted with one group selected from the group consisting of C 1-4 alkylcarbonyl, C 1-4 alkoxycarbonyl, and di(C 1-4 alkyl)aminocarbonyl),

wherein R 61 and R 62 each independently represent a hydrogen atom, a fluorine atom, a chlorine atom, methyl, methoxy, or methylsulfonyl;

(d) when ring C is pyridyl,

R 54 represents:

(i) carboxy,

(ii) carbamoyl,

(iii) C 1-4 alkyl substituted with carboxy (when position α of the carboxy of the C 1-4 alkyl substituted with carboxy is a methylene moiety, said methylene moiety may be replaced with propane-2,2-diyl),

(iv) C 1-4 alkoxy substituted with carboxy (when position α of the carboxy of the C 1-4 alkoxy substituted with carboxy is a methylene moiety, said methylene moiety may be replaced with propane-2,2-diyl),

(v) mono-C 1-4 alkylaminocarbonyl substituted with carboxy (when position α of the carboxy of the mono-C 1-4 alkylaminocarbonyl substituted with carboxy is a methylene moiety, said methylene moiety may be replaced with propane-2,2-diyl), or

(vi) 4- to 6-membered saturated nitrogen-containing heterocyclylcarbonyl substituted with carboxy (the 4- to 6-membered saturated nitrogen-containing heterocyclyl of the 4- to 6-membered saturated nitrogen-containing heterocyclylcarbonyl substituted with carboxy may be substituted with one fluorine atom),

wherein R 61 and R 62 represent a hydrogen atom;

(e) when ring C is pyrazolyl,

R 54 represents carboxy,

wherein R 61 and R 62 represent a hydrogen atom;

(g) when ring C is tetrahydronaphthyl,

R 54 represents carboxy,

wherein R 61 and R 62 represent a hydrogen atom;

(h) when ring C is chromanyl,

R 54 represents carboxy,

wherein R 61 and R 62 represent a hydrogen atom;

(j) when ring C is indazolyl,

R 54 represents C 1-4 alkyl substituted with carboxy,

wherein R 61 and R 62 represent a hydrogen atom;

(n) when ring C is the structure represented by formula [IX-1] above,

R 54 represents:

(i) carboxy,

(ii) C 1-4 alkyl substituted with C 1-4 alkylsulfonylamino, or

(iii) C 1-4 alkyl substituted with C 1-4 alkylsulfonyl(C 1-4 alkyl)amino,

wherein R 61 and R 62 represent a hydrogen atom;

(p) when ring C is the structure represented by formula [IX-2] above,

R 54 is selected from the group consisting of:

(i) carboxy, and

(ii) C 1-4 alkyl substituted with carboxy,

wherein R 61 and R 62 represent a hydrogen atom;

(q) when ring C is the structure represented by formula [IX-3] above,

R 54 represents carboxy,

wherein R 61 and R 62 represent a hydrogen atom;

(r) when ring C is the structure represented by formula [IX-4] above,

R 54 represents carboxy,

wherein R 61 and R 62 represent a hydrogen atom;

W 4 is C 1-3 alkanediyl or the formula —O—CH 2 CH 2 —;

or a pharmaceutically acceptable salt thereof.

(3) In another embodiment, the present invention provides the compound according to (1) or (2),

wherein as regards R 5 of formula [I] above,

(A)

when R 5 represents the structure represented by formula [IV-1] above,

R 51 represents any of the structures represented by formula group [V′″] below,

W 1 represents butane-1,4-diyl, or pentane-1,5-diyl;

(B)

when R 5 represents the structure represented by formula [IV-2] above,

R 52 represents carboxy,

L represents the structure represented by formula [VI-1], formula [VI-4], formula [VI-8], formula [VI-9], formula [VI-10], or formula [VI-12] below:

Y represents the formula —CH 2 —, the formula —CMe 2 -, the formula —O—, the formula —NHCO—, or the formula —CONMe-,

W 2 represents propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, or the formula —O—(CH 2 ) 6 —;

(C)

when R 5 represents the structure represented by formula [IV-3] above,

R 53 represents carboxy, carboxymethyl (the methylene moiety of the carboxymethyl may be replaced with propane-2,2-diyl), or carboxymethoxy (the methylene moiety of the carboxymethoxy is substituted with propane-2,2-diyl);

ring B represents the structure represented by formula [VIII-1], formula [VIII-8], formula [VIII-9], formula [VIII-11], formula [VIII-12], formula [VIII-14], formula [VIII-B], or formula [VIII-7] below,

W 3 represents butane-1,4-diyl, or hexane-1,6-diyl;

(D)

when R 5 represents the structure represented by formula [IV-4] above,

ring C represents:

(a) C 3-6 cycloalkyl,

(b) 4- to 6-membered saturated nitrogen-containing heterocyclyl,

(c) phenyl,

(d) pyridyl,

(g) tetrahydronaphthyl,

(h) chromanyl,

(j) indazolyl,

(p) the structure represented by formula [IX-2] below,

(q) the structure represented by formula [IX-3] below, or

(r) the structure represented by formula [IX-4] below,

wherein

(a) when ring C is C 3-6 cycloalkyl,

ring C is cyclopropyl, cyclobutyl, or cyclohexyl,

R 54 represents:

(i) carboxy, or

(iv) methyl substituted with carboxy, or ethyl substituted with carboxy,

wherein R 61 and R 62 represent a hydrogen atom;

(b) when ring C is 4- to 6-membered saturated nitrogen-containing heterocyclyl, ring C is pipieridin-3-yl;

R 54 represents:

(i) ethylcarbonyl substituted with carboxy, n-butylcarbonyl substituted with carboxy (the methylene moiety at position α of the carboxy of the n-butylcarbonyl substituted with carboxy is replaced with cyclopentane-1,1-diyl), or

(vii) phenylsulfonyl substituted with carboxy;

wherein R 61 and R 62 represent a hydrogen atom;

(c) when ring C is phenyl,

R 54 represents:

(i) carboxy,

(ii) carbamoyl,

(iii) n-propylaminocarbonyl,

(iv) methylaminosulfonyl,

(v) dimethylaminosulfonyl (one methyl of the dimethylaminosuflonyl is substituted with one phenyl, wherein the phenyl is substituted with one methylaminosulfonyl),

(vii) isopropylsulfonylamino,

(viii) methylsulfonylaminocarbonyl,

(x) methyl substituted with carboxy (the methylene moiety at position α of the carboxy of the methyl substituted with carboxy may be replaced with ethane-1,1-diyl, propane-2,2-diyl, cyclopropane-1,1-diyl, tetrahydropyran-4,4-diyl, or piperidine-4,4-diyl, wherein the nitrogen atom of the piperidine-4,4-diyl is substituted with one methylcarbonyl), ethyl substituted with carboxy, n-propyl substituted with carboxy, or n-butyl substituted with carboxy,

(xi) methyl substituted with methylsulfonylaminocarbonyl, or ethyl substituted with methylsulfonylaminocarbonyl,

(xii) methyl substituted with trifluoromethylsulfonylamino,

(xiv) ethyl substituted with methylaminocarbonyl (the methyl of the ethyl substituted with methylaminocarbonyl may be substituted with tetrahydrofuranyl), ethyl substituted with ethylaminocarbonyl (the ethyl of the ethylaminocarbonyl of the ethyl substituted with ethylaminocarbonyl is substituted with one group selected from the group consisting of hydroxy and methoxy), ethyl substituted with n-propylaminocarbonyl (the n-propyl of the ethyl substituted with n-propylaminocarbonyl may be substituted with one group selected from the group consisting of hydroxy and methoxy), or ethyl substituted with isopropylaminocarbonyl (the isopropyl of the ethyl substituted with isopropylaminocarbonyl is substituted with one hydroxy),

(xv) ethyl substituted with dimethylaminocarbonyl,

(xvi) ethyl substituted with oxetanylaminocarbonyl,

(xvii) ethyl substituted with azetidinylcarbonyl (the azetidinyl of the ethyl substituted with azetidinylcarbonyl may be substituted with one to two groups selected from the group consisting of hydroxy and a fluorine atom) or ethyl substituted with pyrrolidinylcarbonyl,

(xviii) halo-methyl substituted with carboxy,

(xix) ethenyl substituted with carboxy,

(xxi) cyclopropyl substituted with carboxy, or cyclohexyl substituted with carboxy,

(xxii) cyclopropyl substituted with dimethylaminocarbonyl,

(xxiii) piperidinyl substituted with carboxy,

(xxiv) phenyl substituted with carboxy,

(xxv) pyridyl substituted with carboxy,

(xxvi) pyrazolyl substituted with carboxy,

(xxvii) pyrazolyl substituted with carboxymethyl,

(xxviii) pyrimidinyl substituted with carboxy,

(xxix) pyrazinyl substituted with carboxy,

(xxx) 2-oxodihydropyridinyl substituted with carboxymethyl,

(xxxi) methylaminocarbonyl substituted with carboxy (the methyl of the methylaminocarbonyl substituted with carboxy may be substituted with one benzyl, and the methylene moiety at position α of the carboxy of the methylaminocarbonyl substituted with carboxy may be replaced with ethane-1,1-diyl), ethylaminocarbonyl substituted with carboxy (the ethyl of the ethylaminocarbonyl substituted with carboxy may be substituted with one phenyl, and the methylene moiety at position α of the carboxy of the ethylaminocarbonyl substituted with carboxy may be replaced with a structure selected from the group consisting of propane-2,2-diyl, cyclopropane-1,1-diyl, and cyclopentane-1,1-diyl), or n-propylaminocarbonyl substituted with carboxy (the methylene moiety at position α of the carboxy of the n-propylaminocarbonyl substituted with carboxy is replaced with propane-2,2-diyl),

(xxxii) phenylmethylaminocarbonyl substituted with carboxy,

(xxxiii) monomethylaminocarbonyl substituted with the structure represented by formula [V-6] below,

(xxxiv) ethyl(methyl)aminocarbonyl substituted with carboxy,

(xxxv) cyclobutylaminocarbonyl substituted with carboxy,

(xxxvi) pyrrolidinylcarbonyl substituted with carboxy (the pyrrolidinyl of the pyrrolidinylcarbonyl substituted with carboxy is substituted with one fluorine atom), or piperidinylcarbonyl substituted with carboxy,

(xxxviii) the structure represented by formula [XI-1] below, which is substituted with carboxy,

(xxxix) the structure represented by formula [XI-2] below, which is substituted with carboxy,

(xxxxiv) ethylsulfonyl substituted with carboxy, or n-butylsulfonyl substituted with carboxy (the methylene moiety at position α of carboxy of the n-butylsulfonyl substituted with carboxy is replaced with propane-2,2-diyl),

(xxxxv) mono-n-propylaminosulfonyl substituted with carboxy (the methylene moiety at position α of the carboxy of the mono-n-propylaminosuflonyl substituted with carboxy is replaced with propane-2,2-diyl),

(xxxxvi) n-propyl(methyl)aminosulfonyl substituted with carboxy (the methylene moiety at position α of the carboxy of the n-propyl(methyl)aminosulfonyl substituted with carboxy is replaced with propane-2,2-diyl),

(xxxxvii) pyrrolidinylsulfonyl substituted with carboxy (the pyrrolidinyl of the pyrrolidinylsulfonyl substituted with carboxy may be substituted with one fluorine atom), piperidinylsulfonyl substituted with carboxy, or morpholinylsulfonyl substituted with carboxy,

(xxxxviii) methoxy substituted with carboxy (the methylene moiety at position α of the carboxy of the methoxy substituted with carboxy may be replaced with propane-2,2-diyl), (xxxxix) hydroxy,

(xxxxxi) isopropyl substituted with hydroxy,

(xxxxxii) haloethyl substituted with hydroxy, halo-n-propyl substituted with hydroxy, or haloisopropyl substituted with hydroxy,

(xxxxxiii) ethylsulfonyl substituted with hydroxy, isobutylsulfonyl substituted with hydroxy, or

(xxxxxiv) cyclobutyl substituted with hydroxy (the cyclobutyl of the cyclobutyl substituted with hydroxy may be substituted with one carboxy), cyclopentyl substituted with hydroxy, wherein R 61 and R 62 each independently represent a hydrogen atom, a fluorine atom, methyl, methoxy, or methylsulfonyl;

(d) when ring C is pyridyl,

ring C is pyridin-2-yl or pyridin-4-yl;

R 54 represents:

(i) carboxy,

(iii) n-propyl substituted with carboxy (the methylene moiety at position α of the carboxy of the n-propyl substituted with carboxy is replaced with propane-2,2-diyl),

(iv) ethoxy substituted with carboxy (the methylene moiety at position α of the carboxy of the ethoxy substituted with carboxy is replaced with propane-2,2-diyl),

(v) mono-n-propylaminocarbonyl substituted with carboxy (the methylene moiety at position α of the carboxy of the mono-n-propylaminocarbonyl substituted with carboxy is replaced with propane-2,2-diyl);

wherein R 61 and R 62 represent a hydrogen atom;

(g) when ring C is tetrahydronaphthyl,

ring C represents the structure represented by formula [XII-1], formula [XII-2], or formula [XII-3] below,

R 54 represents carboxy, wherein R 61 and R 62 represent a hydrogen atom;

(h) when ring C is chromanyl,

ring C represents the structure represented by formula [XIII-1] or formula [XIII-2] below

R 54 represents carboxy, wherein R 61 and R 62 represent a hydrogen atom;

(j) when ring C is indazolyl,

R 54 represents methyl substituted with carboxy, wherein R 61 and R 62 represent a hydrogen atom;

(p) when ring C is the structure represented by formula [IX-2] above,

R 54 represents

(i) carboxy, or

(ii) ethyl substituted with carboxy, wherein R 61 and R 62 represent a hydrogen atom;

(q) when ring C is the structure represented by formula [IX-3] above,

R 54 represents carboxy, wherein R 61 and R 62 represent a hydrogen atom;

(r) when ring C is the structure represented by formula [IX-4] above,

R 54 represents carboxy, wherein R 61 and R 62 represent a hydrogen atom;

W 4 represents methanediyl, ethane-1,2-diyl, propane-1,3-diyl, or the formula —O—CH 2 CH 2 —,

or pharmaceutically acceptable salt thereof.

(4) In another embodiment, the present invention provides the compound according to any one of (1) to (3), wherein the structure represented by formula [II] below is the structure represented by formula [III-1] below:

or a pharmaceutically acceptable salt thereof.

(5) In another embodiment, the present invention provides the compound according to (1), wherein

R 1 represents a hydrogen atom;

R 2 represents a hydrogen atom;

R 3 represents a hydrogen atom;

R 4 represents a hydrogen atom;

wherein

(B)

when R 5 represents the structure represented by formula [IV-2] below

R 52 represents carboxy,

L represents the structure represented by formula [VI-4] or formula [VI-7] below

wherein ring D represents (ii) 4- to 6-membered saturated oxygen-containing hetero ring,

Y represents the formula —CH 2 —, or the formula —O—,

W 2 represents C 7-8 alkanediyl, wherein one of the carbon atoms that constitute the C 7-8 alkanediyl represented by W 2 may be replaced with one oxygen atom;

(C)

when R 5 represents the structure represented by formula [IV-3] below

R 53 represents carboxy,

ring B represents the structure represented by formula [VIII-7] below

W 3 represents hexane-1,6-diyl;

(D)

when R 5 represents the structure represented by formula [IV-4] below

ring C represents (c) phenyl, (d) pyridyl, (g) tetrahydronaphthyl or (h) chromanyl,

W 4 represents methanediyl;

(c) when ring C is phenyl,

R 54 represents

(xxi) C 3-6 cycloalkyl substituted with carboxy, or (xxxxvii) 4- to 6-membered saturated nitrogen-containing heterocyclylsulfonyl, which is substituted with carboxy (the 4- to 6-membered saturated nitrogen-containing heterocyclyl of the 4- to 6-membered saturated nitrogen-containing heterocyclylsulfonyl substituted with carboxy may be substituted with one fluorine atom),

wherein R 61 represents a hydrogen atom and R 62 represents a hydrogen atom;

(d) when ring C is pyridyl,

R 54 represents

(iv) C 1-4 alkoxy substituted with carboxy,

wherein R 61 represents a hydrogen atom and R 62 represents a hydrogen atom;

(g) when ring C is tetrahydronaphthyl,

R 54 represents carboxy,

wherein R 61 represents a hydrogen atom and R 62 represents a hydrogen atom;

(h) when ring C is chromanyl,

R 54 represents carboxy,

wherein R 61 represents a hydrogen atom and R 62 represents a hydrogen atom; or a pharmaceutically acceptable salt thereof.

(6) In another embodiment, the present invention provides the compound according to (1),

wherein formula [I] is formula [I-D′] below,

wherein

R 1 represents a hydrogen atom;

R 2 represents a hydrogen atom;

R 54 represents C 3-6 cycloalkyl substituted with carboxy,

wherein R 61 and R 62 each independently represent a hydrogen atom, a fluorine atom, methyl, or methylsulfonyl;

W 4 represents C 1-3 alkanediyl;

or a pharmaceutically acceptable salt thereof.

(7) In another embodiment, the present invention provides the compound according to (6), wherein formula [I] is formula [I-D′] below,

wherein

R 1 represents a hydrogen atom;

R 2 represents a hydrogen atom;

R 54 represents cyclopropyl substituted with carboxy,

wherein

R 61 represents a fluorine atom that substitutes the benzene ring at ortho position with respect to —W 4 —,

R 62 represents a hydrogen atom;

W 4 represents methanediyl or ethane-1,2-diyl;

or a pharmaceutically acceptable salt thereof.

(8) In another embodiment, the present invention provides the compound according to (7), wherein formula [I] is formula [I-D′] below,

wherein

R 1 represents a hydrogen atom;

R 2 represents a hydrogen atom;

R 54 represents cyclopropyl substituted with carboxy, which substitutes the benzene ring at meta position with respect to —W 4 —,

wherein R 61 represents a fluorine atom that substitutes the benzene ring at ortho position with respect to —W 4 —,

R 62 represents a hydrogen atom;

W 4 represents methanediyl or ethane-1,2-diyl;

or a pharmaceutically acceptable salt thereof.

(9) In another embodiment, the present invention provides the compound according to (6), wherein formula [I] is formula [I-D′] below,

wherein

R 1 represents a hydrogen atom;

R 2 represents a hydrogen atom;

R 54 represents cyclopropyl substituted with carboxy, which substitutes the benzene ring at meta position with respect to —W 4 —,

wherein R 61 and R 62 each independently represent a hydrogen atom or a fluorine atom;

W 4 represents ethane-1,2-diyl;

or a pharmaceutically acceptable salt thereof.

(10) In another embodiment, the present invention provides the compound according to (9), wherein formula [I] is formula [I-D′] below,

wherein

R 1 represents a hydrogen atom;

R 2 represents a hydrogen atom;

R 54 represents cyclopropyl substituted with carboxy, which substitutes the benzene ring at meta position with respect to —W 4 —, wherein R 61 represents a fluorine atom,

R 62 represents a hydrogen atom;

W 4 represents ethane-1,2-diyl;

or a pharmaceutically acceptable salt thereof.

(11) In another embodiment, the present invention provides the compound according to (6), wherein formula [I] is formula [I-D′] below,

wherein

R 1 represents a hydrogen atom;

R 2 represents a hydrogen atom;

R 54 represents cyclopropyl substituted with carboxy,

wherein R 61 and R 62 each identically represent a hydrogen atom;

W 4 represents ethane-1,2-diyl;

or a pharmaceutically acceptable salt thereof.

(12) In another embodiment, the present invention provides the compound according to (1),

wherein formula [I] is formula [I-B] below,

wherein

R 1 represents a hydrogen atom;

R 2 represents a hydrogen atom;

L is the structure represented by formula [VI-1], formula [VI-4], or [VI-7] below,

wherein ring D represents

(i) C 3-6 cycloalkane,

(ii) 4- to 6-membered saturated oxygen-containing hetero ring, or

(iv) 6-membered saturated nitrogen-containing hetero ring (the nitrogen atom of the 6-membered saturated nitrogen-containing hetero ring may be substituted with one C 1-4 alkylcarbonyl);

Y represents the formula —CH 2 —, the formula —O—, or the formula —CONMe-;

W 2 represents C 2-10 alkanediyl,

wherein one of the carbon atoms that constitute C 2-10 alkanediyl represented by W 2 may be replaced with one oxygen atom;

or a pharmaceutically acceptable salt thereof.

(13) In another embodiment, the present invention provides the compound according to (12),

wherein formula [I] is formula [I-B] below,

wherein

R 1 represents a hydrogen atom;

R 2 represents a hydrogen atom;

L represents the structure represented by formula [VI-7] below

wherein ring D represents

(i) C 4 cycloalkane, or

(ii) 4-membered saturated oxygen-containing hetero ring;

Y represents the formula —CH 2 — or the formula —O—;

W 2 represents heptane-1,7-diyl, or a pharmaceutically salt thereof;

or a pharmaceutically acceptable salt thereof.

(14) In another embodiment, the invention provides the compound according to (1), wherein formula [I] is formula [I-B] below,

wherein

R 1 represents a hydrogen atom;

R 2 represents a hydrogen atom;

L represents the structure represented by formula [VI-7] below

wherein ring D represents

(i) C 4 cycloalkane,

(ii) 4-membered saturated oxygen-containing hetero ring, or

(iii) 4-membered saturated sulfur-containing hetero ring (the sulfur atom of the 4-membered saturated sulfur-containing hetero ring is substituted with two oxo),

Y represents the formula —CH 2 — or the formula —O—;

W 2 represents heptane-1,7-diyl;

or a pharmaceutically salt thereof.

(15) In another embodiment, the present invention provides the compound according to any one of (1) to (5), which is shown below:

or a pharmaceutically acceptable salt thereof.

(16) In another embodiment, the present invention provides the compound according to any one of (1) to (6), which is shown below:

or a pharmaceutically acceptable salt thereof.

(17) In another embodiment, the present invention provides the compound according to any one of (1) to (6), which is shown below:

or a pharmaceutically acceptable salt thereof.

(18) In another embodiment, the present invention provides the compound according to any one of (1) to (6), which is shown below:

or a pharmaceutically acceptable salt thereof.

(19) In another embodiment, the present invention provides the compound according to any one of (1) to (6), which is shown below:

or a pharmaceutically acceptable salt thereof.

(20) In another embodiment, the present invention provides the compound according to any one of (1) to (6), which is shown below:

or a pharmaceutically acceptable salt thereof.

(21) In another embodiment, the present invention provides the compound according to any one of (1) to (6), which is shown below:

or a pharmaceutically acceptable salt thereof.

(22) In another embodiment, the present invention provides the compound according to any one of (1) to (6), which is shown below:

or a pharmaceutically acceptable salt thereof.

(23) In another embodiment, the present invention provides the compound according to any one of (1) to (6), which is shown below:

or a pharmaceutically acceptable salt thereof.

(24) In another embodiment, the present invention provides the compound according to any one of (1) to (6), which is shown below:

or a pharmaceutically acceptable salt thereof.

(25) In another embodiment, the present invention provides the compound according to any one of (1) to (6), which is shown below:

or a pharmaceutically acceptable salt thereof.

(26) In another embodiment, the present invention provides the compound according to any one of (1) to (6), which is shown below:

or a pharmaceutically acceptable salt thereof.

(27) In another embodiment, the present invention provides the compound according to any one of (1) to (6), which is shown below:

or a pharmaceutically acceptable salt thereof.

(28) In another embodiment, the present invention provides the compound according to any one of (1) to (6), which is shown below:

or a pharmaceutically acceptable salt thereof.

(29) In another embodiment, the present invention provides the compound according to (1), which is shown below:

or a pharmaceutically acceptable salt thereof.

(30) In another embodiment, the present invention provides the compound according to (1), which is shown below:

or a pharmaceutically acceptable salt thereof.

(31) In another embodiment, the present invention provides the compound according to (1), which is shown below:

or a pharmaceutically acceptable salt thereof.

(32) In another embodiment, the present invention provides the compound according to (1), which is shown below:

or a pharmaceutically acceptable salt thereof.

(33) In another embodiment, the present invention provides the compound according to (1), which is shown below:

or a pharmaceutically acceptable salt thereof.

(34) In another embodiment, the present invention provides the compound according to (1), which is shown below:

or a pharmaceutically acceptable salt thereof.

(35) In another embodiment, the present invention provides the compound according to (1), which is shown below:

or a pharmaceutically acceptable salt thereof.

(36) In another embodiment, the present invention provides the compound according to (1), which is shown below:

or a pharmaceutically acceptable salt thereof.

(37) In another embodiment, the present invention provides the compound according to (1), which is shown below:

or a pharmaceutically acceptable salt thereof.

(38) In another embodiment, the present invention provides the compound according to (1), which is shown below:

or a pharmaceutically acceptable salt thereof.

(39) In another embodiment, the present invention provides the compound according to (1), which is shown below:

or a pharmaceutically acceptable salt thereof.

(40) In another embodiment, the present invention provides a pharmaceutical comprising the compound or pharmaceutically acceptable salt thereof according to any one of (1) to (39) as an active ingredient.

(41) In another embodiment, the present invention provides an agent that inhibits 20-HETE producing enzyme, wherein the agent comprises the compound or pharmaceutically acceptable salt thereof according to any one of (1) to (39) as an active ingredient.

(42) In another embodiment, the present invention provides an agent that prevents or ameliorates polycystic kidney disease, wherein the agent comprises the compound or pharmaceutically acceptable salt thereof according to any one of (1) to (39) as an active ingredient.

Advantageous Effects of Invention

The compound of the present invention (hereinafter also referred to as “the inventive compound”) has an inhibitory effect on 20-HETE producing enzymes.

The present invention provides a compound represented by formula [I] shown above that has an inhibitory effect on 20-HETE producing enzymes or a pharmaceutically acceptable salt thereof.

The compounds of the present invention will be described in more detail below, but the present invention is not limited to the exemplary embodiments.

As used herein, the term “methylene moiety at position α of carboxy” has the same meaning as the carbon atom at position α of carboxy. Similarly, the terms “methylene moiety of carboxymethyl” and “methylene moiety of carboxymethoxy” have the same meaning as the carbon atom of methyl of carboxymethyl and the carbon atom of methoxy of carboxymethoxy, respectively.

The term “halogen atom” refers to a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

The term “C 1-4 alkyl” refers to a straight or branched alkyl group having one to four carbon atoms. Examples of C 1-4 alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

The term “halo-C 1-4 alkyl” refers to a straight or branched alkyl group that is substituted with a halogen atom and has one to four carbon atoms. The halo-C 1-4 alkyl is preferably substituted with one to five halogen atoms, and the halogen atom is preferably a fluorine atom. Examples of halo-C 1-4 alkyl include monofluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl, 2-fluoroethyl, 2-fluoro-2-methylpropyl, 2,2-difluoropropyl, 1-fluoro-2-methylpropan-2-yl, 1,1-difluoro-2-methylpropan-2-yl, 2,2,2-trifluoro-1-methylethyl, and the like.

The term “C 2-4 alkenyl” refers to a straight or branched alkenyl group having two to four carbon atoms. Examples of C 2-4 alkenyl include ethenyl, (E)-prop-1-en-1-yl, (Z)-prop-1-en-1-yl, prop-2-en-1-yl, (Z)-but-2-en-1-yl, and the like.

The term “C 3-6 cycloalkane” refers to a hydrocarbon ring having three to six carbon atoms. Examples of C 3-6 cycloalkane include cyclopropane, cyclobutane, cyclopentane, and cyclohexane.

The term “C 3-6 cycloalkyl” refers to a cyclic alkyl group having three to six carbon atoms. Examples of C 3-6 cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

The term “aryl” refers to a monocyclic or fused polycyclic aromatic hydrocarbon group having 6 to 14 carbon atoms. Examples of aryl include phenyl, naphthyl, anthryl, and the like.

Also, partially-saturated aryl groups are included in “aryl”. The term “partially-saturated aryl group” refers to a partially-saturated fused polycyclic heterocyclic group among the monocyclic or fused polycyclic aromatic hydrocarbon group having 6 to 14 carbon atoms. Examples of partially-saturated aryl groups include dihydroindenyl and the like.

The term “saturated hetero ring” refers to a 3- to 8-membered monocyclic saturated heterocyclic group consisting of one to seven carbon atoms and one or more atoms which may be the same or different and are selected from the group consisting of an oxygen atom, a sulfur atom, and a nitrogen atom. Examples of saturated hetero ring include oxetane, tetrahydrofuran, tetrahydropyran, oxepane, azetidine, pyrrolidine, piperidine, azepane, thietane, tetrahydrothiophenyl, tetrahydrothiopyran, piperazine, pyrazolidine, morpholine, piperazine, thiomorpholine, 1,3-oxadinane, isothiazolidine, and the like.

The term “saturated heterocyclyl” refers to a 3- to 8-membered monocyclic saturated heterocyclic group consisting of one to seven carbon atoms and one or more atoms which may be the same or different and are selected from the group consisting of an oxygen atom, a sulfur atom, and a nitrogen atom. Examples of saturated heterocyclyl include oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, oxepanyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, thietanyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, piperazinyl, pyrazolidinyl, morpholinyl, piperazinyl, thiomorpholinyl, 1,3-oxazinanyl, isothiazolidinyl, and the like.

The term “4- to 6-membered saturated oxygen-containing hetero ring” refers to a 4- to 6-membered monocyclic saturated heterocyclic ring consisting of one oxygen atom and 3 to 5 carbon atoms. Examples of 4- to 6-membered saturated oxygen-containing hetero ring include oxetan, tetrahydrofuran, tetrahydropyrane, and the like.

The term “4- to 6-membered saturated oxygen-containing heterocyclyl” refers to a 4- to 6-membered monocyclic saturated heterocyclic group consisting of one oxygen atom and 3 to 5 carbon atoms. Examples of 4- to 6-membered saturated oxygen-containing heterocyclyl include oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, and the like.

The term “4- to 6-membered saturated sulfur-containing hetero ring” refers to a 4- to 6-membered monocyclic saturated heterocyclic ring consisting of one sulfur atom and 3 to 5 carbon atoms. Examples of 4- to 6-membered saturated sulfur-containing hetero ring include thiethane, tetrahydrothiophene, tetrahydrothiopyrane, and the like.

The term “4- to 6-membered saturated sulfur-containing heterocyclyl” refers to a 4- to 6-membered monocyclic saturated heterocyclic group consisting of one sulfur atom and 3 to 5 carbon atoms. Examples of 4- to 6-membered saturated sulfur-containing heterocyclyl include thietanyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.

The term “4- to 6-membered saturated nitrogen-containing hetero ring” refers to a 4- to 6-membered monocyclic saturated heterocyclic ring that consists of one nitrogen atom and 3 to 5 carbon atoms, and may further contain one heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom. Examples of 4- to 6-membered saturated nitrogen-containing hetero ring include azetidine, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, and the like.

The term “4- to 6-membered saturated nitrogen-containing heterocyclyl” refers to a 4- to 6-membered monocyclic saturated heterocyclic group that consists of one nitrogen atom and 3 to 5 carbon atoms, and may further contain one heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom. Examples of 4- to 6-membered saturated nitrogen-containing heterocyclyl include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and the like.

The term “heteroaryl” refers to a 5- to 7-membered monocyclic aromatic heterocyclic group consisting of one to six carbon atoms and one or more atoms which may be the same or different and are selected from the group consisting of an oxygen atom, a sulfur atom, and a nitrogen atom or a fused polycyclic aromatic heterocyclic group that is composed of 9 to 14 atoms consisting of 1 to 13 carbon atoms and one or more atoms which may be the same or different and are selected from the group consisting of an oxygen atom, a sulfur atom, and a nitrogen atom. Examples of heteroaryl include imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isooxazolyl, oxadiazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, indolyl, benzopyrazolyl, benzotriazolyl, benzofuranyl, benzothiophenyl, quinolyl, isoquinolyl, quinoxalyl, and the like.

Also, partially-saturated heteroaryl groups are included in “heteroaryl”. The term “partially-saturated heteroaryl group” refers to a 5- to 7-membered partially-saturated monocyclic heterocyclic group consisting of one to six carbon atoms and one or more atoms which may be the same or different and are selected from the group consisting of an oxygen atom, a sulfur atom, and a nitrogen atom or a partially-saturated fused polycyclic heterocyclic group that is composed of 9 to 14 atoms consisting of 1 to 13 carbon atoms and one or more atoms which may be the same or different and are selected from the group consisting of an oxygen atom, a sulfur atom, and a nitrogen atom. Examples of partially-saturated heteroaryl group include oxazolidinyl, thiazolinyl, dihydropyridinyl, dihydrobenzofuranyl, chromanyl, dihydropyranopyridinyl, dihydrofuropyridinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, dihydrobenzodioxinyl, tetrahydrotriazoloazepinyl, and the like.

The term “C 1-4 alkoxy” refers to a straight or branched alkoxy group having one to four carbon atoms. Examples of C 1-4 alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy.

The term “monoC 1-4 alkylamino” refers to an amino group having, as a substituent, one “C 1-4 alkyl” group mentioned above. Examples of monoC 1-4 alkylamino include methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino, and tert-butylamino

The term “di(C 1-4 alkyl)amino” refers to an amino group having, as substituents, two “C 1-4 alkyl” groups mentioned above, wherein the C 1-4 alkyl groups may be the same or different. Examples of di(C 1-4 alkyl)amino include dimethylamino, diethylamino, di(n-propyl)amino, di(isopropyl)amino, ethylmethylamino, methyl(n-propyl)amino, and the like.

The term “C 1-4 alkylcarbonyl” refers to a group consisting of the above-mentioned “C 1-4 alkyl” which is bound to carbonyl. Examples of C 1-4 alkylcarbonyl include acetyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, and tert-butylcarbonyl.

The term “saturated heterocyclylcarbonyl” refers to a group consisting of the above-mentioned “saturated heterocyclyl” which is bound to carbonyl. Examples of saturated heterocyclylcarbonyl include oxetanylcarbonyl, tetrahydrofuranylcarbonyl, tetrahydropyranylcarbonyl, oxepanylcarbonyl, azetidinylcarbonyl, pyrrolidinylcarbonyl, piperidinylcarbonyl, azepanylcarbonyl, tetrahydrothiopyranylcarbonyl, morpholinylcarbonyl, piperazinylcarbonyl, thiomorpholinylcarbonyl, isothiazolidinylcarbonyl, and the like.

The “4- to 6-membered saturated oxygen-containing heterocyclylcarbonyl” refers to a group consisting of the above-mentioned “4- to 6-membered saturated oxygen-containing heterocyclyl” which is bound to carbonyl. Examples of 4- to 6-membered saturated oxygen-containing heterocyclylcarbonyl include oxetanylcarbonyl, tetrahydrofuranylcarbonyl, tetrahydropyranylcarbonyl, and the like.

The “4- to 6-membered saturated nitrogen-containing heterocyclylcarbonyl” refers to a group consisting of the above-mentioned “4- to 6-membered saturated nitrogen-containing heterocyclyl” which is bound to carbonyl. Examples of 4- to 6-membered saturated nitrogen-containing heterocyclylcarbonyl include azetidinylcarbonyl, pyrrolidinylcarbonyl, piperidinylcarbonyl, azepanylcarbonyl, morpholinylcarbonyl, piperazinylcarbonyl, thiomorpholinylcarbonyl, isothiazolidinylcarbonyl, and the like.

The term “C 1-4 alkylsulfonyl” refers to a group consisting of the above-mentioned “C 1-4 alkyl” which is bound to sulfonyl. Examples of C 1-4 alkylsulfonyl include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, and tert-butylsulfonyl.

The term “C 1-4 alkylsulfonyloxy” refers to a group consisting of the above-mentioned “C 1-4 alkylsulfonyl” which is bound to an oxygen atom. Examples of C 1-4 alkylsulfonyloxy include methylsulfonyloxy, ethylsulfonyloxy, n-propylsulfonyloxy, isopropylsulfonyloxy, n-butylsulfonyloxy, isobutylsulfonyloxy, sec-butylsulfonyloxy, and tert-butylsulfonyloxy.

The term “saturated heterocyclylsulfonyl” refers to a group consisting of the above-mentioned “saturated heterocyclyl” which is bound to sulfonyl. Examples of saturated heterocyclylsulfonyl include azetidinylsulfonyl, pyrrolidinylsulfonyl, piperidinylsulfonyl, morpholinylsulfonyl, and the like.

The term “4- to 6-membered saturated nitrogen-containing heterocyclylsulfonyl” refers to a group consisting of the above-mentioned “4- to 6-membered saturated nitrogen-containing heterocyclyl” which is bound to sulfonyl. Examples of 4- to 6-membered saturated nitrogen-containing heterocyclylsulfonyl include azetidinylsulfonyl, pyrrolidinylsulfonyl, piperidinylsulfonyl, morpholinylsulfonyl, piperazinylsulfonyl, thiomorpholinylsulfonyl, isothiazolidinylsulfonyl, and the like.

The term “C 1-4 alkylsulfonylamino” refers to an amino group having, as a substituent, one “C 1-4 alkylsulfonyl” mentioned above. Examples of C 1-4 alkylsulfonylamino include methylsulfonylamino, ethylsulfonylamino, n-propylsulfonylamino, isopropylsulfonylamino, n-butylsulfonylamino, isobutylsulfonylamino, sec-butylsulfonylamino, and tert-butylsulfonylamino

The term “C 1-4 alkylsulfonyl(C 1-4 alkyl)amino” refers to an amino group having, as substituents, one “C 1-4 alkylsulfonyl” mentioned above and one “C 1-4 alkyl” mentioned above. Examples of C 1-4 alkylsulfonyl(C 1-4 alkyl)amino include methylsulfonyl(methyl)amino, methylsulfonyl(ethyl)amino, ethylsulfonyl(methyl)amino, n-propylsulfonyl(methyl)amino, isopropylsulfonyl(methyl)amino, n-butylsulfonyl(methyl)amino, isobutylsulfonyl(methyl)amino, sec-butylsulfonyl(methyl)amino, and tert-butylsulfonyl(methyl)amino

The term “C 1-4 alkylsulfonylaminocarbonyl” refers to a group consisting of the above-mentioned “C 1-4 alkylsulfonylamino” which is bound to carbonyl. Examples of C 1-4 alkylsulfonylaminocarbonyl include methylsulfonylaminocarbonyl, ethylsulfonylaminocarbonyl, n-propylsulfonylaminocarbonyl, isopropylsulfonylaminocarbonyl, n-butylsulfonylaminocarbonyl, isobutylsulfonylaminocarbonyl, sec-butylsulfonylaminocarbonyl, and tert-butylsulfonylaminocarbonyl.

The term “C 1-4 alkylsulfonyl(C 1-4 alkyl)aminocarbonyl” refers to a group consisting of the above-mentioned “C 1-4 alkylsulfonyl(C 1-4 alkyl)amino” which is bound to carbonyl. Examples of C 1-4 alkylsulfonyl(C 1-4 alkyl)aminocarbonyl include methylsulfonyl(methyl)aminocarbonyl, methylsulfonyl(ethyl)aminocarbonyl, ethylsulfonyl(methyl)aminocarbonyl, n-propylsulfonyl(methyl)aminocarbonyl, isopropylsulfonyl(methyl)aminocarbonyl, n-butylsulfonyl(methyl)aminocarbonyl, isobutylsulfonyl(methyl)aminocarbonyl, sec-butylsulfonyl(methyl)aminocarbonyl, and tert-butylsulfonyl(methyl)aminocarbonyl.

The term “C 1-4 alkoxycarbonyl” refers to a group consisting of the above-mentioned “C 1-4 alkoxy” which is bound to carbonyl. The C 1-4 alkoxycarbonyl includes methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, and tert-butoxycarbonyl.

The term “monoC 1-4 alkylaminocarbonyl” refers to a group consisting of the above-mentioned “monoC 1-4 alkylamino” which is bound to carbonyl. The monoC 1-4 alkylaminocarbonyl includes methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, n-butylaminocarbonyl, isobutylaminocarbonyl, sec-butylaminocarbonyl, and tert-butylaminocarbonyl.

The term “di(C 1-4 alkyl)aminocarbonyl” refers to a group consisting of the above-mentioned “di(C 1-4 alkyl)amino” which is bound to carbonyl. Examples of di(C 1-4 alkyl)aminocarbonyl include dimethylaminocarbonyl, diethylaminocarbonyl, di(n-propyl)aminocarbonyl, di(isopropyl)aminocarbonyl, ethylmethylaminocarbonyl, methyl(n-propyl)aminocarbonyl, and the like.

The term “C 3-6 cycloalkylaminocarbonyl” refers to a group consisting of an amino group that has, as a substituent, one “C 3-6 cycloalkyl” mentioned above and which is bound to carbonyl. Examples of C 3-6 cycloalkylaminocarbonyl include cyclopropylaminocarbonyl, cyclobutylaminocarbonyl, cyclopentylaminocarbonyl, and cyclohexylaminocarbonyl.

The term “saturated heterocyclylaminocarbonyl” refers to a group consisting of an amino group that has, as a substituent, one “saturated heterocyclyl” mentioned above and which is bound to carbonyl. The saturated heterocyclylaminocarbonyl includes oxetanylaminocarbonyl, tetrahydrofuranylaminocarbonyl, tetrahydropyranylaminocarbonyl, oxepanylaminocarbonyl, azetidinylaminocarbonyl, pyrrolidinylaminocarbonyl, piperidinylaminocarbonyl, azepanylaminocarbonyl, tetrahydrothiopyranylaminocarbonyl, morpholinylaminocarbonyl, piperazinylaminocarbonyl, thiomorpholinylaminocarbonyl, and the like.

The term “4- to 6-membered saturated oxygen-containing heterocyclylaminocarbonyl” refers to a group consisting of an amino group that has, as a substituent, one “4- to 6-membered saturated oxygen-containing heterocyclyl” mentioned above and which is bound to carbonyl. Examples of 4- to 6-membered saturated oxygen-containing heterocyclylaminocarbonyl include oxetanylaminocarbonyl, tetrahydrofuranylaminocarbonyl, tetrahydropyranylaminocarbonyl, and the like.

The term “monoC 1-4 alkylaminosulfonyl” refers to a group consisting of the above-mentioned “monoC 1-4 alkylamino” which is bound to sulfonyl. The monoC 1-4 alkylaminosulfonyl includes methylaminosulfonyl, ethylaminosulfonyl, n-propylaminosulfonyl, isopropylaminosulfonyl, n-butylaminosulfonyl, isobutylaminosulfonyl, sec-butylaminosulfonyl, and tert-butylaminosulfonyl.

The term “di(C 1-4 alkyl)aminosulfonyl” refers to a group consisting of the above-mentioned “di(C 1-4 alkyl)amino” which is bound to sulfonyl. Examples of di(C 1-4 alkyl)aminosulfonyl include dimethylaminosulfonyl, diethylaminosulfonyl, di(n-propyl)aminosulfonyl, di(isopropyl)aminosulfonyl, ethylmethylaminosulfonyl, methyl(n-propyl)aminosulfonyl, and the like.

The term “oxo” refers to a substituent (═O) which involves substitution of the oxygen atom via a double bond. Accordingly, when an oxo group is substituted by a carbon atom, the oxo group and the carbon atom taken together form carbonyl. When one oxo group is substituted by one sulfur atom, the oxo group and the sulfur atom taken together form sulfinyl. When two oxo groups are substituted by one sulfur atom, the oxo groups and the sulfur atom taken together form sulfonyl.

When oxo is substituted with saturated heterocyclyl in the present invention, oxo-substituting saturated heterocyclyl forms and specific examples of such oxo-substituting saturated heterocyclyl include 2-oxopyrrolidinyl, 2-oxopiperidinyl, 2-oxopiperazinyl, 3-oxopiperazinyl, 1,1-dioxidotetrahydrothiophenyl, 1-oxidotetrahydro-2H-thiopyranyl, 1,1-dioxidotetrahydro-2H-thiopyranyl, 1,1-dioxidoisothiazolidinyl, 2-oxo-1,3-oxazolidinyl, 2-oxo-1,3-oxazinanyl, 6-oxo-1,6-dihydropyridinyl, 6-oxo-1,1-dihydropyridazinyl, 1-oxo-1,2,3,4-tetrahydroisoquinolyl-7-yl, and the like.

The term “C 1-3 alkanediyl” refers to a divalent hydrocarbon group formed by removing one hydrogen atom from alkyl having 1 to 3 carbon atoms. The C 1-3 alkanediyl includes methanediyl, ethane-1,1-diyl, ethane-1,2-diyl, propane-1,1-diyl, propane-1,2-diyl, propane-1,3-diyl, and propane-2,2-diyl.

The term “C 2-6 alkanediyl” refers to a divalent hydrocarbon group formed by removing one hydrogen atom from alkyl having 2 to 6 carbon atoms. Examples of C 2-6 alkanediyl include ethane-1,1-diyl, ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, and the like.

The term “C 3-7 alkanediyl” refers to a divalent hydrocarbon group formed by removing one hydrogen atom from alkyl having 3 to 7 carbon atoms. Examples of C 3 -7alkanediyl include propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, and the like.

The term “C 4-5 alkanediyl” refers to a divalent hydrocarbon group formed by removing one hydrogen atom from alkyl having 4 or 5 carbon atoms. Examples of C 4-5 alkanediyl include butane-1,4-diyl, pentane-1,5-diyl, and the like.

The term “C 4-8 alkanediyl” refers to a divalent hydrocarbon group formed by removing one hydrogen atom from alkyl having 4 to 8 carbon atoms. Examples of C 4-8 alkanediyl include butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl, 3,3-dimethyl-propane-1,3-diyl, and the like.

The term “C 4-10 alkanediyl” refers to a divalent hydrocarbon group formed by removing one hydrogen atom from alkyl having 4 to 10 carbon atoms. Examples of C 4-10 alkanediyl include butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl, nonane-1,9-diyl, decane-1,10-diyl, 3,3-dimethyl-propane-1,3-diyl, 8,8-dimethyl-octane-1,8-diyl, and the like.

The term “C 5-10 alkanediyl” refers to a divalent hydrocarbon group formed by removing one hydrogen atom from alkyl having 5 to 10 carbon atoms. Examples of C 5-10 alkanediyl include pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl, nonane-1,9-diyl, decane-1,10-diyl, 3,3-dimethyl-propane-1,3-diyl, 8,8-dimethyl-octane-1,8-diyl, and the like.

The term “benzyl-based protecting group” refers to a group that is benzyl in which the phenyl may be substituted or benzyl in which the methylene may be substituted and that protects a functional group. Examples of the benzyl-based protecting group include benzyl, 4-methoxybenzyl, and the like.

Examples of functional groups to be protected by such a benzyl-based protecting group include hydroxy, carboxy, and the like.

When hydroxy is protected, the group is also referred to as “benzyl ether-based protecting group”. Similarly, when carboxy is protected, the group is also referred to as “benzyl ester-based protecting group”.

The term “acetal-based protecting group” refers to a group that forms an acetal structure together with hydroxy to protect a functional group. Examples of the acetal-based protecting group include methoxymethyl and tetrahydropyranyl.

Examples of functional groups to be protected by such an acetal-based protecting group include hydroxy and the like.

The term “silyl-based protecting group” refers to a group that is silyl substituted with three groups selected from alkyl and aryl and that protects a functional group. Examples of the silyl-based protecting group include trimethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, and the like.

Examples of functional groups to be protected by such a silyl-based protecting group include hydroxy and the like.

The following is one preferred embodiment of compounds of the present invention.

Among the structures represented by formula [II] shown below,

preferred is any of the structures represented by formula group [III] shown below:

More preferred is any of the structures represented by formula group [III-1] shown below:

Preferably, R 1 is a hydrogen atom, a chlorine atom, or methyl. More preferably, R 1 is a hydrogen atom or a chlorine atom. Even more preferably, R 1 is a hydrogen atom.

Preferably, R 2 is a hydrogen atom, a fluorine atom, or methyl. More preferably, R 2 is a hydrogen atom or a fluorine atom. Even more preferably, R 2 is a hydrogen atom.

Preferably, R 3 is a hydrogen atom. Preferably, R 4 is a hydrogen atom.

Preferably, R 5 is as follows:

(A)

when R 5 is the structure represented by formula [IV-1],

preferably, R 51 is any of the structures represented by formula group [V′] shown below:

preferably, W 1 is C 4-10 alkanediyl;

(B)

when R 5 is the structure represented by formula [IV-2],

preferably, R 52 is carboxy;

preferably, L is any of the structures represented by formula group [VI′] shown below:

wherein

preferably, ring D is

(i) C 3-6 cycloalkane,

(ii) 4- to 6-membered saturated oxygen-containing hetero ring, or

(iv) 4- to 6-membered saturated nitrogen-containing hetero ring (the nitrogen atom of the 4- to 6-membered saturated nitrogen-containing hetero ring may be substituted with one C 1-4 alkylcarbonyl);

preferably, Y is the formula —CH 2 —, the formula —CMe 2 -, the formula —O—, the formula —NHCO—, the formula —CONH—, or the formula —CONMe-;

preferably, W 2 is C 2-8 alkanediyl, wherein one of the carbon atoms that constitute C 2-8 alkanediyl represented by W 2 may be replaced with an oxygen atom;

(C)

when R 5 is the structure represented by formula [IV-3],

preferably, R 53 is carboxy, carboxymethyl, or carboxymethoxy, wherein the methylene moiety of the carboxymethyl or carboxymethoxy that is represented by R 53 may be replaced with propane-2,2-diyl;

preferably, ring B is any of the structures represented by formula group [VIII] shown below:

preferably, W 3 is C 4-8 alkanediyl or the formula —SO 2 —W 33 —, wherein preferably, W 33 is C 3-7 alkanediyl;

(D)

when R 5 is the structure represented by formula [IV-4],

preferably, ring C is

(a) C 3-6 cycloalkyl,

(b) 4- to 6-membered saturated nitrogen-containing heterocyclyl,

(c) phenyl,

(d) pyridyl,

(e) pyrazolyl,

(g) tetrahydronaphthyl,

(h) chromanyl,

(j) indazolyl,

(k) tetrahydroisoquinolyl,

(m) 2-oxotetrahydroisoquinolyl,

(n) the structure represented by formula [IX-1] below,

(p) the structure represented by formula [IX-2] below,

(q) the structure represented by formula [IX-3] below, or

(r) the structure represented by formula [IX-4] below:

(a) when ring C is C 3-6 cycloalkyl,

preferably, R 54 is

(i) carboxy, or

(iv) C 1-4 alkyl substituted with carboxy;

preferably, R 61 and R 62 are each a hydrogen atom;

(b) when ring C is 4- to 6-membered saturated nitrogen-containing heterocyclyl, preferably, R 54 is

(i) C 1-4 alkylcarbonyl substituted with carboxy (when position α of the carboxy of the C 1-4 alkylcarbonyl substituted with carboxy is a methylene moiety, the methylene moiety may be replaced with propane-2,2-diyl or cyclopentane-1,1-diyl),

(ii) C 1-4 alkylcarbonyl substituted with sulfamoyl,

(iii) C 1-4 alkylcarbonyl substituted with C 1-4 alkylsulfonylamino,

(iv) phenylmethylcarbonyl substituted with carboxy,

(v) phenylcarbonyl substituted with sulfamoyl,

(vi) dihydropyridinylcarbonyl substituted with oxo,

(vii) phenylsulfonyl substituted with carboxy,

(viii) monoC 1-4 alkylaminocarbonyl substituted with carboxy (when position α of the carboxy of the monoC 1-4 alkylaminocarbonyl substituted with carboxy is a methylene moiety, the methylene moiety may be replaced with propane-2,2-diyl), or

(x) the structure represented by formula [X-2] below, which is substituted with carboxy:

wherein preferably, R 61 and R 62 are each a hydrogen atom;

(c) when ring C is phenyl,

preferably, R 54 is

(i) carboxy,

(ii) carbamoyl,

(iii) monoC 1-4 alkylaminocarbonyl (the C 1-4 alkyl of the monoC 1-4 alkylaminocarbonyl may be substituted with one hydroxy),

(iv) monoC 1-4 alkylaminosulfonyl (the C 1-4 alkyl of the monoC 1-4 alkylaminosulfonyl may be substituted with one indolyl),

(v) di(C 1-4 alkyl)aminosulfonyl (one C 1-4 alkyl of the di(C 1-4 alkyl)aminosulfonyl may be substituted with one phenyl, wherein the phenyl may be substituted with one monoC 1-4 alkylaminosulfonyl),

(vi) phenylaminosulfonyl (the phenyl of the phenylaminosulfonyl may be substituted with one fluorine atom),

(vii) C 1-4 alkylsulfonylamino,

(viii) C 1-4 alkylsulfonylaminocarbonyl,

(ix) C 1-4 alkylsulfonyl(C 1-4 alkyl)aminocarbonyl,

(x) C 1-4 alkyl substituted with carboxy (when position α of the carboxy of the C 1-4 alkyl substituted with carboxy is a methylene moiety, the methylene moiety may be replaced with a structure selected from the group consisting of ethane-1,1-diyl, propane-2,2-diyl, cyclopropane-1,1-diyl, tetrahydropyran-4,4-diyl, and piperidine-4,4-diyl (the nitrogen atom of the piperidine-4,4-diyl is substituted with methylcarbonyl),

(xi) C 1-4 alkyl substituted with methylsulfonylaminocarbonyl,

(xii) C 1-4 alkyl substituted with trifluoromethylsulfonylamino,

(xiii) C 1-4 alkyl substituted with methylsulfonyl(methyl)aminocarbonyl,

(xiv) C 1-4 alkyl substituted with monoC 1-4 alkylaminocarbonyl (the C 1-4 alkyl of the monoC 1-4 alkylaminocarbonyl of the C 1-4 alkyl substituted with monoC 1-4 alkylaminocarbonyl may be substituted with one group selected from the group consisting of hydroxy, C 1-4 alkoxy, 4- to 6-membered saturated oxygen-containing heterocyclyl, di(C 1-4 alkyl)amino, and 4- to 6-membered saturated nitrogen-containing heterocyclylcarbonyl),

(xv) C 1-4 alkyl substituted with di(C 1-4 alkyl)aminocarbonyl (one C 1-4 alkyl of the di(C 1-4 alkyl)aminocarbonyl of the C 1-4 alkyl substituted with di(C 1-4 alkyl)aminocarbonyl may be substituted with one hydroxy),

(xvi) C 1-4 alkyl substituted with 4- to 6-membered saturated oxygen-containing heterocyclylaminocarbonyl,

(xvii) C 1-4 alkyl substituted with 4- to 6-membered saturated nitrogen-containing heterocyclylcarbonyl (the 4- to 6-membered saturated nitrogen-containing heterocyclyl of the C 1-4 alkyl substituted with 4- to 6-membered saturated nitrogen-containing heterocyclylcarbonyl may be substituted with one or two groups selected from the group consisting of hydroxy and a fluorine atom),

(xviii) halo-C 1-4 alkyl substituted with carboxy,

(xix) C 2-4 alkenyl substituted with carboxy,

(xx) C 2-4 alkenyl substituted with di(C 1-4 alkyl)aminocarbonyl,

(xxi) C 3-6 cycloalkyl substituted with carboxy,

(xxii) C 3-6 cycloalkyl substituted with di(C 1-4 alkyl)aminocarbonyl,

(xxiii) 4- to 6-membered saturated nitrogen-containing heterocyclyl substituted with carboxy,

(xxiv) phenyl substituted with carboxy,

(xxv) pyridyl substituted with carboxy,

(xxvi) pyrazolyl substituted with carboxy,

(xxvii) pyrazolyl substituted with carboxymethyl,

(xxviii) pyrimidinyl substituted with carboxy,

(xxix) pyrazinyl substituted with carboxy,

(xxx) 2-oxodihydropyridinyl substituted with carboxymethyl,

(xxxi) monoC 1-4 alkylaminocarbonyl substituted with carboxy (the C 1-4 alkyl of the monoC 1-4 alkylaminocarbonyl substituted with carboxy may be substituted with one group selected from the group consisting of phenyl and benzyl, and when position α of the carboxy of the monoC 1-4 alkylaminocarbonyl substituted with carboxy is a methylene moiety, the methylene moiety may be replaced with a structure selected from the group consisting of ethane-1,1-diyl, propane-2,2-diyl, cyclopropane-1,1-diyl, cyclopentane-1,1-diyl, and tetrahydropyran-4,4-diyl),

(xxxii) phenylC 1-4 alkylaminocarbonyl substituted with carboxy,

(xxxiii) monoC 1-4 alkylaminocarbonyl substituted with the structure represented by formula [V-6] below,

(xxxiv) di(C 1-4 alkyl)aminocarbonyl substituted with carboxy (when position α of the carboxy of the di(C 1-4 alkyl)aminocarbonyl substituted with carboxy is a methylene moiety, the methylene moiety may be replaced with propane-2,2-diyl),

(xxxv) C 3-6 cycloalkylaminocarbonyl substituted with carboxy,

(xxxvi) 4- to 6-membered saturated nitrogen-containing heterocyclylcarbonyl substituted with carboxy (the 4- to 6-membered saturated nitrogen-containing heterocyclyl of the 4- to 6-membered saturated nitrogen-containing heterocyclylcarbonyl substituted with carboxy may be substituted with one fluorine atom),

(xxxvii) 4- to 6-membered saturated nitrogen-containing heterocyclylcarbonyl substituted with carboxymethyl,

(xxxviii) the structure represented by formula [XI-1] below, which is substituted with carboxy,

(xxxix) the structure represented by formula [XI-2] below, which is substituted with carboxy,

(xxxx) the structure represented by formula [XI-3] below, which is substituted with carboxy,

(xxxxiii) the structure represented by formula [XI-6] below, which is substituted with carboxy,

(xxxxiv) C 1-4 alkylsulfonyl substituted with carboxy (when position α of the carboxy of the C 1-4 alkylsulfonyl substituted with carboxy is a methylene moiety, the methylene moiety may be replaced with propane-2,2-diyl),

(xxxxv) monoC 1-4 alkylaminosulfonyl substituted with carboxy (when position α of the carboxy of the monoC 1-4 alkylaminosulfonyl substituted with carboxy is a methylene moiety, the methylene moiety may be replaced with propane-2,2-diyl),

(xxxxvi) di(C 1-4 alkyl)aminosulfonyl substituted with carboxy (when position α of the carboxy of the di(C 1-4 alkyl)aminosulfonyl substituted with carboxy is a methylene moiety, the methylene moiety may be replaced with propane-2,2-diyl),

(xxxxvii) 4- to 6-membered saturated nitrogen-containing heterocyclylsulfonyl substituted with carboxy (the 4- to 6-membered saturated nitrogen-containing heterocyclyl of the 4- to 6-membered saturated nitrogen-containing heterocyclylsulfonyl substituted with carboxy may be substituted with one fluorine atom),

(xxxxviii) C 1-4 alkoxy substituted with carboxy (when position α of the carboxy of the C 1-4 alkoxy substituted with carboxy is a methylene moiety, the methylene moiety may be replaced with propane-2,2-diyl),

(xxxxix) hydroxy,

(xxxxx) C 1-4 alkylsulfonyloxy,

(xxxxxi) C 1-4 alkyl substituted with hydroxy,

(xxxxxii) halo-C 1-4 alkyl substituted with hydroxy,

(xxxxxiii) C 1-4 alkylsulfonyl substituted with hydroxy,

(xxxxxiv) C 3-6 cycloalkyl substituted with hydroxy (the C 3-6 cycloalkyl of the C 3-6 cycloalkyl substituted with hydroxy may be substituted with one group selected from the group consisting of carboxy and di(C 1-4 alkyl)aminocarbonyl), or

(xxxxxv) 4- to 6-membered saturated nitrogen-containing heterocyclyl substituted with hydroxy (the nitrogen atom of the 4- to 6-membered saturated nitrogen-containing heterocyclyl substituted with hydroxy may be substituted with one group selected from the group consisting of C 1-4 alkylcarbonyl, C 1-4 alkoxycarbonyl and di(C 1-4 alkyl)aminocarbonyl), wherein preferably, R 61 and R 62 are each independently a hydrogen atom, a fluorine atom, a chlorine atom, methyl, methoxy, or methylsulfonyl;

(d) when ring C is pyridyl,

preferably, R 54 is

(i) carboxy,

(ii) carbamoyl,

(iii) C 1-4 alkyl substituted with carboxy (when position α of the carboxy of the C 1-4 alkyl substituted with carboxy is a methylene moiety, the methylene moiety may be replaced with propane-2,2-diyl),

(iv) C 1-4 alkoxy substituted with carboxy (when position α of the carboxy of the C 1-4 alkoxy substituted with carboxy is a methylene moiety, the methylene moiety may be replaced with propane-2,2-diyl),

(v) monoC 1-4 alkylaminocarbonyl substituted with carboxy (when position α of the carboxy of the monoC 1-4 alkylaminocarbonyl substituted with carboxy is a methylene moiety, the methylene moiety may be replaced with propane-2,2-diyl), or

(vi) 4- to 6-membered saturated nitrogen-containing heterocyclylcarbonyl substituted with carboxy (the 4- to 6-membered saturated nitrogen-containing heterocyclyl of the 4- to 6-membered saturated nitrogen-containing heterocyclylcarbonyl substituted with carboxy may be substituted with one fluorine atom), wherein preferably, R 61 and R 62 are each a hydrogen atom;

(e) when ring C is pyrazolyl,

preferably, R 54 is carboxy,

wherein preferably, R 61 and R 62 are each a hydrogen atom;

(g) when ring C is tetrahydronaphthyl,

preferably, R 54 is carboxy,

wherein preferably, R 61 and R 62 are each a hydrogen atom;

(h) when ring C is chromanyl,

preferably, R 54 is carboxy,

wherein R 61 and R 62 are each a hydrogen atom;

(j) when ring C is indazolyl,

preferably, R 54 is C 1-4 alkyl substituted with carboxy,

wherein preferably, R 61 and R 62 are each a hydrogen atom;

(k) when ring C is tetrahydroisoquinolyl,

preferably, R 54 is C 1-4 alkylcarbonyl substituted with carboxy,

wherein when position α of the carboxy of the C 1-4 alkylcarbonyl substituted with carboxy is a methylene moiety, the methylene moiety may be replaced with propane-2,2-diyl,

wherein preferably, R 61 and R 62 are each a hydrogen atom;

(m) when ring C is 2-oxotetrahydroisoquinolyl,

preferably, R 54 is C 1-4 alkyl substituted with carboxy, wherein when position α of the carboxy of the C 1-4 alkyl substituted with carboxy is a methylene moiety, the methylene moiety may be replaced with propane-2,2-diyl,

wherein preferably, R 61 and R 62 are each a hydrogen atom;

(n) when ring C is the structure represented by formula [IX-1] above, preferably, R 54 is

(i) carboxy,

(ii) C 1-4 alkyl substituted with C 1-4 alkylsulfonylamino, or

(iii) C 1-4 alkyl substituted with C 1-4 alkylsulfonyl(C 1-4 alkyl)amino, wherein preferably, R 61 and R 62 are each a hydrogen atom;

(p) when ring C is the structure represented by formula [IX-2] above,

preferably, R 54 is

(i) carboxy, or

(ii) C 1-4 alkyl substituted with carboxy,

wherein preferably, R 61 and R 62 are each a hydrogen atom;

(q) when ring C is the structure represented by formula [IX-3] above, preferably, R 54 is carboxy,

wherein preferably, R 61 and R 62 are each a hydrogen atom;

(r) when ring C is the structure represented by formula [IX-4] above, preferably, R 54 is carboxy,

wherein preferably, R 61 and R 62 are each a hydrogen atom;

preferably, W 4 is C 1-3 alkanediyl or the formula —O—CH 2 CH 2 —.

