Title of the Invention: Pyridone Compounds

Technical Field

[0001]

The present Invention relates to a pharmaceutical, in particular, a pyridone compound which is useful as an agent for treating peripheral arterial occlusive disease

Background Art

[0002]

Peripheral arterial occlusive disease, caused by artery stenosis/occlusion due 1 arteriosclerosis and thrombus formation, thus leading the peripheral, in particular, the lower extremities into ischemia, is a disease with symptoms such as coldness, intermittent claudication, pain, ulcers/necrosis of the lower extremities, and the like. As for the diagnosis and treatment of the peripheral arterial occlusive disease, the guidelines are provided in "Trans Atlantic Inter-Society Consensus for Management of Peripheral Arterial Disease (TASC) II" (Eur. J. Vase. Endovasc. Surg, 2007, 33 (1), SI). For ti improvement of the symptoms of the lower extremities, it is important to improve the blood flow into the ischemic part, and treatment for promoting the resumption of the 1 circulation by a pharmaceutical or physical method is carried out. For a drug therapy; drugs having a vasodilating action or a platelet aggregation inhibiting action have bee used.

[0003]
PGE2 is known as one of the metabolites in an arachidonic acid cascade. Tl PGE2 exhibits various physiological activities such as a pain inducing and increasing action, a pro-inflammatory action, an anti-inflammatory action, an uterine contractile action, a digestive peristalsis promoting action, an awaking action, a gastric acid seen inhibiting action, a hypotensive action, a platelet aggregation inhibiting action, an angiogenic action, and the like. It has become clear that there are four subtypes of P receptors, EP1, EP2, EP3 and EP4, which have wide distributions in various tissues, activation of the EP1 receptor is believed to cause the increase in intracellular Ca2+. the EP3 receptor, there exist the receptors having different pathways for second-messenger systems. The activation of the EP2 and EP4 receptors is believed to cause the activa of an adenylate cyclase, and thus to increase the intracellular cAMP level (Phsiol. Rev 1999,79,1193).

[0004]

The EP4 receptor is associated with smooth muscle relaxation through the increase in cAMP (Br. J. Pharmacol., 2001,134, 313). Further, it is suggested that the platelet aggregation inhibiting action is exhibited via EP4 in that the expression of the EP4 receptors (Circulation, 2001,104, 1176) and the cAMP increasing action by PGE2 (Prostaglandins, 1996, 52, 175) are also demonstrated in the platelets. From this, the EP4 agonist is expected to be an agent for treating peripheral arterial occlusive disease, which exhibits a blood flow improving action. In addition to these, it is believed that it is useful as an agent for treating renal diseases, inflammatory diseases, bone diseases, gastric mucosal protection, glaucoma, and the like, from the viewpoint that lil'4 receptor is associated with increase in the renal blood flow (Am. J. Physiol. 279, l'755, 2000), inhibition of the mesanglum cell proliferation (Kid. Int., 1999, 56, 589), inhibition of the inflammatory cytokine production (Diochem. Pharmacol., 2001, 61,1153), osteogenesis (Proc. Natl. Acad. Scl. U.S.A., 2002,99,4580), secretion of the gastrointestinal mucus (Gastroenterology, 1999, 117,1352), intraocular pressure control (Patent Documents 1 to 5), and the like.

[0005]
As compounds having an EP4 receptor agonistic action, following Patent Documents 1 to 7 are reported.

In Patent Document 1, it has been reported that a compound represented by the following formula (A) has an EP4 receptor agonistic action, and is thus useful for the treatment of glaucoma, osteoporosis, and the like.

[Chem. 1]

(For the symbols in the formula, refer to the publication.)

[0006]

In Patent Document 2, it has been reported that a compound represented by the following formula (B) has an EP4 receptor agonistic action, and is thus useful for the treatment of glaucoma, osteoporosis, and the like.

[Chem. 2]

(For the symbols in the formula, refer to the publication.)

[0007]

In Patent Document 3, it has been reported that a compound represented by the following formula (C) has an EP4 receptor agonistic action, and is thus useful for the treatment of glaucoma, osteoporosis, and the like.

[Chem. 31

(For the symbols in the formula, refer to the publication.)

[0008]
In Patent Document 4, it has been reported that a compound represented by the following formula (D) has an EP4 receptor agonistic action, and is thus useful for the treatment of glaucoma, inflammatory bowel disease, and the like.

[Chem. 4]

(For the symbols in the formula, refer to the publication.)

[0009]
In Patent Document 5, it has been reported that a compound represented by the following formula (E) has an EP4 receptor agonistic action, and is thus useful for the treatment of glaucoma, ocular hypertension, and the like.

[Chem. 5]

(For the symbols in the formula, refer to the publication.)

[0010]

In Patent Document 6, it has been reported that a compound represented by the following formula (F) has an EP4 receptor agonistic action, and is thus useful for the treatment of osteoporosis, and other bone diseases.

[Chem. 6]

(For the symbols in the formula, refer to the publication.)

[0011]
In Patent Document 7, which is an application filed by the present Applicant(s) and published after the priority date of the present application, it is reported that a compound represented by the following formula (G) has tin UPR4 agonistic action and is useful against peripheral arterial occlusive disease.

[Chem. 7]

[0012]
Furthermore, the following compounds are reported as a pyridone derivative.

In Patent Document 8, it has been reported that a compound represented by the following formula (H) is useful as an agent for controlling plant disease. Also, it is reported that a compound represented by the following formula (II-1) is useful as a synthesis intermediate. However, there is no disclosure or suggestion of its usefulness as a pharmaceutical.

[Chem. 8]

(For the symbols in the formula, refer to the publication)

[0013]
In Patent Document 9, it has been reported that a wide range of the compound represented by the following formula (J) exhibit an LXR modulating notion, and is thus useful for the treatment of hypercholesterolemia, diabetes, and the like. However, there is no description of specific compounds included in the present invention. In addition, there is no description of the action on the EP4 receptor and the UNCHIIIIONM against peripheral arterial occlusive disease.

[Chem. 9]

(For the symbols in the formula, refer to the publication)

List of the Documents

Patent Documents

[0014]
[Patent Document 1] Pamphlet of International Publication No. WO2005/116010 [Patent Document 2] Pamphlet of International Publication No. WO2007/014454 [Patent Document 3] Pamphlet of International Publication No. WO2007/014462 [Patent Document 4| Pamphlet of International Publication No. WO2006/052630 [Patent Document 5) Pamphlet of International Publication No. WO2006/014207 [Patent Document 6] Pamphlet of International Publication No. WO2006/080323 [Patent Document 7] Pamphlet of International Publication No. WO2008/149965 [Patent Document 8] Specification of European Patent Application Publication No.

535980

[Patent Document 9]

Pamphlet of International Publication No. WO2003/059884
Summary of the Invention Problem that the Invention is to Solve

[0015]

It is an object of the present invention to provide a novel compound which is useful as a novel pharmaceutical having a selective agonistic action to a prostaglandin EP4 receptor, in particular, an agent for treating peripheral arterial occlusive disease.

Means for Solving the Problem
[0016]
The present inventors have conducted extensive studies on compounds having a selective agonistic action to a prostaglandin EP4 receptor, and as a result, have found that a novel pyridone derivative in which a group having an acidic group is substituted at the 1-position in the pyridone ring, the 6-position is bonded with various nitrogen-containing hetero ring groups or aryl via a linking part, and the linking part contains a nitrogen atom has an excellent RP4 receptor agonistic action, thereby completing the present invention.
That is, the present invention relates to a compound represented by the formula (I)
or a pharmaceutically acceptable salt thereof.

[Chem. 10]

[The symbols in the formula have the following meanings:

L1: lower alkylene, lower alkenylene, -(lower alkylene)-0-(lower alkylene)-, or -(lower alkylene)-S-(lower alkylene)-, in which lower alkylene and lower alkenylene in L1 may each be substituted,

L2: lower alkylene, lower alkenylene, -C(O)-, -(lower Hlkylene)-C(O)-, or -(lower
alkenylene)-C(O)-, in which lower alkylene and lower alkenylene in \} may each be
"^ substituted,
R1: R6 or a group represented by the following formulu (II):
[Chem. U|
Ring A: uryl or heteroaryl,
R6: -C02R°, -C(0)N(R°)2, -C(0)N(H)S(0)2-R8, -C(0)N(H)S(0)2N(R°)-R8, -N(R°)C(0)N(II)S(0)2-R8, or a group represented by any one of the following formulae (III) to (XIV):

R°: the same UH or different from each other, each reproNonling -II or lower alkyl,
R8: lower alkyl, halogeno-lower alkyl, -(lower alkylene)-()R°, or -(lower alkylene)-OC(0)R°,
J: a single bond or lower alkylene,
R7: the same us or different from each other, each representing lower alkyl, lower alkenyl, halogen, halogeno-lower alkyl, -OR0, -0-(halogeno-lower alkyl), -O-(cycloalkyl), -0-(lower alkylene)-OR°, -0-(lower alkylene)-aryl, -OC(0)R°, -N(R°)2, -(lower alkylene)-OH, -(lower alkylene)-OR°, -(lower alkylene)-N(R°)2, -(lower alkylene)-cycloalkyl, -(lower alkylene)-aryl, -CO-R0, -S(0)2-R°, -C02R°, -C(0)N(R°)2, aryl, or a hetero ring group, in which aryl and the hetero ring group in R7 may each be substituted,
n: an integer of 0 to 3,
R2: -N(R°)-1 ower alkyl or a group represented by uny one of (he following formulae (XV) to (XVII):
[Chem. 13]
Ring B: cycloulkyl, aryl, or a hetero ring,
Ring C: a nitrogen-containing saturated hetero ring,
7

Ring D: aryl or heteroaryl,
X: a single bond, lower alkylene, -C(O)-, -C(0)-(lower ulkylene)-, or -(lower alkylene)-0-,
R9: H, lower alkyl, -C(0)R°, or aryl, in which aryl in R9 may be substituted,
Y1 and Y2: the same as or different from each other, each representing a single bond, -[C(R10)(Rn)]s-, -[C(R10)(RU)]S-Q-, -Q-[C(R,0)(R'')],-, or -[C(R10)(Rn)]s-Q-[CCR^XR11)],-,
R10 and R11: the same as or different from each other, each representing H, lower alkyl, halogen, halogeno-lower alkyl, -OR0, -N(R°)2, -(lower alkylene)-OH, -(lower alkylene)-OR°, -(lower alkylene)-N(R°)2, or ahetero ring group, or R10 and R11 on the same carbon atom may be combined to form oxo,
Q:0,S(0)p,orN(R12),
R12: H, lower alkyl, -C(0)R°, or -S(0)2-(lower alkyl),
s and t: the same as or different from each other, each representing an integer of 1 to 4,
p: an integer of 0 to 2, and
R3, R4, and R5: the same as or different from each other, each representing H, halogen, -CN, lower alkyl, lower alkenyl, halogeno-lower alkyl, -OR0, -0-(halogeno-lower alkyl), -(lower alkylene)-OR°, -(lower alkylene)-N(R°)2, -C02R°, -C(0)N(R°)2, cycloalkyl, or aryl, in which aryl in R3, R4, and R5 may be substituted].
(In this connection, these symbols represent the same meanings below in the present specification unless otherwise particularly explained.)
[0017]
Further, the present invention also relates to a pluinmiceulicul composition
comprising the pyridone compound represented by the formula (I) or a pharmaceutical^
acceptable salt thereof, anil a pharmaceutical^ acceptable currier, in particular, a
-N pharmaceutical composition which is an EP4 agonist, or an agent for preventing or treating
peripheral arterial occlusive disease. That is, the present invention relates to;
(1) a pharmaceutical composition comprising the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier,
(2) the pharmaceutical composition as described in (1) which is an EP4 agonist,
(3) the pharmaceutical composition as described in (1) which is an agent for preventing or treating peripheral arterial occlusive disease,
(4) use of the compound represented by the formula (I) or a pliarmaceutically acceptable salt thereof for the manufacture of an agent for preventing or treating peripheral arterial occlusive disease, and

(5) a method for preventing or treating peripheral arterial occlusive disease, comprising administering to a patient an effective amount of the compound represented by the formula (I) or a pharmaceutical^ acceptable salt thereof.
Effects of the Invention
[0018]
Since the compound of the formula (I) has an EP4 receptor agonistic action, it is useful as an agent for preventing and/or treating peripheral arterial occlusive disease and the like.
Mode for Carrying Out the Invention
[0019]
Hereinbelow, the present invention will be described in detail.
In the present specification, the "lower alkyl" is linear or branched alkyl having 1 to 6 carbon atoms (which is hereinafter simply referred to as Ci.6) in a certain embodiment, and examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl group, and the like. In another embodiment, it is a CM alkyl group, in a further embodiment, it is methyl, ethyl, n-propyl, isopropyl, n-butyl, or sec-butyl group, and in a further embodiment, it is methyl, ethyl, or n-propyl.
[0020]
The "lower alkenyl" is preferably linear or branched C2.6 alkenyl, specifically, vinyl, allyl, isopropenyl, butenyl, pentenyl, 1-methylvinyl, l-methyl-2-propenyl, 1,3-butadienyl, 1,3-pentadienyl group, or the like. More preferably, it is C2-4 alkenyl, and particularly preferably, vinyl, allyl, or isopropenyl.
[0021]
The "lower alkylene" is linear or branched C1.6 alkylene in n certain embodiment,
s~\ and examples thereof include methylene, ethylene, trimethylene, tetrnmethylene,
pentamethylene, hexamethylene, propylene, methylmethylene, olhylothylene, 1,2-dimethylethylene, 1,1,2,2-tetramethylethylene group, and the like. In another embodiment, it is CM alkylene group, in a further embodiment, it is methylene, ethylene, trimethylene, tetramethylene, pentamethylene, or hexamelhylcno group, and in a further embodiment, it is methylene or ethylene.
[0022]
The "lower alkenylene" is linear or branched C2-6 alkenylene in a certain embodiment, and examples thereof include vinylene, ethylidene, propenylene, butenylene, pentenylene, hexenylene, 1,3-butadienylene, 1,3-pentadienylene group, and the like. In another embodiment, it is a C2-4 alkenylene group, and in a further embodiment, it is vinylene or a propenylene group.

[00231
The "cycloalkyl" is a C3.10 saturated hydrocarbon ring group In a certain embodiment, and may have a bridge. Specifically, it is cyelopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, uclnmaiUyl group, or the like. In another embodiment, it is C3.8 cycloalkyl group, and in a further embodiment, it is cyelopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group.
[0024]
The "halogen" means F, CI, Br, or I.
The "halogeno-lower alkyl" is C1-6 alkyl substituted with one or more halogen. In a certain embodiment, it is lower alkyl substituted with 1 to 5 halogen, in another embodiment, it is fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, or pentafluoroethyl, and in a further embodiment, trifluoromethyl.
[0025]
The "aryl" refers to a C6-14 monocyclic to tricyclic aromatic hydrocarbon ring group, in a certain embodiment, it is phenyl or naphthyl, and in another embodiment, it is phenyl.
[0026]
The "hetero ring" group is a ring group containing i) a monocyclic 3- to 8-
membered, in a certain embodiment, a monocyclic 5- to 7-membered hetero ring,
containing 1 to 4 hetero atoms selected from O, S and N, or ii) a bicyclic or tricyclic hetero
ring containing 1 to 5 hetero atoms selected from oxygen, sulfur, and nitrogen, which is
formed by the condensation of the monocyclic hetero ring with one or two rings selected
from the group consisting of a monocyclic hetero ring, a benzene ring, a C5.8 cycloalkyl
ring, and a C5.8 cycloalkenyl ring. The ring atom, sulfur or nitrogen, may be oxidized to
form an oxide or a dioxide. Specifically, it is aziridinyl, azetidinyl, pyrrolidinyl,
piperidinyl, azepanyl, piperazinyl, morpholinyl, thiomorpholinyl, oxetanyl,
"^ tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydrothiopyranyl, pyrrolyl,
imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, furyl, thienyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, indolyl, indazolyl, benzoimidazolyl, imidazopyridyl, quinolyl, quinazolyl, quinoxalinyl, naphthylidinyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, carbazolyl, dihydroindolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, quinuclidinyl group, or the like. In another embodiment, it is a 5- to 10-membered monocyclic or bicyclic holoro ring group, and in a further embodiment, it is pyrrolidyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyridyl, furyl, or thienyl group.
[0027]
The "heteroaryl" means a ring group containing i) a 5- lo 6-membered monocyclic heteroaryl containing 1 to 4 hetero atoms selected from O, S, and N, or ii) a bicyclic 8- to

10-membered hetero ring and a tricyclic 11- to 14-membered hetero ring, each containing 1 to 5 hetero atoms selected from 0, S, and N, which are each formed by the condensation of the monocyclic heleroaryl with one or two rings selected from the group consisting of a monocyclic heteroaryl find a benzene ring; among the above-dcHcribed "hetero ring" groups. The ring atom, S or N, may be oxidized to form an oxide. Specifically, the it is pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrlmidinyl, pyrazinyl, furyl, thienyl, oxazolyl, oxtidiazolyl, thiazolyl, thiadiazolyl, indolyl, indazolyl, benzoimidazolyl, imidazopyridyl, quinolyl, quinazolyl, quinoxalinyl, naphlhylldlnyl, beiv/.ol\irnnyl, benzothienyl, benzoxazolyl, benzothiazolyl, or carbazolyl group, and In another embodiment, it is pyridyl, furyl, or thienyl group.
[0028]
The "nitrogen-containing saturated hetero ring" group means a saturated hetero ring group containing at least one nitrogen atom, among the above-described "hetero ring" groups, and in a certain embodiment, it is a monocyclic 5- to 7-membered nitrogen-containing saturated hetero ring. Specifically, it is aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, piperazinyl, morpholinyl, or thiomorpholinyl group, and in another embodiment, it is pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl group.
[0029]
The "which may be substituted" refers to "which is unsubstituted" or "which is substituted with 1 to 5 substituents which are the same as or different from each other". The "which is substituted" refers to "which is substituted with 1 to 5 substituents which are the same as or different from each other". Further, if it has a plurality of substituents, the substituents may be the same as or different from each other.
[0030]
Examples of the substituents in the "lower alkylene" and the "lower alkenylene", which may each be substituted, in L1; and the "lower alkylene" and the "lower alkenylene", which may each be substituted, in Lla include halogen or -OR0.
Examples of the substituents in the "lower alkylene" and the "lower alkenylene", which may each be substituted, in L2; and the "lower alkylene" and the "lower alkenylene", which may each be substituted, in L2a include halogen or -OR0.
Examples of the substituents in the "aryl" which may be substituted in R7; the "aryl" which may be substituted in R7a; the "aryl" which may be substituted in R9; and the "aryl" which may be substituted in R3, R4, and R5 include a group selected from the group consisting of lower alkyl, halogen, halogeno-lower alkyl, -OR0, and -0-(halogeno-lower alkyl).
Examples of the substituents acceptable in the "hetero ring" group which may be substituted in R7; and the "hetero ring" group which may bo NiibNtitiilod in R7a include a

group selected from the group consisting of lower alkyl, halogen, halogeno-lower alkyl, -OR0, -O-halogeno-lower alkyl, and oxo.
[0031]
The "selective" in the "the selective agonist to the EP4 receptor" means that the agonistic actions shown in Test Examples 2 and 3 as described below are higher in the subtype EP4 of the prostaglandin receptor than the subtypes EP1, EP2, and EP3. The difference in the agonistic actions is preferably 5-fold or more, more preferably 10-fold or more, and even more preferably 100-fold or more.
[0032]
Certain embodiments of the compound of the present Invention will be described below.
(a) The compound, in which L1 is lower alkylene which may be substituted, in another embodiment, lower alkylene, in a further embodiment, linear (^.4 nlkylene, and in a further embodiment, ethylene.
(b) The compound, in which L2 is lower alkylene or -(lower alkylene)-C(O)-, in another embodiment, lower alkylene, and in a further embodiment, methylene.
(c) The compound, in which R1 is -CO2R0, in another embodiment, a group represented by the formula (II), in a further embodiment, phenyl which is substituted with a group selected from the group consisting of-CO2R0, and the groups represented by the following formula (III), the following formula (IX), the following formula (X), and the following formula (XIV):
[Chem. 14]
and which may be further substituted with 1 to 3 lower alkyl or halogen, and in a further embodiment, phenyl which may be substituted with -CO2H.
(d) The compound, in which Ring A is aryl, and in another embodiment, phenyl.
(e) The compound, in which R6 is -CO2R0, in another embodiment, -C02H, in a further embodiment, a group represented by the following formula (III), the following formula (IX), the following formula (X), or the following formula (XIV):
[Chem. 15]

(f) The compound, in which J is a single bond.
(g) The compound, in which R7 is halogen, lower alkyl, halogeno-lower alkyl, -OR0, or -O-halogeno-lower alkyl.
(h) The compound, in which R2 is -N(lower alkyl>2 or a group represented by the formula (XV) above; in another embodiment, -N(lower alkyl>2, -N(R°)-cycloalkyl, -N(R0)-(aryl which may be substituted with 1 to 3 groups selected from R7), or -N(R°)-(lower alkylene)-(aryl which may be substituted with 1 to 3 groups selected from R7); in a further embodiment, -N(lower alkyl^, -N(R°)-cycloalkyl, -N(R°)-(aryl which may be substituted with 1 to 3 groups selected from the group consisting of halogen, lower alkyl, halogeno-lower alkyl, -OR0, unci -O-halogeno-lower alkyl), or -N(R°)-(lowcr iilkylene)-(aryl which may be substituted with 1 to 3 groups selected from the group consisting of halogen, lower alkyl, halogeno-lower alkyl, -OR0, and -O-halogeno-lower alkyl); in u further embodiment, -N(R°)-(phenyl which may be substituted with 1 to 3 groupN selected IVom R7), and in a further embodiment, -N(R°)-(phenyl which may be substituted with 1 to 3 groups selected from the group consisting of halogen, lower alkyl, halogeno-lower alkyl, -OR0, and -O-halogeno-lower alkyl).
(i) The compound, in which R2 is a group represented by the formula (XVI) above; in another embodiment, a group in which Ring C of the formula (XVI) above is a monocyclic 5- to 7-membered nitrogen-containing saturated hetero ring; in a further embodiment, a group in which Ring C of the formula (XVI) above is a monocyclic 5- to 7-membered nitrogen-containing saturated hetero ring, and R7 is halogen, lower alkyl, lower alkenyl, halogeno-lower alkyl, -OR0, -O-halogeno-lower alkyl, or -(lower alkylene)-cycloalkyl; in a further embodiment, a group in which Ring C of the formula (XVI) above is pyrrolidin-1-yl, and in a further embodiment, Ring C of the formula (XVI) above is pyrrolidin-1-yl, and R7 is halogen, lower alkyl, lower alkenyl, halogeno-lower alkyl, -OR0, -O-halogeno-lower alkyl, or -(lower alkylene)-cycloalkyl.
(j) The compound, in which R2 is a group represented by the formula (XVII) above, in another embodiment, 2,3-dihydro-lH-indol-l-yl which may be substituted with 1 to 3 groups selected from R7 at the 4- to 7-positions; in a further embodiment, 2,3-dihydro-lH-indol-1-yl which may be substituted with 1 to 3 groups selected from the group consisting of halogen, lower alkyl, lower alkenyl, halogeno-lower alkyl, -OR0, and -O-halogeno-lower alkyl at the 4- to 7-positions.
(k) The compound, in which Ring B is aryl, and in another embodiment, phenyl.

