Pyrimidine derivatives

Abstract

A compound represented by general formula (1), which has a strong inhibitory effect on mPGES-1 and is useful as an active ingredient of a drug for treating inflammation and the like. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to novel pyrimidine derivatives, and more specifically, to pyrimidine derivatives having mPGES-1 inhibitory activity and useful as active ingredients of drugs for preventing and / or treating diseases such as inflammation, pain and rheumatism. Background Art

[0002] Prostaglandin E2 (PGE2) participates in inflammation, pain, fever, etc. through PGE receptors, and inflammation can be suppressed by inhibiting the production of PGE2. Nonsteroidal anti-inflammatory drugs (NSAIDs) exert anti-inflammatory effects by inhibiting cyclooxygenase (COX) upstream of the prostaglandin biosynthesis pathway, but since all biosynthesis pathways downstream of prostaglandin production that COX participates in are inhibited in the prostaglandin biosynthesis pathway, gastric mucosal disorders caused by the secretion of gastric mucus and the inhibition of gastric mucosal blood flow are produced as side effects.

[0003] There are two isoenzymes of COX, COX-1 and COX-2. Among them, COX-2 is induced to express in inflammatory tissues by various inflammation-promoting stimuli (e.g., cytokines such as interleukin-1β). Drugs that selectively inhibit this COX-2 inhibit the production of PGI2, which has vasodilation and platelet aggregation effects, but on the other hand, since they do not inhibit the production of thromboxane A2 (TXA2), which is catalyzed by COX-1 and causes vasoconstriction and platelet aggregation, it is believed that the risk of thrombosis is increased, thereby increasing cardiovascular events.

[0004] In the downstream of the PGE2 biosynthetic pathway, PGE2 is biosynthesized by PGH2 through prostaglandin E synthase (PGE Synthase, PGES). There are three enzymes in PGES: mPGES-1 (microsomal prostaglandin E2 synthase-1), mPGES-2 (microsomal prostaglandin E2synthase-2) and cPGES (cytosolic PGE Synthase), among which mPGES-1 is an inducible enzyme of a trimer whose expression rises due to inflammatory stimulation (Proc. Natl. Acad. Sci. USA, 96, pp. 7220-7225, 1999), and it is known to be related to cancer, inflammation, pain, fever, tissue repair, etc.

[0005] The inhibitor of mPGES-1 can selectively inhibit the final stage of the biosynthetic pathway of PGE2 at the inflammatory site (Pharmacol. Rev., 59, pp. 207-224, 2007; J. Biol. Chem., 279, pp. 33684-33695, 2004), and is expected to be an anti-inflammatory agent that does not cause gastric mucosal damage like non-steroidal anti-inflammatory agents. In addition, it is expected that mPGES-1 inhibitors are effective in preventing and / or treating pain, rheumatism, osteoarthritis, fever, Alzheimer's disease, multiple sclerosis, arteriosclerosis, glaucoma and other ocular hypertension, ischemic retinal disease, systemic sclerosis, colorectal cancer and other malignant tumors, or inhibiting PGE2 to produce diseases that show effectiveness (about the use of PGE2, PGES, mPGES-1 and mPGES-1 inhibitors, etc., refer to International Publication WO2015 / 125842). In addition, it is known that mPGES-1 inhibitors increase the production of other prostaglandins as they inhibit the production of PGE2 (J. Biol. Chem., 280, pp. 16579-16585, 2005).

[0006] As mPGES-1 inhibitors, heterocyclic derivatives disclosed in Japanese Patent No. 5601422, substituted pyrimidine compounds disclosed in International Publication WO2015 / 59618, and triazine compounds disclosed in International Publication WO2015 / 125842 are known. Pyrimidine compounds substituted with p-trifluoromethylphenyl and 2-chloro-5-isobutylamide benzyl are disclosed in International Publication WO2015 / 59618 (Example 2), and triazine compounds substituted with p-trifluoromethylphenyl and 2-chloro-5-isobutylamide benzyl are disclosed in International Publication WO2015 / 125842 (Examples 1-28). In addition, pyrimidine derivatives substituted with mPGES-1 inhibitory effects by meta-phenylene are disclosed in International Publication WO2017 / 73709, and pyrimidine derivatives substituted with mPGES-1 inhibitory effects by heterocyclic rings are disclosed in International Publication WO2019 / 44868.

[0007] Prior art literature

[0008] Patent Literature

[0009] Patent Document 1: Japanese Patent No. 5601422

[0010] Patent Document 2: International Publication WO2015 / 59618

[0011] Patent Document 3: International Publication WO2015 / 125842

[0012] Patent Document 4: International Publication WO2017 / 073709

[0013] Patent Document 5: International Publication WO2019 / 44868

[0014] Non-patent literature

[0015] Non-patent document 1: Proc. Natl. Acad. Sci. USA, 96, pp. 7220-7225, 1999

[0016] Non-patent document 2: Pharmacol. Rev., 59, pp. 207-224, 2007

[0017] Non-patent document 3: J. Biol. Chem., 279, pp. 33684-33695, 2004

[0018] Non-patent document 4: J. Biol. Chem., 280, pp. 16579-16585, 2005 Summary of the invention

[0019] Problems to be solved by the invention

[0020] An object of the present invention is to provide a novel compound having an mPGES-1 inhibitory effect and useful as an active ingredient of a drug for preventing and / or treating diseases such as inflammation, pain or rheumatism.

[0021] Means for solving problems

[0022] The present inventors conducted intensive research to solve the above-mentioned problems and found that the pyrimidine derivative represented by the following general formula (1) has a strong inhibitory effect on mPGES-1 and is useful as an active ingredient of drugs for preventing and / or treating diseases such as inflammation, pain or rheumatism, thereby completing the present invention.

[0023] That is, the present invention provides:

[0024] [1] A compound represented by the following general formula (1) or a salt thereof:

[0025] [Chemistry 1]

[0026]

[0027] (Where R 1 and R 2 Each independently represents a hydrogen atom, a halogen atom, a C 1-6 an alkyl group, or an aromatic heterocyclic group which may have a substituent and has 1 or 2 or more hetero atoms constituting the ring, R 1 and R 2 When both represent alkyl groups, they may be bonded to each other to form a C 3-6Alkylene,

[0028] R 3 and R 4 Each independently represents a hydrogen atom, a halogen atom or a C 1-6 alkyl,

[0029] L 1 Indicates -CO-, -SO2- or -CO-C(R 5 )(R 6 )-(R 5 and R 6 Each independently represents a hydrogen atom or a C 1-6 Alkyl, R 5 and R 6 When both represent alkyl groups, they may be bonded to each other to form a C 2-5 alkylene),

[0030] X represents a cyclic hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent and has 1 or 2 or more hetero atoms constituting the ring,

[0031] L 2 Indicates -A 1 -R 7 -A 2 -(A 1 represents a single bond, -CO-, -NH- or -O-, R 7 Represents a single bond or C 1-6 Alkylene, A 2 represents a single bond, -CO-, -NH- or -O-),

[0032] Y represents a hydrogen atom, a cyclic hydrocarbon group which may have a substituent, or a heterocyclic group which may have a substituent and has 1 or 2 or more hetero atoms constituting the ring).

[0033] Furthermore, according to a preferred embodiment of the above invention, the following compound or a salt thereof is provided.

[0034] [2] The compound or salt thereof according to [1] above, wherein R 1 and R 2 are independently a hydrogen atom, a fluorine atom, a C 1-6 an alkyl group (the alkyl group may be substituted with 1 or 2 or more halogen atoms) or an aromatic heterocyclic group having 1 or 2 or more hetero atoms constituting the ring and optionally having a substituent, R 1 and R 2 When both represent alkyl groups, they may bond to each other to form a C 3-5 Alkylene,

[0035] R 3 and R 4are each independently a hydrogen atom, a fluorine atom, a chlorine atom or a C 1-6 an alkyl group (the alkyl group may be substituted by 1 or 2 or more fluorine atoms),

[0036] L 1 is -CO-, -SO2- or -CO-C(R 5 )(R 6 )-(R 5 and R 6 are independently a hydrogen atom or a C 1-6 Alkyl (R 5 and R 6 When both represent alkyl groups, they may bond to each other to form a C 3-5 alkylene),

[0037] X is an aromatic hydrocarbon group which may have a substituent, a saturated or partially saturated cyclic hydrocarbon group which may have a substituent, an aromatic heterocyclic group which may have a substituent and has 1 or 2 or more hetero atoms constituting the ring, or a saturated or partially saturated heterocyclic group which may have a substituent and has 1 or 2 or more hetero atoms constituting the ring,

[0038] L 2 Indicated -A 1 -R 7 -A 2 -Medium, A 1 , R 7 and A 2 All are single bonds, or A 1 is a single bond, R 7 is -CO-, -NH- or -O-, and A 2 is a single bond or C 1-6 Alkylene, or A 1 C 1-6 Alkylene, R 7 is -CO-, -NH- or -O-, and A 2 is a single key),

[0039] Y is a hydrogen atom, an aromatic hydrocarbon group optionally having a substituent, a saturated or partially saturated cyclic hydrocarbon group optionally having a substituent, an aromatic heterocyclic group optionally having a substituent and having 1 or 2 or more hetero atoms constituting the ring, or a saturated or partially saturated heterocyclic group optionally having a substituent and having 1 or 2 or more hetero atoms constituting the ring.

[0040] [3] The compound or a salt thereof according to [1] above, wherein R 1 For hydrogen atoms, fluorine atoms, C 1-6 an alkyl group (the alkyl group may be substituted by 1 or 2 or more fluorine atoms),

[0041] R 2 is a fluorine atom, C1-6 an alkyl group (the alkyl group may be substituted with 1 or 2 or more halogen atoms), or an aromatic heterocyclic group having 1 or 2 or more hetero atoms constituting the ring and optionally having a substituent, R 1 and R 2 When both represent alkyl groups, they may bond to each other to form a C 3-5 Alkylene,

[0042] R 3 and R 4 are each independently a hydrogen atom, a fluorine atom, a chlorine atom or a C 1-6 an alkyl group (the alkyl group may be substituted by 1 or 2 or more fluorine atoms),

[0043] L 1 is -CO-, -SO2- or -CO-C(R 5 )(R 6 )-(R 5 and R 6 are each independently a hydrogen atom or a C 1-6 Alkyl groups (the alkyl groups may be bonded to each other to form C 3-4 alkylene),

[0044] X is a monocyclic or bicyclic aromatic hydrocarbon group which may have a substituent, a monocyclic or bicyclic saturated or partially saturated cyclic hydrocarbon group which may have a substituent, a monocyclic or bicyclic aromatic heterocyclic group which may have a substituent and has 1 or 2 or more hetero atoms constituting the ring, or a monocyclic or bicyclic saturated or partially saturated heterocyclic group which may have a substituent and has 1 or 2 or more hetero atoms constituting the ring,

[0045] L 2 Shown-A 1 -R 7 -A 2 -Medium, A 1 , R 7 and A 2 All are single bonds, or A 1 is a single bond, R 7 is -CO-, -NH- or -O-, and A 2 is a single bond or C 1-4 Alkylene, or A 1 C 1-4 Alkylene, R 7 is -CO-, -NH- or -O-, and A 2 is a single key),

[0046] Y is a hydrogen atom, a monocyclic or bicyclic aromatic hydrocarbon group which may have a substituent, a monocyclic or bicyclic saturated or partially saturated cyclic hydrocarbon group which may have a substituent, a monocyclic or bicyclic aromatic heterocyclic group which may have a substituent and has 1 or 2 or more hetero atoms constituting the ring, or a monocyclic or bicyclic saturated or partially saturated heterocyclic group which may have a substituent and has 1 or 2 or more hetero atoms constituting the ring.

[0047] [4] The compound or a salt thereof according to [1] above, wherein R 1 For hydrogen atoms, fluorine atoms, C 1-6 an alkyl group (the alkyl group may be substituted by 1 or 2 or more fluorine atoms),

[0048] R 2 is a fluorine atom or C 1-6 an alkyl group (the alkyl group may be substituted with 1 or 2 or more fluorine atoms) or a monocyclic aromatic heterocyclic group containing 1 or 2 or more nitrogen atoms constituting the ring and optionally having a substituent,

[0049] R 3 and R 4 are each independently a hydrogen atom, a fluorine atom, a chlorine atom or a C 1-6 an alkyl group (the alkyl group may be substituted by 1 or 2 or more fluorine atoms),

[0050] L 1 is -CO- or -SO2-,

[0051] X is a phenyl group which may have a substituent, a naphthyl group which may have a substituent, a monocyclic or bicyclic 3- to 12-membered saturated or partially saturated cyclic hydrocarbon group which may have a substituent, a monocyclic or bicyclic aromatic heterocyclic group which may have a substituent and contains 1 or 2 or more nitrogen atoms constituting the ring, or a monocyclic or bicyclic saturated or partially saturated heterocyclic group which may have a substituent and contains 1 or 2 or more nitrogen atoms constituting the ring,

[0052] L 2 Shown-A 1 -R 7 -A 2 -Medium, A 1 , R 7 and A 2 All are single bonds, or A 1 is a single bond, R 7 is -O-, and A 2 is a single bond or C 1-4 Alkylene, or A 1 C 1-4 Alkylene, R 7 is -O-, and A 2 is a single bond,

[0053] Y is a hydrogen atom, a monocyclic or bicyclic aromatic hydrocarbon group which may have a substituent, a monocyclic or bicyclic 3- to 12-membered saturated or partially saturated cyclic hydrocarbon group which may have a substituent, a monocyclic or bicyclic aromatic heterocyclic group which may have a substituent and contains 1 or more nitrogen atoms constituting the ring, or a monocyclic or bicyclic saturated or partially saturated heterocyclic group which may have a substituent and contains 1 or more nitrogen atoms constituting the ring.

[0054] [5] The compound or salt thereof according to [1] above, wherein R 1 is a hydrogen atom, a fluorine atom, a methyl group,

[0055] R 2 is a hydrogen atom, a fluorine atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a 1-methyl-1-methoxyethyl group, a cyclopropyl group, a cyclopentyl group, a tert-butyl group, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a pyridyl group, a pyridazinyl group or a pyrazinyl group (wherein the pyridyl group, the pyridazinyl group or the pyrazinyl group may be selected from the following group: C 1-6 Alkyl, C 1-6 Alkoxy, halogen atom, C substituted with 1 or 2 or more fluorine atoms 1-6 Alkyl, C substituted by 1 or 2 or more fluorine atoms 1-6 1 or more substituents in alkoxy and cyano),

[0056] R 3 and R 4 are each independently a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a 1-methyl-1-methoxyethyl group, a cyclopropyl group, a cyclopentyl group, a tert-butyl group, a fluoromethyl group, a difluoromethyl group or a trifluoromethyl group,

[0057] L 1 For -CO-,

[0058] X is a phenyl group which may have a substituent, a naphthyl group which may have a substituent, a monocyclic saturated hydrocarbon group which may have a substituent, a monocyclic aromatic heterocyclic group which may have a substituent and contains one or more nitrogen atoms constituting the ring, or a monocyclic saturated or partially saturated heterocyclic group which may have a substituent and contains one or more nitrogen atoms constituting the ring,

[0059] L 2 Shown-A 1 -R 7 -A 2 -Medium, A 1 , R 7 and A 2 All are single bonds, or A 1 is a single bond, R 7 is -O-, and A 2is a single bond, a methylene group or an ethylene group, or A 1 is methylene or ethylene, R 7 is -O-, and A 2 is a single bond,

[0060] Y is a hydrogen atom, a monocyclic or bicyclic aromatic hydrocarbon group which may have a substituent, a saturated monocyclic 3- to 7-membered cyclic hydrocarbon group which may have a substituent, a monocyclic or bicyclic aromatic heterocyclic group which may have a substituent and contains one or more nitrogen atoms constituting the ring, or a saturated or partially saturated monocyclic or bicyclic heterocyclic group which may have a substituent and contains one or more nitrogen atoms constituting the ring.

[0061] [6] The compound or a salt thereof according to [1] above, wherein R 1 is a hydrogen atom or a fluorine atom,

[0062] R 2 is a hydrogen atom, a fluorine atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a 1-methyl-1-methoxyethyl group, a cyclopropyl group, a cyclopentyl group, a tert-butyl group, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a 2-pyridyl group, a 3-pyridyl group, a 4-pyridyl group, a 3-pyridazinyl group, a 4-pyridazinyl group or a 2-pyrazinyl group (wherein the above-mentioned 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 3-pyridazinyl group, 4-pyridazinyl group or 2-pyrazinyl group may be selected from the following group: C 1-6 Alkyl, C 1-6 Alkoxy, halogen atom, C 1-6 Alkyl, C substituted by 1 or 2 or more fluorine atoms 1-6 1 or more substituents in alkoxy and cyano),

[0063] R 3 is a hydrogen atom or a fluorine atom,

[0064] R 4 is a fluorine atom, a chlorine atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a 1-methyl-1-methoxyethyl group, a cyclopropyl group, a cyclopentyl group, a tert-butyl group, a fluoromethyl group, a difluoromethyl group or a trifluoromethyl group,

[0065] L 1 For -CO-,

[0066] X is a monocyclic saturated hydrocarbon group which may have a substituent or a monocyclic saturated or partially saturated heterocyclic group which may have a substituent and contains 1 or 2 or more nitrogen atoms constituting the ring,

[0067] L 2 is a single bond, -O-, -CH2-O- or -O-CH2-,

[0068] Y is a hydrogen atom, a phenyl group which may have a substituent, a naphthyl group which may have a substituent, or a monocyclic or bicyclic aromatic heterocyclic group which may have a substituent and contains one or more nitrogen atoms constituting the ring.

[0069] [7] The compound or a salt thereof according to [1] above, wherein R 1 is a hydrogen atom or a fluorine atom,

[0070] R 2 is a fluorine atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a 1-methyl-1-methoxyethyl group, a cyclopropyl group, a cyclopentyl group, a tert-butyl group, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a 2-pyridyl group, a 3-pyridyl group, a 4-pyridyl group, a 3-pyridazinyl group, a 4-pyridazinyl group or a 2-pyrazinyl group (wherein the 2-pyridyl group, the 3-pyridyl group, the 4-pyridyl group, the 3-pyridazinyl group, the 4-pyridazinyl group or the 2-pyrazinyl group may have one or more substituents selected from the group consisting of a methyl group, an ethyl group, a methoxy group, an ethoxy group, a fluorine atom, a chlorine atom, a difluoromethyl group, a trifluoromethyl group, a difluoromethoxy group, a trifluoromethoxy group and a cyano group),

[0071] R 3 is a fluorine atom,

[0072] R 4 is methyl, ethyl, propyl, isopropyl, 1-methyl-1-methoxyethyl, cyclopropyl, cyclopentyl, tert-butyl, fluoromethyl, difluoromethyl or trifluoromethyl,

[0073] L 1 For -CO-,

[0074] X is a monocyclic saturated hydrocarbon group which may have a substituent or a monocyclic saturated heterocyclic group which may have a substituent and contains 1 or 2 or more nitrogen atoms constituting the ring,

[0075] L 2 is a single bond, -O- or -O-CH2-,

[0076] Y is a hydrogen atom, a phenyl group which may have a substituent, a naphthyl group which may have a substituent, a pyridyl group which may have a substituent, or a quinolyl group which may have a substituent.

[0077] [8] The compound or a salt thereof according to [1] above, wherein R 1 is a hydrogen atom or a fluorine atom,

[0078] R 2 is methyl, ethyl, propyl, isopropyl, 1-methyl-1-methoxyethyl, cyclopropyl, cyclopentyl, tert-butyl, fluoromethyl, difluoromethyl or trifluoromethyl,

[0079] R 3 is a fluorine atom,

[0080] R 4 is trifluoromethyl,

[0081] L 1 For -CO-,

[0082] X is a 4- to 6-membered saturated hydrocarbon group which may have a substituent or a 4- to 6-membered saturated heterocyclic group which may have a substituent and contains one nitrogen atom constituting the ring,

[0083] L 2 is a single bond, -O- or -O-CH2-,

[0084] Y is a hydrogen atom, a phenyl group which may have a substituent, a naphthyl group which may have a substituent, a pyridyl group which may have a substituent, or a quinolyl group which may have a substituent.

[0085] [9] The compound or a salt thereof according to [1] above, wherein R 1 is a hydrogen atom or a fluorine atom,

[0086] R 2 is methyl, ethyl, propyl, isopropyl, 1-methyl-1-methoxyethyl, cyclopropyl, cyclopentyl, tert-butyl, fluoromethyl, difluoromethyl or trifluoromethyl,

[0087] R 3 is a fluorine atom,

[0088] R 4 is trifluoromethyl,

[0089] L 1 For -CO-,

[0090] X is cyclobutanediyl, cyclopentanediyl, cyclohexanediyl, azetidinediyl, pyrrolidinediyl or piperidinediyl,

[0091] L 2 is a single bond or -O-CH2-,

[0092] Y is a hydrogen atom, a phenyl group, a naphthyl group, a pyridyl group or a quinolyl group (wherein the phenyl group, the naphthyl group, the pyridyl group or the quinolyl group may be selected from the following group: 1-6 Alkyl, C 1-6 Alkoxy, halogen atom, C substituted with 1 or 2 or more fluorine atoms 1-6 Alkyl, C substituted by 1 or 2 or more fluorine atoms 1-6 1 or more substituents in alkoxy and cyano).

[0093]

[10] The compound or salt thereof according to [1] above, wherein R 1 is a hydrogen atom or a fluorine atom,

[0094] R2 is methyl, ethyl, propyl, isopropyl, 1-methyl-1-methoxyethyl, cyclopropyl, cyclopentyl, tert-butyl, fluoromethyl, difluoromethyl or trifluoromethyl,

[0095] R 3 is a fluorine atom,

[0096] R 4 is trifluoromethyl,

[0097] L 1 For -CO-,

[0098] X is 1,3-cyclobutanediyl, 1,4-cyclohexanediyl, 1,3-azetidinediyl or 1,4-piperidinediyl,

[0099] L 2 is a single bond or -O-CH2-,

[0100] Y is a hydrogen atom, a phenyl group, a naphthyl group, a pyridyl group or a quinolyl group (wherein the phenyl group, the naphthyl group, the pyridyl group or the quinolyl group optionally has one or more substituents selected from the following group: a methyl group, an ethyl group, a methoxy group, an ethoxy group, a fluorine atom, a chlorine atom, a difluoromethyl group, a trifluoromethyl group, a difluoromethoxy group, a trifluoromethoxy group and a cyano group).

[0101]

[11] The compound or a salt thereof according to [1] above, wherein R 1 is a hydrogen atom or a fluorine atom,

[0102] R 2 is methyl, ethyl, propyl, isopropyl, 1-methyl-1-methoxyethyl, cyclopropyl, cyclopentyl, tert-butyl, fluoromethyl, difluoromethyl or trifluoromethyl,

[0103] R 3 is a fluorine atom,

[0104] R 4 is trifluoromethyl,

[0105] L 1 For -CO-,

[0106] X is 1,3-cyclobutanediyl,

[0107] L 2 is -O-CH2-,

[0108] Y is a phenyl group (wherein the phenyl group may have one or more substituents selected from the group consisting of a methyl group, an ethyl group, a methoxy group, an ethoxy group, a fluorine atom, a chlorine atom, a difluoromethyl group, a trifluoromethyl group, a difluoromethoxy group, a trifluoromethoxy group and a cyano group).

[0109] From another viewpoint, the present invention provides an mPGES-1 inhibitor comprising a compound represented by the above general formula (1) or a salt thereof; and a PGE2 biosynthesis inhibitor comprising a compound represented by the above general formula (1) or a salt thereof.

[0110] From further other viewpoints, the present invention provides a drug comprising a compound shown in the above-mentioned general formula (1) or a physiologically acceptable salt as an effective ingredient. The above-mentioned drug can be used for, for example, inflammation, pain, rheumatism, osteoarthritis, fever, Alzheimer's disease, multiple sclerosis, arteriosclerosis, glaucoma and other ocular hypertension diseases, ischemic retinal diseases, systemic scleroderma, colorectal cancer and other malignant tumors or suppress PGE2 to produce the prevention and / or treatment of the disease showing effectiveness.

[0111] In addition, the present invention provides the use of the compound represented by the general formula (1) or its salt in the manufacture of the mPGES-1 inhibitor, the PGE2 biosynthesis inhibitor or the drug; a method for inhibiting mPGES-1 in mammals including humans, which comprises the step of administering an effective amount of the compound represented by the general formula (1) or its physiologically acceptable salt to mammals including humans; a method for inhibiting the biosynthesis of PGE2 in mammals including humans, which comprises the step of administering an effective amount of the compound represented by the general formula (1) or its physiologically acceptable salt to mammals including humans; and a method for promoting the production of other prostaglandins in mammals including humans by inhibiting the biosynthesis of PGE2, which comprises the step of administering an effective amount of the compound represented by the general formula (1) or its physiologically acceptable salt to mammals including humans.

[0112] Effects of the Invention

[0113] The compound or its salt shown in the above-mentioned general formula (1) provided by the present invention plays a strong inhibitory effect on mPGES-1, and the biosynthesis of PGE2 can be suppressed.Therefore, the compound or its salt shown in the above-mentioned general formula (1) is useful as an active ingredient for preventing and / or treating malignant tumors such as ocular hypertension, ischemic retinal disease, systemic scleroderma, colorectal cancer, etc., such as inflammation, pain, rheumatism, osteoarthritis, fever, Alzheimer's disease, multiple sclerosis, arteriosclerosis, glaucoma, or suppressing PGE2 to produce a drug showing effectiveness. DETAILED DESCRIPTION

[0114] In the present specification, the term "halogen atom" includes fluorine atom, chlorine atom, iodine atom and iodine atom. As the halogen atom, fluorine atom or chlorine atom is preferred.

[0115] In the present specification, the term "alkyl" includes alkyl groups formed by linear, branched, cyclic or combinations thereof, and the number of carbon atoms is not particularly limited, but is, for example, 1 to 6, preferably 1 to 4. The same applies to the alkyl moiety of other substituents (e.g., alkoxy) having an alkyl moiety.