The following are other preferred embodiments of the compounds of the present invention.

Preferred embodiments of R 1 , R 2 , R 3 , R 4 , and ring A in formula [1] above are as described above.

Another preferred examples of R 5 are as follows:

(A)

when R 5 is the structure represented by formula [IV-1],

another preferred example of R 51 is any of the structures represented by formula group [V′″] shown below:

another preferred example of W 1 is C 4-10 alkanediyl;

(B)

when R 5 is the structure represented by formula [IV-2],

another preferred example of R 52 is carboxy;

another preferred example of L is any of the structures represented by formula group [VI′] shown below:

wherein

another preferred example of ring D is

(i) C 3-6 cycloalkane,

(ii) 4- to 6-membered saturated oxygen-containing hetero ring, or

(iv) 4- to 6-membered saturated nitrogen-containing hetero ring (the nitrogen atom of the 4- to 6-membered saturated nitrogen-containing hetero ring may be substituted with one C 1-4 alkylcarbonyl;

another preferred example of Y is the formula —CH 2 —, the formula —CMe 2 -, the formula —O—, the formula —NHCO—, the formula —CONH—, or the formula —CONMe-;

another preferred example of W 2 is C 2-8 alkanediyl, wherein one of the carbon atoms that constitute C 2-8 alkanediyl represented by W 2 may be replaced with an oxygen atom;

(C)

when R 5 is the structure represented by formula [IV-3],

another preferred example of R 53 is carboxy, carboxymethyl, or carboxymethoxy, wherein the methylene moiety of the carboxymethyl or carboxymethoxy that is represented by

R 53 may be replaced with propane-2,2-diyl;

another preferred example of ring B is any of the structures represented by formula group [VIII] shown below:

another preferred example of W 3 is C 4-8 alkanediyl or the formula —SO 2 —W 33 —, wherein another preferred example of W 3 is C 3-7 alkanediyl;

(D)

when R 5 is the structure represented by formula [IV-4],

another preferred example of ring C is

(a) C 3-6 cycloalkyl,

(b) 4- to 6-membered saturated nitrogen-containing heterocyclyl,

(c) phenyl,

(d) pyridyl,

(e) pyrazolyl,

(g) tetrahydronaphthyl,

(h) chromanyl,

(j) indazolyl,

(n) the structure represented by formula [IX-1] below,

(p) the structure represented by formula [IX-2] below,

(q) the structure represented by formula [IX-3] below, or

(r) the structure represented by formula [IX-4] below

wherein

(a) when ring C is C 3-6 cycloalkyl,

another preferred example of R 54 is

(i) carboxy, or

(iv) C 1-4 alkyl substituted with carboxy;

wherein another preferred example of R 61 and R 62 is a hydrogen atom;

(b) when ring C is 4- to 6-membered saturated nitrogen-containing heterocyclyl, another preferred example of R 54 is

(i) C 1-4 alkylcarbonyl substituted with carboxy (when position α of the carboxy of the C 1-4 alkylcarbonyl substituted with carboxy is a methylene moiety, the methylene moiety may be replaced with cyclopentane-1,1-diyl),

(ii) C 1-4 alkylcarbonyl substituted with sulfamoyl,

(iv) phenylmethylcarbonyl substituted with carboxy,

(v) phenylcarbonyl substituted with sulfamoyl,

(vi) dihydropyridinylcarbonyl substituted with oxo,

(vii) phenylsulfonyl substituted with carboxy,

(viii) monoC 1-4 alkylaminocarbonyl substituted with carboxy (when position α of the carboxy of the monoC 1-4 alkylaminocarbonyl substituted with carboxy is a methylene moiety, the methylene moiety may be replaced with propane-2,2-diyl), or

(x) the structure represented by formula [X-2] below, which is substituted with carboxy:

wherein another preferred example of R 61 and R 62 is a hydrogen atom;

(c) when ring C is phenyl,

another preferred example of R 54 is

(i) carboxy,

(ii) carbamoyl,

(iii) monoC 1-4 alkylaminocarbonyl (the C 1-4 alkyl of the monoC 1-4 alkylaminocarbonyl may be substituted with one hydroxy),

(iv) monoC 1-4 alkylaminosulfonyl,

(v) di(C 1-4 alkyl)aminosulfonyl (one C 1-4 alkyl of the di(C 1-4 alkyl)aminosulfonyl may be substituted with one phenyl, wherein the phenyl may be substituted with one monoC 1-4 alkylaminosulfonyl),

(vi) phenylaminosulfonyl (the phenyl of the phenylaminosulfonyl may be substituted with one fluorine atom),

(vii) C 1-4 alkylsulfonylamino,

(viii) C 1-4 alkylsulfonylaminocarbonyl,

(ix) C 1-4 alkylsulfonyl(C 1-4 alkyl)aminocarbonyl,

(x) C 1-4 alkyl substituted with carboxy (when position α of the carboxy of the C 1-4 alkyl substituted with carboxy is a methylene moiety, the methylene moiety may be replaced with a structure selected from the group consisting of ethane-1,1-diyl, propane-2,2-diyl, cyclopropane-1,1-diyl, tetrahydropyran-4,4-diyl, and piperidine-4,4-diyl (the nitrogen atom of the piperidine-4,4-diyl is substituted with methylcarbonyl),

(xi) C 1-4 alkyl substituted with methylsulfonylaminocarbonyl,

(xii) C 1-4 alkyl substituted with trifluoromethylsulfonylamino,

(xiii) C 1-4 alkyl substituted with methylsulfonyl(methyl)aminocarbonyl,

(xiv) C 1-4 alkyl substituted with monoC 1-4 alkylaminocarbonyl (the C 1-4 alkyl of the monoC 1-4 alkylaminocarbonyl of the C 1-4 alkyl substituted with monoC 1-4 alkylaminocarbonyl may be substituted with one group selected from the group consisting of hydroxy, C 1-4 alkoxy, 4- to 6-membered saturated oxygen-containing heterocyclyl, di(C 1-4 alkyl)amino, and 4- to 6-membered saturated nitrogen-containing heterocyclylcarbonyl),

(xv) C 1-4 alkyl substituted with di(C 1-4 alkyl)aminocarbonyl (one C 1-4 alkyl of the di(C 1-4 alkyl)aminocarbonyl of the C 1-4 alkyl substituted with di(C 1-4 alkyl)aminocarbonyl may be substituted with one hydroxy),

(xvi) C 1-4 alkyl substituted with 4- to 6-membered saturated oxygen-containing heterocyclylaminocarbonyl,

(xvii) C 1-4 alkyl substituted with 4- to 6-membered saturated nitrogen-containing heterocyclylcarbonyl (the 4- to 6-membered saturated nitrogen-containing heterocyclyl of the C 1-4 alkyl substituted with 4- to 6-membered saturated nitrogen-containing heterocyclylcarbonyl may be substituted with one or two groups selected from the group consisting of hydroxy and a fluorine atom),

(xviii) halo-C 1-4 alkyl substituted with carboxy,

(xix) C 2-4 alkenyl substituted with carboxy,

(xx) C 2-4 alkenyl substituted with di(C 1-4 alkyl)aminocarbonyl,

(xxi) C 3-6 cycloalkyl substituted with carboxy,

(xxii) C 3-6 cycloalkyl substituted with di(C 1-4 alkyl)aminocarbonyl,

(xxiii) 4- to 6-membered saturated nitrogen-containing heterocyclyl substituted with carboxy,

(xxiv) phenyl substituted with carboxy,

(xxv) pyridyl substituted with carboxy,

(xxvi) pyrazolyl substituted with carboxy,

(xxvii) pyrazolyl substituted with carboxymethyl,

(xxviii) pyrimidinyl substituted with carboxy,

(xxix) pyrazinyl substituted with carboxy,

(xxx) 2-oxodihydropyridinyl substituted with carboxymethyl,

(xxxi) monoC 1-4 alkylaminocarbonyl substituted with carboxy (the C 1-4 alkyl of the monoC 1-4 alkylaminocarbonyl substituted with carboxy may be substituted with one group selected from the group consisting of phenyl and benzyl, and when position α of the carboxy of the monoC 1-4 alkylaminocarbonyl substituted with carboxy is a methylene moiety, the methylene moiety may be replaced with a structure selected from the group consisting of ethane-1,1-diyl, propane-2,2-diyl, cyclopropane-1,1-diyl, cyclopentane-1,1-diyl, and tetrahydropyran-4,4-diyl),

(xxxii) phenylC 1-4 alkylaminocarbonyl substituted with carboxy,

(xxxiii) monoC 1-4 alkylaminocarbonyl substituted with the structure represented by formula [V-6] below,

(xxxiv) di(C 1-4 alkyl)aminocarbonyl substituted with carboxy (when position α of the carboxy of the di(C 1-4 alkyl)aminocarbonyl substituted with carboxy is a methylene moiety, the methylene moiety may be replaced with propane-2,2-diyl),

(xxxv) C 3-6 cycloalkylaminocarbonyl substituted with carboxy,

(xxxvi) 4- to 6-membered saturated nitrogen-containing heterocyclylcarbonyl substituted with carboxy (the 4- to 6-membered saturated nitrogen-containing heterocyclyl of the 4- to 6-membered saturated nitrogen-containing heterocyclylcarbonyl substituted with carboxy may be substituted with one fluorine atom),

(xxxvii) 4- to 6-membered saturated nitrogen-containing heterocyclylcarbonyl substituted with carboxymethyl,

(xxxviii) the structure represented by formula [XI-1] below, which is substituted with carboxy,

(xxxix) the structure represented by formula [XI-2] below, which is substituted with carboxy,

(xxxx) the structure represented by formula [XI-3] below, which is substituted with carboxy,

(xxxxiii) the structure represented by formula [XI-6] below, which is substituted with carboxy,

(xxxxiv) C 1-4 alkylsulfonyl substituted with carboxy (when position α of the carboxy of the C 1-4 alkylsulfonyl substituted with carboxy is a methylene moiety, the methylene moiety may be replaced with propane-2,2-diyl),

(xxxxv) monoC 1-4 alkylaminosulfonyl substituted with carboxy (when position α of the carboxy of the monoC 1-4 alkylaminosulfonyl substituted with carboxy is a methylene moiety, the methylene moiety may be replaced with propane-2,2-diyl),

(xxxxvi) di(C 1-4 alkyl)aminosulfonyl substituted with carboxy (when position α of the carboxy of the di(C 1-4 alkyl)aminosulfonyl substituted with carboxy is a methylene moiety, the methylene moiety may be replaced with propane-2,2-diyl),

(xxxxvii) 4- to 6-membered saturated nitrogen-containing heterocyclylsulfonyl substituted with carboxy (the 4- to 6-membered saturated nitrogen-containing heterocyclyl of the 4- to 6-membered saturated nitrogen-containing heterocyclylsulfonyl substituted with carboxy may be substituted with one fluorine atom),

(xxxxviii) C 1-4 alkoxy substituted with carboxy (when position α of the carboxy of the C 1-4 alkoxy substituted with carboxy is a methylene moiety, the methylene moiety may be replaced with propane-2,2-diyl),

(xxxxix) hydroxy,

(xxxxx) C 1-4 alkylsulfonyloxy,

(xxxxxi) C 1-4 alkyl substituted with hydroxy,

(xxxxxii) halo-C 1-4 alkyl substituted with hydroxy,

(xxxxxiii) C 1-4 alkylsulfonyl substituted with hydroxy,

(xxxxxiv) C 3-6 cycloalkyl substituted with hydroxy (the C 3-6 cycloalkyl of the C 3-6 cycloalkyl substituted with hydroxy may be substituted with one group selected from the group consisting of carboxy and di(C 1-4 alkyl)aminocarbonyl), or

(xxxxxv) 4- to 6-membered saturated nitrogen-containing heterocyclyl substituted with hydroxy (the nitrogen atom of the 4- to 6-membered saturated nitrogen-containing heterocyclyl substituted with hydroxy may be substituted with one group selected from the group consisting of C 1-4 alkylcarbonyl, C 1-4 alkoxycarbonyl and di(C 1-4 alkyl)aminocarbonyl), wherein another preferred example of R 61 and R 62 is each independently a hydrogen atom, a fluorine atom, a chlorine atom, methyl, methoxy, or methylsulfonyl;

(d) when ring C is pyridyl,

another preferred example of R 54 is

(i) carboxy,

(ii) carbamoyl,

(iii) C 1-4 alkyl substituted with carboxy (when position α of the carboxy of the C 1-4 alkyl substituted with carboxy is a methylene moiety, the methylene moiety may be replaced with propane-2,2-diyl),

(iv) C 1-4 alkoxy substituted with carboxy (when position α of the carboxy of the C 1-4 alkoxy substituted with carboxy is a methylene moiety, the methylene moiety may be replaced with propane-2,2-diyl),

(v) monoC 1-4 alkylaminocarbonyl substituted with carboxy (when position α of the carboxy of the monoC 1-4 alkylaminocarbonyl substituted with carboxy is a methylene moiety, the methylene moiety may be replaced with propane-2,2-diyl), or

(vi) 4- to 6-membered saturated nitrogen-containing heterocyclylcarbonyl substituted with carboxy (the 4- to 6-membered saturated nitrogen-containing heterocyclyl of the 4- to 6-membered saturated nitrogen-containing heterocyclylcarbonyl substituted with carboxy may be substituted with one fluorine atom),

wherein another preferred example of R 61 and R 62 is a hydrogen atom;

(e) when ring C is pyrazolyl,

another preferred example of R 54 is carboxy,

wherein another preferred example of R 61 and R 62 is a hydrogen atom;

(g) when ring C is tetrahydronaphthyl,

another preferred example of R 54 is carboxy,

wherein another preferred example of R 61 and R 62 is a hydrogen atom;

(h) when ring C is chromanyl,

another preferred example of R 54 is carboxy,

wherein another preferred example of R 61 and R 62 is a hydrogen atom;

(j) when ring C is indazolyl,

another preferred example of R 54 is C 1-4 alkyl substituted with carboxy,

wherein another preferred example of R 61 and R 62 is a hydrogen atom;

(n) when ring C is the structure represented by formula [IX-1] above, another preferred example of R 54 is

(i) carboxy,

(ii) C 1-4 alkyl substituted with C 1-4 alkylsulfonylamino, or

(iii) C 1-4 alkyl substituted with C 1-4 alkylsulfonyl(C 1-4 alkyl)amino,

wherein another preferred example of R 61 and R 62 is a hydrogen atom;

(p) when ring C is the structure represented by formula [IX-2] above, another preferred example of R 54 is

(i) carboxy, or

(ii) C 1-4 alkyl substituted with carboxy,

wherein another preferred example of R 61 and R 62 is a hydrogen atom;

(q) when ring C is the structure represented by formula [IX-3] above, another preferred example of R 54 is carboxy,

wherein another preferred example of R 61 and R 62 is a hydrogen atom;

(r) when ring C is the structure represented by formula [IX-4] above, another preferred example of R 54 is carboxy,

wherein another preferred example of R 61 and R 62 is a hydrogen atom;

Another preferred example of W 4 is C 1-3 alkanediyl, or the formula —O—CH 2 CH 2 —.

Here, more preferably, R 5 is,

(A)

when R 5 represents the structure represented by formula [IV-1],

more preferably, R 51 represents any of the structures represented by formula group [VI′] shown below:

more preferably, W 1 represents C 4-5 alkanediyl;

(B)

when R 5 represents the structure represented by formula [IV-2],

more preferably, R 52 represents carboxy;

more preferably, L represents any of the structures represented by formula group [VI] below:

wherein more preferably, ring D represents

(i) C 4-6 cycloalkane,

(ii) 6-membered saturated oxygen-containing hetero ring, or

(iv) 5- to 6-membered saturated nitrogen-containing hetero ring (the nitrogen atom of the 5- to 6-membered saturated nitrogen-containing hetero ring is substituted with C 1 alkylcarbonyl);

more preferably, Y represents the formula —CH 2 —, the formula —CMe 2 -, the formula —O—, the formula —NHCO—, the formula —CONH—, or the formula —CONMe-;

more preferably, W 2 represents C 2-8 alkanediyl,

wherein one of the carbon atoms that constitute C 2-8 alkanediyl represented by W 2 may be replaced with an oxygen atom;

(C)

When R 5 is the structure represented by formula [IV-3];

more preferably, R 53 represents carboxy, carboxymethyl (the methylene moiety of the carboxymethyl may be replaced with propane-2,2-diyl), or carboxymethoxy (the methylene moiety of the carboxymethoxy is replaced with propane-2,2-diyl);

more preferably, ring B represents any of the structures represented by formula group [VIII] below:

more preferably, W 3 represents C 4-6 alkanediyl or the formula —SO 2 —W 33 —,

wherein more preferably, W 33 represents C 4 alkanediyl;

(D)

when R 5 is the structure represented by formula [IV-4],

more preferably, ring C is

(a) C 3-6 cycloalkyl,

(b) 6-membered saturated nitrogen-containing heterocyclyl,

(c) phenyl,

(d) pyridyl,

(e) pyrazolyl,

(g) tetrahydronaphthyl,

(h) chromanyl,

(j) indazolyl,

(n) the structure represented by formula [IX-1] below,

(p) the structure represented by formula [IX-2] below,

(q) the structure represented by formula [IX-3] below, or

(r) the structure represented by formula [IX-4] below,

wherein

(a) when ring C represents C 3-6 cycloalkyl,

more preferably, ring C represents C 3-6 cycloalkyl;

more preferably, R 54 is

(i) carboxy, or

(iv) C 1-2 alkyl substituted with carboxy,

wherein more preferably, R 61 and R 62 represent a hydrogen atom;

(b) when ring C is 4- to 6-membered saturated nitrogen-containing heterocyclyl, more preferably, ring C is 6-membered saturated nitrogen-containing heterocyclyl, more preferably, R 54 is

(i) C 2-4 alkylcarbonyl substituted with carboxy (when position α of the carboxy of the C 2-4 alkylcarbonyl substituted with carboxy is a methylene moiety, the methylene moiety may be replaced with cyclopentane-1,1-diyl),

(ii) C 3 alkylcarbonyl substituted with sulfamoyl,

(iv) phenylmethylcarbonyl substituted with carboxy,

(v) phenylcarbonyl substituted with sulfamoyl,

(vi) dihydopyridinylcarbonyl substituted with oxo,

(vii) phenylsulfonyl substituted with carboxy,

(viii) monoC 3 alkylaminocarbonyl substituted with carboxy (when position α of the carboxy of the monoC 3 alkylaminocarbonyl substituted with carboxy is a methylene moiety, the methylene moiety is replaced with propane-2,2-diyl), or

(x) the structure represented by formula [X-2] below, which is substituted with carboxy:

wherein more preferably, R 61 and R 62 represent a hydrogen atom;

(c) when ring C is phenyl,

more preferably, R 54 is

(i) carboxy,

(ii) carbamoyl,

(iii) monoC 1-3 alkylaminocarbonyl (the C 1-3 alkyl of the monoC 1-3 alkylaminocarbonyl may be substituted with one hydroxy),

(iv) monoC 1 alkylaminosulfonyl,

(v) di(C 1 alkyl)aminosulfonyl (one C 1 alkyl of the di(C 1 alkyl)aminosulfonyl is substituted with one phenyl, wherein the phenyl is substituted with one monoC 1 alkylaminosulfonyl),

(vi) phenylaminosulfonyl (the phenyl of the phenylaminosulfonyl is substituted with one fluorine atom),

(vii) C 3 alkylsulfonylamino,

(viii) C 1 alkylsulfonylaminocarbonyl,

(ix) C 1 alkylsulfonyl(C 1 alkyl)aminocarbonyl,

(x) C 1-4 alkyl substituted with carboxy (when position α of the carboxy of the C 1-4 alkyl substituted with carboxy is a methylene moiety, the methylene moiety may be replaced with ethane-1,1-diyl, propane-2,2-diyl, cyclopropane-1,1-diyl, tetrahydropyran-4,4-diyl, or piperidine-4,4-diyl,

wherein the nitrogen atom of the piperidine-4,4-diyl is substituted with one methylcarbonyl),

(xi) C 1-2 alkyl substituted with methylsulfonylaminocarbonyl,

(xii) C 1 alkyl substituted with trifluoromethylsulfonylamino,

(xiii) C 1-2 alkyl substituted with methylsulfonyl(methyl)aminocarbonyl,

(xiv) C 1-2 alkyl substituted with monoC 1-3 alkylaminocarbonyl (the C 1-3 alkyl of the monoC 1-3 alkylaminocarbonyl of the C 1-2 alkyl substituted with monoC 1-3 alkylaminocarbonyl may be substituted with one group selected from the group consisting of hydroxy, C 1 alkoxy, 5-membered saturated oxygen-containing heterocyclyl, di(C 1 alkyl)amino, and 5-membered saturated nitrogen-containing heterocyclylcarbonyl),

(xv) C 1-2 alkyl substituted with di(C 1-2 alkyl)aminocarbonyl (one C 1-2 alkyl of the di(C 1-2 alkyl)amino of the di(C 1-2 alkyl)aminocarbonyl may be substituted with one hydroxy),

(xvi) C 2 alkyl substituted with 4-membered saturated oxygen-containing heterocyclylaminocarbonyl,

(xvii) C 2 alkyl substituted with 4- to 6-membered saturated nitrogen-containing heterocyclylcarbonyl (the 4- to 6-membered saturated nitrogen-containing heterocyclyl of the C 2 alkyl substituted with 4- to 6-membered saturated nitrogen-containing heterocyclylcarbonyl may be substituted with one or two groups selected from the group consisting of hydroxy and a fluorine atom),

(xviii) halo-C 1 alkyl substituted with carboxy,

(xix) C 2 alkenyl substituted with carboxy,

(xx) C 2 alkenyl substituted with di(C 1 alkyl)aminocarbonyl,

(xxi) C 3-6 cycloalkyl substituted with carboxy,

(xxii) C 3 cycloalkyl substituted with di(C 1 alkyl)aminocarbonyl,

(xxiii) 6-membered saturated nitrogen-containing heterocyclyl substituted with carboxy,

(xxiv) phenyl substituted with carboxy,

(xxv) pyridyl substituted with carboxy,

(xxvi) pyrazolyl substituted with carboxy,

(xxvii) pyrazolyl substituted with carboxymethyl,

(xxviii) pyrimidinyl substituted with carboxy,

(xxix) pyrazinyl substituted with carboxy,

(xxx) 2-oxodihydropyridinyl substituted with carboxymethyl,

(xxxi) monoC 1-3 alkylaminocarbonyl substituted with carboxy (the C 1-3 alkyl of the monoC 1-3 alkylaminocarbonyl substituted with carboxy may be substituted with one group selected from the group consisting of phenyl and benzyl, and when position α of the carboxy of the monoC 1-3 alkylaminocarbonyl substituted with carboxy is a methylene moiety, the methylene moiety may be replaced with a structure selected from the group consisting of ethane-1,1-diyl, propane-2,2-diyl, cyclopropane-1,1-diyl, cyclopentane-1,1-diyl, and tetrahydropyran-4,4-diyl),

(xxxii) phenylC 1 alkylaminocarbonyl substituted with carboxy,

(xxxiii) monoC 1 alkylaminocarbonyl substituted with the structure represented by formula [V-6] below,

(xxxiv) di(C 1-3 alkyl)aminocarbonyl substituted with carboxy (when position α of the carboxy of the di(C 1-3 alkyl)aminocarbonyl substituted with carboxy is a methylene moiety, the methylene moiety may be replaced with propane-2,2-diyl),

(xxxv) C 4-6 cycloalkylaminocarbonyl substituted with carboxy,

(xxxvi) 5- to 6-membered saturated nitrogen-containing heterocyclylcarbonyl substituted with carboxy (the 5- to 6-membered saturated nitrogen-containing heterocyclyl of the 5- to 6-membered saturated nitrogen-containing heterocyclylcarbonyl may be substituted with one fluorine atom),

(xxxvii) 4- to 6-membered saturated nitrogen-containing heterocyclylcarbonyl substituted with carboxymethyl,

(xxxviii) the structure represented by formula [XI-1] below, which is substituted with carboxy,

(xxxix) the structure represented by formula [XI-2] below, which is substituted with carboxy,

(xxxx) the structure represented by formula [XI-3] below, which is substituted with carboxy,

(xxxxiii) the structure represented by formula [XI-6] below, which is substituted with carboxy,

(xxxxiv) C 2-4 alkylsulfonyl substituted with carboxy (when position α of the carboxy of the C 2-4 alkylsulfonyl substituted with carboxy is a methylene moiety, the methylene moiety may be replaced with propane-2,2-diyl),

(xxxxv) monoC 3 alkylaminosulfonyl substituted with carboxy (when position α of the carboxy of the monoC 3 alkylaminosulfonyl substituted with carboxy is a methylene moiety, the methylene moiety is replaced with propane-2,2-diyl),

(xxxxvi) di(C 1-3 alkyl)aminosulfonyl substituted with carboxy (when position α of the carboxy of the di(C 1-3 alkyl)aminosulfonyl substituted with carboxy is a methylene moiety, the methylene moiety is replaced with propane-2,2-diyl),

(xxxxvii) 5- to 6-membered saturated nitrogen-containing heterocyclylsulfonyl substituted with carboxy (the 5- to 6-membered saturated nitrogen-containing heterocyclyl of the 5- to 6-membered saturated nitrogen-containing heterocyclylsulfonyl substituted with carboxy may be substituted with one fluorine atom),

(xxxxviii) C 1 alkoxy substituted with carboxy (when position α of the carboxy of the C 1 alkoxy substituted with carboxy is a methylene moiety, the methylene moiety may be replaced with propane-2,2-diyl),

(xxxxix) hydroxy,

(xxxxx) C 1 alkylsulfonyloxy,

(xxxxxi) C 1-3 alkyl substituted with hydroxy,

(xxxxxii) halo-C 2-3 alkyl substituted with hydroxy,

(xxxxxiii) C 2-4 alkylsulfonyl substituted with hydroxy,

(xxxxxiv) C 4-5 cycloalkyl substituted with hydroxy (the C 4-5 cycloalkyl of the C 4-5 cycloalkyl substituted with hydroxy may be substituted with one group selected from the group consisting of carboxy and di(C 1 alkyl)aminocarbonyl), or

(xxxxxv) 4- to 6-membered saturated nitrogen-containing heterocyclyl substituted with hydroxy (the nitrogen atom of the 4- to 6-membered saturated nitrogen-containing heterocyclyl substituted with hydroxy is substituted with one group selected from the group consisting of C 1 alkylcarbonyl, C 1 alkoxycarbonyl, and di(C 1 alkyl)aminocarbonyl), wherein more preferably, R 61 and R 62 each independently represent a hydrogen atom, a fluorine atom, a chlorine atom, methyl, methoxy, or methylsulfonyl;

(d) when ring C is pyridyl,

more preferably, R 54 is

(i) carboxy,

(ii) carbamoyl,

(iii) C 1-3 alkyl substituted with carboxy (when position α of the carboxy of the C 1-3 alkyl substituted with carboxy is a methylene moiety, the methylene moiety may be replaced with propane-2,2-diyl),

(iv) C 2 alkoxy substituted with carboxy (when position α of the carboxy of the C 2 alkoxy substituted with carboxy is a methylene moiety, the methylene moiety is replaced with propane-2,2-diyl),

(v) monoC 3 alkylaminocarbonyl substituted with carboxy (when position α of the carboxy of the monoC 3 alkylaminocarbonyl substituted with carboxy is a methylene moiety, the methylene moiety is replaced with propane-2,2-diyl), or

(vi) 5-membered saturated nitrogen-containing heterocyclylcarbonyl substituted with carboxy (the 5-membered saturated nitrogen-containing heterocyclyl of the 5-membered saturated nitrogen-containing heterocyclylcarbonyl substituted with carboxy is substituted with one fluorine atom),

wherein more preferably, R 61 and R 62 are each a hydrogen atom;

(e) when ring C is pyrazolyl,

more preferably, R 54 is carboxy,

wherein more preferably, R 61 and R 62 are each a hydrogen atom;

(g) when ring C is tetrahydronaphthyl,

more preferably, R 54 is carboxy,

wherein more preferably, R 61 and R 62 are each a hydrogen atom;

(h) when ring C is chromanyl,

more preferably, R 54 is carboxy,

wherein more preferably, R 61 and R 62 are each a hydrogen atom;

(j) when ring C is indazolyl,

more preferably, R 54 is C 1 alkyl substituted with carboxy,

wherein more preferably, R 61 and R 62 are each a hydrogen atom;

(n) when ring C is the structure represented by formula [IX-1] above,

more preferably, R 54 is

(i) carboxy,

(ii) C 1 alkyl substituted with C 1 alkylsulfonylamino, or

(iii) C 1 alkyl substituted with C 1 alkylsulfonyl(C 1 alkyl)amino;

wherein more preferably, R 61 and R 62 represent a hydrogen atom;

(p) when ring C is the structure represented by formula [IX-2] above,

more preferably, R 54 is

(i) carboxy, or

(ii) C 2 alkyl substituted with carboxy,

wherein more preferably, R 61 and R 62 represent a hydrogen atom;

(q) when ring C is the structure represented by formula [IX-3] above,

more preferably, R 54 represents carboxy;

wherein more preferably, R 61 and R 62 represent a hydrogen atom;

(r) when ring C is the structure represented by formula [IX-4] above,

more preferably, R 54 represents carboxy;

wherein more preferably, R 61 and R 62 represent a hydrogen atom;

more preferably, W 4 is C 1-3 alkanediyl, or the formula —O—CH 2 CH 2 —.

Wherein, one even more preferred R 5 is as follows:

(A)

when R 5 represents the structure represented by formula [IV-1],

even more preferably, R 51 represents any of the structures represented by formula group [V′″] below:

even more preferably, W 1 represents butane-1,4-diyl or pentane-1,5-diyl;

(B)

when R 5 represents the structure represented by formula [IV-2],

even more preferably, R 52 represents carboxy;

even more preferably, L represents the structure represented by formula [VI-1], formula [VI-4], formula [VI-8], formula [VI-9], formula [VI-10], or formula [VI-12] below:

even more preferably, Y represents the formula —CH 2 —, the formula —CMe 2 -, the formula —O—, the formula —NHCO—, or the formula —CONMe-,

even more preferably, W 2 represents propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, or the formula —O—(CH 2 ) 6 —;

(C)

when R 5 is the structure represented by formula [IV-3];

even more preferably, R 53 represents carboxy, carboxymethyl (the methylene moiety of the carboxymethyl may be replaced with propane-2,2-diyl), or carboxymethoxy (the methylene moiety of the carboxymethoxy is replaced with propane-2,2-diyl);

even more preferably, ring B represents the structure represented by formula [VIII-1], formula [VIII-8], formula [VIII-9], formula [VIII-11], formula [VIII-12], formula [VIII-14], formula [VIII-B], or formula [VIII-7] below:

even more preferably, W 3 represents butane-1,4-diyl or hexane-1,6-diyl;

(D)

when R 5 is the structure represented by formula [IV-4],

even more preferably, ring C represents:

(a) C 3-6 cycloalkyl,

(b) 4- to 6-membered saturated nitrogen-containing heterocyclyl,

(c) phenyl,

(d) pyridyl,

(g) tetrahydronaphthyl,

(h) chromanyl,

(j) indazolyl,

(p) the structure represented by formula [IX-2] below,

(q) the structure represented by formula [IX-3] below, or

(r) the structure represented by formula [IX-4] below:

wherein

(a) when ring C represents C 3-6 cycloalkyl,

even more preferably, ring C is cyclopropyl, cyclobutyl, or cyclohexyl;

even more preferably, R 54 represents:

(i) carboxy,

(iv) methyl substituted with carboxy, or ethyl substituted with carboxy,

wherein even more preferably, R 61 and R 62 represent a hydrogen atom;

(b) when ring C is 4- to 6-membered saturated nitrogen-containing heterocyclyl,

even more preferably, ring C is pipieridin-3-yl;

even more preferably, R 54 represents:

(i) ethylcarbonyl substituted with carboxy, n-butylcarbonyl substituted with carboxy (the methylene moiety at position α of the carboxy of the n-butylcarbonyl substituted with carboxy is replaced with cyclopentane-1,1-diyl), or

(vii) phenylsulfonyl substituted with carboxy;

wherein even more preferably, R 61 and R 62 represent a hydrogen atom;

(c) when ring C is phenyl,

even more preferably, R 54 represents:

(i) carboxy,

(ii) carbamoyl,

(iii) n-propylaminocarbonyl,

(iv) methylaminosulfonyl,

(v) dimethylaminosulfonyl (one methyl of the dimethylaminosuflonyl is substituted with one phenyl,

wherein the phenyl is substituted with one methylaminosulfonyl),

(vii) isopropylsulfonylamino,

(viii) methylsulfonylaminocarbonyl,

(x) methyl substituted with carboxy (the methylene moiety at position α of the carboxy of the methyl substituted with carboxy may be replaced with ethane-1,1-diyl, propane-2,2-diyl, cyclopropane-1,1-diyl, tetrahydropyran-4,4-diyl, or piperidine-4,4-diyl,

wherein the nitrogen atom of the piperidine-4,4-diyl is substituted with one methylcarbonyl), ethyl substituted with carboxy, n-propyl substituted with carboxy, or n-butyl substituted with carboxy,

(xi) methyl substituted with methylsulfonylaminocarbonyl, or ethyl substituted with methylsulfonylaminocarbonyl,

(xii) methyl substituted with trifluoromethylsulfonylamino,

(xiv) ethyl substituted with methylaminocarbonyl (the methyl of the ethyl substituted with methylaminocarbonyl may be substituted with tetrahydrofuranyl), ethyl substituted with ethylaminocarbonyl (the ethyl of the ethylaminocarbonyl of the ethyl substituted with ethylaminocarbonyl is substituted with one group selected from the group consisting of hydroxy and methoxy), ethyl substituted with n-propylaminocarbonyl (the n-propyl of the ethyl substituted with n-propylaminocarbonyl may be substituted with one group selected from the group consisting of hydroxy and methoxy), or ethyl substituted with isopropylaminocarbonyl (the isopropyl of the ethyl substituted with isopropylaminocarbonyl is substituted with one hydroxy),

(xv) ethyl substituted with dimethylaminocarbonyl,

(xvi) ethyl substituted with oxetanylaminocarbonyl,

(xvii) ethyl substituted with azetidinylcarbonyl (the azetidinyl of the ethyl substituted with azetidinylcarbonyl may be substituted with one to two groups selected from the group consisting of hydroxy and a fluorine atom), or ethyl substituted with pyrrolidinylcarbonyl,

(xviii) halo-methyl substituted with carboxy,

(xix) ethenyl substituted with carboxy,

(xxi) cyclopropyl substituted with carboxy, or cyclohexyl substituted with carboxy,

(xxii) cyclopropyl substituted with dimethylaminocarbonyl,

(xxiii) piperidinyl substituted with carboxy,

(xxiv) phenyl substituted with carboxy,

(xxv) pyridyl substituted with carboxy,

(xxvi) pyrazolyl substituted with carboxy,

(xxvii) pyrazolyl substituted with carboxymethyl,

(xxviii) pyrimidinyl substituted with carboxy,

(xxix) pyrazinyl substituted with carboxy,

(xxx) 2-oxodihydropyridinyl substituted with carboxymethyl,

(xxxi) methylaminocarbonyl substituted with carboxy (the methyl of the methylaminocarbonyl substituted with carboxy may be substituted with one benzyl, and the methylene moiety at position α of the carboxy of the methylaminocarbonyl substituted with carboxy may be replaced with ethane-1,1-diyl), ethylaminocarbonyl substituted with carboxy (the ethyl of the ethylaminocarbonyl substituted with carboxy may be substituted with one phenyl, and the methylene moiety at position α of the carboxy of the ethylaminocarbonyl substituted with carboxy may be replaced with a structure selected from the group consisting of propane-2,2-diyl, cyclopropane-1,1-diyl, and cyclopentane-1,1-diyl), or n-propylaminocarbonyl substituted with carboxy (the methylene moiety at position α of the carboxy of the n-propylaminocarbonyl substituted with carboxy is replaced with propane-2,2-diyl),

(xxxii) phenylmethylaminocarbonyl substituted with carboxy,

(xxxiii) monomethylaminocarbonyl substituted with the structure represented by formula [V-6] below:

(xxxiv) ethyl(methyl)aminocarbonyl substituted with carboxy,

(xxxv) cyclobutylaminocarbonyl substituted with carboxy,

(xxxvi) pyrrolidinylcarbonyl substituted with carboxy (the pyrrolidinyl of the pyrrolidinylcarbonyl substituted with carboxy is substituted with one fluorine atom), or piperidinylcarbonyl substituted with carboxy,

(xxxviii) the structure represented by formula [XI-1] below, which is substituted with carboxy,

(xxxix) the structure represented by formula [XI-2] below, which is substituted with carboxy:

(xxxxiv) ethylsulfonyl substituted with carboxy, or n-butylsulfonyl substituted with carboxy (the methylene moiety at position α of carboxy of the n-butylsulfonyl substituted with carboxy is replaced with propane-2,2-diyl),

(xxxxv) mono-n-propylaminosulfonyl substituted with carboxy (the methylene moiety at position α of the carboxy of the mono-n-propylaminosuflonyl substituted with carboxy is replaced with propane-2,2-diyl),

(xxxxvi) n-propyl(methyl)aminosulfonyl substituted with carboxy (the methylene moiety at position α of the carboxy of the n-propyl(methyl)aminosulfonyl substituted with carboxy is replaced with propane-2,2-diyl),

(xxxxvii) pyrrolidinylsulfonyl substituted with carboxy (the pyrrolidinyl of the pyrrolidinylsulfonyl substituted with carboxy may be substituted with one fluorine atom), piperidinylsulfonyl substituted with carboxy, morpholinylsulfonyl substituted with carboxy,

(xxxxviii) methoxy substituted with carboxy (the methylene moiety at position α of the carboxy of the methoxy substituted with carboxy may be replaced with propane-2,2-diyl),

(xxxxix) hydroxy,

(xxxxxi) isopropyl substituted with hydroxy,

(xxxxxii) haloethyl substituted with hydroxy, halo-n-propyl substituted with hydroxy, haloisopropyl substituted with hydroxy,

(xxxxxiii) ethylsulfonyl substituted with hydroxy, isobutylsulfonyl substituted with hydroxy, or

(xxxxxiv) cyclobutyl substituted with hydroxy (the cyclobutyl of the cyclobutyl substituted with hydroxy may be substituted with one carboxy), cyclopentyl substituted with hydroxy; wherein even more preferably, R 61 and R 62 each independently represent a hydrogen atom, a fluorine atom, methyl, methoxy, or methylsulfonyl;

(d) when ring C is pyridyl,

even more preferably, ring C is pyridin-2-yl or pyridin-4-yl,

even more preferably, R 54 represents:

(i) carboxy,

(iii) n-propyl substituted with carboxy (the methylene moiety at position α of the carboxy of the n-propyl substituted with carboxy is replaced with propane-2,2-diyl),

(iv) ethoxy substituted with carboxy (the methylene moiety at position α of the carboxy of the ethoxy substituted with carboxy is replaced with propane-2,2-diyl), or

(v) mono-n-propylaminocarbonyl substituted with carboxy (the methylene moiety at position α of the carboxy of the mono-n-propylaminocarbonyl substituted with carboxy is replaced with propane-2,2-diyl);

wherein even more preferably, R 61 and R 62 represent a hydrogen atom;

(g) when ring C is tetrahydronaphthyl,

even more preferably, ring C represents the structure represented by formula [XII-1], formula [XII-2], or formula [XII-3] below:

even more preferably, R 54 represents carboxy;

wherein even more preferably, R 61 and R 62 represent a hydrogen atom;

(h) when ring C is chromanyl,

even more preferably, ring C represents the structure represented by formula [XIII-1] or formula [XIII-2] below:

even more preferably, R 54 represents carboxy;

wherein even more preferably, R 61 and R 62 represent a hydrogen atom;

(j) when ring C is indazolyl,

even more preferably, R 54 represents methyl substituted with carboxy,

wherein even more preferably, R 61 and R 62 represent a hydrogen atom;

(p) when ring C is the structure represented by formula [IX-2] above,

even more preferably, R 54 represents:

(i) carboxy, or

(ii) ethyl substituted with carboxy,

wherein even more preferably, R 61 and R 62 represent a hydrogen atom;

(q) when ring C is the structure represented by formula [IX-3] above,

even more preferably, R 54 represents carboxy;

wherein even more preferably, R 61 and R 62 represent a hydrogen atom;

(r) when ring C is the structure represented by formula [IX-4] above,

even more preferably, R 54 represents carboxy;

wherein even more preferably, R 61 and R 62 represent a hydrogen atom;

even more preferably, W 4 represents methanediyl, ethane-1,2-diyl, propane-1,3-diyl, or the formula —O—CH 2 CH 2 —.

Wherein, another even more preferred R 5 is as follows:

(A)

when R 5 represents the structure represented by formula [IV-1],

even more preferably, R 51 represents the structure represented by formula [V-6] below:

even more preferably, W 1 represents butane-1,4-diyl;

(B)

when R 5 represents the structure represented by formula [IV-2],

even more preferably, R 52 represents carboxy;

even more preferably, L represents the structure represented by formula [VI-1], formula [VI-4], formula [VI-8], formula [VI-9], or formula [VI-10] below:

even more preferably, Y represents the formula —CH 2 —, the formula —O—, or the formula —CONMe-;

even more preferably, W 2 represents pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, or the formula —O—(CH 2 ) 6 —;

(C)

when R 5 is the structure represented by formula [IV-3];

even more preferably, R 53 represents carboxy;

even more preferably, ring B represents the structure represented by formula [VIII-1], formula [VIII-8], formula [VIII-9], or formula [VIII-7] below:

even more preferably, W 3 represents butane-1,4-diyl, or hexane-1,6-diyl;

(D)

when R 5 is the structure represented by formula [IV-4], even more preferably, ring C represents:

(a) C 3-6 cycloalkyl,

(b) 4- to 6-membered saturated nitrogen-containing heterocyclyl,

(c) phenyl,

(d) pyridyl,

(g) tetrahydronaphthyl, or

(h) chromanyl;

wherein

(a) when ring C represents C 3-6 cycloalkyl,

even more preferably, ring C is cyclohexyl;

even more preferably, R 54 represents carboxy;

wherein even more preferably, R 61 and R 62 represent a hydrogen atom;

(b) when ring C is 4- to 6-membered saturated nitrogen-containing heterocyclyl, even more preferably, ring C is pipieridin-3-yl;

even more preferably, R 54 represents:

(i) n-butylcarbonyl substituted with carboxy (the methylene moiety at position α of the carboxy of the n-butylcarbonyl substituted with carboxy is replaced with cyclopentane-1,1-diyl), or

(vii) phenylsulfonyl substituted with carboxy;

wherein even more preferably, R 61 and R 62 represent a hydrogen atom;

(c) when ring C is phenyl,

even more preferably, R 54 represents:

(i) carboxy,

(ii) carbamoyl,

(iii) n-propylaminocarbonyl,

(iv) methylaminosulfonyl,

(v) dimethylaminosulfonyl (one methyl of the dimethylaminosuflonyl is substituted with one phenyl,

wherein the phenyl is substituted with one methylaminosulfonyl),

(vii) isopropylsulfonylamino,

(x) methyl substituted with carboxy, ethyl substituted with carboxy, or n-propyl substituted with carboxy,

(xii) methyl substituted with trifluoromethylsulfonylamino,

(xiv) ethyl substituted with methylaminocarbonyl (the methyl of the ethyl substituted with methylaminocarbonyl may be substituted with one tetrahydrofuranyl), ethyl substituted with ethylaminocarbonyl (the ethyl of the ethylaminocarbonyl of the ethyl substituted with ethylaminocarbonyl is substituted with one group selected from the group consisting of hydroxy and methoxy), ethyl substituted with n-propylaminocarbonyl (the n-propyl of the ethyl substituted with n-propylaminocarbonyl may be substituted with one group selected from the group consisting of hydroxy and methoxy), or ethyl substituted with isopropylaminocarbonyl (the isopropyl of the ethyl substituted with isopropylaminocarbonyl is substituted with one group selected from the group consisting of hydroxy and methoxy),

(xv) ethyl substituted with dimethylaminocarbonyl,

(xvi) C 1-4 alkylethyl substituted with oxetanylaminocarbonyl,

(xvii) ethyl substituted with azetidinylcarbonyl (the azetidinyl of the ethyl substituted with azetidinylcarbonyl may be substituted with one hydroxy or one to two fluorine atoms), or ethyl substituted with pyrrolidinylcarbonyl,

(xix) ethenyl substituted with carboxy,

(xxi) cyclopropyl substituted with carboxy, or cyclohexyl substituted with carboxy,

(xxii) cyclopropyl substituted with dimethylaminocarbonyl,

(xxiv) phenyl substituted with carboxy,

(xxv) pyridyl substituted with carboxy,

(xxvi) pyrazolyl substituted with carboxy,

(xxvii) pyrazolyl substituted with carboxymethyl,

(xxix) pyrazinyl substituted with carboxy,

(xxx) 2-oxodihydropyridinyl substituted with carboxymethyl,

(xxxi) ethylaminocarbonyl substituted with carboxy (the methylene moiety at position α of the carboxy of the ethylaminocarbonyl substituted with carboxy is replaced with cyclopentane-1,1-diyl), n-propylaminocarbonyl substituted with carboxy (the methylene moiety at position α of the carboxy of the n-propylaminocarbonyl substituted with carboxy is replaced with propane-2,2-diyl),

(xxxii) phenylmethylaminocarbonyl substituted with carboxy,

(xxxiii) methylaminocarbonyl substituted with the structure represented by formula [V-6] below:

(xxxvi) pyrrolidinylcarbonyl substituted with carboxy (the pyrrolidinyl of the pyrrolidinylcarbonyl substituted with carboxy is substituted with one fluorine atom),

(xxxix) the structure represented by formula [XI-2] below, which is substituted with carboxy:

(xxxxiv) n-butylsulfonyl substituted with carboxy (the methylene moiety at position α of carboxy of the n-butylsulfonyl substituted with carboxy is replaced with propane-2,2-diyl),

(xxxxvi) n-propyl(methyl)aminosulfonyl substituted with carboxy (the methylene moiety at position α of the carboxy of the n-propyl(methyl)aminosulfonyl substituted with carboxy is replaced with propane-2,2-diyl),

(xxxxvii) piperidinylsulfonyl substituted with carboxy, pyrrolidinylsulfonyl substituted with carboxy (the pyrrolidinyl of the pyrrolidinylsulfonyl substituted with carboxy is substituted with one fluorine atom),

(xxxxix) hydroxy,

(xxxxxi) isopropyl substituted with hydroxy,

(xxxxxii) haloethyl substituted with hydroxy, halo-n-propyl substituted with hydroxy, haloisopropyl substituted with hydroxy,

(xxxxxiii) ethylsulfonyl substituted with hydroxy, isobutylsulfonyl substituted with hydroxy, or

(xxxxxiv) cyclobutyl substituted with hydroxy (the cyclobutyl of the cyclobutyl substituted with hydroxy may be substituted with one carboxy), cyclopentyl substituted with hydroxy; wherein even more preferably, R 61 and R 62 each independently represent a hydrogen atom, a fluorine atom, or methylsulfonyl;

(d) when ring C is pyridyl,

even more preferably, ring C is pyridin-4-yl;

even more preferably, R 54 represents ethoxy substituted with carboxy (the methylene moiety at position α of the carboxy of the ethoxy substituted with carboxy is replaced with propane-2,2-diyl);

wherein even more preferably, R 61 and R 62 represent a hydrogen atom;

(g) when ring C is tetrahydronaphthyl,

even more preferably, ring C represents the structure represented by formula [XII-1] or formula [XII-2] below:

even more preferably, R 54 represents carboxy;

wherein even more preferably, R 61 and R 62 represent a hydrogen atom;

(h) when ring C is chromanyl,

even more preferably, ring C represents the structure represented by formula [XIII-1] or formula [XIII-2] below:

even more preferably, R 54 represents carboxy;

wherein even more preferably, R 61 and R 62 represent a hydrogen atom;

even more preferably, W 4 represents methanediyl, ethane-1,2-diyl, or propane-1,3-diyl.

Other preferred embodiments of the compounds of the present invention are as follows:

Preferred embodiments of R 1 , R 2 , R 3 , R 4 , and ring A in formula [1] above are as described above.