(1) The compound, in which Ring C is a monocyclic 5- to 7-membered nitrogen-containing saturated hetero ring, and in another embodiment, pyrrolidin-1-yl.
(m) The compound, in which the ring formed by combination of Ring D, Y1, and Y2 with a nitrogen atom is 2,3-dihydro-lH-indol-l-yl.
(n) The compound, in which X is a single bond or lower alkylene, and in another embodiment, a single bond.
(0) The compound, in which R3 is halogen, lower nlkyl, or uydoalkyl, and in
another embodiment, CI, methyl, ethyl, or cyclopropyl.
(p) The compound, in which R4 is H.
(q) The compound, in which R5 is H, halogen, or lower alkyl, and in another embodiment, methyl or CI.
(r) The compound formed from the combinations of two or more embodiments of (a) to (q) above.
[0033]
Further, other embodiments of the compound represented by the formula (I) are shown below.
(1) The compound of the formula (I), in which R4 is -II.
(2) The compound as described in (1), in which R5 IN -I I, halogen, or lower alkyl.
(3) The compound as described in (2), in which R3 Is halogen, lower alkyl, or cycloalkyl.
(4) The compound as described in (3), in which L1 is lower alkylene.
(5) The compound as described in (4), in which L2 is lower alkylene.
(6) The compound as described in (5), in which R1 Is -CO2R0; or phenyl which is substituted with u group selected from the group consisting of -CO2R0 and the groups represented by the following formula (III), the following formula (IX), the following formula (X), and the following formula (XIV):
[Chem. 16]
and which may be further substituted with 1 to 3 lower alkyl or halogen.
(7) The compound as described in (6), in which R2 is -N(lower alkyl)2j -N(R°)-cycloalkyl; -N(R°)-(aryl which may be substituted with 1 to 3 groups selected from the group consisting of halogen, lower alkyl, halogeno-lower alkyl, -OR0, and -O-halogeno-lower alkyl); or -N(R°)-(lower alkylene)-(aryl which may be substituted with 1 to 3 groups

selected from the group consisting of halogen, lower alkyl, halogeno-lower alkyl, -OR , and -O-halogeno-lower alkyl).
(8) The compound as described in (6), in which R2 is a group described by the following formula (XVI):
[Chem. 17]
Ring C is a monocyclic 5- to 7-membered nitrogen-containing Ntitumtcil hetero ring, and R is halogen, lower alkyl, lower alkenyl, halogeno-lower alkyl, -OR0, -()-halogeno-lower alkyl, or -(lower alkylcne)-cycloalkyl.
(9) The compound as described in (6), in which R2 IN 2,3-dihydro-lH-indol-l-yl in
which 1 to 3 groups selected from the group consisting of halogen, lower alkyl, lower
alkenyl, halogeno-lower alkyl, -OR0, and -O-halogeno-lower alkyl may be substituted at
the 4- to 7-positions.
(10) The compound of the formula (I), which is selected from the group consisting
of:
4-{2-[6-{[(2S)-2-butylpyrrolidin-l-yl]methyl}-3,5-dichloro-2-oxopyridin-l(2H)-yl]ethyl}benzoic acid,
4-{2-[3,5-dichloro-6-{[(2R)-2-isobutylpyrrolidin-l-yl|melhyl}-2-oxopyridin-l(2H)-yl]ethyl}benzoic acid,
4-{2-[3,5-diclil()ro-2-oxo-6-{[(2S)-2-propylpyrroli(lln-l-yl|niclhyl}pyridin-l(2H)-yl]ethyl}benzoic ucid,
3,5-dichloro-6-{l(2S)-2-propylpyrrolidin-1-yl]methyI} -1 - {2-| 4-( 1 M-tetrazol-5-yl)phenyl]ethyl}pyritlln-2(l Il)-one,
3,5-dichloro-l-{2-l4-(5-oxo-4,5-dihydro-l,3,4-oxudlH/.ol-2-yl)phenyl]ethyl}-6-{[(2S)-2-propylpyrrolltlln-t-yl]methyl}pyridin-2(lH)-ono,
4-{2-[3,5-dichloro-6-{[cyclopentyl(methyl)amin()Jinelliyl}-2-()Xopyridln-l(2H)-yl]ethyl}benzoic ucid,
3,5-dichloro-1 -{2-[4-(5-oxo-4,5-dihydro-l ,3,4-oxadiazol-2-yl)phenyl]ethyl}-6-{[(2R)-2-isobutylpyrrolidin-l-yl]methyl}pyridin-2(lH)-one,
4-{2-[5-cyclopropyl-6-{[(2R)-2-isobutylpyrrolidin-l-yl1methyl}-3-methyl-2-oxopyridin-1 (2H)-yl]ethyl} benzoic acid,
4-{2-[6-{[(2R)-2-isobutylpyrrolidin-l-yl]methyl}-3,5-dimethyl-2-oxopyridin-l(2H)-yl]ethyl} benzoic acid,

1 - {2-[4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl]ethyl} -6- {[(2R)-2-isobutylpyrrolidin-l-yl]methyl}-3,5-dimethylpyridin-2(lH)-one,
5-cyclopropyl-l -{2-[4-(5-oxo-4,5-dihydro-l ,3,4-oxadiazol-2-yl)phenyl]ethyl}-6-{[(2R)-2-isobutylpyrrolidin-1 -yl]methyl} -3-methylpyridin-2( 111)-one,
4- {2-[3,5-dichloro-2-oxo-6-({ [3-(trifluoromethoxy)phenyl]amino} methyl)pyridin-l(2H)-yl]ethyl} benzoic acid,
4-{2-[3-chloro-5-cyclopropyl-2-oxo-6-{[(2S)-2-propylpyrrolidin-l-yl]methyl}pyridin-1 (2H)-yl]ethyl}benzoic acid,
4-{2-[3-chloro-5-cyclopropyl-6-{[(2R)-2-isobutylpyrrolidin-l-yl]methyl}-2-oxopyridin-1 (2H)-yl]ethyl} benzoic acid,
4- {2-[3-chloro-5-ethyl-6- {[(2R)-2-isobutylpyrrolidin-1 -yl]methyl}-2-oxopyridin-1 (2H)-yl]ethyl} benzoic acid,
4-{2-[3,5-dichloro-6-{[methyl(3-methylphenyl)amino]methyl}-2-oxopyridin-l(2H)-yl]ethyl}benzoic acid,
4-{2-[3,5-dichl()ro-6.({methyl[3-(trifluoromethy))phonyl|iiinlno}inethyl)-2-oxopyridin-1 (2H)-yl]ethyl }benzoic acid,
4-{2-[3,5-dichloro-6-{[(3-chlorophenyl)(methyl)amino|molhyl}-2-oxopyridin-l(2H)-yl]ethyl}benzoic acid,
4-{2-[3-chloro-5-cyclopropyl-6-{[methyl(3-methylphenyl)amino]methyl}-2-oxopyridin-1 (2H)-yl] ethyl} benzoic acid,
4-(2-{3,5-dichloro-6-[(6-ethyl-2,3-dihydro-lH-indol-l-yl)methyl]-2-oxopyridin-l(2H)-yl}ethyl)benzoic acid,
4-{2-[3,5-dichloro-2-oxo-6-{[6-(trifluoromethoxy)-2,3-dihydro-lH-indol-l-yl]methyl}pyridin-l (2H)-yl]ethyl}benzoic acid,
4-(2-{3,5-dichloro-6-[(6-ethoxy-2,3-dihydro-lH-in(lol-l-yl)methyll-2-oxopyridin-l(2H)-yl}ethyl)benzoic acid,
4-(2-{3,5-dichloro-6-[(6-fluoro-2,3-dihydro-lH-indol-l-yl)mclhyl]-2-oxopyridin-l(2H)-yl}ethyl)benzoic acid,
4-(2-{3,5-diclil()ro-6-f(6-fluoro-7-methyl-2,3-dihy(lro-lll-iiulol-l-yl)methyl]-2-oxopyridin-1 (2H)-yl}othyl)benzoic acid,
4-(2-{3,5-diclil()ro-6-[(7-ethyl-2,3-dihydro-lII-indol-l-yl)inelhyl]-2-oxopyridin-l(2H)-yl}ethyl)benzolc ncid, and
4-(2-{3,5-(licliloro-6-f(7-methyl-2,3-dihydro-U I-lntlol-1 -yl)methyl|-2-oxopyridin-l(2H)-yl}ethyl)ben/.olc ucid,
or a pharmaceutically acceptable salt thereof.
[0034]
(11) A compound of the formula (Ia) or a pharmaceutical^ acceptable salt thereof:
rChem. 181

[the symbols in the formula represent the following meanings:
Lla: lower alkylene or lower alkenylene, which may each be substituted,
L2a: lower alkylene, lower alkenylene, -C(O)-, -(lower alkylene)-C(O)-, or -(lower
alkenylene)-C(O)-, in which lower alkylene and lower alkenylene in L2* may each be
substituted,
Rla: R6a or a group represented by the following formula (II8): [Chem. 19]
Ring A: aryl or heteroaryl,
R6a: -C02R°, -C(0)N(H)S(0)2-R8a, -C(0)N(H)S(0)2N(R°)-R8a, -N(R°)C(0)N(H)S(0)2-R8a, or a group represented by tiny one ol'llie following formulae (III) to (XIII):
[Chem. 20J
R°: the same us or different from each other, each reprcNcntlng II or lower alkyl, R8a: lower alkyl, halogeno-lower alkyl, or -(lower ulkylono)-()R°, J: a single bond or lower alkylene,
R7a: the same UN or different from each other, etich representing lower alkyl, halogen, halogeno-lower alkyl, -OR0, -0-(halogeno-lower ulkyl), -O-(cycloalkyl), -O-

(lower alkylene)-OR°, -N(R°)2, -(lower alkylene)-OH, -(lower alkylene)-OR°, -(lower alkylene)-N(R°)2, -CO-R0, -S(0)2-R°, -C02R°, -C(0)N(R°)2, aryl, or a hetero ring group, in which aryl and the hetero ring group in R7a may be substituted,
n: an integer of 0 to 3,
R2a: a group represented by any one of the following formulae (XV") to (XVII8):
[Chem. 21]
Ring B: cycloalkyl, aryl, or a hetero ring,
Ring C: a nitrogen-containing saturated hetero ring,
•^ Ring D: aryl or heteroaryl,
X: a single bond, lower alkylene, -C(O)-, -C(0)-(lower alkylene)-, or -(lower alkylene)-0-,
R9: H, lower alkyl, -C(0)R°, or aryl, in which aryl in R9 may be substituted,
Y and Y : the same as or different from each other, each representing a single bond, -[CCR,0XRn)]r. -[C(R10)(Rn)]s-Q-, -Q-[C(R10)(Rn)]r, or -[C(R,0)(Rn)]s-Q-[C(R10)(R11)]r,
R10 and R1': the same as or different from each other, each representing H, lower alkyl, halogen, halogeno-lower alkyl, -OR0, -N(R°)2, -(lower alkylene)-OH, -(lower alkylene)-OR°, -(lower alkylene)-N(R°)2, or a hetero ring group, or R1" and R11 on the same carbon atom may be combined to form oxo,
Q:0,S(0)p,orN(R12),
R12: H, lower alkyl, -C(0)R°, or -S(0)2-(lower alkyl).
s and t: the same as or different from each other, ouch roprenonllng an integer of 1 to 4,
p: an integer of 0 to 2, and
R3a, R4a, and R5a: the same as or different from each other, each representing H, halogen, -CN, lower alkyl, halogeno-lower alkyl, -OR0, -0-(halogeno-lower alkyl), -C02R°, -C(0)N(R°)2, or cycloalkyl].
[0035]
The compound of the formula (I) may in some cases exist in the form of other tautomers or geometrical isomers, depending on the kinds of the Nubatiluents. In the present specification, the compound may be described in only one form of the isomers, but

the present invention Includes such isomers, isolated forms of the Isomers, or a mixture thereof.
Furthermore, the compound of the formula (I) may have asymmetric carbon atoms or axial asymmetries in some cases, and correspondingly, it may exist in the form of optical isomers such as an (R)-form, an (S)-form, and the like. The present invention includes all of the mixture and the isolated form of these optical isomers.
In addition, the pharmaceutically acceptable prodrugs of the compound of the
formula (I) are also included in the present invention. The pharmaceutically acceptable
prodrug refers to a compound having a group which can be converted into an amino group,
OH, CO2H, or the like, of the present invention, by solvolysis or under a physiological
condition. Examples of the group for forming a prodrug include those as described in
Prog. Med., 5,2157-2161 (1985) or "Pharmaceutical Research and Development"
(Hirokawa Publishing Company, 1990), vol. 7, Drug Design, 163-198.
v [0036]
Furthermore, the compound of the formula (I) may form an acid addition salt or salt with a base, depending on the kind of the substituents, and the salt is included in the present invention, as long as it is a pharmaceutically acceptable salt. Specifically, examples thereof include acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, and with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, rumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, aspartic acid, glutamic acid, and the like, and salts with inorganic bases such as sodium, potassium, magnesium, calcium, aluminum, and the like, and organic bases such as methylamine, ethylamine, ethanolamine, lysine, ornithine, and the like, ammonium salts, and others.
Furthermore, the present invention also includes various hydrates or solvates, and
*""* polymorphic crystal substances of the compound of the formula (I) and a pharmaceutically
acceptable salt thereof. Furthermore, the present invention also includes the compounds labeled with various radioactive or non-radioactive isotopes.
[0037] (Production Processes)
The compound of the formula (I) and a pharmaceutical^ acceptable salt thereof can be prepared by applying various known synthesis methods, usiiiu the characteristics based on their basic skeletons or the kinds of the substituents. At this time, depending on the types of the functional groups, it is in some cases effective from the viewpoint of the preparation techniques to substitute the functional group with an appropriate protecting group (a group which is capable of being easily converted into the functional group), during the steps from starting materials to intermediates. Examples of such a functional

group include an amino group, a hydroxyl group, a carboxyl group, and the like, and examples of the protecting group thereof include those as described in "Protective Groups in Organic Synthesis (4th edition, 2007)", edited by Greene anil Wuts, and the like, which may be appropriately selected and used depending on the reaction conditions. In these methods, a desired compound can be obtained by introducing the protecting group to carry out the reaction, and then, if desired, removing the protecting group,
In addition, the prodrug of the compound of the formula (I) can be prepared by introducing a speci fie group during the steps from starting materials to intermediates, in the same manner as for the above protecting groups, or by carrying out the reaction using the compound of the formula (I) obtained. The reaction can be carried out by applying a method known by a person skilled in the art, such as general esterification, amidation, dehydration, and the like.
Hereinbelow, the representative production processes for the compound of the formula (I) will be explained. Each of the production processes may also be carried out with reference to the References appended in the present description. Further, the production processes of the present invention are not limited to the examples as shown below.
[0038]
(Production Process 1)
[Chem. 22]
(In the formula, Lg1 means a leaving group, for example Br. Further, R00 means lower alkylene. The same shall apply hereinafter.)
The compound (I-a) of the present invention can be prepared by the reaction of a compound (1) with a compound (2). Herein, examples of Lg1 include halogen, a methanesulfonyloxy group, a p-toluenesulfonlyoxy group, and the like.
In this reaction, the compound (1) and the compound (2) are used in an equivalent amount or in an excessive amount of either thereof, and the mixture thereof is stirred from under cooling to under heating and reflux, preferably at 0°C to 80°C, usually for 0.1 hour to 5 days, in a solvent which is inert to the reaction or without n Nolvent. Examples of the solvent as used herein are not particularly limited, but include iiiomiillc hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, letrahydrofuran

(THF), dioxane, dimethoxyethane (DME), and the like, halogenated hydrocarbons such as dichloromethane (DCM), 1,2-dichloroethane (DCE), chloroform, unri the like, N,N-dimethylformamide (DM1'), dimethylsulfoxide (DMSO), N-methyl-2-pyrrolidinone (NMP), ethyl acetate, acetonitrile, acetone, methylethylketone, and a mixture thereof. It may be advantageous in some cases for the smooth progreNN of Iho reliction to carry out the reaction in the presence of an organic base such as triethyliunlnc (THA), N,N-diisopropylethyhimine (DIPHA), or N-methylmorpholine (NMM), anil the like, or an inorganic base such us potassium carbonate, sodium carbonnlc, potasNlum hydroxide, and the like. In addition, il may be advantageous in some cases to curry out the reaction in the presence of sodium Iodide or the like, if necessary.
Furthermore, the present reaction can also be curried out UNIIIK u microwave device.
[0039]
(Production Process 2)
[Chem. 23]
The compound (I-b) of the present invention can be prepared by the reaction of a compound (3) with the compound (2).
In the present reaction, the compound (3) and the compound (2) are used in an equivalent amount or in an excessive amount of either thereof, and the mixture thereof is stirred from under cooling to under heating, preferably at -20°C to 60°C, usually for 0.1 hour to 5 days in a solvent which is inert to the reaction in the presence of a condensing agent. Examples of the solvent as used herein are not particularly limited, but include aromatic hydrocarbons such as benzene, toluene, xylene, and the like, halogenated hydrocarbons such as DCM, DCE, chloroform, and the like, ethers such as diethyl ether, THF, dioxane, DME, and the like, DMF, DMSO, ethyl acetate, acetonitrile, or water, and a mixture thereof. Examples of the condensing agent include l-(3-dimethylaminopropyl)-3-ethylcarbodiimide (WSC), dicyclohexylcarbodiimide (DCC), l,l'-carbonyldiimidazole (CDI), diphenylphosphoryl azide (DPPA), and phosphorous oxychloride, but are not limited to these. It may be preferable in some cases for the reaction to use an additive (for example, 1-hydroxybenzotriazole (HOBt)). It may be advantageous in some cases for the smooth progress of the reaction to carry out the reaction in the presence of an

organic base such as TEA, DIPEA, NMM, and the like, or mi Inorganic base such as potassium carbonate, sodium carbonate, potassium hydroxide, und the like.
Furthermore, a method in which the compound (3) is modified into a reactive derivative thereof, and then reacted with the compound (2) can also be used. Examples of the reactive derivative of the compound (3) include acid halides obtained by the reaction with a halogenating agent such as phosphorus oxychloride, thionyl chloride, and the like, mixed acid anhydrides obtained by the reaction with isobutyl ehlorof'ormute or the like, various active esters obtained by the condensation with CD1, IIOBt, or the like, and others. The reaction of such a reactive derivative with the compound (2) can be carried out from under cooling to under heuting, preferably at -20°C to 60°C In u NOIVOIU which is inert to the reaction, such as halogenated hydrocarbons, aromatic hydrocarbons, ethers, and the like.
Furthermore, the present reaction can also be carried out using a microwave
^ device.
[0040)
(Production Process 3)
[Chem. 24]
(In the formula, R means a single bond or [Chem. 25]
9
in which * means a bond to L1. The same shall apply hereinafter.)
The compound (I-c) of the present invention can be prepared by tetrazolylation of a compound (4).
The present reaction can be carried out from at room temperature to under heating, using the compound (4) and an azide compound such as sodium azide, ammonium azide, tri-n-butyltin azide, and the like in an equivalent amount or in an excessive amount of either thereof, in a solvent such as ethers, aromatic hydrocarbons, DMF, and the like. According to the compounds, it may be advantageous in some cases for the progress of the

reaction to carry out the reaction in the presence of ammonium chloride, trlmethylamine hydrochloride, or the like.
[0041]
(Production Process 4)
[Chem. 26]
The compound (I-d) of the present invention can be prepuretl by reacting a compound (5) with a carbonyl compound such as CDI, phosgene, ethyl chloroformate, and the like.
The present reaction can be carried out from at room loinperiilure to under heating, using the compound (5) and the carbonyl compound in an equivalent amount or in an excessive amount of either thereof, in a solvent such as etherN, uromulic hydrocarbons, halogenated hydrocarbons, DMF, and the like. According to the compounds, it may be advantageous in some cases for the progress of the reaction lo curry out the reaction in the presence of an orgunlc base such as triethylamine, N,N-diiNopro|»ylothylHmlne, pyridine, l,8-diazabicyclo[5,4,0|undee-7-ene, and the like, or an inorganic base such as sodium carbonate, potassium carbonate, and the like.
[0042]
(Production Process 5)
[Chem. 27]
The compound (I-e) of the present invention can be prepared by reacting the compound (5) with a thiocarbonyl compound such as l,l'-carbonothiobis(lH-imidazole) and the like.
The present reaction can be carried out from at room temperature to under heating, using the compound (5) and the thiocarbonyl compound in an equivalent amount or in an

excessive amount of either thereof, in a solvent such as ethers, aromatic hydrocarbons, halogenated hydrocarbons, DMF, and the like. According to the compounds, it may be advantageous in some cases for the progress of the reaction to carry out the reaction in the presence of an organic base such as triethylamine, N,N-diisopropylethylamine, pyridine, l,8-diazabicyclo[5,4,0]undec-7-ene, and the like, or an inorganic base such as sodium carbonate, potassium carbonate, and the like. [0043]
(Production Process 6) [Chem. 28]