[0116] In the present specification, the term "alkylene" includes linear or branched alkylene groups, and the carbon number is not particularly limited, and is, for example, 1 to 6, preferably 1 to 4. When two alkyl groups are bonded to form an alkylene group to form a ring structure, the carbon number is not particularly limited, and is, for example, 2 to 6, preferably 3 to 4. In addition, for example, the carbon number is preferably in the range of 3 to 6 or 2 to 5.

[0117] In the present specification, examples of the aromatic hydrocarbon group include monocyclic or bicyclic aromatic hydrocarbon groups, preferably phenyl and naphthyl, but are not limited to these.

[0118] In this specification, the cyclic hydrocarbon group represents a non-aromatic hydrocarbon group, i.e., a saturated or partially saturated cyclic hydrocarbon group, and examples thereof include monocyclic or polycyclic, preferably monocyclic or bicyclic saturated or partially saturated cyclic hydrocarbon groups. Preferred examples include monocyclic or bicyclic 3 to 12-membered saturated or partially saturated cyclic hydrocarbon groups, more preferably monocyclic 3 to 7-membered saturated cyclic hydrocarbon groups, and further preferably 4 to 6-membered saturated hydrocarbon groups. For example, more preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, but not limited thereto.

[0119] In the present specification, examples of the heteroatom constituting the ring contained in the aromatic heterocyclic group or the heterocyclic group include a nitrogen atom, an oxygen atom, and a sulfur atom. When there are two or more heteroatoms constituting the ring, they may be the same or different.

[0120] In the present specification, an aromatic heterocyclic group refers to an aromatic heterocyclic group having 1 or 2 or more hetero atoms constituting a ring, and examples thereof include a monocyclic aromatic heterocyclic group or a condensed polycyclic aromatic heterocyclic group having 1 or 2 or more hetero atoms constituting a ring, and preferably a monocyclic or bicyclic aromatic heterocyclic group having 1 or 2 or more hetero atoms constituting a ring.

[0121] Examples of the monocyclic aromatic heterocyclic group having one or more heteroatoms constituting the ring include 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, (1,2,3-oxazolyl) oxadiazole)-4-yl, (1,2,3-oxadiazole)-5-yl, (1,2,4-oxadiazole)-3-yl, (1,2,4-oxadiazole)-5-yl, (1,2,5-oxadiazole)-3-yl, (1,2,5-oxadiazole)-4-yl, (1,3,4-oxadiazole)-2-yl, (1,3,4-oxadiazole)-5-yl, furazanyl, (1,2,3-thiadiazole)-4-yl, (1,2,3-thiadiazole)-5-yl, (1,2,4-thiadiazole)-3-yl, (1,2,4-thiadiazole)-5-yl, (1,2,5-thiadiazole)-3-yl, (1,2,5 -thiadiazole)-4-yl, (1,3,4-thiadiazole)-2-yl, (1,3,4-thiadiazole)-5-yl, (1H-1,2,3-triazole)-1-yl, (1H-1,2,3-triazole)-4-yl, (1H-1,2,3-triazole)-5-yl, (2H-1,2,3-triazole)-2-yl, (2H-1,2,3-triazole)-4-yl, (1H-1,2,4-triazole)-1-yl, (1H-1,2,4-triazole)-3-yl, (1H-1,2,4-triazole)-5-yl, (4H-1,2,4-triazole)-3-yl, (4H- 1,2,4-triazine)-4-yl, (1H-tetrazole)-1-yl, (1H-tetrazole)-5-yl, (2H-tetrazole)-2-yl, (2H-tetrazole)-5-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, (1,2,3-triazine)-4-yl, (1,2,3-triazine)-5-yl, (1,2,4-triazine)-3-yl, (1,2,4-triazine)-5-yl, (1,2,4-triazine)-6-yl, (1,3,5-triazine)-2-yl, 1-aza 2-aza 3-aza 4-aza 1,4-oxazapine )-2-yl, (1,4-oxazepine )-3-yl, (1,4-oxazepine )-5-yl, (1,4-oxazepine )-6-yl, (1,4-oxazepine )-7-yl, (1,4-thiazepine )-2-yl, (1,4-thiazepine )-3-yl, (1,4-thiazepine )-5-yl, (1,4-thiazepine )-6-yl, (1,4-thiazepine )-7-yl, etc., but are not limited to these.

[0122] Examples of the polycyclic condensed aromatic heterocyclic group having one or more hetero atoms constituting the ring include 2-benzofuranyl, 3-benzofuranyl, 4-benzofuranyl, 5-benzofuranyl, 6-benzofuranyl, 7-benzofuranyl, 1-isobenzofuranyl, 4-isobenzofuranyl, 5-isobenzofuranyl, 2-benzo[b]thienyl, 3-benzo[b]thienyl, 4-benzo[b]thienyl, 5-benzo[b]thienyl, 6-benzo[b]thienyl, 7-benzo[b]thienyl, 1-benzo[c]thienyl, 4-benzo[c]thienyl, 5-benzo[c]thienyl, 1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl, -indolyl, (2H-isoindol)-1-yl, (2H-isoindol)-2-yl, (2H-isoindol)-4-yl, (2H-isoindol)-5-yl, (1H-indazole)-1-yl, (1H-indazole)-3-yl, (1H-indazole)-4-yl, (1H-indazole)-5-yl, (1H-indazole)-6-yl, (1H-indazole)- )-7-yl, (2H-indazole)-1-yl, (2H-indazole)-2-yl, (2H-indazole)-4-yl, (2H-indazole)-5-yl, 2-benzoxazolyl, 4-benzoxazolyl, 5-benzoxazolyl, 6-benzoxazolyl, 7-benzoxazolyl, (1,2-benzisoxazole)-3-yl, (1,2-benzisoxazole)-4-yl, -yl, (1,2-benzisoxazole)-5-yl, (1,2-benzisoxazole)-6-yl, (1,2-benzisoxazole)-7-yl, (2,1-benzisoxazole)-3-yl, (2,1-benzisoxazole)-4-yl, (2,1-benzisoxazole)-5-yl, (2,1-benzisoxazole)-6-yl, (2,1 ...7-yl, (2,1-benzisoxazole)-7-yl, (2,1-benzisoxazole)- oxazolyl)-7-yl, 2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl, (1,2-benzoisothiazolyl)-3-yl, (1,2-benzoisothiazolyl)-4-yl, (1,2-benzoisothiazolyl)-5-yl, (1,2-benzoisothiazolyl)-6-yl, (1,2-benzoisothiazolyl) -7-yl, (2,1-benzisothiazole)-3-yl, (2,1-benzisothiazole)-4-yl, (2,1-benzisothiazole)-5-yl, (2,1-benzisothiazole)-6-yl, (2,1-benzisothiazole)-7-yl, (1,2,3-benzoxadiazole)-4-yl, (1,2,3-benzoxadiazole)-5-yl, (1 ,2,3-benzooxadiazole)-6-yl, (1,2,3-benzooxadiazole)-7-yl, (2,1,3-benzooxadiazole)-4-yl, (2,1,3-benzooxadiazole)-5-yl, (1,2,3-benzothiadiazole)-4-yl, (1,2,3-benzothiadiazole)-5-yl, (1,2,3-benzothiadiazole)-6-yl,(1,2,3-benzothiadiazole)-7-yl, (2,1,3-benzothiadiazole)-4-yl, (2,1,3-benzothiadiazole)-5-yl, (1H-benzotriazole)-1-yl, (1H-benzotriazole)-4-yl, (1H-benzotriazole)-5-yl, (1H-benzotriazole)-6-yl, (1H-benzotriazole)-7-yl, ( 2H-benzotriazole)-2-yl, (2H-benzotriazole)-4-yl, (2H-benzotriazole)-5-yl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl, 3-cinnolinyl, 4-cinnolinyl, 5-cinnolinyl, 6-cinnolinyl, 7-cinnolinyl, 8-cinnolinyl, 2-quinazolinyl, 4-quinazolinyl, 5-quinazolinyl, 6-quinazolinyl, 7-quinazolinyl, 8-quinazolinyl, 2-quinoxalinyl, 5-quinoxalinyl, 6-quinoxalinyl, 1-phthalazinyl, 5-phthalazinyl, 6-phthalazinyl, 2 -naphthyridinyl, 3-naphthyridinyl, 4-naphthyridinyl, 2-purinyl, 6-purinyl, 7-purinyl, 8-purinyl, 2-pteridinyl, 4-pteridinyl, 6-pteridinyl, 7-pteridinyl, 1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl, 9-carbazolyl, 2-(α-carbolinyl) group, 3-(α-carbolinyl) group, 4-(α-carbolinyl) group ) group, 5-(α-carbolinyl) group, 6-(α-carbolinyl) group, 7-(α-carbolinyl) group, 8-(α-carbolinyl) group, 9-(α-carbolinyl) group, 1-(β-carbolinyl) group, 3-(β-carbolinyl) group, 4-(β-carbolinyl) group, 5-(β-carbolinyl) group, 6-(β-carbolinyl) group, 7-(β-carbolinyl) group, 8 -(β-carbolinyl) group, 9-(β-carbolinyl) group, 1-(γ-carbolinyl) group, 2-(γ-carbolinyl) group, 4-(γ-carbolinyl) group, 5-(γ-carbolinyl) group, 6-(γ-carbolinyl) group, 7-(γ-carbolinyl) group, 8-(γ-carbolinyl) group, 9-(γ-carbolinyl) group, 1-acridinyl group, 2-acridinyl group, 3-acridinyl group 4-Acridinyl, 9-Acridinyl, 1-Phenoxazinyl, 2-Phenoxazinyl, 3-Phenoxazinyl, 4-Phenoxazinyl, 10-Phenoxazinyl, 1-Phenothiazinyl, 2-Phenothiazinyl, 3-Phenothiazinyl, 4-Phenothiazinyl, 10-Phenothiazinyl, 1-Phenothiazinyl, 2 ...6-Phenothiazinyl pyridinyl, 7-phenanthridinyl, 8-phenanthridinyl, 9-phenanthridinyl, 10-phenanthridinyl, 2-phenanthrolinyl, 3-phenanthrolinyl, 4-phenanthrolinyl, 5-phenanthrolinyl, 6-phenanthrolinyl, 7-phenanthrolinyl, 8-phenanthrolinyl, 9-phenanthrolinyl, 10-phenanthrolinyl, 1-thianthrenyl, 2-thianthrenyl, 1-indolizinyl, 2-indolizinyl, 3-indolizinyl,5-indolizine, 6-indolizine, 7-indolizine, 8-indolizine, 1-phenoxythiophenyl, 2-phenoxythiophenyl, 3-phenoxythiophenyl, 4-phenoxythiophenyl, thieno[2,3-b]furanyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridinyl, imidazo[11,2-a]pyridinyl, imidazo[1,5-a]pyridinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl, 1,2,4-triazolo[4,3-a]pyridinyl, 1,2,4-triazolo[4,3-a]pyridazinyl, etc., but are not limited to these.

[0123] In the present specification, a heterocyclic group refers to a non-aromatic heterocyclic group, that is, a saturated or partially saturated heterocyclic group having 1 or 2 or more heteroatoms constituting the ring, and examples thereof include monocyclic or polycyclic, preferably monocyclic or bicyclic, saturated or partially saturated heterocyclic groups having 1 or 2 or more heteroatoms constituting the ring. Preferably, it is a monocyclic saturated heterocyclic group containing 1 or 2 or more nitrogen atoms constituting the ring, and more preferably a 4- to 6-membered saturated heterocyclic group containing 1 nitrogen atom constituting the ring.

[0124] Examples of the saturated or partially saturated monocyclic 3- to 7-membered heterocyclic group include, but are not limited to, 1-aziridine, 1-azetidinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, tetrahydrothienyl, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 1-pyrazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, 1-(2-pyrrolinyl) group, 1-(2-imidazolinyl) group, 2-(2-imidazolinyl) group, 1-(2-pyrazolinyl) group, 3-(2-pyrazolinyl) group, piperidino, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 1-homopiperidinyl, 2-tetrahydropyranyl, morpholino, (thiomorpholino)-4-yl, 1-piperazinyl, and 1-homopiperazinyl.

[0125] Examples of the saturated or partially saturated bicyclic 8- to 12-membered heterocyclic group include 2-quinuclidine, 2-chromanyl, 3-chromanyl, 4-chromanyl, 5-chromanyl, 6-chromanyl, 7-chromanyl, 8-chromanyl, 1-isochromanyl, 3-isochromanyl, 4-isochromanyl, 5-isochromanyl, 6-isochromanyl, 7-isochromanyl, 8-isochromanyl, 2-thiochromanyl, 3-thiochromanyl, 4-thiochromanyl, 5-thiochromanyl, 6-thiochromanyl, 7-thiochromanyl, 8-thiochromanyl, 1-isothiochromanyl, 3-isothiochromanyl, 4-isothiochromanyl, 5-isothiochromanyl, 6-isothiochromanyl, 7-isothiochromanyl, 8-isothiochromanyl, 1-indolyl, 2-indolyl, 3-indolyl, 4- indolyl, 5-indolyl, 6-indolyl, 7-indolyl, 1-isoindolyl, 2-isoindolyl, 4-isoindolyl, 5-isoindolyl, 2-(4H-chromenyl)yl, 3-(4H-chromenyl)yl, 4-(4H-chromenyl)yl, 5-(4H-chromenyl)yl, 6-(4H-chromenyl)yl, 7-(4H-chromenyl)yl, 8-(4H-chromenyl)yl ) group, 1-isochromenyl, 3-isochromenyl, 4-isochromenyl, 5-isochromenyl, 6-isochromenyl, 7-isochromenyl, 8-isochromenyl, 1-(1H-pyrrolidinyl) group, 2-(1H-pyrrolidinyl) group, 3-(1H-pyrrolidinyl) group, 5-(1H-pyrrolidinyl) group, 6-(1H-pyrrolidinyl) group, 7-(1H-pyrrolidinyl) group, etc., but are not limited to these.

[0126] In the present specification, the term "optionally having a substituent" for a functional group means, except for cases where it is otherwise specified, that the functional group is unsubstituted or has one or more substituents at chemically possible positions. There are no particular limitations on the type, number and position of the substituents present in the functional group. When there are two or more substituents, they may be the same or different. Examples of the substituents present in the functional group include an alkyl group, a halogen atom, an oxo group, a thio group, a nitro group, a nitroso group, a cyano group, an isocyano group, a cyanooxy group, a thiocyano group, an isocyanooxy group, an isothiocyano group, a hydroxyl group, a sulfanyl group, a carboxyl group, a thiocarbonyl group, an oxalyl group, a mesooxalyl group, a thiocarboxyl group, a dithiocarboxyl group, a carbamoyl group, a thiocarbamoyl group, a sulfo group, a sulfamoyl group, a sulfinyl group, a sulfinamoyl group, a sulfeno group, a sulfenamoyl group, a phosphoryl group, a hydroxyphosphoryl group, a hydrocarbon group, a heterocyclic group, a hydrocarbon ... The invention also includes oxy, heterocyclic-oxy, hydrocarbon-thio, heterocyclic-thio, acyl, amino, hydrazine, hydrazine, diazepine, urea, thiourea, guanidine, amidino, azido, imino, hydroxyamino, hydroxyimino, aminooxy, diazo, semicarbazide, semicarbazone, ureacarbonyl, hydantoyl, phosphine, phosphine, boryl, silyl, stannyl, seleno, oxide, etc., but is not limited to them.

[0127] Such substituents are optionally substituted by other substituents at chemically possible positions on the substituents. There are no particular restrictions on the type of substituents, the number of substituents and the substitution position. When substituted by two or more substituents, they may be the same or different. As such examples, for example, haloalkyl (e.g., trifluoromethyl, etc.), hydroxyalkyl (e.g., hydroxymethyl, etc.), haloalkyl-carbonyl (e.g., trifluoroacetyl, etc.), haloalkyl-sulfonyl (e.g., trifluoromethanesulfonyl, etc.), acyl-oxy, acyl-sulfenyl, N-alkyl-amino, N,N-di(hydrocarbon)-amino, N-heterocyclic-amino, N-hydrocarbon-N-heterocyclic-amino, acyl-amino, di(acyl)-amino and other groups, but are not limited to these.

[0128] Examples of substituents that may be present on the functional group include, for example, 1-6 Alkyl, C 1-6 Alkoxy, halogen atom, C substituted with 1 or 2 or more fluorine atoms 1-6 Alkyl, C substituted by 1 or 2 or more fluorine atoms 1-6 The alkoxy group and the cyano group may have one or two or more substituents, but are not limited to these.

[0129] R 1 and R 2Each independently represents a hydrogen atom, a halogen atom, a C 1-6 An alkyl group or an aromatic heterocyclic group which may have a substituent and has 1 or 2 or more hetero atoms constituting the ring. 1 and R 2 When both represent alkyl groups, they may be bonded to each other to form a C 3-6 Alkylene.

[0130] For example, R 1 and R 2 are independently a hydrogen atom, a fluorine atom, a C 1-6 an alkyl group (the alkyl group may be substituted with 1 or 2 or more halogen atoms), or an aromatic heterocyclic group having 1 or 2 or more hetero atoms constituting the ring and optionally having a substituent, R 1 and R 2 When both represent alkyl groups, they may bond to each other to form a C 3-5 Alkylene.

[0131] Preferred R 1 For hydrogen atoms, fluorine atoms, C 1-6 alkyl (the alkyl may be substituted by 1 or 2 or more fluorine atoms), and R 2 is a fluorine atom, C 1-6 an alkyl group (the alkyl group may be substituted with 1 or 2 or more halogen atoms), or an aromatic heterocyclic group having 1 or 2 or more hetero atoms constituting the ring and optionally having a substituent, R 1 and R 2 When both represent alkyl groups, they may bond to each other to form a C 3-5 Alkylene.

[0132] More preferably R 1 For hydrogen atoms, fluorine atoms, C 1-6 alkyl (the alkyl may be substituted by 1 or 2 or more fluorine atoms), and R 2 is a fluorine atom or C 1-6 An alkyl group (the alkyl group may be substituted by 1 or 2 or more fluorine atoms), or a monocyclic aromatic heterocyclic group containing 1 or 2 or more nitrogen atoms constituting the ring and optionally having a substituent.

[0133] Further optimization of R 1 is a hydrogen atom, a fluorine atom, or a methyl group, and R 2 is a hydrogen atom, a fluorine atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a 1-methyl-1-methoxyethyl group, a cyclopropyl group, a cyclopentyl group, a tert-butyl group, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a pyridyl group, a pyridazinyl group or a pyrazinyl group, wherein the pyridyl group, the pyridazinyl group or the pyrazinyl group may be selected from the following group: 1-6 Alkyl, C 1-6 Alkoxy, halogen atom, C substituted with 1 or 2 or more fluorine atoms1-6 Alkyl, C substituted by 1 or 2 or more fluorine atoms 1-6 One or more substituents in the alkoxy group and the cyano group.

[0134] In a particularly preferred embodiment, R 1 is a hydrogen atom or a fluorine atom, and R 2 is a hydrogen atom, a fluorine atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a 1-methyl-1-methoxyethyl group, a cyclopropyl group, a cyclopentyl group, a tert-butyl group, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a 2-pyridyl group, a 3-pyridyl group, a 4-pyridyl group, a 3-pyridazinyl group, a 4-pyridazinyl group or a 2-pyrazinyl group, wherein the 2-pyridyl group, the 3-pyridyl group, the 4-pyridyl group, the 3-pyridazinyl group, the 4-pyridazinyl group or the 2-pyrazinyl group is optionally selected from the following group: C 1-6 Alkyl, C 1-6 Alkoxy, halogen atom, C substituted with 1 or 2 or more fluorine atoms 1-6 Alkyl, C substituted by 1 or 2 or more fluorine atoms 1-6 One or more substituents in the alkoxy group and the cyano group.

[0135] In a particularly preferred embodiment, R 1 is a hydrogen atom or a fluorine atom, and R 2 is a fluorine atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a 1-methyl-1-methoxyethyl group, a cyclopropyl group, a cyclopentyl group, a tert-butyl group, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a 2-pyridyl group, a 3-pyridyl group, a 4-pyridyl group, a 3-pyridazinyl group, a 4-pyridazinyl group or a 2-pyrazinyl group, and the 2-pyridyl group, the 3-pyridyl group, the 4-pyridyl group, the 3-pyridazinyl group, the 4-pyridazinyl group or the 2-pyrazinyl group optionally has one or more substituents selected from the following group: a methyl group, an ethyl group, a methoxy group, an ethoxy group, a fluorine atom, a chlorine atom, a difluoromethyl group, a trifluoromethyl group, a difluoromethoxy group, a trifluoromethoxy group and a cyano group.

[0136] In another particularly preferred embodiment, R 1 is a hydrogen atom or a fluorine atom, and R 2 is methyl, ethyl, propyl, isopropyl, 1-methyl-1-methoxyethyl, cyclopropyl, cyclopentyl, tert-butyl, fluoromethyl, difluoromethyl or trifluoromethyl.

[0137] R 3 and R 4 Each independently represents a hydrogen atom, a halogen atom or a C 1-6 alkyl.

[0138] Preferred R 3 and R 4 are each independently a hydrogen atom, a fluorine atom, a chlorine atom or a C 1-6Alkyl (the alkyl group may be substituted by 1 or 2 or more fluorine atoms), more preferably R 3 and R 4 Each is independently a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a 1-methyl-1-methoxyethyl group, a cyclopropyl group, a cyclopentyl group, a tert-butyl group, a fluoromethyl group, a difluoromethyl group or a trifluoromethyl group.

[0139] In a more preferred embodiment, R 3 is a hydrogen atom or a fluorine atom, and R 4 It is a fluorine atom, a chlorine atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a 1-methyl-1-methoxyethyl group, a cyclopropyl group, a cyclopentyl group, a tert-butyl group, a fluoromethyl group, a difluoromethyl group or a trifluoromethyl group.

[0140] In a further preferred embodiment, R 3 is a fluorine atom, and R 4 is methyl, ethyl, propyl, isopropyl, 1-methyl-1-methoxyethyl, cyclopropyl, cyclopentyl, tert-butyl, fluoromethyl, difluoromethyl or trifluoromethyl.

[0141] R is particularly preferred 3 is a fluorine atom, and R 4 It is trifluoromethyl.

[0142] L 1 Indicates -CO-, -SO2- or -CO-C(R 5 )(R 6 )-(R 5 and R 6 Each independently represents a hydrogen atom or a C 1-6 Alkyl. 5 and R 6 When both represent alkyl groups, they may be bonded to each other to form a C 2-5 alkylene).

[0143] Preferred L 1 is -CO-, -SO2- or -CO-C(R 5 )(R 6 )-(R 5 and R 6 are independently a hydrogen atom or a C 1-6 Alkyl (R 5 and R 6 When both represent alkyl groups, they may bond to each other to form a C 3-5 Alkylene), more preferably L 1 is -CO-, -SO2- or -CO-C(R 5 )(R 6 )-(R 5 and R 6are independently a hydrogen atom or a C 1-6 Alkyl groups (the alkyl groups may be bonded to each other to form C 3-4 L 1 is -CO- or -SO2-, most preferably L 1 It is -CO-.

[0144] X represents a cyclic hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent and has 1 or 2 or more hetero atoms constituting the ring.

[0145] X is preferably an aromatic hydrocarbon group optionally having a substituent, a saturated or partially saturated cyclic hydrocarbon group optionally having a substituent, an aromatic heterocyclic group optionally having a substituent having 1 or 2 or more hetero atoms constituting the ring, or a saturated or partially saturated heterocyclic group optionally having a substituent having 1 or 2 or more hetero atoms constituting the ring.

[0146] In addition, X is more preferably a monocyclic or bicyclic aromatic hydrocarbon group which may have a substituent, a monocyclic or bicyclic saturated or partially saturated cyclic hydrocarbon group which may have a substituent, a monocyclic or bicyclic aromatic heterocyclic group which may have a substituent and has 1 or 2 or more hetero atoms constituting the ring, or a monocyclic or bicyclic saturated or partially saturated heterocyclic group which may have a substituent and has 1 or 2 or more hetero atoms constituting the ring.

[0147] In a further preferred embodiment, X is a phenyl group optionally having a substituent, a naphthyl group optionally having a substituent, a monocyclic or bicyclic 3- to 12-membered saturated or partially saturated cyclic hydrocarbon group optionally having a substituent, a monocyclic or bicyclic aromatic heterocyclic group containing 1 or more nitrogen atoms constituting the ring which is optionally having a substituent, or a monocyclic or bicyclic saturated or partially saturated heterocyclic group containing 1 or more nitrogen atoms constituting the ring which is optionally having a substituent.

[0148] In a further preferred embodiment, X is a phenyl group optionally having a substituent, a naphthyl group optionally having a substituent, a monocyclic saturated hydrocarbon group optionally having a substituent, a monocyclic aromatic heterocyclic group optionally having a substituent containing 1 or 2 or more nitrogen atoms constituting a ring, or a monocyclic saturated or partially saturated heterocyclic group optionally having a substituent containing 1 or 2 or more nitrogen atoms constituting a ring, or X is a monocyclic saturated hydrocarbon group optionally having a substituent or a monocyclic saturated or partially saturated heterocyclic group optionally having a substituent containing 1 or 2 or more nitrogen atoms constituting a ring, or X is a 4- to 6-membered saturated hydrocarbon group optionally having a substituent or a 4- to 6-membered saturated heterocyclic group optionally having a substituent containing 1 nitrogen atom constituting a ring.

[0149] In a particularly preferred embodiment, X is cyclobutanediyl, cyclopentanediyl, cyclohexanediyl, azetidinediyl, pyrrolidinediyl or piperidinediyl, or X is 1,3-cyclobutanediyl, 1,4-cyclohexanediyl, 1,3-azetidinediyl or 1,4-piperidinediyl, and most preferably X is 1,3-cyclobutanediyl.

[0150] L 2 Indicates -A 1 -R 7 -A 2 -(A 1 represents a single bond, -CO-, -NH- or -O-, R 7 Represents a single bond or C 1-6 Alkylene, A 2 represents a single bond, -CO-, -NH- or -O-).