Other preferred examples of R 5 are as follows:

(A)

when R 5 is the structure represented by formula [IV-1], another preferred example of R 51 is any of the structures represented by formula group [V-b] shown below:

another preferred example of W 1 is C 4-10 alkanediyl;

(B)

when R 5 is the structure represented by formula [IV-2],

another preferred example of R 52 is carboxy;

another preferred example of L is any of the structures represented by formula group [VI-b] shown below:

wherein

another preferred example of ring D is

(i) C 5-6 cycloalkane,

(ii) 4- to 6-membered saturated oxygen-containing hetero ring, or

(iv) 4- to 6-membered saturated nitrogen-containing hetero ring (the nitrogen atom of the 4- to 6-membered saturated nitrogen-containing hetero ring may be substituted with one C 1-4 alkylcarbonyl);

another preferred example of Y is the formula —CH 2 —, the formula —O—, the formula —CONH—, or the formula —CONMe-;

another preferred example of W 2 is C 5-8 alkanediyl, wherein one of the carbon atoms that constitute C 5-8 alkanediyl represented by W 2 may be replaced with an oxygen atom;

(C)

when R 5 is the structure represented by formula [IV-3],

another preferred example of R 53 is carboxy or carboxymethoxy;

another preferred example of ring B is any of the structures represented by formula group [VIII″] shown below:

another preferred example of W 3 is C 4-8 alkanediyl;

(D)

when R 5 is the structure represented by formula [IV-4],

another preferred example of ring C is

(a) C 3-6 cycloalkyl,

(b) 4- to 6-membered saturated nitrogen-containing heterocyclyl,

(c) phenyl,

(d) pyridyl,

(g) tetrahydronaphthyl,

(h) chromanyl,

(k) tetrahydroisoquinolyl,

(m) 2-oxotetrahydroisoquinolyl, or

(n) the structure represented by formula [IX-1] below:

wherein (a) when ring C is C 3-6 cycloalkyl,

another preferred example of R 54 is

(i) carboxy;

wherein another preferred example of R 61 and R 62 is a hydrogen atom;

(b) when ring C is 4- to 6-membered saturated nitrogen-containing heterocyclyl, another preferred example of R 54 is

(i) C 1-4 alkylcarbonyl substituted with carboxy (when position α of the carboxy of the C 1-4 alkylcarbonyl substituted with carboxy is a methylene moiety, the methylene moiety may be replaced with propane-2,2-diyl or cyclopentane-1,1-diyl),

(ii) C 1-4 alkylcarbonyl substituted with sulfamoyl,

(iii) C 1-4 alkylcarbonyl substituted with C 1-4 alkylsulfonylamino,

(v) phenylcarbonyl substituted with sulfamoyl,

(vii) phenylsulfonyl substituted with carboxy, or

(x) the structure represented by formula [X-2] below, which is substituted with carboxy:

wherein another preferred example of R 61 and R 62 is a hydrogen atom;

(c) when ring C is phenyl,

another preferred example of R 54 is

(i) carboxy,

(ii) carbamoyl,

(iii) monoC 1-4 alkylaminocarbonyl (the C 1-4 alkyl of the monoC 1-4 alkylaminocarbonyl may be substituted with one hydroxy),

(iv) monoC 1-4 alkylaminosulfonyl (the C 1-4 alkyl of the monoC 1-4 alkylaminosulfonyl may be substituted with one indolyl),

(v) di(C 1-4 alkyl)aminosulfonyl (one C 1-4 alkyl of the di(C 1-4 alkyl)aminosulfonyl may be substituted with one phenyl, wherein the phenyl may be substituted with one monoC 1-4 alkylaminosulfonyl),

(vi) phenylaminosulfonyl (the phenyl of the phenylaminosulfonyl may be substituted with one fluorine atom),

(vii) C 1-4 alkylsulfonylamino,

(ix) C 1-4 alkylsulfonyl(C 1-4 alkyl)aminocarbonyl,

(x) C 1-4 alkyl substituted with carboxy,

(xii) C 1-4 alkyl substituted with trifluoromethylsulfonylamino,

(xiii) C 1-4 alkyl substituted with methylsulfonyl(methyl)aminocarbonyl,

(xiv) C 1-4 alkyl substituted with monoC 1-4 alkylaminocarbonyl (the C 1-4 alkyl of the monoC 1-4 alkylaminocarbonyl of the C 1-4 alkyl substituted with monoC 1-4 alkylaminocarbonyl may be substituted with one group selected from the group consisting of hydroxy, C 1-4 alkoxy, 4- to 6-membered saturated oxygen-containing heterocyclyl, di(C 1-4 alkyl)amino, and 4- to 6-membered saturated nitrogen-containing heterocyclylcarbonyl),

(xv) C 1-4 alkyl substituted with di(C 1-4 alkyl)aminocarbonyl (one C 1-4 alkyl of di(C 1-4 alkyl)aminocarbonyl of the C 1-4 alkyl substituted with di(C 1-4 alkyl)aminocarbonyl may be substituted with one hydroxy),

(xvi) C 1-4 alkyl substituted with 4- to 6-membered saturated oxygen-containing heterocyclylaminocarbonyl,

(xvii) C 1-4 alkyl substituted with 4- to 6-membered saturated nitrogen-containing heterocyclylcarbonyl (the 4- to 6-membered saturated nitrogen-containing heterocyclyl of the C 1-4 alkyl substituted with 4- to 6-membered saturated nitrogen-containing heterocyclylcarbonyl may be substituted with one or two groups selected from the group consisting of hydroxy and a fluorine atom),

(xix) C 2-4 alkenyl substituted with carboxy,

(xx) C 2-4 alkenyl substituted with di(C 1-4 alkyl)aminocarbonyl,

(xxi) C 3-6 cycloalkyl substituted with carboxy,

(xxii) C 3-6 cycloalkyl substituted with di(C 1-4 alkyl)aminocarbonyl,

(xxiv) phenyl substituted with carboxy,

(xxv) pyridyl substituted with carboxy,

(xxvi) pyrazolyl substituted with carboxy,

(xxvii) pyrazolyl substituted with carboxymethyl,

(xxix) pyrazinyl substituted with carboxy,

(xxx) 2-oxodihydropyridinyl substituted with carboxymethyl,

(xxxi) monoC 1-4 alkylaminocarbonyl substituted with carboxy (the C 1-4 alkyl of the monoC 1-4 alkylaminocarbonyl substituted with carboxy may be substituted with benzyl, and when position α of the carboxy of the monoC 1-4 alkylaminocarbonyl substituted with carboxy is a methylene moiety, the methylene moiety may be replaced with a structure selected from the group consisting of propane-2,2-diyl and cyclopentane-1,1-diyl),

(xxxii) phenylC 1-4 alkylaminocarbonyl substituted with carboxy,

(xxxiii) monoC 1-4 alkylaminocarbonyl substituted with the structure represented by formula [V-6] below:

(xxxiv) di(C 1-4 alkyl)aminocarbonyl substituted with carboxy (when position α of the carboxy of the di(C 1-4 alkyl)aminocarbonyl substituted with carboxy is a methylene moiety, the methylene moiety may be replaced with propane-2,2-diyl),

(xxxvi) 4- to 6-membered saturated nitrogen-containing heterocyclylcarbonyl substituted with carboxy (the 4- to 6-membered saturated nitrogen-containing heterocyclyl of the 4- to 6-membered saturated nitrogen-containing heterocyclylcarbonyl substituted with carboxy may be substituted with one fluorine atom),

(xxxix) the structure represented by formula [XI-2] below, which is substituted with carboxy,

(xxxx) the structure represented by formula [XI-3] below, which is substituted with carboxy:

(xxxxiv) C 1-4 alkylsulfonyl substituted with carboxy (when position α of the carboxy of the C 1-4 alkylsulfonyl substituted with carboxy is a methylene moiety, the methylene moiety may be replaced with propane-2,2-diyl),

(xxxxvi) di(C 1-4 alkyl)aminosulfonyl substituted with carboxy (when position α of the carboxy of the di(C 1-4 alkyl)aminosulfonyl substituted with carboxy is a methylene moiety, the methylene moiety may be replaced with propane-2,2-diyl),

(xxxxvii) 4- to 6-membered saturated nitrogen-containing heterocyclylsulfonyl substituted with carboxy (the 4- to 6-membered saturated nitrogen-containing heterocyclyl of the 4- to 6-membered saturated nitrogen-containing heterocyclylsulfonyl substituted with carboxy may be substituted with one fluorine atom),

(xxxxix) hydroxy,

(xxxxx) C 1-4 alkylsulfonyloxy,

(xxxxxi) C 1-4 alkyl substituted with hydroxy,

(xxxxxii) halo-C 1-4 alkyl substituted with hydroxy,

(xxxxxiii) C 1-4 alkylsulfonyl substituted with hydroxy,

(xxxxxiv) C 3-6 cycloalkyl substituted with hydroxy (the C 3-6 cycloalkyl of the C 3-6 cycloalkyl substituted with hydroxy may be substituted with one group selected from the group consisting of carboxy and di(C 1-4 alkyl)aminocarbonyl), or

(xxxxxv) 4- to 6-membered saturated nitrogen-containing heterocyclyl substituted with hydroxy (the nitrogen atom of the 4- to 6-membered saturated nitrogen-containing heterocyclyl substituted with hydroxy may be substituted with one group selected from the group consisting of C 1-4 alkylcarbonyl, C 1-4 alkoxycarbonyl, and di(C 1-4 alkyl)aminocarbonyl), wherein another preferred example of R 61 and R 62 is each independently a hydrogen atom, a fluorine atom, methyl, or methylsulfonyl;

(d) when ring C is pyridyl,

another preferred example of R 54 is

(ii) carbamoyl,

(iii) C 1-4 alkyl substituted with carboxy,

(iv) C 1-4 alkoxy substituted with carboxy (when position α of the carboxy of the C 1-4 alkoxy substituted with carboxy is a methylene moiety, the methylene moiety may be replaced with propane-2,2-diyl),

(v) monoC 1-4 alkylaminocarbonyl substituted with carboxy (when position α of the carboxy of the monoC 1-4 alkylaminocarbonyl substituted with carboxy is a methylene moiety, the methylene moiety may be replaced with propane-2,2-diyl), or

(vi) 4- to 6-membered saturated nitrogen-containing heterocyclylcarbonyl substituted with carboxy (the 4- to 6-membered saturated nitrogen-containing heterocyclyl of the 4- to 6-membered saturated nitrogen-containing heterocyclylcarbonyl substituted with carboxy may be substituted with one fluorine atom);

wherein another preferred example of R 61 and R 62 is a hydrogen atom;

(g) when ring C is tetrahydronaphthyl,

another preferred example of R 54 is carboxy,

wherein another preferred example of R 61 and R 62 is a hydrogen atom;

(h) when ring C is chromanyl,

another preferred example of R 54 is carboxy,

wherein another preferred example of R 61 and R 62 is a hydrogen atom;

(k) when ring C is tetrahydroisoquinolyl,

another preferred example of R 54 is C 1-4 alkylcarbonyl substituted with carboxy (when c position of the carboxy of the C 1-4 alkylcarbonyl substituted with carboxy is a methylene moiety, the methylene moiety may be replaced with propane-2,2-diyl),

wherein another preferred example of R 61 and R 62 is a hydrogen atom;

(m) when ring C is 2-oxotetrahydroisoquinolyl,

another preferred example of R 54 is C 1-4 alkyl substituted with carboxy (when position α of the carboxy of the C 1-4 alkyl substituted with carboxy is a methylene moiety, the methylene moiety may be replaced with propane-2,2-diyl);

wherein another preferred example of R 61 and R 62 is a hydrogen atom;

(n) when ring C is the structure represented by formula [IX-1] above, another preferred example of R 54 is

(ii) C 1-4 alkyl substituted with C 1-4 alkylsulfonylamino, or

(iii) C 1-4 alkyl substituted with C 1-4 alkylsulfonyl(C 1-4 alkyl)amino;

wherein another preferred example of R 61 and R 62 is a hydrogen atom;

another preferred example of W 4 is C 1-3 alkanediyl.

Here, more preferably, R 5 is as follows:

(A)

when R 5 is the structure represented by formula [IV-1],

more preferably, R 51 is any of the structures represented by formula group [V-b] shown below:

more preferably, W 1 is C 4-6 alkanediyl;

(B)

when R 5 is the structure represented by formula [IV-2],

more preferably, R 52 is carboxy;

more preferably, L is any of the structures represented by formula group [VI-b] shown below:

wherein

more preferably, ring D is

(i) C 5-6 cycloalkane,

(ii) 6-membered saturated oxygen-containing hetero ring, or

(iv) 6-membered saturated nitrogen-containing hetero ring (the nitrogen atom of the 6-membered saturated nitrogen-containing hetero ring is substituted with one C 1 alkylcarbonyl);

more preferably, Y is the formula —CH 2 —, the formula —O—, the formula —CONH—, or the formula —CONMe-;

more preferably, W 2 is C 5-8 alkanediyl, wherein one of the carbon atoms that constitute C 5-8 alkanediyl represented by W 2 may be replaced with an oxygen atom;

(C)

when R 5 is the structure represented by formula [IV-3],

more preferably, R 53 is carboxy;

more preferably, ring B is any of the structures represented by formula group [VIII-b] shown below:

more preferably, W 3 is C 4-6 alkanediyl;

(D)

when R 5 is the structure represented by formula [IV-4],

more preferably, ring C is

(a) C 3-6 cycloalkyl,

(b) 4- to 6-membered saturated nitrogen-containing heterocyclyl,

(c) phenyl,

(d) pyridyl,

(g) tetrahydronaphthyl,

(h) chromanyl,

(k) tetrahydroisoquinolyl,

(m) 2-oxotetrahydroisoquinolyl, or

(n) the structure represented by formula [IX-1] below:

wherein (a) when ring C is C 3-6 cycloalkyl,

more preferably, ring C is C 6 cycloalkyl;

more preferably, R 54 is carboxy;

wherein more preferably, R 61 and R 62 are each a hydrogen atom;

(b) when ring C is 4- to 6-membered saturated nitrogen-containing heterocyclyl, more preferably, ring C is 6-membered saturated nitrogen-containing heterocyclyl; more preferably, R 54 is

(i) C 2-4 alkylcarbonyl substituted with carboxy (when position α of the carboxy of the C 2-4 alkylcarbonyl substituted with carboxy is a methylene moiety, the methylene moiety is replaced with a structure selected from the group consisting of propane-1,1-diyl and cyclopentane-1,1-diyl),

(ii) C 3 alkylcarbonyl substituted with sulfamoyl,

(iii) C 1 alkylcarbonyl substituted with C 2 alkylsulfonylamino,

(v) phenylcarbonyl substituted with sulfamoyl,

(vii) phenylsulfonyl substituted with carboxy, or

(x) the structure represented by formula [X-2] below, which is substituted with carboxy:

wherein more preferably, R 61 and R 62 are each a hydrogen atom;

(c) when ring C is phenyl,

more preferably, R 54 is

(i) carboxy,

(ii) carbamoyl,

(iii) monoC 1-3 alkylaminocarbony (the C 1-3 alkyl of the monoC 1-3 alkylaminocarbonyl may be substituted with one hydroxy),

(iv) monoC 1-2 alkylaminosulfonyl (the C 1-2 alkyl of the monoC 1-2 alkylaminosulfonyl may be substituted with one indolyl),

(iv) monoC 2 alkylaminosulfonyl (the C 2 alkyl of the monoC 2 alkylaminosulfonyl is substituted with one indolyl),

(v) di(C 1 alkyl)aminosulfonyl (the one C 1 alkyl of the di(C 1 alkyl)aminosulfonyl is substituted with one phenyl, wherein the phenyl is substituted with one monoC 1 alkylaminosulfonyl),

(vi) phenylaminosulfonyl (the phenyl of the phenylaminosulfonyl is substituted with one fluorine atom),

(vii) C 3 alkylsulfonylamino,

(ix) C 1 alkylsulfonyl(C 1 alkyl)aminocarbonyl,

(x) C 1-3 alkyl substituted with carboxy,

(xii) C 1 alkyl substituted with trifluoromethylsulfonylamino,

(xiii) C 1-2 alkyl substituted with methylsulfonyl(methyl)aminocarbonyl,

(xiv) C 1-2 alkyl substituted with monoC 1-3 alkylaminocarbonyl (the C 1-3 alkyl of the monoC 1-3 alkylaminocarbonyl of the C 1-2 alkyl substituted with monoC 1-3 alkylaminocarbonyl may be substituted with one group selected from the group consisting of hydroxy, C 1 alkoxy, 5-membered saturated oxygen-containing heterocyclyl, di(C 1 alkyl)amino, and 5-membered saturated nitrogen-containing heterocyclylcarbonyl),

(xv) C 1-2 alkyl substituted with di(C 1-2 alkyl)aminocarbonyl (one C 1-2 alkyl of the di(C 1-2 alkyl)aminocarbonyl may be substituted with one hydroxy),

(xvi) C 2 alkyl substituted with 4-membered saturated oxygen-containing heterocyclylaminocarbonyl,

(xvii) C 2 alkyl substituted with 4- to 6-membered saturated nitrogen-containing heterocyclylcarbonyl (the 4- to 6-membered saturated nitrogen-containing heterocyclyl of the C 2 alkyl substituted with 4- to 6-membered saturated nitrogen-containing heterocyclylcarbonyl may be substituted with one hydroxy or one or two fluorine atoms),

(xix) C 2 alkenyl substituted with carboxy,

(xx) C 2 alkenyl substituted with di(C 1 alkyl)aminocarbonyl,

(xxi) C 3-6 cycloalkyl substituted with carboxy,

(xxii) C 3 cycloalkyl substituted with di(C 1 alkyl)aminocarbonyl,

(xxiv) phenyl substituted with carboxy,

(xxv) pyridyl substituted with carboxy,

(xxvi) pyrazolyl substituted with carboxy,

(xxvii) pyrazolyl substituted with carboxymethyl,

(xxix) pyrazinyl substituted with carboxy,

(xxx) 2-oxodihydropyridinyl substituted with carboxymethyl,

(xxxi) monoC 1-3 alkylaminocarbonyl substituted with carboxy (the C 1-3 alkyl of the monoC 1-3 alkylaminocarbonyl substituted with carboxy may be substituted with one benzyl, and when position α of the carboxy of the monoC 1-3 alkylaminocarbonyl substituted with carboxy is a methylene moiety, the methylene moiety may be replaced with a structure selected from the group consisting of propane-2,2-diyl and cyclopentane-1,1-diyl),

(xxxii) phenylC 1 alkylaminocarbonyl substituted with carboxy,

(xxxiii) monoC 1 alkylaminocarbonyl substituted with the structure represented by formula [V-6] below:

(xxxiv) di(C 1-3 alkyl)aminocarbonyl substituted with carboxy (when position α of the carboxy of the di(C 1-3 alkyl)aminocarbonyl substituted with carboxy is a methylene moiety, the methylene moiety is replaced with propane-2,2-diyl),

(xxxvi) 5-membered saturated nitrogen-containing heterocyclylcarbonyl substituted with carboxy (the 5-membered saturated nitrogen-containing heterocyclyl of the 5-membered saturated nitrogen-containing heterocyclylcarbonyl substituted with carboxy is substituted with one fluorine atom),

(xxxix) the structure represented by formula [XI-2] below, which is substituted with carboxy,

(xxxx) the structure represented by formula [XI-3] below, which is substituted with carboxy,

(xxxxiv) C 4 alkylsulfonyl substituted with carboxy (when position α of the carboxy of the C 4 alkylsulfonyl substituted with carboxy is a methylene moiety, the methylene moiety is replaced with propane-2,2-diyl),

(xxxxvi) di(C 1-3 alkyl)aminosulfonyl substituted with carboxy (when position α of the carboxy of the di(C 1-3 alkyl)aminosulfonyl substituted with carboxy is a methylene moiety, the methylene moiety is replaced with propane-2,2-diyl),

(xxxxvii) 5- to 6-membered saturated nitrogen-containing heterocyclylsulfonyl substituted with carboxy (the 5- to 6-membered saturated nitrogen-containing heterocyclyl of the 5- to 6-membered saturated nitrogen-containing heterocyclylsulfonyl substituted with carboxy may be substituted with one fluorine atom),

(xxxxix) hydroxy,

(xxxxx) C 1 alkylsulfonyloxy,

(xxxxxi) C 1-3 alkyl substituted with hydroxy,

(xxxxxii) halo-C 2-3 alkyl substituted with hydroxy,

(xxxxxiii) C 2-4 alkylsulfonyl substituted with hydroxy,

(xxxxxiv) C 4-5 cycloalkyl substituted with hydroxy (the C 4-5 cycloalkyl of the C 4-5 cycloalkyl substituted with hydroxy may be substituted with one group selected from the group consisting of carboxy and di(C 1 alkyl)aminocarbonyl), or

(xxxxxv) 4- to 6-membered saturated nitrogen-containing heterocyclyl substituted with hydroxy (the nitrogen atom of the 4- to 6-membered saturated nitrogen-containing heterocyclyl substituted with hydroxy is substituted with one group selected from the group consisting of C 1 alkylcarbonyl, C 1 alkoxycarbonyl, and di(C 1 alkyl)aminocarbonyl); wherein more preferably, R 61 and R 62 are each independently a hydrogen atom, a fluorine atom, methyl, or methylsulfonyl;

(d) when ring C is pyridyl,

more preferably, R 54 is

(ii) carbamoyl,

(iii) C 1 alkyl substituted with carboxy,

(iv) C 2 alkoxy substituted with carboxy (when position α of the carboxy of the C 2 alkoxy substituted with carboxy is a methylene moiety, the methylene moiety is replaced with propane-2,2-diyl),

(v) monoC 3 alkylaminocarbonyl substituted with carboxy (when position α of the carboxy of the monoC 3 alkylaminocarbonyl substituted with carboxy is a methylene moiety, the methylene moiety is replaced with propane-2,2-diyl), or

(vi) 5-membered saturated nitrogen-containing heterocyclylcarbonyl substituted with carboxy (the 5-membered saturated nitrogen-containing heterocyclyl of the 5-membered saturated nitrogen-containing heterocyclylcarbonyl substituted with carboxy is substituted with one fluorine atom);

wherein more preferably, R 61 and R 62 are each a hydrogen atom;

(g) when ring C is tetrahydronaphthyl,

more preferably, R 54 is carboxy;

wherein more preferably, R 61 and R 62 are each a hydrogen atom;

(h) when ring C is chromanyl,

more preferably, R 54 is carboxy;

wherein more preferably, R 61 and R 62 are a hydrogen atom;

(k) when ring C is tetrahydroisoquinolyl,

more preferably, R 54 is C 1 alkylcarbonyl substituted with carboxy (the methylene moiety at position α of the carboxy of the C 1 alkylcarbonyl substituted with carboxy is replaced with propane-2,2-diyl);

wherein more preferably, R 61 and R 62 are each a hydrogen atom;

(m) when ring C is 2-oxotetrahydroisoquinolyl,

more preferably, R 54 is C 3 alkyl substituted with carboxy (when position α of the carboxy of the C 3 alkyl substituted with carboxy is a methylene moiety, the methylene moiety is replaced with propane-2,2-diyl);

wherein more preferably, R 61 and R 62 are each a hydrogen atom;

(n) when ring C is the structure represented by formula [IX-1] above, more preferably, R 54 is

(ii) C 1 alkyl substituted with C 1 alkylsulfonylamino, or

(iii) C 1 alkyl substituted with C 1 alkylsulfonyl(C 1 alkyl)amino;

wherein more preferably, R 61 and R 62 are each a hydrogen atom;

more preferably, W 4 is C 1-3 alkanediyl.

Here, even more preferably, R 5 is as follows:

(A)

when R 5 is the structure represented by formula [IV-1],

even more preferably, R 51 is the structure represented by formula [V-2] shown below:

even more preferably, W 1 is hexane-1,6-diyl;

(B)

when R 5 is the structure represented by formula [IV-2],

even more preferably, R 52 is carboxy;

even more preferably, L is a structure represented by formula [VI-1], formula [VI-4], formula [VI-8], formula [VI-10], or formula [VI-11] shown below:

even more preferably, Y is the formula —CH 2 — or the formula —O—;

even more preferably, W 2 is hexane-1,6-diyl, heptane-1,7-diyl, or octane-1,8-diyl;

(C)

when R 5 is the structure represented by formula [IV-3],

even more preferably, R 53 is carboxy;

even more preferably, ring B is the structure represented by formula [VIII-10] shown below:

even more preferably, W 3 is butane-1,4-diyl;

(D)

when R 5 is the structure represented by formula [IV-4],

even more preferably, ring C is

(b) 4- to 6-membered saturated nitrogen-containing heterocyclyl,

(c) phenyl,

(d) pyridyl,

(g) tetrahydronaphthyl,

(h) chromanyl,

(k) tetrahydroisoquinolyl,

(m) 2-oxotetrahydroisoquinolyl, or

(n) the structure represented by formula [IX-1] below:

(b) when ring C is 4- to 6-membered saturated nitrogen-containing heterocyclyl, even more preferably, ring C is piperidine-3-yl or piperidine-4-yl;

even more preferably, R 54 is

(i) ethylcarbonyl substituted with carboxy (the methylene moiety at position α of the carboxy of the ethylcarbonyl substituted with carboxy is replaced with propane-2,2-diyl), n-butylcarbonyl substituted with carboxy (the methylene moiety at position α of the carboxy of the n-butylcarbonyl substituted with carboxy is replaced with cyclopentane-1,1-diyl), or

(vii) phenylsulfonyl substituted with carboxy,

wherein even more preferably, R 61 and R 62 are each a hydrogen atom;

(c) when ring C is phenyl,

even more preferably, R 54 is

(ii) carbamoyl,

(iii) methylaminocarbonyl, n-propylaminocarbonyl,

(iv) ethylaminosulfonyl (the ethyl of the ethylaminosulfonyl is substituted with one indolyl),

(v) dimethylaminosulfonyl (one methyl of the dimethylaminosulfonyl is substituted with one phenyl, wherein the phenyl is substituted with one methylaminosulfonyl),

(vi) phenylaminosulfonyl (the phenyl of the phenylaminosulfonyl is substituted with one fluorine atom),

(ix) methylsulfonyl(methyl)aminocarbonyl,

(x) n-propyl substituted with carboxy,

(xii) methyl substituted with trifluoromethylsulfonylamino,

(xiii) ethyl substituted with methylsulfonyl(methyl)aminocarbonyl,

(xiv) methyl substituted with methylaminocarbonyl, methyl substituted with n-propylaminocarbonyl, ethyl substituted with methylaminocarbonyl (the methyl of the ethyl substituted with methylaminocarbonyl may be substituted with one group selected from the group consisting of tetrahydrofuranyl and piperidinylcarbonyl), ethyl substituted with ethylaminocarbonyl (the ethyl of the ethylaminocarbonyl of the ethyl substituted with ethylaminocarbonyl is substituted with one group selected from the group consisting of hydroxy and methoxy), ethyl substituted with n-propylaminocarbonyl (the n-propyl of the ethyl substituted with n-propylaminocarbonyl may be substituted with one group selected from the group consisting of hydroxy and methoxy), ethyl substituted with isopropylaminocarbonyl (the isopropyl of the ethyl substituted with isopropylaminocarbonyl is substituted with one group selected from the group consisting of hydroxy and methoxy),

(xv) ethyl substituted with dimethylaminocarbonyl, ethyl substituted with ethyl(methyl)aminocarbonyl (the ethyl of the ethyl(methyl)aminocarbonyl of the ethyl substituted with ethyl(methyl)aminocarbonyl is substituted with one hydroxy),

(xvi) ethyl substituted with oxetanylaminocarbonyl,

(xvii) ethyl substituted with azetidinylcarbonyl (the azetidinyl of the ethyl substituted with azetidinylcarbonyl may be substituted with one hydroxy or one or two fluorine atoms), ethyl substituted with pyrrolidinylcarbonyl, ethyl substituted with piperidinylcarbonyl, ethyl substituted with morpholinylcarbonyl,

(xix) ethenyl substituted with carboxy,

(xx) ethenyl substituted with dimethylaminocarbonyl,

(xxii) cyclopropyl substituted with dimethylaminocarbonyl,

(xxiv) phenyl substituted with carboxy,

(xxv) pyridin-3-yl substituted with carboxy, pyridin-4-yl substituted with carboxy,

(xxxix) the structure represented by formula [XI-2] below, which is substituted with carboxy,

(xxxx) the structure represented by formula [XI-3] below, which is substituted with carboxy:

(xxxxiv) n-butylsulfonyl substituted with carboxy (the methylene moiety at position α of the carboxy of the n-butylsulfonyl substituted with carboxy is replaced with propane-2,2-diyl),

(xxxxvii) piperidinylsulfonyl substituted with carboxy,

(xxxxix) hydroxy,

(xxxxx) methylsulfonyloxy,

(xxxxxi) methyl substituted with hydroxy,

(xxxxxii) haloethyl substituted with hydroxy, halo-n-propyl substituted with hydroxy,

(xxxxxiii) isobutylsulfonyl substituted with hydroxy,

(xxxxxiv) cyclobutyl substituted with hydroxy (the cyclobutyl of the cyclobutyl substituted with hydroxy is substituted with one dimethylaminocarbonyl), cyclopentyl substituted with hydroxy, or

(xxxxxv) azetidinyl substituted with hydroxy (the nitrogen atom of the azetidinyl substituted with hydroxy is substituted with one methylcarbonyl), piperidinyl substituted with hydroxy (the nitrogen atom of the piperidinyl substituted with hydroxy is substituted with one group selected from the group consisting of methylcarbonyl, methoxycarbonyl, and dimethylaminocarbonyl),

wherein even more preferably, R 61 and R 62 are each independently a hydrogen atom, a fluorine atom, methyl, or methylsulfonyl;

(d) when ring C is pyridyl,

even more preferably, ring C is pyridin-4-yl;

even more preferably, R 54 is

(ii) carbamoyl, or

(v) n-propylaminocarbonyl substituted with carboxy (the methylene moiety at position α of the carboxy of the n-propylaminocarbonyl substituted with carboxy is replaced with propane-2,2-diyl);

wherein even more preferably, R 61 and R 62 are each a hydrogen atom;

(g) when ring C is tetrahydronaphthyl,

even more preferably, ring C is a structure represented by formula [XII-1] or formula [XII-2] below:

even more preferably, R 54 is carboxy,

wherein even more preferably, R 61 and R 62 are each a hydrogen atom;

(h) when ring C is chromanyl,

even more preferably, ring C is the structure represented by formula [XIII-1] below:

even more preferably, R 54 is carboxy,

wherein even more preferably, R 61 and R 62 are each a hydrogen atom;

(k) when ring C is tetrahydroisoquinolyl,

even more preferably, ring C is the structure represented by formula [XIV-1] below:

even more preferably, R 54 is methylcarbonyl substituted with carboxy (the methylene moiety at position α of the carboxy of the methylcarbonyl substituted with carboxy is replaced with propane-2,2-diyl),

wherein even more preferably, R 61 and R 62 are each a hydrogen atom;

(m) when ring C is 2-oxotetrahydroisoquinolyl,

even more preferably, ring C is the structure represented by formula [XV-1] below:

even more preferably, R 54 is n-propyl substituted with carboxy (the methylene moiety at position α of the carboxy of the n-propyl substituted with carboxy is replaced with propane-2,2-diyl),

wherein even more preferably, R 61 and R 62 are each a hydrogen atom;

(n) when ring C is the structure represented by formula [IX-1] above,

even more preferably, R 54 is

(ii) methyl substituted with methylsulfonylamino, or

(iii) methyl substituted with methylsulfonyl(methyl)amino,

wherein even more preferably, R 61 and R 62 are each a hydrogen atom;

even more preferably, W 4 is methanediyl, ethane-1,2-diyl or propane-1,3-diyl.

Here, other even more preferred examples of R 5 are as follows:

(B)

when R 5 is the structure represented by formula [IV-2],

even more preferably, R 52 is carboxy;

even more preferably, L is a structure represented by formula [VI-1], formula [VI-4], formula [VI-8], formula [VI-10], or formula [VI-11] shown below:

even more preferably, Y is the formula —CH 2 — or the formula —O—;

even more preferably, W 2 is hexane-1,6-diyl, heptane-1,7-diyl, or octane-1,8-diyl;

(C)

when R 5 is the structure represented by formula [IV-3],

even more preferably, R 53 is carboxy;

even more preferably, ring B is the structure represented by formula [VIII-10] shown below:

even more preferably, W 3 is butane-1,4-diyl;

(D)

when R 5 is the structure represented by formula [IV-4],

even more preferably, ring C is

(b) 4- to 6-membered saturated nitrogen-containing heterocyclyl,

(c) phenyl,

(d) pyridyl,

(g) tetrahydronaphthyl,

(h) chromanyl, or

(n) the structure represented by formula [IX-1] below:

wherein (b) when ring C is 4- to 6-membered saturated nitrogen-containing heterocyclyl,

even more preferably, ring C is piperidine-3-yl or piperidine-4-yl;

even more preferably, R 54 is

(i) n-butylcarbonyl substituted with carboxy (the methylene moiety at position α of the carboxy of the n-butylcarbonyl substituted with carboxy is replaced with cyclopentane-1,1-diyl), or

(vii) phenylsulfonyl substituted with carboxy,

wherein even more preferably, R 61 and R 62 are each a hydrogen atom;

(c) when ring C is phenyl,

even more preferably, R 54 is

(ii) carbamoyl,

(iii) methylaminocarbonyl, n-propylaminocarbonyl,

(v) dimethylaminosulfonyl (one methyl of the dimethylaminosulfonyl is substituted with one phenyl, wherein the phenyl is substituted with one methylaminosulfonyl),

(vi) phenylaminosulfonyl (the phenyl of the phenylaminosulfonyl is substituted with one fluorine atom),

(ix) methylsulfonyl(methyl)aminocarbonyl,

(x) n-propyl substituted with carboxy,

(xii) methyl substituted with trifluoromethylsulfonylamino,

(xiii) ethyl substituted with methylsulfonyl(methyl)aminocarbonyl,

(xiv) methyl substituted with methylaminocarbonyl, methyl substituted with n-propylaminocarbonyl, ethyl substituted with methylaminocarbonyl (the methyl of the ethyl substituted with methylaminocarbonyl may be substituted with one group selected from the group consisting of tetrahydrofuranyl and piperidinylcarbonyl), ethyl substituted with ethylaminocarbonyl (the ethyl of the ethylaminocarbonyl of the ethyl substituted with ethylaminocarbonyl is substituted with one group selected from the group consisting of hydroxy and methoxy), ethyl substituted with n-propylaminocarbonyl (the n-propyl of the ethyl substituted with n-propylaminocarbonyl may be substituted with one group selected from the group consisting of hydroxy and methoxy), ethyl substituted with isopropylaminocarbonyl (the isopropyl of the ethyl substituted with isopropylaminocarbonyl is substituted with one group selected from the group consisting of hydroxy and methoxy),

(xv) ethyl substituted with dimethylaminocarbonyl, ethyl substituted with ethyl(methyl)aminocarbonyl (the ethyl of the ethyl(methyl)aminocarbonyl of the ethyl substituted with ethyl(methyl)aminocarbonyl is substituted with one hydroxy),

(xvi) ethyl substituted with oxetanylaminocarbonyl,

(xvii) ethyl substituted with azetidinylcarbonyl (the azetidinyl of the ethyl substituted with azetidinylcarbonyl may be substituted with one hydroxy or one or two fluorine atoms), ethyl substituted with pyrrolidinylcarbonyl, ethyl substituted with piperidinylcarbonyl, ethyl substituted with morpholinylcarbonyl,

(xix) ethenyl substituted with carboxy,

(xx) ethenyl substituted with dimethylaminocarbonyl,

(xxii) cyclopropyl substituted with dimethylaminocarbonyl,

(xxiv) phenyl substituted with carboxy,

(xxv) pyridin-3-yl substituted with carboxy, pyridin-4-yl substituted with carboxy,

(xxxix) the structure represented by formula [XI-2] below, which is substituted with carboxy,

(xxxx) the structure represented by formula [XI-3] below, which is substituted with carboxy:

(xxxxiv) n-butylsulfonyl substituted with carboxy (the methylene moiety at position α of the carboxy of the n-butylsulfonyl substituted with carboxy is replaced with propane-2,2-diyl),

(xxxxvii) piperidinylsulfonyl substituted with carboxy,

(xxxxix) hydroxy,

(xxxxx) methylsulfonyloxy,

(xxxxxi) methyl substituted with hydroxy,

(xxxxxii) haloethyl substituted with hydroxy, halo-n-propyl substituted with hydroxy,

(xxxxxiii) isobutylsulfonyl substituted with hydroxy,

(xxxxxiv) cyclobutyl substituted with hydroxy (the cyclobutyl of the cyclobutyl substituted with hydroxy is substituted with one dimethylamino), cyclopentyl substituted with hydroxy, or

(xxxxxv) azetidinyl substituted with hydroxy (the nitrogen atom of the azetidinyl substituted with hydroxy is substituted with one methylcarbonyl), piperidinyl substituted with hydroxy (the nitrogen atom of the piperidinyl substituted with hydroxy is substituted with one group selected from the group consisting of methylcarbonyl, methoxycarbonyl, and dimethylcarbonyl),

wherein even more preferably, R 61 and R 62 are each independently a hydrogen atom, a fluorine atom, methyl, or methylsulfonyl;

(d) when ring C is pyridyl,

even more preferably, ring C is pyridin-4-yl;

even more preferably, R 54 is carbamoyl,

wherein even more preferably, R 61 and R 62 are each a hydrogen atom;

(g) when ring C is tetrahydronaphthyl,

even more preferably, ring C is a structure represented by formula [XII-1] or formula [XII-2] below:

even more preferably, R 54 is carboxy,

wherein even more preferably, R 61 and R 62 are each a hydrogen atom;

(h) when ring C is chromanyl,

even more preferably, ring C is the structure represented by formula [XIII-1] below:

even more preferably, R 54 is carboxy,

wherein even more preferably, R 61 and R 62 are each a hydrogen atom;

(n) when ring C is the structure represented by formula [IX-1] above, even more preferably, R 54 is

(ii) methyl substituted with methylsulfonylamino, or

(iii) methyl substituted with methylsulfonyl(methyl)amino;

even more preferably, W 4 is methanediyl, ethane-1,2-diyl, or propane-1,3-diyl.

The following are other preferred embodiments of the compounds of the present invention.

Preferred embodiments of R 1 , R 2 , R 3 , R 4 , and ring A in formula [1] above are as described above.

Other preferred examples of R 5 are as follows:

(A)

when R 5 is the structure represented by formula [IV-1],

another preferred example of R 5 is such that

R 51 is the structure represented by formula [V-6] shown below:

W 1 is C 4-10 alkanediyl;

wherein more preferably, R 5 is such that

R 51 is the structure represented by formula [V-6] shown below:

W 1 is C 4 alkanediyl;

wherein even more preferably, R 5 is such that

R 51 is the structure represented by formula [V-6] shown below:

W 1 is butane-1,4-diyl;

(B)

when R 5 is the structure represented by formula [IV-2],

another preferred example of R 5 is such that

R 52 is carboxy;

L is a structure represented by formula [VI-1], formula [VI-4], or formula [VI-7] shown below:

wherein

ring D is

(i) C 3-6 cycloalkane,

(ii) 4- to 6-membered saturated oxygen-containing hetero ring, or

(iv) 6-membered saturated nitrogen-containing hetero ring (the nitrogen atom of the 6-membered saturated nitrogen-containing hetero ring may be substituted with one C 1-4 alkylcarbonyl),

Y is the formula —CH 2 —, the formula —O—, or the formula —CONMe-;

W 2 is C 2-10 alkanediyl, wherein one of the carbon atoms that constitute C 2-10 alkanediyl represented by W 2 may be replaced with an oxygen atom;

wherein more preferably, R 5 is such that

R 52 is carboxy;

L is a structure represented by formula [VI-1] shown below, formula [VI-4] shown below, or formula [VI-7] shown below:

wherein ring D is

C 5-6 cycloalkane, 6-membered saturated oxygen-containing hetero ring, or 6-membered saturated nitrogen-containing hetero ring (the nitrogen atom of the 6-membered saturated nitrogen-containing hetero ring is substituted with one C 1 alkylcarbonyl),

Y is the formula —CH 2 —, the formula —O—, or the formula —CONMe-;

W 2 is C 5-8 alkanediyl, wherein one of the carbon atoms that constitute C 5-8 alkanediyl represented by W 2 may be replaced with an oxygen atom;

wherein even more preferably, R 5 is such that

R 52 is carboxy;

L is a structure represented by formula [VI-1], formula [VI-4], formula [VI-8], formula [VI-9], formula [VI-10], or formula [VI-11] shown below:

Y is the formula —CH 2 —, the formula —O—, or the formula —CONMe-;

W 2 is pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl, or the formula —O—(CH 2 ) 6 —;

(C)

when R 5 is the structure represented by formula [IV-3],

another preferred example of R 5 is such that

R 53 is carboxy;

ring B is a structure represented by formula [VIII-1], formula [VIII-2], formula [VIII-4], or formula [VIII-7] shown below:

W 3 is C 3-7 alkanediyl;

wherein more preferably, R 5 is such that

R 53 is carboxy;

ring B is a structure represented by formula [VIII-1], formula [VIII-2], formula [VIII-4], or formula [VIII-7] shown below:

W 3 is C 4-6 alkanediyl;

wherein even more preferably, R 5 is such that

R 53 is carboxy;

ring B is a structure represented by formula [VIII-1], formula [VIII-8], formula [VIII-9], formula [VIII-10], or formula [VIII-7] shown below:

W 3 is butane-1,4-diyl or hexane-1,6-diyl;

(D)

when R 5 is the structure represented by formula [IV-4],

another preferred example of ring C is

(a) C 3-6 cycloalkyl,

(b) 4- to 6-membered saturated nitrogen-containing heterocyclyl,

(c) phenyl,

(d) pyridyl,

(g) tetrahydronaphthyl,

(h) chromanyl, or

(n) the structure represented by formula [IX-1] below:

wherein

(a) when ring C is C 3-6 cycloalkyl,

another preferred example of R 5 is such that

R 54 is carboxy;

R 61 is a hydrogen atom;

R 62 is a hydrogen atom;

W 4 is C 1-3 alkanediyl;

wherein more preferably, R 5 is such that

ring C is C 6 cycloalkyl;

R 54 is carboxy;

R 61 is a hydrogen atom;

R 62 is a hydrogen atom;

W 4 is C 3 alkanediyl;

wherein even more preferably, R 5 is such that

ring C is cyclohexyl,

R 54 is carboxy;

R 61 is a hydrogen atom;

R 62 is a hydrogen atom;

W 4 is propane-1,3-diyl;

(b) when ring C is 4- to 6-membered saturated nitrogen-containing heterocyclyl, another preferred example of R 5 is such that

R 54 is

C 1-4 alkylcarbonyl substituted with carboxy (when position α of the carboxy of the C 1-4 alkylcarbonyl substituted with carboxy is a methylene moiety, the methylene moiety may be replaced with cyclopentane-1,1-diyl), or

phenylsulfonyl substituted with carboxy;

R 61 is a hydrogen atom;

R 62 is a hydrogen atom;

W 4 is C 1-3 alkanediyl;

wherein more preferably, R 5 is such that

ring C is 5-membered saturated nitrogen-containing heterocyclyl;

R 54 is

(i) C 4 alkylcarbonyl substituted with carboxy (when position α of the carboxy of the C 4 alkylcarbonyl substituted with carboxy is a methylene moiety, the methylene moiety may be replaced with cyclopentane-1,1-diyl), or

(vii) phenylsulfonyl substituted with carboxy,

R 61 is a hydrogen atom;

R 62 is a hydrogen atom;

W 4 is C 1 alkanediyl;

wherein even more preferably, R 5 is such that

ring C is piperidine-3-yl or piperidine-4-yl;

R 54 is

(i) n-butylcarbonyl substituted with carboxy (the methylene moiety at position α of the carboxy of the n-butylcarbonyl substituted with carboxy is replaced with cyclopentane-1,1-diyl), or

(vii) phenylsulfonyl substituted with carboxy;

R 61 is a hydrogen atom;

R 62 is a hydrogen atom;

W 4 is methanediyl;

(c) when ring C is phenyl,

another preferred example of R 5 is such that

R 54 is

R 61 and R 62 are each independently a hydrogen atom, a fluorine atom, methyl, or methylsulfonyl;

W 4 is C 1-3 alkanediyl;

wherein more preferably, R 5 is such that

R 54 is

wherein R 61 and R 62 are each independently a hydrogen atom, a fluorine atom, methyl, or methylsulfonyl;

W 4 is C 1-3 alkanediyl;

wherein even more preferably, R 5 is such that

R 54 is

wherein R 61 and R 62 are each independently a hydrogen atom, a fluorine atom, methyl, or methylsulfonyl;

W 4 is methanediyl, ethane-1,2-diyl, or propane-1,3-diyl;

(d) when ring C is pyridyl,

another preferred example of R 5 is such that

R 54 is

carbamoyl, or

C 1-4 alkoxy substituted with carboxy (when position α of the carboxy of the C 1-4 alkoxy substituted with carboxy is a methylene moiety, the methylene moiety may be replaced with propane-2,2-diyl);

R 61 is a hydrogen atom;

R 62 is a hydrogen atom;

W 4 is C 1-3 alkanediyl;

wherein more preferably, R 5 is such that

R 54 is

(ii) carbamoyl, or

(iv) C 2 alkoxy substituted with carboxy (when position α of the carboxy of the C 2 alkoxy substituted with carboxy is a methylene moiety, the methylene moiety is replaced with propane-2,2-diyl);

R 61 is a hydrogen atom;

R 62 is a hydrogen atom;

W 4 is C 1 alkanediyl;

wherein even more preferably, R 5 is such that

ring C is pyridin-4-yl,

R 54 is

(ii) carbamoyl, or

(iv) ethoxy substituted with carboxy (the methylene moiety at position α of the carboxy of the ethoxy substituted with carboxy is replaced with propane-2,2-diyl);

R 61 is a hydrogen atom;

R 62 is a hydrogen atom;

W 4 is methanediyl;

(g) when ring C is tetrahydronaphthyl,

another preferred example of R 5 is such that

R 54 is carboxy;

R 61 is a hydrogen atom;

R 62 is a hydrogen atom;

W 4 is C 1-3 alkanediyl;

wherein more preferably, R 5 is such that

R 54 is carboxy;

R 61 is a hydrogen atom;

R 62 is a hydrogen atom;

W 4 is C 1 alkanediyl;

wherein even more preferably, R 5 is such that

ring C is a structure represented by formula [XII-1] or formula [XII-2] below:

R 54 is carboxy;

R 61 is a hydrogen atom;

R 62 is a hydrogen atom;

W 4 is methanediyl;

(h) when ring C is chromanyl,

another preferred example of R 5 is such that

R 54 is carboxy;

R 61 is a hydrogen atom;

R 62 is a hydrogen atom;

W 4 is C 1-3 alkanediyl;

wherein even more preferably, R 5 is such that

R 54 is carboxy;

R 61 is a hydrogen atom;

R 62 is a hydrogen atom;

W 4 is C 1 alkanediyl;

wherein even more preferably, R 5 is such that

ring C is a structure represented by formula [XIII-1] or formula [XIII-2] below:

R 54 is carboxy;

R 61 is a hydrogen atom;

R 62 is a hydrogen atom;

W 4 is methanediyl;

(n) when ring C is the structure represented by formula [IX-1] below:

another preferred example of R 5 is such that

R 54 is

C 1-4 alkyl substituted with C 1-4 alkylsulfonylamino, or C 1-4 alkyl substituted with C 1-4 alkylsulfonyl(C 1-4 alkyl)amino;

R 61 is a hydrogen atom;

R 62 is a hydrogen atom;

W 4 is C 1-3 alkanediyl;

wherein more preferably, R 5 is such that

ring C is the structure represented by formula [IX-1] above,

R 54 is

(ii) C 1 alkyl substituted with C 1 alkylsulfonylamino, or

(iii) C 1 alkyl substituted with C 1 alkylsulfonyl(C 1 alkyl)amino,

R 61 is a hydrogen atom;

R 62 is a hydrogen atom;

W 4 is C 1 alkanediyl;

wherein even more preferably, R 5 is such that

ring C is the structure represented by formula [IX-1] above, R 54 is

(ii) methyl substituted with methylsulfonylamino, or

(iii) methyl substituted with methylsulfonyl(methyl)amino,

R 61 is a hydrogen atom;

R 62 is a hydrogen atom;

W 4 is methanediyl.

The “preferred embodiments” described above include compounds or pharmaceutically acceptable salts thereof below:

The “preferred embodiments” described above further include compounds or pharmaceutically acceptable salts thereof below:

One preferred embodiment of compounds of the present invention is a compound represented by formula [I-A] below or a pharmaceutically acceptable salt thereof:

wherein preferred embodiments of R 1 , R 2 , R 51 , and W 1 are as described above.

One more preferred embodiment of formula [I-A] above is such that

R 1 is a hydrogen atom;

R 2 is a hydrogen atom;

R 51 is a structure represented by formula [V-6] or formula [V-8] below:

W 1 is C 4 alkanediyl;

wherein an even more preferred embodiment is such that

R 1 is a hydrogen atom;

R 2 is a hydrogen atom;

R 51 is a structure represented by formula [V-6] or formula [V-8] below:

W 1 is butane-1,4-diyl.

Another more preferred embodiment of formula [I-A] above is such that

R 1 is a hydrogen atom;

R 2 is a hydrogen atom;

R 51 is the structure represented by formula [V-6] below:

W 1 is C 4 alkanediyl;

wherein an even more preferred embodiment is such that

R 1 is a hydrogen atom;

R 2 is a hydrogen atom;

R 51 is the structure represented by formula [V-6] below:

W 1 is butane-1,4-diyl;

wherein a particularly preferred embodiment is such that

the compound represented by formula [I-A] is as follows:

Another preferred embodiment of compounds of the present invention is a compound represented by formula [I-B] below or a pharmaceutically acceptable salt thereof:

wherein preferred embodiments of R 1 , R 2 , L, Y, and W 2 are as described above.

One more preferred embodiment of formula [I-B] above is such that

R 1 is a hydrogen atom;

R 2 is a hydrogen atom;

L is a structure represented by formula [VI-1], formula [VI-4], or formula [VI-7] below:

wherein

ring D is

(i) C 5-6 cycloalkane,

(ii) 6-membered saturated oxygen-containing hetero ring, or

(iv) 6-membered saturated nitrogen-containing hetero ring (the nitrogen atom of the 6-membered saturated nitrogen-containing hetero ring is substituted with one C 1 alkylcarbonyl);

Y is the formula —CH 2 —, the formula —O—, the formula —CONH—, or the formula —CONMe-;

W 2 is C 5-8 alkanediyl,

wherein one of the carbon atoms that constitute C 5-8 alkanediyl represented by W 2 may be replaced with an oxygen atom;

wherein an even more preferred embodiment is such that

R 1 is a hydrogen atom;

R 2 is a hydrogen atom;

L is a structure represented by formula [VI-1], formula [VI-4], formula [VI-8], formula [VI-9], formula [VI-10], or formula [VI-11] below:

Y is the formula —CH 2 —, the formula —O—, the formula —CONH—, or the formula —CONMe-;

W 2 is pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl, or the formula —O—(CH 2 ) 6 —.

Another more preferred embodiment of formula [I-B] above is such that

R 1 is a hydrogen atom;

R 2 is a hydrogen atom;

L is a structure represented by formula [VI-1], formula [VI-4], or formula [VI-7] below:

wherein

ring D is

(i) C 5-6 cycloalkane,

(ii) 6-membered saturated oxygen-containing hetero ring, or

(iv) 6-membered saturated nitrogen-containing hetero ring (the nitrogen atom of the 6-membered saturated nitrogen-containing hetero ring is substituted with one C 1 alkylcarbonyl);

Y is the formula —CH 2 —, the formula —O—, or the formula —CONMe-;

W 2 is C 5-8 alkanediyl,

wherein one of the carbon atoms that constitute C 5-8 alkanediyl represented by W 2 may be replaced with an oxygen atom;

wherein an even more preferred embodiment is such that

R 1 is a hydrogen atom;

R 2 is a hydrogen atom;

L is a structure represented by formula [VI-1], formula [VI-4], formula [VI-8], formula [VI-9], formula [VI-10], or formula [VI-11] below:

Y is the formula —CH 2 —, the formula —O—, or the formula —CONMe-;

W 2 is pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl, or the formula —O—(CH 2 ) 6 —,

wherein a particularly preferred embodiment is such that

the compound represented by formula [I-B] is any of the following:

Another preferred embodiment of compounds of the present invention is a compound represented by formula [I-C] below or a pharmaceutically acceptable salt thereof:

wherein preferred embodiments of R 1 , R 2 , R 53 , ring B, and W 3 are as described above.

One more preferred embodiment of formula [I-C] above is such that

R 1 is a hydrogen atom;

R 2 is a hydrogen atom;

ring B is a structure represented by formula [VIII-1], formula [VIII-2], formula [VIII-4], or formula [VIII-7] below:

R 53 is carboxy;

W 3 is C 4-6 alkanediyl;

wherein an even more preferred embodiment is such that

R 1 is a hydrogen atom;

R 2 is a hydrogen atom;

ring B is a structure represented by formula [VIII-1], formula [VIII-8], formula [VIII-9], formula [VIII-10], or formula [VIII-7] below:

R 53 is carboxy;

W 3 is butane-1,4-diyl or hexane-1,6-diyl.

Another more preferred embodiment of formula [I-C] above is such that

R 1 is a hydrogen atom;

R 2 is a hydrogen atom;

ring B is a structure represented by formula [VIII-1], formula [VIII-2], formula [VIII-4], or formula [VIII-7] below:

R 53 is carboxy;

W 3 is C 4-6 alkanediyl;

wherein an even more preferred embodiment is such that,

R 1 is a hydrogen atom;

R 2 is a hydrogen atom;

ring B is a structure represented by formula [VIII-1], formula [VIII-8], formula [VIII-9], formula [VIII-10], or formula [VIII-7] below:

R 53 is carboxy;

W 3 is butane-1,4-diyl or hexane-1,6-diyl;

wherein a particularly preferred embodiment is such that

the compound represented by formula [1-C] is any of the following:

Another preferred embodiment of compounds of the present invention is a compound represented by formula [I-D] below or a pharmaceutically acceptable salt thereof:

wherein preferred embodiments of R 1 , R 2 , R 54 , ring C, and W 4 are as described above.

In formula [I-D] above,

(a) when ring C is C 3-6 cycloalkyl, one more preferred embodiment is such that

R 1 is a hydrogen atom;

R 2 is a hydrogen atom;

ring C is C 6 cycloalkyl;

R 54 is carboxy;

W 4 is C 3 alkanediyl;

wherein an even more preferred embodiment is such that

R 1 is a hydrogen atom;

R 2 is a hydrogen atom;

ring C is cyclohexyl;

R 54 is carboxy;

W 4 is propane-1,3-diyl.

In formula [I-D] above,

(a) when ring C is C 3-6 cycloalkyl, another more preferred embodiment is such that

R 1 is a hydrogen atom;

R 2 is a hydrogen atom;

ring C is C 6 cycloalkyl;

R 54 is carboxy;

W 4 is C 3 alkanediyl;

wherein an even more preferred embodiment is such that

R 1 is a hydrogen atom;

R 2 is a hydrogen atom;

ring C is cyclohexyl;

R 54 is carboxy;

W 4 is propane-1,3-diyl;

wherein a particularly preferred embodiment is such that

the compound represented by formula [I-D] is as follows:

In formula [I-D] above,

(b) when ring C is 4- to 6-membered saturated nitrogen-containing heterocyclyl, one more preferred embodiment is such that

R 1 is a hydrogen atom;

R 2 is a hydrogen atom;

ring C is 6-membered saturated nitrogen-containing heterocyclyl;

R 54 is

(i) C 4 alkylcarbonyl substituted with carboxy (when position α of the carboxy of the C 4 alkylcarbonyl substituted with carboxy is a methylene moiety, the methylene moiety is replaced with C 5 alkanediyl),

(ii) C 3 alkylcarbonyl substituted with sulfamoyl,

(v) phenylcarbonyl substituted with sulfamoyl,

(vii) phenylsulfonyl substituted with carboxy, or

(x) the structure represented by formula [X-2] below, which is substituted with carboxy:

W 4 is C 1 alkanediyl;

wherein an even more preferred embodiment is such that

R 1 is a hydrogen atom;

R 2 is a hydrogen atom;

ring C is piperidine-3-yl or piperidine-4-yl;

R 54 is

(i) n-butylcarbonyl substituted with carboxy (the methylene moiety at position α of the carboxy of the n-butylcarbonyl substituted with carboxy may be replaced with cyclopentane-1,1-diyl),

(ii) n-propylcarbonyl substituted with sulfamoyl,

(v) phenylcarbonyl substituted with sulfamoyl,

(vii) phenylsulfonyl substituted with carboxy, or

(x) the structure represented by formula [X-2] below, which is substituted with carboxy:

W 4 is methanediyl.

In formula [I-D] above,

(b) when ring C is 4- to 6-membered saturated nitrogen-containing heterocyclyl, another more preferred embodiment is such that

R 1 is a hydrogen atom;

R 2 is a hydrogen atom;

ring C is 6-membered saturated nitrogen-containing heterocyclyl;

R 54 is

(i) C 4 alkylcarbonyl substituted with carboxy (when position α of the carboxy of the C 4 alkylcarbonyl substituted with carboxy is a methylene moiety, the methylene moiety is replaced with cyclopentane-1,1-diyl), or

(vii) phenylsulfonyl substituted with carboxy, and

W 4 is C 1 alkanediyl;

wherein an even more preferred embodiment is such that

R 1 is a hydrogen atom;

R 2 is a hydrogen atom;

ring C is piperidine-3-yl or piperidine-4-yl;

R 54 is

(i) n-butylcarbonyl substituted with carboxy (the methylene moiety at position α of the carboxy of the n-butylcarbonyl substituted with carboxy is replaced with cyclopentane-1,1-diyl), or

(vii) phenylsulfonyl substituted with carboxy, and

W 4 is methanediyl;

wherein a particularly preferred embodiment is such that

the compound represented by formula [I-D] is any of the following:

In formula [I-D] above,

(d) when ring C is pyridyl, one more preferred embodiment is such that

R 1 is a hydrogen atom;

R 2 is a hydrogen atom;

R 54 is

(ii) carbamoyl,

(iii) C 1 alkyl substituted with carboxy,

(iv) C 2 alkoxy substituted with carboxy (when position α of the carboxy of the C 2 alkoxy substituted with carboxy is a methylene moiety, the methylene moiety may be replaced with propane-2,2-diyl), or

(vi) 5-membered saturated heterocyclylcarbonyl substituted with carboxy (the 5-membered saturated heterocyclyl of the 5-membered saturated heterocyclylcarbonyl substituted with carboxy is substituted with one fluorine atom);

W 4 is C 1 alkanediyl;

wherein an even more preferred embodiment is such that

R 1 is a hydrogen atom;

R 2 is a hydrogen atom;

R 54 is

(ii) carbamoyl,

(iii) methyl substituted with carboxy,

(iv) ethoxy substituted with carboxy (the methylene moiety at position α of the carboxy of the ethoxy substituted with carboxy is replaced with propane-2,2-diyl),

(vi) n-propylaminocarbonyl substituted with carboxy (the methylene moiety at position α of the carboxy of the n-propylaminocarbonyl substituted with carboxy is replaced with propane-2,2-diyl), or

pyrrolidinylcarbonyl substituted with carboxy (the pyrrolidinyl of the pyrrolidinylcarbonyl substituted with carboxy is substituted with one fluorine atom);

W 4 is methanediyl.