L1-RX^N
N'

The compound (I-f) of the present invention can be prepared by reacting the compound (5) with thionyl chloride.
65
The present reaction can be carried out from at room temperature to under heating, using the compound (5) and thionyl chloride in an equivalent amount or in an excessive amount of either thereof, in a solvent such as ethers, aromatic hydrocarbons, halogenated hydrocarbons, DMF, and the like. According to the compounds, It may be advantageous in some cases for the progress of the reaction to carry out the reliction in the presence of an organic base such as triolhylumine, N,N-diisopropylethylaminc, pyridine, 1,8-diazabicyclo|5,4,OJundcc-7-cne, and the like, or an inorganic IHINO such as sodium carbonate, potassium carbonate, and the like.
[0044]
(Production Process 7)
[Chem. 29]
R4>Sf^L2-R2 H R4/V\2-R2
(6) (I-g)
24

The compound (I-g) of the present invention can be prepared by reacting a compound (6) with a carbonyl compound such as CDI, phosgene, ethyl chloroformate, and the like.
The present reaction can be carried out from at room temperature to under heating, using the compound (6) and the carbonyl compound in an equivalent amount or in an excessive amount of either thereof, in a solvent such as ethers, aromatic hydrocarbons, halogenated hydrocarbons, DMF, and the like. According to the compounds, it may be advantageous in some cases for the progress of the reaction to carry out the reaction in the presence of an organic base such as triethylamine, N,N-diisopropylethylamine, pyridine, l,8-diazabicyclo[5,4,0]undec-7-ene, and the like, or an inorganic base such as sodium carbonate, potassium carbonate, and the like.
[0045]
References regarding the reactions of Production I'rocoHHCH I to 7 include the following.
"Organic Functional Oroup Preparations", written by N. It. Niuuller and W. Karo, 2nd Edition, Vol. 1, Acuclemic Press Inc., 1991, and "Jikken Kdffaku Koza (Courses in Experimental Chemistry) (5th Edition)", edited by The Chemical Society of Japan, Vol. 14 (2005) (Maruzen)
[0046]
Moreover, several compounds that can be obtained from the formula (I) can be prepared from the compound obtained as described above, by any combination of known processes that can be usually employed by a person skilled in the art, such as alkylation, amidation, a substitution reaction, oxidation, reduction, hytlrolynlH, imtl the like.
For the compounds of the formulae (I-a) and (I-b), obtained by Production Processes 1 to 2 above, when R1 is a carboxylic ester, the compound of the formula (I) in which R1 is -CO2II can be prepared by carrying out a hydrolyNlH reaction.
[0047]
The starting muterials used in the preparation of the compound of the formula (I) can be prepared, for oxumple, using the methods for starting material Nynthesis below, the methods described in Production Examples below, known methods, or methods apparent to a person skilled in the art, or modified methods thereof.
[0048]
(Starting Material Synthesis 1)
[Chem. 30]

\u w \u
(In the formula, Lg3 represents a leaving group).
A starting compound (1) can be prepared by the introduction of a leaving group, Lg1, for example, by bromination, to a compound (9) obtained by an N-alkylation reaction of a compound (7) with a compound (8).
The N-alkylation reaction can be carried out, for example, in the same manner as in Production Process 1.
The bromination can be carried out, for example, by the reaction with N-bromosuccinimide in the presence of a radical initiator such as 2,2'-azobis(isobutyronitrile), benzoyl peroxide, and the like, or by the reaction with N-bromosuccinimide or bromine from at room temperature to under heating in a solvent such as acetic acid, DMF, and the like,.
[0049]
(Starting Material Synthesis 2)
[Chem. 31]
^^ A starting compound (3) can be prepared by converting n compound (10) to a
compound (11), and further, carrying out an oxidation reuclion.
The conversion of the compound (10) to the compound (11) can be carried out, for example, by carrying out oxidation using trimethylamine-N-oxhle, or by carrying out substitution with an ncetoxy group, hydrolysis, and then oxidation.
[0050]
(Starting Material Synthesis 3)
[Chem. 321

(In the formula, Lg4 represents a leaving group such as halogen, a trifluoromethanesulfonyloxy group, and the like, and Rz represents -H or lower alkyl, or two Rzs are combined with each other to represent lower alkylene. The same shall apply hereinafter.)
A compound (14) can be prepared by carrying out a coupling reaction of a compound (12) with a compound (13) in the presence of a base and a palladium catalyst. As the base, for example, sodium carbonate, potassium carbonate, cesium carbonate, or tripotassium phosphate is suitably used, and as the palladium catalyst, for example, tetrakistriphenylphosphine palladium or a catalyst prepared from palladium acetate with tricyclohexylphosphine or dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine is suitably used.
[0051]
(Starting Material Synthesis 4)
[Chem. 33]
(In the formula, Hal represents halogen. The same shull apply hereinafter.)
A compound (16) can be prepared by halogenation of a compound (15).
As the halogenating agent, N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, trichloroisocyanuric acid, bromine, iodine, or the like can be used.
[0052]
Furthermore, the compound (4) can be prepared in (ho mimo munner as in Production Processes 1 and 2 above.
The compound (5) can be prepared by the reaction of the compound (4) with hydroxyamine.
The compound (6) cnn be prepared by amidation ofllio compound of the present invention having u corresponding carboxylic acid with hydrazine.

[0053]
The compound of the formula (I) is isolated and purified as its free compound, pharmaceutically acceptable salts, hydrates, solvates, or polymorphic crystal substances thereof. The pharmaceutically acceptable salt of the compountl of the formula (I) can also be prepared in accordance with a conventional method for a salt formation reaction.
Isolation and purification are carried out by employing general chemical operations such as extraction, fractional crystallization, various types of fractional chromatography, and the like.
Various isomers can be separated by selecting an appropriate starting compound or by making use of the difference in the physicochemical properties between isomers. For example, the optical isomer can be lead into a stereochemically pure isomer by means of general optical resolution methods (for example, fractional crystallization for inducing diastereomer salts with optically active bases or acids, chromatography using a chiral column, etc., and the like). In addition, the isomers can also be prepared from an appropriate optically active starting compound.
[0054]
The pharmacological activity of the compound of the formula (I) was confirmed by the following test. Test Example 1 Evaluation Test on EP4 Receptor Affinity in Rat
(1) Cell culture and transfection
A rat EP4 receptor cDNA was subcloned into an expression vector (pCDNA3.1-V5-His-topo, manufactured by Invitrogen Corporation) to prepare a rat EP4 expression vector. HEK293 cells were cultured in a collagen type I-treated 15 cm dish (manufactured by Asahi Techno Glass Co,. Ltd.) to a confluence of 70%. An Opti-MEM culture medium at 1.2 mL/dish and a transfection reagent (Lipofectamine 2000, manufactured by Invitrogen Corporation) at 60 uL/dish were mixed, followed by being left to stand at room temperature for 5 minutes. Then, the rut Kl'4 rocuplor expression vector at 15 ng/dish was added thereto, followed by being left to NIIIIUI ill room temperature for 30 minutes. The liquid mixture of the transfection reagent WHH niklcd Into the dish, followed by culturing for 20 to 24 hours. The cell culture was carried out in ii (!(.)2 incubator (37°C, 5% C02).
(2) Preparation of Membrane Fraction
The culture medium was removed by suction, 10ml. of cooled PBS was added thereto per 15 cm dish, and the cells were scraped using a cell scraper. After washed with cooled PBS (1,200 rpm, 4°C, 5 minutes), suspended in 6 mL/dish of cooled 20 mM Tris-HC1 (pH 7.4; manufactured by Nacalai Tesque Inc., 5 mM EDTA included) and homogenized using a Polytron, the homogenate was centrifuged (26,000 rpm, 20 minutes, 4°C). The obtained precipitate was resuspended in cooled 20 mM Trls-HCl and

homogenized again using a Polytron, and the homogenate was ccntrifiiged (26,000 rpm, 20 minutes, 4°C). The obtained precipitate was resuspended in 50 mM I IKPES (pH 7.5; manufactured by DoJIndo I laboratories) at 1 mL per dish, homogenized using a Polytron, and freeze-stored at -80°C as a membrane fraction. At this time, a part thereof was used for the measurement of the protein concentration. Measurement of the protein concentration was carried out using a Protein assay stain (manufactured by Bio-Rad Laboratories) in accordance with a standard Protocol as appended in duplicate. (3) Receptor Binding Test
[3H]PGE2 50 uL (final concentration 0.3 nM; manufactured by Perkin Elmer Co., Ltd.), 100 u,L (20 u,g/well) of the membrane fraction prepared from the rat EP4 expression cell, and 50 uL of a test compound were mixed in a 96-well microplate (manufactured by Sumitomo Bakelite Co., Ltd.), incubated at room temperature for 1 hour, then filtered by suction on a microplate (UniFilter-96 GF/B, manufactured by Perkin Elmer Co., Ltd.) using a cell harvester (FilterMate Harvester, manufactured by Perkin Elmer Co., Ltd.), and washed three times with 300 uL/well of a cooled assay buffer (50 mM HEPES, 10 mM MgCh). Dilution of [3H]PGE2 and the membrane fraction was carried out using the assay buffer, and dilution of the test compound and the unlabeled PGE2 was carried out using dimethyl sulfoxide and the assay buffer. The UniFilter-96 GF/B was treated by preliminarily washing twice with 200 uL/well of the cooled assay buffer. The UniFilter-96 GF/B after filtration was dried in a dryer overnight, 50 uL/well of a liquid scintillation cocktail (MicroScint20, manufactured by Perkin Elmer Co., Ltd.) was added thereto, and the radioactivity was then measured using a liquid scintillation counter for a microplate (TopCount, manufactured by Perkin Elmer Co., Ltd.). For measurement of the non¬specific binding, an unlabeled PGE2 (final concentration 1 uM; manufactured by Cayman Chemical Company) was added. All of the measurements were carried out in duplicate, and the specific binding amount was determined by subtracting the non-specific binding amount from the total binding amount.
According to the test method as described above, the rat EP4 receptor affinity (Ki) of the compound of the formula (I) was measured. The Ki values of the representative Example Compounds of the present invention are shown below. In this connection, Ex means Example Compound number.

[0055] Test Example 2 EP4 Receptor Agonistic Action in Rat
The agonistic activity was evaluated by the cAMP increasing action in the rat EP4
receptor expression cells. The rat EP4 receptor expression vector was introduced into
CHO-K1 cells (American Type Culture Collection) to propuro a nil l(l'4 receptor stable
30

expression cell line. These cells were seeded onto a 96-well microplate at 2xl04 cell/well, and used for the experiment the next day. The culture medium of each well was removed by suction, 100 uL/well of an assay culture medium (2 uM indomethacin, 0.1% bovine serum albumin-containing a-MEM) was added thereto, and incubated at 37°C for 1 hour. The culture medium was removed again by suction, and replaced with 100 uL/well of an assay culture medium comprising a test compound and 1 mM IHMX (3-isobutyl-l-methylxanthine). After incubating at 37°C for 30 minutes, the culture medium was removed by suction, 100 uL/well of a cell lysate (0.2% Triton-X 100-containing phosphate buffer physiological saline) was put thereinto, and the plate was Nhakcn for 10 minutes. Using a cAMP femto 2 kit (manufactured by Cis Bio Internntloniil), the cAMP concentration in the coll lysute was measured. Further, the cAMP Increasing action (%) was calculated with the cAMP increasing action by 1 fiM POHj WHS tnkcn as 100%.
The cAMP increasing Hctions (%) of the representative Example compounds of the present invention at 10 fiM are shown in Table 2.
[0056]
Test Example 3 Evaluation on Selectivity: Rat Prostaglandin EP Receptor Agonistic Action/Antagonistic Action
(1) Rat EP1 and Rat EP3 Receptor Agonistic Action/Antagonistic Action
Using rat EP1 or rat EP3P receptor stable expression cells, the intracellular Ca2+ concentration was measured using a fluorescent imaging plate reader (FLIPR manufactured by Molecular Devices Corporation). The agonistic activity was evaluated by the intracellular Ca2+ increasing action of the test compound, and the antagonistic activity was evaluated by the inhibiting action of the test compound on the intracellular Ca2+ increasing action by PGE2.
The cDNA of the rat EP1 or EP3p receptor was subcloned into an expression vector (pCDNA3.1 -V5-His-topo, manufactured by Invitrogen Corporation). This expression vector was introduced into HEK293 cells (American Type Culture Collection) to prepare a rat EP1 or EP3P receptor stable expression cell line. These cells were seeded onto a 96-well poly-D-lysin treated black wall clear bottom plate (manufactured bv

Becton, Dickinson and Company) at 2 to 3xl04 cell/well, ami u«cd for the experiment the next day. The measurement of the intracellular Ca2+ coneuiilmlion was carried out by an FLIPR calcium 3 assay kit (manufactured by Molecular DOVICOH Corporation). The culture medium of each well was removed by suction and replaced with a loading buffer (Hank's balanced salt solution containing 20 mM HEPES-NaOH (pi I 7.4), 2.5 mM Probenecid, 0.1% bovine serum albumin, and a color), followed by incubating at room temperature for 3 hours and loading a color. For the evaluation of the agonistic action, the change in the intracellular Ca2+ concentration was determined from the difference in the maximum value of the intracellular Ca2+ concentration after the addition of the test compound and the value before the addition of the test compound, For the evaluation of the antagonistic action, after incubating the test compound for 5 minutes, PGE2 was added thereto to determine the change in the intracellular Ca2+ concentration by PGE2.
The measurement results of the representative Example compounds of the present invention are shown in Table 3. Further, NE means that the action has no significance.
(2) Rat EP2 Receptor Agonistic Action/Antagonistic Action
For a rat EP2 receptor, stable expression cells were used to carry out a cAMP
assay. The agonistic activity was evaluated by the cAMP increasing action by the test
compound, and the antagonistic activity was evaluated by the inhibiting action of the test
/"*v compound on the cAMP increasing action by PGE2.
The rat EP2 receptor cDNA was subcloned into an expression vector (pCDNA3.1-V5-His-topo, manufactured by Invitrogen Corporation). This expression vector was introduced into CHO-K1 cells (American Type Culture Collection) to prepare a rat EP2 receptor stable expression cell line. These cells were seeded onto a 96-well microplate at 0.5 xlO4 cell/well, and used for the experiment the next day. The culture medium of each well was removed by suction, 100 uL/well of an assay culture medium (oc-MEM containing 2 uM indomethacin and 0.1% bovine serum albumin) was added thereto, and incubated at 37°C for 1 hour. The culture medium was removed again by suction, and replaced with 100 uL/well of an assay culture medium containing a test compound and 1 mM IBMX. After incubating at 37°C for 30 minutes, the culture medium was removed

by suction, 100 ul/well of a cell lysate (0.2% Triton-XlOO-containing phosphate buffer physiological saline) was added thereto, and the plate was shaken for 10 minutes. Using a cAMP femto 2 kit (manufactured by Cis Bio International), !he cAMP concentration in the cell lysate was measured. In this connection, the cAMP Increasing action (%) was calculated with the cAMP increasing action by 1 uM PGK2 WUN taken us 100%.
The results of the representative Example compounds oflho present invention are shown in Table 4.
[0057] Text Example 4 Inhibitory Action on LPS-Induced TNF-u Production in TIIP-1 Cells
Human monocytic cell line THP-1 cells were suspended in nn assay medium (PRMI-1640 containing 10% fetal bovine serum, 100 unit/ml, penicillin O sodium, and 100 ug/mL streptomycin sulfate), and seeded onto a 96-well plate at I X 10s cells/well. 50 uL/well of an assay medium containing a test compound was added thereto, followed by incubation at 37°C for 30 minutes. Further, 50 uL/well of an assay medium containing 1 to 5 }ig/ml, of LPS was added thereto, and the TNI'-u concentration in the assay medium of each well after 3 hours was measured. The measurement was carried out by means of a standard EMS A method. A 96-well plate which had been coated overnight with an anti-human TNF monoclonal antibody (clone: MAbl) (manufactured by Becton, Dickinson and Company) as a capture antibody was washed with a wash buffer (PBS containing 0.05% Tween-20), and PBS containing 10% fetal bovine serum was incubated at room temperature for 1 hour to perform blocking. After washing with a wash buffer, 100 uL/well of the assay medium to be measured was incubated at 4°C overnight. As the standard material to be measured, a recombinant human TNF (manufactured by Becton, Dickinson and Company) was used. After washing with a wash buffer, 100 uL of a biotinylated anti-human TNF monoclonal antibody (clone: MAbl 1) as a detection antibody was treated at room temperature for 1 hour. After washing with a wash buffer, it was treated with 100 uL/well of an HRP-labeled Streptavidin (manufactured by Zymed Laboratories, Inc.) at room temperature for 30 minutes, and washed again. Treatment was conducted using 100 uL/well of a TMB

(3,3',5,5'-tetramethylbenzidine) substrate liquid at room temperature for 20 minutes in a dark room. A 2 M sulfuric acid was added thereto at 50 uL/well to stop the reaction, and an absorbance at 450 nm/570 nm was measured by means of a plate reader SPECRA max (manufactured by Molecular Devices Inc.).
The IC50 values of the representative Example compounds of the present invention are shown in Table 5.
[0058]
Test Example 5 In Vivo TNF-a Production Inhibiting Action In Rut
LPS (10 fig/kg) was administered to caudal veins ol'SD male rats, and after 90
minutes from the administration, the heparin blood was collected from the abdominal vena
cava to prepare a plasinu. The test compound was orally administered 1 hour before the
administration of M'S. The amount of TNF-a in the plasma was meiiNured using a BD
OptEIA rat TNF KLISA set (manufactured by Becton, DickiiiNon und Company) according
to the attached method. The inhibitory rate by the test compound was determined from
"^ the amount of TNI'-u in plasma in a control group (administered with a solvent).
The representative HDjo values of the Example compounds of the present invention are shown in Table 6.

[0059] Test Example 6 Hindlimb Blood Flow Increasing Action in Anesthetized Rat
Wistar male rats were used. The test compound was orally administered, and
after 2 hours, the hindlimb blood was measured using a laser blood How imaging apparatus
^ (PIM II, manufactured by Inlegral Corporation). At 20 minutes before the measurement,
60 mg/kg of pentobarbital was intraperitoneally administered to conduct anesthesia.
When the doses shown in Table 7 were orally administered, the representative Example compounds of the present invention showed the following blood How increasing action, when the blood How of the group administered with the solvent was set as 100%.
[0060]
As a result of each of the tests above, it was confirmed that the compound of the formula (I) has un 151*4 receptor agonistic action, and exhibits an iinti-inflummatory action and a blood How increasing action. Based on this, the compound can be used as an agent for treating peripheral arterial occlusive disease such as arteriosclerosis obliterans, thromboangiitis obliterans, and the like, various symptoms bused on peripheral circulatory disorders (intermittent claudication/numbness in lower extretnilioN due to lumbar spinal stenosis, Raynaud's syndrome, erectile dysfunction, and the like), inflammatory diseases such as ulcerative colitis, Crohn's disease, and the like, renal diseases such as nephritis,

renal failure, and the like, bone diseases such as osteoporosis and the like, and eye diseases such as glaucoma, ocular hypertension, and the like.
[0061]
A preparation comprising one or two or more kinds of the compound of the formula (I) or a pharmaceutical^ acceptable salt thereof as an active ingredient can be prepared in accordance with a generally used method, using a pharmaceutical carrier, excipient, or the like, that is usually used in the art.
The administration can be carried out in any mode of oral administration via tablets, pills, capsules, granules, powders, liquid preparations, or the like, or parenteral administration via injections such as intraarticular, intravenous, intramuscular, or others, suppositories, eye drops, eye ointments, percutaneous liquid preparations, ointments, percutaneous patches, transmucosal liquid preparations, transmucosal patches, inhalations, and the like.
[0062]
Regarding the solid composition for oral administration according to the present invention, tablets, powders, granules, or the like are used. In such a solid composition, one or two or more kinds of active ingredients are mixed with at least one inert excipient, for example, lactose, mannitol, glucose, hydroxypropylcelluloso, mlcrocrystalline cellulose, starch, polyvinyl pyrrolidone, and/or magnesium nluininomolasilicate, or the like. According to a conventional method, the composition limy ootiluln Inert additives for example, a lubricant such as magnesium stearate, a disintegrator Niich as carboxymethylstarch sodium, a stabilizing agent, and a solublll/lng aid. As occasion demands, the tablets or the pills may be coated with a sugar coaling, or a film of a gastric or enteric coating agent.
The liquid composition for oral administration includes pharmaceutical^
acceptable emulsions, soluble liquid preparations, suspensions, syrups, elixirs, or the like,
^ and contains a generally used inert diluent such as purified water or ethanol. In addition
to the inert diluent, this liquid composition may contain an adjuvant such as a solubilizing agent, a moistening agent, and a suspending agent, a sweetener, a flavor, an aroma, and an antiseptic.
Injections for parenteral administration contain sterile aqueous or non-aqueous soluble liquid preparations, suspensions and emulsions. The aqueoiiH solvent includes, for example, distilled water for injection or physiological saline, Examples of the non¬aqueous solvent include propylene glycol, polyethylene glycol, plant oils such as olive oil, alcohols such as ethanol, I'olysorbate 80 (Japanese Pharmacopeia), and the like. Such a composition may further contain a tonicity agent, an antiseptic, a moistening agent, an emulsifying agent, a dispersing agent, a stabilizing agent, or a milubili/ing agent These are sterilized, for example, by filtration through a bacteria relalnlng filler, blending of a