[0151] L 2 Indicates -A 1 -R 7 -A 2 - Medium, preferably A 1 , R 7 and A 2 All are single bonds, or A 1 is a single bond, R 7 is -CO-, -NH- or -O-, and A 2 is a single bond or C 1-6 Alkylene, or A 1 C 1-6 Alkylene, R 7 is -CO-, -NH- or -O-, and A 2 is a single key).

[0152] In addition, L 2 Indicates -A 1 -R 7 -A 2 - Medium, preferably A 1 , R 7 and A 2 All are single bonds, or A 1 is a single bond, R 7 is -CO-, -NH- or -O-, and A 2 is a single bond or C 1-4 Alkylene, or A 1 C 1-4 Alkylene, R 7 is -CO-, -NH- or -O-, and A 2 is a single key).

[0153] Further preferred L 2 Indicates -A 1 -R7 -A 2 -Medium, A 1 , R 7 and A 2 All are single bonds, or A 1 is a single bond, R 7 is -O-, and A 2 is a single bond or C 1-4 Alkylene, or A 1 C 1-4 Alkylene, R 7 is -O-, and A 2 For a single key.

[0154] In another further preferred embodiment, L 2 Indicates -A 1 -R 7 -A 2 -Medium, A 1 , R 7 and A 2 All are single bonds, or A 1 is a single bond, R 7 is -O-, and A 2 is a single bond, methylene or ethylene, or A 1 is methylene or ethylene, R 7 is -O-, and A 2 For a single key.

[0155] L is particularly preferred 2 is a single bond, -O-, -CH2-O- or -O-CH2-, or L 2 is a single bond, -O- or -O-CH2-, or L 2 is a single bond or -O-CH2-, or L 2 It is -O-CH2-.

[0156] Y represents a hydrogen atom, a cyclic hydrocarbon group which may have a substituent, or a heterocyclic group which may have a substituent and has 1 or 2 or more hetero atoms constituting the ring.

[0157] For example, Y is a hydrogen atom, an aromatic hydrocarbon group optionally having a substituent, a saturated or partially saturated cyclic hydrocarbon group optionally having a substituent, an aromatic heterocyclic group optionally having a substituent having 1 or 2 or more hetero atoms constituting the ring, or a saturated or partially saturated heterocyclic group optionally having a substituent having 1 or 2 or more hetero atoms constituting the ring. In another embodiment, for example, Y is a hydrogen atom, a monocyclic or bicyclic aromatic hydrocarbon group optionally having a substituent, a monocyclic or bicyclic saturated or partially saturated cyclic hydrocarbon group optionally having a substituent, a monocyclic or bicyclic aromatic heterocyclic group having 1 or 2 or more hetero atoms constituting the ring, or a monocyclic or bicyclic saturated or partially saturated heterocyclic group optionally having a substituent having 1 or 2 or more hetero atoms constituting the ring.

[0158] In a preferred embodiment, Y is a hydrogen atom, a monocyclic or bicyclic aromatic hydrocarbon group optionally having a substituent, a monocyclic or bicyclic 3- to 12-membered saturated or partially saturated cyclic hydrocarbon group optionally having a substituent, a monocyclic or bicyclic aromatic heterocyclic group containing 1 or more nitrogen atoms constituting the ring and optionally having a substituent, or a monocyclic or bicyclic saturated or partially saturated heterocyclic group containing 1 or more nitrogen atoms constituting the ring and optionally having a substituent.

[0159] In another preferred embodiment, Y is a hydrogen atom, a monocyclic or bicyclic aromatic hydrocarbon group optionally having a substituent, a saturated monocyclic 3- to 7-membered cyclic hydrocarbon group optionally having a substituent, a monocyclic or bicyclic aromatic heterocyclic group optionally having a substituent and containing 1 or more nitrogen atoms constituting the ring, or a saturated or partially saturated monocyclic or bicyclic heterocyclic group optionally having a substituent and containing 1 or more nitrogen atoms constituting the ring.

[0160] More preferably, Y is a hydrogen atom, an optionally substituted phenyl group, an optionally substituted naphthyl group, or an optionally substituted monocyclic or bicyclic aromatic heterocyclic group containing one or more nitrogen atoms constituting the ring.

[0161] In particular, it is preferred that Y is a hydrogen atom, a phenyl group which may have a substituent, a naphthyl group which may have a substituent, a pyridyl group which may have a substituent, or a quinolyl group which may have a substituent.

[0162] In another particularly preferred embodiment, Y is a hydrogen atom, a phenyl group, a naphthyl group, a pyridyl group or a quinolyl group, wherein the phenyl group, the naphthyl group, the pyridyl group or the quinolyl group may have a group selected from the following group: 1-6 Alkyl, C 1-6 Alkoxy, halogen atom, C substituted with 1 or 2 or more fluorine atoms 1-6 Alkyl, C substituted by 1 or 2 or more fluorine atoms 1-6 One or more substituents in the alkoxy group and the cyano group.

[0163] In another particularly preferred embodiment, Y is a hydrogen atom, a phenyl group, a naphthyl group, a pyridyl group or a quinolyl group, and the phenyl group, the naphthyl group, the pyridyl group or the quinolyl group optionally has one or more substituents selected from the following group: a methyl group, an ethyl group, a methoxy group, an ethoxy group, a fluorine atom, a chlorine atom, a difluoromethyl group, a trifluoromethyl group, a difluoromethoxy group, a trifluoromethoxy group and a cyano group.

[0164] In the most preferred embodiment, Y is a phenyl group, which may have one or more substituents selected from the group consisting of a methyl group, an ethyl group, a methoxy group, an ethoxy group, a fluorine atom, a chlorine atom, a difluoromethyl group, a trifluoromethyl group, a difluoromethoxy group, a trifluoromethoxy group and a cyano group.

[0165] Examples of the compound of the present invention included in the general formula (1) include the following compounds:

[0166] N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}-1-(8-methylquinolin-2-yl)piperidine-4-carboxamide;

[0167] N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}-1-[5-(trifluoromethyl)pyridin-2-yl]piperidine-4-carboxamide;

[0168] 1-(4-chlorophenyl)-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}piperidine-4-carboxamide;

[0169] trans-3-[(3-chlorobenzyl)oxy]-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}cyclobutane-1-carboxamide;

[0170] trans-3-[(3-chlorobenzyl)oxy]-N-[2-fluoro-3-(4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]cyclobutane-1-carboxamide;

[0171] trans-4-[(2-chlorobenzyl)oxy]-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}cyclohexane-1-carboxamide;

[0172] trans-3-[(3-chlorobenzyl)oxy]-N-[3-(4-ethyl-5-fluoro-6-oxo-1,6-dihydropyrimidin-2-yl)-2-fluoro-4-(trifluoromethyl)benzyl]cyclobutane-1-carboxamide;

[0173] trans-4-[(2-chlorobenzyl)oxy]-N-[2-fluoro-3-(5-fluoro-4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]cyclohexane-1-carboxamide; and

[0174] trans-4-[(2,4-difluorobenzyl)oxy]-N-[3-(4-ethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-2-fluoro-4-(trifluoromethyl)benzyl]cyclohexane-1-carboxamide

[0175] etc., but not limited to these.

[0176] The compound represented by general formula (1) may be in the form of a salt. The salt is not particularly limited and can be appropriately selected according to the purpose, and examples thereof include alkali metal salts such as sodium and potassium; alkaline earth metal salts such as calcium and magnesium; organic amine salts such as methylamine, ethylamine, and diethanolamine; or mineral salts such as hydrochlorides, sulfates, and nitrates; organic acid salts such as p-toluenesulfonates, maleates, and tartrates.

[0177] The compound represented by the general formula (1) or its salt may exist in the form of a hydrate or a solvate. The type of solvent forming the solvate is not particularly limited, and examples thereof include ethanol, ethyl acetate, acetone, etc. The compound represented by the general formula (1) may exist in the form of optical isomers, diastereomers or geometric isomers depending on the type of substituents, and in addition to any isomer in pure form, any mixture of isomers is also included in the scope of the present invention.

[0178] The compound represented by the general formula (1) or its salt can be easily synthesized from raw material compounds readily available to those skilled in the art by general chemical reactions commonly used by those skilled in the art. The specific production method of the compound of the present invention is shown in the examples of this specification. Those skilled in the art can easily produce the compound of the present invention contained in the general formula (1) by referring to these synthesis methods.

[0179] Synthetic route-1

[0180] [Chemistry 2]

[0181]

[0182] Step-1

[0183] Compound 1 reacts with L through an aromatic nucleophilic substitution reaction. 2 -Y reaction can produce compound 2.

[0184] As the base in this reaction, organic bases (amines, such as methylamine, ethylamine, diethylamine, triethylamine, propylamine, isopropylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-undecene and other mono- to trialkylamines; alkanolamines such as ethanolamine; alkylene polyamines such as ethylenediamine and diethylenetriamine, etc.), inorganic bases (metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, iron hydroxide, aluminum hydroxide; alkali metal carbonates such as sodium carbonate, sodium bicarbonate, potassium carbonate, rubidium carbonate, cesium carbonate; sodium hydride, sodium tert-butoxide, potassium tert-butoxide, potassium fluoride, cesium fluoride, tripotassium phosphate) etc. can be cited. Potassium carbonate, cesium carbonate, tripotassium phosphate are particularly preferred. In addition, a salt may be formed with one of these bases, or with two or more bases.

[0185] The reaction time and reaction temperature may be conventionally used, and the reaction temperature is preferably 20 to 200° C., particularly preferably 80 to 150° C. The reaction time is preferably 0.25 to 24 hours, particularly preferably 1 to 12 hours.

[0186] The solvent used in the present reaction may be any conventional solvent, and N,N-dimethylformamide, N,N-dimethylsulfoxide, N,N-dimethylacetamide, sulfolane, and the like are preferred.

[0187] Step-2

[0188] For compound 1, by using L 2 Buchwald-Hartwig cross-coupling reaction of -Y can produce compound 2.

[0189] Examples of the catalyst / ligand in this reaction include palladium acetate, bis(dibenzylideneacetone)palladium(0), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, 1,1'-bis(diphenylphosphino)ferrocene, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl, (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)methanesulfonic acid, and the like.

[0190] As the base in this reaction, organic bases (amines, such as methylamine, ethylamine, diethylamine, triethylamine, propylamine, isopropylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7- undecene and other mono- to trialkylamines; alkanolamines such as ethanolamine; alkylene polyamines such as ethylenediamine and diethylenetriamine, etc.), inorganic bases (metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, iron hydroxide, aluminum hydroxide; alkali metal carbonates such as sodium carbonate, sodium bicarbonate, potassium carbonate, rubidium carbonate, cesium carbonate; sodium hydride, sodium tert-butoxide, potassium tert-butoxide, potassium fluoride, cesium fluoride, tripotassium phosphate) etc. are listed. Potassium carbonate, cesium carbonate, sodium tert-butoxide, potassium tert-butoxide are particularly preferred. In addition, a salt may be formed with one of these bases, or with two or more bases.

[0191] The reaction time and reaction temperature may be conventionally used, and the reaction temperature is preferably 20 to 200° C., particularly preferably 80 to 150° C. The reaction time is preferably 0.25 to 24 hours, particularly preferably 1 to 12 hours.

[0192] The solvent in the present reaction may be any conventional solvent, and 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylsulfoxide, N,N-dimethylacetamide, and the like are preferred.

[0193] Step-3

[0194] For compound 1, by reacting with L in the presence of a base 2 -Y reaction can produce compound 2.

[0195] As the base in this reaction, organic bases (amines, such as mono- to tri-alkylamines such as methylamine, ethylamine, diethylamine, triethylamine, propylamine, isopropylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]-7-undecene; alkanolamines such as ethanolamine; alkylene polyamines such as ethylenediamine and diethylenetriamine, etc.), inorganic bases (metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, iron hydroxide, aluminum hydroxide; alkali metal carbonates such as sodium carbonate, sodium bicarbonate, potassium carbonate, rubidium carbonate, cesium carbonate; sodium hydride, sodium tert-butoxide, potassium tert-butoxide, potassium fluoride, cesium fluoride, tripotassium phosphate) and the like can be cited. Sodium hydride and diisopropylethylamine are particularly preferred. In addition, a salt may be formed with one of these bases, or with two or more bases.

[0196] The reaction time, reaction temperature and the like may be conventionally used, and the reaction temperature is preferably 0° C. to 200° C. The reaction time is preferably 0.25 to 24 hours, particularly preferably 8 to 24 hours.

[0197] The solvent used in the present reaction may be any conventional solvent, and tetrahydrofuran, N,N-dimethylformamide, or no solvent is preferred.

[0198] Step-4

[0199] Compound 2 obtained in the above steps 1 to 3 can be hydrolyzed under basic conditions to produce compound 3.

[0200] As the base in this reaction, inorganic bases (metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide, iron hydroxide, aluminum hydroxide, etc.; alkali metal carbonates such as sodium carbonate, sodium bicarbonate, potassium carbonate, rubidium carbonate, cesium carbonate, etc.; sodium hydride, sodium tert-butoxide, potassium tert-butoxide, potassium fluoride, cesium fluoride, tripotassium phosphate, etc. can be listed. Particularly preferably, sodium hydroxide, potassium hydroxide, calcium hydroxide, and lithium hydroxide are listed. In addition, a salt can be formed with one of these bases, or with two or more bases.

[0201] The reaction time and reaction temperature may be conventionally used, and the reaction temperature is preferably 0 to 140° C., particularly preferably 20 to 80° C. The reaction time is preferably 0.25 to 48 hours, particularly preferably 1 to 24 hours.

[0202] The solvent in this reaction may be any conventional solvent, and water, methanol, ethanol, 1-propanol, 2-propanol, tetrahydrofuran or the like is preferred.

[0203] Synthetic route-2

[0204] [Chemistry 3]

[0205]

[0206] Step-5

[0207] Compound 6 can be produced by reacting Compound 4 and Compound 5 in the presence of a base in the same manner as the production method disclosed in International Publication No. WO2017 / 073709.

[0208] As the base in this reaction, organic bases (amines, such as methylamine, ethylamine, diethylamine, triethylamine, propylamine, isopropylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-undecene and other mono- to trialkylamines; alkanolamines such as ethanolamine; alkylene polyamines such as ethylenediamine and diethylenetriamine, etc.), inorganic bases (metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, iron hydroxide, aluminum hydroxide; alkali metal carbonates such as sodium carbonate, sodium bicarbonate, potassium carbonate, rubidium carbonate, cesium carbonate; sodium hydride, sodium tert-butoxide, potassium tert-butoxide, potassium fluoride, cesium fluoride, tripotassium phosphate) etc. are listed. Potassium carbonate, sodium hydride, potassium tert-butoxide are particularly preferred. In addition, a salt may be formed with one of these bases, and a salt may be formed with two or more bases.

[0209] The reaction time and reaction temperature may be any conventional reaction time and reaction temperature, and the reaction temperature is preferably 0 to 140° C., particularly preferably 20 to 80° C. The reaction time is preferably 0.25 to 48 hours, particularly preferably 1 to 24 hours.

[0210] The solvent in the present reaction may be any conventional solvent, and water, tetrahydrofuran, N,N-dimethylformamide, methanol, ethanol, 1-propanol, 2-propanol, and the like are preferred.

[0211] Step-6

[0212] Compound 7 can be prepared by hydrolyzing compound 6 under acidic conditions.

[0213] Examples of the reactant include inorganic acids (hydrochloric acid, sulfuric acid, nitric acid, etc.), organic acids (methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, trifluoroacetic acid, mono-, di- or trichloroacetic acid), etc. Among these strong acids, hydrochloric acid is particularly preferred.

[0214] The solvent in the reaction may be any conventional solvent, but no solvent is preferred.

[0215] The reaction time, reaction temperature and the like in the reaction may be any conventional ones, and the reaction temperature is preferably 0 to 150° C., particularly preferably 50 to 130° C. The reaction time is preferably 1 to 48 hours, particularly preferably 12 to 24 hours.

[0216] Step-7

[0217] Compound 3 can be condensed with Compound 7 in the presence of a condensing agent and a base to produce Compound 8 (a compound represented by the general formula (1)).

[0218] The condensing agent may be any conventionally used one, and examples thereof include N,N'-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, N,N'-carbonyldiimidazole, 1-bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, and propylphosphonic anhydride (cyclic trimer).

[0219] As the base in this reaction, organic bases (amines, such as mono- to tri-alkylamines such as methylamine, ethylamine, diethylamine, triethylamine, propylamine, isopropylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]-7-undecene; alkanolamines such as ethanolamine; alkylene polyamines such as ethylenediamine and diethylenetriamine, etc.), inorganic bases (metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, iron hydroxide, aluminum hydroxide; alkali metal carbonates such as sodium carbonate, sodium bicarbonate, potassium carbonate, rubidium carbonate, cesium carbonate; sodium hydride, sodium tert-butoxide, potassium tert-butoxide, potassium fluoride, cesium fluoride, tripotassium phosphate) etc. are listed. Alkali metal bases and organic bases are preferred, and triethylamine, diisopropylethylamine etc. are particularly preferred. In addition, a salt may be formed with one of these bases, or with two or more bases.

[0220] The solvent may be any conventional solvent, and preferably dichloromethane, N,N-dimethylformamide, tetrahydrofuran, ethyl acetate, etc. The reaction temperature is preferably -10°C to 60°C, and the reaction time is preferably 1 hour to 48 hours.

[0221] The compound of the present invention represented by general formula (1) has mPGES-1 inhibitory effect, and can suppress PGE2 biosynthesis based on its inhibitory effect. Therefore, the medicine of the present invention containing the compound of the present invention shown in general formula (1) or physiologically allowed salt as an effective ingredient can be used for the prevention and / or treatment of diseases such as high intraocular pressure such as inflammation, pain, rheumatism, osteoarthritis, fever, Alzheimer's disease, multiple sclerosis, arteriosclerosis, glaucoma, ischemic retinal disease, systemic scleroderma, colorectal cancer, or suppress PGE2 to produce a disease showing effectiveness based on mPGES-1 inhibitory effect.

[0222] More specifically, the drug of the present invention can be used for preventing and / or treating, for example, inflammatory colitis, irritable bowel syndrome, migraine, headache, low back pain, lumbar spinal stenosis, intervertebral disc herniation, temporomandibular joint disease, cervical shoulder-arm syndrome, cervical spondylosis, endometriosis, adenomyosis, premature labor, threatened premature labor, dysmenorrhea, overactive bladder, urinary dysfunction associated with prostatic hypertrophy, nocturnal frequent urination, urinary incontinence, neurogenic bladder, interstitial cystitis, bladder pain syndrome, urinary tract stones, prostatic hypertrophy, chronic prostatitis, pelvic pain syndrome, erectile dysfunction, cognitive impairment, neurodegenerative diseases, Alzheimer's disease, pulmonary hypertension, psoriasis, rheumatic arthritis, rheumatic fever, fibromyalgia, neuralgia, complex regional pain syndrome, Syndrome, fascial disorder, ischemic heart disease, hypertension, angina pectoris, viral infection, bacterial infection, fungal infection, burns, inflammation and pain after surgery, trauma and tooth extraction, malignant tumor, myocardial infarction, atherosclerosis, thrombosis, embolism, type I diabetes, type II diabetes, stroke, gout, arthritis, osteoarthritis, juvenile arthritis, ankylosing spondylitis, tenosynovitis, ligament ossification, systemic lupus erythematosus, vasculitis, pancreatitis, nephritis, conjunctivitis, iritis, scleritis, uveitis, wound treatment, dermatitis, eczema, osteoporosis, asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, allergic diseases, familial adenomatous polyposis, scleroderma, bursitis, uterine fibroids or drugs for pain in cancer. Regarding the association between mPGES-1 inhibition and medical use, for example, reference can be made to International Publication WO2015 / 125842. The disclosures of the above-mentioned international publications and the documents cited therein are all incorporated by reference into the disclosure of the present specification.

[0223] As the drug of the present invention, the compound represented by the above general formula (1) or a physiologically acceptable salt thereof as an active ingredient can be administered, but it is preferred to prepare an oral or parenteral pharmaceutical composition by a method known to those skilled in the art and administer it. Examples of pharmaceutical compositions suitable for oral administration include tablets, powders, capsules, fine granules, liquids, granules, and syrups, and examples of pharmaceutical compositions suitable for parenteral administration include intravenous injections, intramuscular injections, injections, drips, inhalants, eye drops, nasal drops, suppositories, percutaneous absorbents, and transmucosal absorbents, but are not limited thereto.

[0224] The above-mentioned pharmaceutical composition can be manufactured by methods known to those skilled in the art using a general-purpose pharmaceutical composition preparation additive in the industry. The pharmaceutical composition additive is not particularly limited and can be appropriately selected according to the form of the pharmaceutical composition or the purpose of imparting sustained release. For example, excipients, binders, extenders, disintegrants, surfactants, lubricants, dispersants, buffers, preservatives, flavoring agents, spices, film-forming agents, diluents, etc. can be cited, but are not limited to these.

[0225] The dosage of the drug of the present invention is not particularly limited and can be appropriately selected according to the type of disease to be prevented or treated, the purpose of prevention or treatment, the type of active ingredient, the patient's weight, age, symptoms, administration route, etc. For example, in the case of oral administration, the weight of the active ingredient for an adult per day can be used in the range of about 0.01 to 500 mg. However, the dosage can be appropriately selected by those skilled in the art and is not limited to the above range.

[0226] Example

[0227] The present invention will be described in more detail below based on examples, but the present invention is not limited to these examples.

[0228] Reference example

[0229] Reference Example 1: N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}isobutyramide

[0230] 5.00 g of N-[3-carbamimidoyl-2-fluoro-4-(trifluoromethyl)benzyl]isobutyramide·formate, 5.24 g of ethyl 4,4,4-trifluoroacetoacetate, 3.93 g of potassium carbonate, and 50 mL of ethanol were stirred at 55°C for 2 days. 1N hydrochloric acid and water were added, and the mixture was extracted twice with ethyl acetate. The solvent was distilled off under reduced pressure. Purification by silica gel column chromatography gave 5.58 g of the title compound.

[0231] Reference Example 2: 2-[3-(Aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one

[0232] A solution of 860 mg of N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}isobutyramide, 8.6 mL of concentrated hydrochloric acid, and 0.86 mL of acetic acid was stirred at 110°C for 5.5 hours. After cooling, a 6N sodium hydroxide solution was added and the mixture was extracted twice with ethyl acetate. The obtained organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 309 mg of the title compound.

[0233] Reference Example 3: N-[2-Fluoro-3-(4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]isobutyramide

[0234] The title compound was obtained by the same procedure as in Reference Example 1 using N-[3-carbamimidoyl-2-fluoro-4-(trifluoromethyl)benzyl]isobutyramide formate and ethyl 3-oxobutyrate.

[0235] Reference Example 4: 2-[3-(Aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-methylpyrimidin-4(3H)-one

[0236] The title compound was obtained by the same operation as in Reference Example 2 using N-[2-fluoro-3-(4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]isobutyramide.

[0237] Reference Example 5: N-[3-(4-ethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-2-fluoro-4-(trifluoromethyl)benzyl]isobutyramide

[0238] The title compound was obtained by the same procedures as in Reference Example 1 using N-[3-carbamimidoyl-2-fluoro-4-(trifluoromethyl)benzyl]isobutyramide formate and ethyl 3-oxopentanoate.

[0239] Reference Example 6: 2-[3-(Aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-ethylpyrimidin-4(3H)-one

[0240] The title compound was obtained by the same operation as in Reference Example 2 using N-[3-(4-ethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-2-fluoro-4-(trifluoromethyl)benzyl]isobutyramide.

[0241] Reference Example 7: N-[3-(4,5-dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-2-fluoro-4-(trifluoromethyl)benzyl]isobutyramide

[0242] The title compound was obtained by the same procedure as in Reference Example 1 using N-[3-carbamimidoyl-2-fluoro-4-(trifluoromethyl)benzyl]isobutyramide formate and ethyl 2-methylacetoacetate.

[0243] Reference Example 8: 2-[3-(Aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-5,6-dimethylpyrimidin-4(3H)-one

[0244] The title compound was obtained by the same operation as in Reference Example 2 using N-[3-(4,5-dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-2-fluoro-4-(trifluoromethyl)benzyl]isobutyramide.

[0245] Reference Example 9: N-[2-Fluoro-3-(4-oxo-4,5,6,7-tetrahydro-3H-cyclopenta[d]pyrimidin-2-yl)-4-(trifluoromethyl)benzyl]isobutyramide

[0246] The title compound was obtained by the same procedures as in Reference Example 1 using N-[3-carbamimidoyl-2-fluoro-4-(trifluoromethyl)benzyl]isobutyramide formate and ethyl 2-oxocyclopentylcarboxylate.

[0247] Reference Example 10: 2-[3-(Aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-3,5,6,7-tetrahydro-4H-cyclopenta[d]pyrimidin-4-one

[0248] The title compound was obtained by the same procedure as in Reference Example 2 using N-[2-fluoro-3-(4-oxo-4,5,6,7-tetrahydro-3H-cyclopenta[d]pyrimidin-2-yl)-4-(trifluoromethyl)benzyl]isobutyramide.

[0249] Reference Example 11: N-[2-Fluoro-3-(5-fluoro-4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]isobutyramide

[0250] The title compound was obtained by the same operation as in Reference Example 1 using N-[3-carbamimidoyl-2-fluoro-4-(trifluoromethyl)benzyl]isobutyramide formate and ethyl 2-fluoroacetoacetate.

[0251] Reference Example 12: 2-[3-(Aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-5-fluoro-6-methylpyrimidin-4(3H)-one

[0252] The title compound was obtained by the same operation as in Reference Example 2 using N-[2-fluoro-3-(5-fluoro-4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]isobutyramide.

[0253] Reference Example 13: N-[3-(4-ethyl-5-fluoro-6-oxo-1,6-dihydropyrimidin-2-yl)-2-fluoro-4-(trifluoromethyl)benzyl]isobutyramide

[0254] The title compound was obtained by the same operation as in Reference Example 1 using N-[3-carbamimidoyl-2-fluoro-4-(trifluoromethyl)benzyl]isobutyramide formate and ethyl 2-fluoro-3-oxopentanoate.