In formula [I-D] above,

(d) when ring C is pyridyl, another more preferred embodiment is such that

R 1 is a hydrogen atom;

R 2 is a hydrogen atom;

R 54 is

(ii) carbamoyl, or

(iv) C 2 alkoxy substituted with carboxy (when position α of the carboxy of the C 2 alkoxy substituted with carboxy is a methylene moiety, the methylene moiety is replaced with propane-2,2-diyl);

W 4 is C 1 alkanediyl;

wherein an even more preferred embodiment is such that

R 1 is a hydrogen atom;

R 2 is a hydrogen atom;

ring C is pyridin-4-yl;

R 54 is

(ii) carbamoyl, or

(iv) ethoxy substituted with carboxy (the methylene moiety at position α of the carboxy of the ethoxy substituted with carboxy is replaced with propane-2,2-diyl);

W 4 is methanediyl;

wherein a particularly preferred embodiment is such that

the compound represented by formula [I-D] is any of the following:

In formula [I-D] above,

(g) when ring C is tetrahydronaphthyl, one more preferred embodiment is such that

R 1 is a hydrogen atom;

R 2 is a hydrogen atom;

R 54 is carboxy;

W 4 is C 1 alkanediyl;

wherein an even more preferred embodiment is such that

R 1 is a hydrogen atom;

R 2 is a hydrogen atom;

ring C is a structure represented by formula [XII-1] or formula [XII-2] below:

R 54 is carboxy;

W 4 is methanediyl.

In formula [I-D] above,

(g) when ring C is tetrahydronaphthyl, another more preferred embodiment is such that

R 1 is a hydrogen atom;

R 2 is a hydrogen atom;

R 54 is carboxy;

W 4 is C 1 alkanediyl;

wherein an even more preferred embodiment is such that

R 1 is a hydrogen atom;

R 2 is a hydrogen atom;

ring C is a structure represented by formula [XII-1] or formula [XII-2] below:

R 54 is carboxy;

W 4 is methanediyl;

wherein a particularly preferred embodiment is such that

the compound represented by formula [I-D] is any of the following:

In formula [I-D] above,

(h) when ring C is chromanyl, one more preferred embodiment is such that

R 1 is a hydrogen atom;

R 2 is a hydrogen atom;

R 54 is carboxy;

W 4 is C 1 alkanediyl;

wherein an even more preferred embodiment is such that

R 1 is a hydrogen atom;

R 2 is a hydrogen atom;

ring C is a structure represented by formula [XIII-1] or formula [XIII-2] below:

R 54 is carboxy;

W 4 is methanediyl.

In formula [I-D] above,

(h) when ring C is chromanyl, another more preferred embodiment is such that

R 1 is a hydrogen atom;

R 2 is a hydrogen atom;

R 54 is carboxy;

W 4 is C 1 alkanediyl;

wherein an even more preferred embodiment is such that

R 1 is a hydrogen atom;

R 2 is a hydrogen atom;

ring C is a structure represented by formula [XIII-1] or formula [XIII-2] below:

R 54 is carboxy;

W 4 is methanediyl;

wherein a particularly preferred embodiment is such that

the compound represented by formula [I-D] is any of the following:

In formula [I-D] above,

(n) when ring C is the structure represented by formula [IX-1] below:

one more preferred embodiment is such that

R 1 is a hydrogen atom;

R 2 is a hydrogen atom;

R 54 is

(ii) C 1 alkyl substituted with C 1 alkylsulfonylamino, or

(iii) C 1 alkyl substituted with C 1 alkylsulfonyl(C 1 alkyl)amino;

W 4 is C 1 alkanediyl;

wherein an even more preferred embodiment is such that

R 1 is a hydrogen atom;

R 2 is a hydrogen atom;

R 54 is

(ii) methyl substituted with methylsulfonylamino, or

(iii) methyl substituted with methylsulfonyl(methyl)amino, and

W 4 is methanediyl.

In formula [I-D] above,

(n) when ring C is the structure represented by formula [IX-1] below:

another more preferred embodiment is such that

R 1 is a hydrogen atom;

R 2 is a hydrogen atom;

R 54 is

(ii) C 1 alkyl substituted with C 1 alkylsulfonylamino, or

(iii) C 1 alkyl substituted with C 1 alkylsulfonyl(C 1 alkyl)amino;

W 4 is C 1 alkanediyl;

wherein an even more preferred embodiment is such that

R 1 is a hydrogen atom;

R 2 is a hydrogen atom;

R 54 is

(ii) methyl substituted with methylsulfonylamino, or

(iii) methyl substituted with methylsulfonyl(methyl)amino, and

W 4 is methanediyl;

wherein a particularly preferred embodiment is such that

the compound represented by formula [I-D] is any of the following:

Another preferred embodiment of compounds of the present invention is a compound represented by formula [I-D′] below or a pharmaceutically acceptable salt thereof.

wherein preferred embodiments of R 1 , R 2 , R 54 , R 61 , R 62 , and W 4 are as described above.

In formula [I-D′] above, one more preferred embodiment is such that

R 1 is a hydrogen atom;

R 2 is a hydrogen atom;

R 54 is

wherein R 61 and R 62 are each independently a hydrogen atom, a fluorine atom, methyl, or methylsulfonyl;

W 4 is C 1-3 alkanediyl;

wherein an even more preferred embodiment is such that

R 1 is a hydrogen atom;

R 2 is a hydrogen atom;

R 54 is

wherein R 61 and R 62 are each independently a hydrogen atom, a fluorine atom, methyl, or methylsulfonyl;

W 4 is methanediyl, ethane-1,2-diyl, or propane-1,3-diyl;

in formula [I-D′] above, another more preferred embodiment is such that

R 1 is a hydrogen atom;

R 2 is a hydrogen atom;

R 54 is

wherein R 61 and R 62 are each independently a hydrogen atom, a fluorine atom, methyl, or methylsulfonyl;

W 4 is C 1-3 alkanediyl;

wherein an even more preferred embodiment is such that

R 1 is a hydrogen atom;

R 2 is a hydrogen atom;

R 54 is

wherein R 61 and R 62 are each independently a hydrogen atom, a fluorine atom, methyl, or methylsulfonyl;

W 4 is methanediyl, ethane-1,2-diyl, or propane-1,3-diyl;

wherein a particularly preferred embodiment is such that

the compound represented by formula [I-D] is any of the following:

The “preferred embodiments” described above include compounds or pharmaceutically acceptable salts thereof below:

Another preferred embodiment of compounds of the present invention is a compound represented by formula [1-E] below or a pharmaceutically acceptable salt thereof:

wherein preferred embodiments of R 1 , R 2 , and R 5 are as described above.

In formula [I-E] above, one more preferred embodiment is such that

R 1 is a hydrogen atom;

R 2 is a hydrogen atom;

(B)

when R 5 is the structure represented by formula [IV-2] below:

L is a structure represented by formula [VI-4] or formula [VI-7] below:

wherein

ring D is (ii) 6-membered saturated oxygen-containing hetero ring;

R 52 is carboxy;

Y is the formula —CH 2 —, or the formula —O—;

W 2 is C 7-8 alkanediyl,

wherein one of the carbon atoms that constitute C 7-8 alkanediyl represented by W 2 may be replaced with an oxygen atom;

(C)

when R 5 is the structure represented by formula [IV-3] below:

ring B is the structure represented by formula [VIII-7] below:

R 53 is carboxy;

W 3 is C 6 alkanediyl;

(D)

when R 5 is the structure represented by formula [IV-4] below:

ring C is

(c) phenyl,

(d) pyridyl,

(g) tetrahydronaphthyl, or

(h) chromanyl;

wherein

(c)

when ring C is phenyl,

R 54 is

(xxi) C 3 cycloalkyl substituted with carboxy, or

(xxxxvii) 5- or 6-membered saturated nitrogen-containing heterocyclylsulfonyl substituted with carboxy (the 5- or 6-membered saturated nitrogen-containing heterocyclyl of the 5- or 6-membered saturated nitrogen-containing heterocyclylsulfonyl substituted with carboxy may be substituted with one fluorine atom);

R 61 is a hydrogen atom;

R 62 is a hydrogen atom;

W 4 is C 1 alkanediyl;

(d)

when ring C is pyridyl,

R 54 is (iv) C 2 alkoxy substituted with carboxy (when position α of the carboxy of the C 2 alkoxy substituted with carboxy is a methylene moiety, the methylene moiety is replaced with propane-2,2-diyl);

R 61 is a hydrogen atom;

R 62 is a hydrogen atom;

W 4 is C 1 alkanediyl;

(g)

when ring C is tetrahydronaphthyl,

R 54 is carboxy;

R 61 is a hydrogen atom;

R 62 is a hydrogen atom;

W 4 is C 1 alkanediyl;

(h)

when ring C is chromanyl,

R 54 is carboxy;

R 61 is a hydrogen atom;

R 62 is a hydrogen atom;

W 4 is C 1 alkanediyl;

wherein in formula [1-E] above, an even more preferred embodiment is such that

R 1 is a hydrogen atom;

R 2 is a hydrogen atom;

(B)

when R 5 is the structure represented by formula [IV-2] below:

L is a structure represented by formula [VI-4] or formula [VI-10] below:

R 52 is carboxy;

Y is the formula —CH 2 — or the formula —O—;

W 2 is heptane-1,7-diyl, octane-1,8-diyl, or the formula —O—(CH 2 ) 6 —;

(C)

when R 5 is the structure represented by formula [IV-3] below:

ring B is the structure represented by formula [VIII-7] below:

R 53 is carboxy;

W 3 is hexane-1,6-diyl;

(D)

when R 5 is the structure represented by formula [IV-4] below:

ring C is

(c) phenyl,

(d) pyridyl,

(g) tetrahydronaphthyl, or

(h) chromanyl,

(c)

when ring C is phenyl,

R 54 is

(xxi) cyclopropyl substituted with carboxy, or

(xxxxvii) 4- to 6-membered saturated nitrogen-containing heterocyclylsulfonyl substituted with carboxy (the 4- to 6-membered saturated nitrogen-containing heterocyclyl of the 4- to 6-membered saturated nitrogen-containing heterocyclylsulfonyl substituted with carboxy may be substituted with one fluorine atom), piperidinylsulfonyl substituted with carboxy, pyrrolidinylsulfonyl substituted with carboxy (the pyrrolidinyl of the pyrrolidinylsulfonyl substituted with carboxy is substituted with one fluorine atom);

R 61 is a hydrogen atom;

R 62 is a hydrogen atom;

W 4 is methanediyl;

(d)

when ring C is pyridyl,

ring C is pyridin-4-yl;

R 54 is (iv) ethoxy substituted with carboxy (the methylene moiety at position α of the carboxy of the ethoxy substituted with carboxy is replaced with propane-2,2-diyl);

R 61 is a hydrogen atom;

R 62 is a hydrogen atom;

W 4 is methanediyl;

(g)

when ring C is tetrahydronaphthyl,

ring C is a structure represented by formula [XII-1] or formula [XII-2] below:

R 54 is carboxy;

R 61 is a hydrogen atom;

R 62 is a hydrogen atom;

W 4 is methanediyl;

(h)

when ring C is chromanyl,

ring C is a structure represented by formula [XIII-1] or formula [XIII-2] below:

R 54 is carboxy;

R 61 is a hydrogen atom;

R 62 is a hydrogen atom;

W 4 is methanediyl.

In formula [I-E] above, one particularly preferred embodiment is such that the compound represented by formula [I-E] is any of the following:

In formula [I-E] above, another particularly preferred embodiment is such that the compound represented by formula [I-E] is as follows:

In formula [I-E] above, another particularly preferred embodiment is such that the compound represented by formula [I-E] is as follows:

In formula [I-E] above, another particularly preferred embodiment is such that the compound represented by formula [I-E] is as follows:

In formula [I-E] above, another particularly preferred embodiment is such that the compound represented by formula [I-E] is as follows:

In formula [I-E] above, another particularly preferred embodiment is such that the compound represented by formula [I-E] is as follows:

In formula [I-E] above, another particularly preferred embodiment is such that the compound represented by formula [I-E] is as follows:

In formula [I-E] above, another particularly preferred embodiment is such that the compound represented by formula [I-E] is as follows:

In formula [I-E] above, another particularly preferred embodiment is such that the compound represented by formula [I-E] is as follows:

In formula [I-E] above, another particularly preferred embodiment is such that the compound represented by formula [I-E] is as follows:

In formula [I-E] above, another particularly preferred embodiment is such that the compound represented by formula [I-E] is as follows:

In formula [I-E] above, another particularly preferred embodiment is such that the compound represented by formula [I-E] is as follows:

In formula [I-E] above, another particularly preferred embodiment is such that the compound represented by formula [I-E] is as follows:

In formula [I-E] above, another particularly preferred embodiment is such that the compound represented by formula [I-E] is as follows:

Other preferred embodiments of the compound represented by formula [I-D′], among compounds of the present invention, or a pharmaceutically acceptable salt thereof are (101) to (106) below.

(101) A compound, wherein formula [I] is formula [I-D′] below:

wherein

R 1 is a hydrogen atom;

R 2 is a hydrogen atom;

R 54 is C 3-6 cycloalkyl substituted with carboxy,

wherein R 61 and R 62 are each independently a hydrogen atom, a fluorine atom, methyl, or methylsulfonyl;

W 4 is C 1-3 alkanediyl.

(102) A compound or a pharmaceutically acceptable salt thereof, wherein formula [I] is formula [I-D′] below:

wherein

R 1 is a hydrogen atom;

R 2 is a hydrogen atom;

R 54 is cyclopropyl substituted with carboxy,

wherein

R 61 is a fluorine atom that substitutes the benzene ring at ortho position with respect to —W 4 —,

R 62 is a hydrogen atom;

W 4 is methanediyl or ethane-1,2-diyl.

(103) A compound or a pharmaceutically acceptable salt thereof, wherein formula [I] is formula [I-D′] below:

wherein

R 1 is a hydrogen atom;

R 2 is a hydrogen atom;

R 54 is cyclopropyl substituted with carboxy, which substitutes the benzene ring at meta position with respect to —W 4 —,

wherein

R 61 is a fluorine atom that substitutes the benzene ring at ortho position with respect to —W 4 —,

R 62 is a hydrogen atom;

W 4 is methanediyl or ethane-1,2-diyl.

(104) A compound or a pharmaceutically acceptable salt thereof, wherein formula [I] is formula [I-D′] below:

wherein

R 1 is a hydrogen atom;

R 2 is a hydrogen atom;

R 54 is cyclopropyl substituted with carboxy, which substitutes the benzene ring at meta position with respect to —W 4 —,

wherein R 61 and R 62 are each independently a hydrogen atom or a fluorine atom;

W 4 is ethane-1,2-diyl.

(105) A compound or a pharmaceutically acceptable salt thereof, wherein formula [I] is formula [I-D′] below:

wherein

R 1 is a hydrogen atom;

R 2 is a hydrogen atom;

R 54 is cyclopropyl substituted with carboxy, which substitutes the benzene ring at meta position with respect to —W 4 —,

wherein

R 61 is a fluorine atom,

R 62 is a hydrogen atom;

W 4 is ethane-1,2-diyl.

(106) A compound or a pharmaceutically acceptable salt thereof, wherein formula [I] is formula [I-D′] below:

wherein

R 1 is a hydrogen atom;

R 2 is a hydrogen atom;

R 54 is cyclopropyl substituted with carboxy,

wherein R 61 and R 62 are each identically a hydrogen atom;

W 4 is ethane-1,2-diyl.

Other preferred embodiments of the compound represented by formula [I-B], among compounds of the present invention, or a pharmaceutically acceptable salt thereof are (201) to (203) below.

(201) A compound or a pharmaceutically acceptable salt thereof, wherein formula [I] is formula [I-B] below:

wherein

R 1 is a hydrogen atom;

R 2 is a hydrogen atom;

L is a structure represented by formula [VI-1], formula [VI-4], or formula [VI-7] below:

wherein ring D is

(i) C 3-6 cycloalkane,

(ii) 4- to 6-membered saturated oxygen-containing hetero ring, or

(iv) 6-membered saturated nitrogen-containing hetero ring (the nitrogen atom of the 6-membered saturated nitrogen-containing hetero ring may be substituted with one C 1-4 alkylcarbonyl);

Y is the formula —CH 2 —, the formula —O—, or the formula —CONMe-;

W 2 is C 2-10 alkanediyl,

wherein one of the carbon atoms that constitute C 2-10 alkanediyl represented by W 2 may be replaced with one oxygen atom.

(202) A compound or a pharmaceutically acceptable salt thereof, wherein formula [I] is formula [I-B] below:

wherein

R 1 is a hydrogen atom;

R 2 is a hydrogen atom;

L is the structure represented by formula [VI-7] below:

wherein ring D is

(i) C 4 cycloalkane, or

(ii) 4-membered saturated oxygen-containing hetero ring;

Y is the formula —CH 2 — or the formula —O—;

W 2 is heptane-1,7-diyl.

(203) A compound or a pharmaceutically acceptable salt thereof, wherein formula [I] is formula [I-B] below:

wherein

R 1 is a hydrogen atom;

R 2 is a hydrogen atom;

L is the structure represented by formula [VI-7] below:

wherein ring D is

(i) C 4 cycloalkane,

(ii) 4-membered saturated oxygen-containing hetero ring, or

(iii) 4-membered saturated sulfur-containing hetero ring (the sulfur atom of the 4-membered saturated sulfur-containing hetero ring is substituted with two oxo);

Y is the formula —CH 2 — or the formula —O—;

W 2 is heptane-1,7-diyl.

The compounds of the present invention are those having the basic skeleton of which is pyridine substituted with an azole such as pyrazolyl, and pharmaceutically acceptable salt of such compounds may also be used.

The compounds of the present invention also include tautomers. To give an example of tautomersism, the structure represented by formula [II] shown below:

assumes the structure represented by formula [III-1] shown below:

to form a compound (hereinafter referred to as compound [I-1]) and a tautomer thereof (hereinafter referred to as a compound [I-1-α]), both being shown below.

Examples of the pharmaceutically acceptable salt include: acid addition salts such as mineral acid salts such as hydrochloride, hydrobromide, hydroiodide, phosphate, sulfate, and nitrate, sulfonic acid salts such as methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and trifluoromethanesulfonate, and organic acid salts such as oxalate, tartrate, citrate, maleate, succinate, acetate, trifluoroacetate, benzoate, mandelate, ascorbate, lactate, gluconate, and malate; amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate, and aspartate; or inorganic salts such as lithium salt, sodium salt, potassium salt, calcium salt, and magnesium salt or salts formed with organic bases, such as ammonium salt, triethylamine salt, diisopropylamine salt, and cyclohexylamine salt. Note that salts include hydrous salts.

The compound of the present invention may have an asymmetric center, and in that case, various optical isomers occur. Accordingly, the compound of the present invention may occur as a separate optically active substance (R) or (S), and as a racemate or an (RS) mixture. Also, when the compound has two or more asymmetric centers, diastereomers also result from the respective optical isomerisms. The compound of the present invention also includes mixtures containing all these forms in any proportions. For example, a diastereomer can be separated by methods well known to those skilled in the art such as a fractional crystallization method, and, also, an optically active substance can be obtained by techniques in organic chemistry that are well known for this purpose. Also, the compound of the present invention may occur as geometric isomers such as a cis and a trans form. Moreover, the compound of the present invention has tautomerism and occurs as various tautomers. The compound of the present invention also includes those isomers as well as mixtures containing those isomers in any proportions.

Moreover, when the compound of the present invention or a salt thereof forms a hydrate or a solvate, these are also included within the scope of the compound of the present invention or a salt thereof.

The 20-HETE producing enzymes refer to cytochrome P450 4A11 and 4F2 that catalyze hydroxylation at ω-position of arachidonic acid to produce 20-HETE using arachidonic acid as a substrate.

Now, as already described above, 20-HETE displays diverse functions in a living body and is involved in the onset of polycystic kidney disease and the pathologies of various cerebrovascular diseases, renal diseases, cardiovascular diseases, and the like.

Accordingly, by inhibiting the 20-HETE producing enzymes, it is possible to prevent or ameliorate polycystic kidney disease, diseases associated with polycystic kidney disease, and symptoms associated with polycystic kidney disease. Also, it is possible to prevent or ameliorate hypertension, cerebrovascular diseases, ischemic heart diseases, chronic renal failure, arteriosclerosis, fatty liver, and cancer.

The compound of the present invention acts to inhibit the 20-HETE producing enzymes. Thus, the compound of the present invention can be used as a 20-HETE producing enzyme inhibitor or an active ingredient of a prophylactic or ameliorating agent for polycystic kidney disease.

Also, it is possible to use the compound of the present invention as an active ingredient of a prophylactic or ameliorating agent for hypertension, cerebrovascular diseases, ischemic heart diseases, chronic renal failure, arteriosclerosis, fatty liver, and cancer.

Here, “polycystic kidney disease” includes “autosomal dominant polycystic kidney disease” and “autosomal recessive polycystic kidney disease”, and in which a great number of cysts progressively develop and increase in both kidneys due to genetic mutation. Examples of “diseases associated with polycystic kidney disease” include chronic renal failure, hypertension, vascular disorders, hepatic and pancreatic cysts, urinary tract infections, hepatobiliary infections, urolithiasis, and the like. Also, “symptoms associated with polycystic kidney disease” include pain, hematuria, and abdominal distention.

The action of the compound of the present invention for inhibiting the 20-HETE producing enzymes can be evaluated by known procedures such as the method described in the following Test Examples of the present specification.

Concerning the pharmaceutical according to the present invention, the contained inventive compound, i.e., the compound inhibiting the 20-HETE producing enzymes, or a pharmaceutically acceptable salt thereof, can be administered either alone or in combination with a pharmaceutically or pharmacologically acceptable additive.

Additives that can be used include excipients or diluents in common use, and if necessary, binders, disintegrants, lubricants, coating agents, sugar coating agents, pH adjusters, solubilizers, or aqueous or nonaqueous solvents that are in general use. Specific examples include water, lactose, dextrose, fructose, sucrose, sorbitol, mannitol, polyethylene glycol, propylene glycol, starch, cornstarch, gum, gelatin, alginate, calcium silicate, calcium phosphate, cellulose, water syrup, methylcellulose, polyvinylpyrrolidone, alkylparahydroxybenzoate, talc, stearic acid, magnesium stearate, agar, pectin, gum arabic, glycerin, sesame oil, olive oil, soybean oil cacao butter, ethylene glycol, low viscosity hydroxypropylcellulose (HPC-L), microcrystalline cellulose, carboxymethylcellulose (CMC), sodium carboxymethylcellulose (CMC-Na), and other commonly used additives.

The pharmaceutical according to the present invention may be in any form selected from a solid composition, a liquid composition, and other compositions, and an optimum form is selected as necessary.

The pharmaceutical according to the present invention can be produced by adding the above-mentioned additives to the compound of the present invention and preparing a tablet, pill, capsule, granule, dust, powder, liquid, emulsion, suspension, injection, or the like by a commonly used formulating technique.

Also, the pharmaceutical according to the present invention can be formulated by forming a clathrate from the compound of the present invention and α, β, or γ-cyclodextrin or methylated cyclodextrin or the like.

The pharmaceutical according to the present invention can be a single preparation (a combined drug) containing the compound of the present invention and concomitantly usable compound(s), or two or more preparations (combination drugs) obtained by separately formulating the respective compounds.

When these compounds are separately formulated as two or more preparations, the individual preparations can be administered simultaneously or at certain time intervals. In the latter case, whichever may be administered earlier. The two or more preparations can each be administered a different number of times a day. Also, the two or more preparations can be administered through different routes as well.

When these compounds are separately formulated as two preparations, they may be administered simultaneously or at extremely short intervals, and in such a case, it is preferred that a package insert, a sales brochure, or the like of a commercially available pharmaceutical state to the effect that the preparations are used in combination.

It is also preferred to formulate these active ingredients separately and form a kit composed of two preparations.

When the compound of the present invention is used as a 20-HETE producing enzyme inhibitor or the like, the compound of the present invention may be orally administered as it is. Alternatively, the compound of the present invention may be orally administered in the form of an agent containing the compound as an active ingredient.

When the compound of the present invention is used as a prophylactic or ameliorating agent or the like for polycystic kidney disease, the compound of the present invention may be orally administered as it is. Alternatively, the compound of the present invention may be orally administered in the form of an agent containing the compound as an active ingredient.

The dosage of the compound of the present invention varies with the subject to which it is administered, the route of administration, the disease to be treated, the symptoms, and the like; take, for example, the case of oral administration to an adult patient, and the dosage is normally 0.1 mg to 1000 mg, preferably 1 mg to 200 mg, as a single dose and this dosage is desirably administered 1 to 3 times a day or once every 2 to 3 days.

Examples of producing preparations of the compound of the present invention are described below.

Preparation Example 1

Granules containing the following ingredients are produced.

Ingredients: Compound represented by formula [I] or pharmaceutically acceptable salt thereof, lactose, cornstarch, and HPC-L.

The compound represented by formula [I] or a pharmaceutically acceptable salt thereof and lactose are sieved. Cornstarch is sieved. These are mixed in a mixer. An aqueous solution of HPC-L is added to the mixed powder, and the mixture is kneaded, granulated (extrusion-granulated), and then dried. The resulting dried granules are passed through a vibrating sieve to give granules.

Preparation Example 2

A powder for encapsulation containing the following ingredients is produced.

Ingredients: Compound represented by formula [I] or pharmaceutically acceptable salt thereof, lactose, cornstarch, and magnesium stearate.

The compound represented by formula [I] or a pharmaceutically acceptable salt thereof and lactose are sieved. Cornstarch is sieved. These and magnesium stearate are mixed in a mixer to give a powder. Capsules can be filled with the resulting powder.

Preparation Example 3

Granules for encapsulation containing the following ingredients are produced.

Ingredients: Compound represented by formula [I] or pharmaceutically acceptable salt thereof, lactose, cornstarch, and HPC-L.

The compound represented by formula [I] or a pharmaceutically acceptable salt thereof and lactose are sieved. Cornstarch is sieved. These are mixed in a mixer. An aqueous solution of HPC-L is added to the mixed powder, and the mixture is kneaded, granulated, and then dried. The resulting dried granules are passed through a vibrating sieve for classification to give granules. Capsules can be filled with the resulting granules.

Preparation Example 4

A tablet containing the following ingredients is produced.

Ingredients: Compound represented by formula [I] or pharmaceutically acceptable salt thereof, lactose, microcrystalline cellulose, magnesium stearate, and CMC-Na.

The compound represented by formula [I] or a pharmaceutically acceptable salt thereof, lactose, microcrystalline cellulose, and CMC-Na are sieved and mixed. Magnesium stearate is added to the mixed powder to give a mixed powder for pharmaceutical preparation. This mixed powder is directly pressed to give a tablet.

Hereinafter, the production method for compound [I] according to the present invention will be described in detail, but the production method is not particularly limited to the examples given below. The solvent which is used in the reaction may be any solvent as long as it does not interfere with the respective reactions, and it is not particularly limited to the following description.

Compound [I] of the present invention can be produced by methods known per se, for example, production methods 1 to 44 shown below, or modifications thereof.

In addition, in the production of compound [I] of the present invention, the order of the respective steps in each production method can be appropriately changed.

In each of the following production methods, starting compounds may be used in a salt form thereof; and examples of the salt include the previously described “pharmaceutically acceptable salts”.

Among compound [I] of the present invention, methods for producing the compound in which the structure represented by formula [II] below is a structure of formula [III-1] below (hereinafter also referred to as compound [I-1]) are shown in production methods 1 to 35; methods for producing the compound in which the structure represented by formula [II] below is a structure of formula [III-2] below (hereinafter also referred to as compound [I-2]) are shown in production methods 36 to 38; methods for producing the compound in which the structure represented by formula [II] below is a structure of formula [III-3] below (hereinafter also referred to as compound [I-3]) are shown in production methods 39 to 41; and methods for producing the compound in which the structure represented by formula [II] below is a structure of formula [III-4] or formula [III-5] below (hereinafter also referred to as compound [I-4] and compound [I-5], respectively) are shown in production methods 42 to 44.

Compound [1-e] which is an intermediate in the production of compound [I-1] of the present invention can be produced, for example, by production method 1 below or a method pursuant thereto.

Production Method 1

[In the scheme,

R 1 , R 2 , R 3 , and R 4 are the same as defined above;

X A represents a chlorine atom or a bromine atom; and

G represents a boronic acid group or a boronic acid ester group, and

Pro 1 represents a protecting group for hydroxy, as exemplified by:

(i) benzyl, 4-methoxybenzyl, and the like (protecting groups which form a benzyl ether structure together with the hydroxy, and herein also referred to as “benzyl ether-based protecting group”);

(ii) methoxymethyl, tetrahydropyranyl, and the like (protecting groups which form an acetal structure together with the hydroxy, and herein also referred to as “acetal-based protecting group”);

(iii) trimethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, and the like (protecting groups which form a silyl ether structure together with the hydroxy, and herein also referred to as “silyl ether-based protecting group”); and

Pro 2 represents a protecting group for azoles which are typified by pyrazolyl, for example, tetrahydropyranyl, triphenylmethyl, and the like]

[Step 1-1]

This step is a method of producing compound [1-b] by protecting the hydroxy of compound [1-a] with protecting group Pro′.

This reaction can be carried out by the method described in the literature (Protective Groups in Organic Synthesis, 4th edition, 2007, edited by G. M. Wuts and T. W. Greene), or a method pursuant thereto.

[Step 1-2]

This step is a method of producing compound [1-d] by reacting compound [1-b] with compound [1-c].

This reaction is a so-called Suzuki-Miyaura coupling reaction that can be carried out by a process which is described in the literature (Tetrahedron Letters, Vol. 20, page 3437, 1979, Chemical Reviews, Volume 95, page 2457, 1995) in the presence of a palladium catalyst and a base, or a process pursuant thereto.

The amount of compound [1-c] which is used in the present reaction is 1 to 5 equivalents, and preferably 1 to 3 equivalents, with respect to 1 equivalent of compound [1-b].

Examples of the palladium catalysts include tetrakis(triphenylphosphine)palladium(0), a [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct, and bis(triphenylphosphine)palladium(II) dichloride. The amount of the palladium catalyst to be used is usually 0.001 to 0.5 equivalents, and preferably 0.001 to 0.3 equivalents, with respect to 1 equivalent of compound [1-b].

Examples of the base include: alkali metal carbonates such as potassium carbonate, cesium carbonate, and sodium carbonate, or aqueous solutions thereof; potassium fluoride; cesium fluoride; and triethylamine. The amount of the base to be used is usually 1 to 5 equivalents, and preferably 1 to 3 equivalents, with respect to 1 equivalent of compound [1-b].

Examples of the reaction solvent include solvents that do not interfere with reactions, such as N,N-dimethylformamide, dimethylsulfoxide, toluene, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, ethanol, and water; and these solvents may be mixed with each other at an appropriate ratio and used.

These reactions can be carried out usually at room temperature to reflux temperature for 1 to 24 hours, and can be also carried out under microwave irradiation.

As described above, as compound [I′] of the present invention includes a tautomer thereof, compound [1-d] and the like, which are substituted with protecting group Pro 2 of pyrazolyl, may include an isomer thereof. As examples of the isomers, compound [1-d] and its isomer [1-d-α] are shown below.

[Step 1-3]

This step is a method of producing compound [1-e] by deprotecting the hydroxy of compound [1-d] by removing protecting group Pro′.

(i) When Pro′ is a benzyl ether-based protecting group such as benzyl and 4-methoxybenzyl, the present reaction can be carried out in a solvent which does not interfere with the reaction, in the presence of a metal catalyst and a hydrogen source.

Examples of the metal catalyst which is used in the present reaction include palladium carbon and palladium hydroxide carbon. The amount of the metal catalyst to be used is 0.001 to 1 equivalent, and preferably 0.01 to 0.5 equivalents, with respect to 1 equivalent of compound

A hydrogen pressure which is used in the present reaction is ordinary pressure to 10 atm, and preferably ordinary pressure to 4 atm.

Examples of the solvent which is used in the present reaction include methanol, ethanol, water, tetrahydrofuran, and ethyl acetate; and these solvents may be mixed with each other at an appropriate ratio and used.

The present reaction can be carried out usually at room temperature to reflux temperature for 1 to 24 hours.

(ii) When Pro 1 is an acetal-based protecting group such as methoxymethyl and tetrahydropyranyl, the present reaction can be carried out in a solvent which does not interfere with the reaction in the presence of an acid.

Examples of the acid which is used in the present reaction include hydrochloric acid and trifluoroacetic acid. The amount of the acid to be used is 1 to 5 equivalents, and preferably 1 to 3 equivalents, with respect to 1 equivalent of compound

Examples of the solvent which is used in the present reaction include solvents that do not interfere with reactions, such as methanol, ethanol, water, dichloromethane, and chloroform; and these solvents may be mixed with each other at an appropriate ratio and used.

The present reaction can be carried out usually at room temperature to reflux temperature for 1 to 24 hours.

(iii) When Pro 1 is a silyl ether-based protecting group such as trimethylsilyl, triisopropylsilyl, and tert-butyldimethylsilyl, the present reaction can be carried out in a solvent which does not interfere with the reaction in the presence of an acid.

Examples of the acid which is used in the present reaction include hydrochloric acid, acetic acid, and trifluoroacetic acid. The amount of the acid to be used is 1 to 5 equivalents, and preferably 1 to 3 equivalents, with respect to 1 equivalent of compound [1-d].

Examples of the solvent which is used in the present reaction include solvents that do not interfere with reactions, such as tetrahydrofuran, methanol, ethanol, and water; and these solvents may be mixed with each other at an appropriate ratio and used.

The present reaction can be carried out usually at room temperature to reflux temperature for 1 to 24 hours.

In addition, the present reaction can also be carried out in a solvent which does not interfere with the reaction in the presence of a fluoride ion.

Examples of the fluoride ion source which is used in the present reaction include potassium fluoride and tetrabutylammonium fluoride. The amount of the fluoride ion source to be used is 1 to 5 equivalents, and preferably 1 to 3 equivalents, with respect to 1 equivalent of compound [1-d].

Examples of the solvent which is used in the present reaction include solvents that do not interfere with reactions, such as tetrahydrofuran, N,N-dimethylformamide, methanol, and ethanol; and these solvents may be mixed with each other at an appropriate ratio and used.

The present reaction can be carried out usually at room temperature to reflux temperature for 1 to 24 hours.

Compound [1-e] thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, and chromatography.

Incidentally, compounds [1-a] and [1-c] which are used as starting compounds in production method 1 above can be produced by a method known per se, or can be obtained by purchasing commercial products.

Among compound [1-e] which is an intermediate in the production of compound [I] of the present invention, compound [2-b] in which R 1 is a chlorine atom or a bromine atom can be produced, for example, by production method 2 below or a method pursuant thereto.

Production Method 2

[In the scheme,

R 2 , R 3 , R 4 , and Pro 2 are the same as defined above; and

X A′ represents a chlorine atom or a bromine atom.]

[Step 2-1]

This step is a method of producing compound [2-b] by reacting compound [2-a] which is that type of compound [1-e] in which R 1 is a hydrogen atom with a halogenating agent.

Examples of the halogenating agent which is used in the present reaction include N-chlorosuccinimide (NCS) and N-bromosuccinimide (NBS). The amount of the reagent to be used is 1 to 5 equivalents, and preferably 1 to 1.1 equivalents, with respect to 1 equivalent of compound [2-a].

Examples of the solvent which is used in the present reaction include solvents that do not interfere with reactions, such as chloroform, dichloromethane, carbon tetrachloride, acetonitrile, ethyl acetate, N,N-dimethylformamide, and water; and these solvents may be mixed with each other at an appropriate ratio and used.

The present reaction can be carried out usually at 0° C. to reflux temperature for 1 to 48 hours.

In addition, the present reaction can be similarly carried out for an unprotected substrate, that is, when Pro 2 is a hydrogen atom.

Compound [2-a] which is used as a starting compound in production method 2 above can be produced by production method 1 above, a method pursuant thereto, or a method known per se.

Among compound [1-e] which is an intermediate in the production of compound [I] of the present invention, compound [3-e] in which R 1 is difluoromethyl can be produced, for example, by production method 3 below or a method pursuant thereto.

Production Method 3

[In the scheme,

R 2 , R 3 , R 4 , Pro′, and Pro 2 are the same as defined above.]

[Step 3-1]

This step is a method of producing compound [3-b] by regioselectively brominating compound [3-a] which is that type of compound [1-d] in which R 1 is a hydrogen atom.

The present reaction can be carried out by the method described in step 2-1 of production method 2 or a method pursuant thereto.

[Step 3-2]

This step is a method of producing compound [3-c] by reacting compound [3-b] with an alkyl lithium compound and then reacting the resulting reaction intermediate with a formamide compound.

Examples of the alkyl lithium compound which is used in the reaction with compound [3-b] include n-butyl lithium. The amount of the alkyl lithium compound to be used is 1 to 5 equivalents, and preferably 1 to 3 equivalents, with respect to 1 equivalent of compound [3-b].

Examples of the solvent which is used in the present reaction include solvents that do not interfere with reactions, such as diethyl ether, tetrahydrofuran, 1,4-dioxane, toluene, and xylene; and these solvents may be mixed with each other at an appropriate ratio and used.

The present reaction can be carried out usually at −80° C. to −50° C. for 0.1 to 1 hour.

Examples of the formamide compound which is used in the reaction with the reaction intermediate to be generated include N,N-dimethyl formamide and N-methoxy-N-methylformamide. The amount of the formamide compound to be used is 1 to 5 equivalents, and preferably 1 to 3 equivalents, with respect to 1 equivalent of compound [3-b].

The present reaction can be carried out usually at −80° C. to room temperature for 0.1 to 24 hours.

[Step 3-3]

This step is a method of producing compound [3-d] by converting the formyl of compound [3-c] to difluoromethyl.

Examples of the fluorinating reagent which is used in the reaction with compound [3-c] include tetrafluoro sulfur (IV), (N,N-diethylamino)sulfur trifluoride (DAST), and bis(2-methoxyethyl)aminosulfur trifluoride (BAST). The amount of the fluorinating reagent to be used is 1 to 5 equivalents, and preferably 1 to 3 equivalents, with respect to 1 equivalent of compound [3-c].

Examples of the solvent to be used in the present reaction include solvents that do not interfere with reactions, such as dichloromethane, chloroform, acetonitrile, tetrahydrofuran, 1,4-dioxane, toluene, and xylene; and these solvents may be mixed with each other at an appropriate ratio and used.

The present reaction can be carried out usually at room temperature to reflux temperature for 1 to 24 hours.

[Step 3-4]

This step is a method of producing compound [3-e] by deprotecting compound [3-d] by removing protecting group Pro′.

This step can be carried out by step 1-3 of production method 1 or a method pursuant thereto.

Compound [3-e] thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, and chromatography.

Incidentally, compound [3-a] which is used as a starting compound in production method 3 can be obtained by steps 1-1 and 1-2 of production method 1 or a method pursuant thereto.

Compound [4-c] which is an intermediate in the production of that type of compound [I-1] of the present invention in which the structure represented by R 5 is a structure shown in formula [IV-1] below can be produced, for example, by production method 4 below or a method pursuant thereto.

Production Method 4

[In the scheme,

R 1 , R 2 , R 3 , R 4 , Pro 2 , R 51 , and W 1 are the same as defined above; LG 1 represents hydroxy or a leaving group; and

the “leaving group” represented by LG 1 refers to, for example, a halogen atom such as a chlorine atom and a bromine atom, C 1-4 alkylsulfonyloxy such as methanesulfonyloxy, or arylsulfonyloxy such as p-toluenesulfonyloxy.]

[Step 4-1]

This step is a method of producing compound [4-b] by reacting compound [1-e] with compound [4-a].

(i) When LG 1 in compound [4-a] is hydroxy, the present reaction can be carried out by a known method, i.e., the so-called “Mitsunobu reaction” (page 1, Synthesis, 1981).

The amount of compound [4-a] which is used in the present reaction is 1 to 5 equivalents, and preferably 1 to 3 equivalents, with respect to 1 equivalent of compound [1-e].

Examples of the azo compound which is used in the present reaction include bis(2-methoxyethyl) azodicarboxylate, diisopropyl azodicarboxylate, and 1,1′-azobis(N,N-dimethylformamide). The amount of the azo compound to be used is 1 to 5 equivalents, and preferably 1 to 3 equivalents, with respect to 1 equivalent of compound [1-e].

Examples of the phosphine compound which is used in the present reaction include triphenylphosphine and tributylphosphine. The amount of the phosphine compound to be used is 1 to 5 equivalents, and preferably 1 to 3 equivalents, with respect to 1 equivalent of compound [1-e].

Examples of the solvent which is used in the present reaction include solvents that do not interfere with reactions, such as tetrahydrofuran, 1,4-dioxane, diethyl ether, chloroform, dichloromethane, toluene, N,N-dimethylformamide, and dimethyl sulfoxide; and these solvents may be mixed with each other at an appropriate ratio and used.

The present reaction can be carried out usually at room temperature to reflux temperature for 1 to 24 hours.

The present reaction may also be carried out by the method described in Tetrahedron Letters, Vol. 36, page 2531, 1995 or Tetrahedron Letters, Vol. 37, page 2463, 1996.

Examples of the reagent which is used in the present reaction include cyanomethylenetrimethylphosphorane and cyanomethylenetributylphosphorane. The amount of the reagent to be used is 1 to 5 equivalents, and preferably 1 to 3 equivalents, with respect to 1 equivalent of compound [1-e].

Examples of the solvent which is used in the present reaction are the same as those used in the Mitsunobu reaction described above.

The present reaction can be carried out usually at room temperature to reflux temperature for 1 to 24 hours.

(ii) When LG 1 in compound [4-a] is a leaving group, the present reaction can be carried out in the presence of a base.

The amount of compound [4-a] which is used in the present reaction is 1 to 5 equivalents, and preferably 1 to 3 equivalents, with respect to 1 equivalent of compound [1-e].

Examples of the base which is used in the present reaction include amines such as triethylamine, N,N-diisopropylethylamine, and 1,8-diazabicyclo[4,3,0]undec-7-ene, alkali metal hydrides such as sodium hydride, alkali metal hydroxides such as potassium hydroxide, alkali metal carbonates such as cesium carbonate, potassium carbonate, and sodium carbonate, and alkoxy alkali metal such as potassium tert-butoxide. The amount of the base to be used is 1 to 5 equivalents, and preferably 1 to 3 equivalents, with respect to 1 equivalent of compound [1-e].

Examples of the solvent which is used in the present reaction include solvents that do not interfere with reactions, such as tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide, N, N-dimethylacetamide, and N-methylpyrrolidone; and these solvents may be mixed with each other at an appropriate ratio and used.

The present reaction can be carried out usually at room temperature to reflux temperature for 1 to 24 hours.

When LG 1 in compound [4-a] is hydroxy, the present reaction can also be carried out after hydroxy is converted to a leaving group.

The hydroxy may be converted to a leaving group by a usual method. For example, compound [4-a] in which LG 1 is a leaving group may be prepared by the reaction with (a) a halogenating reagent or (b) a sulfonate esterification reagent in the presence of a base in a solvent which does not interfere with the reaction.

Examples of (a) halogenating reagent used in the present reaction include thionyl chloride, phosphoryl chloride, N-chlorosuccinimide, bromine, and N-bromosuccinimide. The amount of the halogenating reagent to be used is 1 to 5 equivalents, and preferably 1 to 3 equivalents, with respect to 1 equivalent of the compound having hydroxy.

Examples of the solvent which is used in the present reaction include solvents that do not interfere with reactions, such as chloroform and dichloromethane; and these solvents may be mixed with each other at an appropriate ratio and used.

The present reaction can be carried out usually at room temperature to reflux temperature for 1 to 24 hours.

Furthermore, examples of (b) sulfonate esterification reagent used in the present reaction include methanesulfonyl chloride, trifluoromethanesulfonyl chloride, and p-toluenesulfonyl chloride. The amount of the sulfonate esterification reagent to be used is 1 to 5 equivalents, and preferably 1 to 3 equivalents, with respect to 1 equivalent of the compound having hydroxy.

Examples of the base which is used in the present reaction include triethylamine, N,N-diisopropylethylamine, pyridine, and 4-dimethylaminopyridine. The amount of the base to be used is 1 to 5 equivalents, and preferably 1 to 3 equivalents, with respect to 1 equivalent of the sulfonate esterification reagent to be used.

Examples of the solvent which is used in the present reaction include solvents that do not interfere with reactions, such as chloroform and dichloromethane; and these solvents may be mixed with each other at an appropriate ratio and used.

The present reaction can be carried out usually at room temperature to reflux temperature for 1 to 24 hours.

[Step 4-2]

This step is a method of producing compound [4-c] by deprotecting the pyrazolyl of compound [4-b] by removing protecting group Pro 2 under an acidic condition.

Examples of the acid which is used in the present reaction include hydrochloric acid, formic acid, and trifluoroacetic acid. The amount of the acid to be used is 1 equivalent to a solvent amount, and preferably 1 to 10 equivalents, with respect to 1 equivalent of compound [4-b].

Examples of the solvent which is used in the present reaction include solvents that do not interfere with reactions, such as methanol, ethanol, tetrahydrofuran, water, ethyl acetate, and 1,4-dioxane; and these solvents may be mixed with each other at an appropriate ratio and used.

The present reaction can be carried out usually at 0° C. to reflux temperature for 1 to 24 hours.

Compound [4-c] thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, and chromatography.

Compounds [1-e] and [4-a] which are used as starting compounds in production method 4 above can be produced by production method 1 above, a method pursuant thereto, or a method known per se, or can be obtained by purchasing commercial products.

Among compound [I-1] of the present invention, compound [5-e] in which the structure represented by R 5 is a structure shown in formula [IV-2] below and R 52 is carboxy can be produced, for example, by production method 5 below or a method pursuant thereto.

Production Method 5

[In the scheme,

R 1 , R 2 , R 3 , R 4 , Pro 2 , L, Y, W 2 , and LG 1 are the same as defined above; and

Pro 3 represents primary or secondary alkyl such as methyl, ethyl, and 2-propyl; a benzyl-based protecting group such as benzyl and 4-methoxybenzyl; or tert-butyl]

[Step 5-1]

This step is a method of producing compound [5-b] by reacting compound [1-e] with compound [5-a].

This reaction can be carried out by the method described in step 4-1 of production method 4 or a method pursuant thereto.

There are several synthesis pathways for production of compound [5-e]. Steps 5-2 to 5-6 therefor will be sequentially described.

(i) When Pro 3 in compound [5-b] is primary or secondary alkyl such as methyl, ethyl, and 2-propyl, or (ii) when Pro 3 in compound [5-b] is a benzyl-based protecting group such as benzyl and 4-methoxybenzyl, compound [5-e] can be produced via compound [5-c] by methods described in steps 5-2 and 5-3.

[Step 5-2]

This step is a method of producing compound [5-c] by deprotecting compound [5-b] by removing protecting group Pro 3 .

(i) When Pro 3 in compound [5-b] is primary or secondary alkyl such as methyl, ethyl, and 2-propyl, the present reaction can be carried out under a basic condition.

Examples of the base which is used in the present reaction include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide. The amount of the base to be used is 1 to 100 equivalents, and preferably 1 to 10 equivalents, with respect to 1 equivalent of compound [5-b].

Examples of the solvent which is used in the present reaction include solvents that do not interfere with reactions, such as methanol, ethanol, 2-propanol, acetone, tetrahydrofuran, 1,4-dioxane, and water; and these solvents may be mixed with each other at an appropriate ratio and used.

The present reaction can be carried out usually at 0° C. to reflux temperature for 1 to 24 hours.

(ii) When Pro 3 in compound [5-b] is a benzyl-based protecting group such as benzyl and 4-methoxybenzyl, the present reaction can be carried out by the method described in (i) or the method described in step 1-3 (i) of production method 1, or a method pursuant thereto.

[Step 5-3]

This step is a method of producing compound [5-e] by deprotecting the pyrazolyl of compound [5-c] by removing protecting group Pro 2 under an acidic condition.

This reaction can be carried out by the method described in step 4-2 of production method 4 or a method pursuant thereto.

(i) When Pro 3 in compound [5-b] is primary or secondary alkyl such as methyl, ethyl, and 2-propyl, (ii) when Pro 3 in compound [5-b] is a protecting group such as benzyl and 4-methoxybenzyl, or (iii) when Pro 3 in compound [5-b] is tert-butyl, compound [5-e] can be produced via compound [5-d] by methods described in steps 5-4 and 5-5.

[Step 5-4]

This step is a method of producing compound [5-d] by deprotecting the pyrazolyl of compound [5-b] by removing protecting group Pro 2 under an acidic condition.

(i) When Pro 3 in compound [5-b] is primary or secondary alkyl such as methyl, ethyl, and 2-propyl, or (ii) when Pro 3 in compound [5-b] is a benzyl-based protecting group such as benzyl and 4-methoxybenzyl, the present reaction can be carried out by the method described in step 4-2 of production method 4 or a method pursuant thereto.

(iii) When Pro 3 in compound [5-b] is tert-butyl, the present reaction can be carried out under a relatively moderately acidic condition.

Examples of the acid which is used in the present reaction include hydrochloric acid, formic acid, and trifluoroacetic acid. The amount of the acid to be used is 1 equivalent to a solvent amount, and preferably 1 to 10 equivalents, with respect to 1 equivalent of compound [5-b].

Examples of the solvent which is used in the present reaction include solvents that do not interfere with reactions, such as methanol, ethanol, tetrahydrofuran, water, ethyl acetate, and 1,4-dioxane; and these solvents may be mixed with each other at an appropriate ratio and used.

The present reaction can be carried out usually at 0° C. to room temperature for 1 to 24 hours.

[Step 5-5]

This step is a method of producing compound [5-e] by deprotecting compound [5-d] by removing protecting group Pro 3 .

(i) When Pro 3 in compound [5-d] is primary or secondary alkyl such as methyl, ethyl, and 2-propyl, the present reaction can be carried out by the method described in step 5-2 (i) of production method 5 or a method pursuant thereto.

(ii) When Pro 3 in compound [5-d] is a benzyl-based protecting group such as benzyl and 4-methoxybenzyl, the present reaction can be carried out by the method described in (i) or the method described in step 1-3 of production method 1, or a method pursuant thereto.

(iii) When Pro 3 in compound [5-d] is tert-butyl, the present reaction can be carried out under an acidic condition.

Examples of the acid which is used in the present reaction include hydrochloric acid and trifluoroacetic acid. The amount of the acid to be used is 1 equivalent to a solvent amount, and preferably 1 to 10 equivalents, with respect to 1 equivalent of compound [5-d].

Examples of the solvent which is used in the present reaction include solvents that do not interfere with reactions, such as methanol, ethanol, tetrahydrofuran, water, ethyl acetate, and 1,4-dioxane; and these solvents may be mixed with each other at an appropriate ratio and used.

The present reaction can be carried out usually at 50° C. to reflux temperature for 1 to 24 hours.

When Pro 3 in compound [5-b] is 4-methoxybenzyl or tert-butyl, compound [5-e] can be produced by step 5-6.

[Step 5-6]

This step is a method of producing compound [5-e] by deprotecting compound [5-b] by removing protecting groups Pro 2 and Pro 3 under an acidic condition.

This reaction can be carried out by the method described in step 5-5 (iii) of production method 5 or a method pursuant thereto.

Compound [5-e] thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, and chromatography.

Compounds [1-e] and [5-a] which are used as starting compounds in production method 5 above can be produced by production method 1 above, a method pursuant thereto, or a method known per se, or can be obtained by purchasing commercial products.

Alternatively, compound [5-e] can be produced, for example, by production method 6 below or a method pursuant thereto.

Production Method 6

[In the scheme,

R 1 , R 2 , R 3 , R 4 , X A , Pro 2 , Pro 3 , W 2 , Y, L, LG 1 , and G are the same as defined above.]

[Step 6-1]

This step is a method of producing compound [6-a] by reacting compound [1-a] with compound [5-a].

This reaction can be carried out by the method described in step 4-1 of production method 4 or a method pursuant thereto.

[Step 6-2]

This step is a method of producing compound [5-b] by reacting compound [6-a] with compound [1-c].

This reaction can be carried out by the method described in step 1-2 of production method 1 or a method pursuant thereto.

Compound [5-e] may be derived from compound [5-b] thus obtained by the method described in steps 5-2 to 5-6 of production method 5 or a method pursuant thereto.

Compounds [1-a], [5-a], and [1-c] which are used as starting compounds in production method 6 above can be produced by a method known per se, or can be obtained by purchasing commercial products.

Among compound [I-1] of the present invention, compound [7-f] which is that type of compound [5-e] in which Y is the formula —O— can be produced, for example, by production method 7 below or a method pursuant thereto.

Production Method 7

[In the scheme,

R 1 , R 2 , R 3 , R 4 , Pro 2 , Pro 3 , LG 1 , W 2 , and L are the same as defined above;

LG 2 represents, independently of LG 1 , a leaving group such as hydroxy; a halogen atom such as a chlorine atom and a bromine atom; C 1-4 alkylsulfonyloxy such as methanesulfonyloxy; and arylsulfonyloxy such as p-toluenesulfonyloxy.]

[Step 7-1]

This step is a method of producing compound [7-b] by reacting compound [1-e] with compound [7-a].

This reaction can be carried out by the method described in step 4-1 of production method 4 or a method pursuant thereto.

[Step 7-2]

This step is a method of producing compound [7-d] by reacting compound [7-b] with compound [7-c].

This reaction can be carried out by the method described in step 4-1(ii) of production method 4 or a method pursuant thereto.

[Step 7-3]

This step is a method of producing compound [7-e] by deprotecting the pyrazolyl of compound [7-d] by removing protecting group Pro 2 under an acidic condition.

This reaction can be carried out by the method described in step 4-2 of production method 4 or the method described in step 5-4 of production method 5, or a method pursuant thereto.

[Step 7-4]

This step is a method of producing compound [7-f] by deprotecting compound [7-e] by removing protecting group Pro 3 .

This reaction can be carried out by the method described in step 5-5 of production method 5 or a method pursuant thereto.

Steps 7-3 and 7-4 above may be carried out in the reversed order.

Compound [7-f] thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, and chromatography.

Incidentally, compounds [1-e], [7-a], and [7-c] which are used as starting compounds in production method 7 above can be produced by the method described in production method 1 above, a method pursuant thereto, or a method known per se, or can be obtained by purchasing commercial products.

Among compound [I-1] of the present invention, compound [8-g] which is that type of compound [5-e] in which Y is the formula —NHCO— can be produced, for example, by production method 8 below or a method pursuant thereto.

Production Method 8

[In the scheme,

R 1 , R 2 , R 3 , R 4 , Pro 2 , Pro 3 , LG 1 , W 2 , and L are the same as defined above; and

Pro 3 ′ represents primary or secondary alkyl such as methyl, ethyl, and isopropyl; or a benzyl-based protecting group such as benzyl and 4-methoxybenzyl.]

[Step 8-1]

This step is a method of producing compound [8-b] by reacting compound [1-e] with compound [8-a].

This reaction can be carried out by the method described in step 4-1 of production method 4 or a method pursuant thereto.

[Step 8-2]

This step is a method of producing compound [8-c] by removing Pro 3 ′ in compound [8-b] under a basic condition.

This reaction can be carried out by the method described in step 5-2 (i) of production method 5 or a method pursuant thereto.

[Step 8-3]

This step is a method of producing compound [8-e] by reacting compound [8-c] with compound [8-d].

This reaction is a so-called condensation reaction that can be carried out by a known method, for example, by using a condensation agent in the presence or absence of a base and an additive.

The amount of compound [8-d] to be used in the present reaction is 1 to 5 equivalents, and preferably 1 to 3 equivalents, with respect to 1 equivalent of compound [8-c].

Examples of the condensation agent include O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), dicyclohexylcarbodiimide (CDI), (1H-benzotriazol-1-yloxy)(tripyrrolidin-1-yl)phosphonium hexafluorophosphate (PyBOP), propylphosphonic anhydride (T3P), and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM). The amount of the condensation agent to be used is 1 to 5 equivalents, and preferably 1 to 3 equivalents, with respect to 1 equivalent of compound [8-c].

Examples of the additive which is used in the present reaction include N-hydroxybenzotriazole monohydrate (HOBt) and N-hydroxysuccinimide. The amount of the additive to be used is 1 to 5 equivalents, and preferably 1 to 2 equivalents, with respect to 1 equivalent of compound [8-c].

Examples of the base which is used in the present reaction include tertiary aliphatic amines such as N,N-diisopropylethylamine and triethylamine, and pyridine. The amount of the base to be used is 1 to 5 equivalents, and preferably 1 to 2 equivalents, with respect to 1 equivalent of compound [8-c].

Examples of the solvent which is used in the present reaction include solvents that do not interfere with reactions, such as N,N-dimethylformamide, dichloromethane, chloroform, 1,2-dichloroethane, toluene, tetrahydrofuran, and water; and these solvents may be mixed with each other at an appropriate ratio and used.

The present reaction can be carried out usually at 0° C. to reflux temperature for 1 to 24 hours.

[Step 8-4]

This step is a method of producing compound [8-f] by deprotecting the pyrazolyl of compound [8-e] by removing protecting group Pro 2 under an acidic condition.

This reaction can be carried out by the method described in step 4-2 of production method 4 or the method described in step 5-4 of production method 5, or a method pursuant thereto.