bactericide, or irradiation. In addition, these can also be used by preparing a sterile solid composition, and dissolving or suspending it in sterile water or a sterile solvent for injection prior to its use.
[0063]
The agent for external use includes ointments, plasters, creams, jellies, cataplasms, sprays, lotions, eye drops, eye ointments, and the like. The agents contain generally used ointment bases, lotion bases, aqueous or non-aqueous liquid preparations, suspensions, emulsions, and the like. Examples of the ointment bases or the lotion bases include polyethylene glycol, propylene glycol, white vaseline, bleached bee wax, polyoxyethylene hydrogenated castor oil, glyceryl monostearate, stearyl alcohol, cetyl alcohol, lauromacrogol, sorbitan sesquioleate, and the like.
Regarding the transmucosal agents such as an inhalation, a transnasal agent, and the like, those in the form of a solid, liquid, or semi-solid state are used, and can be prepared in accordance with a conventionally known method. For example, a known excipient, and also a pH adjusting agent, an antiseptic, a surfactant, a lubricant, a stabilizing agent, a thickening agent, or the like may be appropriately added thereto. For their administration, an appropriate device for inhalation or blowing can be used. For example, a compound may be administered alone or as a powder of formulated mixture, or as a solution or suspension in combination with a pharmaceutically acceptable carrier, using a conventionally known device or sprayer, such as a measured administration inhalation device, and the like. The dry powder inhaler or the like may be for single or multiple administration use, and a dry powder or a powder-containing capsule may be used. Alternatively, this may be in a form such as a pressurized aerosol spray which uses an appropriate propellent, for example, a suitable gas such as ehlorolluoroalkane, hydrofluoroalkane, curbon dioxide, and the like, or other IbniiN,
[0064]
^ Generally, in the case of oral administration, the dully (IOHO IN from about 0.001 to
100 mg/kg, preferably from 0.1 to 30 mg/kg, and more prel'unibly 0.1 lo 10 mg/kg, per body weight, administered in one portion or in 2 to 4 divided porlloim. In the case of intravenous administration, the daily dose is suitably administered from about 0.0001 to 10 mg/kg per body weight, once a day or two or more times a day. In addition, a transmucosal agent is administered at a dose from about 0.001 to 100 mg/kg per body weight, once a day or two or more times a day. The dose is appropriately decided in response to the individual case by taking the symptoms, the age, the gender, and the like into consideration.
[0065]
The compound of the formula (I) can be used in combination with various agents for treating or preventing the above diseases for which the compound of the formula (I) is

considered to be effective, The combined preparation mny be lulminlntered simultaneously, or sepurulely and continuously or at a desired lime interval. The preparations to be co-udministered may be a combination drug, or may be prepared individually.
Examples
[0066]
Hereinbelow, the production processes for the compound of the formula (I) are described with reference to Examples in more detail. The present invention is not limited to the compounds as described in Examples below. In addition, the production processes for the starting compounds are shown in Production Examples. Further, the production processes for the compound of the formula (I) are not limited to the production methods of specific Examples as shown below, but the compound of the formula (I) can be prepared by the combination of these production processes therefor or the methods obvious to a skilled person in the art.
[0067]
In addition, the following abbreviations are used in Production Examples,
Examples, and Tables below. Pre: Production Example number, Ex: Example number,
No: Compound number, Str: Structural Formula (The description of IIC1, TFA, and fum in
the structural formula means that the compounds are hydrochloride, trifluoroacetate, and
fumarate, respectively), Syn: Production Process (The number shows that it was prepared
using a corresponding starting material in the same manner as the Example compound
having the number as the Example number. For example, Example Compound 55 each
shows that it was prepared in the same manner as for Example Compound 1). PSyn:
Production Process (The number shows that it was prepared using a corresponding starting
material in the same manner as the compound having the number as the Production
-^ Example number. For example, Production Example Compound 57 each shows that it
was prepared in the same manner as for Production Example Compound 2.), Dat: Physicochemical Data (NMR: 8 (ppm) in 1H NMR in DMSO-dft, FAIR: FAB-MS (cation) (which means (Mill)1 unless otherwise specified), FAIl-: I'AM-MN (union) (whichmeans (M-H)' unless otherwise specified), ESI+: ESI-MS (cation) (which mentis (M+H)+ unless otherwise specified), HSJ-: ESI-MS (anion) (which means (M-H)" unless otherwise specified), EI: EI-MN (which means (M)+ unless otherwise upodlled), CI-!-: CI-MS (cation) (which means (MHI)', unless otherwise specified), APCII: Al'( 'I-MN (cation) (which means (M+H)+ unless otherwise specified), APCI/ESI+: metming the simultaneous measurement of APCI+ and ESI+, Elemental Analysis: Analysis of Elements, Found: Found Values (%), calc: Calculated Values (%)).
[0068]

Production Example 1
To a solution of i.O g of 3,5-dichloro-6-methylpyridln-2(l ll)-nne in 15 ml of DME was added 777 mg of potassium carbonate at room temperature, followed by stirring at 80°C for 30 minutes, and then 1.63 g of methyl 4-(2-iodoelliyl)ben/,oHte was added thereto, followed by healing and reflux for 12 hours. Further, 777 mg of potassium carbonate and 1.63 g of methyl 4-(2-iodoethyl)benzoate were added thereto, followed by stirring at the same temperature for 12 hours. Again, the same operations were repeated. Under ice-cooling, ethyl acetate and 1 M hydrochloric acid were added thereto to carry out a liquid separation operation. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained solid was washed with a mixed solvent of ethyl acetate and n-hexane to collect 317 mg of 3,5-dichloro-6-methylpyridin-2( 11 l)-one. On the other hand, after the mother liquid was concentrated under reduced pressure, the residue was purified by silica gel column chromatography to obtain 538 mg of methyl 4-|2-(3,5-dichloro-6-methyl-2-oxopyridin-1 (2H)-yl)ethyl]benzoate.
[0069]
Production Example 2
To a solution of 444 mg of tert-butyl 4-[2-(3,5-dichloro-6-methyl-2-oxopyridin-l(2H)-yl)ethyl]benzoate in 10 ml of carbon tetrachloride were added 210 mg of N-bromosuccinimide and 19 mg of 2,2'-azobis(isobutyronitrile), followed by heating and reflux for 1 hour. After leaving it to be cooled at room temperature, chloroform and saturated aqueous sodium bicarbonate were added thereto to carry out a liquid separation operation. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 393 mg of tert-butyl 4-{2-[6-(bromomethyl)-3,5-dichloro-2-oxopyridin-l(2H)-yl]ethyl}benzoate.
[0070]
Production Example 3
To a solution of 390 mg of tert-butyl 4-{2-[6-(bromomethyl)-3,5-dichloro-2-oxopyridin-l(2H)-yl]ethyl}benzoate in 10 ml of acetone was added 347 mg of sodium acetate, followed by stirring at 70°C for 6 hours. After leaving it to be cooled at room temperature, a saturated aqueous ammonium chloride solution and ethyl acetate were added thereto to carry out a liquid separation operation. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 369 mg of tert-butyl 4-{2-[6-(acetoxymelhyl)-3,5-dlchloro-2-oxopyridin-l(2II)-yl|ethyI}benzoate.
[0071]
Production Example 4

To a solution of 365 mg of tert-butyl 4-{2-[6-(acetoxymethyl)-3,5-dichloro-2-oxopyridin-l(2H)-yl]ethyl}benzoate in 10 ml of methanol wns added 343 mg of potassium carbonate at room temperature, followed by stirring for 30 minutes, lithyl acetate and a saturated aqueous ammonium chloride solution were added thereto to curry out a liquid separation operation. The organic layer was washed with Niituruted brine, dried over anhydrous sodium stil lute, and concentrated under reduced procure. The obtained solid was washed with a mixed solvent of ethyl acetate and n-hexmic lo obtain 251 mg of tert-butyl 4-{2-[3,5-dlchloro-6-(hydroxymethyl)-2-oxopyridin-l(2l l)-yl|olhyl}benzoate. On the other hand, the mother liquid was concentrated under reduced preNNure, and the residue was purified by silica gel column chromatography to obtain 54 mg of tert-butyl 4-{2-[3,5-dichloro-6-(hydroxyinclhyl)-2-oxopyridin-l(2H)-yl]ethyl}bon/,iiiito.
[0072]
Production Hxumple 5
To a solution of 22.8 g of methyl 4-{2-[6-(acetoxymethyl)-3,5-dichloro-2-oxopyridin-l(2H)-yl]ethyI}benzoate in 250 ml of methanol was Nlowly added 25 ml of concentrated sulfuric acid at room temperature, followed by stirring for 10 minutes and then heating and reflux for 2 hours. After leaving it to be cooled at room temperature, water was added thereto, and the precipitated solid was collected by filtration. The obtained solid was purified by silica gel column chromatography to obtain 16.8 g of methyl 4-{2-[3,5-dichloro-6-(hydroxymethyl)-2-oxopyridin-l (21 l)-yl]ethyl}benzoate.
[0073]
Production Example 6
To a solution of 301 mg of tert-butyl 4-{2-[3,5-dichloro-6-(hydroxymethyl)-2-oxopyridin-l(2H)-yl] ethyl }benzoate in 8 ml of chloroform was added 1.3 g of manganese dioxide at room temperature, followed by stirring for 3 days. The reaction solution was filtered through Celite and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 240 mg of tert-butyl 4-[2-(3,5-dichloro-6-formyl-2-oxopyridin-l(2H)-yl)ethyl]benzoate.
[0074]
Production Example 7
To a solution of 2.93 g of methyl 4-{2-[6-(bromomethyl)-3,5-dichloro-2-oxopyridin-l(2H)-yl]ethyl}benzoate in 58 ml of DMF were slowly added 2.22 g of sodium carbonate and 1.55 g of trimethylamine N-oxide, and the pressure of the reaction system was reduced using an aspirator, followed by stirring at 40°C for 15 minutes. Ethyl acetate and water were added to the reaction solution to carry out a liquid separation operation, and the organic layer was washed with water and saturated brine in this order, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was

purified by silica gel column chromatography to obtain 1.65 g (if methyl 4-[2-(3,5-dichloro-6-formyl-2-oxopyridin-l(2H)-yl)ethyl]benzoate as u pule yellow solid.
[0075]
Production Example 8
To a mixed solution of 300 mg of methyl 4-[2-(3,5-dichloro-6-formyl-2-oxopyridin-l(2H)-yl)ethyl]benzoate in 1.8 ml of tert-butylalcohol, 0.3 ml of acetonitrile, and 0.6 ml of water were added 383 mg of sodium chlorite, 102 mg of sodium dihydrogen phosphate, and 0.45 ml of 2-methyl-2-butene at room temperulure, followed by stirring for 2 hours. To the reaction solution was added sodium hydrogen Nulllte, und then ethyl acetate and saturated aqueous sodium bicarbonate were addeil thereto to carry out a liquid separation operation. The aqueous layer was made weakly acidic by the addition of 1 M hydrochloric acid, and ethyl ucetate was added thereto to carry out n liquid separation operation again. The organic layer was dried over anhydrmiN Nodluni HiillUte and concentrated under reduced pressure to obtain 182 mg of 3,5-illchloro-l-{2-|4-(methoxycarbonyl)phenyl|ethyl}-6-oxo-l,6-dihydropyridino 2-ciuboxyllc acid.
[0076]
Production Example 9
To a suspension of 62.7 g of 4-hydroxy-6-melhyl-2l l-pynm-2-one in 40 ml of water was added 497 ml of a 1 M aqueous sodium hydroxide solution, followed by stirring at room temperature for 15 minutes. Then, 50 g of 4-(2-aminoethyl)benzoic acid hydrochloride was added thereto, followed by stirring at 80°C for 24 hours. After leaving it to be cooled, 249 ml of 1 M hydrochloric acid and 200 ml of methanol were added thereto, followed by stirring for 30 minutes. The precipitated solid was collected by filtration to obtain 64.6 g of 4-[2-(4-hydroxy-6-methyl-2-oxopyridin-1(211)-yl)ethyl]benzoic acid.
[0077]
Production Example 10
To a suspension of 67.8 g of 4-[2-(4-hydroxy-6-melhyl-2-oxopyridin-l(2H)-yl)ethyl]benzoic acid in 500 ml of methanol was slowly added 50 ml of concentrated sulfuric acid, followed by heating and reflux for 4 hours. After leaving it to be cooled, 1.50 L of water was added, and the precipitated solid was collected by filtration to obtain 69.2 g of methyl 4-[2-(4-hydroxy-6-methyl-2-oxopyridin-l(2II)-yl]benzoate.
[0078]
Production Example 11
To a suspension of 69.2 g of methyl 4-[2-(4-hydroxy-6-methyl-2-oxopyridin-l(2H)-yl]benzoate in 500 ml of pyridine was added 60 ml of trifluoromethanesulfonic anhydride at 5°C over about 1 hour, followed by stirring at the same temperature for 2 hours. Then, 500 ml of 1 M hydrochloric acid and 500 ml of water were added thereto in

this order, and the precipitated solid was collected by filtration to obtain a pale brown solid. Ethyl acetate unci water were added to the obtained Nolld to winy out a liquid separation operation, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 84.0 g of methyl 4-{2-|6-methyl-2-oxo-4-{[(trifluoromethyl)Nuironly|oxy}pyridin-l(2H)-yl]ethyl}benzoate. Further, ethyl acetate and water were added to the mother liquid to carry out a liquid separation operation, and the same operations were carried out to obtain 20.2 g of methyl 4-{2-[6-methyl-2-oxo-4-{[(trifluoromethyl)sulfonly]oxy}pyridin-l(2H)-yl]ethyl}benzoate.
[0079]
Production Example 12
To a solution of 56 g of methyl 4-{2-[6-methyl-2-oxo-4-{[(trifluoromethyl)sullbnly]oxy}pyridin-l(2H)-yl]ethyl}ben/oate In 300 ml of ethyl acetate were added 28 ml of N-ethyl-N-isopropylpropan-2-aminc and 2.8 g of 10% palladium-carbon (water-containing product), followed by stirring at mom temperature for 4 hours under a hydrogen atmosphere. The reaction solution was Ultcred through Celite, and water and ethyl acetate were added to the filtrate to carry out a liquid separation operation. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was made into powders with ethyl acetate to obtain 21.3 g of methyl 4-[2-(6-methyl-2-oxopyrldln-1(21 l)-yl)ethyl]benzoate as a white solid, On the other hand, the mother liquid was concentrated under reduced pressure, and then (ho residue was purified by silica gel column chromatography to obtain 12.3 g of methyl 4-f 2-(6-methyl-2-oxopyridin-l(21I)-yl)ethylJbenzoate as a pale brown solid.
[0080]
Production Example 13
^ To a mixed liquid of 65.0 g of methyl 4-[2-(6-methyl-2-oxopyridin-l(2H)-
yl)ethyl]benzoate, 500 ml of acetic acid, and 300 ml of water was added 64 g of N-chlorosuccinimide, followed by stirring at room temperature for 30 minutes, and then at 70°C overnight. After leaving it to be cooled at room temperature, 1 L of water was added thereto and the precipitated solid was collected by filtration. The obtained solid was washed under heating with a mixed solvent of ethyl acetate and hexane to obtain 58.8 g of methyl 4-[2-(3,5-dichloro-6-methyl-2-oxopyridin-l(2H)-yl)ethyl]benzoate.
[0081]
Production Example 14
To a solution of 3.0 g of methyl 4-[2-(6-methyl-2-oxopyridin-l(2H)-yl)ethyl]benzoate in 60 ml of acetic acid was added 2.0 g of N-bromosuccinimide, followed by stirring at room temperature for 3 hours. Water and ethyl acetate were added

thereto to carry out a liquid separation operation, and the organic layer was washed with saturated brine, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 2.2 g of methyl 4-[2-(5-bromo-6-methyl-2-oxopyridin4 (2H)-yl)ethyl]benzoate.
[0082]
Production Example 15
To a mixed liquid ol'21.5 g of methyl 4-[2-(3,5-dluhloro-6-mothyl-2-oxopyridin-l(2H)-yl)ethyl]benzoate in 130 ml of THF and 70 ml of mellumnl WIIH added 76 ml of a 1 M aqueous sodium hydroxide solution, followed by stirring ill 7()"(' for 4 hours. After leaving it to be cooled tit room temperature, the reaction solution WIIH neutralized with 1 M hydrochloric acid, and the precipitated solid was collected by nitration to obtain 19.6 g of 4-[2-(3,5-dichloro-6-methyl-2-oxopyridin-l(2H)-yl)ethyl|ben/oicucid.
[0083]
^ Production Example 16
To a mixed solution of 19.6 g of 4-[2-(3,5-dichloro-6-methyl-2-oxopyridin-l(2H)-
yl)ethyl]benzoic acid in 150 ml of THF and 150 ml of tert-butylalcohol were slowly added
16 g of di-tert-butyl dicarbonate and 3.7 g of N,N-dimethylpyridin-4-innine, followed by
stirring at 60°C overnight. After leaving it to be cooled at room temperature, 16 g of di-
tert-butyl dicarbonate and 3.7 g of N,N-dimethylpyridin-4-amine were added thereto,
followed by stirring at 60°C overnight. After leaving it to be cooled at room temperature
again, 7.0 g of di-terl-butyl dicarbonate was added thereto, followed by stirring at 60°C
overnight. After leaving it to be cooled at room temperature, water and ethyl acetate were
added thereto to carry out a liquid separation operation. The organic layer was washed
with saturated brine, then dried over anhydrous sodium sulfate, and concentrated under
reduced pressure. The residue was purified by silica gel column chromatography to
obtain 18.8 goftcrt-luilyl 4-|2-(3,5-dichloro-6-methyl-2-oxopyrl(lln-l(2ll)-
■^ yl)ethyl]benzoate.
[0084]
Production Example 17
To a solution of 2.0 g of methyl 4-(2-bromoethyl)bcnzoate in 50 ml of acetone was added 2.6 g of sodium iodide at room temperature, followed by stirring overnight. The precipitated solid was removed by filtration, and then the filtrate was concentrated under reduced pressure. Water and ethyl acetate were added to the residue to carry out a liquid separation operation. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain 2.4 g of methyl 4-(2-iodoethyl)benzoate.
[0085]
Production Example 18

To a mixed solution of 1.06 g of methyl 4-[2-(3-chloro-6-methyl-2-oxopyridin-l(2H)-yl)ethyl]benzoate in 30 ml of acetic acid and 10 ml of water was added 648 mg of N-bromosuccinimide at room temperature, followed by stirring overnight. Water was added thereto and the precipitated solid was collected by filtration to obtain 1.27 g of methyl 4-[2-(5-bromo-3-chloro-6-methyl-2-oxopyridin-l(2H)-yl)ethyl]benzoate as a pale brown solid.
[0086]
Production Example 19
To a solution of 1.0 g of methyl 4-{2-[3-chloro-6-methyI-2-oxo-4-{[(trifluoromethyl)sulfonly]oxy}pyridin-l(2H)-yl]ethyl}ben/oiile in 20 ml of THF were added 1.23 ml of triethylamine and 170 u.1 of formic acid in IhiH order under ice-cooling, followed by stirring lor 5 minutes. 75 mg of palladium acetate und 174 mg of triphenylphosphine were added thereto at room temperature, followed by stirring at 60°C for 3 hours. Ethyl acetate nnd 1 M hydrochloric acid wore milled thereto under ice-cooling to carry out n liquid separation operation. The organic Inyor was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 520 mg of methyl 4-[2-(3-chloro-6-methyl-2-oxopyridin-l(2H)-yl)ethyl]benzoate as a pale yellow solid.
[0087]
Production Example 20
To a suspension of a mixture of 5.0 g of methyl 4-[2-(4-hydroxy-6-methyl-2-oxopyridin-l(2H)-yl)ethyl]benzoate in 20 ml of acetic acid und 5.0 ml of water was added 2.33 g of N-chlorosucclnimide at room temperature, followed by stirring at 80°C overnight. After cooling, water was added thereto and the precipitated solid was collected by filtration to obluin 4.48 g of methyl 4-[2-(3-chloro-4-hydroxy-6-methyl-2-oxopyridin-l(2Il)-yl)olhyl|benzoate as apale brown solid.
[0088]
Production Example 21
To a mixed Nolulion of 170 mg of methyl 4-[2-(6-methyl-2-oxo-5-phenylpyridin-l(2H)-yl)ethyl]beuzonte in 4.0 ml of acetic acid and 1.0 nil of wnter WIIH udded 78 mg of N-chlorosuccinimlde ul room temperature, followed by Htlnlnu nt HM)"(J overnight. After cooling, water and chloroform were added thereto to carry out n liquid Neparation operation, the organic layer was washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 100 mg of methyl 4-[2-(3-chloro-6-methyl-2-oxo-5-phenylpyridin-l(2H)-yl)ethyl]benzoate.