[0255] Reference Example 14: 2-[3-(Aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-ethyl-5-fluoropyrimidin-4(3H)-one

[0256] The title compound was obtained by the same operation as in Reference Example 2 using N-[3-(4-ethyl-5-fluoro-6-oxo-1,6-dihydropyrimidin-2-yl)-2-fluoro-4-(trifluoromethyl)benzyl]isobutyramide.

[0257] Reference Example 15: N-{3-[4-(difluoromethyl)-6-oxo-1,6-dihydropyrimidin-2-yl]-2-fluoro-4-(trifluoromethyl)benzyl}isobutyramide

[0258] The title compound was obtained by the same operation as in Reference Example 1 using N-[3-carbamimidoyl-2-fluoro-4-(trifluoromethyl)benzyl]isobutyramide formate and ethyl 4,4-difluoroacetoacetate.

[0259] Reference Example 16: 2-[3-(Aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(difluoromethyl)pyrimidin-4(3H)-one

[0260] The title compound was obtained by the same operation as in Reference Example 2 using N-{3-[4-(difluoromethyl)-6-oxo-1,6-dihydropyrimidin-2-yl]-2-fluoro-4-(trifluoromethyl)benzyl}isobutyramide.

[0261] Reference Example 17: N-[2-Fluoro-3-(6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]isobutyramide

[0262] The title compound was obtained by the same procedure as in Reference Example 1 using N-[3-carbamimidoyl-2-fluoro-4-(trifluoromethyl)benzyl]isobutyramide formate and ethyl propiolate.

[0263] Reference Example 18: 2-[3-(Aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]pyrimidin-4(3H)-one

[0264] The title compound was obtained by the same operation as in Reference Example 2 using N-[2-fluoro-3-(6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]isobutyramide.

[0265] Reference Example 19: N-{4-chloro-2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]benzyl}isobutyramide

[0266] The title compound was obtained by the same operation as in Reference Example 1 using N-(3-carbamimidoyl-4-chloro-2-fluorobenzyl)isobutyramide hydrochloride and ethyl 4,4,4-trifluoroacetoacetate.

[0267] Reference Example 20: 2-[3-(Aminomethyl)-6-chloro-2-fluorophenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one

[0268] The title compound was obtained by the same operation as in Reference Example 2 using N-{4-chloro-2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]benzyl}isobutyramide.

[0269] Reference Example 21: N-{3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}isobutyramide

[0270] The title compound was obtained by the same operation as in Reference Example 1 using N-[3-carbamimidoyl-4-(trifluoromethyl)benzyl]isobutyramide formate and ethyl 4,4,4-trifluoroacetoacetate.

[0271] Reference Example 22: 2-[5-(Aminomethyl)-2-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one

[0272] The title compound was obtained by the same procedure as in Reference Example 2 using N-{3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}isobutyramide.

[0273] Reference Example 23: 1-(8-Methylquinolin-2-yl)azetidine-3-carboxylic acid methyl

[0274] A solution of 533 mg of 2-chloro-8-methylquinoline, 910 mg of methyl azetidine-3-carboxylate·hydrochloride, and 1.66 g of potassium carbonate in 6 mL of dimethyl sulfoxide was stirred at 110°C for 2 days. Water was added, and the mixture was extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the mixture was purified by silica gel column chromatography to obtain 398 mg of the title compound.

[0275] Reference Example 24: 1-(8-Methylquinolin-2-yl)azetidine-3-carboxylic acid

[0276] To a solution of 394 mg of methyl 1-(8-methylquinolin-2-yl)azetidine-3-carboxylate in 4 mL of methanol was added 4.6 mL of 1N aqueous sodium hydroxide solution, and the mixture was stirred at 50°C for 3 hours. 1N hydrochloric acid was added, and the mixture was extracted twice with ethyl acetate, and the combined organic layers were dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain 204 mg of the title compound.

[0277] Reference Example 25: Ethyl 1-(imidazo[1,2-b]pyridazin-6-yl)piperidine-4-carboxylate

[0278] The title compound was obtained by the same operation as in Reference Example 23 using 6-chloroimidazo[1,2-b]pyridazine and ethyl 4-piperidincarboxylate. The obtained compound was used in the next reaction without purification.

[0279] Reference Example 26: 1-(Imidazolo[1,2-b]pyridazin-6-yl)piperidine-4-carboxylic acid

[0280] The title compound was obtained by the same operation as in Reference Example 24 using ethyl 1-(imidazo[1,2-b]pyridazin-6-yl)piperidine-4-carboxylate.

[0281] Reference Example 27: Ethyl 1-(3-methylimidazo[1,2-b]pyridazin-6-yl)piperidine-4-carboxylate

[0282] The title compound was obtained by the same operation as in Reference Example 23 using 6-chloro-3-methylimidazo[1,2-b]pyridazine and ethyl 4-piperidincarboxylate. The obtained compound was used in the next reaction without purification.

[0283] Reference Example 28: 1-(3-Methylimidazo[1,2-b]pyridazin-6-yl)piperidine-4-carboxylic acid

[0284] The title compound was obtained by the same procedure as in Reference Example 24 using ethyl 1-(3-methylimidazo[1,2-b]pyridazin-6-yl)piperidine-4-carboxylate.

[0285] Reference Example 29: 4-Fluoro-1-(8-methylquinolin-2-yl)piperidine-4-carboxylic acid ethyl ester

[0286] The title compound was obtained by the same operation as in Reference Example 23 using 2-chloro-8-methylquinoline and ethyl 4-fluoropiperidine-4-carboxylate hydrochloride.

[0287] Reference Example 30: 4-Fluoro-1-(8-methylquinolin-2-yl)piperidine-4-carboxylic acid

[0288] The title compound was obtained by the same operation as in Reference Example 24 using ethyl 4-fluoro-1-(8-methylquinolin-2-yl)piperidine-4-carboxylate.

[0289] Reference Example 31: 4-Fluoro-1-[5-(trifluoromethyl)pyridin-2-yl]piperidine-4-carboxylic acid

[0290] The title compound was obtained by the same procedures as in Reference Examples 23 and 24 using 2-chloro-5-(trifluoromethyl)pyridine and ethyl 4-fluoropiperidine-4-carboxylate hydrochloride.

[0291] Reference Example 32: Ethyl 1-[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]piperidine-4-carboxylate

[0292] The title compound was obtained by the same operation as in Reference Example 23 using 2,3-difluoro-5-(trifluoromethyl)pyridine and ethyl 4-piperidincarboxylate.

[0293] Reference Example 33: 1-[3-Fluoro-5-(trifluoromethyl)pyridin-2-yl]piperidine-4-carboxylic acid

[0294] The title compound was obtained by the same operation as in Reference Example 24 using ethyl 1-[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]piperidine-4-carboxylate.

[0295] Reference Example 34: 1-[5-(Trifluoromethoxy)pyridin-2-yl]piperidine-4-carboxylic acid

[0296] The title compound was obtained by the same operation as in Reference Example 24 using ethyl 1-[5-(trifluoromethoxy)pyridin-2-yl]piperidine-4-carboxylate.

[0297] Reference Example 35: Ethyl 1-(5-chloro-6-methylpyridin-2-yl)piperidine-4-carboxylate

[0298] The title compound was obtained by the same operation as in Reference Example 23 using 3,6-dichloromethylpyridine and ethyl 4-piperidincarboxylate. The obtained compound was used in the next reaction without purification.

[0299] Reference Example 36: 1-(5-chloro-6-methylpyridin-2-yl)piperidine-4-carboxylic acid

[0300] The title compound was obtained by the same operation as in Reference Example 24 using ethyl 1-(5-chloro-6-methylpyridin-2-yl)piperidine-4-carboxylate.

[0301] Reference Example 37: Ethyl 1-[5-(trifluoromethyl)pyrazin-2-yl]piperidine-4-carboxylate

[0302] The title compound was obtained by the same operation as in Reference Example 23 using 2-chloro-5-(trifluoromethyl)pyrazine and ethyl 4-piperidincarboxylate.

[0303] Reference Example 38: 1-[5-(Trifluoromethyl)pyrazin-2-yl]piperidine-4-carboxylic acid

[0304] The title compound was obtained by the same operation as in Reference Example 24 using ethyl 1-[5-(trifluoromethyl)pyrazin-2-yl]piperidine-4-carboxylate.

[0305] Reference Example 39: Ethyl 1-(4-chloro-3-fluorophenyl)piperidine-4-carboxylate

[0306] To a solution of 234 μL of 4-bromo-1-chloro-2-fluorobenzene in 13 mL of 1,2-dimethoxyethane, 447 μL of ethyl 4-piperidinate, 1.89 g of cesium carbonate, and 99 mg of (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate were added, and microwaves were irradiated at 130°C for 60 minutes. Celite filtration was performed, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography, and the solvent was distilled off under reduced pressure to obtain 195 mg of the title compound.

[0307] Reference Example 40: 1-(4-Chloro-3-fluorophenyl)piperidine-4-carboxylic acid

[0308] 2.0 mL of 1N sodium hydroxide was added to a solution of 195 mg of ethyl 1-(4-chloro-3-fluorophenyl)piperidine-4-carboxylate in 2 mL of methanol, and the mixture was stirred at 50°C for 2 hours. 2.0 mL of 1N hydrochloric acid was added for neutralization, and the precipitated solid was washed with hexane and filtered to obtain 150 mg of the title compound.

[0309] Reference Example 41: Ethyl 1-[3-(difluoromethyl)phenyl]piperidine-4-carboxylate

[0310] The title compound was obtained by the same operation as in Reference Example 39 using 1-bromo-3-(difluoromethyl)benzene and ethyl 4-piperidincarboxylate.

[0311] Reference Example 42: 1-[3-(Difluoromethyl)phenyl]piperidine-4-carboxylic acid

[0312] The title compound was obtained by the same operation as in Reference Example 40 using ethyl 1-[3-(difluoromethyl)phenyl]piperidine-4-carboxylate.

[0313] Reference Example 43: 1-[4-(Difluoromethoxy)phenyl]piperidine-4-carboxylic acid

[0314] The title compound was obtained by the same operation as in Reference Example 40 using ethyl 1-[4-(difluoromethoxy)phenyl]piperidine-4-carboxylate.

[0315] Reference Example 44: Ethyl trans-4-[(2-chlorobenzyl)oxy]cyclohexane-1-carboxylate

[0316] To 244 μL of ethyl trans-4-hydroxycyclohexane-1-carboxylate, add 215 μL of 1-(bromomethyl)-2-chlorobenzene and 638 μL of N,N-diisopropylethylamine, and stir at 150°C for 2.5 hours. After adding 8 mL of 1N hydrochloric acid, extract with ethyl acetate, wash with water and saturated brine once each, dry with magnesium sulfate, and distill off the solvent under reduced pressure to obtain 533 mg of the title compound. The obtained compound was used in the following reaction without purification.

[0317] Reference Example 45: trans-4-[(2-chlorobenzyl)oxy]cyclohexane-1-carboxylic acid

[0318] To a solution of 533 mg of ethyl trans-4-[(2-chlorobenzyl)oxy]cyclohexane-1-carboxylate in 4 mL of methanol was added 5.39 mL of 1N sodium hydroxide, and the mixture was stirred at room temperature overnight. 5.39 mL of 1N hydrochloric acid was added for neutralization, and the precipitated solid was washed with hexane and filtered to obtain 177 mg of the title compound.

[0319] Reference Example 46: Ethyl trans-4-[(3-chlorobenzyl)oxy]cyclohexane-1-carboxylate

[0320] The title compound was obtained by the same operation as in Reference Example 44 using ethyl trans-4-hydroxycyclohexane-1-carboxylate and 1-(bromomethyl)-3-chlorobenzene. The obtained compound was used in the next reaction without purification.

[0321] Reference Example 47: trans-4-[(3-chlorobenzyl)oxy]cyclohexane-1-carboxylic acid

[0322] The title compound was obtained by the same operation as in Reference Example 45 using ethyl trans-4-[(3-chlorobenzyl)oxy]cyclohexane-1-carboxylate. The obtained compound was used in the next reaction without purification.

[0323] Reference Example 48: Ethyl trans-4-{[3-(trifluoromethyl)benzyl]oxy}cyclohexane-1-carboxylate

[0324] The title compound was obtained by the same operation as in Reference Example 44 using ethyl trans-4-hydroxycyclohexane-1-carboxylate and 1-(bromomethyl)-3-(trifluoromethyl)benzene.

[0325] Reference Example 49: trans-4-{[3-(trifluoromethyl)benzyl]oxy}cyclohexane-1-carboxylic acid

[0326] The title compound was obtained by the same operation as in Reference Example 45 using ethyl trans-4-[(3-{trifluoromethyl}benzyl)oxy]cyclohexane-1-carboxylate.

[0327] Reference Example 50: Ethyl trans-4-{[4-(trifluoromethyl)benzyl]oxy}cyclohexane-1-carboxylate

[0328] The title compound was obtained by the same operation as in Reference Example 44 using ethyl trans-4-hydroxycyclohexane-1-carboxylate and 1-(bromomethyl)-4-(trifluoromethyl)benzene.

[0329] Reference Example 51: trans-4-{[4-(trifluoromethyl)benzyl]oxy}cyclohexane-1-carboxylic acid

[0330] The title compound was obtained by the same operation as in Reference Example 45 using ethyl trans-4-{[4-(trifluoromethyl)benzyl]oxy}cyclohexane-1-carboxylate.

[0331] Reference Example 52: Ethyl trans-4-[(2,4-difluorobenzyl)oxy]cyclohexane-1-carboxylate

[0332] The title compound was obtained by the same operation as in Reference Example 44 using ethyl trans-4-hydroxycyclohexane-1-carboxylate and 1-(bromomethyl)-2,4-difluorobenzene.

[0333] Reference Example 53: trans-4-[(2,4-difluorobenzyl)oxy]cyclohexane-1-carboxylic acid

[0334] The title compound was obtained by the same operation as in Reference Example 45 using ethyl trans-4-[(2,4-difluorobenzyl)oxy]cyclohexane-1-carboxylate.

[0335] Reference Example 54: Ethyl trans-4-[(3,4-difluorobenzyl)oxy]cyclohexane-1-carboxylate

[0336] The title compound was obtained by the same operation as in Reference Example 44 using ethyl trans-4-hydroxycyclohexane-1-carboxylate and 1-(bromomethyl)-3,4-difluorobenzene.

[0337] Reference Example 55: trans-4-[(3,4-difluorobenzyl)oxy]cyclohexane-1-carboxylic acid

[0338] The title compound was obtained by the same operation as in Reference Example 45 using ethyl trans-4-[(3,4-difluorobenzyl)oxy]cyclohexane-1-carboxylate.

[0339] Reference Example 56: Ethyl trans-4-[(3,5-difluorobenzyl)oxy]cyclohexane-1-carboxylate

[0340] The title compound was obtained by the same operation as in Reference Example 44 using ethyl trans-4-hydroxycyclohexane-1-carboxylate and 1-(bromomethyl)-3,5-difluorobenzene.

[0341] Reference Example 57: trans-4-[(3,5-difluorobenzyl)oxy]cyclohexane-1-carboxylic acid

[0342] The title compound was obtained by the same operation as in Reference Example 45 using ethyl trans-4-[(3,5-difluorobenzyl)oxy]cyclohexane-1-carboxylate.

[0343] Reference Example 58: trans-4-[(4-chloro-2-fluorobenzyl)oxy]cyclohexane-1-carboxylic acid ethyl ester

[0344] The title compound was obtained by the same operation as in Reference Example 44 using ethyl trans-4-hydroxycyclohexane-1-carboxylate and 1-(bromomethyl)-4-chloro-2-fluorobenzene.

[0345] Reference Example 59: trans-4-[(4-chloro-2-fluorobenzyl)oxy]cyclohexane-1-carboxylic acid

[0346] The title compound was obtained by the same operation as in Reference Example 45 using ethyl trans-4-[(4-chloro-2-fluorobenzyl)oxy]cyclohexane-1-carboxylate.

[0347] Reference Example 60: Ethyl trans-4-[(3-chloro-5-fluorobenzyl)oxy]cyclohexane-1-carboxylate

[0348] The title compound was obtained by the same operation as in Reference Example 44 using ethyl trans-4-hydroxycyclohexane-1-carboxylate and 1-(bromomethyl)-3-chloro-5-fluorobenzene.

[0349] Reference Example 61: trans-4-[(3-chloro-5-fluorobenzyl)oxy]cyclohexane-1-carboxylic acid

[0350] The title compound was obtained by the same operation as in Reference Example 45 using ethyl trans-4-[(3-chloro-5-fluorobenzyl)oxy]cyclohexane-1-carboxylate.

[0351] Reference Example 62: Methyl 3-[(2-chlorobenzyl)oxy]cyclobutane-1-carboxylate

[0352] To a solution of 700 mg of trans-3-hydroxycyclobutanecarboxylic acid methyl ester in 5 mL of N,N-dimethylformamide was added 236 mg of sodium hydride under ice cooling, and stirred at this temperature for 1 hour. 1.30 g of 2-chlorobenzyl chloride was added, and stirred at room temperature for 11 hours. 2N hydrochloric acid and water were added, and extracted with ethyl acetate 3 times. The combined organic layer was washed with brine, dried with sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 588 mg of the title compound. The obtained compound was directly used in the following reaction.

[0353] Reference Example 63: trans-3-[(2-chlorobenzyl)oxy]cyclobutane-1-carboxylic acid

[0354] Reference Example 64: cis-3-[(2-chlorobenzyl)oxy]cyclobutane-1-carboxylic acid

[0355] To a solution of 588 mg of methyl 3-[(2-chlorobenzyl)oxy]cyclobutane-1-carboxylate in 6 mL of tetrahydrofuran and 2 mL of water, 166 mg of lithium hydroxide was added and stirred at room temperature for 12 hours. 2N hydrochloric acid and water were added, and the mixture was extracted three times with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography, and further purified by preparative HPLC and chiral SFC to obtain 44 mg of trans-3-[(2-chlorobenzyl)oxy]cyclobutane-1-carboxylate and 247 mg of cis-3-[(2-chlorobenzyl)oxy]cyclobutane-1-carboxylate.

[0356] Reference Example 65: trans-3-[(3-chlorobenzyl)oxy]cyclobutane-1-carboxylic acid

[0357] Reference Example 66: cis-3-[(3-chlorobenzyl)oxy]cyclobutane-1-carboxylic acid

[0358] The title compound was obtained by the same procedures as in Reference Examples 62 to 64 using methyl trans-3-hydroxycyclobutanecarboxylate and 3-chlorobenzyl chloride.

[0359] Reference Example 67: trans-3-[(4-chlorobenzyl)oxy]cyclobutane-1-carboxylic acid

[0360] Reference Example 68: cis-3-[(4-chlorobenzyl)oxy]cyclobutane-1-carboxylic acid

[0361] The title compound was obtained by the same procedures as in Reference Examples 62 to 64 using methyl trans-3-hydroxycyclobutanecarboxylate and 4-chlorobenzyl chloride.

[0362] Reference Example 69: trans-3-{[2-(trifluoromethyl)benzyl]oxy}cyclobutane-1-carboxylic acid

[0363] Reference Example 70: cis-3-{[2-(trifluoromethyl)benzyl]oxy}cyclobutane-1-carboxylic acid

[0364] The title compound was obtained by the same procedures as in Reference Examples 62 to 64 using methyl trans-3-hydroxycyclobutanecarboxylate and 2-(trifluoromethyl)benzyl chloride.

[0365] Reference Example 71: trans-3-{[3-(trifluoromethyl)benzyl]oxy}cyclobutane-1-carboxylic acid

[0366] Reference Example 72: cis-3-{[3-(trifluoromethyl)benzyl]oxy}cyclobutane-1-carboxylic acid

[0367] The title compound was obtained by the same procedures as in Reference Examples 62 to 64 using methyl trans-3-hydroxycyclobutanecarboxylate and 3-(trifluoromethyl)benzyl chloride.

[0368] Reference Example 73: trans-3-{[4-(trifluoromethyl)benzyl]oxy}cyclobutane-1-carboxylic acid

[0369] Reference Example 74: cis-3-{[4-(trifluoromethyl)benzyl]oxy}cyclobutane-1-carboxylic acid

[0370] The title compound was obtained by the same procedures as in Reference Examples 62 to 64 using methyl trans-3-hydroxycyclobutanecarboxylate and 4-(trifluoromethyl)benzyl chloride.

[0371] Reference Example 75: trans-3-[(2,4-difluorobenzyl)oxy]cyclobutane-1-carboxylic acid

[0372] The title compound was obtained by the same procedures as in Reference Examples 62 to 64 using methyl trans-3-hydroxycyclobutanecarboxylate and 2,4-difluorobenzyl bromide.

[0373] Reference Example 76: trans-3-[(4-chloro-2-fluorobenzyl)oxy]cyclobutane-1-carboxylic acid

[0374] The title compound was obtained by the same procedures as in Reference Examples 62 to 64 using methyl trans-3-hydroxycyclobutanecarboxylate and 4-chloro-2-fluorobenzyl bromide.

[0375] Reference Example 77: trans-3-[(3,4-difluorobenzyl)oxy]cyclobutane-1-carboxylic acid

[0376] The title compound was obtained by the same procedures as in Reference Examples 62 to 64 using methyl trans-3-hydroxycyclobutanecarboxylate and 3,4-difluorobenzyl bromide.

[0377] Reference Example 78: trans-3-[(3,5-difluorobenzyl)oxy]cyclobutane-1-carboxylic acid

[0378] The title compound was obtained by the same procedures as in Reference Examples 62 to 64 using methyl trans-3-hydroxycyclobutanecarboxylate and 3,5-difluorobenzyl bromide.

[0379] Reference Example 79: trans-3-[(3-fluorobenzyl)oxy]cyclobutane-1-carboxylic acid

[0380] The title compound was obtained by the same procedures as in Reference Examples 62 to 64 using methyl trans-3-hydroxycyclobutanecarboxylate and 3-fluorobenzyl bromide.

[0381] Reference Example 80: trans-3-[(2,3-difluorobenzyl)oxy]cyclobutane-1-carboxylic acid

[0382] The title compound was obtained by the same procedures as in Reference Examples 62 to 64 using methyl trans-3-hydroxycyclobutanecarboxylate and 2,3-difluorobenzyl bromide.

[0383] Reference Example 81: trans-3-[(2-chloro-4-fluorobenzyl)oxy]cyclobutane-1-carboxylic acid

[0384] The title compound was obtained by the same procedures as in Reference Examples 62 to 64 using methyl trans-3-hydroxycyclobutanecarboxylate and 2-chloro-4-fluorobenzyl bromide.

[0385] Reference Example 82: trans-3-[(3-chloro-2-fluorobenzyl)oxy]cyclobutane-1-carboxylic acid

[0386] The title compound was obtained by the same procedures as in Reference Examples 62 to 64 using methyl trans-3-hydroxycyclobutanecarboxylate and 3-chloro-2-fluorobenzyl bromide.

[0387] Reference Example 83: trans-3-[(5-chloro-2-fluorobenzyl)oxy]cyclobutane-1-carboxylic acid

[0388] The title compound was obtained by the same procedures as in Reference Examples 62 to 64 using methyl trans-3-hydroxycyclobutanecarboxylate and 5-chloro-2-fluorobenzyl bromide.

[0389] Reference Example 84: trans-3-[(3-chloro-4-fluorobenzyl)oxy]cyclobutane-1-carboxylic acid

[0390] Reference Example 85: cis-3-[(3-chloro-4-fluorobenzyl)oxy]cyclobutane-1-carboxylic acid

[0391] The title compound was obtained by the same procedures as in Reference Examples 62 to 64 using ethyl 3-hydroxycyclobutanecarboxylate and 3-chloro-4-fluorobenzyl bromide.

[0392] Reference Example 86: trans-3-[(3-chloro-5-fluorobenzyl)oxy]cyclobutane-1-carboxylic acid

[0393] Reference Example 87: cis-3-[(3-chloro-5-fluorobenzyl)oxy]cyclobutane-1-carboxylic acid

[0394] The title compound was obtained by the same procedures as in Reference Examples 62 to 64 using ethyl 3-hydroxycyclobutanecarboxylate and 3-chloro-5-fluorobenzyl bromide.

[0395] Reference Example 88: Ethyl 4-{[5-(trifluoromethyl)pyridin-2-yl]oxy}cyclohexane-1-carboxylate

[0396] The title compound was obtained by the same operation as in Reference Example 62 using 2-chloro-5-(trifluoromethyl)pyridine and ethyl 4-hydroxycyclohexane-1-carboxylate.

[0397] Reference Example 89: 4-{[5-(Trifluoromethyl)pyridin-2-yl]oxy}cyclohexane-1-carboxylic acid

[0398] The title compound was obtained by the same procedures as in Reference Examples 63 and 64 using ethyl 4-{[5-(trifluoromethyl)pyridin-2-yl]oxy}cyclohexane-1-carboxylate.

[0399] Reference Example 90: Ethyl trans-3-{[5-(trifluoromethyl)pyridin-2-yl]oxy}cyclobutane-1-carboxylate

[0400] The title compound was obtained by the same operation as in Reference Example 62 using 2-chloro-5-(trifluoromethyl)pyridine and ethyl trans-3-hydroxycyclobutane-1-carboxylate.

[0401] Reference Example 91: trans-3-{[5-(trifluoromethyl)pyridin-2-yl]oxy}cyclobutane-1-carboxylic acid

[0402] The title compound was obtained by the same procedures as in Reference Examples 63 and 64 using ethyl trans-3-{[5-(trifluoromethyl)pyridin-2-yl]oxy}cyclobutane-1-carboxylate.

[0403] Reference Example 92: Ethyl cis-3-{[5-(trifluoromethyl)pyridin-2-yl]oxy}cyclobutane-1-carboxylate

[0404] The title compound was obtained by the same operation as in Reference Example 62 using 2-chloro-5-(trifluoromethyl)pyridine and ethyl cis-3-hydroxycyclobutane-1-carboxylate.