[Step 8-5]

This step is a method of producing compound [8-g] by deprotecting compound [84] by removing protecting group Pro 3 .

This reaction can be carried out by the method described in step 5-5 of production method 5 or a method pursuant thereto.

Steps 8-4 and 8-5 above may be carried out in the reversed order.

Compound [8-g] thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, and chromatography.

Incidentally, compounds [1-e], [8-a], and [8-d] which are used as starting compounds in production method 8 above can be produced by production method 1 above, a method pursuant thereto, or a method known per se, or can be obtained by purchasing commercial products.

Among compound [I-1] of the present invention, compound [9-e] in which the structure represented by R 5 is a structure represented by formula [IV-3] below and R 53 is the formula HOC(═O)-L 1 - can be produced, for example, by production method 9 below or a method pursuant thereto.

Production Method 9

[In the scheme,

R 1 , R 2 , R 3 , R 4 , Pro 2 , Pro 3 , LG 1 , ring B, and W 3 are the same as defined above; and

L 1 represents a single bond, the formula —CH 2 —, or the formula —CH 2 O— (in these formulas, methanediyl may be replaced with any of the structures represented by formula group [VII].]

[Step 9-1]

This step is a method of producing compound [9-b] by reacting compound [1-e] with compound [9-a].

This reaction can be carried out by the method described in step 4-1 of production method 4 or a method pursuant thereto.

There are several synthesis pathways for production of compound [9-e]. Steps 9-2 to 9-6 therefor will be sequentially described.

(i) When Pro 3 in compound [9-b] is primary or secondary alkyl such as methyl, ethyl, and 2-propyl, or (ii) when Pro 3 in compound [9-b] is a benzyl-based protecting group such as benzyl and 4-methoxybenzyl, compound [9-e] can be produced via compound [9-c] by methods described in steps 9-2 and 9-3.

[Step 9-2]

This step is a method of producing compound [9-c] by deprotecting compound [9-b] by removing protecting group Pro 3 .

This reaction can be carried out by the method described in step 5-2 of production method 5 or a method pursuant thereto.

[Step 9-3]

This step is a method of producing compound [9-e] by deprotecting the pyrazolyl of compound [9-c] by removing protecting group Pro 2 under an acidic condition.

This reaction can be carried out by the method described in step 4-2 of production method 4 or a method pursuant thereto.

(i) When Pro 3 in compound [9-b] is primary or secondary alkyl such as methyl, ethyl, and 2-propyl, (ii) when Pro 3 in compound [9-b] is a benzyl-based protecting group such as benzyl and 4-methoxybenzyl, or (iii) when Pro 3 in compound [9-b] is tert-butyl, compound [9-e] can be produced via compound [9-d] by methods described in steps 9-4 and 9-5.

[Step 9-4]

This step is a method of producing compound [9-d] by deprotecting the pyrazolyl of compound [9-b] by removing protecting group Pro 2 under an acidic condition.

This reaction can be carried out by the method described in step 5-4 of production method 5, or a method pursuant thereto.

[Step 9-5]

This step is a method of producing compound [9-e] by deprotecting compound [9-d] by removing protecting group Pro 3 .

This reaction can be carried out by the method described in step 5-5 of production method 5 or a method pursuant thereto.

When Pro 3 in compound [9-b] is 4-methoxybenzyl or tert-butyl, compound [9-e] can be produced by a method described in step 9-6.

[Step 9-6]

This step is a method of producing compound [9-e] by deprotecting compound [9-b] by removing protecting groups Pro 2 and Pro 3 under an acidic condition.

This reaction can be carried out by the method described in step 5-5 (iii) of production method 5 or a method pursuant thereto.

Compound [9-e] thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, and chromatography.

Compounds [1-e] and [9-a] which are used as starting compounds in production method 9 above can be produced by production method 1 above, a method pursuant thereto, or a method known per se, or can be obtained by purchasing commercial products.

Alternatively, compound [9-b] can be produced, for example, by production method 10 below or a method pursuant thereto.

Production Method 10

[In the scheme,

R 1 , R 2 , R 3 , R 4 , X A , Pro 2 , Pro 3 , W 3 , ring B, L 1 , LG 1 , and G are the same as defined above.]

[Step 10-1]

This step is a method of producing compound [10-a] by reacting compound [1-a] with compound [9-a].

This reaction can be carried out by the method described in step 4-1 of production method 4 or a method pursuant thereto.

[Step 10-2]

This step is a method of producing compound [9-b] by reacting compound [10-a] with compound [1-c].

This reaction can be carried out by the method described in step 1-2 of production method 1 or a method pursuant thereto.

Compound [9-e] may be derived from compound [9-b] thus obtained by the method described in steps 9-2 to 9-6 of production method 9 or a method pursuant thereto.

Compounds [1-a], [9-a], and [1-c] which are used as starting compounds in production method 10 above can be produced by a method known per se, or can be obtained by purchasing commercial products.

Among compound [I-1] of the present invention, compound [11-g] can be produced, for example, by production method 11 below or a method pursuant thereto.

Production Method 11

[In the scheme,

R 1 , R 2 , R 3 , R 4 , Pro 2 , Pro 3 , and LG 1 are the same as defined above;

W 31 represents C 2-6 alkanediyl;

Ar represents aryl or heteroaryl; and

X B represents a bromine atom or an iodine atom.]

[Step 11-1]

This step is a method of producing compound [11-b] by reacting compound [1-e] with compound [11-a].

This reaction can be carried out by the method described in step 4-1 of production method 4 or a method pursuant thereto.

[Step 11-2]

This step is a method of producing compound [11-d] by reacting compound [11-b] with compound [11-c].

This reaction is a so-called Sonogashira reaction (“Handbook of Organopalladium Chemistry for Organic Synthesis”, Chapter III.2.8., pp 493-535) that can be carried out in the presence of a palladium catalyst, a copper(I) salt, and a base by a process which is described in the literature or a process pursuant thereto.

The amount of compound [11-c] to be used in the present reaction is usually 1 to 5 equivalents, and preferably 1 to 2 equivalents, with respect to 1 equivalent of compound [11-b].

Examples of the palladium catalyst which is used in the present reaction include tetrakis(triphenylphosphine)palladium(0), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex, and bis(triphenylphosphine)palladium(II) dichloride. The amount of the palladium catalyst to be used is usually 0.001 to 0.5 equivalents, and preferably 0.005 to 0.3 equivalents, with respect to 1 equivalent of compound [11-b].

Examples of the copper(I) salt which is used in the present reaction include copper(I) iodide. The amount of the copper(I) salt to be used is usually 0.01 to 1 equivalent, and preferably 0.02 to 0.3 equivalents, with respect to 1 equivalent of compound [11-b].

Examples of the base which is used in the present reaction include amine such as triethylamine and N,N-diisopropylethylamine. The amount of the base to be used is usually 2 equivalents to a solvent amount, and preferably 2 to 5 equivalents, with respect to 1 equivalent of compound [11-b].

Examples of the reaction solvent which is used in the present reaction include solvents that do not interfere with reactions, such as N,N-dimethylformamide, diethyl ether, 1,4-dioxane, tetrahydrofurane, and 1,2-dimethoxyethane; and these solvents may be mixed with each other at an appropriate ratio and used.

These reactions can be carried out usually at room temperature to reflux temperature for 1 to 24 hours, and can be also carried out under microwave irradiation.

[Step 11-3]

This step is a method of producing compound [11-e] by catalytic hydrogenation of the alkyne of compound [11-d].

This reaction can be carried out in a solvent which does not interfere with the reaction, in the presence of a metal catalyst and a hydrogen source.

Examples of the metal catalyst which is used in the present reaction include palladium carbon, palladium hydroxide carbon, palladium (ethylenediamine complex) carbon, and tris(triphenylphosphine)rhodium(I) chloride. The amount of the metal catalyst to be used is 0.001 to 1 equivalent, and preferably 0.01 to 0.5 equivalents, with respect to 1 equivalent of compound [11-d].

A hydrogen pressure which is used in the present reaction is ordinary pressure to 10 atm, and preferably ordinary pressure to 4 atm.

Examples of the solvent which is used in the present reaction include methanol, ethanol, water, tetrahydrofuran, chloroform, and ethyl acetate; and these solvents may be mixed with each other at an appropriate ratio and used.

The present reaction can be carried out usually at room temperature to reflux temperature for 1 to 24 hours.

[Step 11-4]

This step is a method of producing compound [11-f] by deprotecting the pyrazolyl of compound [11-e] by removing protecting group Pro 2 under an acidic condition.

This reaction can be carried out by the method described in step 4-2 of production method 4 or the method described in step 5-4 of production method 5, or a method pursuant thereto.

[Step 11-5]

This step is a method of producing compound [11-g] by deprotecting compound [11-f] by removing protecting group Pro 3 .

This reaction can be carried out by the method described in step 5-5 of production method 5 or a method pursuant thereto.

Steps 11-4 and 11-5 above may be carried out in the reversed order.

Compound [11-g] thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, and chromatography.

Compounds [1-e], [11-a], and [11-c] which are used as starting compounds in production method 11 above can be produced by production method 1 above, a method pursuant thereto, or a method known per se, or can be obtained by purchasing commercial products.

Among compound [I-1] of the present invention, compound [12-f] can be produced, for example, by production method 12 below or a method pursuant thereto.

Production Method 12

[In the scheme,

R 1 , R 2 , R 3 , R 4 , Pro 2 , Pro 3 , and LG 1 are the same as defined above;

R 7 and R 8 each independently represent a hydrogen atom or methyl,

wherein R 7 and R 8 may form, together with the adjacent carbon atom, C 3-6 cycloalkane, 4- to 6-membered saturated oxygen-containing hetero ring, 4- to 6-membered saturated sulfur-containing hetero ring (the sulfur atom of the 4- to 6-membered saturated sulfur-containing hetero ring may be substituted with 1 or 2 oxo), or 4- to 6-membered saturated nitrogen-containing hetero ring (the nitrogen atom of the 4- to 6-membered saturated nitrogen-containing hetero ring may be substituted with one C 1-4 alkylcarbonyl); and

W 32 represents C 4-8 alkanediyl.]

[Step 12-1]

This step is a method of producing compound [12-b] by reacting compound [1-e] with compound [12-a].

This reaction can be carried out by the method described in step 4-1 of production method 4 or a method pursuant thereto.

[Step 12-2]

This step is a method of producing compound [12-d] by reacting compound [12-b] with compound [12-c].

This reaction is a so-called Huisgen cyclization reaction (Angew. Chem., Int. Ed. Engl. 1963, 2, 565.) that can be carried out using a copper catalyst in the presence or absence of an additive by a process which is described in the literature or a process pursuant thereto.

The amount of compound [12-c] to be used in the present reaction is usually 1 to 5 equivalents, and preferably 1 to 2 equivalents, with respect to compound [12-b].

Examples of the copper catalyst which is used in the present reaction include copper sulfate, copper iodide, copper acetate, and copper trifluoromethanesulfonate-benzene complex. The amount of the copper catalyst to be used is usually 0.01 to 0.5 equivalents, and preferably 0.05 to 0.2 equivalents, with respect to 1 equivalent of compound [12-b].

Examples of the additive which is used in the present reaction include sodium ascorbate. The amount of the additive to be used is usually 0.02 to 1 equivalent, and preferably 0.1 to 0.4 equivalents, with respect to 1 equivalent of compound [12-b].

Examples of the reaction solvent which is used in the present reaction include solvents that do not interfere with reactions, such as N,N-dimethylformamide, ethanol, methanol, 1,4-dioxane, tetrahydrofurane, and water; and these solvents may be mixed with each other at an appropriate ratio and used.

These reactions can be carried out usually at room temperature to reflux temperature for 1 to 24 hours.

[Step 12-3]

This step is a method of producing compound [12-e] by deprotecting the pyrazolyl of compound [12-d] by removing protecting group Pro 2 under an acidic condition.

This reaction can be carried out by the method described in step 4-2 of production method 4 or the method described in step 5-4 of production method 5, or a method pursuant thereto.

[Step 12-4]

This step is a method of producing compound [124] by deprotecting compound [12-e] by removing protecting group Pro 3 .

This reaction can be carried out by the method described in step 5-5 of production method 5 or a method pursuant thereto.

Steps 12-3 and 12-4 above may be carried out in the reversed order.

Compound [124] thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, and chromatography.

Compounds [1-e], [12-a], and [12-c] which are used as starting compounds in production method 12 above can be produced by production method 1 above, a method pursuant thereto, or a method known per se, or can be obtained by purchasing commercial products.

Compound [13-f] as compound [I-1] of the present invention can be produced, for example, by production method 13 below or a method pursuant thereto.

Production Method 13

[In the scheme,

R 1 , R 2 , R 3 , R 4 , Pro 2 , Pro 3 , LG 1 , LG 2 , W 3 , and L 1 are the same as defined above; and ring B 1 represents nitrogen-containing heterocyclyl.]

[Step 13-1]

This step is a method of producing compound [13-b] by reacting compound [1-e] with compound [13-a].

This reaction can be carried out by the method described in step 4-1 of production method 4 or a method pursuant thereto.

[Step 13-2]

This step is a method of producing compound [13-d] by reacting compound [13-b] with compound [13-c].

When LG 2 in compound [13-b] is a leaving group, the present reaction can be carried out in the presence of a base.

The amount of compound [13-c] which is used in the present reaction is 1 to 5 equivalents, and preferably 1 to 3 equivalents, with respect to 1 equivalent of compound [13-b].

Examples of the base which is used in the present reaction include amines such as triethylamine, N,N-diisopropylethylamine, and 1,8-diazabicyclo[4,3,0]undec-7-ene, alkali metal hydrides such as sodium hydride, alkali metal hydroxides such as potassium hydroxide, alkali metal carbonates such as cesium carbonate, potassium carbonate, and sodium carbonate, and alkoxy alkali metal such as potassium tert-butoxide. The amount of the base to be used is 1 to 5 equivalents, and preferably 1 to 3 equivalents, with respect to 1 equivalent of compound [13-b].

Examples of the solvent which is used in the present reaction include solvents that do not interfere with reactions, such as tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide, N, N-dimethylacetamide, and N-methylpyrrolidone; and these solvents may be mixed with each other at an appropriate ratio and used.

The present reaction can be carried out usually at room temperature to reflux temperature for 1 to 24 hours.

When LG 2 in compound [13-b] is hydroxy, the present reaction can also be carried out after hydroxy is converted to a leaving group.

The hydroxy may be converted to a leaving group by a usual method. For example, compound [13-b] in which LG 2 is a leaving group may be prepared by the reaction with (a) a halogenating reagent or (b) a sulfonate esterification reagent in the presence of a base in a solvent which does not interfere with the reaction.

Examples of (a) halogenating reagent used in the present reaction include thionyl chloride, phosphoryl chloride, N-chlorosuccinimide, bromine, and N-bromosuccinimide. The amount of the halogenating reagent to be used is 1 to 5 equivalents, and preferably 1 to 3 equivalents, with respect to 1 equivalent of the compound having hydroxy.

Examples of the solvent which is used in the present reaction include solvents that do not interfere with reactions, such as chloroform and dichloromethane; and these solvents may be mixed with each other at an appropriate ratio and used.

The present reaction can be carried out usually at room temperature to reflux temperature for 1 to 24 hours.

Furthermore, examples of (b) sulfonate esterification reagent used in the present reaction include methanesulfonyl chloride, trifluoromethanesulfonyl chloride, and p-toluenesulfonyl chloride. The amount of the sulfonate esterification reagent to be used is 1 to 5 equivalents, and preferably 1 to 3 equivalents, with respect to 1 equivalent of the compound having hydroxy.

Examples of the base which is used in the present reaction include triethylamine, N,N-diisopropylethylamine, pyridine, and 4-dimethylaminopyridine. The amount of the base to be used is 1 to 5 equivalents, and preferably 1 to 3 equivalents, with respect to 1 equivalent of the sulfonate esterification reagent to be used.

Examples of the solvent which is used in the present reaction include solvents that do not interfere with reactions, such as chloroform and dichloromethane; and these solvents may be mixed with each other at an appropriate ratio and used.

The present reaction can be carried out usually at room temperature to reflux temperature for 1 to 24 hours.

[Step 13-3]

This step is a method of producing compound [13-e] by deprotecting the pyrazolyl of compound [13-d] by removing protecting group Pro 2 under an acidic condition.

This reaction can be carried out by the method described in step 4-2 of production method 4 or the method described in step 5-4 of production method 5, or a method pursuant thereto.

[Step 13-4]

This step is a method of producing compound [134] by deprotecting compound [13-e] by removing protecting group Pro 3 .

This reaction can be carried out by the method described in step 5-5 of production method 5 or a method pursuant thereto.

Steps 13-3 and 13-4 above may be carried out in the reversed order.

Compound [134] thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, and chromatography.

Compounds [1-e], [13-a], and [13-c] which are used as starting compounds in production method 13 above can be produced by production method 1 above, a method pursuant thereto, or a method known per se, or can be obtained by purchasing commercial products.

Among compound [I-1] of the present invention, compound [14-e] in which the structure represented by R 5 is a structure represented by formula [1V-4] below and R 54 is the formula HOC(═O)—R 54′ — can be produced, for example, by production method 14 below or a method pursuant thereto.

Production Method 14

[In the scheme,

R 1 , R 2 , R 3 , R 4 , Pro 2 , Pro 3 , LG 1 , ring C, W 4 , R 61 , and R 62 are the same as defined above; and a group represented by formula [IV-4′] below represents a group below selected from R 54 ;

wherein

(a) when ring C is C 3-6 cycloalkyl,

the group represented by formula [IV-4′] above is

carboxy, or

C 1-4 alkyl substituted with carboxy;

(b) when ring C is 4- to 6-membered saturated nitrogen-containing heterocyclyl, the group represented by formula [IV-4′] above is

C 1-4 alkylcarbonyl substituted with carboxy, phenylmethylcarbonyl substituted with carboxy, phenylsulfonyl substituted with carboxy, monoC 1-4 alkylaminocarbonyl substituted with carboxy, the structure represented by formula [X-1] below, which is substituted with carboxy, the structure represented by formula [X-2] below, which is substituted with carboxy, or the structure represented by formula [X-3] below, which is substituted with carboxy,

wherein when position α of the carboxy of the C 1-4 alkylcarbonyl substituted with carboxy, C 1-4 alkylsulfonyl substituted with carboxy, and monoC 1-4 alkylaminocarbonyl substituted with carboxy is a methylene moiety, the methylene moiety may be replaced with a structure selected from structure group α above;

(c) when ring C is phenyl,

the group represented by formula [IV-4′] above is

(d) when ring C is pyridyl,

the group represented by formula [IV-4′] above is

(i) carboxy,

(iii) C 1-4 alkyl substituted with carboxy,

(iv) C 1-4 alkoxy substituted with carboxy,

(v) monoC 1-4 alkylaminocarbonyl substituted with carboxy, or

(vi) 4- to 6-membered saturated nitrogen-containing heterocyclylcarbonyl substituted with carboxy (the 4- to 6-membered saturated nitrogen-containing heterocyclyl of the 4- to 6-membered saturated nitrogen-containing heterocyclylcarbonyl substituted with carboxy may be substituted with one fluorine atom),

wherein when position α of the carboxy of the C 1-4 alkyl substituted with carboxy, C 1-4 alkoxy substituted with carboxy, and monoC 1-4 alkylaminocarbonyl substituted with carboxy is a methylene moiety, the methylene moiety may be replaced with a structure selected from structure group α above;

(e) when ring C is pyrazolyl,

the group represented by formula [IV-4′] above is carboxy;

(f) when ring C is triazolyl,

the group represented by formula [IV-4] above is C 1-4 alkyl substituted with carboxy, wherein when position α of the carboxy of the C 1-4 alkyl substituted with carboxy is a methylene moiety, the methylene moiety may be replaced with a structure selected from structure group α above;

(g) when ring C is tetrahydronaphthyl,

the group represented by formula [IV-4′] above is carboxy;

(h) when ring C is chromanyl,

the group represented by formula [IV-4′] above is carboxy;

(j) when ring C is indazolyl,

the group represented by formula [IV-4] above is C 1-4 alkyl substituted with carboxy, wherein when position α of the carboxy of the C 1-4 alkyl substituted with carboxy is a methylene moiety, the methylene moiety may be replaced with a structure selected from structure group α above;

(k) when ring C is tetrahydroisoquinolyl,

the group represented by formula [IV-4] above is C 1-4 alkylcarbonyl substituted with carboxy, wherein when position α of the carboxy of the C 1-4 alkylcarbonyl substituted with carboxy is a methylene moiety, the methylene moiety may be replaced with a structure selected from structure group α above;

(m) when ring C is 2-oxotetrahydroisoquinolyl,

the group represented by formula [IV-4] above is C 1-4 alkyl substituted with carboxy, wherein when position α of the carboxy of the C 1-4 alkyl substituted with carboxy is a methylene moiety, the methylene moiety may be replaced with a structure selected from structure group α above;

(n) when ring C is the group represented by formula [IX-1] above, the group represented by formula [IV-4] above is

carboxy, or C 1-4 alkyl substituted with C 1-4 alkylsulfonylamino (the C 1-4 alkyl of the C 1-4 alkylsulfonylamino of the C 1-4 alkyl substituted with C 1-4 alkylsulfonylamino is substituted with one carboxy),

wherein when the group represented by formula [IV-4] above is (ii) C 1-4 alkyl substituted with C 1-4 alkylsulfonylamino, and the C 1-4 alkyl of the C 1-4 alkylsulfonylamino of the C 1-4 alkyl substituted with C 1-4 alkylsulfonylamino is substituted with one carboxy, and if position α of the carboxy of C 1-4 alkylsulfonylamino substituted with carboxy is a methylene moiety, the methylene moiety may be replaced with a structure selected from structure group α above;

(p) when ring C is the group represented by formula [IX-2] above, the group represented by formula [IV-4] above is carboxy;

(q) when ring C is the group represented by formula [IX-3] above, the group represented by formula [IV-4] above is

carboxy, or C 1-4 alkyl substituted with carboxy,

wherein when position α of the carboxy of the C 1-4 alkyl substituted with carboxy is a methylene moiety, the methylene moiety may be replaced with a structure selected from structure group α above;

(r) when ring C is the group represented by formula [IX-4] above, the group represented by formula [IV-4] above is carboxy.]

[Step 14-1]

This step is a method of producing compound [14-b] by reacting compound [1-e] with compound [14-a].

This reaction can be carried out by the method described in step 4-1 of production method 4 or a method pursuant thereto.

There are several synthesis pathways for production of compound [14-e]. Steps 14-2 to 14-6 therefor will be sequentially described.

(i) When Pro 3 in compound [14-b] is primary or secondary alkyl such as methyl, ethyl, and 2-propyl, or (ii) when Pro 3 in compound [14-b] is a protecting group such as benzyl and 4-methoxybenzyl, compound [14-e] can be produced via compound [14-c] by methods described in steps 14-2 and 14-3.

[Step 14-2]

This step is a method of producing compound [14-c] by deprotecting compound [14-b] by removing protecting group Pro 3 .

This reaction can be carried out by the method described in step 5-2 of production method 5 or a method pursuant thereto.

[Step 14-3]

This step is a method of producing compound [14-e] by deprotecting the pyrazolyl of compound [14-c] by removing protecting group Pro 2 under an acidic condition.

This reaction can be carried out by the method described in step 4-2 of production method 4 or a method pursuant thereto.

(i) When Pro 3 in compound [14-b] is primary or secondary alkyl such as methyl, ethyl, and 2-propyl, (ii) when Pro 3 in compound [14-b] is a protecting group such as benzyl and 4-methoxybenzyl, or (iii) when Pro 3 in compound [14-b] is tert-butyl, compound [14-e] can be produced via compound [14-d] by methods described in steps 14-4 and 14-5.

[Step 14-4]

This step is a method of producing compound [14-d] by deprotecting the pyrazolyl of compound [14-b] by removing protecting group Pro 2 under an acidic condition.

This reaction can be carried out by the method described in step 5-4 of production method 5 or a method pursuant thereto.

[Step 14-5]

This step is a method of producing compound [14-e] by deprotecting compound [14-d] by removing protecting group Pro 3 .

This reaction can be carried out by the method described in step 5-5 of production method 5 or a method pursuant thereto.

When Pro 3 in compound [14-b] is 4-methoxybenzyl or tert-butyl, compound [14-e] can be produced by step 14-6.

[Step 14-6]

This step is a method of producing compound [14-e] by deprotecting compound [14-b] by removing protecting groups Pro 2 and Pro 3 under an acidic condition.

This reaction can be carried out by the method described in step 5-5 (iii) of production method 5 or a method pursuant thereto.

Compound [14-e] thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, and chromatography.

Compounds [1-e] and [14-a] which are used as starting compounds in production method 14 above can be produced by production method 1 above, a method pursuant thereto, or a method known per se, or can be obtained by purchasing commercial products.

Alternatively, compound [14-b] can be produced, for example, by production method 15 below or a method pursuant thereto.

Production Method 15

[In the scheme,

R 1 , R 2 , R 3 , R 4 , R 54′ , R 61 , R 62 , X A , Pro 2 , Pro 3 , W 4 , ring C, LG 1 , and G are the same as defined above.]

[Step 15-1]

This step is a method of producing compound [15-a] by reacting compound [1-a] with compound [14-a].

This reaction can be carried out by the method described in step 4-1 of production method 4 or a method pursuant thereto.

[Step 15-2]

This step is a method of producing compound [14-b] by reacting compound [15-a] with compound [1-c].

This reaction can be carried out by the method described in step 1-2 of production method 1 or a method pursuant thereto.

Compound [14-e] may be derived from compound [14-b] thus obtained by the method described in steps 14-2 to 14-6 of production method 14 or a method pursuant thereto.

Compounds [1-a], [14-a], and [1-c] which are used as starting compounds in production method 15 above can be produced by a method known per se, or can be obtained by purchasing commercial products.

Among compound [I-1] of the present invention, compound [16-f] can be produced, for example, by production method 16 below or a method pursuant thereto.

Production Method 16

[In the scheme,

R 1 , R 2 , R 3 , R 4 , Pro 2 , Pro 3 , LG 1 , Ar and X B are the same as defined above.]

[Step 16-1]

This step is a method of producing compound [16-b] by reacting compound [1-e] with compound [16-a].

This reaction can be carried out by the method described in step 4-1 of production method 4 or a method pursuant thereto.

[Step 16-2]

This step is a method of producing compound [16-c] by reacting compound [16-b] with compound [11-c].

This reaction can be carried out by the method described in step 11-2 of production method 11 or a method pursuant thereto.

[Step 16-3]

This step is a method of producing compound [16-d] by catalytic hydrogenation of the alkyne of compound [16-c].

This reaction can be carried out by the method described in step 11-3 of production method 11 or a method pursuant thereto.

[Step 16-4]

This step is a method of producing compound [16-e] by deprotecting the pyrazolyl of compound [16-d] by removing protecting group Pro 2 under an acidic condition.

This reaction can be carried out by the method described in step 4-2 of production method 4 or the method described in step 5-4 of production method 5, or a method pursuant thereto.

[Step 16-5]

This step is a method of producing compound [164] by deprotecting compound [16-e] by removing protecting group Pro 3 .

This reaction can be carried out by the method described in step 5-5 of production method 5 or a method pursuant thereto.

Steps 16-4 and 16-5 above may be carried out in the reversed order.

Compound [164] thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, and chromatography.

Compounds [1-e], [11-c], and [16-a] which are used as starting compounds in production method 16 above can be produced by production method 1 above, a method pursuant thereto, or a method known per se, or can be obtained by purchasing commercial products.

Among compound [I-1] of the present invention, compound [17-g] can be produced, for example, by production method 17 below or a method pursuant thereto.

Production Method 17

R 1 , R 2 , R 3 , R 4 , Pro 2 , Pro 3 , W 4 , LG 1 , and Pro 3 are the same as defined above;

X C represents a bromine atom or an iodine atom; and

L 2 represents a single bond or methanediyl.]

[Step 17-1]

This step is a method of producing compound [17-b] by reacting compound [1-e] with compound [17-a].

This reaction can be carried out by the method described in step 4-1 of production method 4 or a method pursuant thereto.

[Step 17-2]

This step is a method of producing compound [17-d] by reacting compound [17-b] with compound [17-c].

This reaction is a so-called Heck reaction that can be carried out in the presence of a palladium catalyst and a base by a process which is described in the literature (Angewandte Chemie International Edition in English, Volume 33, page 2379, 1995) or a process pursuant thereto.

The amount of compound [17-c] to be used in the present reaction is usually 1 to 5 equivalents, and preferably 1 to 1.5 equivalents, with respect to 1 equivalent of compound [17-b].

Examples of the palladium catalyst which is used in the present reaction include tetrakis(triphenylphosphine)palladium(0), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct, and bis(triphenylphosphine)palladium(II) dichloride. The amount of the palladium catalyst to be used in the present reaction is usually 0.01 to 0.2 equivalents, and preferably 0.01 to 0.1 equivalents, with respect to 1 equivalent of compound [17-b].

Examples of the base which is used in the present reaction include triethylamine, N-ethyl-N,N-diisopropylamine, potassium carbonate, calcium carbonate, cesium carbonate, potassium t-butoxide, and potassium acetate. The amount of the base to be used in the present reaction is usually 1 to 5 equivalents, and preferably 1 to 3 equivalents, with respect to 1 equivalent of compound [17-b].

Examples of the solvent which is used in the present reaction include solvents that do not interfere with reactions, such as acetonitrile, toluene, tetrahydrofuran, and N,N-dimethylformamide; and these solvents may be mixed with each other at an appropriate ratio and used.

These reactions can be carried out usually at room temperature to reflux temperature for 1 to 24 hours, and can be also carried out under microwave irradiation.

[Step 17-3]

This step is a method of producing compound [17-e] by catalytic hydrogenation of the alkene of compound [17-d].

This reaction can be carried out by the method described in step 11-3 of production method 11 or a method pursuant thereto.

[Step 17-4]

This step is a method of producing compound [174] by deprotecting the pyrazolyl of compound [17-e] by removing protecting group Pro 2 under an acidic condition.

This reaction can be carried out by the method described in step 4-2 of production method 4 or the method described in step 5-4 of production method 5, or a method pursuant thereto.

[Step 17-5]

This step is a method of producing compound [17-g] by deprotecting compound [17-f] by removing protecting group Pro 3 .

This reaction can be carried out by the method described in step 5-5 of production method 5 or a method pursuant thereto.

Steps 17-4 and 17-5 above may be carried out in the reversed order.

Compound [17-g] thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, and chromatography.

Compounds [1-e], [17-a], and [17-c] which are used as starting compounds in production method 17 above can be produced by production method 1 above, a method pursuant thereto, or a method known per se, or can be obtained by purchasing commercial products.

Among compound [I-1] of the present invention, compound [18-d] can be produced, for example, by production method 18 below or a method pursuant thereto.

Production Method 18

[In the scheme,

R 1 , R 2 , R 3 , R 4 , Pro 2 , Pro 3 , W 4 , X C , Ar, and G are the same as defined above.]

[Step 18-1]

This step is a method of producing compound [18-b] by reacting compound [17-b] with compound [18-a].

This reaction can be carried out by the method described in step 1-2 of production method 1 or a method pursuant thereto.

[Step 18-2]

This step is a method of producing compound [18-c] by deprotecting the pyrazolyl of compound [18-b] by removing protecting group Pro 2 under an acidic condition.

This reaction can be carried out by the method described in step 4-2 of production method 4 or the method described in step 5-4 of production method 5, or a method pursuant thereto.

[Step 18-3]

This step is a method of producing compound [18-d] by deprotecting compound [18-c] by removing protecting group Pro 3 .

This reaction can be carried out by the method described in step 5-5 of production method 5 or a method pursuant thereto.

Steps 18-2 and 18-3 above may be carried out in the reversed order.

Compound [18-d] thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, and chromatography.

Compounds [17-b] and [18-a] which are used as starting compounds in production method 18 above can be produced by production method 17 above, a method pursuant thereto, or a method known per se, or can be obtained by purchasing commercial products.

Among compound [I-1] of the present invention, compound [19-d] can be produced, for example, by production method 19 below or a method pursuant thereto.

Production Method 19

[In the scheme,

R 1 , R 2 , R 3 , R 4 , Pro 2 , Pro 3 , W 4 , and X C are the same as defined above;

R 7′ and R 8′ each independently represent a hydrogen atom or methyl,

wherein R 7′ and R 8′ may form, together with the adjacent carbon atom, C 3-6 cycloalkane, 4- to 6-membered saturated oxygen-containing hetero ring, or 4- to 6-membered saturated sulfur-containing hetero ring (the sulfur atom of the 4- to 6-membered saturated sulfur-containing hetero ring may be substituted with 1 or 2 oxo); and

M represents a metal such as lithium and zinc.]

[Step 19-1]

This step is a method of producing compound [19-b] by reacting compound [17-b] with compound [19-a].

This reaction can be carried out by reacting compound [19-a] with compound [17-b] in the presence of a palladium catalyst, wherein compound [19-a] is (i) generated by allowing a metal fluoride to react with a silylenol ether, or (ii) generated by allowing a metal amide to react with an ester.

(i) When compound [19-a] is generated by allowing a metal fluoride to react with a silylenol ether, the amount of the silylenol ether to be used in the present reaction is 1 to 5 equivalents, and preferably 1 to 2 equivalents, with respect to 1 equivalent of compound [17-b].

Examples of the metal fluoride which is used in the present reaction include cesium fluoride and zinc fluoride. The amount of the metal fluoride to be used is 1 to 5 equivalents, and preferably 1 to 2 equivalents, with respect to 1 equivalent of compound [17-b].

(ii) When compound [19-a] is generated by allowing a metal amide to react with an ester, the amount of the ester to be used in the present reaction is 1 to 5 equivalents, and preferably 1 to 2 equivalents, with respect to 1 equivalent of compound [17-b].

Examples of the metal amide which is used in the present reaction include lithium diisopropylamide (LDA) and lithium bis(trimethylsilyl)amide (LHMDS). The amount of the metal amide to be used is 1 to 5 equivalents, and preferably 1 to 2 equivalents, with respect to 1 equivalent of compound [17-b].

Examples of the reaction solvent which is used in the present reaction include solvents that do not interfere with reactions, such as toluene, 1,4-dioxane, tetrahydrofuran, and 1,2-dimethoxyethane; and these solvents may be mixed with each other at an appropriate ratio and used.

These reactions can be carried out usually at room temperature to reflux temperature for 1 to 24 hours, and can be also carried out under microwave irradiation.

[Step 19-2]

This step is a method of producing compound [19-c] by deprotecting the pyrazolyl of compound [19-b] by removing protecting group Pro 2 under an acidic condition.

This reaction can be carried out by the method described in step 4-2 of production method 4 or the method described in step 5-4 of production method 5, or a method pursuant thereto.

[Step 19-3]

This step is a method of producing compound [19-d] by deprotecting compound [19-c] by removing protecting group Pro 3 .

This reaction can be carried out by the method described in step 5-5 of production method 5 or a method pursuant thereto.

Steps 19-2 and 19-3 above may be carried out in the reversed order.

Compound [19-d] thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, and chromatography.

Compound [17-b] which is used as a starting compound in production method 19 above, and the silylenol ether and the ester which are used to generate compound [19-a] can be produced by production method 17 above, a method pursuant thereto, or a method known per se, or can be obtained by purchasing commercial products.

Among compound [I-1] of the present invention, compound [20-f] can be produced, for example, by production method 20 below or a method pursuant thereto.

Production Method 20

[In the scheme,

R 1 , R 2 , R 3 , R 4 , Pro 2 , Pro 3 , W 4 , X C , and M are the same as defined above; ring D represents 4- to 6-membered saturated nitrogen-containing heterocyclyl;

R 9 represents C 1-4 alkylcarbonyl, C 1-4 alkoxycarbonyl, monoC 1-4 alkylaminocarbonyl, or di(C 1-4 alkyl)aminocarbonyl; and

Pro 4 represents a protecting group for amino, as exemplified by tert-butoxycarbonyl, benzyloxycarbonyl, and the like.

[Step 20-1]

This step is a method of producing compound [20-b] by reacting compound [17-b] with compound [20-a].

This reaction can be carried out by the method described in step 19-1 of production method 19 or a method pursuant thereto.

[Step 20-2]

This step is a method of producing compound [20-c] by deprotecting the nitrogen atom in 4- to 6-membered saturated nitrogen-containing heterocyclyl of compound [20-b] by removing protecting group Pro 4 .

(i) When protecting group Pro 4 is tert-butoxycarbonyl, the present reaction can be carried out in a solvent which does not interfere with the reaction, in the presence of an acid.

Examples of the reagent which is used in the present reaction include mineral acid such as hydrochloric acid and organic acid such as trifluoroacetic acid. The amount of the reagent to be used is 1 to 5 equivalents, and preferably 1 to 3 equivalents, with respect to 1 equivalent of compound [20-b].

Examples of the solvent which is used in the present reaction include methanol, ethanol, water, tetrahydrofuran, and ethyl acetate; and these solvents may be mixed with each other at an appropriate ratio and used.

The present reaction can be carried out usually at room temperature to reflux temperature for 1 to 24 hours.

The present reaction can also be carried out in a solvent which does not interfere with the reaction in the presence of a Lewis acid.

Examples of the reagent which is used in the present reaction include trimethylsilyl trifluoromethanesulfonate and tert-butyldimethylsilyl trifluoromethanesulfonate. The amount of the reagent to be used is 1 to 5 equivalents, and preferably 1 to 3 equivalents, with respect to 1 equivalent of compound [20-b].

For example, 2,6-lutidine may be used as an additive in the present reaction. The amount to be used is 1 to 10 equivalents, and preferably 2 to 5 equivalents, with respect to 1 equivalent of compound [20-b].

Examples of the solvent which is used in the present reaction include dichloromethane, chloroform, and toluene; and these solvents may be mixed with each other at an appropriate ratio and used.

The present reaction can be carried out usually at −80° C. to room temperature for 1 to 24 hours.

(ii) When protecting group Pro 4 is benzyloxycarbonyl, this step can be carried out in a solvent which does not interfere with the reaction, in the presence of a metal and a hydrogen source.

Examples of the metal which is used in the present reaction include palladium. The amount of the metal to be used is 0.1 to 1 equivalent, and preferably 0.1 to 0.5 equivalents, with respect to 1 equivalent of compound [20-b].

A hydrogen pressure which is used in the present reaction is ordinary pressure to 10 atm, and preferably ordinary pressure to 4 atm.

Examples of the solvent which is used in the present reaction include methanol, ethanol, water, tetrahydrofuran, chloroform, and ethyl acetate; and these solvents may be mixed with each other at an appropriate ratio and used.

The present reaction can be carried out usually at room temperature to reflux temperature for 1 to 24 hours.

[Step 20-3]

This step is a method of producing compound [20-d] by reacting compound [20-c] with a carboxylic acid, acid halide, acid anhydride, active ester, isocyanate, or amine corresponding to R 9 .

(i) When the reagent to be used in the present reaction is a carboxylic acid, the present reaction can be carried out by the method described in step 8-3 of production method 8 or a method pursuant thereto.

(ii) When the reagent to be used in the present step is an acid chloride, an acid anhydride, or an active ester such as succinimide ester, the present reaction can be carried out by a known method, for example, in the presence of a base.

The amount of the acid chloride to be used in the present reaction is 1 to 5 equivalents, and preferably 1 to 3 equivalents, with respect to 1 equivalent of compound [20-c].

Examples of the base which is used in the present reaction include triethylamine, pyridine, 4-dimethylaminopyridine, and N,N-diisopropylethylamine. The amount of the base to be used is usually 1 to 5 equivalents, and preferably 1 to 3 equivalents, with respect to 1 equivalent of compound [20-c].

Examples of the solvent which is used in the present reaction include solvents that do not interfere with reactions, such as chloroform, dichloromethane, toluene, diethyl ether, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, and acetonitrile; and these solvents may be mixed with each other at an appropriate ratio and used.

The present reaction can be carried out usually at 0° C. to room temperature for 1 to 24 hours.

(iii) When the reagent to be used in the present step reaction is isocyanate, the present reaction can be carried out in a solvent which does not interfere with the reaction, in the presence or absence of a base.

The amount of the isocyanate to be used in the present reaction is 1 to 5 equivalents, and preferably 1 to 3 equivalents, with respect to 1 equivalent of compound [20-c].

Examples of the base which is used in the present reaction include triethylamine, pyridine, 4-dimethylaminopyridine, and N,N-diisopropylethylamine. The amount of the base to be used is usually 1 to 5 equivalents, and preferably 1 to 3 equivalents, with respect to 1 equivalent of compound [20-c].

Examples of the solvent which is used in the present reaction include solvents that do not interfere with reactions, such as chloroform, dichloromethane, diethyl ether, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, and dimethyl sulfoxide; and these solvents may be mixed with each other at an appropriate ratio and used.

The present reaction can be carried out usually at 0° C. to room temperature for 1 to 24 hours.

(iv) When the reagent to be used in the present step allows amine to react, the present reaction can be carried out by allowing 4-nitrophenyl chloroformate, dicyclohexylcarbodiimide (CDI), triphosgene, etc., to act in a solvent which does not interfere with the reaction, in the presence of a base.

The amount of the amine to be used in the present reaction is 1 to 5 equivalents, and preferably 1 to 3 equivalents, with respect to 1 equivalent of compound [20-c].

Examples of the base which is used in the present reaction include triethylamine, pyridine, 4-dimethylaminopyridine, and N,N-diisopropylethylamine. The amount of the base to be used is usually 1 to 5 equivalents, and preferably 1 to 3 equivalents, with respect to 1 equivalent of compound [20-c].

The amount of 4-nitrophenyl chloroformate or dicyclohexylcarbodiimide (CDI) to be used in the present reaction is 1 to 5 equivalents, and preferably 1 to 3 equivalents, with respect to 1 equivalent of compound [20-c].

Examples of the solvent which is used in the present reaction include solvents that do not interfere with reactions, such as chloroform, dichloromethane, diethyl ether, tetrahydrofuran, ethyl acetate, and acetonitrile; and these solvents may be mixed with each other at an appropriate ratio and used.

The present reaction can be carried out usually at 0° C. to reflux temperature for 1 to 24 hours.

[Step 20-4]

This step is a method of producing compound [20-e] by deprotecting the pyrazolyl of compound [20-d] by removing protecting group Pro 2 under an acidic condition.

This reaction can be carried out by the method described in step 4-2 of production method 4 or the method described in step 5-4 of production method 5, or a method pursuant thereto.

[Step 20-5]

This step is a method of producing compound [20-f] by deprotecting compound [20-e] by removing protecting group Pro 3 .

This reaction can be carried out by the method described in step 5-5 of production method 5 or a method pursuant thereto.

Steps 20-4 and 20-5 above may be carried out in the reversed order.

Compound [204] thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, and chromatography.

Compound [17-b] which is used as a starting compound in production method 20 above, and the silylenol ether and the ester which are used to generate compound [20-a] can be produced by production method 17 above, a method pursuant thereto, or a method known per se, or can be obtained by purchasing commercial products.

Among compound [I-1] of the present invention, compound [21-d] can be produced, for example, by production method 21 below or a method pursuant thereto.

Production Method 21

[In the scheme,

R 1 , R 2 , R 3 , R 4 , Pro 2 , Pro 3 , W 4 , and X C are the same as defined above; and ring E represents 4- to 6-membered saturated nitrogen-containing heterocyclyl or nitrogen-containing heteroaryl.]

[Step 21-1]

This step is a method of producing compound [21-b] by reacting compound [17-b] with compound [21-a].

This reaction is a so-called Ullmann-type coupling reaction that can be carried out in a solvent which does not interfere with the reaction, in the presence of a copper salt, a ligand, and a base.

Examples of the copper salt which is used in the present reaction include copper(I) iodide, copper(I) bromide, copper(I) chloride, copper(I) oxide, and copper(I) trifluoromethanesulfonate-benzene complex. The amount of the copper salt to be used is 0.1 to 2 equivalents, and preferably 0.1 to 0.5 equivalents, with respect to 1 equivalent of compound [17-b].

Examples of the ligand which is used in the present reaction include 2-isobutyrylcyclohexanone, L-proline, and trans-N,N′-dimethylcyclohexane-1,2-diamine. The amount of the ligand to be used is 0.1 to 2 equivalents, and preferably 0.1 to 0.5 equivalents, with respect to 1 equivalent of compound [17-b].

Examples of the base which is used in the present reaction include potassium carbonate, potassium phosphate, cesium carbonate, N,N-diisopropylethylamine, and triethylamine. The amount of the base to be used is 1 to 5 equivalents, and preferably 1 to 2 equivalents, with respect to 1 equivalent of compound [17-b].

Examples of the solvent which is used in the present reaction include solvents that do not interfere with reactions, such as dimethyl sulfoxide, N,N-dimethylformamide, N-methylpyrrolidone, 1,4-dioxane, acetonitrile, and toluene; and these solvents may be mixed with each other at an appropriate ratio and used.

The present reaction can be carried out usually at reflux temperature for 1 to 24 hours.

[Step 21-2]

This step is a method of producing compound [21-c] by deprotecting the pyrazolyl of compound [21-b] by removing protecting group Pro 2 under an acidic condition.

This reaction can be carried out by the method described in step 4-2 of production method 4 or the method described in step 5-4 of production method 5, or a method pursuant thereto.

[Step 21-3]

This step is a method of producing compound [21-d] by deprotecting compound [21-c] by removing protecting group Pro 3 .

This reaction can be carried out by the method described in step 5-5 of production method 5 or a method pursuant thereto.

Steps 21-2 and 21-3 above may be carried out in the reversed order.

Compound [21-d] thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, and chromatography.

Compounds [17-b] and [21-a] which are used as starting compounds in production method 21 above can be produced by production method 17 above, a method pursuant thereto, or a method known per se, or can be obtained by purchasing commercial products.

Among compound [I-1] of the present invention, compound [22-e] can be produced, for example, by production method 22 below or a method pursuant thereto.

Production Method 22

[In the scheme,

R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , Pro 2 , Pro 3 , and LG 1 are the same as defined above; and W 41 represents C 1-3 alkanediyl.]

[Step 22-1]

This step is a method of producing compound [22-b] by reacting compound [1-e] with compound [22-a].

This reaction can be carried out by the method described in step 4-1 of production method 4 or a method pursuant thereto.

[Step 22-2]

This step is a method of producing compound [22-c] by reacting compound [22-b] with compound [12-c].

This reaction can be carried out by the method described in step 12-2 of production method 12 or a method pursuant thereto.

[Step 22-3]

This step is a method of producing compound [22-d] by deprotecting the pyrazolyl of compound [22-c] by removing protecting group Pro 2 under an acidic condition.

This reaction can be carried out by the method described in step 4-2 of production method 4 or the method described in step 5-4 of production method 5, or a method pursuant thereto.

[Step 22-4]

This step is a method of producing compound [22-e] by deprotecting compound [22-d] by removing protecting group Pro 3 .

This reaction can be carried out by the method described in step 5-5 of production method 5 or a method pursuant thereto.

Steps 22-3 and 22-4 above may be carried out in the reversed order.

Compound [22-e] thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, and chromatography.

Compounds [1-e], [22-a], and [12-c] which are used as starting compounds in production method 22 above can be produced by production method 1 above, a method pursuant thereto, or a method known per se, or can be obtained by purchasing commercial products.

Among compound [I-1] of the present invention, compound [23-e] can be produced, for example, by production method 23 below or a method pursuant thereto.

Production Method 23

[In the scheme,

R 1 , R 2 , R 3 , R 4 , W 4 , LG 1 , Pro 2 , and Pro 3 are the same as defined above.]

[Step 23-1]

This step is a method of producing compound [23-b] by reacting compound [1-e] with compound [23-a].

This reaction can be carried out by the method described in step 4-1 of production method 4 or a method pursuant thereto.

[Step 23-2]

This step is a method of producing compound [23-c] by reacting trimethylsulfoxonium iodide with a base and then with compound [23-b].

The reaction of trimethylsulfoxonium iodide with a base can be carried out by a known method, for example, the method described in WO2002/002522 or a method pursuant thereto.

The amount of the trimethylsulfoxonium iodide to be used in the present reaction is usually 1 to 10 equivalents, and preferably 1 to 5 equivalents, with respect to 1 equivalent of compound [23-b].

Examples of the base which is used in the present reaction include sodium hydride, potassium tert-butoxide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, sodium methoxide, and sodium ethoxide. The amount of the base to be used is usually 1 to 10 equivalents, and preferably 1 to 5 equivalents, with respect to 1 equivalent of compound [23-b].

Examples of the solvent which is used in the present reaction include dimethyl sulfoxide, tetrahydrofuran, dimethoxyethane, 1,4-dioxane, diethyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, and dichloromethane; and these solvents may be mixed with each other at an appropriate ratio and used.

The present reaction can be carried out usually at 0° C. to reflux temperature for 0.5 to 72 hours.

[Step 23-3]

This step is a method of producing compound [23-d] by deprotecting the pyrazolyl of compound [23-c] by removing protecting group Pro 2 under an acidic condition.

This reaction can be carried out by the method described in step 4-2 of production method 4 or the method described in step 5-4 of production method 5, or a method pursuant thereto.

[Step 23-4]

This step is a method of producing compound [23-e] by deprotecting compound [23-d] by removing protecting group Pro 3 .

This reaction can be carried out by the method described in step 5-5 of production method 5 or a method pursuant thereto.

Steps 23-3 and 23-4 above may be carried out in the reversed order.

Compound [23-e] thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, and chromatography.

Compounds [1-e] and [23-a] which are used as starting compounds in production method 23 above can be produced by production method 1 above, a method pursuant thereto, or a method known per se, or can be obtained by purchasing commercial products.

Among compound [I-1] of the present invention, compound [24-e] can be produced, for example, by production method 24 below or a method pursuant thereto.

Production Method 24

[In the scheme,

R 1 , R 2 , R 3 , R 4 , Pro 2 , W 4 , and LG 1 are the same as defined above;

R 10 represents a hydrogen atom or a fluorine atom;

R 1 represents C 1-4 alkyl, halo-C 1-4 alkyl, or aryl; and

R 12 represents a hydrogen atom, C 1-4 alkyl, halo-C 1-4 alkyl, or aryl.]

[Step 24-1]

This step is a method of producing compound [24-b] by reacting compound [1-e] with compound [24-a].

This reaction can be carried out by the method described in step 4-1 of production method 4 or a method pursuant thereto.

[Step 24-2]

This step is a method of producing compound [24-d] by reacting compound [24-b] with an alkyl lithium compound and then reacting the resulting reaction intermediate with a carbonyl compound represented by compound [24-c].

Examples of the alkyl lithium compound which is used in the reaction with compound [24-b] include n-butyl lithium. The amount of the alkyl lithium compound to be used is 1 to 5 equivalents, and preferably 1 to 3 equivalents, with respect to 1 equivalent of compound [24-b].

Examples of the solvent to be used in the present reaction include solvents that do not interfere with reactions, such as diethyl ether, tetrahydrofuran, 1,4-dioxane, toluene, and xylene; and these solvents may be mixed with each other at an appropriate ratio and used.

The present reaction can be carried out usually at −80° C. to −50° C. for 0.1 to 1 hour.

The amount of compound [24-c] to be used in the reaction with the reaction intermediate to be generated is 1 to 5 equivalents, and preferably 1 to 3 equivalents, with respect to 1 equivalent of compound [24-b].

The present reaction can be carried out usually at −80° C. to room temperature for 0.1 to 24 hours.

[Step 24-3]

This step is a method of producing compound [24-e] by deprotecting the pyrazolyl of compound [24-d] by removing protecting group Pro 2 under an acidic condition.

This reaction can be carried out by the method described in step 4-2 of production method 4 or a method pursuant thereto.

Compound [24-e] thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, and chromatography.

Incidentally, compounds [1-e], [24-a], and [24-c] which are used as starting compounds in production method 24 above can be produced by production method 1 above, a method pursuant thereto, or a method known per se, or can be obtained by purchasing commercial products.

Among compound [I-1] of the present invention, compound [25-f] can be produced, for example, by production method 25 below or a method pursuant thereto.

Production Method 25

[In the scheme,

R 1 , R 2 , R 3 , R 4 , R 9 , R 10 , Pro 2 , Pro 4 , and W 4 are the same as defined above;

ring D′ represents 4- to 6-membered saturated nitrogen-containing heterocyclyl (the 4- to 6-membered saturated nitrogen-containing heterocyclyl is substituted with one oxo at a carbon atom not adjacent to the nitrogen atom); and

Pro 5 represents a protecting group for hydroxy, as exemplified by a silyl-based protecting group or the like such as trimethylsilyl, triisopropylsilyl, and tert-butyldimethylsilyl.]

[Step 25-1]

This step is a method of producing compound [25-b] by reacting compound [24-b] with an alkyl lithium compound and then reacting the resulting reaction intermediate with a carbonyl compound represented by compound [25-a].

This reaction can be carried out by the method described in step 24-2 of production method 24 or a method pursuant thereto.

[Step 25-2]

This step is a method of producing compound [25-c] by protecting the hydroxy of compound [25-b] with protecting group Pro 5 .

Examples of the reagent which is used in the present reaction include trimethylsilyl chloride and trimethylsilyl triflate. The amount of the reagent to be used is 1 to 5 equivalents, and preferably 1 to 3 equivalents, with respect to 1 equivalent of compound [25-b].

Examples of the base which is used in the present reaction include imidazole, triethylamine, pyridine, and 2,6-lutidine. The amount of the base to be used is 1 to 5 equivalents, and preferably 1 to 3 equivalents, with respect to 1 equivalent of compound [25-b].

Examples of the solvent which is used in the present reaction include solvents that do not interfere with reactions, such as chloroform, dichloromethane, 1,4-dioxane, ethyl acetate, tetrahydrofuran, and N,N-dimethylformamide; and these solvents may be mixed with each other at an appropriate ratio and used.

The present reaction can be carried out usually at 0° C. to room temperature for 1 to 24 hours.

[Step 25-3]

This step is a method of producing compound [25-d] by deprotecting the nitrogen atom in 4- to 6-membered saturated nitrogen-containing heterocyclyl of compound [25-c] by removing protecting group Pro 4 .

This reaction can be carried out by the method described in step 20-2 of production method 20 or a method pursuant thereto.

[Step 25-4]

This step is a method of producing compound [25-e] by reacting compound [25-d] with a carboxylic acid, acid halide, acid anhydride, active ester, isocyanate, or amine corresponding to R 9 .

This reaction can be carried out by the method described in step 20-3 of production method 20 or a method pursuant thereto.

[Step 25-5]

This step is a method of producing compound [254] by deprotecting the pyrazolyl of compound [25-e] by removing protecting group Pro 2 under an acidic condition.

This reaction can be carried out by the method described in step 4-2 of production method 4 or a method pursuant thereto.

Compound [254] thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, and chromatography.

Compounds [24-b] and [25-a] which are used as starting compounds in production method 25 above can be produced by production method 24 above, a method pursuant thereto, or a method known per se, or can be obtained by purchasing commercial products.

Among compound [I-1] of the present invention, compound [26-d] can be produced, for example, by production method 26 below or a method pursuant thereto.

Production Method 26

[In the scheme,

R 1 , R 2 , R 3 , R 4 , R 10 , Pro 2 , Pro 3 , and W 4 are the same as defined above.]

[Step 26-1]

This step is a method of producing compound [26-b] by reacting compound [24-b] with an alkyl lithium compound and then reacting the resulting reaction intermediate with a carbonyl compound represented by compound [26-a].

This reaction can be carried out by the method described in step 24-2 of production method 24 or a method pursuant thereto.

[Step 26-2]

This step is a method of producing compound [26-c] by deprotecting the pyrazolyl of compound [26-b] by removing protecting group Pro 2 under an acidic condition.

This reaction can be carried out by the method described in step 4-2 of production method 4 or the method described in step 5-4 of production method 5, or a method pursuant thereto.

[Step 26-3]

This step is a method of producing compound [26-d] by deprotecting compound [26-c] by removing protecting group Pro 3 .

This reaction can be carried out by the method described in step 5-5 of production method 5 or a method pursuant thereto.

Steps 26-2 and 26-3 above may be carried out in the reversed order.

Compound [26-d] thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, and chromatography.

Compounds [24-b] and [26-a] which are used as starting compounds in production method 26 above can be produced by production method 24 above, a method pursuant thereto, or a method known per se, or can be obtained by purchasing commercial products.

Among compound [I-1] of the present invention, compound [27-c] can be produced, for example, by production method 27 below or a method pursuant thereto.

Production Method 27

[In the scheme,

R 1 , R 2 , R 3 , R 4 , Pro 2 , W 4 , and X C are the same as defined above.]

[Step 27-1]

This step is a method of producing compound [27-b] by reacting compound [17-b] with potassium disulfite and sodium formate in the presence of a palladium catalyst and then reacting the resulting sodium sulfinate intermediate with compound [27-a] as an epoxide.

(i) Preparation of the sodium sulfinate intermediate in the present reaction can be carried out by a known method, for example, the method described in Organic Letters, 2013, 15, 6226 or a method pursuant thereto.

Examples of the palladium catalyst which is used in the present reaction include palladium(II) acetate, and the amount is 0.01 to 0.1 equivalents, and preferably 0.03 to 0.07 equivalents, with respect to 1 equivalent of compound [17-b].