[0089]
Production Example 22
To a solution of 500 mg of methyl 4-[2-(5-bromo-6-methyl-2-oxopyridin-l(2H)-yl)ethyl]benzoate in 10 ml of 1,4-dioxane were added 261 mg of phenylboronic acid, 485 mg of tripotassium phosphate, and 165 mg of tetrakistriphenylphosphine palladium at room temperature, followed by stirring at 90°C overnight. After cooling, the insoluble materials were removed by filtration using Celite and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 170 mg of methyl 4-[2-(6-methyl-2-oxo-5-phenylpyridin-1 (2H)-yl)ethyl]benzoate.
[0090]
Production Example 23
To a solution of 1.0 g of tert-butyl (2R)-2-(hydroxymethyl)pyrrolidine-l-carboxylate in 10 ml of DMF was added 325 mg of 55% sodium hydride (oily) under ice-cooling, and then 872 mg of 3-bromo-2-methylprop-l-ene was added thereto, followed by stirring at room temperature overnight. Water and ethyl acetate were added to the reaction solution to carry out a liquid separation operation, (he organic layer was washed with a saturated aqueous sodium chloride solution and then tilled over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.1 g of colorless oily tert-butyl (2R)-2-{[(2-methylprop-2-en-l-yl)oxy]methyl}pyrrolidine-l-c«rh(iHyliilo.
[0091]
Production Example 24
To a solution of 940 mg of tert-butyl (2R)-2-{[(2-methylprop-2-en-l-yl)oxy]methyl} pyrrolidine- 1-carboxylate in 10 ml of ethanol was added 150 mg of 10% palladium carbon, followed by stirring at room temperature for 24 hours under a hydrogen atmosphere. After filtration using Celite, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 792 mg of colorless oily tert-butyl (2R)-2-(isobutoxymethyl)pyrrolldliie-l-earboxylate.
[0092]
Production Example 25
To a solution of 785 mg of tert-butyl (2R)-2-(isobuloxyinolhyl)pyrrolidine-l-carboxylate in 5.0 ml of ethyl acetate was added 5.0 ml of 4 M hydrogen chloride-ethyl acetate at room temperature, followed by stirring overnight. The solvent was evaporated under reduced pressure to obtain 610 mg of colorless oily (2K)-2-(isobutoxymcthyl)pyiTolidine hydrochloride.
[0093|
Production Example 26

A solution of 2.0 g of l-(3-fluorophenyl)acetone and 7.39 ml of methylamine (40% methanol solution) in 20 ml of methanol was stirred at room temperature overnight. 603 mg of sodium borohydride was added thereto at room temperature, followed by stirring overnight. Water and ethyl acetate were added thereto to carry out a liquid separation operation, the organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 529 mg of pale brown oily l-(3-trifluorophenyl)-N-methy lpropan-2-amine.
[0094]
Production Example 27
(1) To a suspension of 1.46 g of magnesium and a catalytic amount of iodide in 4.0 ml of THF was slowly added a solution of 4.47 g of (bromomethyl)cyclobutane in 27 ml of THF, followed by heating, to prepare a Grignard reagent. The Grignard reagent prepared was added dropwise to a solution of 4.0 g of 4-chlorobutanoyl chloride and 150 mg of iron (III) acetylacetonate in 40 ml of THF at -78°C under an argon atmosphere, followed by stirring at the same temperature for 30 minutes. A saturated aqueous ammonium chloride solution and ethyl acetate were added to the reaction solution to carry out a liquid separation operation. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 4.49 g of 5-chloro-l-cyclobutylpciituu-2-nne us a colorless oily substance.
(2) A mixture of 4.49 g of the colorless oily substance obtained, 3.88 g of (2S)-2-amino-2-phenylethanol, 4.48 ml of N-ethyl-N-isopropylpropun-2-uinluo, unci 2.25 ml of chloroform were stirred ut room temperature for 7 days. To the reaction product was added diethyl ether, unci the supernatant was removed. ThoNe operations were repeated three times, followed by concentration under reduced pressure. The residue was purified by silica gel column chromatography to obtain 5.7 g of a pale yellow oily substance including rel-(3R,7aR)-7a-(cyclobutylmethyl)-3-phenylhexahydropyrrolo[2,1 -b][l,3]oxazole. ESI+: 258
(3) To a solution of 5.7 g of the pale yellow oily substance including rel-(3R,7aR)-7a-(cyclobutylmethyl)-3-phenylhexahydropyrrolo[2,l-b]f l,3|oxn/,olo in 171 ml of THF was added dropwise 30.5 ml of lithium triethylborohydride (1.09 M solution in THF) under ice-cooling under an argon atmosphere, followed by stirring ut 4°C overnight. To the reaction solution was added water, and then ethyl acetate was uclclccl thereto to carry out a liquid separation operation. The organic layer was washed with n suturuted aqueous sodium chloride solution unci then dried over anhydrous sodium sulfate, and the solvent

was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 4.48 g of yellow oily (2S)-2-[(2R)-2-(cyclobutylmethyl)pyrrol idon-1 -yl]-2-phenylethanol.
[0095]
Production Example 28
To a solution of 4.48 g of (2S)-2-[(2R)-2-(cyclobutylmelhyl)pyrrolidon-l-yl]-2-phenylethanol in 90 ml of methanol was added 900 mg of 10% palladium carbon, followed by stirring at room temperature for 4 days under a hydrogen atmosphere of 3 atm. After filtration using Celite, the solvent was evaporated under reduced pressure. To the residue was added a 4 M hydrogen chloride-ethyl acetate solution to make it into hydrochloride, followed by addition of n-hexane, and the supernatant was removed. These operations were repeated three times, and then the remaining material was made into powders from a mixed solvent of diethyl ether and ethyl acetate to obtain 1.5 g of (2R)-2-(cyclobutylmethyl)pyrrolidine hydrochloride as a white solid.
[0096]
Production Example 29
To a solution of 3.25 g of tert-butyl 4-[2-(5-bromo-6-methyl-2-oxopyridin-l(2H)-
yl)ethyl]benzoate in 60 ml of toluene was added 3.0 ml of water, and then 1.0 g of
cyclopropylboronic acid, 7.0 g of tripotassium phosphate, 186 mg of palladium acetate,
and 464 mg of tricyclohexylphosphine were added thereto in this order at room
temperature, followed by heating and reflux overnight. After cooling, water and ethyl
acetate were added thereto, the insoluble materials were removed using Celite and then a
liquid separation operation was carried out. The organic layer was washed with 0.5 M
hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution, and a
saturated aqueous sodium chloride solution in this order, and dried over anhydrous sodium
sulfate, and the solvent was evaporated under reduced pressure. The residue was purified
' by silica gel column chromatography to obtain 2.17 g of terl-hulyl 4-|2-(5-cyclopropyl-6-
methyl-2-oxopyridin-l(2II)-yl)ethyl]benzoate as a pale yellow milid.
[0097]
Production Example 30
To a solution of 353 mg of tert-butyl 4-[2-(5-cyelopmpyl-n-inolhyl-2-oxopyridin-l(2H)-yl)ethyl]benzoiUe In 8.0 ml of DMF was added a solution of 93 mg of trichloroisocyanuric acid in 2.0 ml of DMF at -5°C under cooling, followed by stirring at the same temperature for 1 hour. Water and ethyl acetate were added thereto to carry out a liquid separation operation, the organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column

chromatography to obtain 231 mg of tert-butyl 4-[2-(3-chloro-5-cyclopropyl-6-methyl-2-oxopyridin-l(2M)-yl)elhyl|bonzoate as a pale yellow solid,
[0098]
Production I ixample 31
To a solution of 1.0 g of (lS,2S)-2-(benzyloxy)eyelopei»tamunlne In 20 ml of THF were added 659 mg of sodium hydrogen carbonate and 1.37 g of di-tert-butyl dicarbonate at room temperature, followed by stirring for 12 hours. Water and ethyl acetate were added thereto to carry out a liquid separation operation, the organic layer was washed with 1 M hydrochloric acid and a saturated aqueous sodium chloride solution in this order, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.51 g of tert-butyl [(lS,2S)-2-(benzyloxy)cyclopentyl]carbamate as a white solid.
[0099]
Production Example 32
To a solution of 626 mg of tert-butyl [(lS,2S)-2-(benzyloxy)cyclopentyl]carbamate in 13 ml of DMF was added 141 mg of 55% sodium hydride (oily) under ice-cooling, followed by stirring at room temperature for 10 minutes. At the same temperature, 0.4 ml of methyl iodide was added thereto, followed by stirring at 55°C overnight. Water and ethyl acetate were added thereto under ice-cooling to carry out a liquid separation operation, followed by washing sequentially with a saturated aqueous sodium chloride solution and then drying over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 423 mg of colorless oily tert-butyl |(lS,2S)-2-(benzyloxy)cyclopentyl]methylcarbamate.
[0100]
Production Example 33
To a solution of 589 mg of tert-butyl [(lS,2S)-2-(benzyloxy)cyclopentyl]methylcarbamate in 5.0 ml of ethanol was added 100 mg of 10% palladium hydroxide, followed by stirring at room temperature for 3 hours under a hydrogen atmosphere. After filtration using Celite, the solvent was evaporated under reduced pressure to obtain 436 mg of colorless oily tert-butyl [(1 S,2S)-2-hydroxycyclopentyl]methylcarbamate.
[0101]
Production Example 34
To a solution of 280 mg of tert-butyl [(lS,2S)-2-hydroxycyclopentyl|inothylcarbamate in 5.0 ml of DMI1' WIIN mliloil K.1 mg of 55% sodium hydride (oily) under Ice-cooling, followed by stirring at room temperature for 10 minutes. At the same temperature, 0.11 ml of methyl iodide was added thereto, followed by stirring

overnight. Water and ethyl acetate were added thereto under Ice-cooling to carry out a liquid separation operation, followed by washing with a saturated m|iieous sodium chloride solution and then drying over anhydrous sodium sulfate, uiul the Nolvunt was evaporated under reduced pressure. The residue was purified by silicti go I column chromatography to obtain 253 mg of colorless oily tert-butyl [(lS,2S)-2-methoxycyelopentyl|melhylcarbamate.
[0102|
Production Example 35
To a solution of 250 mg of tert-butyl [(lS,2S)-2-methoxycyclopenlyl Jmcthylcarbamate in 2.0 ml of ethyl ucoluto WHN added 2.0 ml of 4 M hydrogen chloride-ethyl acetate at room temperature, followed by stirring for 3 hours. The solvent was evaporated under reduced pressure to obtain 182 mg of colorless oily (lS,2S)-2-methoxy-N-methylcyclopentanamine hydrochloride.
[0103]
Production Example 36
To a suspension of 1.8 g of (methoxymethyl)(triphenyl)phosplionium chloride in 10 ml of THF was added 586 mg of potassium tert-butoxide under Ice-cooling, followed by stirring for 10 minutes. At the same temperature, a solution of 1.0 g of methyl 4-[2-(3,5-dichloro-6-formyl-2-oxopyridin-l(2H)-yl)ethyl]benzoate in 10 ml of THF was added dropwise thereto, followed by stirring for 10 minutes. Separately, a reagent prepared from a solution of 484 mg of (methoxymethyl)(triphenyl)phosphonium chloride in 10 ml of THF, and 158 mg of potassium tert-butoxide was added to the reaction system under ice-cooling, followed by stirring for 10 minutes. Water and ethyl acetate were added to the reaction solution to carry out a liquid separation operation, the organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 534 mg of yellow oily methyl 4-{2-[3,5-dichloro-6-(2-methoxyvinyl)-2-oxopyridin-l(2H)-yl)ethyl]benzoate.
[0104]
Production Example 37
To a solution of 530 mg of methyl 4-{2-[3,5-dichloro-6-(2-methoxyvinyl)-2-oxopyridin-l(2H)-yl)ethyl]benzoate in 5.0 ml of DCM was added 10 ml of formic acid at room temperature, followed by stirring at 70°C for 5 hours. After cooling, the reaction solution was evaporated under reduced pressure, and then the residue was purified by silica gel column chromatography to obtain 422 mg of yellow oily methyl 4-{2-[3,5-dichloro-2-oxo-6-(2-oxoethyl)pyridin-1 (2H)-yl]ethyl}benzoate.
[0105]
Production'Example 38

To a solution of 719 mg of tert-butyl [(lR,2R)-2-hydroxycyclopentyl]methylcarbamate in 4.0 ml of pyridine was added 2.0 ml of acetic anhydride under ice-cooling, followed by stirring at room temperature for 19 hours. After concentration under reduced pressure, the residue was purified by silica gel column chromatography to obtain 800 mg of colorless oily (lR,2R)-2-|(lert-butoxycarbonyl)(methyl)amino]cyclopentyl acetate.
[0106]
Production Example 39
To a solution of 255 mg of tert-butyl [3-(trifluoromclhoxy)plionyl1carbarnate in 6.0 ml of DMF was added 40 mg of 55% sodium hydride (oily) under Ice-cooling, followed by stirring ul room temperature for 1 hour. At the same temperature, 300 mg of methyl 4-{2-[6-(bromomethyl)-3-chloro-5-cyclopropyl-2-oxopyrldln-1(211)-yl]ethyl}benzoate WNN added, followed by stirring overnight, To the reaction solution was added water, and the precipitated solid was collected by nidation, The obtuined solid was purified by silica gel column chromatography to obtain 400 nig ol'inolhyl 4-{2-[6-({(tert-butoxycarbonyl)|3-(trlfluoromethoxy)phenyl]amiiU)}inelhyl)-3-chloro-5-cyclopropyl-2-oxopyridin-1 (2H)-yl]ethyl}benzoate.
[0107]
Production Example 40
To a mixture of 400 mg of methyl 4-{2-[6-({(tert-butoxycarbonyl)[3-(trifluoromethoxy)phenyl]amino}methyl)-3-chloro-5-cyclopropyl-2-oxopyridin-l(2H)-yl]ethyl}benzoate in 2.0 ml of methanol and 4.0 ml of TUP was added 2.0 ml of a 1 M aqueous sodium hydroxide solution at room temperature, followed by stirring at 65°C for 2 hours. After cooling, the reaction system was neutralized by the addition of 1 M hydrochloric acid. Water was added thereto, and the precipitated solid was collected by filtration to obtain 300 mg of 4-{2-[6-({(tert-butoxycarbonyl)[3-(trifluoromethoxy)phenyl]amino}methyl)-3-chloro-5-cyclopropyl-2-oxopyridin-l(2H)-yl]ethyl}benzoic acid.
[0108]
Production Example 41
To a solution of 1.0 g of tert-butyl 4-[2-(5-cyclopropyl-6-methyl-2-oxopyridin-l(2H)-yl)ethyl]benzoate in 15 ml of acetic acid was added 600 mg of N-bromosuccinimide at room temperature, followed by stirring overnight. Water was added thereto and the precipitated solid was collected by filtration to obtain 1.2 g of tert-butyl 4-[2-(3-bromo-5-cyclopropyl-6-methyl-2-oxopyridin-1 (2H)-yl)ethyl]benzoate.
[0109]
Production Example 42

To a solution of 50 mg of methyl 4-[2-(3,5,6-trimethyl-2-oxopyridin-l(2H)-yl)ethyl]benzoatc in 3.0 mg of acetic acid was added 33 mg of N-bioinoNticcinimide at room temperature, followed by stirring at 60°C for 4 hours, A Her cooling, water and ethyl acetate were added thereto to carry out a liquid separation operation. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 43 mg of methyl 4-{2-[6-(bromomethyl)-3,5-dimethyl-2-oxopyridin-l(2H)-yl]ethyl}benzoate.
[0110]
Production Example 43
To a solution of 1.0 g of methyl 4-[2-(3,5-dibromo-6-melhyl-2-oxopyridin-l(2H)-yl)ethyl]benzoate in 20 ml of toluene was added 2.0 ml of water, unci then 841 mg of a 2,4,6-trivinylcyclolrlboroxanc/pyridine complex, 2.47 g of IrlpoluNNlum phosphate, 52 mg of palladium acetate, unci 191 mgof dicyclohexyl(2',6'-diiiie!hoxyblphenyl-2-yl)phosphine were added thereto in this order at room temperature, followed by healing and reflux for 1.5 hours. Alter cooling, filtration was conducted using Milieu gel, and the effluent including the obtained methyl 4-t2-(6-methyl-2-oxo-3,5-cllvlnylpyrldln-1(211)-yl)ethyl]benzoato in ethyl acetate was used in the next reaction IIN it WON. TO the obtained effluent was added 200 mg of 10% palladium carbon at room temperature, followed by thoroughly stirring overnight under a hydrogen atmosphere. Aller llltratlon using Celite, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 403 mg of yellow oily methyl 4-[2-(3,5-diethyl-6-methyl-2-oxopyridin-1 (211)-yl)ethyl]benzoate.
[0111]
Production Example 44
To a solution of 530 mg of methyl 4-[2-(3-chloro-6-methyl-2-oxo-5-vinylpyridin-l(2H)-yl)ethyl]benzoate in 11 ml of ethyl acetate was added 170 mg of 10% palladium carbon, followed by stirring for 4 hours under a hydrogen atmosphere. After filtration using Celite, the solvent was evaporated under reduced pressure to obtain 500 mg of methyl 4-[2-(3-chloro-5-ethyl-6-methyl-2-oxopyridin-1 (211)-yl)ethyl]benzoate.
[0112]
Production Example 45
To a solution of 220 mg of methyl 4-[2-(5-bromo-3-chloro-6-methyl-2-oxopyridin-l(2H)-yl)ethyl]benzoate in 10 ml of toluene was added 500 ul of water at room temperature, and then 288 mg of 2-isopropenyl-4,4,5,5-tetramethyl-l,3,2-dioxaborane, 364 mg of tripotassium phosphate, 19 mg of palladium acetate, and 48 mg of tricyclohexylphosphine were added thereto, followed by stirring at 80°C overnight. After cooling, water and ethyl acetate were added thereto, followed by filtration using Celite, and

a liquid separation operation was carried out. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 143 mg of pale yellow oily methyl 4-[2-(3-chloro-5-isopropenyl-6-methyl-2-oxopyridin-l(2H)-yl)ethyl|hen/,oHle.
[0113]
Production Example 46
To a solution of 1.0 g of methyl 4-[2-(5-bromo-3-cliloio-o-melhyl-2-oxopyridin-l(2H)-yl)ethyl]benzoale in 18 ml of toluene was added 1.6 ml of water at room temperature, and then 600 mg of a 2,4,6-trivinylcyclotriboroxane/pyridine complex, 1.66 g of tripotassium phosphate, 58 mg of palladium acetate, and 213 mg of dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine were added thereto, followed by stirring at 90°C overnight. After cooling, water and ethyl acetate were added thereto, followed by filtration using Celite, and a liquid separation operation was carried out. The organic layer was washed with a saturated aqueous sodium chloride solution untl then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 300 mg of methyl 4-[2-(3-chloro-6-methyl-2-oxo-5-vinylpyridin-l(2H)-yl)ethyl|bon/oHle.
[0114]
Production Example 47
To a solution of 530 mg of methyl 4-[2-(5-cyclopropyl-3,6-dlmcthyl-2-
oxopyridin-l(2ll)-yl)clhyl|benzoate in 11 ml of carbon tetrachloride was added 100 u,l of
bromine at room temperature, followed by stirring at 90°C overnight. Aller cooling, a
saturated aqueous Noilluin hydrogen carbonate solution and chloroform were added thereto
to carry out a liquid separation operation. The organic layer waH wished with a saturated
aqueous sodium chloride solution and then dried over anhydrous sodium sulfate, and the
/•-* solvent was evaporated under reduced pressure. The residue was purified by silica gel
column chromatography to obtain 350 mg of methyl 4-{2-[6-(bromomethyl)-5-cyclopropyl-3-methyl-2-oxopyridin-l(2H)-yl]ethyl}benzoate.
[0115]
Production Example 48
To a solution of 200 mg of methyl 4-[2-(3-bromo-5-cyclopropyl-6-methyl-2-oxopyridin-l(2H)-yl)ethyl]benzoate in 4.0 ml of toluene was added 1.0 ml of water at room temperature, and then 61 mg of methylboronic acid, 326 mg of tripotassium phosphate, 6.0 mg of palladium acetate, and 21 mg of dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine were added thereto, followed by stirring at 90°C overnight. After cooling, water and ethyl acetate were added thereto, filtration was conducted using Celite, and a liquid separation operation Was carried out. The organic

layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 120 mg of pale yellow oily methyl 4-[2-(5-cyclopropyl-3,6-dimethyl-2-oxopyridin-1 (2H)-yl)ethyl]benzoate.
[0116]
Production Example 49
To a solution of 5.57 g of methyl 4-[2-(5-chloro-6-methyl-2-oxopyridin-l(2H)-yl)ethyl]benzoate in 100 ml of toluene was added 5.0 ml of water al room temperature, and then 3.8 g of cyclopropylboronic monohydrate, 15.5 g of trlpoliiNNlum phosphate, 409 mg of palladium acetate, and 1.5 g of dicyclohexyl^^'-dimellioxyblphenyl^-yDphosphine were added thereto, followed by heating and reflux for 4 hourN. AIW cooling, 1 M hydrochloric acid and ethyl acetate were added thereto, llllntllon WIIN conducted using Celite, and a liquid separation operation was carried out. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 4.68 g of methyl 4-[2-(5-cyclopropyl-6-methyl-2-oxopyridin-l(2H)-yl)ethyl]benzoate as a pale yellow solid.
[0117]
Production Example 50
To a solution of 1.0 g of methyl 4-[2-(3-bromo-5-ehloro-f)-nielhyl-2-oxopyridin-
l(2H)-yl)ethyl]benz.oate in 20 ml of 1,4-dioxane were added 233 mg of methylboronic
acid, 883 mg of tripotassium phosphate, and 601 mg of tetrakislriphenylphosphine
palladium at room temperature, followed by stirring at 90°(! for 5 dayN. After cooling,
the insoluble materials were removed by filtration using Celite, and the solvent was
evaporated under reduced pressure. The residue was purllled by silica gel column
chromatography to obtain 425 mg of methyl 4-[2-(5-chloro-3,6-dlmelhyl-2-oxopyridin-
*^ l(2H)-yl)ethyl|ben/(Hite.
[0118|
Production Example 51
To a solution of 231 mg of tert-butyl 4-[2-(3-chloro-5-oyclopn>pyl-6-methyl-2-oxopyridin-l(2Il)-yl)ethyl|benzoate in 5.0 ml of carbon tetrachloride were added 111 mg of N-bromosuccinlmlde and 5 mg of 2,2'-azobis(isobutyronitrilo), followed by heating and reflux overnight. After cooling, chloroform and water were added thereto to carry out a liquid separation operation. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 189 mg of tert-butyl 4-{2-[6-(bromomethyl)-3-chloro-5-cyclopropyl-2-oxopyridin-l(2H)-yl]ethyl}benzoate in a pale yellow amorphous state.