[0405] Reference Example 93: cis-3-{[5-(trifluoromethyl)pyridin-2-yl]oxy}cyclobutane-1-carboxylic acid

[0406] The title compound was obtained by the same procedures as in Reference Examples 63 and 64 using ethyl cis-3-{[5-(trifluoromethyl)pyridin-2-yl]oxy}cyclobutane-1-carboxylate.

[0407] Reference Example 94: trans-3-(4-chlorophenoxy)cyclobutane-1-carboxylic acid

[0408] The title compound was obtained by the same procedures as in Reference Examples 63 and 64 using ethyl trans-3-(4-chlorophenoxy)cyclobutane-1-carboxylate.

[0409] Reference Example 95: cis-3-(4-chlorophenoxy)cyclobutane-1-carboxylic acid

[0410] The title compound was obtained by the same procedures as in Reference Examples 63 and 64 using ethyl cis-3-(4-chlorophenoxy)cyclobutane-1-carboxylate.

[0411] Example

[0412] Example 1: N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}-1-(imidazo[1,2-b]pyridazin-6-yl)piperidine-4-carboxamide

[0413] To a solution of 144 mg of 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one·hydrochloride in 5 mL of N,N-dimethylformamide, 108 mg of 1-(imidazo[1,2-b]pyridazin-6-yl)piperidine-4-carboxylic acid, 205 μL of triethylamine, and 167 mg of O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate were added, and the mixture was stirred overnight at room temperature. After extraction with ethyl acetate, the mixture was washed with a saturated aqueous ammonium chloride solution, water, and saturated brine, respectively, and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography and dried under reduced pressure to obtain 30 mg of the title compound.

[0414] Example 2: N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}-4-(imidazo[1,2-b]pyridazin-6-yl)benzamide

[0415] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one 2,2,2-trifluoroacetate and 4-(imidazo[1,2-b]pyridazin-6-yl)benzoic acid.

[0416] Example 3: N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}-1-(3-methylimidazo[1,2-b]pyridazin-6-yl)piperidine-4-carboxamide

[0417] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and 1-(3-methylimidazo[1,2-b]pyridazin-6-yl)piperidine-4-carboxylic acid.

[0418] Example 4: N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}-1-(8-methylquinolin-2-yl)piperidine-4-carboxamide

[0419] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and 1-(8-methylquinolin-2-yl)piperidine-4-carboxylic acid.

[0420] Example 5: N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}-1-(quinolin-2-yl)piperidine-4-carboxamide

[0421] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and 1-(quinolin-2-yl)piperidine-4-carboxylic acid.

[0422] Example 6: N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}-1-(8-methylquinolin-2-yl)azetidine-3-carboxamide

[0423] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and 1-(8-methylquinolin-2-yl)azetidine-3-carboxylic acid.

[0424] Example 7: N-[2-fluoro-3-(6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]-1-(8-methylquinolin-2-yl)piperidine-4-carboxamide

[0425] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]pyrimidin-4(3H)-one and 1-(8-methylquinolin-2-yl)piperidine-4-carboxylic acid.

[0426] Example 8: N-[4-chloro-3-(6-oxo-1,6-dihydropyrimidin-2-yl)benzyl]-1-(8-methylquinolin-2-yl)piperidine-4-carboxamide

[0427] The title compound was obtained by the same procedures as in Example 1 using 2-[5-(aminomethyl)-2-chlorophenyl]pyrimidin-4(3H)-one and 1-(8-methylquinolin-2-yl)piperidine-4-carboxylic acid.

[0428] Example 9: N-[2-Fluoro-3-(4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]-1-(8-methylquinolin-2-yl)piperidine-4-carboxamide

[0429] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-methylpyrimidin-4(3H)-one and 1-(8-methylquinolin-2-yl)piperidine-4-carboxylic acid.

[0430] Example 10: N-[3-(4-ethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-2-fluoro-4-(trifluoromethyl)benzyl]-1-(8-methylquinolin-2-yl)piperidine-4-carboxamide

[0431] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-ethylpyrimidin-4(3H)-one and 1-(8-methylquinolin-2-yl)piperidine-4-carboxylic acid.

[0432] Example 11: N-[2-fluoro-3-(4-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]-1-(8-methylquinolin-2-yl)piperidine-4-carboxamide

[0433] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-isopropylpyrimidin-4(3H)-one and 1-(8-methylquinolin-2-yl)piperidine-4-carboxylic acid.

[0434] Example 12: N-{3-[4-(difluoromethyl)-6-oxo-1,6-dihydropyrimidin-2-yl]-2-fluoro-4-(trifluoromethyl)benzyl}-1-(8-methylquinolin-2-yl)piperidine-4-carboxamide

[0435] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(difluoromethyl)pyrimidin-4(3H)-one and 1-(8-methylquinolin-2-yl)piperidine-4-carboxylic acid.

[0436] Example 13: N-[3-(4,5-dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-2-fluoro-4-(trifluoromethyl)benzyl]-1-(8-methylquinolin-2-yl)piperidine-4-carboxamide

[0437] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-5,6-dimethylpyrimidin-4(3H)-one and 1-(8-methylquinolin-2-yl)piperidine-4-carboxylic acid.

[0438] Example 14: N-[2-Fluoro-3-(5-fluoro-4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]-1-(8-methylquinolin-2-yl)piperidine-4-carboxamide

[0439] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-5-fluoro-6-methylpyrimidin-4(3H)-one and 1-(8-methylquinolin-2-yl)piperidine-4-carboxylic acid.

[0440] Example 15: 4-Fluoro-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}-1-(8-methylquinolin-2-yl)piperidine-4-carboxamide

[0441] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and 4-fluoro-1-(8-methylquinolin-2-yl)piperidine-4-carboxylic acid.

[0442] Example 16: N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}-4-(pyridazin-3-yl)benzamide

[0443] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one 2,2,2-trifluoroacetate and 4-(pyridazin-3-yl)benzoic acid.

[0444] Example 17: N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}-1-(6-methylpyridin-2-yl)piperidine-4-carboxamide

[0445] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and 1-(6-methylpyridin-2-yl)piperidine-4-carboxylic acid.

[0446] Example 18: N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}-1-(5-methylpyridin-2-yl)piperidine-4-carboxamide

[0447] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and 1-(5-methylpyridin-2-yl)piperidine-4-carboxylic acid.

[0448] Example 19: N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}-1-(pyridin-2-yl)piperidine-4-carboxamide

[0449] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and 1-(pyridin-2-yl)piperidine-4-carboxylic acid.

[0450] Example 20: N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}-1-[5-(trifluoromethyl)pyridin-2-yl]piperidine-4-carboxamide

[0451] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and 1-[5-(trifluoromethyl)pyridin-2-yl]piperidine-4-carboxylic acid.

[0452] Example 21: N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}-1-[6-(trifluoromethyl)pyridin-3-yl]piperidine-4-carboxamide

[0453] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and 1-[6-(trifluoromethyl)pyridin-3-yl]piperidine-4-carboxylic acid.

[0454] Example 22: N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}-1-[6-(trifluoromethyl)pyridin-2-yl]piperidine-4-carboxamide

[0455] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and 1-[6-(trifluoromethyl)pyridin-2-yl]piperidine-4-carboxylic acid.

[0456] Example 23: N-[3-(4-ethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-2-fluoro-4-(trifluoromethyl)benzyl]-1-[5-(trifluoromethyl)pyridin-2-yl]piperidine-4-carboxamide

[0457] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-ethylpyrimidin-4(3H)-one and 1-[5-(trifluoromethyl)pyridin-2-yl]piperidine-4-carboxylic acid.

[0458] Example 24: N-[3-(4-ethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-2-fluoro-4-(trifluoromethyl)benzyl]-1-(6-methylpyridin-2-yl)piperidine-4-carboxamide

[0459] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-ethylpyrimidin-4(3H)-one and 1-(6-methylpyridin-2-yl)piperidine-4-carboxylic acid.

[0460] Example 25: N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}-1-[5-(trifluoromethyl)pyridin-2-yl]azetidine-3-carboxamide

[0461] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and 1-[5-(trifluoromethyl)pyridin-2-yl]azetidine-3-carboxylic acid.

[0462] Example 26: N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}-1-[6-(trifluoromethyl)pyridin-2-yl]azetidine-3-carboxamide

[0463] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and 1-[6-(trifluoromethyl)pyridin-2-yl]azetidine-3-carboxylic acid.

[0464] Example 27: 1-(5-chloropyridin-2-yl)-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}piperidine-4-carboxamide

[0465] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and 1-(5-chloropyridin-2-yl)piperidine-4-carboxylic acid.

[0466] Example 28: N-[2-Fluoro-3-(6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]-1-[5-(trifluoromethyl)pyridin-2-yl]piperidine-4-carboxamide

[0467] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]pyrimidin-4(3H)-one and 1-[5-(trifluoromethyl)pyridin-2-yl]piperidine-4-carboxylic acid.

[0468] Example 29: N-{3-[4-(difluoromethyl)-6-oxo-1,6-dihydropyrimidin-2-yl]-2-fluoro-4-(trifluoromethyl)benzyl}-1-[5-(trifluoromethyl)pyridin-2-yl]piperidine-4-carboxamide

[0469] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(difluoromethyl)pyrimidin-4(3H)-one and 1-[5-(trifluoromethyl)pyridin-2-yl]piperidine-4-carboxylic acid.

[0470] Example 30: 1-(3,5-dichloropyridin-2-yl)-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}piperidine-4-carboxamide

[0471] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and 1-(3,5-dichloropyridin-2-yl)piperidine-4-carboxylic acid.

[0472] Example 31: N-{4-chloro-2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]benzyl}-1-(8-methylquinolin-2-yl)piperidine-4-carboxamide

[0473] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-6-chloro-2-fluorophenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and 1-(8-methylquinolin-2-yl)piperidine-4-carboxylic acid.

[0474] Example 32: N-{4-chloro-2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]benzyl}-1-[5-(trifluoromethyl)pyridin-2-yl]piperidine-4-carboxamide

[0475] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-6-chloro-2-fluorophenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and 1-[5-(trifluoromethyl)pyridin-2-yl]piperidine-4-carboxylic acid.

[0476] Example 33: N-[2-Fluoro-3-(5-fluoro-4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]-1-[5-(trifluoromethyl)pyridin-2-yl]piperidine-4-carboxamide

[0477] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-5-fluoro-6-methylpyrimidin-4(3H)-one and 1-[5-(trifluoromethyl)pyridin-2-yl]piperidine-4-carboxylic acid.

[0478] Example 34: N-[2-Fluoro-3-(4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]-1-[5-(trifluoromethyl)pyridin-2-yl]piperidine-4-carboxamide

[0479] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-methylpyrimidin-4(3H)-one and 1-[5-(trifluoromethyl)pyridin-2-yl]piperidine-4-carboxylic acid.

[0480] Example 35: N-[3-(4,5-dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-2-fluoro-4-(trifluoromethyl)benzyl]-1-[5-(trifluoromethyl)pyridin-2-yl]piperidine-4-carboxamide

[0481] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-5,6-dimethylpyrimidin-4(3H)-one and 1-[5-(trifluoromethyl)pyridin-2-yl]piperidine-4-carboxylic acid.

[0482] Example 36: N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}-1-[5-(trifluoromethyl)pyrazin-2-yl]piperidine-4-carboxamide

[0483] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and 1-[5-(trifluoromethyl)pyrazin-2-yl]piperidine-4-carboxylic acid.

[0484] Example 37: 1-(5-chloro-3-fluoropyridin-2-yl)-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}piperidine-4-carboxamide

[0485] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and 1-(5-chloro-3-fluoropyridin-2-yl)piperidine-4-carboxylic acid.

[0486] Example 38: 4-Fluoro-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}-1-[5-(trifluoromethyl)pyridin-2-yl]piperidine-4-carboxamide

[0487] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and 4-fluoro-1-[5-(trifluoromethyl)pyridin-2-yl]piperidine-4-carboxylic acid.

[0488] Example 39: N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}-1-[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]piperidine-4-carboxamide

[0489] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and 1-[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]piperidine-4-carboxylic acid.

[0490] Example 40: N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}-1-[5-(trifluoromethoxy)pyridin-2-yl]piperidine-4-carboxamide

[0491] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and 1-[5-(trifluoromethoxy)pyridin-2-yl]piperidine-4-carboxylic acid.

[0492] Example 41: N-[2-Fluoro-3-(4-oxo-4,5,6,7-tetrahydro-3H-cyclopenta[d]pyrimidin-2-yl)-4-(trifluoromethyl)benzyl]-1-[5-(trifluoromethyl)pyridin-2-yl]piperidine-4-carboxamide

[0493] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-3,5,6,7-tetrahydro-4H-cyclopenta[d]pyrimidin-4-one and 1-[5-(trifluoromethyl)pyridin-2-yl]piperidine-4-carboxylic acid.

[0494] Example 42: N-[3-(4-ethyl-5-fluoro-6-oxo-1,6-dihydropyrimidin-2-yl)-2-fluoro-4-(trifluoromethyl)benzyl]-1-[5-(trifluoromethyl)pyridin-2-yl]piperidine-4-carboxamide

[0495] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-ethyl-5-fluoropyrimidin-4(3H)-one and 1-[5-(trifluoromethyl)pyridin-2-yl]piperidine-4-carboxylic acid.

[0496] Example 43: 1-(5-chloropyridin-2-yl)-N-[3-(4,5-dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-2-fluoro-4-(trifluoromethyl)benzyl]piperidine-4-carboxamide

[0497] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-5,6-dimethylpyrimidin-4(3H)-one and 1-(5-chloropyridin-2-yl)piperidine-4-carboxylic acid.

[0498] Example 44: 1-(3,5-dichloropyridin-2-yl)-N-[2-fluoro-3-(5-fluoro-4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]piperidine-4-carboxamide

[0499] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-5-fluoro-6-methylpyrimidin-4(3H)-one and 1-(3,5-dichloropyridin-2-yl)piperidine-4-carboxylic acid.

[0500] Example 45: 1-(3,5-dichloropyridin-2-yl)-N-{3-[4-(difluoromethyl)-6-oxo-1,6-dihydropyrimidin-2-yl]-2-fluoro-4-(trifluoromethyl)benzyl}piperidine-4-carboxamide

[0501] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(difluoromethyl)pyrimidin-4(3H)-one and 1-(3,5-dichloropyridin-2-yl)piperidine-4-carboxylic acid.

[0502] Example 46: 1-(3,5-dichloropyridin-2-yl)-N-[2-fluoro-3-(4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]piperidine-4-carboxamide

[0503] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-methylpyrimidin-4(3H)-one and 1-(3,5-dichloropyridin-2-yl)piperidine-4-carboxylic acid.

[0504] Example 47: N-[3-(4-ethyl-5-fluoro-6-oxo-1,6-dihydropyrimidin-2-yl)-2-fluoro-4-(trifluoromethyl)benzyl]-1-[5-(trifluoromethoxy)pyridin-2-yl]piperidine-4-carboxamide

[0505] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-ethyl-5-fluoropyrimidin-4(3H)-one and 1-[5-(trifluoromethoxy)pyridin-2-yl]piperidine-4-carboxylic acid.

[0506] Example 48: N-[2-Fluoro-3-(5-fluoro-4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]-1-[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]piperidine-4-carboxamide

[0507] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-5-fluoro-6-methylpyrimidin-4(3H)-one and 1-[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]piperidine-4-carboxylic acid.

[0508] Example 49: N-[2-Fluoro-3-(4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]-1-[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]piperidine-4-carboxamide

[0509] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-methylpyrimidin-4(3H)-one and 1-[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]piperidine-4-carboxylic acid.

[0510] Example 50: N-{3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}-1-[5-(trifluoromethyl)pyridin-2-yl]piperidine-4-carboxamide

[0511] The title compound was obtained by the same procedures as in Example 1 using 2-[5-(aminomethyl)-2-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and 1-[5-(trifluoromethyl)pyridin-2-yl]piperidine-4-carboxylic acid.

[0512] Example 51: 4-Fluoro-N-[2-fluoro-3-(5-fluoro-4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]-1-[5-(trifluoromethyl)pyridin-2-yl]piperidine-4-carboxamide

[0513] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-5-fluoro-6-methylpyrimidin-4(3H)-one and 4-fluoro-1-[5-(trifluoromethyl)pyridin-2-yl]piperidine-4-carboxylic acid.

[0514] Example 52: 1-(5-chloro-3-fluoropyridin-2-yl)-N-[2-fluoro-3-(5-fluoro-4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]piperidine-4-carboxamide

[0515] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-5-fluoro-6-methylpyrimidin-4(3H)-one and 1-(5-chloro-3-fluoropyridin-2-yl)piperidine-4-carboxylic acid.

[0516] Example 53: N-[2-Fluoro-3-(4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]-1-[5-(trifluoromethoxy)pyridin-2-yl]piperidine-4-carboxamide

[0517] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-methylpyrimidin-4(3H)-one and 1-[5-(trifluoromethoxy)pyridin-2-yl]piperidine-4-carboxylic acid.

[0518] Example 54: 1-(5-chloro-6-methylpyridin-2-yl)-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}piperidine-4-carboxamide

[0519] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and 1-(5-chloro-6-methylpyridin-2-yl)piperidine-4-carboxylic acid.

[0520] Example 55: N-{3-[4-(difluoromethyl)-6-oxo-1,6-dihydropyrimidin-2-yl]-2-fluoro-4-(trifluoromethyl)benzyl}-1-[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]piperidine-4-carboxamide

[0521] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(difluoromethyl)pyrimidin-4(3H)-one and 1-[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]piperidine-4-carboxylic acid.

[0522] Example 56: 4-Fluoro-N-[2-fluoro-3-(4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]-1-[5-(trifluoromethyl)pyridin-2-yl]piperidine-4-carboxamide

[0523] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-methylpyrimidin-4(3H)-one and 4-fluoro-1-[5-(trifluoromethyl)pyridin-2-yl]piperidine-4-carboxylic acid.

[0524] Example 57: 1-(5-chloropyridin-2-yl)-N-[3-(4-ethyl-5-fluoro-6-oxo-1,6-dihydropyrimidin-2-yl)-2-fluoro-4-(trifluoromethyl)benzyl]piperidine-4-carboxamide

[0525] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-ethyl-5-fluoropyrimidin-4(3H)-one and 1-(5-chloropyridin-2-yl)piperidine-4-carboxylic acid.

[0526] Example 58: N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}-1-(4-fluorophenyl)piperidine-4-carboxamide

[0527] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and 1-(4-fluorophenyl)piperidine-4-carboxylic acid.

[0528] Example 59: N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}-1-(3-methylphenyl)piperidine-4-carboxamide

[0529] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and 1-(3-methylphenyl)piperidine-4-carboxylic acid.

[0530] Example 60: N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}-1-(4-fluoro-3-methylphenyl)piperidine-4-carboxamide

[0531] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and 1-(4-fluoro-3-methylphenyl)piperidine-4-carboxylic acid.

[0532] Example 61: N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}-1-(4-methylphenyl)piperidine-4-carboxamide

[0533] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and 1-(4-methylphenyl)piperidine-4-carboxylic acid.

[0534] Example 62: 1-(3-chlorophenyl)-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}piperidine-4-carboxamide

[0535] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and 1-(3-chlorophenyl)piperidine-4-carboxylic acid.

[0536] Example 63: N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}-1-[4-(trifluoromethyl)phenyl]piperidine-4-carboxamide

[0537] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and 1-[4-(trifluoromethyl)phenyl]piperidine-4-carboxylic acid.

[0538] Example 64: 1-(4-chlorophenyl)-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}piperidine-4-carboxamide

[0539] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and 1-(4-chlorophenyl)piperidine-4-carboxylic acid.

[0540] Example 65: 1-[3-(Difluoromethyl)phenyl]-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}piperidine-4-carboxamide

[0541] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and 1-[3-(difluoromethyl)phenyl]piperidine-4-carboxylic acid.

[0542] Example 66: 1-(3,4-dichlorophenyl)-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}piperidine-4-carboxamide

[0543] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and 1-(3,4-dichlorophenyl)piperidine-4-carboxylic acid.

[0544] Example 67: N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}-1-[3-(trifluoromethyl)phenyl]piperidine-4-carboxamide

[0545] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and 1-[3-(trifluoromethyl)phenyl]piperidine-4-carboxylic acid.

[0546] Example 68: N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}-1-[4-(trifluoromethoxy)phenyl]piperidine-4-carboxamide

[0547] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and 1-[4-(trifluoromethoxy)phenyl]piperidine-4-carboxylic acid.

[0548] Example 69: 1-(2,3-dichlorophenyl)-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}piperidine-4-carboxamide

[0549] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and 1-(2,3-dichlorophenyl)piperidine-4-carboxylic acid.

[0550] Example 70: 1-(4-chloro-2-fluorophenyl)-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}piperidine-4-carboxamide

[0551] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and 1-(4-chloro-2-fluorophenyl)piperidine-4-carboxylic acid.

[0552] Example 71: 1-[4-(difluoromethoxy)phenyl]-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}piperidine-4-carboxamide

[0553] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and 1-[4-(difluoromethoxy)phenyl]piperidine-4-carboxylic acid.

[0554] Example 72: N-[2-Fluoro-3-(5-fluoro-4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]-1-[4-(trifluoromethoxy)phenyl]piperidine-4-carboxamide

[0555] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-5-fluoro-6-methylpyrimidin-4(3H)-one and 1-[4-(trifluoromethoxy)phenyl]piperidine-4-carboxylic acid.

[0556] Example 73: 1-(3,4-dichlorophenyl)-N-[2-fluoro-3-(5-fluoro-4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]piperidine-4-carboxamide

[0557] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-5-fluoro-6-methylpyrimidin-4(3H)-one and 1-(3,4-dichlorophenyl)piperidine-4-carboxylic acid.

[0558] Example 74: N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}-1-[3-(trifluoromethoxy)phenyl]piperidine-4-carboxamide

[0559] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and 1-[3-(trifluoromethoxy)phenyl]piperidine-4-carboxylic acid.

[0560] Example 75: 1-(2-chloro-4-cyanophenyl)-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}piperidine-4-carboxamide

[0561] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and 1-(2-chloro-4-cyanophenyl)piperidine-4-carboxylic acid.

[0562] Example 76: 1-(4-chlorophenyl)-N-[2-fluoro-3-(4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]piperidine-4-carboxamide

[0563] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-methylpyrimidin-4(3H)-one and 1-(4-chlorophenyl)piperidine-4-carboxylic acid.

[0564] Example 77: 1-(4-chlorophenyl)-N-[2-fluoro-3-(5-fluoro-4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]piperidine-4-carboxamide

[0565] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-5-fluoro-6-methylpyrimidin-4(3H)-one and 1-(4-chlorophenyl)piperidine-4-carboxylic acid.

[0566] Example 78: 1-(4-chlorophenyl)-N-[3-(4,5-dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-2-fluoro-4-(trifluoromethyl)benzyl]piperidine-4-carboxamide

[0567] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-5,6-dimethylpyrimidin-4(3H)-one and 1-(4-chlorophenyl)piperidine-4-carboxylic acid.

[0568] Example 79: 1-(4-chlorophenyl)-N-[3-(4-ethyl-5-fluoro-6-oxo-1,6-dihydropyrimidin-2-yl)-2-fluoro-4-(trifluoromethyl)benzyl]piperidine-4-carboxamide

[0569] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-ethyl-5-fluoropyrimidin-4(3H)-one and 1-(4-chlorophenyl)piperidine-4-carboxylic acid.

[0570] Example 80: N-[3-(4-ethyl-5-fluoro-6-oxo-1,6-dihydropyrimidin-2-yl)-2-fluoro-4-(trifluoromethyl)benzyl]-1-[4-(trifluoromethoxy)phenyl]piperidine-4-carboxamide

[0571] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-ethyl-5-fluoropyrimidin-4(3H)-one and 1-[4-(trifluoromethoxy)phenyl]piperidine-4-carboxylic acid.

[0572] Example 81: 1-(4-chloro-3-fluorophenyl)-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}piperidine-4-carboxamide

[0573] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and 1-(4-chloro-3-fluorophenyl)piperidine-4-carboxylic acid.

[0574] Example 82: 1-(3,5-dichlorophenyl)-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}piperidine-4-carboxamide

[0575] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and 1-(3,5-dichlorophenyl)piperidine-4-carboxylic acid.

[0576] Example 83: 1-(4-chloro-3-methoxyphenyl)-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}piperidine-4-carboxamide

[0577] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and 1-(4-chloro-3-methoxyphenyl)piperidine-4-carboxylic acid.

[0578] Example 84: 1-(3,4-dichlorophenyl)-N-{3-[4-(difluoromethyl)-6-oxo-1,6-dihydropyrimidin-2-yl]-2-fluoro-4-(trifluoromethyl)benzyl}piperidine-4-carboxamide

[0579] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(difluoromethyl)pyrimidin-4(3H)-one and 1-(3,4-dichlorophenyl)piperidine-4-carboxylic acid.

[0580] Example 85: N-{3-[4-(difluoromethyl)-6-oxo-1,6-dihydropyrimidin-2-yl]-2-fluoro-4-(trifluoromethyl)benzyl}-1-[4-(trifluoromethoxy)phenyl]piperidine-4-carboxamide

[0581] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(difluoromethyl)pyrimidin-4(3H)-one and 1-[4-(trifluoromethoxy)phenyl]piperidine-4-carboxylic acid.

[0582] Example 86: 1-(3,4-dichlorophenyl)-N-[2-fluoro-3-(4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]piperidine-4-carboxamide

[0583] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-methylpyrimidin-4(3H)-one and 1-(3,4-dichlorophenyl)piperidine-4-carboxylic acid.

[0584] Example 87: N-[2-Fluoro-3-(4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]-1-[4-(trifluoromethoxy)phenyl]piperidine-4-carboxamide

[0585] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-methylpyrimidin-4(3H)-one and 1-[4-(trifluoromethoxy)phenyl]piperidine-4-carboxylic acid.

[0586] Example 88: 1-(3-chloro-4-fluorophenyl)-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}piperidine-4-carboxamide

[0587] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and 1-(3-chloro-4-fluorophenyl)piperidine-4-carboxylic acid.