Examples of the solvent which is used in the present reaction include solvents that do not interfere with reactions, such as N,N-dimethylformamide, dimethyl sulfoxide, and acetonitrile; and these solvents may be mixed with each other at an appropriate ratio and used.

The present reaction can be carried out usually at 50° C. to 100° C. for 1 to 24 hours, and can be also carried out under microwave irradiation.

(ii) The reaction of the sodium sulfinate intermediate generated and epoxide [27-a] can be carried out by a known method, for example, the method described in. The Journal of Organic Chemistry, 1985, 50, 1327 or Tetrahedron Letters, 2009, 50, 5009, or a method pursuant thereto.

The amount of the epoxide to be used in the present reaction is 1 to 5 equivalents, and preferably 1 to 3 equivalents, with respect to 1 equivalent of compound [17-b].

Examples of the solvent which is used in the present reaction include solvents that do not interfere with reactions, such as water, toluene, N,N-dimethylformamide, dimethyl sulfoxide, and acetonitrile; and these solvents may be mixed with each other at an appropriate ratio and used.

The present reaction can be carried out usually at room temperature to 100° C. for 1 to 24 hours.

[Step 27-2]

This step is a method of producing compound [27-c] by reacting compound [27-b] under an acidic condition to deprotect the pyrazolyl by removing protecting group Pro 2 .

This reaction can be carried out by the method described in step 4-2 of production method 4 or a method pursuant thereto.

Compound [27-c] thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, and chromatography.

Incidentally, compounds [17-b] and [27-a] which are used as starting compounds in production method 27 above can be produced by production method 17 above, a method pursuant thereto, or a method known per se, or can be obtained by purchasing commercial products.

Among compound [I-1] of the present invention, compound [28-d] can be produced, for example, by production method 28 below or a method pursuant thereto.

Production Method 28

[In the scheme,

R 1 , R 2 , R 3 , R 4 , Pro 2 , W 4 , and X C are the same as defined above;

n represents an integer of 0 to 2; and

R 13 and R 14 each independently represent a hydrogen atom or methyl.]

[Step 28-1]

This step is a method of producing compound [28-b] by reacting compound [17-b] with potassium disulfite and sodium formate in the presence of a palladium catalyst and then reacting the resulting sodium sulfinate intermediate with compound [28-a] as an alkyl bromide.

(i) Preparation of the sodium sulfinate intermediate in the present reaction can be carried out by the method described in step 27-1 (i) of production method 27 or a method pursuant thereto.

(ii) The reaction of the sodium sulfinate intermediate generated and alkyl bromide [28-a] can be carried out by mixing them in a solvent which does not interfere with the reaction.

Examples of the solvent which is used in the present reaction include solvents that do not interfere with reactions, such as N,N-dimethylformamide and dimethyl sulfoxide; and these solvents may be mixed with each other at an appropriate ratio and used.

The present reaction can be carried out usually at room temperature to 100° C. for 1 to 24 hours.

[Step 28-2]

This step is a method of producing compound [28-c] by deprotecting the pyrazolyl of compound [28-b] by removing protecting group Pro 2 under an acidic condition.

This reaction can be carried out by the method described in step 4-2 of production method 4 or the method described in step 5-4 of production method 5, or a method pursuant thereto.

[Step 28-3]

This step is a method of producing compound [28-d] by ring-opening the 2-sulfonylcycloalkanone of compound [28-c].

This reaction is a so-called retro-Aldol reaction that can be carried out in the presence of a base under heating.

Examples of the base which is used in the present reaction include sodium hydroxide and potassium hydroxide. The amount of the base to be used is 1 to 5 equivalents, and preferably 1 to 3 equivalents, with respect to 1 equivalent of compound [28-c].

Examples of the solvent which is used in the present reaction include solvents that do not interfere with reactions, such as water, N,N-dimethylformamide, dimethyl sulfoxide, and tetrahydrofuran; and these solvents may be mixed with each other at an appropriate ratio and used.

The present reaction can be carried out usually at 50° C. to reflux temperature for 1 to 24 hours.

Compound [28-d] thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, and chromatography.

Incidentally, compound [17-b] and compound [28-a] which are used as starting compounds in production method 28 above can be produced by production method 17 above, a method pursuant thereto, or a method known per se, or can be obtained by purchasing commercial products.

Among compound [I-1] of the present invention, compounds [29-f] and [29-j] can be produced, for example, by production method 29 below or a method pursuant thereto.

Production Method 29

[In the scheme,

R 1 , R 2 , R 3 , R 4 , Pro 2 , Pro 3′ , LG 1 , W 4 , and ring D are the same as defined above;

a group represented by formula [IV-4″-1] below:

represents a group below selected from R 54

carbamoyl, monoC 1-4 alkylaminocarbonyl (the C 1-4 alkyl of the monoC 1-4 alkylaminocarbonyl may be substituted with one hydroxy), C 1-4 alkyl substituted with monoC 1-4 alkylaminocarbonyl (the C 1-4 alkyl of the monoC 1-4 alkylaminocarbonyl of the C 1-4 alkyl substituted with monoC 1-4 alkylaminocarbonyl may be substituted with one group selected from the group consisting of hydroxy, C 1-4 alkoxy, 4- to 6-membered saturated oxygen-containing heterocyclyl, di(C 1-4 alkyl)amino, and 4- to 6-membered saturated nitrogen-containing heterocyclylcarbonyl), C 2-4 alkenyl substituted with di(C 1-4 alkyl)aminocarbonyl, C 3-6 cycloalkyl substituted with di(C 1-4 alkyl)aminocarbonyl, C 1-4 alkylsulfonylaminocarbonyl, C 1-4 alkyl substituted with C 1-4 alkylsulfonylaminocarbonyl, C 1-4 alkylsulfonyl(C 1-4 alkyl)aminocarbonyl, C 1-4 alkyl substituted with C 1-4 alkylsulfonyl(C 1-4 alkyl)aminocarbonyl, C 1-4 alkyl substituted with di(C 1-4 alkyl)aminocarbonyl (one C 1-4 alkyl of the di(C 1-4 alkyl)aminocarbonyl of the C 1-4 alkyl substituted with di(C 1-4 alkyl)aminocarbonyl may be substituted with one hydroxy), or C 1-4 alkyl substituted with 4- to 6-membered saturated oxygen-containing heterocyclylaminocarbonyl;

a group represented by formula [IV-4″-2] below:

represents a group below selected from R 54

C 1-4 alkyl substituted with 4- to 6-membered saturated nitrogen-containing heterocyclylcarbonyl (the 4- to 6-membered saturated nitrogen-containing heterocyclyl of the C 1-4 alkyl substituted with 4- to 6-membered saturated nitrogen-containing heterocyclylcarbonyl may be substituted with one or two groups selected from the group consisting of hydroxy and a fluorine atom), C 1-4 alkyl substituted with 4- to 6-membered saturated oxygen- and nitrogen-containing heterocyclylcarbonyl;

R 5A represents

a single bond, C 1-4 alkyl, halo-C 1-4 alkyl, C 2-4 alkenyl, or C 3-6 cycloalkyl (the C 3-6 cycloalkyl may be substituted with one hydroxy); ring C 1 represents phenyl (the phenyl may be substituted with one fluorine atom) or pyridyl;

R 15 represents a hydrogen atom, C 1-4 alkyl (the C 1-4 alkyl may be substituted with one group selected from the group consisting of hydroxy, C 1-4 alkoxy, 4- to 6-membered saturated oxygen-containing heterocyclyl, di(C 1-4 alkyl)amino, and 4- to 6-membered saturated nitrogen-containing heterocyclylcarbonyl), C 1-4 alkylsulfonyl, or oxetanyl;

R 16 represents a hydrogen atom or C 1-4 alkyl; and

R 17 represents a hydrogen atom, a fluorine atom, or hydroxy.]

[Step 29-1]

This step is a method of producing compound [29-b] by reacting compound [1-e] with compound [29-a].

This reaction can be carried out by the method described in step 4-1 of production method 4 or a method pursuant thereto.

[Step 29-2]

This step is a method of producing compound [29-c] by removing Pro 3 ′ in compound [29-b] under a basic condition.

This reaction can be carried out by the method described in step 5-2 of production method 5 or a method pursuant thereto.

[Step 29-3]

This step is a method of producing compound [29-e] by reacting compound [29-c] with compound [29-d].

This reaction can be carried out by the method described in step 8-3 of production method 8 or a method pursuant thereto.

[Step 29-4]

This step is a method of producing compound [294] by reacting compound [29-e] under an acidic condition to deprotect the pyrazolyl by removing protecting group Pro 2 .

This reaction can be carried out by the method described in step 4-2 of production method 4 or a method pursuant thereto.

[Step 29-5]

This step is a method of producing compound [29-b] by reacting compound [29-c] with compound [29-g].

This reaction can be carried out by the method described in step 8-3 of production method 8 or a method pursuant thereto.

[Step 29-6]

This step is a method of producing compound [29-j] by reacting compound [29-b] under an acidic condition to deprotect the pyrazolyl by removing protecting group Pro 2 .

This reaction can be carried out by the method described in step 4-2 of production method 4 or a method pursuant thereto.

Compounds [29-f] and [29-j] thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, and chromatography.

Compounds [1-e], [29-a], [29-d], and [29-g] which are used as starting compounds in production method 29 above can be produced by production method 1 above, a method pursuant thereto, or a method known per se, or can be obtained by purchasing commercial products.

Among compound [I-1] of the present invention, compounds [30-g] and [30-m] can be produced, for example, by production method 30 below or a method pursuant thereto.

Production Method 30

[In the scheme,

R 1 , R 2 , R 3 , R 4 , W 4 , Pro 2 , Pro 3 , Pro 3′ , LG 1 , and L 2 are the same as defined above;

a group represented by formula [IV-4″-3] below:

represents a group below selected from R 54

monoC 1-4 alkylaminocarbonyl substituted with carboxy (the C 1-4 alkyl of the monoC 1-4 alkylaminocarbonyl substituted with carboxy may be substituted with one phenyl, and when position α of the carboxy of the monoC 1-4 alkylaminocarbonyl substituted with carboxy is a methylene moiety, the methylene moiety may be replaced with a structure selected from structure group α above), di(C 1-4 alkyl)aminocarbonyl substituted with carboxy, phenylmethylaminocarbonyl substituted with carboxy, C 3-6 cycloalkylaminocarbonyl substituted with carboxy, or the structure represented by formula [VIII-7] below, which is substituted with carboxy;

a group represented by formula [IV-4″-4] below:

represents a group below selected from R 54

4- to 6-membered saturated nitrogen-containing heterocyclylcarbonyl substituted with carboxy (the 4- to 6-membered saturated nitrogen-containing heterocyclyl of the 4- to 6-membered saturated nitrogen-containing heterocyclylcarbonyl substituted with carboxy may be substituted with one fluorine atom), 4- to 6-membered saturated nitrogen-containing heterocyclylcarbonyl substituted with carboxymethyl, the structure represented by formula [XI-1] below, which is substituted with carboxy, the structure represented by formula [XI-2] below, which is substituted with carboxy, the structure represented by formula [XI-3] below, which is substituted with carboxy, the structure represented by formula [XI-4] below, which is substituted with carboxy, the structure represented by formula [XI-5] below, which is substituted with carboxy;

R 5B represents

C 1-4 alkyl (the C 1-4 alkyl may be substituted with one phenyl, and when position α of the carboxy is a methylene moiety, the methylene moiety may be replaced with a structure selected from structure group α above), C 3-6 cycloalkyl, phenylmethyl, the structure represented by formula [VIII-7] below;

ring C 2 represents phenyl or pyridyl;

R 18 represents a hydrogen atom or C 1-4 alkyl;

ring F represents

4- to 6-membered nitrogen-containing heterocyclyl (the 4- to 6-membered nitrogen-containing heterocyclyl may be substituted with one fluorine atom),

the structure represented by formula [XI-1] above,

the structure represented by formula [XI-2] above,

the structure represented by formula [XI-3] above,

the structure represented by formula [XI-4] above, or

the structure represented by formula [XI-5] above.]

[Step 30-1]

This step is a method of producing compound [30-b] by reacting compound [1-e] with compound [30-a].

This reaction can be carried out by the method described in step 4-1 of production method 4 or a method pursuant thereto.

[Step 30-2]

This step is a method of producing compound [30-c] by removing Pro 3 ′ in compound [30-b] under a basic condition.

This reaction can be carried out by the method described in step 5-2 of production method 5 or a method pursuant thereto.

[Step 30-3]

This step is a method of producing compound [30-e] by reacting compound [30-c] with compound [30-d].

This reaction can be carried out by the method described in step 8-3 of production method 8 or a method pursuant thereto.

[Step 30-4]

This step is a method of producing compound [304] by reacting compound [30-e] under an acidic condition to deprotect the pyrazolyl by removing protecting group Pro 2 .

This reaction can be carried out by the method described in step 4-2 of production method 4 or the method described in step 5-4 of production method 5, or a method pursuant thereto.

[Step 30-5]

This step is a method of producing compound [30-g] by deprotecting compound [30-f] by removing protecting group Pro 3 .

This reaction can be carried out by the method described in step 5-5 of production method 5 or a method pursuant thereto.

[Step 30-6]

This step is a method of producing compound [30-j] by reacting compound [30-c] with compound [30-h].

This reaction can be carried out by the method described in step 8-3 of production method 8 or a method pursuant thereto.

[Step 30-7]

This step is a method of producing compound [30-k] by reacting compound [30-j] under an acidic condition to deprotect the pyrazolyl by removing protecting group Pro 2 .

This reaction can be carried out by the method described in step 4-2 of production method 4 or the method described in step 5-4 of production method 5, or a method pursuant thereto.

[Step 30-8]

This step is a method of producing compound [30-m] by deprotecting compound [30-k] by removing protecting group Pro 3 .

This reaction can be carried out by the method described in step 5-5 of production method 5 or a method pursuant thereto.

Steps 30-4 and 30-5, and steps 30-7 and 30-8 above may be carried out in the reversed order.

Compounds [30-g] and [30-m] thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, and chromatography.

Compounds [1-e], [30-a], [30-d], and [30-b] which are used as starting compounds in production method 30 above can be produced by production method 1 above, a method pursuant thereto, or a method known per se, or can be obtained by purchasing commercial products.

Among compound [I-1] of the present invention, compound [31-f] can be produced, for example, by production method 31 below or a method pursuant thereto.

Production Method 31

[In the scheme,

R 1 , R 2 , R 3 , R 4 , W 4 , Pro 2 , Pro 4 , and LG 1 are the same as defined above; m represents an integer of 0 to 2; and

R 19 represents C 1-4 alkyl substituted with sulfamoyl, C 1-4 alkyl substituted with C 1-4 alkylsulfonylamino, phenyl substituted with sulfamoyl, or dihydropyridine substituted with oxo.]

[Step 31-1]

This step is a method of producing compound [31-b] by reacting compound [1-e] with compound [31-a].

This reaction can be carried out by the method described in step 4-1 of production method 4 or a method pursuant thereto.

[Step 31-2]

This step is a method of producing compound [31-c] by deprotecting the nitrogen atom in 4- to 6-membered saturated nitrogen-containing heterocyclyl of compound [31-b] by removing protecting group Pro 4 .

This reaction can be carried out by the method described in step 20-2 of production method 20 or a method pursuant thereto.

[Step 31-3]

This step is a method of producing compound [31-e] by reacting compound [31-c] with compound [31-d].

This reaction can be carried out by the method described in step 8-3 of production method 8 or a method pursuant thereto.

[Step 31-4]

This step is a method of producing compound [314] by reacting compound [31-e] under an acidic condition to deprotect the pyrazolyl by removing protecting group Pro 2 .

This reaction can be carried out by the method described in step 4-2 of production method 4 or a method pursuant thereto.

Compound [314] thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, and chromatography.

Compounds [1-e], [31-a] and [31-d] which are used as starting compounds in production method 31 above can be produced by production method 1 above, a method pursuant thereto, or a method known per se, or can be obtained by purchasing commercial products.

Among compound [I-1] of the present invention, compound [32-d] can be produced, for example, by production method 32 below or a method pursuant thereto.

Production Method 32

[In the scheme,

R 1 , R 2 , R 3 , R 4 , W 4 , Pro 2 , Pro 3 , and m are the same as defined above; and

R 5C represents C 1-4 alkanediyl, the formula —(C 1-4 alkane)-NH—, the formula —(C 6 H 4 )—CH 2 —, a structure represented by formula [X-1′], formula [X-2′], or formula [X-3′] below.]

[Step 32-1]

This step is a method of producing compound [32-b] by reacting compound [31-c] with compound [32-a] or the corresponding alkylamine (the alkyl of the alkylamine is substituted with alkoxycarbonyl).

This reaction can be carried out by the method described in step 20-3 of production method 20 or a method pursuant thereto.

[Step 32-2]

This step is a method of producing compound [32-c] by reacting compound [32-b] under an acidic condition to deprotect the pyrazolyl by removing protecting group Pro 2 .

This reaction can be carried out by the method described in step 4-2 of production method 4 or the method described in step 5-4 of production method 5, or a method pursuant thereto.

[Step 32-3]

This step is a method of producing compound [32-d] by deprotecting compound [32-c] by removing protecting group Pro 3 .

This reaction can be carried out by the method described in step 5-5 of production method 5 or a method pursuant thereto.

Steps 32-2 and 32-3 above may be carried out in the reversed order.

Compound [32-d] thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, and chromatography.

Compounds [31-c] and [32-a] which are used as starting compounds in production method 32 above can be produced by production method 31 above, a method pursuant thereto, or a method known per se, or can be obtained by purchasing commercial products.

Among compound [I-1] of the present invention, compound [33-e] can be produced, for example, by production method 33 below or a method pursuant thereto.

Production Method 33

[In the scheme,

R 1 , R 2 , R 3 , R 4 , W 4 , LG 1 , Pro 2 , and Pro 3 are the same as defined above; and

R 20 represents a hydrogen atom or methyl.]

[Step 33-1]

This step is a method of producing compound [33-b] by reacting compound [1-e] with compound [33-a].

This reaction can be carried out by the method described in step 4-1 of production method 4 or a method pursuant thereto.

[Step 33-2]

This step is a method of producing compound [33-c] by methylating position α of the carbonyl of the ester of compound [33-b].

This reaction can be carried out by using methyl iodide and sodium hydride, and (i) when slightly excessive amounts of the reagents are used, a monomethyl form in which R 20 is a hydrogen atom is obtained as a main product, and (ii) when highly excessive amounts of the reagents are used, a dimethyl form in which R 20 is methyl is obtained as a main product.

(i) When the monomethyl form is obtained as a main product, the amount of the methyl iodide to be used in the present reaction is 1 to 1.5 equivalents, and preferably 1 to 1.1 equivalents, with respect to 1 equivalent of compound [33-b].

The amount of the sodium hydride to be used in the present reaction is 1 to 2 equivalents, and preferably 1 to 1.2 equivalents, with respect to 1 equivalent of compound [33-b].

(ii) When the dimethyl form is obtained as a main product, the amount of the methyl iodide to be used in the present reaction is 2 to 5 equivalents, and preferably 2 to 4 equivalents, with respect to 1 equivalent of compound [33-b].

The amount of the sodium hydride to be used in the present reaction is 2 to 5 equivalents, and preferably 2 to 4.2 equivalents, with respect to 1 equivalent of compound [33-b].

Examples of the solvent which is used in the present reaction include tetrahydrofuran, N,N-dimethylformamide, and dimethyl sulfoxide; and these solvents may be mixed with each other at an appropriate ratio and used.

The present reaction can be carried out usually at 0° C. to room temperature for 1 to 24 hours.

[Step 33-3]

This step is a method of producing compound [33-d] by reacting compound [33-c] under an acidic condition to deprotect the pyrazolyl by removing protecting group Pro 2 .

This reaction can be carried out by the method described in step 4-2 of production method 4 or the method described in step 5-4 of production method 5, or a method pursuant thereto.

[Step 33-4]

This step is a method of producing compound [33-e] by deprotecting compound [33-d] by removing protecting group Pro 3 .

This reaction can be carried out by the method described in step 5-5 of production method 5 or a method pursuant thereto.

Steps 33-3 and 33-4 above may be carried out in the reversed order.

Compound [33-e] thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, and chromatography.

Compounds [1-e] and [33-a] which are used as starting compounds in production method 33 above can be produced by production method 1 above, a method pursuant thereto, or a method known per se, or can be obtained by purchasing commercial products.

Among compound [I-1] of the present invention, compound [34-e] can be produced, for example, by production method 34 below or a method pursuant thereto.

Production Method 34

[In the scheme,

R 1 , R 2 , R 3 , R 4 , W 4 , LG 1 , and Pro 2 are the same as defined above;

R 61′ represents a hydrogen atom, a fluorine atom, methylsulfonyl, or methyl;

R 62′ represents a hydrogen atom or a fluorine atom;

R 21 represents a hydrogen atom or C 1-4 alkylsulfonyl; and

Pro 6 represents a protecting group for hydroxy, as exemplified by acetyl, or a benzyl-based protecting group such as benzyl and 4-methoxybenzyl.]

[Step 34-1]

This step is a method of producing compound [34-b] by reacting compound [1-e] with compound [34-a].

This reaction can be carried out by the method described in step 4-1 of production method 4 or a method pursuant thereto.

[Step 34-2]

This step is a method of producing compound [34-c] by deprotecting the hydroxy of compound [34-b] by removing protecting group Pro 6 .

(i) When protecting group Pro 6 is acetyl or the like, this reaction can be carried out by the method described in step 5-2 of production method 5 or a method pursuant thereto.

(ii) When protecting group Pro 6 is a benzyl-based protecting group such as benzyl and 4-methoxybenzyl, this reaction can be carried out by the method described in step 1-3 of production method 1 or a method pursuant thereto.

[Step 34-3]

This step is a method of producing compound [34-d] by reacting compound [34-c] with the corresponding sulfonyl chloride.

The amount of the sulfonyl chloride to be used in the present reaction is 1 to 5 equivalents, and preferably 1 to 3 equivalents, with respect to 1 equivalent of compound [34-c].

Examples of the base which is used in the present reaction include triethylamine, pyridine, 4-dimethylaminopyridine, and N,N-diisopropylethylamine. The amount of the base to be used is usually 1 to 5 equivalents, and preferably 1 to 3 equivalents, with respect to 1 equivalent of compound [34-c].

Examples of the solvent which is used in the present reaction include solvents that do not interfere with reactions, such as chloroform, dichloromethane, toluene, diethyl ether, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, and acetonitrile; and these solvents may be mixed with each other at an appropriate ratio and used.

The present reaction can be carried out usually at 0° C. to room temperature for 1 to 24 hours.

[Step 34-4]

This step is a method of producing compound [34-e] by reacting compound [34-d] under an acidic condition to deprotect the pyrazolyl by removing protecting group Pro 2 .

This reaction can be carried out by the method described in step 4-2 of production method 4 or a method pursuant thereto.

[Step 34-5]

This step is a method of producing compound [34-e] in which R 21 is a hydrogen atom from compound [34-c].

This reaction can be carried out by the method described in step 4-2 of production method 4 or a method pursuant thereto.

When that type of compound [34-e] in which R 21 is a hydrogen atom is produced, steps 34-2 and 34-5 above may be carried out in the reversed order.

[Step 34-6]

This step is a method of producing compound [34-e] in which R 21 is a hydrogen atom from compound [34-c] in which Pro 6 is 4-methoxybenzyl.

This reaction can be carried out by the method described in step 4-2 of production method 4 or the method described in step 5-5 of production method 5, or a method pursuant thereto.

Compound [34-e] thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, and chromatography.

Incidentally, compounds [1-e] and [34-a] which are used as starting compounds in production method 34 above can be produced by production method 1 above, a method pursuant thereto, or a method known per se, or can be obtained by purchasing commercial products.

Among compound [I-1] of the present invention, compound [35-g] can be produced, for example, by production method 35 below or a method pursuant thereto.

Production Method 35

[In the scheme,

R 1 , R 2 , R 3 , R 4 , W 4 , LG 1 , Pro 2 , and Pro 4 are the same as defined above;

L 3 represents a single bond or C 1-4 alkyl;

ring C 3 represents phenyl, C 3-6 cycloalkyl, or the structure represented by formula [IX-1] below:

R 22 represents C 1-4 alkylsulfonyl;

R 23 represents a hydrogen atom or C 1-4 alkyl; and

LG 3 represents a leaving group selected from the group consisting of a halogen atom such as a chlorine atom and a bromine atom, C 1-4 alkylsulfonyloxy such as methanesulfonyloxy, and arylsulfonyloxy such as p-toluenesulfonyloxy.]

[Step 35-1]

This step is a method of producing compound [35-b] by reacting compound [1-e] with compound [35-a].

This reaction can be carried out by the method described in step 4-1 of production method 4 or a method pursuant thereto.

[Step 35-2]

This step is a method of producing compound [35-c] by deprotecting the amino of compound [35-b] by removing protecting group Pro 4 .

This reaction can be carried out by the method described in step 20-2 of production method 20 or a method pursuant thereto.

[Step 35-3]

This step is a method of producing compound [35-d] by reacting compound [35-c] with the corresponding sulfonyl chloride.

This reaction can be carried out by the method described in step 34-3 of production method 34 or a method pursuant thereto.

[Step 35-4]

This step is a method of producing compound [35-f] by reacting compound [35-d] with compound [35-e].

This reaction can be carried out by the method described in step 7-2 of production method 7 or a method pursuant thereto.

[Step 35-5]

This step is a method of producing compound [35-g] by reacting compound [34-f] under an acidic condition to deprotect the pyrazolyl by removing protecting group Pro 2 .

This reaction can be carried out by the method described in step 4-2 of production method 4 or a method pursuant thereto.

[Step 35-6]

This step is a method of producing compound [35-g] in which R 23 is a hydrogen atom from compound [35-d].

This reaction can be carried out by the method described in step 4-2 of production method 4 or a method pursuant thereto.

Compound [35-g] thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, and chromatography.

Compounds [1-e] and [35-a] which are used as starting compounds in production method 35 above can be produced by production method 1 above, a method pursuant thereto, or a method known per se, or can be obtained by purchasing commercial products.

Among compound [I-2] of the present invention, compound [36-e] in which the structure represented by R 5 is a structure shown in formula [IV-2] below and R 52 is carboxy can be produced, for example, by production method 36 below or a method pursuant thereto.

Production Method 36

[In the scheme,

R 1 , R 2 , R 3 , R 4 , X A , Pro 2 , Pro 3 , W 2 , Y, L, and G are the same as defined above.]

[Step 36-1]

This step is a method of producing compound [36-b] by reacting compound [6-a] with compound [36-a].

This reaction can be carried out by the method described in step 1-2 of production method 1 or a method pursuant thereto.

There are several synthesis pathways for production of compound [36-e]. Steps 36-2 to 36-6 therefor will be sequentially described.

(i) When Pro 3 in compound [36-b] is primary or secondary alkyl such as methyl, ethyl, and 2-propyl, or (ii) when Pro 3 in compound [36-b] is a benzyl-based protecting group such as benzyl and 4-methoxybenzyl, compound [36-e] can be produced via compound [36-c] by methods described in steps 36-2 and 36-3.

[Step 36-2]

This step is a method of producing compound [36-c] by deprotecting compound [36-b] by removing protecting group Pro 3 .

This reaction can be carried out by the method described in step 5-2 of production method 5 or a method pursuant thereto.

[Step 36-3]

This step is a method of producing compound [36-e] by deprotecting the pyrazolyl of compound [36-c] by removing protecting group Pro 2 under an acidic condition.

This reaction can be carried out by the method described in step 4-2 of production method 4 or a method pursuant thereto.

(i) When Pro 3 in compound [36-b] is primary or secondary alkyl such as methyl, ethyl, and 2-propyl, (ii) when Pro 3 in compound [36-b] is a benzyl-based protecting group such as benzyl and 4-methoxybenzyl, or (iii) when Pro 3 in compound [36-b] is tert-butyl, compound [36-e] can be produced via compound [36-d] by methods described in steps 36-4 and 36-5.

[Step 36-4]

This step is a method of producing compound [36-d] by deprotecting the pyrazolyl of compound [36-b] by removing protecting group Pro 2 under an acidic condition.

This reaction can be carried out by the method described in step 5-4 of production method 5 or a method pursuant thereto.

[Step 36-5]

This step is a method of producing compound [36-e] by deprotecting compound [36-d] by removing protecting group Pro 3 .

This reaction can be carried out by the method described in step 5-5 of production method 5 or a method pursuant thereto.

When Pro 3 in compound [36-b] is 4-methoxybenzyl or tert-butyl, compound [36-e] can be produced by a method described in step 36-6.

[Step 36-6]

This step is a method of producing compound [36-e] by deprotecting compound [36-b] by removing protecting groups Pro 2 and Pro 3 under an acidic condition.

This reaction can be carried out by the method described in step 5-5 (iii) of production method 5 or a method pursuant thereto.

Compound [36-e] thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, and chromatography.

Incidentally, compounds [6-a] and [36-a] which are used as starting compounds in production method 36 above can be produced by production method 6 above, a method pursuant thereto, or a method known per se, or can be obtained by purchasing commercial products.

Among compound [I-2] of the present invention, compound [37-d] in which the structure represented by R 5 is a structure represented by formula [IV-3] below and R 53 is the formula HOC(═O)-L 1 - can be produced, for example, by production method 37 below or a method pursuant thereto.

Production Method 37

[In the scheme,

R 1 , R 2 , R 3 , R 4 , X A , Pro 2 , Pro 3 , W 3 , ring B, L 1 , and G are the same as defined above.]

[Step 37-1]

This step is a method of producing compound [37-a] by reacting compound [10-a] with compound [36-a].

This reaction can be carried out by the method described in step 1-2 of production method 1 or a method pursuant thereto.

There are several synthesis pathways for production of compound [37-d]. Steps 37-2 to 37-6 therefor will be sequentially described.

(i) When Pro 3 in compound [37-a] is primary or secondary alkyl such as methyl, ethyl, and 2-propyl, or (ii) when Pro 3 in compound [37-a] is a benzyl-based protecting group such as benzyl and 4-methoxybenzyl, compound [37-d] can be produced via compound [37-b] by methods described in steps 37-2 and 37-3.

[Step 37-2]

This step is a method of producing compound [37-b] by deprotecting compound [37-a] by removing protecting group Pro 3 .

This reaction can be carried out by the method described in step 5-2 of production method 5 or a method pursuant thereto.

[Step 37-3]

This step is a method of producing compound [37-d] by deprotecting the pyrazolyl of compound [37-b] by removing protecting group Pro 2 under an acidic condition.

This reaction can be carried out by the method described in step 4-2 of production method 4 or a method pursuant thereto.

(i) When Pro 3 in compound [37-a] is primary or secondary alkyl such as methyl, ethyl, and 2-propyl, (ii) when Pro 3 in compound [37-a] is a benzyl-based protecting group such as benzyl and 4-methoxybenzyl, or (iii) when Pro 3 in compound [37-a] is tert-butyl, compound [37-d] can be produced via compound [37-c] by methods described in steps 37-4 and 37-5.

[Step 37-4]

This step is a method of producing compound [37-c] by deprotecting the pyrazolyl of compound [37-a] by removing protecting group Pro 2 under an acidic condition.

This reaction can be carried out by the method described in step 5-4 of production method 5 or a method pursuant thereto.

[Step 37-5]

This step is a method of producing compound [37-d] by deprotecting compound [37-c] by removing protecting group Pro 3 .

This reaction can be carried out by the method described in step 5-5 of production method 5 or a method pursuant thereto.

When Pro 3 in compound [37-a] is 4-methoxybenzyl or tert-butyl, compound [37-d] can be produced by a method described in step 37-6.

[Step 37-6]

This step is a method of producing compound [37-d] by deprotecting compound [37-a] by removing protecting groups Pro 2 and Pro 3 under an acidic condition.

This reaction can be carried out by the method described in step 5-5 (iii) of production method 5 or a method pursuant thereto.

Compound [37-d] thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, and chromatography.

Incidentally, compounds [10-a] and [36-a] which are used as starting compounds in production method 37 above can be produced by production method 10 above, a method pursuant thereto, or a method known per se, or can be obtained by purchasing commercial products.

Among compound [I-2] of the present invention, compound [38-d] in which the structure represented by R 5 is a structure represented by formula [IV-4] below and R 54 is the formula HOC(═O)—R 54′ — can be produced, for example, by production method 38 below or a method pursuant thereto.

Production Method 38

[In the scheme,

R 1 , R 2 , R 3 , R 4 , X A , R 54′ , R 61 , R 62 , Pro 2 , Pro 3 , W 4 , ring C, and G are the same as defined above.]

[Step 38-1]

This step is a method of producing compound [38-a] by reacting compound [15-a] with compound [36-a].

This reaction can be carried out by the method described in step 1-2 of production method 1 or a method pursuant thereto.

There are several synthesis pathways for production of compound [38-d]. Steps 38-2 to 38-6 therefor will be sequentially described.

(i) When Pro 3 in compound [38-a] is primary or secondary alkyl such as methyl, ethyl, and 2-propyl, or (ii) when Pro 3 in compound [38-a] is a benzyl-based protecting group such as benzyl and 4-methoxybenzyl, compound [38-d] can be produced via compound [38-b] by methods described in steps 38-2 and 38-3.

[Step 38-2]

This step is a method of producing compound [38-b] by deprotecting compound [38-a] by removing protecting group Pro 3 .

This reaction can be carried out by the method described in step 5-2 of production method 5 or a method pursuant thereto.

[Step 38-3]

This step is a method of producing compound [38-d] by deprotecting the pyrazolyl of compound [38-b] by removing protecting group Pro 2 under an acidic condition.

This reaction can be carried out by the method described in step 4-2 of production method 4 or a method pursuant thereto.

(i) When Pro 3 in compound [38-a] is primary or secondary alkyl such as methyl, ethyl, and 2-propyl, (ii) when Pro 3 in compound [38-a] is a benzyl-based protecting group such as benzyl and 4-methoxybenzyl, or (iii) when Pro 3 in compound [38-a] is tert-butyl, compound [38-d] can be produced via compound [38-c] by methods described in steps 38-4 and 38-5.

[Step 38-4]

This step is a method of producing compound [38-c] by deprotecting the pyrazolyl of compound [38-a] by removing protecting group Pro 2 under an acidic condition.

This reaction can be carried out by the method described in step 5-4 of production method 5 or a method pursuant thereto.

[Step 38-5]

This step is a method of producing compound [38-d] by deprotecting compound [38-c] by removing protecting group Pro 3 .

This reaction can be carried out by the method described in step 5-5 of production method 5 or a method pursuant thereto.

When Pro 3 in compound [38-a] is 4-methoxybenzyl or tert-butyl, compound [38-d] can be produced by step 38-6.

[Step 38-6]

This step is a method of producing compound [38-d] by deprotecting compound [38-a] by removing protecting groups Pro 2 and Pro 3 under an acidic condition.

This reaction can be carried out by the method described in step 5-5 (iii) of production method 5 or a method pursuant thereto.

Compound [38-d] thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, and chromatography.

Incidentally, compounds [15-a] and [36-a] which are used as starting compounds in production method 38 above can be produced by production method 15 above, a method pursuant thereto, or a method known per se, or can be obtained by purchasing commercial products.

Among compound [I-3] of the present invention, compound [39-c] in which the structure represented by R 5 is a structure represented by formula [IV-2] below and R 52 is carboxy can be produced, for example, by production method 39 below or a method pursuant thereto.

Production Method 39

[In the scheme,

R 1 , R 2 , R 3 , R 4 , X A , Pro 3 , W 2 , Y, and L are the same as defined above.]

[Step 39-1]

This step is a method of producing compound [39-b] by reacting compound [6-a] with compound [39-a].

This reaction applies a so-called Stille-Kelly reaction to intermolecular heterocoupling, and can be carried out in the presence of a palladium catalyst and an organodistannane.

The type and amount of the catalyst to be used in the present reaction is the same as those in step 1-2 of production method 1 or those pursuant thereto.

Examples of the organodistannane which is used in the present reaction include bis(trimethylstannane) and bis(tributylstannane). The amount of the organodistannane to be used is 1 to 3 equivalents, and preferably 1 to 1.5 equivalents, with respect to compound [6-a].

Examples of the reaction solvent which is used in the present reaction include solvents that do not interfere with reactions, such as toluene, xylene, 1,4-dioxane, tetrahydrofuran, and 1,2-dimethoxyethane; and these solvents may be mixed with each other at an appropriate ratio and used.

These reactions can be carried out usually at room temperature to reflux temperature for 1 to 24 hours, and can be also carried out under microwave irradiation.

[Step 39-2]

This step is a method of producing compound [39-c] by deprotecting compound [39-b] by removing protecting group Pro 3 .

This reaction can be carried out by the method described in step 5-5 of production method 5 or a method pursuant thereto.

Compound [39-c] thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, and chromatography.

Compounds [6-a] and [39-a] which are used as starting compounds in production method 39 above can be produced by production method 6 above, a method pursuant thereto, or a method known per se, or can be obtained by purchasing commercial products.

Among compound [I-3] of the present invention, compound [40-b] in which the structure represented by R 5 is a structure represented by formula [IV-3] below and R 53 is the formula HOC(═O)-L 1 - can be produced, for example, by production method 40 below or a method pursuant thereto.

Production Method 40

[In the scheme,

R 1 , R 2 , R 3 , R 4 , X A , Pro 3 , W 3 , ring B, and L 1 are the same as defined above.]

[Step 40-1]

This step is a method of producing compound [40-a] by reacting compound [10-a] with compound [39-a].

This reaction can be carried out by the method described in step 39-1 of production method 39 or a method pursuant thereto.

[Step 40-2]

This step is a method of producing compound [40-b] by deprotecting compound [40-a] by removing protecting group Pro 3 .

This reaction can be carried out by the method described in step 5-5 of production method 5 or a method pursuant thereto.

Compound [40-b] thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, and chromatography.

Incidentally, compounds [10-a] and [39-a] which are used as starting compounds in production method 40 above can be produced by production method 10 above, a method pursuant thereto, or a method known per se, or can be obtained by purchasing commercial products.

Among compound [I-3] of the present invention, compound [41-b] in which the structure represented by R 5 is a structure represented by formula [IV-4] below and R 54 is the formula HOC(═O)—R 54′ — can be produced, for example, by production method 41 below or a method pursuant thereto.

Production Method 41

[In the scheme,

R 1 , R 2 , R 3 , R 4 , X A , R 54′ , R 61 , R 62 , PRO 3 , W 4 , and ring C are the same as defined above.]

[Step 41-1]

This step is a method of producing compound [41-a] by reacting compound [15-a] with compound [39-a].

This reaction can be carried out by the method described in step 39-1 of production method 39 or a method pursuant thereto.

[Step 41-2]

This step is a method of producing compound [41-b] by deprotecting compound [41-a] by removing protecting group Pro 3 .

This reaction can be carried out by the method described in step 5-5 of production method 5 or a method pursuant thereto.

Compound [41-b] thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, and chromatography.

Incidentally, compounds [15-a] and [39-a] which are used as starting compounds in production method 41 above can be produced by production method 15 above, a method pursuant thereto, or a method known per se, or can be obtained by purchasing commercial products.

Among compound [I-4] or [I-5] of the present invention, compound [42-c] in which the structure represented by R 5 is a structure represented by formula [IV-2] below and R 52 is carboxy can be produced, for example, by production method 42 below or a method pursuant thereto.

Production Method 42

[In the scheme,

R 1 , R 2 , R 3 , R 4 , Pro 3 , W 2 , Y, and L are the same as defined above; and

Q 1 represents an oxygen atom or a sulfur atom.]

[Step 42-1]

This step is a method of producing compound [42-b] by reacting compound [6-a] with compound [42-a].

This reaction is a so-called Heck-type reaction that can be carried out in the presence of a palladium catalyst and a base.

The type and amount of the palladium catalyst to be used in the present reaction are the same as those in step 17-2 of production example 17 or those pursuant thereto.

Examples of the base which is used in the present reaction include potassium acetate, tetrabutylammonium acetate, and cesium pivalate. The amount of the base to be used is 1 to 3 equivalents, and preferably 1 to 1.5 equivalents, with respect to compound [6-a].

Examples of the reaction solvent to be used in the present reaction include solvents that do not interfere with reactions, such as toluene, N,N-dimethylacetamide, 1,4-dioxane, and water; and these solvents may be mixed with each other at an appropriate ratio and used.

These reactions can be carried out usually at reflux temperature for 1 to 24 hours, and can be also carried out under microwave irradiation.

[Step 42-2]

This step is a method of producing compound [42-c] by deprotecting compound [42-b] by removing protecting group Pro 3 .

This reaction can be carried out by the method described in step 5-5 of production method 5 or a method pursuant thereto.

Compound [42-c] thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, and chromatography.

Compounds [6-a] and [42-a] which are used as starting compounds in production method 42 above can be produced by production method 6 above, a method pursuant thereto, or a method known per se, or can be obtained by purchasing commercial products.

Among compound [I-4] or [I-5] of the present invention, compound [43-b] in which the structure represented by R 5 is a structure represented by formula [IV-3] below and R 53 is the formula HOC(═O)-L 1 - can be produced, for example, by production method 43 below or a method pursuant thereto.

Production Method 43

[In the scheme,

R 1 , R 2 , R 3 , R 4 , Pro 3 , X A , W 3 , ring B, L 1 , and Q 1 are the same as defined above.]

[Step 43-1]

This step is a method of producing compound [43-a] by reacting compound [10-a] with compound [42-a].

This reaction can be carried out by the method described in step 42-1 of production method 42 or a method pursuant thereto.

[Step 43-2]

This step is a method of producing compound [43-b] by deprotecting compound [43-a] by removing protecting group Pro 3 .

This reaction can be carried out by the method described in step 5-5 of production method 5 or a method pursuant thereto.

Compound [43-b] thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, and chromatography.

Compounds [10-a] and [42-a] which are used as starting compounds in production method 43 above can be produced by production method 10 above, a method pursuant thereto, or a method known per se, or can be obtained by purchasing commercial products.

Among compound [I-4] or [I-5] of the present invention, compound [44-b] in which the structure represented by R 5 is a structure represented by formula [IV-4] below and R 54 is the formula HOC(═O)—R 54′ — can be produced, for example, by production method 44 below or a method pursuant thereto.

Production Method 44

[In the scheme,

R 1 , R 2 , R 3 , R 4 , R 54′ , R 61 , R 62 , Pro 3 , X A , W 4 , ring C, and Q 1 are the same as defined above.]

[Step 44-1]

This step is a method of producing compound [44-a] by reacting compound [15-a] with compound [42-a].

This reaction can be carried out by the method described in step 42-1 of production method 42 or a method pursuant thereto.

[Step 44-2]

This step is a method of producing compound [44-b] by deprotecting compound [44-a] by removing protecting group Pro 3 .

This reaction can be carried out by the method described in step 5-5 of production method 5 or a method pursuant thereto.

Compound [44-b] thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, and chromatography.

Compounds [15-a] and [42-a] which are used as starting compounds in production method 44 above can be produced by production method 15 above, a method pursuant thereto, or a method known per se, or can be obtained by purchasing commercial products.

The present invention will be described in more detail with reference to the following Reference Examples, Examples, and Test Examples, but these examples do not limit the present invention, and may be varied in such a range as not to deviate from the scope of the present invention.

In the following Reference Examples and Examples, packed columns (Reveleris (registered trademark) Flash Cartridges Silica manufactured by Grace or Biotage (registered trademark) SNAP Cartridge HP-Sphere manufactured by Biotage AB) were used for silica gel column chromatography. Packed columns (Reveleris (registered trademark) Flash Cartridges Amino manufactured by Grace or Biotage (registered trademark) SNAP Cartridge KP-NH manufactured by Biotage AB) were used for NH silica gel column chromatography. PLC plate 20×20 cm silica gel 60F254, 2 mm manufactured by Merck KGaA was used for preparative thin-layer chromatography. Unless otherwise stated, the ratio of eluent solvents is expressed as a volume ratio. The phase separator used was ISOLUTE (registered trademark) Phase Separator manufactured by Biotage AB.

Abbreviations used herein have the following meanings:

s: singlet

d: doublet

t: triplet

q: quartet

quin: quintet

sxt: sextet

spt: septet

dd: double doublet

dt: double triplet

td: triple doublet

tt: triple triplet

qd: quarter doublet

m: multiplet

br: broad

J: coupling constant

Hz: Hertz

CHLOROFORM-d: deuterated chloroform

DMSO-d 6 : deuterated dimethyl sulfoxide

MeOH-d 4 : deuterated methanol

ACETONE-d 6 : deuterated acetone

D 2 O: deuterated water

THP: tetrahydropyranyl

TMS: trimethylsilyl

Rf: retardation factor

1 H-NMR (proton nuclear magnetic resonance spectrum) was measured using tetramethylsilane as an internal standard with Fourier transformed NMR as described below, and all δ values are expressed in ppm.

200 MHz: Gemini2000 (Agilent Technologies, Inc.)

300 MHz: Inova300 (Agilent Technologies, Inc.)

400 MHz: AVANCE III HD400 (Bruker Corporation)

500 MHz: JNM-ECA500 (JEOL Ltd.)

600 MHz: JNM-ECA600 (JEOL Ltd.)

ACD/Spectrus Processor 2015 ACD/Labs 2015 Release (File Version S30S41, Build 76327, 28 Feb. 2015) (trade name) or the like was used for analysis. Very broad proton peaks shown by hydroxy, amino, amide, pyrazole, or the like are not indicated in some cases.

In analysis of compounds, there may be a proton unidentifiable because of overlapping with a peak from water or a solvent.

Mass Spectrum (MS) was measured on the following devices:

PlatformLC (Waters Corporation)

LCMS-2010EV (Shimadzu Corporation)

LCMS-IT-TOF (Shimadzu Corporation)

Agilent 6130 (Agilent Technologies, Inc.)

Agilent 6150 (Agilent Technologies, Inc.)

Ionization techniques used were Electrospray Ionization (ESI), Electron Ionization (EI), and dual ionization of ESI and Atmospheric Pressure Chemical Ionization (APCI). The values actually measured (which are described as “Found”) are reported. Generally, molecular ion peaks are detected. However, for compounds having tert-butoxycarbonyl (-Boc), fragment ion peaks, which are peaks derived from the compounds that have lost tert-butoxycarbonyl or tert-butyl, may be also detected. For compounds having tetrahydropyranyl (THP), fragment ion peaks, which are peaks derived from the compounds that have lost tetrahydropyranyl, may be also detected. For compounds having hydroxy (—OH), fragment peaks, which are peaks derived from compounds that have lost H 2 O or an OH radical, may be also detected. For salts, molecular ion peaks of free forms or fragment ion peaks are typically observed.

LC-MS was performed in the Examples and Reference Examples under the following conditions:

HPLC: Agilent 1290 Infinity

MS: Agilent 6130 or 6150

[HPLC Conditions]

Column: Acquity UPLC CSH C18, 1.7 μm, 2.1x×50 mm (WATERS Corporation)

Solvent: solution A; water with 0.1% formic acid, solution B; acetonitrile with 0.1% formic acid

(Method A)

Gradient: 0.00 min (solution A/solution B=80/20), 1.20 min (solution A/solution B=1/99), 1.40 min (solution A/solution B=1/99), 1.41 min (solution A/solution B=80/20), 1.50 min (solution A/solution B=80/20)

(Method B)

Gradient: 0.00 min (solution A/solution B=95/5), 0.80 min (solution A/solution B=60/40), 1.08 min (solution A/solution B=1/99), 1.38 min (solution A/solution B=1/99), 1.41 min (solution A/solution B=95/5), 1.50 min (solution A/solution B=80/20) (Method C)

Gradient: 0.00 min (solution A/solution B=70/30), 0.80 min (solution A/solution B=1/99), 1.40 min (solution A/solution B=1/99), 1.42 min (solution A/solution B=70/30), 1.50 min (solution A/solution B=70/30)

Injection volume: 0.5 μL; Flow rate: 0.8 mL/min

Detection: UV 210 nm, 254 nm

HPLC equipped with evaporative light scattering detector (ELSD): Agilent 385-ELSD

MS condition

Ionization: ESI or ESI/APCI multimode

Purification by preparative HPLC was performed in the Examples and Reference Examples under the following conditions:

Equipment: High-throughput purification system from Gilson, Inc.

Column: Triart C18, 5 μm, 30×50 mm (YMC Co., Ltd.) or X-Bridge Prep C18 5 um OBD,

30×50 (Waters Corporation)

Solvent: solution A; water with 0.1% formic acid, solution B; acetonitrile with 0.1% formic acid, or solution A; water with 0.1% trifluoroacetic acid, solution B; acetonitrile with 0.1% trifluoroacetic acid

(Method A)

Gradient: 0.00 min (solution A/solution B=90/10), 2.00 min (solution A/solution B=90/10), 11.0 min (solution A/solution B=20/80), 12.0 min (solution A/solution B=5/95), 13.52 min (solution A/solution B=5/95), 15.0 min (solution A/solution B=90/10) (Method B)

Gradient: 0.00 min (solution A/solution B=95/5), 3.00 min (solution A/solution B=95/5), 8.53 min (solution A/solution B=80/20), 10.0 min (solution A/solution B=80/20), 11.0 min (solution A/solution B=50/50), 12.02 min (solution A/solution B=5/95), 13.5 min (solution A/solution B=5/95), 13.65 min (solution A/solution B=95/5), 15.0 min (solution A/solution B=95/5) (Method C)

Gradient: 0.00 min (solution A/solution B=80/20), 2.00 min (solution A/solution B=80/20), 10.0 min (solution A/solution B=5/95), 11.5 min (solution A/solution B=1/99), 13.5 min (solution A/solution B=1/99), 13.55 min (solution A/solution B=80/20), 15.0 min (solution A/solution B=5/95), 15.0 min (solution A/solution B=95/5)

Flow rate: 40 mL/min

Detection: UV 210 nm, UV 254 nm

HPLC equipped with ELSD: SofTA MODEL 300S ELSD

Purification by preparative LC-MS was performed in the Examples and Reference Examples under the following conditions:

HPLC: Agilent 1260 Infinity

[HPLC Conditions]

Column: X-SELECT CSH C18, 5 μm, OBD, 30×50 (Waters Corporation)

Solvent: solution A; water with 0.1% formic acid, solution B; acetonitrile with 0.1% formic acid, or solution A; water with 0.1% trifluoroacetic acid, solution B; acetonitrile with 0.1% trifluoroacetic acid

(Method A)

Gradient: 0.00 min (solution A/solution B=90/10), 0.50 min (solution A/solution B=90/10), 7.50 min (solution A/solution B=20/80), 7.95 min (solution A/solution B=20/80), 8.00 min (solution A/solution B=5/95), 9.00 min (solution A/solution B=5/95), 9.05 min (solution A/solution B=90/10), 10.0 min (solution A/solution B=90/10)

(Method B)

Gradient: 0.00 min (solution A/solution B=95/5), 0.50 min (solution A/solution B=95/5), 7.50 min (solution A/solution B=50/50), 7.95 min (solution A/solution B=50/50), 8.00 min (solution A/solution B=5/95), 9.00 min (solution A/solution B=5/95), 9.05 min (solution A/solution B=95/5), 10.00 min (solution A/solution B=95/5)

(Method C)

Gradient: 0.00 min (solution A/solution B=80/20), 0.50 min (solution A/solution B=80/20), 7.00 min (solution A/solution B=5/95), 7.45 min (solution A/solution B=5/95), 7.50 min (solution A/solution B=1/99), 9.00 min (solution A/solution B=1/99), 9.20 min (solution A/solution B=80/20), 10.0 min (solution A/solution B=80/20)

Flow rate: 50 mL/min

Detection: UV 210 nm, UV 254 nm

MS: Agilent 6130

HPLC equipped with ELSD: Agilent 385 ELSD

MS condition

Ionization: ESI or ESI/APCI multimode

Chiral HPLC analysis was performed in the Examples and Reference Examples under the following conditions:

HPLC: Agilent 1260 Infinity or 1100 Series

[HPLC Conditions]

Detection: UV 210 nm, 254 nm

Preparative chiral HPLC was performed in the Examples and Reference Examples under the following conditions:

HPLC: High-throughput purification system from Gilson, Inc. or preparative LC system from

Waters Corporation

[HPLC Conditions]

Detection: UV 210 nm, 254 nm

Chiral suprecritical fluid chromatography (SFC) analysis was performed in the Examples and Reference Examples under the following conditions:

SFC: UPC 2 from Waters Corporation

[SFC Conditions]

Detection: UV 210 nm, 254 nm

Preparative chiral SFC was performed in the Examples and Reference Examples under the following conditions:

SFC: SFC 30 from Waters Corporation

[SFC Conditions]

Detection: UV 210 nm, 254 nm

The polarimeter used was Autopol V from Rudolph Research Analytical, and the sodium D line (589 nm) was used as a light source.

The microwave reactor used was Initiator from Biotage AB or MONOWAVE 300 from Anton-Paar GmbH.

Compound names were designated using Molecular to Chemical Name (version 1), as a component of PipelinePilot 9.5 from OpenEye Scientific Software.

Conformations of compounds in the Reference Examples and Examples are shown in the absolute configuration of its asymmetric carbon. A compound with the designation of absolute configuration of its asymmetric carbon is an optically active substance.

The present invention will be described in more detail with reference to the following Reference Examples, Examples, Test Examples, and Preparation Examples, but these examples do not limit the present invention, and may be varied in such a range as not to deviate from the scope of the present invention.

Reference Example 1-1

6-[2-(2-Oxanyl)-3-pyrazolyl]-3-pyridinol

(1) Potassium carbonate (20.65 g) and benzyl bromide (10.6 mL) were added to a solution of commercially available 2-bromo-5-hydroxypyridine (13.00 g) in acetone (250 mL) under ice cooling, and the mixture was stirred at room temperature for 2 hours. After the solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was separated by a phase separator, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=9:1 to 4:1) to give 2-bromo-5-(benzyloxy)pyridine (16.71 g) as a colorless powder.

(2) To the compound (10.00 g) obtained in (1) above, 1-(2-tetrahydropyranyl)1H-pyrazole-5-boronic acid pinacol ester (15.80 g), sodium carbonate (12.04 g), and 1,1′-bis(diphenylphosphino)ferrocene palladium(II) dichloromethane complex (1.55 g), 1,2-dimethoxyethane (120 mL) and water (60 mL) were added, and the resultant mixture was heated to reflux at 100° C. under a nitrogen atmosphere for 7 hours. After cooling to room temperature, the resultant solution was passed through Celite (registered trademark) to remove insolubles, and the filtrate was concentrated under reduced pressure, and water was added to the residue, and the mixture was extracted with chloroform. The organic layer was separated by a phase separator, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=7:3 to 1:1) to give 2-[2-(2-oxanyl)-3-pyrazolyl]-5-phenylmethoxypyridine (11.04 g) as a light orange oil.

(3) To a solution of the compound (11.04 g) obtained in (2) above in ethanol (40 mL) and ethyl acetate (40 mL), palladium carbon (1.10 g) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 2 hours. After the reaction solution was filtered through Celite (registered trademark), the filtrate was concentrated, the obtained residue was purified by silica gel column chromatography (chloroform only to chloroform:methanol=92:8), and was powdered from diethyl ether/hexane to give the title compound (6.18 g) as a colorless powder.

1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 1.43-1.70 (m, 3H) 1.83-1.91 (m, 1H) 1.94-2.03 (m, 1H) 2.30-2.42 (m, 1H) 3.41-3.54 (m, 1H) 3.81-3.88 (m, 1H) 6.11-6.17 (m, 1H) 6.56-6.60 (m, 1H) 7.24-7.29 (m, 1H) 7.48-7.59 (m, 2H) 8.20-8.24 (m, 1H) 10.21 (s, 1H).

MS ESI/APCI Multi posi: 246[M+H] + .

The compounds of Reference Examples 1-2 and 1-3 below were synthesized using a commercially available compound, according to the method described in Reference Example 1-1. The structures, NMR data, and MS data of these compounds are shown in Table 1-5.

Reference Example 2-1

6-[4-(Difluoromethyl)-2-(2-oxanyl)-3-pyrazolyl]-3-pyridinol

(1) To a solution of the compound (700 mg) obtained in Reference Example 1-1-(2) in chloroform (10 mL), N-bromosuccinimide (557 mg) was added at room temperature, and the mixture was stirred for 1 hour. The reaction solution was poured into a saturated aqueous solution of sodium hydrogen carbonate and extracted with chloroform. The organic layer was separated by a phase separator and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=7:3) to give 2-[4-bromo-2-(2-oxanyl)-3-pyrazolyl]-5-phenylmethoxypyridine (710 mg) as a pale yellow oil.

(2) A solution of the compound (710 mg) obtained in (1) above in tetrahydrofuran (10 mL) was cooled to −78° C. under a nitrogen atmosphere, and n-butyl lithium (1.60 mol/L n-hexane solution, 1.18 mL) was added dropwise thereto and the mixture was stirred for 45 minutes. To the reaction solution, N,N-dimethylformamide (0.15 mL) was added dropwise. The temperature of the solution was gradually increased to room temperature and the solution was stirred for 1 hour. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was separated by a phase separator, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1 to 1:1) to give a mixture (630 mg) containing 1-(2-oxanyl)-5-(5-phenylmethoxy-2-pyridinyl)-4-pyrazolecarboxaldehyde as a pale yellow oil.