[0119]
Production Example 52
To a solution of 2.0 g of 4-{2-[6-(bromomethyl)-3,5-dichloro-2-oxopyridin-l(2H)-yl]ethyl}benzonitrile in 40 ml of DMF were added 430 mg of potussium carbonate and 466 mg of (2R)-2-isobutylpyrrolidine hydrochloride at room temperature, followed by stirring overnight. Water and ethyl acetate were added thereto to carry out a liquid separation operation, the organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 400 mg of 4-{2-[3,5-dichloro-2-oxo-6-{[(2R)-2-isobutylpyrpyrrolidin-l-yl]methyl}pyridin-l(2H)-yl]ethyl}benzonitrile as a white solid.
[0120]
Production Example 53
To a solution of 170 mg of 4-{2-[3,5-dichloro-2<>xo-fi-([(2N)-2-propylpyrrolidin-l-yl]methyl}pyridin-l(2ll)-yl|ethyl}benzonitrile in 4.0 ml oI'DMHO were udtled 170 ul of triethylamine and 85 mg of hydroxylamine hydrochloride lit room tomperuture, followed by stirring at 100°C overnight. After cooling, water was added (herein, and the precipitated solid WUN collected by filtration to obtain 180 inu ul 4-12~\ l,5-dichloro-2-oxo-6-{[(2S)-2-propylpyrrolitlin-l-yl]methyl}pyridin-l(2H)-yl|o(l»yl|-N'-hydroxybenzenecarboxyimidamide.
[0121]
Production Example 54
To a solution of 500 mg of 4-{2-[3,5-dichloro-2-oxo-6-{[(2R)-2-isobutylpyrrolidin-l-yl]methyl}pyridin-l(2H)-yl]ethyl}benzoic acid trifluoroacete in 10 ml of DMF were added 148 ul of triethylamine, 206 mg of l-(3-dimethylominopropyl)-3-ethylcarbodiimide hydrochloride, 191 mg of HOBt, and 58 mg of hydrazine monohydrate in this order at room temperature, followed by stirring at the MIIIIIO temperature overnight. Water and ethyl acetate were added to the reaction solution to curry mil u liquid separation operation. The organic layer was washed with a saturated m|iiemiN sodium chloride solution and then dried over anhydrous sodium sulfate, and I ho mtlvonl was evaporated under reduced pressure The residue was purified by silica gel column chromatography to obtain 400 mg of 4-{2-|3,5-dlehloro-2-oxo-6-{[(2R)-2-isobulylpyrrolldln-l-yl]methyl}pyridln-l(2ll)-yl|olhyl}benzohydrazine.
[0122]
Production Example 55
To a solulion of 4.0 g of methyl 4-[2-(5-cyclopropyl-3,6-dlmelhyl-2-oxopyridin-l(2H)-yl)ethyl|ben/.oalo in 150 ml of acetic acid was added 1.0 g ol'lrlchloroisocyanuric acid at room temperature, followed by stirring at the same temperature for 4 hours. Water

and ethyl acetate were added thereto to carry out a liquid separation operation. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 4.4 g of methyl 4-[2-[6-(bromomethyl)-5-cyclopropyl-3-methyl-2-oxopyridin-l(21 l)-yl]ethyl]benzoate in a colorless amorphous state.
[0123]
Production Example 56
To a solution of 1.3 g of methyl 4-[2-(3,6-dimethyl-2-oxopyridin-l(2H)-yl)ethyl]benzoate in 26 ml of acetic acid was added 1.8 g of N-bromosuccinimide at room temperature, followed by stirring at 90°C overnight. After cooling, water and chloroform were added thereto to carry out a liquid separation operation. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.8 g of methyl 4-{2-[5-bromo-6-(bromomethyl)-3-methyl-2-oxopyridin-l(2H)-yl]ethyl}benzoate.
[0124]
The Production Example Compounds 57 to 99 were prepared in the same manner as the methods of Production Examples 1 to 56 above using the respective corresponding starting materials. The structures, the production proccHNtm, mid the phyfiieoohemical data of the Production Example Compounds are shown in TublcM K to 24.
[01251
Example 1
To a solution of 500 mg of methyl 4-{2-[6-(bromonietliyl)-H,5-dlchloro-2-
oxopyridin-l(2H)-yl|othyl}benzoate in 10 ml of DMF were luldeil 200 mg of potassium
carbonate and 200 mg of 3-isopropyl-N-methylbenzenamine, followed by stirring at 60°C
/-v overnight. After leaving it to be cooled at room temperature, water and ethyl acetate were
added thereto to carry out a liquid separation operation. The organic layer was washed with saturated brine, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 420 mg of methyl 4-{2-[3,5-dichloro-6-{[(3-isopropylphenyl)(methyl)amino]methyl}-2-oxopyridin-l (21 l)-yl |cthyl} benzoate.
[0126]
Example 2
To a solution ol'173 mg of tert-butyl (4-ethylpyridln-2-yl)oinbumate in 3.0 ml of DMF was added 28 mg of 55% sodium hydride (oily), followed by Ntlrring for 30 minutes, and then 300 mg of tort-butyl 4-{2-[6-(bromomethyl)-3,5-(llchloro-2-oxopyrldin-l(2H)-yl]ethyl}benzonto WIIN added thereto, followed by stirring tit the mime temperature as room

temperature overnight. Ethyl acetate and water were addeil to the rcuction solution to carry out a liquid separation operation. The organic layer was washed with water and saturated brine in this order, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 300 mg of tert-butyl 4-{2-[6-{[(tert-butoxycarbonyl)(4-elhylpyridin-2-yl)amino]methyl} -3,5-dichloro-2-oxopyridin-1 (2H)-yl]ethy I} benzoate.
[0127]
Example 3
A solution of 254 mg of methyl 4-{2-[5-bromo-6-(bromomcthyl)-2-oxopyridin-l(2H)-yl]ethyl}benzoate and 157 mg of 6-methylindoline in 2.5 ml of NMP was stirred at 140°C for 10 minutes using a microwave device (INITIATOR 60 manufactured by Biotage Japan Ltd.). After leaving it to be cooled at room temperature, ethyl acetate and water were added to the reaction solution to carry out a liquid separation operation. The organic layer was washed with water and saturated brine, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 170 mg of methyl 4-(2-{5-bromo-6-[(6-methyl-2,3-dihydro-1 H-indol-1 -yl)methyl]-2-oxopyridin-1 (2H)-yl} ethyl)benzoate.
[0128]
Example 4
To a solution of 200 mg of tert-butyl 4-{2-[6-(bromomethyl)-3,5-dichloro-2-oxopyridin-l(2H)-yl]ethyl}benzoate in 2.0 ml of DMF were added 55 mg of sodium carbonate and 66 mg of 4-propylpiperidine, followed by stirring at room temperature overnight. Ethyl acetate and water were added to the reaction solution to carry out a liquid separation operation. The organic layer was washed with water and saturated brine in this order, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column cliioiiinloyiiiphy to obtain 215 mg of tert-butyl 4-{2-|3,5-dichloro-2-oxo-6-[(4-propylplperldlii-1-yDmethyl ]pyridin-l(2Il)-yl]ethyl} benzoate.
[0129]
Example 5
To a solution of 420 mg of methyl 4-{2-[3,5-dichloro-6-{|(3-isopropylphenyl)(methyl)amino]methyl}-2-oxopyridin-l(2Il)-yl|ethyl}benzoate in 8.0 ml of 1,4-dioxane was added 1.0 ml of 6 M hydrochloric acid, followed by stirring at 90°C overnight. After leaving it to be cooled at room temperature, chloroform and water were added thereto to carry out a liquid separation operation. The organic layer was washed with saturated brine, then dried over anhydrous sodium suH*ule, mid concentrated under reduced pressure. The residue was dissolved in a 1 M aqueous sodium hydroxide solution, followed by addition of 1 M hydrochloric acid, and the precipitated solid was

collected by filtration. The Holid was dried and then rcproclplliiUscI with ethanol to obtain 177mgof4-{2-|3,5-(llcliloro-6-{[(3-isopropylphenyl)(methyl)ninliio|methyl}-2-oxopyridin-1 (21 l)-yl|othyl}benzoic acid as a colorless solid.
[0130]
Example 6
To a solution of 100 mg of tert-butyl 4-{2-[3,5-dichloro-6-{|methyl(3-methylphenyl)amino|methyl}-2-oxopyridin-l(2H)-yl]ethyI}ben/.oale in 2.0 ml of DCM was added 500 uL of trifluoroacetic acid, followed by stirring at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and then to the residue were added a 1 M aqueous sodium hydroxide solution and water, followed by dissolution. The solution was neutralized by the addition of 1 M hydrochloric acid, and the precipitated solid was collected by filtration to obtain 62 mg of 4-{2-[3,5-dichloro-6-{[methyl(3-methylphenyl)amino]methyl}-2-oxopyridin-l(2II)-yl]ethyl}benzoicacid.
[0131]
Example 7
To a solution of 295 mg of tert-butyl 4-{2-[6-{[(tert-butoxycarbonyI)(4-ethylpyridin-2-yl)amino]methyl} -3,5-dichloro-2-oxopyridin-1 (2H)-yl jethyl} benzoate in 2.9 ml of DCM was added 2.9 ml of trifluoroacetic acid, followed by stirring at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, and then the residue was washed with ethyl acetate to obtain 265 mg of 4-{2-[3,5-dichloro-6-{[(4-ethylpyridin-2-yl)amino]methyl}-2-oxopyridin-l(211)-yl |ethyl}benzoic acid trifluoroacetate.
[0132]
Example 8
To a solution of 20 mg of 3,5-dichloro-l-{2-[4-(methoxycarbonyl)phenyl]ethyl}-6-oxo-l,6-dihydropyridine-2-carboxylic acid in 1 ml of THF were added 11 uL of oxalyl dichloride and 4 ul of DMF, followed by stirring at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure. The obtained residue was added to a separately prepared solution of 20 mg of 3-ethyhmillnc anil 11 mg of triethylamine in 1 ml of TIIF, followed by stirring at room tomporiiluro for 2 hours. Water and ethyl aceliile wore added thereto to carry out it ll<|iilmmomelhyI)-2-oxopyridin-l(2H)-yl]ethyl}benzoule and 176 mg of 7-ethylindoline in 2.5 ml of NMP was stirred at 140°C for 10 minutes using a microwave device. After leuving it to be cooled at room temperature, ethyl acetate and water were added thereto to carry out a liquid separation operation. The organic layer was washed with water and saturated brine, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain methyl 4-(2-{5-bromo-6-[(7-ethyl-2,3-dihydro-llI-indol-l-yl)methyl]-2-oxopyridin-l(2H)-yl}otliyl)beiv/,oute. To a solution of the present compound in 2.5 ml of 1,4-dioxane was added 2.5 ml of 6 M hydrochloric acid at room temperature, followed by heating and reflux overnight under an argon atmosphere. After leaving it to be cooled at room temperature, llio Holvent was evaporated under reduced pressure and the precipitated solid WIIM washed with ethyl acetate to obtain 237 mg of 4-(2-{5-bromo-6-[(7-ethyl-2,3-dihydro-11 l-lndol-1 -yl)methyl]-2-oxopyridin-l(2ll)-yl}ethyl)bonzoic acid.
[0138J
Example 14
A solution of 250 mg of methyl 4-{2-[5-bromo-o-(broiuomethyl)-2-oxopyridin-l(2H)-yl]ethyl}bcnzoutc find 240 mg of 7-(trifluoromethyl)-l,2,.l,4-tolnihydroquinoline in 2.5 ml of NMP wus stirred at 140°C for 10 minutes using a microwave device. After leaving it to be cooletl at room temperature, ethyl acetate and water were added thereto to carry out a liquid separation operation. The organic layer was washed with water and saturated brine, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain methyl 4-{2-[3,5-dichloro-2-oxo-6-{[7-(trifluoromethyl)-3,4-dihydroqulnolin-l(2II)-yl]ethyl}benzoate. To a solution of the present compound in 2.5 ml of Tl-IF was added 2.0 ml of a 1 M aqueous sodium hydroxide solution, followed by heating and reflux for 2 days under an argon atmosphere. After leaving it to be cooled at room temperature, the reaction solution was neutralized by the addition of 1 M hydrochloric acid. After the solvent was evaporated under reduced pressure, the precipitated solid was collected by filtration to obtain 145 mg of 4-{2-[3,5-dichloro-2-oxo-6-{[7-(trifluoromethyl)-3,4-dihydroquinolin-1 (211)-yl]ethyl} benzoic acid.
[0139]
Example 15
To a solution of 250 mg of methyl 4-{2-[6-(bromomelhyl)-3,5-dichloro-2-oxopyridin-l(2H)-yl]ethyl}benzoate in 2.5 ml of NMP were added 247 mg of potassium carbonate and 120 mg of 6-ethylindoline hydrochloride, followed by stirring at 60°C overnight. After leaving it to be cooled at room temperature, water and ethyl acetate were added to the reaction solution to carry out a liquid separation operation. The organic

layer was washed with saturated brine, then dried over anhydroiiN (indium sulfate, and concentrated under reduced pressure. The residue was purified by HIIIOU gel column chromatography to oblain methyl 4-(2-{3,5-dichloro-6-|(6-elhyl-2,3-dlhydro-lII-indol-l-yl)methyl]-2-oxopyriilin-l(21I)-yl}ethyl)benzoate. To a Niiliilinn of llic present compound in 2.5 ml of 1,4-dloxane was added 2.5 ml of 6 M hydrochloric ucld at room temperature, followed by heating and reflux overnight under an argon atmosphere. After leaving it to be cooled at room temperature, the solvent was evaporated under reduced pressure, and the precipitated solid was collected by filtration to obtain 196 mg of 4-(2-{3,5-dichloro-6-[(6-ethyl-2,3-dihydro-lH-indol-l-yl)methyl]-2-oxopyridin-l(2H)-yl}ethyl)benzoic acid.
[0140]
Example 16
To a solution of 77 mg of indoline in 2.0 ml of DM I1' was added 58 mg of
^^ potassium tert-butoxide, followed by stirring at room temperature for 30 minutes, and then
200 mg of tert-butyl 4-{2-f6-(bromomethyl)-3,5-dichloro-2-nxnpyrldln-l(2H)-
yl]ethyl}benzoate WHH added thereto, followed by stirring al Iho name temperature
overnight. Ethyl acetate and water were added to the reaction Nolutloii to carry out a
liquid separation operation, and the organic layer was washed with water and saturated
brine in this order, then dried over anhydrous sodium sulfate, and concentrated under
reduced pressure. The residue was purified by silica gel column chromatography to
obtain 180 mgof tort-butyl 4-(2-|3,5-dichloro-6-(2,3-dlhydro-IIMndnl-l-ylmethyl)-2-
oxopyridin-l(2l l)-yl |elhyl }bcn/,oate. To a solution of the presont compound in 1.8 ml of
DCM was added 1.8 ml of trilluoroacetic acid, followed by Mining at room temperature
for 4 hours. The solvent was evaporated under reduced pressure ami the precipitated
solid was washed with ethyl acetate to obtain 70 mg of 4-{2-[3,5-diehloro-6-(2,3-dihydro-
lH-indol-1 -ylmethyl)-2-oxopyridin-l(2H)-yl]ethyl}benzoic acid.
*^ [0141]
Example 17
A solution of 600 mg of tert-butyl 4-{2-[6-(bromomethyl)-3,5-dichloro-2-oxopyridin-l(2H)-yl]elhyl}benzoate and 1.0 g of (2S)-2-propylpyrrolidlne in 6.0 ml of NMP was stirred at 140°C for 10 minutes using a microwave device. After leaving it to be cooled at room temperature, ethyl acetate and water were added thereto to carry out a liquid separation operation. The organic layer was washed with saturated brine, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. To a solution of the obtained compound in 6.0 ml of DCM was added 6.0 ml of trifluoroacetic acid, followed by stirring at room temperature for 4 hours. The solvent was evaporated under reduced pressure and the precipitated solid was washed with ethyl acetate to obtain 628 mg of 4-{2-[3,5-

dichloro-2-oxo-6-{[(2S)-2-propylpyrrolidin-l-yl]methyl}pyridin-l(2II)-yl]ethyl}benzoic acid trifluoroacetate.
[0142]
Example 18
To a solution of 600 mg of tert-butyl 4-{2-[6-(bromomelhyl)-3,5-dichloro-2-oxopyridin-l(2H)-yl]ethyl}benzoate in 6.0 ml of NMP were milled 539 mg of potassium carbonate and 255 nig of(2K)-2-isobutylpyrrolidine hydrochloride, followed by stirring at 60°C overnight. After leaving it to be cooled at room temperature, ethyl acetate and water were added thereto to carry out a liquid separation operation, The organic layer was washed with Haturutcd brine and then dried over anhydioiiN sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography, and to a solution of the obtained compound in 6.0 ml of DCM was added 6.0 ml of trifluoroacetic acid, followed by stirring at room temperature for 4 hours. After the solvent was evaporated under reduced pressure, the precipitated solid was washed with ethyl acetate to obtain 518 mg of 4-{2-[3,5-dichloro-6-{[(2R)-2-isobutylpyrrolidin-1 -yl]methyl}-2-oxopyridin-l(2H)-yl]ethyl}benzoic acid trifluoroacetate.
[0143]
Example 19
A solution of 100 mg of tert-butyl 4-{2-[6-(bromomelhyl)-3,5-dichloro-2-oxopyridin-l(2H)-yl|ethyl}benzoate and 84 mg ofN-methyl-3-(lrlfluoromethoxy)aniline in 2.0 ml of NM1* WIIH Nlirred at 140°C for 10 minutes usiny n microwave device. After leaving it to be cooled nl room temperature, ethyl acetate and water were added to the reaction solution to carry out a liquid separation operation, The organic layer was washed with saturated brine ami then dried over anhydrous sodium sull'iilc, and the solvent was evaporated under reduced pressure. The residue wus purl lied by NIIICII gel column chromatography to obtain 51 mgof4-{2-[3,5-dichloro-6-(|tnethyl|3-(trifluoromethoxy)phenyl |amlno}methyl)-2-oxopyridln-1(211)-yl |ethyl} benzoic acid.
[0144]
Example 20
To a solution of 200 mg of tert-butyl 4-{2-[6-(bromomethyl)-3,5-dichloro-2-oxopyridin-l(2H)-yl]ethyl}benzoate in 6.0 ml of DMF were added 96 mg of potassium carbonate and 76 mg of N-methylcyclopentanamine hydrochloride at room temperature, followed by stirring overnight. Water and ethyl acetate were added to the reaction solution to carry out a liquid separation operation. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 203 mg of tert-butyl 4-{2-[3,5-dichloro-6-

{[cyclopentyl(methyl)amino]methyl}-2-oxopyridin-l(2H)-yl]ethyl}benzoate as a white solid.
[0145]
Example 21
A mixed solution of 150 mg of tert-butyl 4-{2-[6-(bromomethyl)-3,5-dichloro-2-oxopyridin-l(2H)-yl]ethyl}benzoate, 45 mg of potassium carbonate, 91 mg of N,5-dimethyl-l,3-thiazol-2-amine, and 5.0 ml of NMP was stirred at 110°C for 10 minutes using a microwave device. After cooling, ethyl acetate and water were added to the reaction solution to carry out a liquid separation operation. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over nnhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 139 mg oltorl-biilyl 4-{2-|3,5-dichloro-6-{[methyl(5-methyl-l,3-thia/()l-2-yl)amino]methyl}-2-oxopyihllii-l(2ll)-yl|ethyl}benzoate as a white solid.
[0146]
Example 22
A solution of 20 mg of methyl 4-{2-[6-(bromomethyl)-3-ehloro-5-cyclopropyl-2-oxopyridin-l(2H)-yl]ethyl}benzoate, 120 mg of N-methyl-3-(trliluorornethyl)aniline hydrochloride, and 200 u,l of N-ethyl-N-isopropylpropan-2-amine in 4.0 ml of NMP was stirred at 140°C for 10 minutes using a microwave device. After cooling, water and ethyl acetate were added thereto to carry out a liquid separation operation. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography lo obtain 240 mg of methyl 4-{2-[3-chloro-5-cyclopr()pyl-6-({methyl[3-(trifluoromethyl)phenyl|amlno}methyl)-2-oxopyridin-l(2H)-yl]othyl}benzoate.
[0147]
Example 23
To a solution of 450 mg of tert-butyl 4-{2-[3-bromo-6-(hromomethyl)-5-cyclopropyl-2-oxopyrldln-l(2lI)-yl]ethyl}benzoate in 9.0 ml of l)Mlv were added 220 ul ofN-ethyl-N-isopropylpropun-2-amine and 190 mg of (2U)-2-lNolwtylpyrrolldlne hydrochloride at room temperature, followed by stirring oven night, Water and ethyl acetate were added to the reliction solution to carry out a liquid Hopnralinn operation. The organic layer was WDNIICCI with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 350 mg of tert-butyl 4-{2-[3-bromo-5-cyclopropyl-6-{[(2R)-2-isobutylpyrrolidin-l -yl |methyl}-2-oxopyridin-l(2H)-yl]ethyl}benzoate as a white solid.