[0588] Example 89: 1-(4-chlorophenyl)-N-[2-fluoro-3-(4-oxo-4,5,6,7-tetrahydro-3H-cyclopenta[d]pyrimidin-2-yl)-4-(trifluoromethyl)benzyl]piperidine-4-carboxamide

[0589] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-3,5,6,7-tetrahydro-4H-cyclopenta[d]pyrimidin-4-one and 1-(4-chlorophenyl)piperidine-4-carboxylic acid.

[0590] Example 90: 1-(2-chloro-4-cyanophenyl)-N-[3-(4-ethyl-5-fluoro-6-oxo-1,6-dihydropyrimidin-2-yl)-2-fluoro-4-(trifluoromethyl)benzyl]piperidine-4-carboxamide

[0591] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-ethyl-5-fluoropyrimidin-4(3H)-one and 1-(2-chloro-4-cyanophenyl)piperidine-4-carboxylic acid.

[0592] Example 91: 1-(4-chloro-3-fluorophenyl)-N-[2-fluoro-3-(5-fluoro-4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]piperidine-4-carboxamide

[0593] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-5-fluoro-6-methylpyrimidin-4(3H)-one and 1-(4-chloro-3-fluorophenyl)piperidine-4-carboxylic acid.

[0594] Example 92: 1-(4-chloro-3-fluorophenyl)-N-{3-[4-(difluoromethyl)-6-oxo-1,6-dihydropyrimidin-2-yl]-2-fluoro-4-(trifluoromethyl)benzyl}piperidine-4-carboxamide

[0595] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(difluoromethyl)pyrimidin-4(3H)-one and 1-(4-chloro-3-fluorophenyl)piperidine-4-carboxylic acid.

[0596] Example 93: 1-(4-chloro-3-methoxyphenyl)-N-[2-fluoro-3-(4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]piperidine-4-carboxamide

[0597] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-methylpyrimidin-4(3H)-one and 1-(4-chloro-3-methoxyphenyl)piperidine-4-carboxylic acid.

[0598] Example 94: N-[2-Fluoro-3-(4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]-1-[3-(trifluoromethyl)phenyl]piperidine-4-carboxamide

[0599] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-methylpyrimidin-4(3H)-one and 1-[3-(trifluoromethyl)phenyl]piperidine-4-carboxylic acid.

[0600] Example 95: 1-(4-chloro-3-fluorophenyl)-N-[2-fluoro-3-(4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]piperidine-4-carboxamide

[0601] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-methylpyrimidin-4(3H)-one and 1-(4-chloro-3-fluorophenyl)piperidine-4-carboxylic acid.

[0602] Example 96: 1-(4-chloro-3-methoxyphenyl)-N-[3-(4-ethyl-5-fluoro-6-oxo-1,6-dihydropyrimidin-2-yl)-2-fluoro-4-(trifluoromethyl)benzyl]piperidine-4-carboxamide

[0603] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-ethyl-5-fluoropyrimidin-4(3H)-one and 1-(4-chloro-3-methoxyphenyl)piperidine-4-carboxylic acid.

[0604] Example 97: N-[2-Fluoro-3-(5-fluoro-4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]-1-[3-(trifluoromethyl)phenyl]piperidine-4-carboxamide

[0605] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-5-fluoro-6-methylpyrimidin-4(3H)-one and 1-[3-(trifluoromethyl)phenyl]piperidine-4-carboxylic acid.

[0606] Example 98: 1-(4-chloro-3-methoxyphenyl)-N-[3-(4-ethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-2-fluoro-4-(trifluoromethyl)benzyl]piperidine-4-carboxamide

[0607] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-ethylpyrimidin-4(3H)-one and 1-(4-chloro-3-methoxyphenyl)piperidine-4-carboxylic acid.

[0608] Example 99: trans-4-[(2-chlorobenzyl)oxy]-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}cyclohexane-1-carboxamide

[0609] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and trans-4-[(2-chlorobenzyl)oxy]cyclohexane-1-carboxylic acid.

[0610] Example 100: trans-4-[(3-chlorobenzyl)oxy]-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}cyclohexane-1-carboxamide

[0611] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and trans-4-[(3-chlorobenzyl)oxy]cyclohexane-1-carboxylic acid.

[0612] Example 101: trans-4-[(4-chlorobenzyl)oxy]-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}cyclohexane-1-carboxamide

[0613] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and trans-4-[(4-chlorobenzyl)oxy]cyclohexane-1-carboxylic acid.

[0614] Example 102: trans-4-[(2-chlorobenzyl)oxy]-N-[2-fluoro-3-(5-fluoro-4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]cyclohexane-1-carboxamide

[0615] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-5-fluoro-6-methylpyrimidin-4(3H)-one and trans-4-[(2-chlorobenzyl)oxy]cyclohexane-1-carboxylic acid.

[0616] Example 103: trans-4-[(2-chlorobenzyl)oxy]-N-{3-[4-(difluoromethyl)-6-oxo-1,6-dihydropyrimidin-2-yl]-2-fluoro-4-(trifluoromethyl)benzyl}cyclohexane-1-carboxamide

[0617] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(difluoromethyl)pyrimidin-4(3H)-one and trans-4-[(2-chlorobenzyl)oxy]cyclohexane-1-carboxylic acid.

[0618] Example 104: trans-4-[(4-chlorobenzyl)oxy]-N-[2-fluoro-3-(5-fluoro-4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]cyclohexane-1-carboxamide

[0619] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-5-fluoro-6-methylpyrimidin-4(3H)-one and trans-4-[(4-chlorobenzyl)oxy]cyclohexane-1-carboxylic acid.

[0620] Example 105: trans-4-[(4-chlorobenzyl)oxy]-N-[2-fluoro-3-(4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]cyclohexane-1-carboxamide

[0621] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-methylpyrimidin-4(3H)-one and trans-4-[(4-chlorobenzyl)oxy]cyclohexane-1-carboxylic acid.

[0622] Example 106: trans-4-[(2,4-difluorobenzyl)oxy]-N-[2-fluoro-3-(4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]cyclohexane-1-carboxamide

[0623] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-methylpyrimidin-4(3H)-one and trans-4-[(2,4-difluorobenzyl)oxy]cyclohexane-1-carboxylic acid.

[0624] Example 107: trans-4-[(3,4-difluorobenzyl)oxy]-N-[2-fluoro-3-(4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]cyclohexane-1-carboxamide

[0625] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-methylpyrimidin-4(3H)-one and trans-4-[(3,4-difluorobenzyl)oxy]cyclohexane-1-carboxylic acid.

[0626] Example 108: trans-4-[(2-chlorobenzyl)oxy]-N-[2-fluoro-3-(4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]cyclohexane-1-carboxamide

[0627] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-methylpyrimidin-4(3H)-one and trans-4-[(2-chlorobenzyl)oxy]cyclohexane-1-carboxylic acid.

[0628] Example 109: trans-N-[2-fluoro-3-(4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]-4-{[3-(trifluoromethyl)benzyl]oxy}cyclohexane-1-carboxamide

[0629] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-methylpyrimidin-4(3H)-one and trans-4-{[3-(trifluoromethyl)benzyl]oxy}cyclohexane-1-carboxylic acid.

[0630] Example 110: trans-N-[2-fluoro-3-(4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]-4-{[4-(trifluoromethyl)benzyl]oxy}cyclohexane-1-carboxamide

[0631] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-methylpyrimidin-4(3H)-one and trans-4-{[4-(trifluoromethyl)benzyl]oxy}cyclohexane-1-carboxylic acid.

[0632] Example 111: trans-4-[(3-chlorobenzyl)oxy]-N-[2-fluoro-3-(4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]cyclohexane-1-carboxamide

[0633] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-methylpyrimidin-4(3H)-one and trans-4-[(3-chlorobenzyl)oxy]cyclohexane-1-carboxylic acid.

[0634] Example 112: trans-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}-4-{[3-(trifluoromethyl)benzyl]oxy}cyclohexane-1-carboxamide

[0635] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and trans-4-{[3-(trifluoromethyl)benzyl]oxy}cyclohexane-1-carboxylic acid.

[0636] Example 113: trans-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}-4-{[4-(trifluoromethyl)benzyl]oxy}cyclohexane-1-carboxamide

[0637] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and trans-4-{[4-(trifluoromethyl)benzyl]oxy}cyclohexane-1-carboxylic acid.

[0638] Example 114: trans-4-[(2,4-difluorobenzyl)oxy]-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}cyclohexane-1-carboxamide

[0639] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and trans-4-[(2,4-difluorobenzyl)oxy]cyclohexane-1-carboxylic acid.

[0640] Example 115: trans-4-[(3,4-difluorobenzyl)oxy]-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}cyclohexane-1-carboxamide

[0641] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and trans-4-[(3,4-difluorobenzyl)oxy]cyclohexane-1-carboxylic acid.

[0642] Example 116: trans-4-[(4-chlorobenzyl)oxy]-N-{3-[4-(difluoromethyl)-6-oxo-1,6-dihydropyrimidin-2-yl]-2-fluoro-4-(trifluoromethyl)benzyl}cyclohexane-1-carboxamide

[0643] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(difluoromethyl)pyrimidin-4(3H)-one and trans-4-[(4-chlorobenzyl)oxy]cyclohexane-1-carboxylic acid.

[0644] Example 117: trans-4-[(3,5-difluorobenzyl)oxy]-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}cyclohexane-1-carboxamide

[0645] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and trans-4-[(3,5-difluorobenzyl)oxy]cyclohexane-1-carboxylic acid.

[0646] Example 118: trans-4-[(4-chloro-2-fluorobenzyl)oxy]-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}cyclohexane-1-carboxamide

[0647] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and trans-4-[(4-chloro-2-fluorobenzyl)oxy]cyclohexane-1-carboxylic acid.

[0648] Example 119: trans-4-[(3-chloro-5-fluorobenzyl)oxy]-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}cyclohexane-1-carboxamide

[0649] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and trans-4-[(3-chloro-5-fluorobenzyl)oxy]cyclohexane-1-carboxylic acid.

[0650] Example 120: trans-4-[(3,5-difluorobenzyl)oxy]-N-[2-fluoro-3-(4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]cyclohexane-1-carboxamide

[0651] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-methylpyrimidin-4(3H)-one and trans-4-[(3,5-difluorobenzyl)oxy]cyclohexane-1-carboxylic acid.

[0652] Example 121: trans-4-[(4-chloro-2-fluorobenzyl)oxy]-N-[2-fluoro-3-(4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]cyclohexane-1-carboxamide

[0653] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-methylpyrimidin-4(3H)-one and trans-4-[(4-chloro-2-fluorobenzyl)oxy]cyclohexane-1-carboxylic acid.

[0654] Example 122: trans-4-[(3-chloro-5-fluorobenzyl)oxy]-N-[2-fluoro-3-(4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]cyclohexane-1-carboxamide

[0655] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-methylpyrimidin-4(3H)-one and trans-4-[(3-chloro-5-fluorobenzyl)oxy]cyclohexane-1-carboxylic acid.

[0656] Example 123: trans-4-[(3-chlorobenzyl)oxy]-N-[2-fluoro-3-(5-fluoro-4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]cyclohexane-1-carboxamide

[0657] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-5-fluoro-6-methylpyrimidin-4(3H)-one and trans-4-[(3-chlorobenzyl)oxy]cyclohexane-1-carboxylic acid.

[0658] Example 124: trans-4-[(2-chlorobenzyl)oxy]-N-[3-(4-ethyl-5-fluoro-6-oxo-1,6-dihydropyrimidin-2-yl)-2-fluoro-4-(trifluoromethyl)benzyl]cyclohexane-1-carboxamide

[0659] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-ethyl-5-fluoropyrimidin-4(3H)-one and trans-4-[(2-chlorobenzyl)oxy]cyclohexane-1-carboxylic acid.

[0660] Example 125: trans-4-[(4-chlorobenzyl)oxy]-N-[3-(4-ethyl-5-fluoro-6-oxo-1,6-dihydropyrimidin-2-yl)-2-fluoro-4-(trifluoromethyl)benzyl]cyclohexane-1-carboxamide

[0661] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-ethyl-5-fluoropyrimidin-4(3H)-one and trans-4-[(4-chlorobenzyl)oxy]cyclohexane-1-carboxylic acid.

[0662] Example 126: trans-4-[(2,4-difluorobenzyl)oxy]-N-[2-fluoro-3-(5-fluoro-4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]cyclohexane-1-carboxamide

[0663] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-5-fluoro-6-methylpyrimidin-4(3H)-one and trans-4-[(2,4-difluorobenzyl)oxy]cyclohexane-1-carboxylic acid.

[0664] Example 127: trans-4-[(3,4-difluorobenzyl)oxy]-N-[2-fluoro-3-(5-fluoro-4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]cyclohexane-1-carboxamide

[0665] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-5-fluoro-6-methylpyrimidin-4(3H)-one and trans-4-[(3,4-difluorobenzyl)oxy]cyclohexane-1-carboxylic acid.

[0666] Example 128: trans-4-[(4-chloro-2-fluorobenzyl)oxy]-N-[2-fluoro-3-(5-fluoro-4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]cyclohexane-1-carboxamide

[0667] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-5-fluoro-6-methylpyrimidin-4(3H)-one and trans-4-[(4-chloro-2-fluorobenzyl)oxy]cyclohexane-1-carboxylic acid.

[0668] Example 129: trans-4-[(2,4-difluorobenzyl)oxy]-N-[3-(4-ethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-2-fluoro-4-(trifluoromethyl)benzyl]cyclohexane-1-carboxamide

[0669] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-ethylpyrimidin-4(3H)-one and trans-4-[(3-chlorobenzyl)oxy]cyclohexane-1-carboxylic acid.

[0670] Example 130: trans-N-[2-fluoro-3-(5-fluoro-4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]-4-{[3-(trifluoromethyl)benzyl]oxy}cyclohexane-1-carboxamide

[0671] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-5-fluoro-6-methylpyrimidin-4(3H)-one and trans-4-{[3-(trifluoromethyl)benzyl]oxy}cyclohexane-1-carboxylic acid.

[0672] Example 131: trans-4-[(3-chloro-5-fluorobenzyl)oxy]-N-[2-fluoro-3-(5-fluoro-4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]cyclohexane-1-carboxamide

[0673] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-5-fluoro-6-methylpyrimidin-4(3H)-one and trans-4-[(3-chloro-5-fluorobenzyl)oxy]cyclohexane-1-carboxylic acid.

[0674] Example 132: trans-4-[(2,4-difluorobenzyl)oxy]-N-[3-(4-ethyl-5-fluoro-6-oxo-1,6-dihydropyrimidin-2-yl)-2-fluoro-4-(trifluoromethyl)benzyl]cyclohexane-1-carboxamide

[0675] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-ethyl-5-fluoropyrimidin-4(3H)-one and trans-4-[(2,4-difluorobenzyl)oxy]cyclohexane-1-carboxylic acid.

[0676] Example 133: trans-4-[(3,4-difluorobenzyl)oxy]-N-[3-(4-ethyl-5-fluoro-6-oxo-1,6-dihydropyrimidin-2-yl)-2-fluoro-4-(trifluoromethyl)benzyl]cyclohexane-1-carboxamide

[0677] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-ethyl-5-fluoropyrimidin-4(3H)-one and trans-4-[(3,4-difluorobenzyl)oxy]cyclohexane-1-carboxylic acid.

[0678] Example 134: trans-3-(Benzyloxy)-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}cyclobutane-1-carboxamide

[0679] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and trans-3-(benzyloxy)cyclobutane-1-carboxylic acid.

[0680] Example 135: cis-3-(Benzyloxy)-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}cyclobutane-1-carboxamide

[0681] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and cis-3-(benzyloxy)cyclobutane-1-carboxylic acid.

[0682] Example 136: trans-3-[(2-chlorobenzyl)oxy]-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}cyclobutane-1-carboxamide

[0683] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and trans-3-[(2-chlorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0684] Example 137: cis-3-[(2-chlorobenzyl)oxy]-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}cyclobutane-1-carboxamide

[0685] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and cis-3-[(2-chlorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0686] Example 138: trans-3-[(3-chlorobenzyl)oxy]-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}cyclobutane-1-carboxamide

[0687] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and trans-3-[(3-chlorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0688] Example 139: cis-3-[(3-chlorobenzyl)oxy]-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}cyclobutane-1-carboxamide

[0689] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and cis-3-[(3-chlorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0690] Example 140: trans-3-[(4-chlorobenzyl)oxy]-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}cyclobutane-1-carboxamide

[0691] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and trans-3-[(4-chlorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0692] Example 141: cis-3-[(4-chlorobenzyl)oxy]-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}cyclobutane-1-carboxamide

[0693] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and cis-3-[(4-chlorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0694] Example 142: trans-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}-3-{[2-(trifluoromethyl)benzyl]oxy}cyclobutane-1-carboxamide

[0695] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and trans-3-{[2-(trifluoromethyl)benzyl]oxy}cyclobutane-1-carboxylic acid.

[0696] Example 143: cis-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}-3-{[2-(trifluoromethyl)benzyl]oxy}cyclobutane-1-carboxamide

[0697] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and cis-3-{[2-(trifluoromethyl)benzyl]oxy}cyclobutane-1-carboxylic acid.

[0698] Example 144: trans-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}-3-{[3-(trifluoromethyl)benzyl]oxy}cyclobutane-1-carboxamide

[0699] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and trans-3-{[3-(trifluoromethyl)benzyl]oxy}cyclobutane-1-carboxylic acid.

[0700] Example 145: cis-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}-3-{[3-(trifluoromethyl)benzyl]oxy}cyclobutane-1-carboxamide

[0701] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and cis-3-{[3-(trifluoromethyl)benzyl]oxy}cyclobutane-1-carboxylic acid.

[0702] Example 146: trans-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}-3-{[4-(trifluoromethyl)benzyl]oxy}cyclobutane-1-carboxamide

[0703] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and trans-3-{[4-(trifluoromethyl)benzyl]oxy}cyclobutane-1-carboxylic acid.

[0704] Example 147: cis-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}-3-{[4-(trifluoromethyl)benzyl]oxy}cyclobutane-1-carboxamide

[0705] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and cis-3-{[4-(trifluoromethyl)benzyl]oxy}cyclobutane-1-carboxylic acid.

[0706] Example 148: trans-3-[(2,4-difluorobenzyl)oxy]-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}cyclobutane-1-carboxamide

[0707] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and trans-3-[(2,4-difluorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0708] Example 149: trans-3-[(4-chloro-2-fluorobenzyl)oxy]-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}cyclobutane-1-carboxamide

[0709] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and trans-3-[(4-chloro-2-fluorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0710] Example 150: trans-3-[(3,4-difluorobenzyl)oxy]-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}cyclobutane-1-carboxamide

[0711] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and trans-3-[(3,4-difluorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0712] Example 151: trans-3-[(3,5-difluorobenzyl)oxy]-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}cyclobutane-1-carboxamide

[0713] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and trans-3-[(3,5-difluorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0714] Example 152: trans-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}-3-[(3-fluorobenzyl)oxy]cyclobutane-1-carboxamide

[0715] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and trans-3-[(3-fluorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0716] Example 153: trans-3-[(2,3-difluorobenzyl)oxy]-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}cyclobutane-1-carboxamide

[0717] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and trans-3-[(2,3-difluorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0718] Example 154: trans-3-[(2-chloro-4-fluorobenzyl)oxy]-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}cyclobutane-1-carboxamide

[0719] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and trans-3-[(2-chloro-4-fluorobenzyl)oxy]cyclobutane-1carboxylic acid.

[0720] Example 155: trans-3-[(3-chloro-2-fluorobenzyl)oxy]-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}cyclobutane-1-carboxamide

[0721] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and trans-3-[(3-chloro-2-fluorobenzyl)oxy]cyclobutane-1carboxylic acid.

[0722] Example 156: trans-3-[(5-chloro-2-fluorobenzyl)oxy]-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}cyclobutane-1-carboxamide

[0723] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and trans-3-[(5-chloro-2-fluorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0724] Example 157: trans-3-[(3-chloro-4-fluorobenzyl)oxy]-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}cyclobutane-1-carboxamide

[0725] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and trans-3-[(3-chloro-4-fluorobenzyl)oxy]cyclobutane-1carboxylic acid.

[0726] Example 158: cis-3-[(3-chloro-4-fluorobenzyl)oxy]-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}cyclobutane-1-carboxamide

[0727] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and cis-3-[(3-chloro-4-fluorobenzyl)oxy]cyclobutane-1carboxylic acid.

[0728] Example 159: trans-3-[(3-chloro-5-fluorobenzyl)oxy]-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}cyclobutane-1-carboxamide

[0729] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and trans-3-[(3-chloro-5-fluorobenzyl)oxy]cyclobutane-1carboxylic acid.

[0730] Example 160: cis-3-[(3-chloro-5-fluorobenzyl)oxy]-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}cyclobutane-1-carboxamide

[0731] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and cis-3-[(3-chloro-5-fluorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0732] Example 161: trans-3-[(2-chlorobenzyl)oxy]-N-{3-[4-(difluoromethyl)-6-oxo-1,6-dihydropyrimidin-2-yl]-2-fluoro-4-(trifluoromethyl)benzyl}cyclobutane-1-carboxamide

[0733] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(difluoromethyl)pyrimidin-4(3H)-one and trans-3-[(2-chlorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0734] Example 162: trans-3-[(3-chlorobenzyl)oxy]-N-{3-[4-(difluoromethyl)-6-oxo-1,6-dihydropyrimidin-2-yl]-2-fluoro-4-(trifluoromethyl)benzyl}cyclobutane-1-carboxamide

[0735] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(difluoromethyl)pyrimidin-4(3H)-one and trans-3-[(3-chlorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0736] Example 163: trans-3-[(4-chlorobenzyl)oxy]-N-{3-[4-(difluoromethyl)-6-oxo-1,6-dihydropyrimidin-2-yl]-2-fluoro-4-(trifluoromethyl)benzyl}cyclobutane-1-carboxamide

[0737] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(difluoromethyl)pyrimidin-4(3H)-one and trans-3-[(4-chlorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0738] Example 164: trans-N-{3-[4-(difluoromethyl)-6-oxo-1,6-dihydropyrimidin-2-yl]-2-fluoro-4-(trifluoromethyl)benzyl}-3-{[2-(trifluoromethyl)benzyl]oxy}cyclobutane-1-carboxamide

[0739] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(difluoromethyl)pyrimidin-4(3H)-one and trans-3-{[2-(trifluoromethyl)benzyl]oxy}cyclobutane-1-carboxylic acid.

[0740] Example 165: trans-N-{3-[4-(difluoromethyl)-6-oxo-1,6-dihydropyrimidin-2-yl]-2-fluoro-4-(trifluoromethyl)benzyl}-3-{[3-(trifluoromethyl)benzyl]oxy}cyclobutane-1-carboxamide

[0741] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(difluoromethyl)pyrimidin-4(3H)-one and trans-3-{[3-(trifluoromethyl)benzyl]oxy}cyclobutane-1-carboxylic acid.

[0742] Example 166: trans-N-{3-[4-(difluoromethyl)-6-oxo-1,6-dihydropyrimidin-2-yl]-2-fluoro-4-(trifluoromethyl)benzyl}-3-{[4-(trifluoromethyl)benzyl]oxy}cyclobutane-1-carboxamide

[0743] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(difluoromethyl)pyrimidin-4(3H)-one and trans-3-{[4-(trifluoromethyl)benzyl]oxy}cyclobutane-1-carboxylic acid.

[0744] Example 167: trans-3-[(2,4-difluorobenzyl)oxy]-N-{3-[4-(difluoromethyl)-6-oxo-1,6-dihydropyrimidin-2-yl]-2-fluoro-4-(trifluoromethyl)benzyl}cyclobutane-1-carboxamide

[0745] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(difluoromethyl)pyrimidin-4(3H)-one and trans-3-[(2,4-difluorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0746] Example 168: trans-3-[(4-chloro-2-fluorobenzyl)oxy]-N-{3-[4-(difluoromethyl)-6-oxo-1,6-dihydropyrimidin-2-yl]-2-fluoro-4-(trifluoromethyl)benzyl}cyclobutane-1-carboxamide

[0747] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(difluoromethyl)pyrimidin-4(3H)-one and trans-3-[(4-chloro-2-fluorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0748] Example 169: trans-3-[(3,4-difluorobenzyl)oxy]-N-{3-[4-(difluoromethyl)-6-oxo-1,6-dihydropyrimidin-2-yl]-2-fluoro-4-(trifluoromethyl)benzyl}cyclobutane-1-carboxamide

[0749] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(difluoromethyl)pyrimidin-4(3H)-one and trans-3-[(3,4-difluorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0750] Example 170: trans-3-[(3,5-difluorobenzyl)oxy]-N-{3-[4-(difluoromethyl)-6-oxo-1,6-dihydropyrimidin-2-yl]-2-fluoro-4-(trifluoromethyl)benzyl}cyclobutane-1-carboxamide

[0751] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(difluoromethyl)pyrimidin-4(3H)-one and trans-3-[(3,5-difluorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0752] Example 171: trans-N-{3-[4-(difluoromethyl)-6-oxo-1,6-dihydropyrimidin-2-yl]-2-fluoro-4-(trifluoromethyl)benzyl}-3-[(3-fluorobenzyl)oxy]cyclobutane-1-carboxamide

[0753] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(difluoromethyl)pyrimidin-4(3H)-one and trans-3-[(3-fluorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0754] Example 172: trans-3-[(2,3-difluorobenzyl)oxy]-N-{3-[4-(difluoromethyl)-6-oxo-1,6-dihydropyrimidin-2-yl]-2-fluoro-4-(trifluoromethyl)benzyl}cyclobutane-1-carboxamide

[0755] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(difluoromethyl)pyrimidin-4(3H)-one and trans-3-[(2,3-difluorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0756] Example 173: trans-3-[(2-chloro-4-fluorobenzyl)oxy]-N-{3-[4-(difluoromethyl)-6-oxo-1,6-dihydropyrimidin-2-yl]-2-fluoro-4-(trifluoromethyl)benzyl}cyclobutane-1-carboxamide

[0757] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(difluoromethyl)pyrimidin-4(3H)-one and trans-3-[(2-chloro-4-fluorobenzyl)oxy]cyclobutane-1carboxylic acid.