(3) Bis(2-methoxyethyl)aminosulfur trifluoride (BAST) (491 μL) and ethanol (7 μL) were added to a solution of the compound (622 mg) obtained in (2) above in chloroform (10 mL), and the mixture was stirred at room temperature for 1 hour, and then at 50° C. for 3 hours. The reaction solution was added dropwise to a saturated aqueous solution of sodium hydrogen carbonate and extracted with chloroform. The organic layer was separated by a phase separator, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=9:1 to 13:7) to give 2-[4-(difluoromethyl)-2-(2-oxanyl)-3-pyrazolyl]-5-phenylmethoxypyridine (196 mg) as a pale yellow oil.

(4) The compound (196 mg) obtained in (3) above was used to perform the synthesis process according to the method described in Reference Example 1-1-(3) thereby giving the title compound (149 mg) as a colorless amorphous substance.

1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.50-1.80 (m, 3H) 1.89-2.15 (m, 2H) 2.44-2.55 (m, 1H) 3.47-3.58 (m, 1H) 4.00-4.09 (m, 1H) 5.41-5.52 (m, 1H) 6.50-6.83 (m, 1H) 7.28-7.33 (m, 1H) 7.49-7.55 (m, 1H) 7.83 (s, 1H) 8.36-8.42 (m, 1H).

MS ESI/APCI Multi posi: 296[M+H] + .

MS ESI/APCI Multi nega: 294[M−H] − .

Reference Example 3-1

6-[4-Chloro-2-(2-oxanyl)-3-pyrazolyl]-3-pyridinol

To a solution of the compound (300 mg) obtained in Reference Example 1-1 in chloroform (6.2 mL), N-chlorosuccinimide (109 mg) was added, and the mixture was stirred at 70° C. for 6 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1 to 1:1) to give the title compound (217 mg) as a colorless powder.

1 H NMR (400 MHz, CHLOROFOLM-d) δ ppm 1.47-1.74 (m, 4H) 1.93-2.14 (m, 2H) 2.37-2.51 (m, 1H) 3.48 (td, J=11.3, 2.4 Hz, 1H) 3.93-4.00 (m, 1H) 5.75 (dd, J=9.8, 2.4 Hz, 1H) 7.24-7.30 (m, 1H) 7.59 (d, J=8.4 Hz, 2H) 8.35 (d, J=2.8 Hz, 1H).

MS ESI/APCI Multi posi: 280[M+H] + .

MS ESI/APCI Multi nega: 278[M−H] − .

Reference Example 4-1

2-[2-(2-Oxanyl)-3-pyrazolyl]-5-(4-piperidinylmethoxy)pyridine

(1) To a solution of the compound (1.00 g) obtained in Reference Example 1-1 in tetrahydrofuran (40 mL), (phenylmethyl) 4-(hydroxymethyl)-1-piperidinecarboxylate (1.11 g), tributylphosphine (1.50 mL), and 1,1′-azobis(N,N-dimethylformamide) (1.04 g) were added, and the mixture was stirred at 60° C. for 3 hours, and then at room temperature overnight. After the reaction solution was concentrated, water was added to the concentrated solution, and the mixture was extract with ethyl acetate. After the extracted substance was dried over anhydrous sodium sulfate, the drying agent was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=9:1 to ethyl acetate only) to give (phenylmethyl) 4-[[6-[2-(2-oxanyl)-3-pyrazolyl]-3-pyridinyl]oxymethyl]-1-piperidinecarboxylate (1.01 g) as a colorless oil.

(2) To a solution of the compound (1.01 g) obtained in (1) above in methanol (15 mL), palladium carbon (200 mg) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 30 minutes. After the reaction solution was filtered through Celite (registered trademark), the filtrate was concentrated, the obtained residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=1:1 to ethyl acetate only to chloroform:methanol=19:1 to 9:1) to give the title compound (561 mg) as a colorless oil.

1 H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.23-1.38 (m, 3H) 1.51-1.80 (m, 3H) 1.82-1.87 (m, 2H) 1.93-2.04 (m, 2H) 2.06-2.12 (m, 1H) 2.49-2.57 (m, 1H) 2.67 (td, J=12.2, 2.5 Hz, 2H) 3.12-3.17 (m, 2H) 3.59 (td, J=11.6, 2.5 Hz, 1H) 3.89 (d, J=6.6 Hz, 2H) 4.02-4.07 (m, 1H) 6.08 (dd, J=9.9, 2.5 Hz, 1H) 6.49 (d, J=1.7 Hz, 1H) 7.23-7.27 (m, 1H) 7.53 (d, J=8.7 Hz, 1H) 7.59 (d, J=1.7 Hz, 1H) 8.36 (d, J=2.9 Hz, 1H).

MS ESI/APCI Multi posi: 343[M+H] + .

The compounds of Reference Examples 4-2 to 4-4 below were synthesized using a commercially available compound, according to the method described in Reference Example 4-1. The structures, NMR data, and MS data of them are shown in Table 2-1.

Reference Example 5-1

5-[[(3R)-3-Piperidinyl]methoxy]-2-(1H-pyrazol-5-yl)pyridine

Water (4 mL) and trifluoroacetic acid (1 mL) were added to a solution of the compound (2.00 g) obtained in Reference Example 4-2 in methanol (20 mL), and the mixture was stirred at 60° C. for 3 hours. After the reaction solution was concentrated, the residue was neutralized with saturated sodium hydrogen carbonate and was concentrated again. The obtained residue was purified by NH silica gel column chromatography (n-hexane:ethyl acetate=1:1 to ethyl acetate only to chloroform:methanol=9:1) to give the title compound (625 mg) as a colorless powder.

1 H NMR (600 MHz, DMSO-d 6 ) δ ppm 1.15-1.25 (m, 1H) 1.30-1.42 (m, 1H) 1.53-1.61 (m, 1H) 1.76-1.89 (m, 2H) 2.07 (br s, 1H) 2.33 (dd, J=11.8, 9.7 Hz, 1H) 2.41-2.47 (m, 1H) 2.82 (dt, J=11.9, 3.6 Hz, 1H) 3.02 (dd, J=11.8, 2.7 Hz, 1H) 3.91 (d, J=6.6 Hz, 2H) 6.72 (d, J=2.1 Hz, 1H) 7.37-7.47 (m, 1H) 7.60-7.76 (m, 1H) 7.78-7.88 (m, 1H) 8.26 (d, J=2.9 Hz, 1H) 12.94 (br s, 1H).

MS ESI/APCI Multi posi: 259[M+H] + .

Reference Example 6-1

5-[(3-Bromophenyl)methoxy]-2-[2-(2-oxanyl)-3-pyrazolyl]pyridine

To a solution of the compound (3.00 g) obtained in Reference Example 1-1 in toluene (31 mL), 3-bromobenzyl alcohol (2.73 g) and cyanomethylene tributylphosphorane (9.63 mL) were added, and the mixture was stirred at 100° C. for 1.5 hours. The reaction mixture was concentrated, and the obtained residue was purified by silica gel column chromatography (n-hexane only to ethyl acetate only) to give the title compound (4.70 g) as a brown oil.

1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.51-1.83 (m, 3H) 1.97-2.13 (m, 2H) 2.45-2.61 (m, 1H) 3.52-3.68 (m, 1H) 3.97-4.08 (m, 1H) 5.13 (s, 2H) 5.99-6.21 (m, 1H) 6.50 (d, J=1.9 Hz, 1H) 7.23-7.42 (m, 3H) 7.47-7.52 (m, 1H) 7.52-7.57 (m, 1H) 7.59 (d, J=1.9 Hz, 1H) 7.60-7.65 (m, 1H) 8.41-8.46 (m, 1H).

MS ESI/APCI Multi posi: 414[M+H] + .

Reference Example 6-2

5-[3-(3-Bromophenyl)propoxy]-2-[2-(2-oxanyl)-3-pyrazolyl]pyridine

The compound (500 mg) obtained in Reference Example 1-1, 3-(3-bromophenyl)-1-propanol (515 mg), and triphenylphosphine (762 mg) were dissolved in tetrahydrofuran (6.45 mL). Bis(2-methoxyethyl) azodicarboxylate (680 mg) was added to the solution under ice cooling, the air in the flask was purged with nitrogen, and the solution was then stirred at room temperature overnight. After the reaction solution was concentrated under reduced pressure, the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=9:1 to 7:13) to give a mixture containing the title compound (636 mg) as a colorless oil.

1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.50-1.60 (m, 1H) 1.61-1.81 (m, 2H) 1.97-2.21 (m, 4H) 2.48-2.60 (m, 1H) 2.78-2.88 (m, 2H) 3.55-3.65 (m, 1H) 4.01-4.09 (m, 3H) 6.09 (dd, J=10.0, 2.3 Hz, 1H) 6.50 (s, 1H) 7.13-7.25 (m, 4H) 7.28-7.39 (m, 2H) 7.50-7.55 (m, 1H) 7.57-7.61 (m, 1H) 8.37 (d, J=2.9 Hz, 1H).

MS ESI/APCI Multi posi: 442[M+H] + .

The compounds of Reference Examples 6-2 to 6-7 below were synthesized using a commercially available compound, according to the method described in Reference Example 6-2. The structures, NMR data, and MS data of them are shown in Table 3-1.

Reference Example 7-1

[3-[[6-[2-(2-Oxanyl)-3-pyrazolyl]-3-pyridinyl]oxymethyl]-1-bicyclo[1.1.1]pentanyl]methanamine

(1) The compound (421 mg) obtained in Reference Example 1-1 and methyl 1-(hydroxymethyl)bicyclo[1.1.1]pentane-3-carboxylate (295 mg) were used to perform the synthesis process according to the method described in Reference Example 6-1 thereby giving methyl 3-[[[6-[1-(oxan-2-yl)-1H-pyrazol-5-yl]pyridin-3-yl]oxy]methyl]bicyclo[1.1.1]pentane-1-carboxylate (684 mg) as a colorless oil.

(2) To a solution of the compound (684 mg) obtained in (1) above in methanol (10 mL), lithium borohydride (148 mg) was added, and the mixture was stirred at room temperature for 17 hours. Lithium borohydride (74.0 mg) was further added thereto, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction solution, and the solvent was distilled off. The resultant was extracted with chloroform, and the organic layer was separated by a phase separator and then was concentrated under reduced pressure to give [3-[[[6-[1-(oxan-2-yl)-1H-pyrazol-5-yl]pyridin-3-yl]oxy]methyl]bicyclo[1.1.1]pentan-1-yl]methanol (495 mg) as a colorless oil. The obtained compound was used for the next reaction without being purified.

(3) Triethylamine (201 μL) and methanesulfonyl chloride (94.8 μL) were added to a solution of the compound (395 mg) obtained in (2) above in ethyl acetate (2 mL), and the mixture was stirred at room temperature for 1 hour. After impurities were filtered off, the filtrate was concentrated to give [3-[[[6-[1-(oxan-2-yl)-1H-pyrazol-5-yl]pyridin-3-yl]oxy]methyl]bicyclo[1.1.1]pentan-1-yl]methyl methanesulfonate (481 mg) as a colorless oil. The obtained compound was used for the next reaction without being purified.

(4) Sodium azide (216 mg) was added to a solution of the compound (481 mg) obtained in (3) above in N,N-dimethylformamide (5 mL), and the mixture was stirred at 80° C. for 1 hour. Water was added to the reaction mixture, and the resultant mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure to give 5-[[3-(azidomethyl)bicyclo[1.1.1]pentan-1-yl]methoxy]-2-[1-(oxan-2-yl)-1H-pyrazol-5-yl]pyridine (422 mg) as a brown oil. The obtained compound was used for the next reaction without being purified.

(5) To a solution of the compound (422 mg) obtained in (4) above in methanol (6 mL), palladium carbon (42.2 mg) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 2 hours. The reaction mixture was filtered through Celite (registered trademark), and then the filtrate was concentrated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (chloroform only to chloroform:methanol=9:1) to give the title compound (358 mg) as a brown oil.

1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.49-1.58 (m, 1H) 1.62-1.80 (m, 7H) 1.87-2.25 (m, 3H) 2.47-2.60 (m, 1H) 2.72-2.79 (m, 2H) 3.54-3.63 (m, 1H) 4.02-4.09 (m, 3H) 6.05-6.10 (m, 1H) 6.49 (d, J=1.8 Hz, 1H) 7.24 (dd, J=8.7, 3.0 Hz, 1H) 7.52 (d, J=8.7 Hz, 1H) 7.59 (d, J=1.8 Hz, 1H) 8.37 (d, J=3.0 Hz, 1H).

MS ESI/APCI Multi posi: 355 [M+H] + .

Reference Example 8-1

5-[(3-Bromo-4-fluorophenyl)methoxy]-2-[2-(2-oxanyl)-3-pyrazolyl]pyridine

To a solution of the compound (872 mg) obtained in Reference Example 1-1 in N,N-dimethylformamide (10 mL), potassium carbonate (983 mg), 3-bromo-4-fluorobenzyl bromide (1.00 g) and sodium iodide (53.3 mg) were added, and the mixture was stirred at 60° C. for 2 hours. Water was added to the reaction mixture, and the resultant mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=7:3) to give the title compound (1.51 g) as a yellow oil.

1 H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.51-1.57 (m, 1H) 1.64-1.79 (m, 2H) 1.99-2.05 (m, 1H) 2.07-2.12 (m, 1H) 2.50-2.57 (m, 1H) 3.57-3.62 (m, 1H) 4.02-4.06 (m, 1H) 5.10 (s, 2H) 6.08-6.11 (m, 1H) 6.51 (d, J=1.7 Hz, 1H) 7.14-7.20 (m, 1H) 7.31 (dd, J=8.7, 2.9 Hz, 1H) 7.34-7.39 (m, 1H) 7.56 (d, J=8.7 Hz, 1H) 7.59 (d, J=1.7 Hz, 1H) 7.65-7.70 (m, 1H) 8.43 (d, J=2.9 Hz, 1H).

MS ESI/APCI Multi posi: 432[M+H] + .

Reference Example 8-2

5-[(4-Iodophenyl)methoxy]-2-[2-(2-oxanyl)-3-pyrazolyl]pyridine

To a solution of the compound (500 mg) obtained in Reference Example 1-1 in N,N-dimethylformamide (1.41 mL), 4-iodobenzyl bromide (150 mg) and potassium carbonate (87.5 mg) were added, and the mixture was stirred at room temperature overnight. The reaction solution was poured into water, and the resultant mixture was extracted three times with ethyl acetate. The organic layers were combined, washed with brine, separated from the aqueous layer by a phase separator, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=19:1 to 2:3) to give the title compound (195 mg) as a pale yellow gum-like substance.

1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.50-1.60 (m, 1H) 1.61-1.80 (m, 2H) 1.96-2.14 (m, 2H) 2.47-2.60 (m, 1H) 3.55-3.64 (m, 1H) 4.00-4.08 (m, 1H) 5.11 (s, 2H) 6.09 (dd, J=10.1, 2.4 Hz, 1H) 6.50 (d, J=1.8 Hz, 1H) 7.16-7.24 (m, 2H) 7.28-7.34 (m, 1H) 7.50-7.64 (m, 2H) 7.75 (d, J=8.3 Hz, 2H) 8.42 (d, J=2.7 Hz, 1H).

MS ESI/APCI Multi posi: 462[M+H] + .

The compound of Reference Example 8-3 below was synthesized using 3-iodobenzyl bromide, according to the method described in Reference Example 8-2. The structure, NMR data, and MS data of it are shown in Table 4-1.

Reference Example 9-1

Trimethyl-[[4 [3-[[6-[2-(2-oxanyl)-3-pyrazolyl]-3-pyridinyl][oxymethyl]phenyl]-4-piperidinyl]oxy]silane

(1) To a suspension of the compound (421 mg) obtained in Reference Example 6-1 and molecular sieves of 4 angstroms (200 mg) in tetrahydrofuran (5 mL), n-butyl lithium (2.6 mol/L n-hexane solution, 508 μL) was added dropwise at −78° C., and the mixture was stirred for 10 minutes. To the mixture, 1-(tert-butoxycarbamoyl)-4-piperidone (405 mg) was added all at once at −78° C., the temperature of the mixture was gradually increased, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, the resultant mixture was extracted with ethyl acetate, and the organic layer was then washed with brine and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=9:1 to 1:9) to give tert-butyl 4-hydroxy-4-{3-[({6-[1-(oxan-2-yl)-1H-pyrazol-5-yl]pyridin-3-yl}oxy)methyl]phenyl}piperidine-1-carboxylate (402 mg) as a yellow amorphous substance.

(2) To a solution of the compound (348 mg) obtained in (1) above in chloroform (6 mL), 2,6-lutidine (754 μL) and trimethylsilyl trifluoromethanesulfonate (470 μL) were added under ice cooling, and the mixture was stirred at the same temperature for 30 minutes. A saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, and the resultant mixture was extracted with chloroform. The organic layer was separated by a phase separator, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=3:2) to give the title compound (200 mg) as a colorless oil.

1 H NMR (600 MHz, CHLOROFORM-d) δ ppm −0.12 (s, 9H) 1.50-2.11 (m, 9H) 2.50-2.56 (m, 1H) 2.90-2.97 (m, 2H) 3.09-3.15 (m, 2H) 3.56-3.61 (m, 1H) 4.02-4.06 (m, 1H) 5.17 (s, 2H) 6.09 (dd, J=10.1, 2.3 Hz, 1H) 6.48-6.50 (m, 1H) 7.28-7.44 (m, 4H) 7.49-7.59 (m, 3H) 8.45 (d, J=2.9 Hz, 1H).

MS ESI/APCI Multi posi: 507[M+H] + .

The compound of Reference Example 9-2 below was synthesized using the compound obtained in Reference Example 6-1, according to the method described in Reference Example 9-1. The structure, NMR data, and MS data of it are shown in Table 5-1.

Reference Example 10-1

3-[[6-[2-(2-Oxanyl)-3-pyrazolyl]-3-pyridinyl]oxymethyl]benzoic Acid

(1) The compound (1.14 g) obtained in Reference Example 1-1 and commercially available methyl (3-bromomethyl)benzoate (1.17 g) were used to perform the synthesis process according to the method described in Reference Example 1-1-(1) thereby giving methyl 3-[[6-[2-(2-oxanyl)-3-pyrazolyl]-3-pyridinyl]oxymethyl]benzoate (1.83 g) as a colorless amorphous substance.

(2) To a solution of the compound (1.83 g) obtained in (1) above in methanol (10 mL) and tetrahydrofuran (10 mL), an aqueous solution of 1 mol/L sodium hydroxide (5.6 mL) was added, and the mixture was stirred at room temperature for 20 hours. A saturated aqueous solution of ammonium chloride was added to the reaction solution, the resultant mixture was extracted with chloroform, and the organic layer was separated by a phase separator. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1 to ethyl acetate only to chloroform:methanol=9:1) to give the title compound (1.70 g) as a colorless solid.

1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.51-1.60 (m, 1H) 1.61-1.82 (m, 2H) 1.97-2.15 (m, 2H) 2.47-2.61 (m, 1H) 3.55-3.66 (m, 1H) 4.01-4.09 (m, 1H) 5.23 (s, 2H) 6.07 (dd, J=10.0, 2.3 Hz, 1H) 6.51 (d, J=1.7 Hz, 1H) 7.35 (dd, J=8.7, 3.1 Hz, 1H) 7.52-7.63 (m, 3H) 7.72 (d, J=7.7 Hz, 1H) 8.11 (d, J=7.7 Hz, 1H) 8.21 (s, 1H) 8.48 (d, J=2.8 Hz, 1H).

MS ESI/APCI Multi posi: 380[M+H] + .

MS ESI/APCI Multi nega: 378[M−H] − .

The compounds of Reference Examples 10-2 and 10-3 below were synthesized using a commercially available compound, according to the method described in Reference Example 10-1. The structures, NMR data, and MS data of them are shown in Table 6-1.

Reference Example 11-1

Ethyl 2-[3-(bromomethyl)phenyl]acetate

To a solution of ethyl m-toluylacetate (5.00 g) in acetonitrile (15 mL), 2,2′-azobis(isobutyronitrile) (46 mg) was added, and the mixture was stirred under heating at 90° C. A solution of N-bromosuccinimide (5.24 g) and 2,2′-azobis(isobutyronitrile) (46 mg) in acetonitrile (40 mL), which had been separately prepared, were added dropwise to the reaction solution, and the resultant mixture was stirred at the same temperature for 30 minutes. The solvent was distilled off under reduced pressure, and diethyl ether was added to the residue. The precipitate was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=4:1) to give the title compound (2.30 g) as a pale yellow oil.

1 H NMR (200 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J=7.2 Hz, 3H) 3.61 (s, 2H) 4.16 (q, J=7.2 Hz, 2H) 4.48 (s, 2H) 7.19-7.38 (m, 4H).

MS ESI/APCI Multi posi: 257[M+H] + .

Reference Example 11-2

Ethyl 5-(bromomethyl)-2-fluorobenzoate

To a solution of ethyl 2-fluoro-5-methylbenzoate (243 mg) in carbon tetrachloride (6.7 mL), N-bromosuccinimide (261 mg) and 2,2′-azobis(isobutyronitrile) (22 mg) were added, and the mixture was stirred at an outer temperature of 65° C. for 2 hours. After the reaction solution was concentrated under reduced pressure, the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=49:1 to 17:3) to give the title compound (208 mg) as a colorless oil.

1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.36-1.46 (m, 3H) 4.34-4.45 (m, 2H) 4.48 (s, 2H) 7.07-7.16 (m, 1H) 7.48-7.58 (m, 1H) 7.92-7.98 (m, 1H).

MS ESI/APCI Multi posi: 283[M+Na] + .

The compound of Reference Example 11-3 below was synthesized using a commercially available compound, according to the method described in Reference Example 11-2. The structure, NMR data, and MS data of it are shown in Table 7-1.

Reference Example 12-1

Methyl 1-[3-(bromomethyl)phenyl]-1-cyclopropanecarboxylate

(1) A solution of commercially available 1-(3-methylphenyl)-1-cyclopropanecarboxylic acid (150 mg) in toluene:methanol (1:1, 1.70 mL) was ice-cooled under a nitrogen atmosphere, trimethylsilyldiazomethane (2.0 mol/L diethyl ether solution, 1.10 mL) was added to the solution, and the mixture was stirred at room temperature for 3 hours. Acetic acid was added thereto under ice cooling to stop the reaction, and the solution was concentrated under reduced pressure to give methyl 1-(3-methylphenyl)-1-cyclopropanecarboxylate (160 mg).

(2) To a solution of the compound (160 mg) obtained in (1) above in carbon tetrachloride (1.7 mL), N-bromosuccinimide (180 mg) and 2,2′-azobis(isobutyronitrile) (126 mg) were added, and the mixture was stirred under a nitrogen atmosphere at 80° C. for 4 hours. The reaction mixture was cooled to room temperature, and water was added thereto and the reaction mixture was extracted with chloroform. The organic layer was passed through a phase separator, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1 to 1:1) to give the title compound (74 mg).

1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.18-1.25 (m, 2H) 1.60-1.67 (m, 2H) 3.63 (s, 3H) 4.49 (s, 2H) 7.23-7.38 (m, 4H).

Reference Example 13-1

Methyl[2-(3-bromomethyl)phenyl]-5-pyrimidinecarboxylate

(1) A solution of methyl 2-chloro-5-pyrimidinecarboxylate (170 mg), (3-methylphenyl)boronic acid (174 mg), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (80 mg), and potassium carbonate (272 mg) in 1,4-dioxane:water (5:1, 6 mL) was stirred at an outer temperature of 90° C. for 5 hours. After cooling to room temperature, the solution was diluted with ethyl acetate and filtered through Celite (registered trademark), and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane:ethyl acetate) to give methyl 2-(3-methylphenyl)-5-pyrimidinecarboxylate (100 mg) as a colorless solid.

(2) The compound (100 mg) obtained in (2) above was used to perform the synthesis process according to the method described in Reference Example 12-1-(2) thereby giving the title compound (70 mg) as a colorless solid.

1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.07 (s, 3H) 4.61 (s, 2H) 7.44-7.60 (m, 2H) 7.87 (d, J=4.9 Hz, 1H) 8.47 (d, J=7.6 Hz, 1H) 8.55 (s, 1H) 9.04 (d, J=4.9 Hz, 1H).

MS ESI posi: 307[M+H] + .

Reference Example 13-2

Methyl 2-[3-(bromomethyl)phenyl]-4-pyrimidinecarboxylate

(1) A solution of methyl 2-chloro-4-pyrimidinecarboxylate (150 mg), (3-methylphenyl)boronic acid (122 mg), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (56 mg), and potassium carbonate (191 mg) in N,N-dimethylformamide (3.5 mL) was stirred under heating at an outer temperature of 90° C. for 2 hours. After cooling to room temperature, the solution was diluted with ethyl acetate and filtered through Celite (registered trademark), and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane:ethyl acetate) to give methyl 5-(3-methylphenyl)-2-pyrimidinecarboxylate (135 mg) as a pale red solid.

(2) The compound (130 mg) obtained in (1) above was used to perform the synthesis process according to the method described in Reference Example 12-1-(2) thereby giving the title compound (106 mg) as a colorless solid.

1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.07 (s, 3H) 4.61 (s, 2H) 7.44-7.62 (m, 2H) 7.87 (d, J=4.9 Hz, 1H) 8.47 (d, J=7.8 Hz, 1H) 8.54-8.57 (m, 1H) 9.04 (d, J=5.0 Hz, 1H).

MS ESI posi: 307[M+H] + .

The compound of Reference Example 13-3 below was synthesized using a commercially available compound, according to the method described in Reference Example 13-2. The structure, NMR data, and MS data of it are shown in Table 8-1.

Reference Example 14-1

Ethyl 2-[[4-(bromomethyl)-2-pyridinyl]oxy]-2-methylpropanoate

(1) 4-Methyl-2-pyridinol (300 mg) and ethyl 2-hydroxy-2-methylpropanoate (550 μL) were used to perform the synthesis process according to the method described in Reference Example 6-2 thereby giving ethyl 2-methyl-2-[(4-methyl-2-pyridinyl)oxy]propanoate (409 mg) as a colorless oil.

(2) To a solution of the compound (409 mg) obtained in (1) above in carbon tetrachloride (15 mL), N-bromosuccinimide (652 mg) and 2,2′-azobis(isobutyronitrile) (30 mg) were added, and the mixture was stirred at 80° C. for 9 hours. A saturated aqueous solution of sodium hydrogen carbonate was added to the reaction solution, and the resultant mixture was extracted with chloroform. The organic layer was separated by a phase separator, and concentrated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (10 mL), N,N-diisopropylethylamine (957 μL) and diethyl phosphite (709 μL) were added thereto, and the resultant mixture was stirred at room temperature for 8 hours. Water was added to the reaction solution, and the resultant mixture was extracted with chloroform. The organic layer was separated by a phase separator, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1). The purified residue was dried under reduced pressure to give the title compound (395 mg) as a pale yellow oil.

1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.12 (t, J=7.1 Hz, 3H) 1.66 (s, 6H) 4.14 (q, J=7.1 Hz, 2H) 4.32 (s, 2H) 6.75 (s, 1H) 6.84 (d, J=5.3 Hz, 1H) 8.00 (d, J=5.3 Hz, 1H).

MS ESI posi: 302[M+H] + .

The compound of Reference Example 14-2 below was synthesized using a commercially available compound, according to the method described in Reference Example 14-1. The structure, NMR data, and MS data of the compound are shown in Table 9-1.

Reference Example 15-1

Methyl 2-[3-(2-hydroxyethyl)phenyl]acetate

(1) A borane-tetrahydrofuran complex (0.90 mol/L tetrahydrofuran solution, 6.0 mL) was added to a solution of 2-[3-(carboxymethyl)phenyl]acetic acid (1.00 g) in tetrahydrofuran (10 mL) under a nitrogen atmosphere with ice cooling, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of sodium dihydrogen phosphate (15 mL) was added to stop the reaction, and the resultant mixture was extracted with ethyl acetate. The obtained organic layer was separated from the aqueous layer by passing through a phase separator, and then concentrated under reduced pressure to give 2-[3-(2-hydroxyethyl)phenyl]acetic acid as a crude product.

(2) The crude product obtained in (1) above was used to perform the synthesis process according to the method described in Reference Example 12-1-(1), and the product was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1 to 1:1) to give the title compound (130 mg) as a colorless oil.

1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.86 (t, J=6.4 Hz, 2H) 3.62 (s, 2H) 3.70 (s, 3H) 3.86 (t, J=6.4 Hz, 2H) 7.12-7.19 (m, 3H) 7.26-7.32 (m, 1H).

The compound of Reference Example 15-2 below was synthesized using a commercially available compound, according to the method described in Reference Example 15-1. The structure, NMR data, and MS data of the compound are shown in Table 10-1.

Reference Example 16-1

Methyl 3-[[(3R)-3-(hydroxymethyl)-1-piperidinyl]sulfonyl]benzoate

(1) Triethylamine (0.13 mL) and 3-chlorosulfonylbenzoic acid (100 mg) were added to a solution of commercially available [(3R)-3-piperidinyl]methanol (55 mg) in chloroform (4.5 mL) under ice cooling, and the mixture was stirred at room temperature for 2.5 hours. A saturated aqueous solution of sodium dihydrogen phosphate was added to stop the reaction, and the resultant mixture was extracted with ethyl acetate. The obtained organic layer was separated from the aqueous layer by passing through a phase separator, and concentrated under reduced pressure to give 3-[[(3R)-3-(hydroxymethyl)-1-piperidinyl]sulfonyl]benzoic acid as a crude product.

(2) The crude product obtained in (1) above was used to perform the synthesis process according to the method described in Reference Example 12-1-(1) thereby giving the title compound (30 mg) as a colorless oil.

1 H NMR (400 MHz, CHLOROFOLM-d) δ ppm 1.00-1.14 (m, 1H) 1.61-1.82 (m, 4H) 1.84-1.96 (m, 1H) 2.35 (t, J=10.5 Hz, 1H) 2.44-2.57 (m, 1H) 3.49-3.62 (m, 3H) 3.62-3.77 (m, 1H) 3.97 (s, 3H) 7.63 (t, J=7.8 Hz, 1H) 7.95 (d, J=7.8 Hz, 1H) 8.26 (d, J=7.8 Hz, 1H) 8.41 (s, 1H).

MS ESI/APCI Multi posi: 314[M+H] + , 336[M+Na] + .

Reference Example 17-1

Methyl 4-[[3-(bromomethyl)phenyl]sulfonylamino]-2,2-dimethylbutanoic Acid

Triethylamine (0.08 mL) and 3-(bromomethyl)benzenesulfonyl chloride (78 mg) were added to a solution of methyl 4-amino-2,2-dimethylbutanoate hydrochloride (50 mg) in chloroform (2.8 mL) under a nitrogen atmosphere, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous solution of ammonium chloride was added to stop the reaction, and the reaction mixture was extracted with chloroform. The obtained organic layer was separated from the aqueous layer by passing through a phase separator, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1 to 2:3) to give the title compound (64 mg).

1 H NMR (400 MHz, CHLOROFOLM-d) δ ppm 1.15 (s, 6H) 1.74 (t, J=7.4 Hz, 2H) 2.97-3.03 (m, 2H) 3.66 (s, 3H) 4.51 (s, 2H) 4.53-4.60 (m, 1H) 7.48-7.55 (m, 1H) 7.61 (d, J=7.8 Hz, 1H) 7.78 (d, J=7.8 Hz, 1H) 7.87 (s, 1H).

MS ESI/APCI Multi posi: 378[M+H] + , 400[M+Na] + .

MS ESI/APCI Multi nega: 376[M−H] − .

The compounds of Reference Examples 17-2 to 17-4 below were synthesized using a commercially available compound, according to the method described in Reference Example 17-1. The structures and MS data of the compounds are shown in Table 11-1.

Reference Example 17-5 Ethyl 1-[3-(bromomethyl)phenyl]sulfonyl-4-piperidinecarboxylate

To a solution of ethyl 4-piperidinecarboxylate (245 mg) in chloroform (3 mL), 3-(bromomethyl)benzenesulfonyl chloride (400 mg) was added, and the mixture was stirred at room temperature for 2 hours. To the reaction solution, 2 mol/L hydrochloric acid was added, and the resultant mixture was extracted with chloroform. The organic layer was separated by a phase separator, and concentrated under reduced pressure to give a mixture (573 mg) containing the title compound.

MS ESI posi: 390[M+H] + .

The compound of Reference Example 17-6 below was synthesized using a commercially available compound, according to the method described in Reference Example 17-5. The structure and MS data of the compound are shown in Table 11-2.

Reference Example 18-1

Methyl 4-[[3-(bromomethyl)phenyl]sulfonyl-methylamino]-2,2-dimethylbutanoate

(1) Sodium hydride (60% mineral oil dispersion, 156 mg) was added to a solution of 2,2-dimethyl-4-[[(2-methylpropan-2-yl)oxy-oxomethyl]amino]butanoic acid (300 mg) in tetrahydrofuran (4.3 mL) under a nitrogen atmosphere, and the mixture was stirred at room temperature for 30 minutes, and methyl iodide (0.24 mL) was then added thereto, and the mixture was stirred at room temperature for 22 hours. A saturated aqueous solution of ammonium chloride was added to stop the reaction, and the resultant mixture was extracted with ethyl acetate. The obtained organic layer was passed through a phase separator, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=9:1 to 1:4) to give 2,2-dimethyl-4-[methyl-[(2-methylpropan-2-yl)oxy-oxomethyl]amino]butanoic acid (185 mg) as a colorless oil.

(2) To a solution of the compound (185 mg) obtained in (1) above in methanol (1.5 mL), 2 mol/L hydrogen chloride-methanol solution (1.9 mL) was added, and the mixture was stirred at 70° C. for 2 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give methyl 2,2-dimethyl-4-(methylamino)butanoate hydrochloride (137 mg) as a colorless powder.

(3) The compound (60 mg) obtained in (2) above and 3-(bromomethyl)benzenesulfonyl chloride were used to perform the synthesis process according to the method described in Reference Example 16-1-(1) thereby giving the title compound (63 mg) as a colorless oil.

1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.21 (s, 6H) 1.77-1.84 (m, 2H) 2.73 (s, 3H) 3.01-3.07 (m, 2H) 3.67 (s, 3H) 4.63 (s, 2H) 7.52 (t, J=7.9 Hz, 1H) 7.59-7.63 (m, 1H) 7.68-7.76 (m, 1H) 7.80 (s, 1H).

Reference Example 19-1

Methyl 2-[3-(2-bromoethoxy)phenyl]acetate

To a solution of methyl 2-(3-hydroxyphenyl)acetate (1.12 g) in N,N-dimethylformamide (6.61 mL), 1,2-dibromoethane (8.54 mL) and cesium carbonate (3.23 g) were added, and the mixture was stirred at an outer temperature of 90° C. for 6.5 hours, and then at an outer temperature of 120° C. for 1 hour. After cooling to room temperature, the reaction solution was poured into water, and the resultant mixture was extracted with ethyl acetate three times. The organic layers were combined, washed twice with brine, separated from the aqueous layer by a phase separator, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=7:3) to give the title compound (811 mg) as a pale yellow oil.

1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.58-3.66 (m, 4H) 3.70 (s, 3H) 4.26-4.32 (m, 2H) 6.79-6.93 (m, 3H) 7.22-7.27 (m, 1H).

Reference Example 19-2

tert-Butyl 2-[3-(hydroxymethyl)phenoxy]acetate

Potassium carbonate (5.57 g) and tert-butyl 2-bromoacetate (3.93 mL) were added to a solution of 3-(hydroxymethyl)phenol (2.50 g) in acetone (100 mL), and the mixture was stirred at room temperature for 2 days. Insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=19:1). The purified residue was dried under reduced pressure to give the title compound (3.36 g) as a light orange oil.

1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.49 (s, 9H) 4.52 (s, 2H) 4.67 (d, J=6.1 Hz, 2H) 6.80-6.85 (m, 1H) 6.91-7.00 (m, 2H) 7.24-7.30 (m, 1H).

MS ESI/APCI Multi posi: 261 [M+Na] + .

Reference Example 19-3

Ethyl 2-[3-(hydroxymethyl)phenoxy]-2-methylpropanoate

Ethyl 2-bromo-2-methylpropanoate (1.04 g) and cesium carbonate (2.17 g) were added to a solution of 3-(hydroxymethyl)phenol (550 mg) in acetonitrile (5 mL), and the mixture was stirred at 85° C. for 8 hours. The reaction solution was poured into 2 mol/L hydrochloric acid, and the resultant mixture was extracted with chloroform. The organic layer was separated by a phase separator, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=9:1 to 3:2). The purified residue was dried under reduced pressure to give the title compound (642 mg) as a colorless oil.

1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.25 (t, J=7.1 Hz, 3H) 1.60 (s, 6H) 4.24 (q, J=7.1 Hz, 2H) 4.64 (s, 2H) 6.72-6.78 (m, 1H) 6.88 (s, 1H) 6.99 (d, J=7.5 Hz, 1H) 7.19-7.25 (m, 1H).

MS ESI/APCI Multi posi: 261 [M+Na] + .

Reference Example 20-1

Methyl 8-hydroxyoctanoate

8-Hydroxyoctanoic acid (719 mg) was used to perform the synthesis process according to the method described in Reference Example 12-1-(1) thereby giving the title compound (694 mg) as a colorless oil.

1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.28-1.42 (m, 6H) 1.49-1.69 (m, 4H) 2.25-2.36 (m, 2H) 3.57-3.71 (m, 5H).

MS ESI/APCI Multi posi: 175[M+H] + , 197[M+Na] + .

The compound of Reference Example 20-2 below was synthesized using a commercially available compound, according to the method described in Reference Example 20-1. The structure, NMR data, and MS data of the compound are shown in Table 12-1.

Reference Example 21-1

tert-Butyl 5-hydroxypentanoate

(1) To a solution of oxane-2,6-dione (6.85 g), N-hydroxysuccinimide (2.07 g), and 4-(dimethylamino)pyridine (0.73 g) in toluene (30 mL), tert-butanol (5.78 g) and triethylamine (2.51 mL) were added, and the mixture was heated to reflux for 17 hours. The reaction solution was diluted with ethyl acetate, and sequentially washed with an aqueous solution of 10% citric acid and brine. The organic layer was dried over anhydrous magnesium sulfate, the solid was filtered off, and the filtrate was then concentrated under reduced pressure. Diethyl ether was added to the residue, petroleum ether was added thereto with stirring at −20° C., and the precipitated solid was filtered off. The filtrate was concentrated, and the obtained residue was purified by silica gel column chromatography (n-hexane only to n-hexane:diethyl ether=7:3) to give 5-[(2-methylpropan-2-yl)oxy]-5-oxopentanoic acid (2.88 g) as a colorless oil.

(2) The compound (1.44) obtained in (1) above was used to perform the synthesis process according to the method described in Reference Example 15-1-(1) thereby giving the title compound (1.32 g) as a colorless oil.

1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.45 (s, 9H) 1.57-1.71 (m, 4H) 2.26 (t, J=7.0 Hz, 2H) 3.65 (t, J=6.1 Hz, 2H).

MS ESI posi: 197[M+Na] + .

Reference Example 22-1

tert-Butyl 4-hydroxy-4-oxanecarboxylate

(1) Boc 2 O (13 mL) and 4-(dimethylamino)pyridine (1.4 g) were added to a solution of tetrahydropyran-4-carboxylic acid (5 g) in tert-butanol (38 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=3:1) to give tert-butyl 4-oxanecarboxylate (6.65 g) as a colorless oil.

(2) n-Butyl lithium (1.6 mol/L n-hexane solution, 18 mL) was added dropwise to a solution of diisopropylamine (6.8 mL) in tetrahydrofuran (70 mL) under a nitrogen atmosphere at a temperature of −60° C. or lower, and the mixture was stirred at the same temperature for 40 minutes. Subsequently, a solution of the compound (5 g) obtained in (1) above in tetrahydrofuran (19 mL) was added dropwise thereto, the mixture was stirred at the same temperature for 40 minutes, and triethyl phosphite (14 mL) was then added dropwise thereto, and oxygen gas was passed therethrough at a temperature of −60° C. or lower for 1.5 hours, and at room temperature for 1.5 hours. An aqueous solution of potassium hydrogen sulfate was added thereto under ice cooling, and the resultant mixture was extracted with ethyl acetate. The organic layer was sequentially washed with a saturated aqueous solution of sodium hydrogen carbonate, water, and brine, and then dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=17:3 to 1:1) to give the title compound (3.75 g) as a colorless powder.

1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.39-1.61 (m, 11H) 2.00-2.19 (m, 2H) 3.16 (s, 1H) 3.72-3.91 (m, 4H).

MS ESI/APCI Multi posi: 225 [M+Na] + .

Reference Example 23-1

5-(Hydroxymethyl)-2-methylphenyl Acetate

(1) Acetic anhydride (2.00 mL) was added to a solution of commercially available 3-hydroxy-4-methylbenzoic acid (500 mg) in pyridine (2.00 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was diluted with ethyl acetate, and washed twice with 2 mol/L hydrochloric acid, and then with brine. The organic layer was dried over anhydrous magnesium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was recrystallized from a n-hexane:chloroform mixed solution to give 3-acetyloxy-4-methylbenzoic acid (313 mg).

(2) The compound (300 mg) obtained in (1) above was used to perform the synthesis process according to the method described in Reference Example 15-1-(1) thereby giving the title compound (235 mg).

1 H NMR (600 MHz, CHLOROFORM-d) δ ppm 2.17 (s, 3H) 2.32 (s, 3H) 4.64 (s, 2H) 7.02 (d, J=1.4 Hz, 1H) 7.13 (dd, J=7.8, 1.4 Hz, 1H) 7.21 (d, J=7.8 Hz, 1H).

The compounds of Reference Examples 23-2 and 23-3 below were synthesized using the corresponding commercially available benzoic acid, according to the method described in Reference Example 23-1. The structures and NMR data of them are shown in Table 13-1.

Reference Example 24-1

2-(2-Phenylmethoxyphenyl)ethanol

(1) Potassium hydroxide (477 mg) was added to a suspension of commercially available 2-(2-hydroxyphenyl)acetic acid (500 mg) in ethanol (3 mL), and the mixture was stirred at room temperature for 10 minutes. Benzyl bromide (468 μL) was added to this solution, and the resultant mixture was stirred at 60° C. for 2 hours. After cooling to room temperature, water was added to the reaction solution, pH was adjusted to 2 with 2 mol/L hydrochloric acid, then, the resultant solution was further diluted with water, and the diluted solution was extracted twice with chloroform. The organic layer was dried over magnesium sulfate, the drying agent was filtered off, and the filtrate was then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=99:1 to 19:1) to give 2-(2-phenylmethoxyphenyl)acetic acid (313 mg).

(2) The compound (310 mg) obtained in (1) above was used to perform the synthesis process according to the method described in Reference Example 15-1-(1) thereby giving the title compound (250 mg) as a colorless oily compound.

1 H NMR (600 MHz, CHLOROFORM-d) δ ppm 2.96 (t, J=6.3 Hz, 2H) 3.86 (t, J=6.3 Hz, 2H) 5.09 (s, 2H) 6.90-6.96 (m, 2H) 7.18-7.23 (m, 2H) 7.31-7.35 (m, 1H) 7.36-7.44 (m, 4H).

The compound of Reference Example 24-2 below was synthesized using the corresponding commercially available phenylacetic acid, according to the method described in Reference Example 24-1. The structure and NMR data of it are shown in Table 14-1.

Reference Example 25-1

3-[3-[(4-Methoxyphenyl)methoxy]phenyl]-1-propanol

(1) Potassium carbonate (641 mg) was added to a solution of methyl 3-(3-hydroxyphenyl)propanoate (588 mg) in acetone (10.3 mL). The mixture was ice-cooled, to which 4-methoxybenzyl chloride (501 μL) was added, and the mixture was stirred at room temperature overnight. The mixture was heated to an outer temperature of 60° C., to which potassium carbonate (641 mg) and 4-methoxybenzyl chloride (501 μL) were then added, and the resultant mixture was stirred for 3.5 hours. After cooling to room temperature, insolubles were filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=4:1) to give methyl 3-[3-[(4-methoxyphenyl)methoxy]phenyl]propanoate (756 mg) as a colorless oil.

(2) Lithium borohydride (3 mol/L tetrahydrofuran solution, 1.66 mL) was added to a solution of the compound (756 mg) obtained in (1) above in tetrahydrofuran (6.22 mL), and the mixture was stirred at room temperature overnight. Lithium borohydride (3 mol/L tetrahydrofuran solution, 1.66 mL) was further added to the mixture, and the mixture was then stirred at an outer temperature of 60° C. for 2 hours. After cooling to room temperature, the reaction solution was diluted with water, and the diluted solution was extracted three times with ethyl acetate. The organic layers were combined, washed with brine, separated from the aqueous layer by a phase separator, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=9:1 to 1:4) to give the title compound (680 mg) as a colorless oil.

1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.85-1.93 (m, 2H) 2.66-2.71 (m, 2H) 3.67 (t, J=6.4 Hz, 2H) 3.82 (s, 3H) 4.98 (s, 2H) 6.78-6.85 (m, 3H) 6.89-6.95 (m, 2H) 7.17-7.23 (m, 1H) 7.36 (d, J=8.7 Hz, 2H).

Reference Example 26-1

3-(Chloromethyl)-N-methylbenzenesulfonamide

(1) To a solution of commercially available 3-chlorosulfonylbenzoic acid (2.01 g) in chloroform (30 mL), N,N-diisopropylethylamine (2.38 mL) and methylamine (9.8 mol/L methanol solution, 980 μL) were added, and the mixture was stirred at room temperature for 2 hours. Thereto, N,N-diisopropylethylamine (2.38 mL) and methylamine (9.8 mol/L methanol solution, 980 μL) were further added, and the mixture was stirred for 2 hours. Water and 2 mol/L hydrochloric acid were added thereto under ice cooling, and the resultant mixture was extracted with ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, the drying agent was filtered off, and the filtrate was concentrated under reduced pressure to give 3-(methylsulfamoyl)benzoic acid (1.54 g) as a yellow powder. The obtained compound was used for the next reaction without being purified.

(2) The compound (1.54 g) obtained in (1) above was used to perform the synthesis process according to the method described in Reference Example 15-1-(1) thereby giving 3-(hydroxymethyl)-N-methylbenzene-1-sulfonamide (1.53 g) as a colorless oil.

(3) Thionyl chloride (778 μL) was added to a solution of the compound (1.53 g) obtained in (2) above in chloroform (20 mL), and the mixture was stirred at room temperature for 2 hours. Thionyl chloride (778 μL) was further added thereto, and the mixture was stirred at room temperature for 1 hour, and at 50° C. for 2 hours. The solvent was distilled off, and the obtained residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=7:3) to give the title compound (769 mg) as a colorless oil.

1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.67-2.71 (m, 3H) 4.44 (br s, 1H) 4.63 (s, 2H) 7.48-7.59 (m, 1H) 7.59-7.69 (m, 1H) 7.78-7.86 (m, 1H) 7.86-7.94 (m, 1H).

MS ESI/APCI Multi posi: 242[M+Na] + .

Reference Example 27-1

Methyl 2-[3-(hydroxymethyl)phenyl]benzoate

(1) 2-(3-Methoxycarbonylphenyl)benzoic acid (535 mg) was used to perform the synthesis process according to the method described in Reference Example 25-1-(2) thereby giving a mixture (361 mg) containing 2-[3-(hydroxymethyl)phenyl]benzoic acid.

(2) Potassium carbonate (433 mg) and methyl iodide (143 μL) were added to a solution of the mixture (361 mg) obtained in (1) above in acetone (5.22 mL), and the resultant mixture was stirred at an outer temperature of 60° C. for 2 hours. After cooling to room temperature, potassium carbonate (433 mg) and methyl iodide (143 μL) were further added thereto, and the resultant mixture was stirred at room temperature for 2 days. The solvent was distilled off under reduced pressure, and the residue was distributed into diethyl ether and water. The aqueous layer was extracted with diethyl ether. The organic layers were combined, sequentially washed with an aqueous solution of 1 mol/L potassium hydroxide and brine, separated from the aqueous layer by a phase separator, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=19:1 to 3:2) to give a mixture (141 mg) containing the title compound as a colorless oil.

1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J=5.9 Hz, 1H) 3.65 (s, 3H) 4.74 (d, J=5.9 Hz, 2H) 7.22-7.26 (m, 1H) 7.32-7.44 (m, 5H) 7.50-7.56 (m, 1H) 7.81-7.86 (m, 1H).

MS ESI/APCI Multi posi: 225[M-OH] + .

Reference Example 28-1

Methyl 5-(hydroxymethyl)-2-methoxybenzoate

Sodium borohydride (184 mg) was added to a solution of methyl 5-formyl-2-methoxybenzoate (860 mg) in methanol (18 mL) under ice cooling, and the mixture was stirred at the same temperature for 2.5 hours. Water and a saturated aqueous solution of ammonium chloride were added thereto, and methanol was distilled off under reduced pressure. The obtained aqueous layer was extracted with chloroform, and the organic layer was separated by a phase separator and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1 to 1:4) to give the title compound (870 mg) as a colorless oil.

1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.60-1.69 (m, 1H) 3.89 (s, 3H) 3.91 (s, 3H) 4.60-4.69 (m, 2H) 6.94-7.02 (m, 1H) 7.43-7.52 (m, 1H) 7.75-7.84 (m, 1H).

MS ESI/APCI Multi posi: 197[M+H] + .

Reference Example 29-1

tert-Butyl 4-(8-hydroxyoctyl)-4-oxanecarboxylate

(1) To a solution of diisopropylamine (300 μL) in tetrahydrofuran (5 mL), n-butyl lithium (2.67 mol/L n-hexane solution, 790 μL) was added dropwise under a nitrogen atmosphere with ice cooling, and the mixture was stirred at the same temperature for 30 minutes. A solution of the compound (300 mg) obtained in Reference Example 22-1-(1) in tetrahydrofuran (2 mL) was added dropwise thereto at a temperature of −60° C. or lower, and the mixture was stirred at the same temperature for 45 minutes. Subsequently, a solution of 2-(8-bromooctoxy)oxane (620 mg) in tetrahydrofuran (1 mL) was added dropwise thereto at the same temperature, and the mixture was stirred at room temperature overnight. A saturated aqueous solution of ammonium chloride was added dropwise thereto under ice cooling, and the resultant mixture was extracted with diethyl ether. After the organic layer was washed with brine, the organic layer was dried over anhydrous magnesium sulfate, the drying agent was filtered off, and the filtrate was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=49:1 to 3:1) to give tert-butyl 4-[8-(2-oxanyloxy)octyl]-4-oxanecarboxylate (314 mg) as a colorless oil.

(2) To a solution of the compound (311 mg) obtained in (1) above in methanol (3.9 mL), p-toluenesulfonic acid monohydrate (15 mg) was added, and the mixture was stirred at room temperature overnight. A saturated aqueous solution of sodium hydrogen carbonate was added to the reaction solution, and the resultant mixture was extracted with chloroform. The organic layer was separated by a phase separator, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1 to 1:1) to give the title compound (237 mg) as a colorless oil.

1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.13-1.63 (m, 25H) 1.95-2.06 (m, 2H) 3.39-3.51 (m, 2H) 3.58-3.69 (m, 2H) 3.76-3.86 (m, 2H).

MS ESI/APCI Multi posi: 337[M+Na] + .

Reference Example 30-1

tert-Butyl 1-acetyl-4-(6-hydroxyhexyl)-4-piperidinecarboxylate

(1) Boc 2 O (6.0 mL) and 4-dimethylaminopyridine (799 mg) were added to a solution of 1-[(2-methylpropan-2-yl)oxy-oxomethyl]-4-piperidinecarboxylic acid (5.0 g) in t-butanol (22 mL), and the mixture was stirred at room temperature for 14 hours. A saturated aqueous solution of sodium hydrogen carbonate (10 mL) was added to stop the reaction, and the resultant mixture was extracted with hexane. The obtained organic layer was separated from the aqueous layer by passing through a phase separator, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=9:1) to give ditert-butyl piperidine-1,4-dicarboxylate (5.6 g) as a colorless solid.

(2) The compound (571 mg) obtained in (1) above and 2-(6-bromohexoxy)oxane (530 mg) were used to perform the synthesis process according to the method described in Reference Example 29-1-(1) thereby giving ditert-butyl 4-[6-(2-oxanyloxy)hexyl]piperidine-1,4-dicarboxylate (362 mg) as a colorless oil.

(3) A solution of 4 mol/L hydrogen chloride-1,4-dioxane (1.9 mL) was added to a solution of the compound (362 mg) obtained in (2) above in 1,4-dioxane (3.8 mL) under ice cooling, and the mixture was stirred at room temperature for 4.5 hours. Triethylamine (2.0 mL) was added to stop the reaction. The resultant solution was filtered through Celite (registered trademark), and the filtrate was concentrated under reduced pressure. The residue was dissolved in chloroform (7.7 mL), and triethylamine (0.22 mL) and acetic anhydride (0.11 mL) were added thereto, and the resultant mixture was stirred at room temperature for 14 hours. A saturated aqueous solution of ammonium chloride (8 mL) was added to stop the reaction, and the resultant mixture was extracted with chloroform. The obtained organic layer was separated from the aqueous layer by passing through a phase separator, and concentrated under reduced pressure. The obtained residue was dissolved in methanol (1.5 mL), water (0.50 mL) and trifluoroacetic acid (0.25 mL) were added thereto under ice cooling, and the resultant mixture was stirred at room temperature for 4 hours. A saturated aqueous solution of sodium hydrogen carbonate (5 mL) was added to stop the reaction, and the resultant mixture was extracted with ethyl acetate. The obtained organic layer was separated from the aqueous layer by passing through a phase separator, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=7:3 to 1:9 to chloroform:methanol=17:3) to give the title compound (70 mg) as a colorless oil.

MS ESI posi: 328[M+H] + , 350[M+Na] + .

The compound of Reference Example 30-2 below was synthesized using a commercially available compound, according to the method described in Reference Example 30-1. The structure, NMR data, and MS data of the compound are shown in Table 15-1.

Reference Example 31-1

tert-Butyl 4-(6-hydroxyhexyl)-1,1-dioxo-4-thiancarboxylate

(1) 4-Thiancarboxylic acid (1.0 g) was used to perform the synthesis process according to the method described in Reference Example 30-1-(1) thereby giving tert-butyl 4-thiancarboxylate (1.53 g) as a colorless oil.

(2) The compound (400 mg) obtained in (1) above was used to perform the synthesis process according to the method described in Reference Example 29-1-(1) thereby giving tert-butyl 4-[6-(2-oxanyloxy)hexyl]-4-thiancarboxylate (463 mg) as a colorlessoil.

(3) To a solution of the compound (463 mg) obtained in (2) above in chloroform (6.0 mL), meta-chloroperbenzoic acid (650 mg) was added under ice cooling, and the mixture was stirred at room temperature for 12 hours. A mixed solution of saturated aqueous solution of sodium thiosulfate:saturated aqueous solution of sodium hydrogen carbonate (1:1) was added to stop the reaction, and the reaction mixture was extracted with chloroform. The obtained organic layer was separated from the aqueous layer by passing through a phase separator, and concentrated under reduced pressure to give tert-butyl 4-[6-(2-oxanyloxy)hexyl]-1,1-dioxo-4-thiancarboxylate as a crude product.

(4) Water (0.5 mL) and trifluoroacetic acid (0.25 mL) were added to a solution of the crude product obtained in (3) above in methanol (1.5 mL) under ice cooling, and the mixture was stirred at room temperature for 4.5 hours. A saturated aqueous solution of sodium hydrogen carbonate (5 mL) was added to stop the reaction, and the resultant mixture was extracted with ethyl acetate. The obtained organic layer was separated from the aqueous layer by passing through a phase separator, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=7:3 to 1:4) to give the title compound (372 mg) as a colorless oil.

1 H NMR (400 MHz, CHLOROFOLM-d) δ ppm 1.19-1.40 (m, 5H) 1.48 (s, 9H) 1.50-1.63 (m, 6H) 1.92-2.07 (m, 2H) 2.40-2.49 (m, 2H) 2.88-3.14 (m, 4H) 3.64 (t, J=6.5 Hz, 2H).

MS ESI posi: 357[M+Na] + .

Reference Example 32-1

Ethyl 9-hydroxy-2,2-dimethylnonanoate

(1) To a solution of 7-bromo-1-heptanol (1.5 g) in chloroform (15 mL), 3,4-dihydro-2H-pyran (840 μL) and p-toluenesulfonic acid monohydrate (150 mg) were added, and the mixture was stirred at room temperature overnight. A saturated aqueous solution of sodium hydrogen carbonate was added to the reaction solution, and the resultant mixture was extracted with diethyl ether and washed with brine. The organic layer was separated by a phase separator, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=49:1 to 9:1) to give 2-(7-bromoheptoxy)oxane (1.1 g) as a colorless oil.

(2) The compound (865 mg) obtained in (1) above and ethyl isobutyrate (345 μL) were used to perform the synthesis process according to the method described in Reference Example 29-1-(1) thereby giving ethyl 2,2-dimethyl-9-(2-oxanyloxy)nonanoate (722 mg) as a colorless oil.