[0148]
Example 24
A solution of 120 mg of methyl 4-{2-[6-(bromomethyl)-5-cyclopropyl-3-methyl-2-oxopyridin-l(2H)-yl]ethyl}benzoate, 75 mg of N-methyl-3-(trifluoromethyl)aniline hydrochloride, and 90 mg of potassium carbonate in 2.4 ml of NMP WHS stirred at 140°C for 15 minutes using a microwave device. After cooling, water and ethyl acetate were added thereto to carry out a liquid separation operation. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 120 mg of methyl 4-{2-[5-cyclopropyl-3-methyl-6-({methyl[3-(trifluoromethyl)phenyl]amino}methyl)-2-oxopyridin-l(2H)-yl]ethyl}benzoate.
[0149]
Example 25
To a solution of 100 mg of tert-butyl 4-{2-[6-(bromomethyl)-3,5-dichloro-2-oxopyridin-l(2H)-yljethyl}benzoate in 3.0 ml of DMF were added 83 mg of 3-chloro-N,2-dimethylaniline hydrochloride and 70 mg of N-ethyl-N-lNopiopylpropitn-2-nmine at room temperature, followed by utirring at 70°C overnight. 50 my, of poliiNMlum carbonate was added thereto at the mime temperature, followed by stirring for 5 IHHHH. After cooling, water and ethyl acetulu were added thereto to carry out a liquid Hcpiinillon operation. The organic layer was wanhed wllh a saturated aqueous sodium chlorUlu uolutlon and then dried over anhydrous sodium Niilfute, and the solvent was evaponiled under reduced pressure. The residue was purified by silica gel column chromatography lo obtain 10 mg of colorless oily tert-butyl 4-{2-[3,5-dichloro-6-{[(3-chloro-2-methylphenyl)(melhyl)amino]methyl}-2-oxopyridin-1 (2H)-yl]ethyl }benzoate.
[0150]
Example 26
To a solution of 200 mg of tert-butyl 4-{2-[3,5-dichloro-6-{[cyclopentyl(methyl)umino]methyl}-2-oxopyridin-l(211)-yl|ethyl)benzoate in 2.0 ml of DCM was added 2.0 ml of trifluoroacetic acid at room temperature, followed by stirring at the same temperature for 4 hours. After the solvent was evaporated under reduced pressure, the residue WIIN made into powders by the addition of ethyl acetate to obtain 191 mgof4-{2-[3,5-dlchloro-6-{|cyclopentyl(methyl)amino|melhyl}-2-oxopyridin-l(2H)-yljethyl}benzoic acid Irilluoroacetate as a white solid.
[0151]
Example 27
To a solution of 80 tug of tert-butyl 4-{2-[5-cyelopiopyl-6-{|( JR)-2-isobutylpyrrolidin-l-yl|methyl}-3-methyl-2-oxopyriclln-l (21 l)-yl|olhyl}bcnzoate in 1.6 ml

of DCM was added 500 u,l of trifluoroacetic acid at room temperature, followed by stirring overnight. After the solvent was evaporated under reduced pressure, to the residue were added a 1 M aqueous sodium hydroxide solution and water, followed by dissolution. The solution was neutralized by the addition of 1 M hydrochloric ucid, unci then chloroform was added thereto to carry out a liquid separation operation. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. To a solution of the residue in 1.7 ml of ethyl acetate was added 500 f.tl of a 4 M hydrogen chloride-ethyl acetate solution under ice-cooling, followed by stirring at room temperature for 3 hours. After the solvent was evaporated under reduced pressure, the obtained hydrochloride was made into powders with a mixed solvent of ethyl acetate and n-hexane to obtain 26 mg of 4-{2-[5-cyclopropyl-6-{[(2R)-2-isobutylpyrrolidin-l-yl]methyl}-3-methyl-2-oxopyridin-l(2II)-yl]ethyl}benzoic acid as a colorless solid.
[0152]
Example 28
^ To a solution of 100 mg of methyl 4-{2-[5-bromo-3-chloro-6-{[(2R)-2-
isobutylpyrrolidin-l-yl]methyl}-2-oxopyridin-l(2H)-yl]ethyl}benzoate in 4.0 ml of 1,4-dioxane was added 330 u.1 of 6 M hydrochloric acid at room temperature, followed by stirring at 90°C overnight. After cooling, the reaction solution was neutralized by the addition of a 1 M aqueous sodium hydroxide solution, then water was added thereto, and the precipitated solid was collected by filtration to obtain 58 mg of 4-{2-[5-bromo-3-chloro-6-{[(2R)-2-isobutylpyrrolidin-l-yl]methyl}-2-oxopyridin-l(2II)-yl]ethyl}benzoic acid as a colorless solid.
[0153]
Example 29
To a mixture of 190 mg of methyl 4-{2-[3-chloro-5-oyi'lopmpyl-2-oxo-6-{[(2S)-2-propylpyrrolidin-l-yl|inelhyl}pyridin-l(2H)-yl]ethyl}ben/nalo in o,() ml of Tl IF and 1.0 ml of methanol was added 1.25 ml of a 1 M aqueous sodium hydroxide solution at room temperature, followed by stirring at 60°C for 4 hours. Alter cooling, the reaction solution was neutralized by the addition of 1 M hydrochloric acid, and then ethyl acetate was added thereto to carry out a liquid separation operation. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. To a solution of the residue in 5.0 ml of ethyl acetate was added 1.0 ml of a 4 M hydrogen chloride-ethyl acetate solution under ice-cooling, followed by stirring at room temperature for 30 minutes. After the solvent was evaporated under reduced proNmire, the obtained hydrochloride was mude into powders with a mixed solvent of methanol and ethyl acetate to obtain 171 mg of 4-{2-[3-chloro-5-cyclopropyl-2-oxo-6-{f(2N)-2-propylpyrrolidin-l-yl]methyl}pyridin-l(2II)-yl|ethyl}benzoic acid as a white nolld.
[0154]

Example 30
To a solution of 205 mg of tert-butyl 4-{2-[6-{[butyl(melhyl)ninino]methyl}-3,5-dichloro-2-oxopyridin-l(2H)-yl]ethyl}benzoate in 2.0 ml ofclhyl aoelute was added 2.0 ml of a 4 M hydrogen chloride-ethyl acetate solution at room temperature, followed by stirring for 6 hours. After the solvent was evaporated under reduceil pressure, to the residue was added water, followed by dissolution. The reaction solution was neutralized by the addition of a saturated aqueous sodium hydrogen carbonate solution, and chloroform was added thereto to carry out a liquid separation operation. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over unhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 37 mg of 4-{2-[6-{[butyl(methyl)amino]methyl}-3,5-dichloro-2-oxopyridin-1 (2H)-yl]ethyl}benzoic acid as a white solid.
[0155]
Example 31
To a mixture of 143 mg of methyl 4-{2-[6-{[(2R)-2-isobutylpyrrolidin-l-yl]methyl}-3,5-dimethyl-2-oxopyridin-l(2H)-yl]ethyl}benzoate in 2.0 ml of THF and 2.0 ml of methanol was added 1.0 ml of a 1 M aqueous sodium hydroxide solution at room temperature, followed by stirring for 22 hours. The reaction solution was neutralized by the addition of 1 M hydrochloric acid, and then chloroform was added thereto to carry out a liquid separation operation. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. To 2.0 ml of a solution of the residue in 1,4-dioxane was added 168 ul of a 4 M hydrogen chloride-1,4-didxane solution under ice-cooling, followed by stirring at room temperature for 30 minutes. After the solvent was evaporated under reduced pressure, the obtained hydrochloride was made into powders from ethyl acetate to obtain 96 mg of 4-{2-[6-{[(2R)-2-isobutylpyrrolidin-l-yl]methyl}-3,5-dimethyl-2-oxopyridin-l(2H)-yl]ethyl}ben/,olc acid hydrochloride as a white solid.
[0156]
Example 32
A solution of 201 mg of tert-butyl 4-{2-[5-bromo-n (limiiiomulhyl)-2-oxopyridin-l(2H)-yl]ethyl}benzoato, 214 mg of N-methyl-3-(trifluoroiiiolliyr)iiiilllne hydrochloride, and 0.14 ml of triethylamlne In 2.0 ml ofNMP was stirred lit I40°C for 30 minutes using a microwave device. After cooling, ethyl acetate and water were added to the reaction solution to carry out a liquid separation operation. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography, and then the obtained solid was made into powders with

diethylether to obtain 47 mg of 4-{2-[5-bromo-6-({mcthyl|3-(trifluoromethoxy)pllOllyl|andno}methyl)-2-oxopyridin-l(2ll)^ white solid.
[0157|
Example 33
To a solution of 100 mg of tert-butyl 4-{2-[6-(bromomelhyl)-3,5-dichloro-2-oxopyridin-l(2H)-yl|ethyl}benzoate in 2.0 ml of DMF were added 39 mg of potassium carbonate and 42 mg of 3-methoxy-N-methylbenzylamine ul room temperature, followed by stirring overnight. After cooling, water and ethyl acetule were added to the reaction solution to carry out a liquid separation operation. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and to a solution of the residue in 2.0 ml of DCM was added 500 ul of trifluoroacetic acid at room temperature, followed by stirring overnight. The solvent was evaporated under reduced pressure and the residue was made into powders from a mixed solvent of ethyl acetate and n-hexane to obtain 77 mgof4-{2-[3,5-dichloro-6-{[(3-methoxybenzyl)(methyl)amino]methyl}-2-oxopyridin-l(2H)-yl]ethyl}benzoic acid trifluoroacetate as a white solid.
[0158]
Example 34
A solution of 200 mg of methyl 4-{2-[6-(bromomethyl)-3-chloro-5-cyclopropyl-2-
oxopyridin-l(2H)-yl]ethyl}benzoate, 77 mg of 3-methoxy-N-methylaniline, and 80 mg of
potassium carbonate in 4.0 ml of DMF was stirred at 140°C for 10 minutes using a
microwave device. After cooling, ethyl acetate and water were added to the reaction
solution to carry out a liquid separation operation. The organic layer was washed with a
saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate,
and the solvent was evaporated under reduced pressure. The residue was purified by
v silica gel column chromatography to obtain 200 mg of methyl 4- {2-| 3-chloro-5-
cyclopropyl-6-{[(3-melhoxyphenyl)(methyl)amino]methyl}-2-oxopyridin-l(2H)-yl] ethyl }benzoate.
To a mixture of 200 mg of the obtained methyl 4-{2-[3-chloro-5-cyclopropyl-6-{[(3-methoxyphenyl)(methyl)amino]methyl}-2-oxopyridin-l(2ll)-yl|ethyl}benzoatein4.0 ml of THF and 2.0 ml of methanol was added 1.25 ml of a I M aqueoiiN sodium hydroxide solution at room temperature, followed by stirring at 65"C lor 2 IIOIICN, After cooling, the reaction solution WBN neutralized by the addition of 1 M hydrochloric acid, then water was added thereto, and the precipitated solid was collected by llllrallon, The obtained solid was purified by silica gel column chromatography to obtain ol mg ul 4-{2-|3-chloro-5-cyclopropyl-6-{[(3-methoxyphenyl)(methyl)amino]methyl} -2-oxopyi ldin-1 (211)-yl]ethyl}benzoic acid.

[0159]
Example 35
To a solution of 120 mg of 4-{2-[3,5-dichloro-2-oxo-o-{|(2N)-2-propylpyrrolidin-l-yl]methyl}pyritlln-1 (21 l)-yl]ethyl}benzoic acid in 4.0 ml of 1,4-dloxane wus added 70 mg of CDI at room (emperulure, followed by stirring overnight. It was poured into 4.0 ml of 28% aqueous ammonia at the same temperature, followed by Nllrrhig for I hour. Water and chloroform were addeil to the reaction solution to curry out a liquid separation operation. The organic layer was washed with a saturated m|UtmiiN sodium chloride solution and then dried over anhydrous sodium sulfate, and llie solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 40 mg of 4-{2-|3,5-dlchloro-2-oxo-6-{[(2S)-2-propylpyrrolldln-l-yl]methyl}pyridin-l(2II)-yl]ethyl}benzamide.
[0160]
Example 36
To a solution of 800 mg of methyl 4-{2-[5-bromo-3-chloro-6-{[(2R)-2-isobutylpyrrolidin-l-yl]methyl}-2-oxopyridin-l(2H)-yl]ethyl}benzoate in 16 ml of 1,4-dioxane were added 122 mg of methylboronic acid, 466 mg of tripotassium phosphate, and 181 mg of tetrakistriphenylphosphine palladium at room temperature, followed by stirring at 90°C overnight. After cooling, water and ethyl acetate were added thereto, and then the insoluble materials were removed by filtration using Celite to carry out a liquid separation operation. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 200 mg of methyl 4-{2-[3-chloro-6-{[(2R)-2-isobutylpyrrolidin-1 -yl]methyl} -5-methy 1-2-oxopyridin-1 (2H)-yl]ethyl} benzoate.
[0161]
-^ Example 37
To a solution of 270 mg of methyl 4-{2-[3,5-dichloro-2-oxo-6-(2-oxoethyl)pyridin-l(2H)-yl]ethyl}benzoate in 15 ml of chloroform were added 143 mg of (2S)-2-propylpyrrolidine hydrochloride, 78 mg of sodium acetate, and 249 mg of sodium triacetoxyborohydride at room temperature, followed by stirring for 1 hour. Saturated sodium hydrogen carbonate and chloroform were added to the reaction solution to carry out a liquid separation operation. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 270 mg of yellow oily methyl 4-{2-[3,5-dichloro-2-oxo-6-{2-[(2S)-2-propylpyrrolidin-l-yl]ethyl}pyridin-l(2II)-yl|ethyl}benzoate.
[0162]
Example 38

A mixture of 130 mg of 4-{2-[6-({[(lR,2R)-2-acetoxycyclopentyl](methyl)amino}methyl)-3,5-dichloro-2-oxopyridin-l(2H)-yl]ethyl}benzoic acid trifluoroacetate, 50 mg of potassium carbonate, and 3.0 ml of methanol was stirred at room temperature overnight, and then stirred ul 60°C for 3 hours. After cooling, the mixture was neutralized (pH=7) by the slow addition of 1 M hydrochloric acid, followed by addition of ethyl acetate to carry out n liquid separation operation. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography. To a solution of the obtained compound in 3.0 ml of ethyl acelalo solution was added 500 u.1 of 4 M hydrogen chloride-ethyl acetate solution under ice-cooling, followed by stirring at room temperature lor 30 minutes. After the solvent was evaporated under reduced pressure, the obtained hydrochloride was made into powders wild u mixed solvent of ethyl acetate and n-hexane to obtain 10 mg of 4-{2-[3,5-dichloro o-(l|( lK,il<)-2-hydroxycyclopentyl|(melhyl)umino}methyl)-2-oxopyridln-l(2ll)-yl|olhyl}benzoicacid hydrochloride as a white solid.
[0163]
Example 39
To a solution of 250 mg of 4-{2-[6-({(tert-butoxycarbonyl)[3-(trifluoromethoxy)phenyl]amino}methyl)-3-chloro-5-cyclopropyl-2-oxopyridin-l(2H)-yl]ethyl}benzoic acid in 2.0 ml of ethyl acetate was added 0.1 ml of 4 M hydrogen chloride-ethyl acetate solution at room temperature, followed by stirring overnight. The precipitated solid was collected by filtration to obtain 200 mg of 4-{2-|3-chloro-5-cyclopropyl-2-oxo-6-( {[3-(trifluoromethoxy)phenyl]amino) methyl)pyridin-l (2H)-yl]ethyl} benzoic acid.
[0164]
Example 40
To a solution of 350 mg of tert-butyl 4-{2-[3-bromo-5-cyclopropyl-6-{[(2R)-2-isobutylpyrrolidin-l-yl]methyl}-2-oxopyridin-l(2H)-yl]ethyl}benzoate in 3.5 ml of 1,4-dioxane were added 100 mg of methylboronic acid, 470 mg of tripotassium phosphate, and 75 mg of tetrakistriphenylphosphine palladium at room temperature, followed by stirring at 90°C for 3 days. After cooling, water and ethyl acetate were added thereto, and then the insoluble materials were removed by filtration using Celite to carry out a liquid separation operation. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 80 mg of tert-butyl 4-{2-[5-cyclopropyl-6-{[(2R)-2-isobutylpyrrolidin-l-yl]methyl}-3-methyl-2-oxopyridin-l(2H)-yl]ethyl}benzoate.

[0165]
Example 41
To a solution of 200 mg of methyl 4-[2-(5-bromo-1 ehloio d mcthyl-2-
oxopyridine-l(2I l)-elhyl)bcnzoate in 2.0 ml of toluene wa« lukloil 400 fil of water, and
then 428 mg of 2-(trilluoromethoxy)phenylboronic acid, 552 mg oftripotassium
phosphate, 12 mg of palladium acetate, and 43 mg of dicyclohexyI(2\6'-
dimethoxybiphenyl-2-yl)phosphine were added in this order at room temperature, followed
by reflux at 90°C overnight. After cooling, water and ethyl acetate were added thereto,
and then the insoluble materials were removed by filtration using Celite to carry out a
liquid separation operation. The organic layer was washed with u Niilumted aqueous
sodium chloride solution and then dried over anhydrous sodium sullalu, and the solvent
was evaporated under reduced pressure. The residue was purlllecl by Hilica gel column
chromatography to obtain a preparation of 240 mg of methyl 4-(2-{6-methyl-2-oxy-3,5-
bis[2-(trifluoromelh(»xy)phcnyl|pyridin-l(2H)-yl}ethyl)beii/ojilo.
^ To a solution of 240 mg of the obtained methyl 4-(2-{o-mothyl-2-oxy-3,5-bis[2-
(trifluoromethoxy)phonyl|pyridin-l(2H)-yl}ethyl)benzoalc in 4,8 ml of carbon tetrachloride were added % mg of N-bromosuccinimide ami 4.2 nig of 2,2'-azobis(isobutyronllrllo), followed by heating and reflux overnight. After cooling, chloroform and water were added thereto to carry out a liquid depuration operation. The organic layer was wushod with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 240 mg of methyl 4-{2-[6-(bromomethyl)-2-oxo-3,5-bis|2-(trifluoromethoxy)phenyl]pyridin-l(2H)-yl]ethyl}benzoate.
To a solution of 140 mg of the crude material of the obtained methyl 4-{2-[6-(bromomethyl)-2-oxo-3,5-bis[2-(trifluoromethoxy)phenyl Jpyridin-1 (21 l)-yl]ethyl}benzoate in DMF were added 85 mg of potassium carbonate and 50 mg of (2R)-2-isobutylpyrrolidine hydrochloride at room temperature, followed by stirring overnight. Water was added thereto, and the precipitated solid was collected by nitration to obtain 150 mg of methyl 4-{2-[6-{[(2R)-2-isobutylpyrrolidin-l-yl|methyl)-2-oxo-3,5-bis[2-(trifluoromethoxy)pheny 1 ] pyridin-1 (2H)-yl]ethyl} benzoate.
To a mixed solution of 150 mg of the obtained methyl 4-{2-[6-{[(2R)-2-isobutylpyrrolidin-l-yl]methyl}-2-oxo-3,5-bis[2-(trifluoromethoxy)phenyl]pyridin-l(2H)-yl]ethyl}benzoate in 3.0 ml of THF and 1.5 ml of methanol were added 1.0 ml of a 1 M aqueous sodium hydroxide solution, followed by stirring at 65°C for 3 hours. After cooling, the reaction system was neutralized by the addition of 1 M hydrochloric acid, and chloroform was added thereto to carry out a liquid separation operation. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. To a solution of the residue in 2.0 ml of ethyl acetate was added 500 u-1

of a 4 M hydrogen chloride-ethyl acetate solution under ice-cooling, followed by stirring at room temperature for 30 minutes. After the solvent was evaporated under reduced pressure, the obtained hydrochloride was made into powders with a mixed solvent of ethyl acetate and n-hexane to obtain 60 mg of 4-{2-[6-{[(2R)-2-isobiilylpyirolidin-l-yl]methyl}-2-oxo-3,5-bis[2-(lrilluoromothoxy)phenyl]pyridin-l(2l l)-yl |ulliyl)lwir/olu acid hydrochloride.
[0166]
Example 42
To a suspension of 100 mg of 4-{2-[3,5-dichloro-2-ox«i-6-{|(2S)-2-propylpyrrolidin-l-yljmethyl}pyridin-l(2H)-yl]ethyl}ben/onitillc in 2.0 ml of toluene were added 80 mg of sodium azide and 170 mg of triethylamine hydrochloride at room temperature, followed by stirring at 100°C for 3 days. After cooling, water and ethyl acetate were added thereto to carry out a liquid separation operation. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was made into powders with a mixed solvent of ethyl acetate-n-hexaneto obtain 51 mg ol'3,5-dichloro-6-{[(2S)-2-propylpyrrolidin-l-yl|methyl}-l-{2-[4-(lH-tetrazol-5-yl)phenylJethyl}pyridin-2(lH)-one as a white solid.
[0167]
Example 43
To a solution of 50 nig of 4-{2-[3,5-dichloro-2-oxo-o-{|(2S)-2-propylpyrrolidin-l-yl]methyl}pyridin-l(2ll)-yl|clhyl}-N'-hydroxybenzenecarboxyliiildainlde in 1.0 ml of DMF was added 30 nig ol'C'DI at room temperature, followed by stirring at 80°C overnight. After cooling, water was added thereto, and the precipitated solid was collected by filtration to obtain 6.0 mg of 3,5-dichloro-l-(2|4( Voxo 4,5-dlhydro-l,2,4-oxadiazol-3-yl)plionyl|olliyl}-6-{[(2S)-2-propylpyrrolidln-l-yl|iuothyl)pyrldln-2(lII)-one.
[0168]
—^ Example 44
To a solution of 50 mg of 4-{2-[3,5-dichloro-2-oxo-6-{|(2S)-2-propylpyrrolidin-l-yl]methyl}pyridin-l(211)-yl]ethyl}-N'-hydroxybenzenecarboxyiinidamide in 1.0 ml of 1,4-dioxane were added 29 mg of l,8-diazabicyclo[5,4,0]undec-7-cne and 33 mg of 1,1'-carbonothiobis(lll-imldazole) at room temperature, followed by stirring at 80°C overnight. After cooling, water was added thereto and the precipitated solid was collected by filtration to obtain 36 mg of 3,5-dichloro-6-{[(2S)-2-propylpyrrolidin-l-yl|methyl}-l-{2-[4-(5-thioxo-4,5-dihydro-l ,2,4-oxadiazol-3-yl)phenyl]ethyl}pyridin-2( 111)-one.
[0169]
Example 45
To 50 mg of 4-{2-[3,5-dichloro-2-oxo-6-{[(2S)-2-propylpyrrolidin-l-yl]methyl}pyridin-l(2H)-yl]ethyl}-N'-hydroxybenzenecarboxyimidamide were added 1.0