[0758] Example 174: trans-3-[(3-chloro-2-fluorobenzyl)oxy]-N-{3-[4-(difluoromethyl)-6-oxo-1,6-dihydropyrimidin-2-yl]-2-fluoro-4-(trifluoromethyl)benzyl}cyclobutane-1-carboxamide

[0759] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(difluoromethyl)pyrimidin-4(3H)-one and trans-3-[(3-chloro-2-fluorobenzyl)oxy]cyclobutane-1carboxylic acid.

[0760] Example 175: trans-3-[(5-chloro-2-fluorobenzyl)oxy]-N-{3-[4-(difluoromethyl)-6-oxo-1,6-dihydropyrimidin-2-yl]-2-fluoro-4-(trifluoromethyl)benzyl}cyclobutane-1-carboxamide

[0761] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(difluoromethyl)pyrimidin-4(3H)-one and trans-3-[(5-chloro-2-fluorobenzyl)oxy]cyclobutane-1carboxylic acid.

[0762] Example 176: trans-3-[(3-chloro-4-fluorobenzyl)oxy]-N-{3-[4-(difluoromethyl)-6-oxo-1,6-dihydropyrimidin-2-yl]-2-fluoro-4-(trifluoromethyl)benzyl}cyclobutane-1-carboxamide

[0763] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(difluoromethyl)pyrimidin-4(3H)-one and trans-3-[(3-chloro-4-fluorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0764] Example 177: trans-3-[(3-chloro-5-fluorobenzyl)oxy]-N-{3-[4-(difluoromethyl)-6-oxo-1,6-dihydropyrimidin-2-yl]-2-fluoro-4-(trifluoromethyl)benzyl}cyclobutane-1-carboxamide

[0765] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(difluoromethyl)pyrimidin-4(3H)-one and trans-3-[(3-chloro-5-fluorobenzyl)oxy]cyclobutane-1carboxylic acid.

[0766] Example 178: trans-3-[(2-chlorobenzyl)oxy]-N-[2-fluoro-3-(4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]cyclobutane-1-carboxamide

[0767] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-methylpyrimidin-4(3H)-one and trans-3-[(2-chlorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0768] Example 179: trans-3-[(3-chlorobenzyl)oxy]-N-[2-fluoro-3-(4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]cyclobutane-1-carboxamide

[0769] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-methylpyrimidin-4(3H)-one and trans-3-[(3-chlorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0770] Example 180: trans-3-[(4-chlorobenzyl)oxy]-N-[2-fluoro-3-(4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]cyclobutane-1-carboxamide

[0771] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-methylpyrimidin-4(3H)-one and trans-3-[(4-chlorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0772] Example 181: trans-N-[2-fluoro-3-(4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]-3-{[2-(trifluoromethyl)benzyl]oxy}cyclobutane-1-carboxamide

[0773] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-methylpyrimidin-4(3H)-one and trans-3-{[2-(trifluoromethyl)benzyl]oxy}cyclobutane-1-carboxylic acid.

[0774] Example 182: trans-N-[2-fluoro-3-(4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]-3-{[3-(trifluoromethyl)benzyl]oxy}cyclobutane-1-carboxamide

[0775] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-methylpyrimidin-4(3H)-one and trans-3-{[3-(trifluoromethyl)benzyl]oxy}cyclobutane-1-carboxylic acid.

[0776] Example 183: trans-N-[2-fluoro-3-(4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]-3-{[4-(trifluoromethyl)benzyl]oxy}cyclobutane-1-carboxamide

[0777] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-methylpyrimidin-4(3H)-one and trans-3-{[4-(trifluoromethyl)benzyl]oxy}cyclobutane-1-carboxylic acid.

[0778] Example 184: trans-3-[(2,4-difluorobenzyl)oxy]-N-[2-fluoro-3-(4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]cyclobutane-1-carboxamide

[0779] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-methylpyrimidin-4(3H)-one and trans-3-[(2,4-difluorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0780] Example 185: trans-3-[(4-chloro-2-fluorobenzyl)oxy]-N-[2-fluoro-3-(4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]cyclobutane-1-carboxamide

[0781] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-methylpyrimidin-4(3H)-one and trans-3-[(4-chloro-2-fluorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0782] Example 186: trans-3-[(3,4-difluorobenzyl)oxy]-N-[2-fluoro-3-(4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]cyclobutane-1-carboxamide

[0783] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-methylpyrimidin-4(3H)-one and trans-3-[(3,4-difluorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0784] Example 187: trans-3-[(3,5-difluorobenzyl)oxy]-N-[2-fluoro-3-(4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]cyclobutane-1-carboxamide

[0785] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-methylpyrimidin-4(3H)-one and trans-3-[(3,5-difluorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0786] Example 188: trans-N-[2-fluoro-3-(4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]-3-[(3-fluorobenzyl)oxy]cyclobutane-1-carboxamide

[0787] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-methylpyrimidin-4(3H)-one and trans-3-[(3-fluorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0788] Example 189: trans-3-[(2,3-difluorobenzyl)oxy]-N-[2-fluoro-3-(4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]cyclobutane-1-carboxamide

[0789] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-methylpyrimidin-4(3H)-one and trans-3-[(2,3-difluorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0790] Example 190: trans-3-[(2-chloro-4-fluorobenzyl)oxy]-N-[2-fluoro-3-(4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]cyclobutane-1-carboxamide

[0791] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-methylpyrimidin-4(3H)-one and trans-3-[(2-chloro-4-fluorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0792] Example 191: trans-3-[(3-chloro-2-fluorobenzyl)oxy]-N-[2-fluoro-3-(4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]cyclobutane-1-carboxamide

[0793] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-methylpyrimidin-4(3H)-one and trans-3-[(3-chloro-2-fluorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0794] Example 192: trans-3-[(5-chloro-2-fluorobenzyl)oxy]-N-[2-fluoro-3-(4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]cyclobutane-1-carboxamide

[0795] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-methylpyrimidin-4(3H)-one and trans-3-[(5-chloro-2-fluorobenzyl)oxy]cyclobutane-1carboxylic acid.

[0796] Example 193: trans-3-[(3-chloro-4-fluorobenzyl)oxy]-N-[2-fluoro-3-(4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]cyclobutane-1-carboxamide

[0797] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-methylpyrimidin-4(3H)-one and trans-3-[(3-chloro-4-fluorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0798] Example 194: trans-3-[(3-chloro-5-fluorobenzyl)oxy]-N-[2-fluoro-3-(4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]cyclobutane-1-carboxamide

[0799] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-methylpyrimidin-4(3H)-one and trans-3-[(3-chloro-5-fluorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0800] Example 195: trans-3-[(2-chlorobenzyl)oxy]-N-[3-(4-ethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-2-fluoro-4-(trifluoromethyl)benzyl]cyclobutane-1-carboxamide

[0801] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-ethylpyrimidin-4(3H)-one and trans-3-[(2-chlorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0802] Example 196: trans-3-[(3-chlorobenzyl)oxy]-N-[3-(4-ethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-2-fluoro-4-(trifluoromethyl)benzyl]cyclobutane-1-carboxamide

[0803] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-ethylpyrimidin-4(3H)-one and trans-3-[(3-chlorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0804] Example 197: trans-3-[(4-chlorobenzyl)oxy]-N-[3-(4-ethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-2-fluoro-4-(trifluoromethyl)benzyl]cyclobutane-1-carboxamide

[0805] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-ethylpyrimidin-4(3H)-one and trans-3-[(4-chlorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0806] Example 198: trans-N-[3-(4-ethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-2-fluoro-4-(trifluoromethyl)benzyl]-3-{[2-(trifluoromethyl)benzyl]oxy}cyclobutane-1-carboxamide

[0807] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-ethylpyrimidin-4(3H)-one and trans-3-{[2-(trifluoromethyl)benzyl]oxy}cyclobutane-1-carboxylic acid.

[0808] Example 199: trans-N-[3-(4-ethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-2-fluoro-4-(trifluoromethyl)benzyl]-3-{[3-(trifluoromethyl)benzyl]oxy}cyclobutane-1-carboxamide

[0809] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-ethylpyrimidin-4(3H)-one and trans-3-{[3-(trifluoromethyl)benzyl]oxy}cyclobutane-1-carboxylic acid.

[0810] Example 200: trans-N-[3-(4-ethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-2-fluoro-4-(trifluoromethyl)benzyl]-3-{[4-(trifluoromethyl)benzyl]oxy}cyclobutane-1-carboxamide

[0811] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-ethylpyrimidin-4(3H)-one and trans-3-{[4-(trifluoromethyl)benzyl]oxy}cyclobutane-1-carboxylic acid.

[0812] Example 201: trans-3-[(2,4-difluorobenzyl)oxy]-N-[3-(4-ethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-2-fluoro-4-(trifluoromethyl)benzyl]cyclobutane-1-carboxamide

[0813] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-ethylpyrimidin-4(3H)-one and trans-3-[(2,4-difluorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0814] Example 202: trans-3-[(4-chloro-2-fluorobenzyl)oxy]-N-[3-(4-ethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-2-fluoro-4-(trifluoromethyl)benzyl]cyclobutane-1-carboxamide

[0815] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-ethylpyrimidin-4(3H)-one and trans-3-[(4-chloro-2-fluorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0816] Example 203: trans-3-[(3,4-difluorobenzyl)oxy]-N-[3-(4-ethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-2-fluoro-4-(trifluoromethyl)benzyl]cyclobutane-1-carboxamide

[0817] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-ethylpyrimidin-4(3H)-one and trans-3-[(3,4-difluorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0818] Example 204: trans-3-[(3,5-difluorobenzyl)oxy]-N-[3-(4-ethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-2-fluoro-4-(trifluoromethyl)benzyl]cyclobutane-1-carboxamide

[0819] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-ethylpyrimidin-4(3H)-one and trans-3-[(3,5-difluorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0820] Example 205: trans-N-[3-(4-ethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-2-fluoro-4-(trifluoromethyl)benzyl]-3-[(3-fluorobenzyl)oxy]cyclobutane-1-carboxamide

[0821] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-ethylpyrimidin-4(3H)-one and trans-3-[(3-fluorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0822] Example 206: trans-3-[(2,3-difluorobenzyl)oxy]-N-[3-(4-ethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-2-fluoro-4-(trifluoromethyl)benzyl]cyclobutane-1-carboxamide

[0823] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-ethylpyrimidin-4(3H)-one and trans-3-[(2,3-difluorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0824] Example 207: trans-3-[(2-chloro-4-fluorobenzyl)oxy]-N-[3-(4-ethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-2-fluoro-4-(trifluoromethyl)benzyl]cyclobutane-1-carboxamide

[0825] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-ethylpyrimidin-4(3H)-one and trans-3-[(2-chloro-4-fluorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0826] Example 208: trans-3-[(3-chloro-2-fluorobenzyl)oxy]-N-[3-(4-ethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-2-fluoro-4-(trifluoromethyl)benzyl]cyclobutane-1-carboxamide

[0827] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-ethylpyrimidin-4(3H)-one and trans-3-[(3-chloro-2-fluorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0828] Example 209: trans-3-[(5-chloro-2-fluorobenzyl)oxy]-N-[3-(4-ethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-2-fluoro-4-(trifluoromethyl)benzyl]cyclobutane-1-carboxamide

[0829] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-ethylpyrimidin-4(3H)-one and trans-3-[(5-chloro-2-fluorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0830] Example 210: trans-3-[(3-chloro-4-fluorobenzyl)oxy]-N-[3-(4-ethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-2-fluoro-4-(trifluoromethyl)benzyl]cyclobutane-1-carboxamide

[0831] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-ethylpyrimidin-4(3H)-one and trans-3-[(3-chloro-4-fluorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0832] Example 211: trans-3-[(3-chloro-5-fluorobenzyl)oxy]-N-[3-(4-ethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-2-fluoro-4-(trifluoromethyl)benzyl]cyclobutane-1-carboxamide

[0833] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-ethylpyrimidin-4(3H)-one and trans-3-[(3-chloro-5-fluorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0834] Example 212: trans-3-[(2-chlorobenzyl)oxy]-N-[2-fluoro-3-(5-fluoro-4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]cyclobutane-1-carboxamide

[0835] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-5-fluoro-6-methylpyrimidin-4(3H)-one and trans-3-[(2-chlorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0836] Example 213: trans-3-[(3-chlorobenzyl)oxy]-N-[2-fluoro-3-(5-fluoro-4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]cyclobutane-1-carboxamide

[0837] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-5-fluoro-6-methylpyrimidin-4(3H)-one and trans-3-[(3-chlorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0838] Example 214: trans-3-[(4-chlorobenzyl)oxy]-N-[2-fluoro-3-(5-fluoro-4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]cyclobutane-1-carboxamide

[0839] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-5-fluoro-6-methylpyrimidin-4(3H)-one and trans-3-[(4-chlorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0840] Example 215: trans-N-[2-fluoro-3-(5-fluoro-4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]-3-{[2-(trifluoromethyl)benzyl]oxy}cyclobutane-1-carboxamide

[0841] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-5-fluoro-6-methylpyrimidin-4(3H)-one and trans-3-{[2-(trifluoromethyl)benzyl]oxy}cyclobutane-1-carboxylic acid.

[0842] Example 216: trans-N-[2-fluoro-3-(5-fluoro-4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]-3-{[3-(trifluoromethyl)benzyl]oxy}cyclobutane-1-carboxamide

[0843] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-5-fluoro-6-methylpyrimidin-4(3H)-one and trans-3-{[3-(trifluoromethyl)benzyl]oxy}cyclobutane-1-carboxylic acid.

[0844] Example 217: trans-N-[2-fluoro-3-(5-fluoro-4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]-3-{[4-(trifluoromethyl)benzyl]oxy}cyclobutane-1-carboxamide

[0845] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-5-fluoro-6-methylpyrimidin-4(3H)-one and trans-3-{[4-(trifluoromethyl)benzyl]oxy}cyclobutane-1-carboxylic acid.

[0846] Example 218: trans-3-[(2,4-difluorobenzyl)oxy]-N-[2-fluoro-3-(5-fluoro-4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]cyclobutane-1-carboxamide

[0847] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-5-fluoro-6-methylpyrimidin-4(3H)-one and trans-3-[(2,4-difluorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0848] Example 219: trans-3-[(4-chloro-2-fluorobenzyl)oxy]-N-[2-fluoro-3-(5-fluoro-4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]cyclobutane-1-carboxamide

[0849] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-5-fluoro-6-methylpyrimidin-4(3H)-one and trans-3-[(4-chloro-2-fluorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0850] Example 220: trans-3-[(3,4-difluorobenzyl)oxy]-N-[2-fluoro-3-(5-fluoro-4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]cyclobutane-1-carboxamide

[0851] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-5-fluoro-6-methylpyrimidin-4(3H)-one and trans-3-[(3,4-difluorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0852] Example 221: trans-3-[(3,5-difluorobenzyl)oxy]-N-[2-fluoro-3-(5-fluoro-4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]cyclobutane-1-carboxamide

[0853] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-5-fluoro-6-methylpyrimidin-4(3H)-one and trans-3-[(3,5-difluorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0854] Example 222: trans-N-[2-fluoro-3-(5-fluoro-4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]-3-[(3-fluorobenzyl)oxy]cyclobutane-1-carboxamide

[0855] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-5-fluoro-6-methylpyrimidin-4(3H)-one and trans-3-[(3-fluorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0856] Example 223: trans-3-[(2,3-difluorobenzyl)oxy]-N-[2-fluoro-3-(5-fluoro-4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]cyclobutane-1-carboxamide

[0857] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-5-fluoro-6-methylpyrimidin-4(3H)-one and trans-3-[(2,3-difluorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0858] Example 224: trans-3-[(2-chloro-4-fluorobenzyl)oxy]-N-[2-fluoro-3-(5-fluoro-4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]cyclobutane-1-carboxamide

[0859] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-5-fluoro-6-methylpyrimidin-4(3H)-one and trans-3-[(2-chloro-4-fluorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0860] Example 225: trans-3-[(3-chloro-2-fluorobenzyl)oxy]-N-[2-fluoro-3-(5-fluoro-4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]cyclobutane-1-carboxamide

[0861] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-5-fluoro-6-methylpyrimidin-4(3H)-one and trans-3-[(3-chloro-2-fluorobenzyl)oxy]cyclobutane-1carboxylic acid.

[0862] Example 226: trans-3-[(5-chloro-2-fluorobenzyl)oxy]-N-[2-fluoro-3-(5-fluoro-4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]cyclobutane-1-carboxamide

[0863] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-5-fluoro-6-methylpyrimidin-4(3H)-one and trans-3-[(5-chloro-2-fluorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0864] Example 227: trans-3-[(3-chloro-4-fluorobenzyl)oxy]-N-[2-fluoro-3-(5-fluoro-4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]cyclobutane-1-carboxamide

[0865] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-5-fluoro-6-methylpyrimidin-4(3H)-one and trans-3-[(3-chloro-4-fluorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0866] Example 228: trans-3-[(3-chloro-5-fluorobenzyl)oxy]-N-[2-fluoro-3-(5-fluoro-4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-(trifluoromethyl)benzyl]cyclobutane-1-carboxamide

[0867] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-5-fluoro-6-methylpyrimidin-4(3H)-one and trans-3-[(3-chloro-5-fluorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0868] Example 229: trans-3-[(2-chlorobenzyl)oxy]-N-[3-(4-ethyl-5-fluoro-6-oxo-1,6-dihydropyrimidin-2-yl)-2-fluoro-4-(trifluoromethyl)benzyl]cyclobutane-1-carboxamide

[0869] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-ethyl-5-fluoropyrimidin-4(3H)-one and trans-3-[(2-chlorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0870] Example 230: trans-3-[(3-chlorobenzyl)oxy]-N-[3-(4-ethyl-5-fluoro-6-oxo-1,6-dihydropyrimidin-2-yl)-2-fluoro-4-(trifluoromethyl)benzyl]cyclobutane-1-carboxamide

[0871] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-ethyl-5-fluoropyrimidin-4(3H)-one and trans-3-[(3-chlorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0872] Example 231: trans-3-[(4-chlorobenzyl)oxy]-N-[3-(4-ethyl-5-fluoro-6-oxo-1,6-dihydropyrimidin-2-yl)-2-fluoro-4-(trifluoromethyl)benzyl]cyclobutane-1-carboxamide

[0873] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-ethyl-5-fluoropyrimidin-4(3H)-one and trans-3-[(4-chlorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0874] Example 232: trans-N-[3-(4-ethyl-5-fluoro-6-oxo-1,6-dihydropyrimidin-2-yl)-2-fluoro-4-(trifluoromethyl)benzyl]-3-{[2-(trifluoromethyl)benzyl]oxy}cyclobutane-1-carboxamide

[0875] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-ethyl-5-fluoropyrimidin-4(3H)-one and trans-3-{[2-(trifluoromethyl)benzyl]oxy}cyclobutane-1-carboxylic acid.

[0876] Example 233: trans-N-[3-(4-ethyl-5-fluoro-6-oxo-1,6-dihydropyrimidin-2-yl)-2-fluoro-4-(trifluoromethyl)benzyl]-3-{[3-(trifluoromethyl)benzyl]oxy}cyclobutane-1-carboxamide

[0877] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-ethyl-5-fluoropyrimidin-4(3H)-one and trans-3-{[3-(trifluoromethyl)benzyl]oxy}cyclobutane-1-carboxylic acid.

[0878] Example 234: trans-N-[3-(4-ethyl-5-fluoro-6-oxo-1,6-dihydropyrimidin-2-yl)-2-fluoro-4-(trifluoromethyl)benzyl]-3-{[4-(trifluoromethyl)benzyl]oxy}cyclobutane-1-carboxamide

[0879] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-ethyl-5-fluoropyrimidin-4(3H)-one and trans-3-{[4-(trifluoromethyl)benzyl]oxy}cyclobutane-1-carboxylic acid.

[0880] Example 235: trans-3-[(2,4-difluorobenzyl)oxy]-N-[3-(4-ethyl-5-fluoro-6-oxo-1,6-dihydropyrimidin-2-yl)-2-fluoro-4-(trifluoromethyl)benzyl]cyclobutane-1-carboxamide

[0881] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-ethyl-5-fluoropyrimidin-4(3H)-one and trans-3-[(2,4-difluorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0882] Example 236: trans-3-[(4-chloro-2-fluorobenzyl)oxy]-N-[3-(4-ethyl-5-fluoro-6-oxo-1,6-dihydropyrimidin-2-yl)-2-fluoro-4-(trifluoromethyl)benzyl]cyclobutane-1-carboxamide

[0883] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-ethyl-5-fluoropyrimidin-4(3H)-one and trans-3-[(4-chloro-2-fluorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0884] Example 237: trans-3-[(3,4-difluorobenzyl)oxy]-N-[3-(4-ethyl-5-fluoro-6-oxo-1,6-dihydropyrimidin-2-yl)-2-fluoro-4-(trifluoromethyl)benzyl]cyclobutane-1-carboxamide

[0885] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-ethyl-5-fluoropyrimidin-4(3H)-one and trans-3-[(3,4-difluorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0886] Example 238: trans-3-[(3,5-difluorobenzyl)oxy]-N-[3-(4-ethyl-5-fluoro-6-oxo-1,6-dihydropyrimidin-2-yl)-2-fluoro-4-(trifluoromethyl)benzyl]cyclobutane-1-carboxamide

[0887] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-ethyl-5-fluoropyrimidin-4(3H)-one and trans-3-[(3,5-difluorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0888] Example 239: trans-N-[3-(4-ethyl-5-fluoro-6-oxo-1,6-dihydropyrimidin-2-yl)-2-fluoro-4-(trifluoromethyl)benzyl]-3-[(3-fluorobenzyl)oxy]cyclobutane-1-carboxamide

[0889] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-ethyl-5-fluoropyrimidin-4(3H)-one and trans-3-[(3-fluorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0890] Example 240: trans-3-[(2,3-difluorobenzyl)oxy]-N-[3-(4-ethyl-5-fluoro-6-oxo-1,6-dihydropyrimidin-2-yl)-2-fluoro-4-(trifluoromethyl)benzyl]cyclobutane-1-carboxamide

[0891] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-ethyl-5-fluoropyrimidin-4(3H)-one and trans-3-[(2,3-difluorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0892] Example 241: trans-3-[(2-chloro-4-fluorobenzyl)oxy]-N-[3-(4-ethyl-5-fluoro-6-oxo-1,6-dihydropyrimidin-2-yl)-2-fluoro-4-(trifluoromethyl)benzyl]cyclobutane-1-carboxamide

[0893] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-ethyl-5-fluoropyrimidin-4(3H)-one and trans-3-[(2-chloro-4-fluorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0894] Example 242: trans-3-[(3-chloro-2-fluorobenzyl)oxy]-N-[3-(4-ethyl-5-fluoro-6-oxo-1,6-dihydropyrimidin-2-yl)-2-fluoro-4-(trifluoromethyl)benzyl]cyclobutane-1-carboxamide

[0895] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-ethyl-5-fluoropyrimidin-4(3H)-one and trans-3-[(3-chloro-2-fluorobenzyl)oxy]cyclobutane-1carboxylic acid.

[0896] Example 243: trans-3-[(5-chloro-2-fluorobenzyl)oxy]-N-[3-(4-ethyl-5-fluoro-6-oxo-1,6-dihydropyrimidin-2-yl)-2-fluoro-4-(trifluoromethyl)benzyl]cyclobutane-1-carboxamide

[0897] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-ethyl-5-fluoropyrimidin-4(3H)-one and trans-3-[(5-chloro-2-fluorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0898] Example 244: trans-3-[(3-chloro-4-fluorobenzyl)oxy]-N-[3-(4-ethyl-5-fluoro-6-oxo-1,6-dihydropyrimidin-2-yl)-2-fluoro-4-(trifluoromethyl)benzyl]cyclobutane-1-carboxamide

[0899] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-ethyl-5-fluoropyrimidin-4(3H)-one and trans-3-[(3-chloro-4-fluorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0900] Example 245: trans-3-[(3-chloro-5-fluorobenzyl)oxy]-N-[3-(4-ethyl-5-fluoro-6-oxo-1,6-dihydropyrimidin-2-yl)-2-fluoro-4-(trifluoromethyl)benzyl]cyclobutane-1-carboxamide

[0901] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-ethyl-5-fluoropyrimidin-4(3H)-one and trans-3-[(3-chloro-5-fluorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0902] Example 246: trans-3-[(3-chlorobenzyl)oxy]-N-[3-(4,5-dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-2-fluoro-4-(trifluoromethyl)benzyl]cyclobutane-1-carboxamide

[0903] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-5,6-dimethylpyrimidin-4(3H)-one and trans-3-[(3-chlorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0904] Example 247: trans-3-[(3-chlorobenzyl)oxy]-N-[2-fluoro-3-(4-oxo-4,5,6,7-tetrahydro-3H-cyclopenta[d]pyrimidin-2-yl)-4-(trifluoromethyl)benzyl]cyclobutane-1-carboxamide

[0905] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-3,5,6,7-tetrahydro-4H-cyclopenta[d]pyrimidin-4-one and trans-3-[(3-chlorobenzyl)oxy]cyclobutane-1-carboxylic acid.

[0906] Example 248: N-{2-Fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}-4-{[5-(trifluoromethyl)pyridin-2-yl]oxy}cyclohexane-1-carboxamide

[0907] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and 4-{[5-(trifluoromethyl)pyridin-2-yl]oxy}cyclohexane-1-carboxylic acid (Reference Example 89).

[0908] Example 249: trans-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}-3-{[5-(trifluoromethyl)pyridin-2-yl]oxy}cyclobutane-1-carboxamide

[0909] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and trans-3-{[5-(trifluoromethyl)pyridin-2-yl]oxy}cyclobutane-1-carboxylic acid (Reference Example 91).

[0910] Example 250: cis-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}-3-{[5-(trifluoromethyl)pyridin-2-yl]oxy}cyclobutane-1-carboxamide

[0911] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and cis-3-{[5-(trifluoromethyl)pyridin-2-yl]oxy}cyclobutane-1-carboxylic acid (Reference Example 93).