(3) To a solution of the compound obtained in (2) above in ethanol (23 mL), p-toluenesulfonic acid monohydrate (87 mg) was added, and the mixture was stirred at room temperature overnight. A saturated aqueous solution of sodium hydrogen carbonate was added to the reaction solution, and the resultant mixture was extracted with ethyl acetate. After the organic layer was washed with brine, the organic layer was dried over anhydrous magnesium sulfate, the drying agent was filtered off, and the filtrate was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=17:3 to 3:2) to give the title compound (469 mg) as a colorless oil.

1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.10-1.67 (m, 21H) 3.60-3.68 (m, 2H) 4.05-4.17 (m, 2H).

MS ESI/APCI Multi posi: 231[M+H] + .

Reference Example 33-1

Ethyl 6-hydroxy-2,2-dimethylhexanoate

(1) 2-(4-Bromobutoxy)oxane (735 mg) was used to perform the synthesis process according to the method described in Reference Example 32-1-(2) thereby giving ethyl 2,2-dimethyl-6-(2-oxanyloxy)hexanoate (411 mg) as a colorless oil.

(2) The compound (411 mg) obtained in (1) above was used to perform the synthesis process according to the method described in Reference Example 32-1-(3) thereby giving the title compound (266 mg) as a colorless oil.

1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.17 (s, 6H) 1.20-1.61 (m, 10H) 3.60-3.69 (m, 2H) 4.12 (q, J=7.1 Hz, 2H).

MS ESI/APCI Multi posi: 189[M+H] + .

The compounds of Reference Examples 33-2 and 33-3 below were synthesized using a commercially available compound, according to the method described in Reference Example 33-1. The structures, NMR data, and MS data of the compounds are shown in Table 16-1.

Reference Example 33-4

Methyl 1-(4-hydroxybutyl)-1-cyclopentanecarboxylate

(1) Methyl cyclopentanecarboxylate (200 mg) and 2-(4-bromobutoxy)oxane (389 mg) were used to perform the synthesis process according to the method described in Reference Example 29-1-(1) thereby giving methyl 1-[4-(2-oxanyloxy)butyl]-1-cyclopentanecarboxylate (250 mg) as a colorless oil.

(2) The compound obtained in (1) above was used to perform, under ice cooling, the synthesis process according to the method described in Reference Example 31-1-(4) thereby giving the title compound (152 mg) as a colorless oil.

1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.21-1.33 (m, 2H) 1.40-1.58 (m, 4H) 1.59-1.69 (m, 6H) 2.05-2.15 (m, 2H) 3.63 (t, J=6.5 Hz, 2H) 3.67 (s, 3H).

The compounds of Reference Examples 33-5 to 33-8 below were synthesized using a commercially available compound, according to the method described in Reference Example 33-4. The structures, NMR data, and MS data of the compounds are shown in Table 16-2.

Reference Example 34-1

Ethyl 7-hydroxy-2,2-dimethylheptanoate

(1) Ethyl 2-methylpropanoate (0.12 mL) and 5-bromopentoxymethylbenzene (120 mg) were used to perform the synthesis process according to the method described in Reference Example 29-1-(1) thereby giving ethyl 2,2-dimethyl-7-phenylmethoxyheptanoate (72 mg) as a colorless oil.

(2) The compound (72 mg) obtained in (1) above was used to perform the synthesis process according to the method described in Reference Example 1-1-(3) thereby giving the title compound (35 mg) as a colorless oil.

1 H NMR (400 MHz, CHLOROFOLM-d) δ ppm 1.16 (s, 6H) 1.20-1.40 (m, 7H) 1.48-1.63 (m, 4H) 3.63 (q, J=6.2 Hz, 2H) 4.11 (q, J=7.2 Hz, 2H).

The compounds of Reference Examples 34-2 to 34-4 below were synthesized using a commercially available compound, according to the method described in Reference Example 34-1. The structures, NMR data, and MS data of the compounds are shown in Table 17-1.

Reference Example 35-1

tert-Butyl 1-acetyl-4-(7-hydroxyheptyl)-4-piperidinecarboxylate

(1) The compound (570 g) obtained in Reference Example 30-1-(1) and the compound (560 mg) obtained in Reference Example 32-1-(1) were used to perform the synthesis process according to the method described in Reference Example 31-1-(2) thereby giving ditert-butyl 4-[7-(2-oxanyloxy)heptyl]piperidine-1,4-dicarboxylate (557 mg) as a colorless oil.

(2) The compound (557 mg) obtained in (1) above was used to perform the synthesis process according to the method described in Reference Example 30-1-(3) thereby giving the title compound (231 mg) as a colorless oil.

1 H NMR (400 MHz, CHLOROFOLM-d) δ ppm 1.21-1.67 (m, 24H) 2.00-2.18 (m, 5H) 2.73 (t, J=11.7 Hz, 1H) 3.17 (t, J=11.7 Hz, 1H) 3.56-3.73 (m, 3H) 4.29-4.41 (m, 1H).

MS ESI posi: 342[M+H] + .

Reference Example 36-1

(Phenylmethyl) 1-(7-hydroxyheptoxy)-1-cyclopentanecarboxylate

(1) 1-Hydroxy-1-cyclopentanecarboxylic acid (1 g) was used to perform the synthesis process according to the method described in Reference Example 8-2 thereby giving (phenylmethyl) 1-hydroxy-1-cyclopentanecarboxylate (888 mg) as a colorless oil.

(2) Sodium iodide (983 mg) was added to a solution of the compound (916 mg) obtained in Reference Example 32-1-(1) in acetone (6.6 mL), and the mixture was stirred while being heated to reflux for 8 hours. The reaction solution was concentrated under reduced pressure, and the residue was diluted with diethyl ether, and sequentially washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, the drying agent was filtered off, and the filtrate was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=49:1 to 91:9) to give 2-(7-iodoheptoxy)oxane (953 mg) as a colorless oil.

(3) Sodium hydride (60% mineral oil dispersion, 124 mg) was added to a solution of the compound (682 mg) obtained in (1) above in N,N-dimethylformamide (9 mL) under ice cooling, and the mixture was stirred at room temperature for 45 minutes. A solution of the compound (841 mg) obtained in (2) above in N,N-dimethylformamide (1.3 mL) was added thereto under ice cooling, and the resultant mixture was stirred at room temperature overnight. Water was added to the reaction solution under ice cooling, the resultant mixture was extracted with a n-hexane:ethyl acetate mixed solution, and the organic layer was sequentially washed with water and brine. After the organic layer was dried over anhydrous magnesium sulfate, the drying agent was filtered off, and the filtrate was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=49:1 to 17:3) to give (phenylmethyl) 1-[7-(2-oxanyloxy)heptoxy]-1-cyclopentanecarboxylate (140 mg) as a colorless oil.

(4) The compound (135 mg) obtained in (3) above was used to perform the synthesis process according to the method described in Reference Example 29-1-(2) thereby giving the title compound (96 mg) as a colorless oil.

1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.09-1.62 (m, 10H) 1.63-1.84 (m, 4H) 1.88-2.09 (m, 4H) 3.23-3.36 (m, 2H) 3.56-3.69 (m, 2H) 5.18 (s, 2H) 7.28-7.43 (m, 5H).

MS ESI/APCI Multi posi: 357[M+Na] + .

Reference Example 37-1

Methyl 3-(6-hydroxyhexoxy)-2,2-dimethylpropanoate

(1) Methyl 3-hydroxy-2,2-dimethylpropanoate (490 μL) and 6-bromohexoxymethylbenzene (800 mg) were used to perform the synthesis process according to the method described in Reference Example 36-1-(3) thereby giving methyl 2,2-dimethyl-3-(6-phenylmethoxyhexoxy)propanoate (252 mg) as a colorless oil.

(2) The compound (250 mg) obtained in (1) above was used to perform the synthesis process according to the method described in Reference Example 1-1-(3) by giving the title compound (142 mg) as a colorless oil.

1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.18 (s, 6H) 1.30-1.64 (m, 8H) 3.30-3.48 (m, 4H) 3.57-3.75 (m, 5H).

MS ESI/APCI Multi posi: 255 [M+Na] + .

Reference Example 38-1

Ethyl 2-[3-(4-hydroxybutoxy)propoxy]-2-methylpropanoate

(1) Propane-1,3-diol (3.7 mL) and 2-(4-bromobutoxy)oxane (1.5 g) were used to perform the synthesis process according to the method described in Reference Example 36-1-(3) thereby giving 3-[4-(2-oxanyloxy)butoxy]-1-propanol (870 mg) as a colorless oil.

(2) Triethylamine (1 mL) and trimethylamine hydrochloride (36 mg) were added to a solution of the compound (870 mg) obtained in (1) above and p-toluenesulfonyl chloride (928 mg) in toluene (18 mL) under ice cooling, and the mixture was stirred at room temperature for 12 hours. The reaction solution was diluted with ethyl acetate, and the organic layer was washed with a saturated aqueous solution of ammonium chloride and water, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform:methanol) to give 3-[4-(2-oxanyloxy)butoxy]propyl 4-methylbenzenesulfonate (1.4 g) as a colorless oil.

(3) Sodium hydride (60% mineral oil dispersion, 124 mg) was added to a solution of ethyl 2-hydroxy-2-methylpropanoate (616 mg) in N,N-dimethylformamide (10 mL) under ice cooling, and the mixture was stirred at the same temperature for 30 minutes. A solution of the compound (600 mg) obtained in (2) above in N,N-dimethylformamide (5 mL) was slowly added dropwise to that mixed solution, and the resultant mixture was stirred at 35° C. for 7 hours, and at room temperature for 10 hours. The reaction solution was diluted with diethyl ether, and washed with a saturated aqueous solution of ammonium chloride. The organic layers were collected and concentrated, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate) to give a mixture (60 mg) containing ethyl 2-methyl-2-[4-[4-(2-oxanyloxy)butoxy]butoxy]propanoate.

(4) To a solution of the mixture (130 mg) obtained in (3) above in ethanol (0.5 mL), 2 mol/L hydrochloric acid (0.16 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with water, and the diluted reaction solution was extracted with ethyl acetate, and the extracted substance was then concentrated under reduced pressure to give the title compound (100 mg) as a colorless oil.

1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.28 (t, J=7.2 Hz, 3H) 1.41 (s, 6H) 1.61-1.73 (m, 4H) 1.84 (t, J=6.4 Hz, 2H) 2.23-2.36 (m, 1H) 3.40-3.49 (m, 4H) 3.54 (t, J=6.4 Hz, 2H) 3.59-3.72 (m, 2H) 4.19 (q, J=7.1 Hz, 2H).

The compound of Reference Example 38-2 below was synthesized using a commercially available compound, according to the method described in Reference Example 38-1. The structure and NMR data of the compound are shown in Table 18-1.

Reference Example 38-3

(Phenylmethyl) 1-[2-(4-hydroxybutoxy)ethoxy]-1-cyclopentanecarboxylate

(1) Sodium hydride (60% mineral oil dispersion, 1.93 g) was added to a solution of ethane-1,2-diol (6.0 mL) in N,N-dimethylformamide (21 mL) under ice cooling, the mixture was stirred at the same temperature for 30 minutes, 2-(4-bromobutoxy)oxane (1.94 mL) was subsequently added thereto, and the resultant mixture was stirred at room temperature overnight. A saturated aqueous solution of ammonium chloride was added thereto under ice cooling, and the resultant mixture was extracted with ethyl acetate. The organic layer was sequentially washed with water and brine, and the organic layer was separated by a phase separator, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1 to 1:9) to give 2-[4-(2-oxanyloxy)butoxy]ethanol (1.76 g) as a colorless oil.

(2) Triethylamine (2.3 mL), trimethylamine hydrochloride (77 mg), and p-toluenesulfonyl chloride (2.0 g) were added to a solution of the compound (1.8 g) obtained in (1) above in toluene (40 mL), and the mixture was stirred at room temperature overnight. Water was added to the reaction solution under ice cooling, the resultant mixture was extracted with diethyl ether, and the organic layer was sequentially washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, the drying agent was filtered off, and the filtrate was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=19:1 to 7:3) to give 2-[4-(2-oxanyloxy)butoxy]ethyl 4-methylbenzenesulfonate (2.4 g) as a colorless oil.

(3) The compound (202 mg) obtained in (2) above and the compound (100 mg) obtained in Reference Example 36-1-(1) were used to perform the synthesis process according to the method described in Reference Example 36-1-(3) thereby giving a crude product (81 mg) containing (phenylmethyl) 1-[2-[4-(2-oxanyloxy)butoxy]ethoxy]-1-cyclopentanecarboxylate as a colorless oil.

(4) The compound (275 mg) obtained in (3) above was used to perform the synthesis process according to the method described in Reference Example 29-1-(2) thereby giving the title compound (180 mg) as a colorless oil.

1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.37-2.17 (m, 12H) 3.41-3.72 (m, 8H) 5.11-5.24 (m, 2H) 7.22-7.46 (m, 5H).

MS ESI/APCI Multi posi: 359[M+Na] + .

Reference Example 38-4

Ethyl 2-[2-(4-hydroxybutoxy)ethoxy]-2-methylpropanoate

(1) The compound (500 mg) obtained in Reference Example 38-3-(2) and ethyl 2-hydroxy-2-methylpropanoate (540 μL) were used to perform the synthesis process according to the method described in Reference Example 36-1-(3) thereby giving ethyl 2-methyl-2-[2-[4-(2-oxanyloxy)butoxy]ethoxy]propanoate (372 mg) as a colorless oil.

(2) The compound (372 mg) obtained in (1) above was used to perform the synthesis process according to the method described in Reference Example 29-1-(2) thereby giving the title compound (48 mg) as a colorless oil.

1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.28 (t, J=7.1 Hz, 3H) 1.43 (s, 6H) 1.49-1.79 (m, 4H) 3.44-3.79 (m, 8H) 4.19 (q, J=7.1 Hz, 2H).

MS ESI/APCI Multi posi: 271 [M+Na] + .

Reference Example 39-1

Ethyl 2-[6-(hydroxymethyl)-2-pyridinyl]acetate

(1) Potassium cyanide (354 mg) was added to a solution of [6-(bromomethyl)-2-pyridinyl]methanol (544 mg) in ethanol:water (2:1, 8.07 mL), and the mixture was heated to reflux for 3 hours. After the mixture was cooled to room temperature, the solvent was distilled off under reduced pressure. The residue was suspended in ethanol and insolubles were filtered off, and the filtrate was then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform:ethyl acetate=19:1 to 3:2) to give 2-[6-(hydroxymethyl)-2-pyridinyl]acetonitrile (309 mg) as a pale gray solid.

(2) Water (1.42 mL) and potassium hydroxide (654 mg) were added to a solution of the compound (309 mg) obtained in (1) above in ethanol (1.42 mL), and the mixture was heated to reflux for 3.5 hours. After the mixture was cooled to room temperature, the solvent was distilled off under reduced pressure. The residue was adjusted to acidic condition (about pH 2) with concentrated hydrochloric acid, and volatile components were distilled off under reduced pressure. The residue was suspended in ethanol, insolubles were filtered off, and the obtained filtrate was concentrated under reduced pressure to give a mixture (430 mg) containing 2-[6-(hydroxymethyl)-2-pyridinyl]acetic acid.

(3) Cesium carbonate (969 mg) and ethyl iodide (174 μL) were added to a solution of the mixture (430 mg) obtained in (2) above in N,N-dimethylformamide (3.97 mL), and the mixture was stirred at room temperature overnight. Water was added to the mixture, and the resultant mixture was extracted four times with ethyl acetate. The organic layers were combined, washed with brine, separated from the aqueous layer by a phase separator, and then concentrated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (n-hexane:ethyl acetate=9:1 to 2:3) to give the title compound (326 mg) as a pale yellow oil.

1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.27 (t, J=7.2 Hz, 3H) 3.75-3.82 (m, 1H) 3.85 (s, 2H) 4.19 (q, J=7.2 Hz, 2H) 4.74 (d, J=3.2 Hz, 2H) 7.13 (d, J=7.8 Hz, 1H) 7.21 (d, J=7.8 Hz, 1H) 7.66 (dd, J=7.8 Hz, 1H).

MS ESI/APCI Multi posi: 196[M+H] + .

Reference Example 40-1

Propan-2-yl 2-(2-hydroxyethyl)benzoate

(1) Imidazole (677 mg) and tert-butyldimethylchlorosilane (825 mg) were added to a solution of commercially available 2-(2-bromophenyl)ethanol (1.0 g) in N,N-dimethylformamide (8.3 mL), and the mixture was stirred at room temperature for 3 hours. A saturated aqueous solution of ammonium chloride (10 mL) was added to stop the reaction, and the resultant mixture was extracted with diethyl ether. The obtained organic layer was passed through a phase separator, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=99:1 to 10:1) to give 2-(2-bromophenyl)ethoxy-tert-butyl-dimethylsilane (1.2 g).

(2) A solution of the compound (300 mg) obtained in (1) above in tetrahydrofuran (12 mL) was cooled to −78° C. under a nitrogen atmosphere, n-butyl lithium (1.6 mol/L n-hexane solution, 0.80 mL) was added thereto, and the mixture was stirred at −78° C. for 30 minutes. Isopropyl chloroformate (0.34 mL) was added thereto, and the resultant mixture was stirred at −78° C. for 1.5 hours. A saturated aqueous solution of ammonium chloride (10 mL) was added to stop the reaction, and the resultant mixture was extracted with ethyl acetate. The obtained organic layer was passed through a phase separator, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=99:1 to 2:1) to give propan-2-yl 2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]benzoate (229 mg).

(3) A solution of the compound (229 mg) obtained in (2) above in tetrahydrofuran (14 mL) was ice-cooled, acetic acid (0.22 mL) and tetrabutylammonium fluoride (1.0 mol/L tetrahydrofuran solution, 0.78 mL) were added thereto, and the mixture was stirred at room temperature for 22 hours. A saturated aqueous solution of ammonium chloride (10 mL) was added to stop the reaction, and the resultant mixture was extracted with ethyl acetate. The obtained organic layer was passed through a phase separator, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1 to 1:1) to give the title compound (121 mg) as a colorless oil.

1 H NMR (400 MHz, CHLOROFOLM-d) δ ppm 1.38 (d, J=6.3 Hz, 6H) 3.19 (t, J=6.3 Hz, 2H) 3.91 (t, J=6.3 Hz, 2H) 5.24 (spt, J=6.3 Hz, 1H) 7.20-7.33 (m, 2H) 7.42-7.48 (m, 1H) 7.85 (d, J=7.9 Hz, 1H).

MS ESI/APCI Multi posi: 209[M+H] + .

The compound of Reference Example 40-2 below was synthesized using a commercially available compound, according to the method described in Reference Example 40-1. The structure and NMR data of the compound are shown in Table 19-1.

Reference Example 41-1

(Phenylmethyl) (E)-3-[2-(2-hydroxyethyl)phenyl]-2-propenoate

Triethylamine (0.17 mL), tri(o-toluyl)phosphine (60 mg), and palladium(II) acetate (22 mg) were added to a solution of commercially available 2-(2-bromophenyl)ethanol (200 mg) and commercially available (phenylmethyl) 2-propenoate (0.17 mL) in N,N-dimethylformamide (5.0 mL) under a nitrogen atmosphere, and the mixture was stirred at 60° C. for 1.5 hours, and at 80° C. for 2 hours. The reaction mixture was cooled to room temperature and filtered through Celite (registered trademark), and the filtrate was concentrated under reduced pressure. A saturated aqueous solution of ammonium chloride was added to the residue, and the resultant mixture was extracted with diethyl ether. The obtained organic layer was passed through a phase separator, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1 to 1:2) to give the title compound (180 mg).

1 H NMR (400 MHz, CHLOROFOLM-d) δ ppm 3.04 (t, J=6.7 Hz, 2H) 3.83 (t, J=6.7 Hz, 2H) 5.26 (s, 2H) 6.43 (d, J=15.8 Hz, 1H) 7.23-7.45 (m, 8H) 7.59 (d, J=7.6 Hz, 1H) 8.07 (d, J=15.8 Hz, 1H).

The compounds of Reference Examples 41-2 and 41-3 below were synthesized using a commercially available compound, according to the method described in Reference Example 41-1. The structures, NMR data, and MS data of the compounds are shown in Table 20-1.

Reference Example 42-1

Ethyl (E)-3-[3-(methylsulfonyloxymethyl)phenyl]-2-propenoate

(1) Triethylamine (15 mL), ethyl acrylate (17 mL), palladium(II) acetate (360 mg), and tri(o-toluyl)phosphine (1.95 g) were added to a solution of 3-bromobenzyl alcohol (10.0 g) in acetonitrile (100 mL), and the mixture was heated to 95° C. and stirred for 3 hours. The solvent was distilled off under reduced pressure, water was added to the residue, and the resultant mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the drying agent was filtered off. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=7:3 to 1:1) to give ethyl (E)-3-[3-(hydroxymethyl)phenyl]-2-propenoate (11.41 g) as a pale yellow oil.

(2) Methanesulfonyl chloride (619 μL) was added to a mixed solution of the compound (1.50 g) obtained in (1) above, triethylamine (1.11 mL), and ethyl acetate (10 mL) under ice cooling, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was filtered through Celite (registered trademark) to separate precipitates. The solvent was distilled off under reduced pressure to give the title compound (2.68 g) as a pale yellow oil.

1 H NMR (200 MHz, CHLOROFORM-d) δ ppm 1.30-1.40 (m, 3H) 2.97 (s, 3H) 4.27 (q, J=7.3 Hz, 2H) 5.25 (s, 2H) 6.47 (d, J=16.0 Hz, 1H) 7.39-7.47 (m, 2H) 7.51-7.60 (m, 2H) 7.68 (d, J=16.0 Hz, 1H).

Reference Example 43-1

Ethyl 3-[3-(methylsulfonyloxymethyl)phenyl]propanoate

(1) Tris(triphenylphosphine)rhodium(I) chloride (449 mg) was added to a solution of the compound (1.00 g) obtained in Reference Example 42-1-(1) in ethanol (10 mL), and the mixture was stirred under a hydrogen atmosphere at room temperature for 4 hours. The reaction solution was filtered through Celite (registered trademark), and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:2) to give ethyl 3-[3-(hydroxymethyl)phenyl]propanoate (1.24 g) as a pale yellow oil.

(2) Methanesulfonyl chloride (413 μL) was added to a mixed solution of the compound (1.01 g) obtained in (1) above, triethylamine (1.01 mL), and ethyl acetate (15 mL) under ice cooling, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was filtered through Celite (registered trademark) to separate precipitates. The solvent was distilled off under reduced pressure to give the title compound (2.00 g) as a reddish brown oil.

1 H NMR (200 MHz, CHLOROFORM-d) δ ppm 1.24 (t, J=7.2 Hz, 3H) 2.57-2.68 (m, 2H) 2.90-3.03 (m, 5H) 4.13 (q, J=7.2 Hz, 2H) 5.22 (s, 2H) 7.19-7.36 (m, 4H).

Reference Example 44-1

Ethyl 3-[4-(hydroxymethyl)phenyl]propanoate

(1) Commercially available (4-iodophenyl)methanol (520 mg) and commercially available ethyl acrylate (0.29 mL) were used to perform the synthesis process according to the method described in Reference Example 41-1 thereby giving ethyl (E)-3-[4-(hydroxymethyl)phenyl]-2-propenoate (630 mg) as a crude product.

(2) The crude product (200 mg) obtained in (1) above was used to perform the synthesis process according to the method described in Reference Example 43-1-(1) thereby giving the title compound (104 mg) as a colorless oil.

1 H NMR (400 MHz, CHLOROFOLM-d) δ ppm 1.24 (t, J=7.2 Hz, 3H) 2.61 (t, J=7.8 Hz, 2H) 2.88 (s, 1H) 2.95 (t, J=7.8 Hz, 2H) 4.13 (q, J=7.2 Hz, 2H) 4.66 (s, 2H) 7.20 (d, J=8.0 Hz, 2H) 7.29 (d, J=8.0 Hz, 2H).

The compound of Reference Example 44-2 below was synthesized using a commercially available compound, according to the method described in Reference Example 44-1. The structure and NMR data of the compound are shown in Table 21-1.

Reference Example 44-3

Methyl 4-[2-(hydroxymethyl)phenyl]butanoate

(1) Triethylamine (0.14 mL), tri(o-toluyl)phosphine (52 mg), and palladium(II) acetate (19 mg) were added to a solution of (2-iodophenyl)methanol (200 mg) and methyl 3-butenoate (0.11 mL) in acetonitrile (4.3 mL) under a nitrogen atmosphere, and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was cooled to room temperature and filtered through Celite (registered trademark), and the filtrate was concentrated under reduced pressure. A saturated aqueous solution of ammonium chloride (8 mL) was added to the residue, and the resultant mixture was extracted with diethyl ether. The obtained organic layer was passed through a phase separator, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1 to 1:1) to give methyl (E)-4-[2-(hydroxymethyl)phenyl]-3-butenoate (56 mg).

(2) The compound (56 mg) obtained in (1) above was used to perform the synthesis process according to the method described in Reference Example 43-1-(1) thereby giving the title compound (47 mg) as a light yellow oil.

1 H NMR (400 MHz, CHLOROFOLM-d) δ ppm 1.85-2.06 (m, 2H) 2.40 (t, J=7.2 Hz, 2H) 2.68-2.80 (m, 2H) 3.66 (s, 3H) 4.65-4.82 (m, 2H) 7.17-7.41 (m, 4H).

The compound of Reference Example 44-4 below was synthesized using a commercially available compound, according to the method described in Reference Example 44-3. The structure and NMR data of the compound are shown in Table 21-2.

Reference Example 44-5

Ethyl 3-[3-(2-hydroxyethyl)phenyl]propanoate

(1) Commercially available 2-(3-bromophenyl)ethanol (300 mg) and commercially available ethyl acrylate (0.18 mL) were used to perform the synthesis process according to the method described in Reference Example 41-1 thereby giving ethyl (E)-3-[3-(2-hydroxyethyl)phenyl]-2-propenoate (236 mg) as a yellow oil.

(2) The compound (236 mg) obtained in (1) above was used to perform the synthesis process according to the method described in Reference Example 1-1-(3) thereby giving the title compound (214 mg) as a yellow oil.

1 H NMR (400 MHz, CHLOROFOLM-d) δ ppm 1.15-1.31 (m, 5H) 2.55-2.69 (m, 3H) 2.80-3.00 (m, 3H) 4.13 (q, J=7.1 Hz, 2H) 6.95-7.40 (m, 4H).

The compound of Reference Example 44-6 below was synthesized using a commercially available compound, according to the method described in Reference Example 44-5. The structure and NMR data of the compound are shown in Table 21-3.

Reference Example 45-1

3-[3,4-Difluoro-5-[(4-methoxyphenyl)methoxy]phenyl]-1-propanol

(1) 5-Bromo-2,3-difluorophenol (588 mg) was used to perform the synthesis process according to the method described in Reference Example 25-1-(1) thereby giving 5-bromo-1,2-difluoro-3-[(4-methoxyphenyl)methoxy]benzene (464 mg) as a colorless solid.

(2) The compound (200 mg) obtained in (1) above, palladium(II) acetate (6.82 mg), and tris(o-toluyl)phosphine (18.5 mg) were weighted in a pressure-resistant tube and dissolved in N,N-dimethylformamide (1.22 mL), and the air in the container was purged with nitrogen and the container was then sealed. Triethylamine (119 μL) and ethyl acrylate (132 μL) were added to the mixture with a syringe, and the resultant mixture was stirred at an outer temperature of 90° C. overnight. After cooling to room temperature, the container was opened, and palladium(II) acetate (13.6 mg), tris(o-toluyl)phosphine (37.0 mg), triethylamine (119 μL), and ethyl acrylate (132 μL) were added thereto, and the air in the container was purged with nitrogen and the container was then sealed. After stirring at an outer temperature of 120° C. for 2.5 hours, the mixture was cooled to room temperature. The mixture was poured into water, and the formed precipitate was collected by filtration, washed with water, and then dissolved in chloroform. After separating from the aqueous layer by a phase separator, the resultant was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=4:1). The obtained crude product was dissolved in a n-hexane:ethyl acetate (1:2) mixed solution, and insolubles were filtered off. The filtrate was concentrated under reduced pressure to give ethyl (E)-3-[3,4-difluoro-5-[(4-methoxyphenyl)methoxy]phenyl]-2-propenoate (184 mg) as a colorless solid.

(3) A palladium carbon-ethylenediamine complex (8.40 mg) was added to a solution of the compound (84.0 mg) obtained in (2) above in tetrahydrofuran:methanol=1:1 (1.58 mL), and the mixture was stirred under a hydrogen atmosphere at room temperature overnight. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=4:1) to give ethyl 3-[3,4-difluoro-5-[(4-methoxyphenyl)methoxy]phenyl]propanoate (35.9 mg) as a colorless oil.

(4) The compound (35.9 mg) obtained in (3) above was used to perform the synthesis process according to the method described in Reference Example 25-1-(2) thereby giving the title compound (30.5 mg) as a colorless oil.

1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.78-1.87 (m, 2H) 2.58-2.67 (m, 2H) 3.59-3.67 (m, 2H) 3.82 (s, 3H) 5.06 (s, 2H) 6.58-6.65 (m, 2H) 6.89-6.94 (m, 2H) 7.31-7.39 (m, 2H).

Reference Example 46-1

Ethyl 2-(3-hydroxypropyl)benzoate

(1) Triethylamine (1.51 mL), copper(I) iodide (55 mg), and bis(triphenylphosphine)palladium(II) dichloride (140 mg) were added to a solution of ethyl 2-iodobenzoate (1.0 g) and 2-propyn-1-ol (0.25 mL) in acetonitrile (7.2 mL) under a nitrogen atmosphere, and the mixture was stirred at 60° C. for 4 hour. The reaction solution was cooled to room temperature and filtered through Celite (registered trademark), and the filtrate was concentrated under reduced pressure. A saturated aqueous solution of ammonium chloride (8 mL) was added to the residue, and the resultant mixture was extracted with ethyl acetate. The obtained organic layer was passed through a phase separator, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1 to 1:1) to give ethyl 2-(3-hydroxyprop-1-inyl)benzoate (732 mg).

(2) The compound (732 mg) obtained in (1) above was used to perform the synthesis process according to the method described in Reference Example 1-1-(3) thereby giving the title compound (387 mg) as a light yellow oil.

1 H NMR (400 MHz, CHLOROFOLM-d) δ ppm 1.39 (t, J=7.2 Hz, 3H) 1.86-1.97 (m, 2H) 2.25 (t, J=5.9 Hz, 1H) 3.06 (t, J=7.4 Hz, 2H) 3.56-3.70 (m, 2H) 4.36 (q, J=7.2 Hz, 2H) 7.22-7.32 (m, 2H) 7.37-7.50 (m, 1H) 7.87 (dd, J=7.8, 1.3 Hz, 1H).

MS ESI/APCI Multi posi: 209[M+H] + .

The compounds of Reference Examples 46-2 to 46-5 below were synthesized using a commercially available compound, according to the method described in Reference Example 46-1. The structures, NMR data, and MS data of the compounds are shown in Table 22-1.

Reference Example 46-6

(Phenylmethyl) 4-[6-(hydroxymethyl)-2-pyridinyl]-2,2-dimethylbutanoate

(1) Triethylamine (0.69 mL), copper(I) iodide (9.4 mg), and bis(triphenylphosphine)palladium(II) dichloride (35 mg) were added to a solution of (6-bromo-2-pyridinyl)methanol (195 mg) and (phenylmethyl) 2,2-dimethyl-3-butynoate (0.19 mL) in N,N-dimethylformamide (4.9 mL) under a nitrogen atmosphere, and the mixture was stirred at 60° C. for 3 hours. The temperature of the mixture was returned to room temperature, a saturated aqueous solution of ammonium chloride (8 mL) was added to the mixture, the resulting mixture was filtered through Celite (registered trademark), and the filtrate was extracted with ethyl acetate. The obtained organic layer was passed through a phase separator, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:2 to 1:9) to give (phenylmethyl) 4-[6-(hydroxymethyl)-2-pyridinyl]-2,2-dimethyl-3-butynoate (206 mg).

(2) Tris(triphenylphosphine)rhodium(I) chloride (50 mg) was added to a solution of the compound (206 mg) obtained in (1) above in ethanol (6.7 mL), and the mixture was stirred under a hydrogen atmosphere at room temperature for 14 hours, and at 80° C. for 22 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=7:3 to 1:4) to give the title compound (80 mg) as a colorless oil.

1 H NMR (400 MHz, CHLOROFOLM-d) δ ppm 1.29 (s, 6H) 1.91-2.05 (m, 2H) 2.62-2.74 (m, 2H) 4.70 (s, 2H) 5.13 (s, 2H) 6.82-7.10 (m, 2H) 7.29-7.40 (m, 4H) 7.42-7.72 (m, 2H).

MS ESI posi: 314[M+H] + .

Reference Example 47-1

(Phenylmethyl) 4-[4-(hydroxymethyl)-2-pyridinyl]-2,2-dimethylbutanoate

(1) Pyridinium p-toluenesulfonate (103 mg) and 3,4-dihydro-2H-pyran (0.74 mL) were added to a solution of (2-bromo-4-pyridinyl)methanol (784 mg) in chloroform (8.2 mL), and the mixture was stirred at room temperature for 17 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=3:2) to give 2-bromo-4-(2-oxanyloxymethyl)pyridine (1.1 g) as a colorless oil.

(2) The compound (283 mg) obtained in (1) above and commercially available (phenylmethyl) 2,2-dimethyl-3-butynoate (0.19 mL) were used to perform the synthesis process according to the method described in Reference Example 46-6-(1) thereby giving (phenylmethyl) 2,2-dimethyl-4-[4-(2-oxanyloxymethyl)-2-pyridinyl]-3-butynoate (250 mg) as a colorless oil.

(3) The compound (250 mg) obtained in (2) above was used to perform the synthesis process according to the method described in Reference Example 43-1-(1) thereby giving (phenylmethyl) 2,2-dimethyl-4-[4-(2-oxanyloxymethyl)-2-pyridinyl]butanoate (152 mg) as a colorless oil.

(4) A 4 mol/L hydrogen chloride-1,4-dioxane solution (0.96 mL) was added to a solution of the compound (152 mg) obtained in (3) above in 1,4-dioxane (1.9 mL), and the mixture was stirred at room temperature for 14 hours. A saturated aqueous solution of sodium hydrogen carbonate (5 mL) was added to stop the reaction, and the resultant mixture was extracted with ethyl acetate. The obtained organic layer was passed through a phase separator, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=7:3 to 1:4) to give the title compound (61 mg) as a colorless oil.

1 H NMR (400 MHz, CHLOROFOLM-d) δ ppm 1.28 (s, 6H) 1.95-2.02 (m, 2H) 2.67-2.75 (m, 2H) 4.68 (s, 2H) 5.12 (s, 2H) 7.03 (s, 1H) 7.08 (d, J=5.0 Hz, 1H) 7.26-7.56 (m, 5H) 8.46 (d, J=5.0 Hz, 1H).

MS ESI posi: 314[M+H] + .

Reference Example 48-1

Ethyl 6-[3-(hydroxymethyl)phenyl]-2-pyridinecarboxylate

Ethyl 6-bromo-2-pyridinecarboxylate (600 mg) and [3-(hydroxymethyl)phenyl]boronic acid (515 mg) were used to perform the synthesis process according to the method described in Reference Example 13-1-(1) thereby giving the title compound (680 mg) as a pale red oil.

1 H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.44 (t, J=7.0 Hz, 3H) 1.70-1.79 (m, 1H) 4.47 (q, J=7.0 Hz, 2H) 4.78 (d, J=6.2 Hz, 2H) 7.41-7.50 (m, 2H) 7.84-7.91 (m, 2H) 7.95 (d, J=7.4 Hz, 1H) 8.03 (dd, J=7.0, 1.2 Hz, 1H) 8.06 (s, 1H).

MS ESI/APCI Multi posi: 258[M+H] + .

The compounds of Reference Examples 48-2 to 48-6 below were synthesized using a commercially available compound, according to the method described in Reference Example 48-1. The structures, NMR data, and MS data of the compounds are shown in Table 23-1.

Reference Example 49-1

tert-Butyl 2-[4-[3-(hydroxymethyl)phenyl]-1-pyrazolyl]acetate

(1) Cesium carbonate (5.3 g) was added to a solution of 4-bromo-1H-pyrazole (2 g) in N,N-dimethylformamide (40 mL), and the mixture was stirred at room temperature. To this mixture, tert-butyl 2-bromoacetate (3.2 g) was slowly added under ice cooling, and the resultant mixture was stirred at room temperature 14 hours. Water was added to the reaction solution, and the resultant mixture was extracted with ethyl acetate. The organic layer was washed twice with water and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=9:1) to give tert-butyl 2-(4-bromo-1-pyrazolyl)acetate (3.2 g) as a colorless oil.

(2) The compound (300 mg) synthesized in (1) above and [3-(hydroxymethyl)phenyl]boronic acid (227 mg) were used to perform the synthesis process according to the method described in Reference Example 13-1-(1) thereby giving the title compound (260 mg) as a dark brown oil.

1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.49 (s, 9H) 1.60-1.67 (m, 1H) 4.72 (d, J=6.0 Hz, 2H) 4.84 (s, 2H) 7.20-7.25 (m, 1H) 7.32-7.39 (m, 1H) 7.40-7.45 (m, 1H) 7.51 (s, 1H) 7.74 (s, 1H) 7.84 (s, 1H).

MS ESI/APCI Multi posi: 289[M+H] + .

Reference Example 49-2

Propan-2-yl 2-[5-[3-(hydroxymethyl)phenyl]-2-oxo-1-pyridinyl]acetate

(1) Potassium carbonate (1.3 g) and isopropyl bromoacetate (1.2 mL) were added to a solution of 5-bromo-1H-pyridin-2-one (1.50 g) in N,N-dimethylformamide (8.6 mL), and the mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of ammonium chloride (10 mL) was added to stop the reaction, and the resultant mixture was extracted with ethyl acetate. The obtained organic layer was passed through a phase separator, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=7:3 to 3:7) to give propan-2-yl 2-(5-bromo-2-oxo-1-pyridinyl)acetate (1.2 g) as a colorless solid.

(2) Potassium carbonate (100 mg) and tetrakis(triphenylphosphine)palladium(0) (42 mg) were added to a solution of the compound (100 mg) obtained in (1) above and commercially available [3-(hydroxymethyl)phenyl]boronic acid (58 mg) in dimethoxyethane:water (4:1, 4.5 mL) under a nitrogen atmosphere, and the mixture was stirred at 120° C. for 30 minutes under microwave irradiation. The reaction mixture was filtered through Celite (registered trademark), a saturated aqueous solution of ammonium chloride (5 mL) was added to the filtrate, and the resultant mixture was extracted with ethyl acetate. The obtained organic layer was passed through a phase separator, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=7:3 to 1:9) to give the title compound (73 mg) as a brown amorphous substance.

1 H NMR (400 MHz, CHLOROFOLM-d) δ ppm 1.29 (d, J=6.3 Hz, 6H) 1.86 (t, J=5.7 Hz, 1H) 4.68 (s, 2H) 4.75 (d, J=5.7 Hz, 2H) 5.11 (spt, J=6.3 Hz, 1H) 6.67 (d, J=9.4 Hz, 1H) 7.29-7.50 (m, 5H) 7.62-7.74 (m, 1H).

MS ESI posi: 302[M+H] + .

Reference Example 49-3 Propan-2-yl 2-[4-[3-(hydroxymethyl)phenyl]-2-oxo-1-pyridinyl]acetate

(1) 4-Iodo-1H-pyridin-2-one (1.0 g) was used to perform the synthesis process according to the method described in Reference Example 49-2-(1) thereby giving propan-2-yl 2-(4-iodo-2-oxo-1-pyridinyl)acetate (1.2 g) as a colorless solid.

(2) The compound (150 mg) obtained in (1) above and [3-(hydroxymethyl)phenyl]boronic acid (75 mg) were used to perform the synthesis process according to the method described in Reference Example 49-2-(2) thereby giving the title compound (93 mg) as a colorless oil.

1 H NMR (400 MHz, CHLOROFOLM-d) δ ppm 1.29 (d, J=6.3 Hz, 6H) 1.94 (t, J=5.8 Hz, 1H) 4.65 (s, 2H) 4.77 (d, J=5.8 Hz, 2H) 5.12 (spt, J=6.3 Hz, 1H) 6.48 (dd, J=7.1, 2.0 Hz, 1H) 6.78 (d, J=1.8 Hz, 1H) 7.28 (s, 1H) 7.42-7.54 (m, 3H) 7.59 (s, 1H).

MS ESI posi: 302[M+H] + .

Reference Example 50-1

tert-Butyl 2-[4-(4-hydroxybutyl)-1-pyrazolyl]acetate

(1) The compound (500 mg) synthesized in Reference Example 49-1-(1) and tert-butyl-dimethyl-[(E)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-enoxy]silane (777 mg) were used to perform the synthesis process according to the method described in Reference Example 13-1-(1) thereby giving tert-butyl 2-[4-[(E)-4-[tert-butyl(dimethyl)silyl]oxybut-1-enyl]-1-pyrazolyl]acetate (520 mg) as a pale yellow oil.

(2) Palladium hydroxide carbon (115 mg) was added to a solution of the compound (200 mg) obtained in (1) above in ethyl acetate (5.5 mL), and the mixture was stirred under a hydrogen atmosphere at room temperature for 4 hours. The resultant mixture was diluted with ethyl acetate, filtered through Celite (registered trademark), and then concentrated under reduced pressure to give a mixture containing tert-butyl 2-[4-[4-[tert-butyl(dimethyl)silyl]oxybutyl]-1-pyrazolyl]acetate.

(3) Tetrabutylammonium fluoride (1 mol/L tetrahydrofuran solution, 0.54 mL) was added to a solution of the mixture obtained in (2) above in tetrahydrofuran (2 mL), and the resultant mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and purified by silica gel column chromatography (hexane:ethyl acetate) to give the title compound (95 mg) as a pale yellow oil.

1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.47 (s, 9H) 1.60-1.70 (m, 5H) 2.46-2.58 (m, 2H) 3.60-3.75 (m, 2H) 4.72-4.77 (m, 2H) 7.24 (s, 1H) 7.37 (s, 1H).

MS ESI/APCI Multi posi: 255 [M+H] + .

The compound of Reference Example 50-2 below was synthesized using a commercially available compound, according to the method described in Reference Example 50-1. The structure, NMR data, and MS data of the compound are shown in Table 24-1.

Reference Example 51-1

Ethyl 2-[4-(4-hydroxybutyl)-1-pyrazolyl]-2-methylpropanoate

(1) 3-Bromo-1H-pyrazole (500 mg) and ethyl 2-bromo-2-methylpropanoate (796 mg) were used to perform the synthesis process according to the method described in Reference Example 49-1-(1) thereby giving ethyl 2-(4-bromo-1-pyrazolyl)-2-methylpropanoate (839 mg) as a colorless oil.

(2) The compound (100 mg) obtained in (1) above was used to perform the synthesis process according to the method described in Reference Example 50-1-(1) thereby giving ethyl 2-[3-[(E)-4-[tert-butyl(dimethyl)silyl]oxybut-1-enyl]-1-pyrazolyl]-2-methylpropanoate (95 mg) as a colorless oil.

(3) The compound (90 mg) obtained in (2) above was used to perform the synthesis process according to the method described in Reference Example 50-1-(2) thereby giving a mixture containing ethyl 2-[3-[4-[tert-butyl(dimethyl)silyl]oxybutyl]-1-pyrazolyl]-2-methylpropanoate.

(4) The mixture obtained in (3) above was used to perform the synthesis process according to the method described in Reference Example 50-1-(3) thereby giving the title compound (47 mg) as a colorless oil.

1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.21 (t, J=7.2 Hz, 3H) 1.60-1.68 (m, 4H) 1.83 (s, 6H) 2.51 (t, J=7.0 Hz, 2H) 3.64-3.71 (m, 2H) 4.16 (q, J=7.2 Hz, 2H) 7.34 (s, 1H) 7.38 (s, 1H).

The compound of Reference Example 51-2 below was synthesized using a commercially available compound, according to the method described in Reference Example 51-1. The structure and NMR data of the compound are shown in Table 25-1.

Reference Example 52-1

Methyl 4-[7-(hydroxymethyl)-1-oxo-3,4-dihydroisoquinolin-2-yl]-2,2-dimethylbutanoate

(1) Sodium hydride (60% mineral oil dispersion, 50 mg) was added to a solution of 7-bromo-3,4-dihydro-2H-isoquinolin-1-one (216 mg) in N,N-dimethylformamide (3 mL) under ice cooling, and the mixture was stirred at room temperature for 1 hour. A solution of methyl 4-bromo-2,2-dimethylbutanoate (250 mg) in N,N-dimethylformamide (1 mL) was added to the reaction solution, and the resultant mixture was stirred at 90° C. for 2.5 hours. A saturated aqueous solution of ammonium chloride was added thereto, the resultant mixture was extracted with ethyl acetate, and the organic layers were collected and washed with brine. After concentrating under reduced pressure, the concentrated solution was purified by silica gel column chromatography (n-hexane:ethyl acetate=19:1 to 13:7) to give methyl 4-(7-bromo-1-oxo-3,4-dihydroisoquinolin-2-yl)-2,2-dimethylbutanoate (163 mg) as a colorless oil.

(2) The compound (160 mg) obtained in (1) above and potassium vinyltrifluoroborate (109 mg) were used to perform the synthesis process according to the method described in Reference Example 13-1-(1) thereby giving methyl 4-(7-ethenyl-1-oxo-3,4-dihydroisoquinolin-2-yl)-2,2-dimethylbutanoate (110 mg) as a colorless oil.

(3) The compound (105 mg) obtained in (2) above and N-methylmorpholine-N-oxide (102 mg) were dissolved in tert-butyl alcohol (1.7 mL), tetrahydrofuran (1.7 mL), and water (0.35 mL), and an aqueous solution of 4% osmium tetroxide (45 μL) was added thereto, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous solution of sodium thiosulfate was added to the reaction solution, and the resultant mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure to give a mixture (110 mg) containing methyl 4-[7-(1,2-dihydroxyethyl)-1-oxo-3,4-dihydroisoquinolin-2-yl]-2,2-dimethylbutanoate.

(4) Sodium periodate (77 mg) was added to a solution of the mixture (110 mg) obtained in (3) above in tetrahydrofuran (1.6 mL), and the mixture was stirred at room temperature 30 minutes. The mixture was diluted with water, and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure to give a mixture containing methyl 4-(7-formyl-1-oxo-3,4-dihydroisoquinolin-2-yl)-2,2-dimethylbutanoate.

(5) Sodium borohydride (15 mg) was added to a solution of the mixture obtained in (4) above in methanol (1.6 mL) at −20° C., and the mixture was stirred for 30 minutes. The mixture was diluted with water, and extracted with ethyl acetate. The extracted substance was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform:methanol) to give the title compound (80 mg) as a colorless oil.

1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.27 (s, 6H) 1.62-1.72 (m, 1H) 1.81-1.93 (m, 2H) 2.98 (t, J=6.6 Hz, 2H) 3.50-3.61 (m, 4H) 3.67 (s, 3H) 4.68-4.74 (m, 2H) 7.18 (d, J=7.7 Hz, 1H) 7.45 (d, J=7.7 Hz, 1H) 8.03 (s, 1H).

MS ESI posi: 306[M+H] + .

Reference Example 53-1

Ethyl 7-(hydroxymethyl)-3,4-dihydro-2H-1-benzopyran-2-carboxylate

(1) Palladium carbon (981 mg) was added to a solution of commercially available ethyl 7-hydroxy-4-oxo-1-benzopyran-2-carboxylate (3.27 g) in acetic acid (30 mL), and the mixture was stirred under a hydrogen atmosphere (50 psi) at 30° C. for 12 hours. After the reaction solution was filtered through Celite (registered trademark), the filtrate was concentrated. Ethyl acetate was added to the obtained residue, which was sequentially washed with a saturated aqueous solution of sodium hydrogen carbonate and brine. The organic layer was separated by a phase separator, and concentrated under reduced pressure. Diethyl ether and n-hexane were added to the obtained residue, and the precipitated solid was collected by filtration to give ethyl 7-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxylate (2.91 g) as a colorless powder.

(2) Pyridine (730 μL) was added to a solution of the compound (1.00 g) obtained in (1) above in chloroform (15 mL), and trifluoromethanesulfonic anhydride (910 μL) was added dropwise thereto under ice cooling. The temperature of the mixture was increased to room temperature, and the mixture was stirred for 1 hour. To the reaction solution, 1 mol/L hydrochloric acid (20 mL) and water (5 mL) were added under ice cooling, and the resultant mixture was stirred. The organic layer was separated by a separatory funnel, and washed with a saturated aqueous solution of sodium hydrogen carbonate. After passing through a phase separator, the resultant was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=9:1 to 1:1) to give ethyl 7-(trifluoromethylsulfonyloxy)-3,4-dihydro-2H-1-benzopyran-2-carboxylate (1.61 g) as a colorless oil.

(3) The compound (400 mg) obtained in (2) above and potassium vinyltrifluoroborate (272 mg) were used to perform the synthesis process according to the method described in Reference Example 13-1-(1) thereby giving ethyl 7-ethenyl-3,4-dihydro-2H-1-benzopyran-2-carboxylate (212 mg) as a colorless oil.

(4) The compound (212 mg) obtained in (3) above and N-methylmorpholine-N-oxide (267 mg) were dissolved in tert-butyl alcohol (4.6 mL), tetrahydrofuran (4.6 mL), and water (0.91 mL), and an aqueous solution of 4% osmium tetroxide (118 μL) was added thereto, and the mixture was stirred at room temperature for 2 hours, and then at 60° C. for 20 minutes. A saturated aqueous solution of sodium thiosulfate was added to the reaction solution, and the resultant mixture was extracted with ethyl acetate. After passing through a phase separator, the resultant was concentrated under reduced pressure to give a mixture (271 mg) containing ethyl 7-(1,2-dihydroxyethyl)-3,4-dihydro-2H-1-benzopyran-2-carboxylate.

(5) The compound (271 mg) obtained in (4) above was used to perform the synthesis process according to the method described in Reference Example 52-1-(4) thereby giving a mixture (217 mg) containing ethyl 7-formyl-3,4-dihydro-2H-1-benzopyran-2-carboxylate.

(6) Sodium borohydride (46 mg) was added to a solution of the mixture obtained in (5) above in ethanol (4.6 mL) under ice cooling, and the mixture was stirred at the same temperature for 30 minutes. A saturated aqueous solution of ammonium chloride and water were added thereto, and the resultant mixture was extracted with ethyl acetate. The organic layer was separated by a phase separator, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=9:1 to 1:1) to give the title compound (170 mg) as a colorless oil.

1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.29 (t, J=7.1 Hz, 3H) 2.13-2.33 (m, 2H) 2.68-2.88 (m, 2H) 4.25 (q, J=7.1 Hz, 2H) 4.62 (d, J=6.0 Hz, 2H) 4.69-4.76 (m, 1H) 6.88 (d, J=7.7 Hz, 1H) 6.94 (s, 1H) 7.02 (d, J=7.7 Hz, 1H).

MS ESI posi: 259[M+Na] + .

Reference Example 54-1

Ethyl 3-[3-(hydroxymethyl)phenyl]-1-cyclohexanecarboxylate

(1) Trifluoromethanesulfonic anhydride (562 μL) was added to a solution of ethyl 3-oxo-1-cyclohexanecarboxylate (500 μL) and 2,4,6-tri-tert-butylpyridine (905 mg) in chloroform (6.36 mL) under ice cooling, and the mixture was stirred at room temperature overnight. The mixture was diluted with chloroform, and sequentially washed with 1 mol/L hydrochloric acid and brine. The organic layer was separated by a phase separator, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=93:7) to give ethyl 3-(trifluoromethylsulfonyloxy)-1-cyclohex-3-enecarboxylate (529 mg) as a colorless oil.

(2) The compound (136 mg) obtained in (1) above, [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (18.4 mg), and potassium fluoride (91.5 mg) were weighed in a three-necked flask, the container was sealed, and the air in the container was then purged with nitrogen. To this mixture, a solution of [3-(hydroxymethyl)phenyl]boronic acid (88.9 mg) in tetrahydrofuran (2.93 mL) was added, and the mixture was stirred at room temperature for 3 days. The mixture was diluted with ethyl acetate, and sequentially washed with a saturated aqueous solution of sodium hydrogen carbonate and brine. The organic layer was separated by a phase separator, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=7:3) to give ethyl 3-[3-(hydroxymethyl)phenyl]-1-cyclohex-3-enecarboxylate (92.1 mg) as a yellow oil.

(3) The compound (87.9 mg) obtained in (2) above was used to perform the synthesis process according to the method described in Reference Example 45-1-(3) thereby giving the title compound (73.6 mg) as a colorless oil.

1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.20-1.34 (m, 3H) 1.41-1.77 (m, 5H) 1.83-2.34 (m, 4H) 2.41-2.84 (m, 2H) 4.08-4.24 (m, 2H) 4.65-4.73 (m, 2H) 7.14-7.32 (m, 4H).

Reference Example 54-2

Ethyl 4-[3-(hydroxymethyl)phenyl]-1-cyclohexanecarboxylate

(1) Ethyl 4-(trifluoromethylsulfonyloxy)-1-cyclohex-3-enecarboxylate (131 mg) was used to perform the synthesis process according to the method described in Reference Example 54-1-(2) thereby giving ethyl 4-[3-(hydroxymethyl)phenyl]-1-cyclohex-3-enecarboxylate (77.5 mg) as a yellow oil.

(2) The compound (92.2 mg) obtained in (1) above was used to perform the synthesis process according to the method described in Reference Example 45-1-(3) thereby giving the title compound (85.1 mg) as a white oil.

1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.23-1.32 (m, 3H) 1.42-1.83 (m, 6H) 1.93-2.15 (m, 2H) 2.21-2.72 (m, 3H) 4.11-4.24 (m, 2H) 4.64-4.71 (m, 2H) 7.11-7.33 (m, 4H).

MS ESI/APCI Multi posi: 245[M-OH] + .

Reference Example 55-1

(3-Methylsulfonyl-5-phenylmethoxyphenyl)methanol

(1) Potassium carbonate (1.63 g) and benzyl bromide (842 μL) were added to a solution of 3-bromo-5-(hydroxymethyl)phenol (1.20 g) in acetone (20 mL), and the mixture was stirred at room temperature for 5 hours. The reaction solution was filtered through Celite (registered trademark), and the filtrate was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1 to 2:3). The purified residue was dried under reduced pressure to give (3-bromo-5-phenylmethoxyphenyl)methanol (1.71 g) as a pale yellow oil.

(2) The compound (200 mg) obtained in (1) above, copper(I) iodide (26 mg), L-proline (31 mg), sodium hydroxide (11 mg), sodium methanesulfinate (139 mg), and dimethyl sulfoxide (3 mL) were mixed, and the mixture was stirred at 150° C. for 50 minutes under microwave irradiation. A saturated aqueous solution of ammonium chloride was added to the reaction solution, and the resultant mixture was extracted with ethyl acetate. The organic layer was separated by a phase separator, and concentrated under reduced pressure. The resultant was dried under reduced pressure to give the title compound (210 mg) as a light orange oil.

1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.03 (s, 3H) 4.74-4.78 (m, 2H) 5.13 (s, 2H) 7.28 (s, 1H) 7.32-7.45 (m, 6H) 7.53 (s, 1H).

MS ESI/APCI Multi nega: 201[M-Bn] − .

Reference Example 56-1

[4-[(4-Methoxyphenyl)methoxy]-3-methylsulfonylphenyl]methanol

(1) Sodium hydride (60% mineral oil dispersion, 811 mg) was added to a solution of 3-bromo-4-hydroxybenzoic acid (2.00 g) in N,N-dimethylformamide (18 mL) under ice cooling, and the mixture was stirred at room temperature for 30 minutes. At the same temperature, 4-methoxybenzyl chloride (2.61 mL) was slowly added thereto, and the resultant mixture was stirred at room temperature for 65 hours. A saturated aqueous solution of ammonium chloride was added thereto under ice cooling, the resultant mixture was extracted with ethyl acetate, and the extracted substance was sequentially washed with water and brine. After drying over anhydrous sodium sulfate, the drying agent was filtered off, and the filtrate was concentrated. The resultant was recrystallized from a diethyl ether:n-hexane mixed solution to give (4-methoxyphenyl)methyl 3-bromo-4-[(4-methoxyphenyl)methoxy]benzoate (3.10 g) as a colorless powder.

(2) In a test tube for a microwave reaction, sodium methanesulfinate (66.9 mg), a copper(I) trifluoromethanesulfonate benzene complex (33.0 mg), and N,N′-dimethylethylenediamine (14.1 μL) were added to a solution of the compound (100 mg) obtained in (1) above in dimethyl sulfoxide (2 mL), and the test tube was sealed. The mixture was stirred at 150° C. for 1 hour under microwave irradiation. After extraction with ethyl acetate, the extracted substance was sequentially washed with water and brine, and the organic layer was separated by a phase separator and then concentrated. The resultant was purified by preparative thin layer chromatography (n-hex