ml of DCM, 15 ul of pyridine, and 13 u.1 of thionyl chloride in this order at room temperature, and the present mixture was stirred at the same temperature overnight. 1 M hydrochloric acid and chloroform were added to the reaction solution to carry out a liquid separation operation. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. To a solution of the residue in 2.0 ml of ethyl acetate was added 500 p.1 of a 4 M hydrogen chloride-ethyl acetute solution under ice-cooling, followed by stirring at room temperature for 30 minutes. After the solvent was evaporated under reduced pressure, the obtained hydrochloride WHS made into powders with a mixed solvent of ethyl acetate and n-heximo to obtain H.O mg of 3,5-dichloro-l-{2-[4-(2-oxldo-3l l-l,2,3,5-oxathiazol-4-yl)pheiiyl|olhyl | "f»-(|(2S)-2-propylpyrrolidin-l-yl|methyl}pyridin-2(lH)-onehydrochlnihlo,
[0170|
Example 46
To a mixture of 120 mg of 3-{[(4-{2-[3,5-dichloro-2-oxo-o-||(2S)-2-propylpyrrolidin-l-yl|melhyl}pyridin-l(2H)-yl]ethyl}ben/(»yl)iimim)|Nulfonly}propyl acetate in 2.0 ml of TIIF and 1.0 ml of methanol was added 1.0 ml of a 1 M aqueous sodium hydroxide solution at room temperature, followed by stirring for 3 hours. After cooling, the reaction solution was neutralized by the addition of 1 M hydrochloric acid, then water was added thereto, and the precipitated solid was collected by filtration. The obtained solid was purified by silica gel column chromatography to obtain 13 mg of 4-{2-[3,5-dichloro-2-oxo-6-{|(2S)-2-propylpyrrolidin-l-yl]methyl)pyiUlln-l(2II)-yl]ethyl}-N-[(3-hydroxypropyl)sulfonly]benzamide.
[0171]
Example 47
To a solution of 400 mg of 4-{2-[3,5-dichloro-2-oxn-r)-(|(2U)-2-
isobutylpyrrolidin-l-yl|inethyl}pyridin-l(2H)-yl]ethyl}ben/,oliyilrH/lnB in 8.0 ml of 1,4-
/-v dioxane was added 209 nig of N.N'-carbonyldiimidazole at room temperature, followed by
stirring at 65°C overnight. After cooling, water and ethyl iiecliilo wore added thereto to carry out a liquid Nopunition operation. The organic layer WIIN WUNIHUI with u saturated aqueous sodium chloride Nolution and then dried over anliydioiiH Nodluni mil late, and the solvent was evuponitod under reduced pressure. The residue WIIN purl Med by silica gel column chromatography to obtain 400 mg of 3,5-dichloro-l-{2-|4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl]ethyl} -6- {[(2R)-2-isobutylpy rrol Id I n-1 -y 11 methyl} pyridin-2(lH)-one. To a solution of the obtained 400 mg of 3,5-dichloro-l-{2-[4-(5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-yl)phenyl]ethyl}-6-{[(2R)-2-isobutylpyiTolldin-l-yl]methyl}pyridin-2(l I I)-one in 8.0 ml of ethyl acetate was added 2.0 ml of a 4 M hydrogen chloride-ethyl acetate solution under ice-cooling, followed by stirring at room temperature for 30 minutes. After the solvent was evaporated under reduced pressure, it

was made into powders with ethanol to obtain 195 mg of 3,5-dichloro-l-{2-[4-(5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-yl)phenyl]ethyl}-6-{[(2R)-2-isobutylpyrrolidin-l-yl]methyl}pyridin-2(Hl)-one hydrochloride as a white solid.
[0172]
Example 48
To a solution of 100 mg of 4-{2-[3,5-dichloro-2-oxo-6-{[(2S)-2-propylpyrrolidin-
l-yl]methyl}pyridin-l(2H)-yl]ethyl}benzohydrazine in 2.0 ml of ethanol were added 19
mg of potassium hydroxide and 51 mg of carbon disulfide at room temperature, followed
by stirring at 65°C overnight. After cooling, the reaction solution was acidified by the
addition of 1 M hydrochloric acid, then water was added thereto, and the precipitated solid
was collected by filtration to obtain 78 mg of 3,5-dichloro-6-{[(2S)-2-propylpyrrolidin-l-
yl]methyl}-l-{2-[4-(5-thioxo-4,5-dihydro-l,3,4-oxadiazol-2-yl)phenyl|ethyl}pyridin-
2(lH)-one.
^ [0173]
Example 49
To a solution of 100 mg of 4-{2-[3,5-dichloro-6-(|molhyl| V-(trifluoromethyl)plienyl|Hmino}methyl)-2-oxopyridin-l(2ll)yl|o!hyl|bcn/,oicacidin2.0 ml of DMF were udded 47 mg of l-(3-dimethylaminopropyl|- \ elhylcnrbodiimide hydrochloride, 43 mg of I lOItt, and 14 mg of hydrazine monoliydrnto In this order at room temperature, followed by stirring at the same temperature overnight. Water and ethyl acetate were added to the reaction solution to carry out a liquid separation operation. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain a crude material of 4-{2-[3,5-dichloro-6-({methyl[3-(trifluoromethyl)phenyl]amino}methyl)-2-oxopyridin-l (211)-yl (ethyl} benzohydrazine.
To a solution of the crude material of the obtained 4-{2-|3,5-dlehloro-6-
f~* ({methyl[3-(trifluoromethyl)phenyl]amino}methyl)-2-oxopyridln-1 (21 ()-
yl]ethyl}benzohydrazlne in 1.8 ml of 1,4-dioxane were added 40 fil oftriethylamine and 35 mg of N,N'-carbonyldlimidazole at room temperature, followed by Hllrring at 65°C overnight. After cooling, water was added thereto and the precipitated solid was collected by nitration to obtain 70 mg of 3,5-dichloro-6-({mclliyl|3-(trifluoromethyl)plicnyl|amino}methyl)-l-{2-[4-(5-oxo-4,5-illliydro-l,3,4-oxH/.ol-2-yl)phenyl |ethyl) pyrldlu-1 (21 l)-one.
[0174]
Example 50
To a solution of 150 mg of 4-{2-[3,5-dichloro-2-oxo-r)-{|(2U)-2-isobutylpyrrolidln-l-yl|methyl}pyridin-l(2H)-yl]ethyl}-N,-hydroxybenzenecarboxyimidamide in 2.3 ml of THF was added 69 mg of 1,1'-

carbonothiobis(lll-imidazole) at room temperature, followed by stirring at the same temperature for 2 hours. Water and ethyl acetate were added to the reaction solution to carry out a liquid separation operation. The organic layer was washed with a saturated sodium chloride and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. To a solution of the residue in 2.3 ml of THF was added 204 u.1 of a boron trifluoride/ethyl ether complex at room temperature, followed by stirring at the same temperature for 1 hour. Water was added thereto and the precipitated solid was collected by filtration to obtain 72 mg of S.S-dichloro^-d^R^-isobutylpyrrolidon-l-ylJmethylH-^-^-CS-oxo^.S-dihydro-l^-thto^^ yl)phenyl]ethyl}pyridin-2( 1 H)-one.
[0175]
Example 51
To a solution of 200 mg of 4-{2-[3,5-dichloro-2-oxo-6-{[(2S)-2-propylpyrrolidin-l-yl]methyl}pyridin-l(2H)-yl]ethyl}benzoic acid trifluoroacetate in 2.0 ml of 1,4-dioxane was added 90 mg of CDI at room temperature, followed by stirring overnight. Separately, to a solution of 90 mg of 3-(aminosulfonly)propyl acetate in 2.0 ml of 1,4-dioxane was added 80 u,L of l,8-diazabicyclo[5,4,0]undec-7-ene, and the thus prepared reaction solution was udded to the above-described reaction system al room temperature, followed by stirring at 60°C overnight. After cooling, waler was added thereto and the precipitated solid WHN collected by filtration. The obtained Niiliri WHN purified by silica gel column chromatography to obtain 120 mg of 3-{[(4-{2-|.1,.1-illulil»ii»-2-oxo-6-{[(2S)-2-propylpyrrolidin-l-yl|melhyl}pyridin-l(2H)-yl]ethyl}bon/,i»yl)iiminn|Hullbnly}propyl acetate.
[0176]
Example 52
To a solution of 800 mg of (lR,2R)-2-[(tert-
P-+. butoxycarbonyl)(methyl)amino]cyclopentyl acetate in 4.0 ml of ethyl acetate was added
4.0 ml of 4 M hydrogen chloride-ethyl acetate at room temperature, followed by stirring overnight. The solvent was evaporated under reduced pressure to obtain 605 mg of (lR,2R)-2-(methylamino)cyclopentyl acetate hydrochloride as a colorless oily substance. A mixed solution of 157 mg of the obtained colorless oily NiibNtanee, 150 mg of tert-butyl 4-{2-[6-(bromomethyl)-3,5-dichloro-2-oxopyridin-l(2H)-yl|ethyl}ben/oate, 0.13 ml of triethylamine, and 5.0 ml of DMF was stirred at room temperature overnight. A saturated aqueous sodium hydrogen carbonate solution and ethyl acetate wore added to the reaction solution to carry out a liquid Heparation operation. The orpnlc layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate, and the solvent was ovaporutcd under reduced pressure. The rcrtiduo was purified by silica gel column chromatography to obtain 153 mg of pale yellow oily tert-butyl 4-{2-[6-

({[(lR,2R)-2-acetoxycyclopentyl](methyl)amino}methyl)-3,5-cllchI()ro-2-oxopyridin-l(2H)-yl]ethyl}ben7.onte.
[0177]
Example 53
To a solution of 150 mg of tert-butyl 4-{2-[6-({[(l R,2R)-2-acetoxycyclopentyl](methyl)amino}methyl)-3,5-dichloro-2-oxopyrldin-l(2H)-yl]ethyl}benzoate in 2.0 ml of DCM was added 2.0 ml of trlfluoroacetic acid at room temperature, followed by stirring for 5 hours. After the solvent was evaporated under reduced pressure, it was made into powders with ethyl acetate to obtain 20 mg of 4-{2-[6-({[(lR,2R)-2-acetoxycyclopentyl](methyl)amino}methyl)-3,5-dichloro-2-oxopyridin-l(2H)-yl]ethyl}benzoic acid trifluoroacetate as a white solid.
[0178]
Example 54
To a solution of 350 mg of methyl 4-{2-[5-bromo-6-{[(2R)-2-isobutylpyrrolidin-l-yl]methyl}-3-methyl-2-oxopyridin-l(2H)-yl]ethyl}benzoate in 7.0 ml of toluene was added 1.8 ml of water at room temperature, and then 120 mg of a 2,4,6-trivinylcyclotriboroxane/pyridine complex, 304 mg of tripotassium phosphate, 16 mg of palladium acetate, and 59 mg of dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine were added thereto, followed by stirring at 90°C overnight. After cooling, water and ethyl acetate were added thereto, filtration was conducted using Celite, and a liquid separation operation was carried out. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 60 mg of methyl 4-{2-[6-{|(2K)-2-iNt)butylpyrrolidin-l-yl]methyl}-3-methyl-2-oxo-5-vinylpyridin-l(2H)-yl]ethyl}l)on/onlo,
[0179|
The Example Compounds 55 to 352 shown in Tabic* Iwlow were prepared in the same production procmseN as the Examples 1 to 54 using lliu roNpoollvo corresponding starting materials. The Nlruclures, the production proccsHtiH, mill 11 lit phynicochemical data of each of the Example Compounds are shown in Tables 2.1 lo KM).
[0180]
Furthermore, the structures of the other compounds of the present invention are shown in Table 101. These can be easily synthesized by using the preparation methods as described above, or the methods described in Examples and methods obvious to a skilled person in the art, or modified methods thereof.[01861 [Table 131


[01871] [Table 14]

[0188] [Table]51

[0189] [Table 16]

[0190] [Table 17]

[0191] [Table18]|

[0192] [Table 19]

[0193] [Table 20]

[0194] [Table 21]

[0195] [Table 22]

[01961 [Table 23]

[0197] [Table 24]

[0198] [Table 25]

[0199] [Table 26]

[0200] [Table 27]

[0201] [Table 28]

[0202] [Table 29]

[0203] [Table30]

[0204] [Table 31]

[0205] [Table 32]

[0206] [Table 33]

[0207] [Table 34]

[0208] [Table 35]

[0209] [Table 36|

[0210] [Table 37]|

[0211] [Table 38]

[0212] [Table39]

[0213] [Table 40]

[0214] [Table 41]

[0215] [Table 42]

[0216] [Table 43]

[0217] [Table44]

[0218] [Table 45]

[0219] [Table 46]

[02201 [Table 47]

[0221] [Table 48]

[Q222] [Table 49]

[0223] [Table 50]

[0224] [Table 51]

[0225] [Table 52]

[0226] [Table 53]

[0227] [Table 54]

[02281 [Table 551

[0229] [Table 56]

[0230] _[Table 57]

[0231] [Table 581]

[0232] [Table 59]

[0233] [Table 60]

[0234] [Table 61]

[0235] [Table 62]

[0236] [Table 63]

[0237] [fTable 64]

[0238] [Table 65]

[0239] ,[Table 66]

[0240] [Table 67]

[0241] [Table 68]

[0242] [Table 691]

[0243] [Table 70]

[0244] [Table71]

[0245] [Table 72]

[0246] [Table73]

[0247] [Table 74]

[0248] fTable 75]

[0249] [Table 76]

[0250] [Table 77]

[02511 [Table 78]

[0252] [Table 791

[0253] [Table 80]

[0254] [Table 81]

[0255] [Table 82]

[0256] [Table 83]

[0257] [Table 84]

[0258] [Table 85]

[0259] [Table 86]

[0260] [Table 87]

[02611 [Table 88]

[02621 [Table 89]

[0263] [Table 90]

[0264] [Table 91]

[0265] [Table 92]

[0266] [Table 93]

[0267] [Table 94]

[0268][Table95]

[0269] [Table 961]

[0270] [Table 97]

[0271] [Table 98]

[0272] [Table 99]

[0273] [Tablel00]

[0274] [Table 1011]

Sequence Listing Free Text
[0275]
The nucleotide sequence of a rat EP4 (Sequence Number I) IN described in the numeral index <400> of the following Sequence Listing.

1. A compound of the formula (I) or a pharmaceulically acceptable salt thereof: [Chem. 34]
[wherein the NymholN in the formula have the following meanings:
L1: lower alkylono, lower alkenylene, -(lower iilkylono)-()-(lowor alkylene)-, or -(lower alkylcno)-N-(lowor alkylene)-, in which lower nlkylonu and lower alkenylene in L1 may each be Hiil>n!lUited,
L2: lower alkylene, lower alkenylene, -C(O)-, -(lower ulkylcuo)-C'(C))-, or -(lower alkenylene)-C(O)-, in which lower alkylene and lower alkenylene In \l may each be substituted,
R1: R6 or a group represented by the following formula (II):
[Chem. 35]
Ring A: aryl or heteroaryl,
R6: -C02R°, -C(0)N(R°)2, -C(0)N(H)S(0)2-R8, -C(0)N(I I)S(0)2N(R°)-R8, -N(R°)C(0)N(H)S(0)2-R8, or a group represented by any one of the following formulae (III) to (XIV):

R°: the Hinno HN or different from each other, each icpiuNuntliiK -II »r lower alkyl,
R8: lower alkyl, halogeno-lower alkyl, -(lower alkylonuM )l<", or -(lower alkylene)-OC(0)R°,
J: a single bond or lower alkylene,
R7: the same as or different from each other, each representing lower alkyl, lower alkenyl, halogen, halogeno-lower alkyl, -OR0, -0-(halogeno-lower nlkyl), -O-(cycloalkyl), -0-(lower alkylene)-OR°, -0-(lower alkylene)-aryl, -OC(0)R°, -N(I<")2, -(lower alkylene)-OH, -(lower alkylene)-OR°, -(lower alkylene)-N(R°)2, -(lower alkylone)-cycloalkyl, -(lower alkylene)-aryl, -CO-R0, -S(0)2-R°, -C02R", -C(())N(R°)2, aryl, or a hetero ring group, in which aryl and the hetero ring group in R7 may euch be substituted,
n: an integer of 0 to 3,
R2: -N(R°)-lower alkyl or a group represented by any one of the following formulae (XV) to (XVII):
[Chem. 37]
Ring B: cycloalkyl, aryl, or a hetero ring,
Ring C: a nitrogen-containing saturated hetero ring,

Ring D: aryl or heteroaryl,
X: a single bond, lower alkylene, -C(O)-, -C(0)-(lower alkylene)-, or -(lower alkylene)-0-,
R9: II, lower alkyl, -C(0)R°, or aryl, in which aryl In U" may ho substituted,
Y and Y : the same as or different from each other, each roproNenting a single bond, -[C(R,0)(R")lri -|C(R,0)(R")]S.Q-, -Q-[C(R,0)(R,I)|.., or -|< ,(KI0)(R,,)].-Q-[CCR^XR1')],-,
R and R : the same as or different from each other, each representing H, lower alkyl, halogen, halogeno-lower alkyl, -OR0, -N(R°)2, -(lower alkylene)-OH, -(lower alkylene)-OR°, -(lower alkylene)-N(R°)2, or a hetero ring group, or R10 and R11 on the same carbon atom may be combined to form oxo,
Q:0,S(0)p,orN(R12),
R12: H, lower alkyl, -C(0)R°, or -S(0)2-(lower alkyl),
s and t: the same as or different from each other, each roproNenting an integer of 1
""" to 4,
p: an integer of 0 to 2, and
R3, R4, and It1*: the same as or different from each other, each representing H, halogen, -CN, lower alkyl, lower alkenyl, halogeno-lower alkyl, -OR", -0-(halogeno-lower alkyl), -(lower alkylenc)-OR°, -(lower alkylene)-N(R°)2, -COjU", -C(())N(R°)2, cycloalkyl, or aryl, in which aryl in R\ R4, and R5 may be substituted].
2. The compound us described in claim 1, wherein R4 IN -II.
3. The compound as described in claim 2, wherein R1 IN -II, halogen, or lower alkyl.
4. The compound as described in claim 3, wherein R3 is halogen, lower alkyl, or cycloalkyl.
5. The compound as described in claim 4, wherein L1 is lower alkylene.
6. The compound as described in claim 5, wherein I? is lower alkylene.
7. The compound as described in claim 6, wherein R1 is -CC)2R°; or phenyl which is substituted with a group selected from the group consisting of-C02R° and the groups represented by the following formula (III), the following formula (IX), the following formula (X), and the following formula (XIV):

[Chem. 38]
v
and which may be further substituted with 1 to 3 lower alkyl or halogen.
8. The compound us described in claim 7, wherein U'; h -N(lower alkyl)2; -N(R°)-cycloulkyl; -N(R°)-(aryl which may be subtilItiitod with 1 to 3 groups selected from the group consisting of halogen, lower alkyl, linlogoini lower alkyl, -OR0, and -O-halogeno-lowor ulkyl); or -N(R°)-(lower alkylene)-(niyl which nuty be substituted with 1 to 3 groups selected from the group consisting of halogen, lower alkyl, halogeno-lower alkyl, -OR0, and -O-halogeno-lower alkyl).
9. The compound as described in claim 7, wherein R2 is a group described by tb following formula (XVI):
[Chem. 39]
Ring C is a monocyclic 5- to 7-membered nitrogen-contuinlng wiUiralod liutero ring, and R7 is halogen, lower alkyl, lower alkenyl, halogeno-lower alkyl, -()U°, -(Mialogcno-lower alkyl, or -(lower alkyleno)-cycloalkyl.
10. The compoiiiul us described in claim 7, whuruin \i' IH2, I illhytlro-lll-indol-l-yl in which 1 to 3 groups selected from the group consisting of halogen, lower alkyl, lower alkenyl, halogeno-lower alkyl, -OR0, and -O-halogeno-lowor alkyl may be substituted at the 4- to 7-positions.
11. The compound as described in claim 1, which is selected from the group consisting of:
4-{2-[6-{|(2S)-2-butylpyrrolidin-l-yl]methyl}-3,5-dichloro-2-oxopyridin-l(2H)-yl]ethyl}benzoic acid,
4-{2-[3,5-dichloro-6-{[(2R)-2-isobutylpyrrolidin-l -yl |methyl} -2-oxopyridin-l(2H)-yl]ethyl}benzoic acid,

4-{2-[3,5-dichloro-2-oxo-6-{[(2S)-2-propylpyrrolidin-l-yl]methyl}pyridin-l(2H)-yl]ethyl}benzoic acid,
3,5-dichloro-6- {[(2S)-2-propylpyrrolidin-l -yl]methy 1} -1 - {2-f 4-( 1 H-tetrazol-5-yl)phenyl]ethyl} pyridin-2( 1 H)-one,
3,5-dichloro-l-{2-[4-(5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-yl)phenyl]ethyl}-6-{[(2S)-2-propylpyrrolidin-l-yl]methyl}pyridin-2(lH)-one,
4- {2-[3,5-dichloro-6- {[cyclopentyl(methyl)amino]methyl} -2-oxopyridin-1 (2H)-yl]ethyl}benzoic acid,
3,5-dichloro-l-{2-[4-(5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-yl)phenyl]ethyl}-6-{[(2R)-2-isobutylpyrrolidin-1 -yl]methyl}pyridin-2(l H)-one,
4-{2-[5-cyclopropyl-6-{[(2R)-2-isobutylpyrrolidin-l-yl|methyl}-3-methyl-2-oxopyridin-1 (2H)-yl]ethyl} benzoic acid,
4-{2-[6-{[(2R)-2-isobutylpyrrolidin-l-yl]methyl}-3,5-(llmolliyl-2-oxopyridin-l(2H)-yl]ethyl} benzoic ucid,
l-{2-t4-(5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-yl)plionyl|dhyl)-6-{[(2R)-2-isobutylpyrrolidin-l-yl]mcthyl}-3,5-dimethylpyridin-2(lll)-