[0912] Example 251: trans-3-(2-chlorophenoxy)-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}cyclobutane-1-carboxamide

[0913] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and trans-3-(2-chlorophenoxy)cyclobutane-1-carboxylic acid.

[0914] Example 252: cis-3-(2-chlorophenoxy)-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}cyclobutane-1-carboxamide

[0915] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and cis-3-(2-chlorophenoxy)cyclobutane-1-carboxylic acid.

[0916] Example 253: trans-3-(3-chlorophenoxy)-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}cyclobutane-1-carboxamide

[0917] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and trans-3-(3-chlorophenoxy)cyclobutane-1-carboxylic acid.

[0918] Example 254: cis-3-(3-chlorophenoxy)-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}cyclobutane-1-carboxamide

[0919] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and cis-3-(3-chlorophenoxy)cyclobutane-1-carboxylic acid.

[0920] Example 255: trans-3-(4-chlorophenoxy)-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}cyclobutane-1-carboxamide

[0921] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and trans-3-(4-chlorophenoxy)cyclobutane-1-carboxylic acid (Reference Example 94).

[0922] Example 256: cis-3-(4-chlorophenoxy)-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}cyclobutane-1-carboxamide

[0923] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and cis-3-(4-chlorophenoxy)cyclobutane-1-carboxylic acid (Reference Example 95).

[0924] Example 257: cis-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}-3-isobutoxycyclobutane-1-carboxamide

[0925] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and cis-3-isobutoxycyclobutane-1-carboxylic acid.

[0926] Example 258: 4-(3,4-dichlorophenoxy)-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}piperidine-1-carboxamide

[0927] To a solution of 20 mg of 4-(3,4-dichlorophenoxy)piperidine hydrochloride and 39 μL of triethylamine in 5.7 μL of tetrahydrofuran, 7.3 mg of triphosgene was added. After stirring at room temperature for 1 hour, 50 mg of 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one was added and stirred at room temperature overnight. Aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, dried with magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by preparative HPLC to obtain 8 mg of the title compound.

[0928] Example 259: N-{2-Fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}-4-[2-(trifluoromethyl)phenoxy]piperidine-1-carboxamide

[0929] The title compound was obtained by the same procedures as in Example 258 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and 4-[2-(trifluoromethyl)phenoxy]piperidine-1-carboxylic acid.

[0930] Example 260: N-{2-Fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}-4-[4-(trifluoromethyl)phenoxy]piperidine-1-carboxamide

[0931] The title compound was obtained by the same procedures as in Example 258 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and 4-[4-(trifluoromethyl)phenoxy]piperidine-1carboxylic acid.

[0932] Example 261: N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}-3-{[3-(trifluoromethyl)benzyl]oxy}azetidine-1-carboxamide

[0933] The title compound was obtained by the same procedures as in Example 258 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and 3-{[3-(trifluoromethyl)benzyl]oxy}azetidine-1-carboxylic acid.

[0934] Example 262: N-{2-Fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}-3-{[3-(trifluoromethyl)phenoxy]methyl}azetidine-1-carboxamide

[0935] The title compound was obtained by the same procedures as in Example 258 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and 3-{[3-(trifluoromethyl)phenoxy]methyl}azetidine-1carboxylic acid.

[0936] Example 263: N-(2-Fluoro-3-{6-oxo-4-[5-(trifluoromethyl)pyridin-2-yl]-1,6-dihydropyrimidin-2-yl}-4-(trifluoromethyl)benzyl)benzamide

[0937] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-[5-(trifluoromethyl)pyridin-2-yl]pyrimidin-4(3H)-one and benzoic acid.

[0938] Example 264: N-(2-Fluoro-3-{6-oxo-4-[5-(trifluoromethyl)pyridin-2-yl]-1,6-dihydropyrimidin-2-yl}-4-(trifluoromethyl)benzyl)picolinamide

[0939] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-[5-(trifluoromethyl)pyridin-2-yl]pyrimidin-4(3H)-one and 2-picolinic acid.

[0940] Example 265: N-(2-Fluoro-3-{6-oxo-4-[5-(trifluoromethyl)pyridin-2-yl]-1,6-dihydropyrimidin-2-yl}-4-(trifluoromethyl)benzyl)-[1,1'-biphenyl]-4-carboxamide

[0941] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-[5-(trifluoromethyl)pyridin-2-yl]pyrimidin-4(3H)-one and 4-bibenzoic acid.

[0942] Example 266: 3-(Benzyloxy)-N-(2-fluoro-3-{6-oxo-4-[5-(trifluoromethyl)pyridin-2-yl]-1,6-dihydropyrimidin-2-yl}-4-(trifluoromethyl)benzyl)cyclobutane-1-carboxamide

[0943] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-[5-(trifluoromethyl)pyridin-2-yl]pyrimidin-4(3H)-one and 3-(benzyloxy)cyclobutane-1-carboxylic acid.

[0944] Example 267: N-(2-Fluoro-3-{6-oxo-4-[5-(trifluoromethyl)pyridin-2-yl]-1,6-dihydropyrimidin-2-yl}-4-(trifluoromethyl)benzyl)-1-(imidazo[1,2-b]pyridazin-6-yl)piperidine-4-carboxamide

[0945] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-[5-(trifluoromethyl)pyridin-2-yl]pyrimidin-4(3H)-one and 1-(imidazo[1,2-b]pyridazin-6-yl)piperidine-4-carboxylic acid.

[0946] Example 268: N-(2-Fluoro-3-{6-oxo-4-[5-(trifluoromethyl)pyridin-2-yl]-1,6-dihydropyrimidin-2-yl}-4-(trifluoromethyl)benzyl)benzenesulfonamide

[0947] The title compound was obtained by the same procedures as in Example 272 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-[5-(trifluoromethyl)pyridin-2-yl]pyrimidin-4(3H)-one and benzenesulfonyl chloride.

[0948] Example 269: N-(2-Fluoro-3-{6-oxo-4-[5-(trifluoromethyl)pyridin-2-yl]-1,6-dihydropyrimidin-2-yl}-4-(trifluoromethyl)benzyl)-2-(trifluoromethyl)benzenesulfonamide

[0949] The title compound was obtained by the same procedures as in Example 272 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-[5-(trifluoromethyl)pyridin-2-yl]pyrimidin-4(3H)-one and 2-(trifluoromethyl)benzenesulfonyl chloride.

[0950] Example 270: N-(2-Fluoro-3-{6-oxo-4-[5-(trifluoromethyl)pyridin-2-yl]-1,6-dihydropyrimidin-2-yl}-4-(trifluoromethyl)benzyl)-4-(trifluoromethyl)benzenesulfonamide

[0951] The title compound was obtained by the same procedures as in Example 272 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-[5-(trifluoromethyl)pyridin-2-yl]pyrimidin-4(3H)-one and 4-(trifluoromethyl)benzenesulfonyl chloride.

[0952] Example 271: N-(2-Fluoro-3-{6-oxo-4-[5-(trifluoromethyl)pyridin-2-yl]-1,6-dihydropyrimidin-2-yl}-4-(trifluoromethyl)benzyl)-[1,1'-biphenyl]-4-sulfonamide

[0953] The title compound was obtained by the same procedures as in Example 272 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-[5-(trifluoromethyl)pyridin-2-yl]pyrimidin-4(3H)-one and 4-biphenylsulfonyl chloride.

[0954] Example 272: N-{2-Fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}-2-(trifluoromethyl)benzenesulfonamide

[0955] Under ice cooling, 237 μL of triethylamine and 49 μL of 2-(trifluoromethyl)benzenesulfonyl chloride were added to a solution of 99.7 mg of 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidine-4(3H)-one·2,2,2-trifluoroacetate in 2 mL of N,N-dimethylformamide, and stirred at room temperature overnight. Saturated aqueous ammonium chloride solution was added, extracted three times with ethyl acetate, and the combined organic layers were washed with water and saturated brine. The organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 5.8 mg of the title compound.

[0956] Example 273: N-{2-Fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}-2-(trifluoromethyl)benzamide

[0957] The title compound was obtained by the same procedures as in Example 272 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one 2,2,2-trifluoroacetate and 2-(trifluoromethyl)benzoyl chloride.

[0958] Example 274: 2,3-Dichloro-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}benzamide

[0959] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and 2,3-dichlorobenzoic acid.

[0960] Example 275: N-{2-Fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}-1-[2-(4-fluorophenyl)acetyl]piperidine-4-carboxamide

[0961] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and 1-[2-(4-fluorophenyl)acetyl]piperidine-4-carboxylic acid.

[0962] Example 276: N-{2-Fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}-1-[2-(4-fluorophenyl)acetyl]azetidine-3-carboxamide

[0963] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and 1-[2-(4-fluorophenyl)acetyl]azetidine-3-carboxylic acid.

[0964] Example 277: 1-Benzyl-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}piperidine-4-carboxamide

[0965] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and 1-benzylpiperidine-4-carboxylic acid.

[0966] Example 278: N-{2-Fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}-1-phenethylpiperidine-4-carboxamide

[0967] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and 1-phenethylpiperidine-4-carboxylic acid.

[0968] Example 279: trans-4-(4-chlorophenyl)-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}cyclohexane-1-carboxamide

[0969] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and trans-4-(4-chlorophenyl)cyclohexane-1-carboxylic acid.

[0970] Example 280: N-{2-Fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}-2,3-dihydro-1H-indene-2-carboxamide

[0971] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and indan-2-carboxylic acid.

[0972] Example 281: 1-(4-chlorophenyl)-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}cyclopentane-1-carboxamide

[0973] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and 1-(4-chlorophenyl)cyclopentane-1-carboxylic acid.

[0974] Example 282: 2-(4-chlorophenyl)-N-{2-fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}-2-methylpropanamide

[0975] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and 2-(4-chlorophenyl)-2-methylpropionic acid.

[0976] Example 283: N-{2-Fluoro-3-[6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl]-4-(trifluoromethyl)benzyl}-2-[4-(trifluoromethyl)phenyl]acetamide

[0977] The title compound was obtained by the same procedures as in Example 1 using 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4(3H)-one and 4-(trifluoromethyl)phenylacetic acid.

[0978] The chemical structural formulas and NMR spectrum data of the compounds obtained in Reference Examples and Examples are shown below.

[0979] [Table 1]

[0980]

[0981] [Table 2]

[0982]

[0983] [Table 3]

[0984]

[0985] [Table 4]

[0986]

[0987] [Table 5]

[0988]

[0989] [Table 6]

[0990]

[0991] [Table 7]

[0992]

[0993] [Table 8]

[0994]

[0995] [Table 9]

[0996]

[0997] [Table 10]

[0998]

[0999] [Table 11]

[1000]

[1001] [Table 12]

[1002]

[1003] [Table 13]

[1004]

[1005] [Table 14]

[1006]

[1007] [Table 15]

[1008]

[1009] [Table 16]

[1010]

[1011] [Table 17]

[1012]

[1013] [Table 18]

[1014]

[1015] [Table 19]

[1016]

[1017] [Table 20]

[1018]

[1019] [Table 21]

[1020]

[1021] [Table 22]

[1022]

[1023] [Table 23]

[1024]

[1025] [Table 24]

[1026]

[1027] [Table 25]

[1028]

[1029] [Table 26]

[1030]

[1031] [Table 27]

[1032]

[1033] [Table 28]

[1034]

[1035] [Table 29]

[1036]

[1037] [Table 30]

[1038]

[1039] [Table 31]

[1040]

[1041] [Table 32]

[1042]

[1043] [Table 33]

[1044]

[1045] [Table 34]

[1046]

[1047] [Table 35]

[1048]

[1049] [Table 36]

[1050]

[1051] [Table 37]

[1052]

[1053] [Table 38]

[1054]

[1055] [Table 39]

[1056]

[1057] [Table 40]

[1058]

[1059] [Table 41]

[1060]

[1061] [Table 42]

[1062]

[1063] [Table 43]

[1064]

[1065] [Table 44]

[1066]

[1067] [Table 45]

[1068]

[1069] [Table 46]

[1070]

[1071] [Table 47]

[1072]

[1073] [Table 48]

[1074]

[1075] [Table 49]

[1076]

[1077] [Table 50]

[1078]

[1079] [Table 51]

[1080]

[1081] [Table 52]

[1082]

[1083] [Table 53]

[1084]

[1085] [Table 54]

[1086]

[1087] Test Example 1: mPGES-1 inhibitory activity test

[1088] Microsomes were prepared from COS-1 cells transfected with a plasmid encoding human mPGES-1 cDNA at one time and used as mPGES-1 enzyme. The mPGES-1 enzyme was diluted with sodium phosphate buffer (pH 7.2) containing reduced glutathione (2.5 mM) and EDTA (1 mM), and DMSO or a DMSO solution of the test compound (final DMSO concentration 2%) was added and pre-incubated at 4°C for 15 minutes. Next, PGH2 (Prostaglandin H2) was added as a substrate to a final concentration of 1 μM to start the enzyme reaction. After incubation at 4°C for 4 minutes, ferric chloride (25 mM) and citric acid (50 mM) solutions were added to stop the enzyme reaction. The generated PGE2 (Prostaglandin E2) was measured using Prostaglandin E2 Express EIA kit (Cayman Chemical). IC was determined using standard methods. 50 The results are shown in the following table.

[1089] [Table 55]

[1090]

[1091] [Table 56]

[1092]

Claims

1. A compound represented by the following general formula (1) or a salt thereof, [Chemistry 1] In formula (1), R 1 and R 2 Each independently represents a hydrogen atom, a halogen atom, a C 1-6 an alkyl group, or an aromatic heterocyclic group which may have a substituent and has 1 or 2 or more hetero atoms constituting the ring, R 1 and R 2 When both represent alkyl groups, they may be bonded to each other to form a C group optionally having a substituent. 3-6 Alkylene, R 3 and R 4 Each independently represents a hydrogen atom, a halogen atom or a C 1-6 alkyl, L 1 Indicates -CO-, -SO2- or -CO-C(R 5 )(R 6 )-, R 5 and R 6 Each independently represents a hydrogen atom or a C 1-6 Alkyl, R 5 and R 6 When both represent alkyl groups, they may be bonded to each other to form a C 2-5 Alkylene, X represents a cyclic hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent and has 1 or 2 or more hetero atoms constituting the ring, L 2 Indicates -A 1 -R 7 -A 2 -, A 1 represents a single bond, -CO-, -NH- or -O-, R 7 Represents a single bond or C 1-6 Alkylene, A 2 represents a single bond, -CO-, -NH- or -O-, Y represents a hydrogen atom, a cyclic hydrocarbon group which may have a substituent, or a heterocyclic group which may have a substituent and has 1 or 2 or more hetero atoms constituting the ring.

2. The compound or salt thereof according to claim 1, wherein R 1 and R 2 are independently a hydrogen atom, a fluorine atom, a C 1-6 an alkyl group (the alkyl group may be substituted with 1 or 2 or more halogen atoms) or an aromatic heterocyclic group having 1 or 2 or more hetero atoms constituting the ring and optionally having a substituent, R 1 and R 2 When both represent alkyl groups, they may bond to each other to form a C 3-5 Alkylene, R 3 and R 4 are each independently a hydrogen atom, a fluorine atom, a chlorine atom or a C 1-6 an alkyl group, which may be substituted by 1 or 2 or more fluorine atoms, L 1 is -CO-, -SO2- or -CO-C(R 5 )(R 6 )-, R 5 and R 6 are each independently a hydrogen atom or a C 1-6 Alkyl, R 5 and R 6 When both represent alkyl groups, they may be bonded to each other to form C 3-5 Alkylene, X is an aromatic hydrocarbon group which may have a substituent, a saturated or partially saturated cyclic hydrocarbon group which may have a substituent, an aromatic heterocyclic group which may have a substituent and has 1 or 2 or more hetero atoms constituting the ring, or a saturated or partially saturated heterocyclic group which may have a substituent and has 1 or 2 or more hetero atoms constituting the ring, L 2 Indicates -A 1 -R 7 -A 2 -Medium, A 1 , R 7 and A 2 All are single bonds, or A 1 is a single bond, R 7 is -CO-, -NH- or -O-, and A 2 is a single bond or C 1-6 Alkylene, or A 1 C 1-6 Alkylene, R 7 is -CO-, -NH- or -O-, and A 2 is a single bond, Y is a hydrogen atom, an aromatic hydrocarbon group optionally having a substituent, a saturated or partially saturated cyclic hydrocarbon group optionally having a substituent, an aromatic heterocyclic group optionally having a substituent and having 1 or 2 or more hetero atoms constituting the ring, or a saturated or partially saturated heterocyclic group optionally having a substituent and having 1 or 2 or more hetero atoms constituting the ring.

3. The compound or salt thereof according to claim 1, wherein R 1 For hydrogen atoms, fluorine atoms, C 1-6 an alkyl group, which may be substituted by 1 or 2 or more fluorine atoms, R 2 is a fluorine atom, C 1-6 an alkyl group (the alkyl group may be substituted with 1 or 2 or more halogen atoms) or an aromatic heterocyclic group having 1 or 2 or more hetero atoms constituting the ring and optionally having a substituent, R 1 and R 2 When both represent alkyl groups, they may be bonded to each other to form C 3-5 Alkylene, R 3 and R 4 are each independently a hydrogen atom, a fluorine atom, a chlorine atom or a C 1-6 an alkyl group, which may be substituted by 1 or 2 or more fluorine atoms, L 1 is -CO-, -SO2- or -CO-C(R 5 )(R 6 )-,R 5 and R 6 are independently a hydrogen atom or a C 1-6 Alkyl groups can be bonded to each other to form C 3-4 Alkylene, X is a monocyclic or bicyclic aromatic hydrocarbon group which may have a substituent, a monocyclic or bicyclic saturated or partially saturated cyclic hydrocarbon group which may have a substituent, a monocyclic or bicyclic aromatic heterocyclic group which may have a substituent and has 1 or 2 or more hetero atoms constituting the ring, or a monocyclic or bicyclic saturated or partially saturated heterocyclic group which may have a substituent and has 1 or 2 or more hetero atoms constituting the ring, L 2 Indicates -A 1 -R 7 -A 2 -Medium, A 1 , R 7 and A 2 All are single bonds, or A 1 is a single bond, R 7 is -CO-, -NH- or -O-, and A 2 is a single bond or C 1-4 Alkylene, or A 1 C 1-4 Alkylene, R 7 is -CO-, -NH- or -O-, and A 2 is a single bond, Y is a hydrogen atom, a monocyclic or bicyclic aromatic hydrocarbon group which may have a substituent, a monocyclic or bicyclic saturated or partially saturated cyclic hydrocarbon group which may have a substituent, a monocyclic or bicyclic aromatic heterocyclic group which may have a substituent and has 1 or 2 or more hetero atoms constituting the ring, or a monocyclic or bicyclic saturated or partially saturated heterocyclic group which may have a substituent and has 1 or 2 or more hetero atoms constituting the ring.

4. The compound or salt thereof according to claim 1, wherein R 1 For hydrogen atoms, fluorine atoms, C 1-6 an alkyl group, which may be substituted by 1 or 2 or more fluorine atoms, R 2 is a fluorine atom or C 1-6 an alkyl group (the alkyl group may be substituted with 1 or 2 or more fluorine atoms), or a monocyclic aromatic heterocyclic group containing 1 or 2 or more nitrogen atoms constituting the ring and optionally having a substituent, R 3 and R 4 are each independently a hydrogen atom, a fluorine atom, a chlorine atom or a C 1-6 an alkyl group, which may be substituted by 1 or 2 or more fluorine atoms, L 1 is -CO- or -SO2-, X is a phenyl group which may have a substituent, a naphthyl group which may have a substituent, a monocyclic or bicyclic 3- to 12-membered saturated or partially saturated cyclic hydrocarbon group which may have a substituent, a monocyclic or bicyclic aromatic heterocyclic group which may have a substituent and contains 1 or 2 or more nitrogen atoms constituting the ring, or a monocyclic or bicyclic saturated or partially saturated heterocyclic group which may have a substituent and contains 1 or 2 or more nitrogen atoms constituting the ring, L 2 Indicates -A 1 -R 7 -A 2 -Medium, A 1 , R 7 and A 2 All are single bonds, or A 1 is a single bond, R 7 is -O-, and A 2 is a single bond or C 1-4 Alkylene, or A 1 C 1-4 Alkylene, R 7 is -O-, and A 2 is a single bond, Y is a hydrogen atom, a monocyclic or bicyclic aromatic hydrocarbon group which may have a substituent, a monocyclic or bicyclic 3- to 12-membered saturated or partially saturated cyclic hydrocarbon group which may have a substituent, a monocyclic or bicyclic aromatic heterocyclic group which may have a substituent and contains 1 or more nitrogen atoms constituting the ring, or a monocyclic or bicyclic saturated or partially saturated heterocyclic group which may have a substituent and contains 1 or more nitrogen atoms constituting the ring.

5. The compound or salt thereof according to claim 1, wherein R 1 is a hydrogen atom, a fluorine atom, a methyl group, R 2 is a hydrogen atom, a fluorine atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a 1-methyl-1-methoxyethyl group, a cyclopropyl group, a cyclopentyl group, a tert-butyl group, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a pyridyl group, a pyridazinyl group or a pyrazinyl group, wherein the pyridyl group, the pyridazinyl group or the pyrazinyl group may be selected from the following group: C 1-6 Alkyl, C 1-6 Alkoxy, halogen atom, C substituted with 1 or 2 or more fluorine atoms 1-6 Alkyl, C substituted by 1 or 2 or more fluorine atoms 1-6 1 or more substituents in alkoxy and cyano), R 3 and R 4 are each independently a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a 1-methyl-1-methoxyethyl group, a cyclopropyl group, a cyclopentyl group, a tert-butyl group, a fluoromethyl group, a difluoromethyl group or a trifluoromethyl group, L 1 For -CO-, X is a phenyl group which may have a substituent, a naphthyl group which may have a substituent, a monocyclic saturated hydrocarbon group which may have a substituent, a monocyclic aromatic heterocyclic group which may have a substituent and contains one or more nitrogen atoms constituting the ring, or a monocyclic saturated or partially saturated heterocyclic group which may have a substituent and contains one or more nitrogen atoms constituting the ring, L 2 Indicates -A 1 -R 7 -A 2 -Medium, A 1 , R 7 and A 2 All are single bonds, or A 1 is a single bond, R 7 is -O-, and A 2 is a single bond, a methylene group or an ethylene group, or A 1 is methylene or ethylene, R 7 is -O-, and A 2 is a single bond, Y is a hydrogen atom, a monocyclic or bicyclic aromatic hydrocarbon group which may have a substituent, a saturated monocyclic 3- to 7-membered cyclic hydrocarbon group which may have a substituent, a monocyclic or bicyclic aromatic heterocyclic group which may have a substituent and contains one or more nitrogen atoms constituting the ring, or a saturated or partially saturated monocyclic or bicyclic heterocyclic group which may have a substituent and contains one or more nitrogen atoms constituting the ring.

6. The compound or salt thereof according to claim 1, wherein R 1 is a hydrogen atom or a fluorine atom, R 2 is a hydrogen atom, a fluorine atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a 1-methyl-1-methoxyethyl group, a cyclopropyl group, a cyclopentyl group, a tert-butyl group, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a 2-pyridyl group, a 3-pyridyl group, a 4-pyridyl group, a 3-pyridazinyl group, a 4-pyridazinyl group or a 2-pyrazinyl group (wherein the above-mentioned 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 3-pyridazinyl group, 4-pyridazinyl group or 2-pyrazinyl group may be selected from the following group: C 1-6 Alkyl, C 1-6 Alkoxy, halogen atom, C substituted with 1 or 2 or more fluorine atoms 1-6 Alkyl, C substituted by 1 or 2 or more fluorine atoms 1-6 1 or more substituents in alkoxy and cyano), R 3 is a hydrogen atom or a fluorine atom, R 4 is a fluorine atom, a chlorine atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a 1-methyl-1-methoxyethyl group, a cyclopropyl group, a cyclopentyl group, a tert-butyl group, a fluoromethyl group, a difluoromethyl group or a trifluoromethyl group, L 1 For -CO-, X is a monocyclic saturated hydrocarbon group which may have a substituent or a monocyclic saturated or partially saturated heterocyclic group which may have a substituent and contains 1 or 2 or more nitrogen atoms constituting the ring, L 2 is a single bond, -O-, -CH2-O- or -O-CH2-, Y is a hydrogen atom, a phenyl group which may have a substituent, a naphthyl group which may have a substituent, or a monocyclic or bicyclic aromatic heterocyclic group which may have a substituent and contains one or more nitrogen atoms constituting the ring.

7. The compound or salt thereof according to claim 1, wherein R 1 is a hydrogen atom or a fluorine atom, R 2 is a fluorine atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a 1-methyl-1-methoxyethyl group, a cyclopropyl group, a cyclopentyl group, a tert-butyl group, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a 2-pyridyl group, a 3-pyridyl group, a 4-pyridyl group, a 3-pyridazinyl group, a 4-pyridazinyl group or a 2-pyrazinyl group, wherein the 2-pyridyl group, the 3-pyridyl group, the 4-pyridyl group, the 3-pyridazinyl group, the 4-pyridazinyl group or the 2-pyrazinyl group may have one or more substituents selected from the group consisting of a methyl group, an ethyl group, a methoxy group, an ethoxy group, a fluorine atom, a chlorine atom, a difluoromethyl group, a trifluoromethyl group, a difluoromethoxy group, a trifluoromethoxy group and a cyano group), R 3 is a fluorine atom, R 4 is methyl, ethyl, propyl, isopropyl, 1-methyl-1-methoxyethyl, cyclopropyl, cyclopentyl, tert-butyl, fluoromethyl, difluoromethyl or trifluoromethyl, L 1 For -CO-, X is a monocyclic saturated hydrocarbon group which may have a substituent or a monocyclic saturated heterocyclic group which may have a substituent and contains 1 or 2 or more nitrogen atoms constituting the ring, L 2 is a single bond, -O- or -O-CH2-, Y is a hydrogen atom, a phenyl group which may have a substituent, a naphthyl group which may have a substituent, a pyridyl group which may have a substituent, or a quinolyl group which may have a substituent.

8. The compound or salt thereof according to claim 1, wherein R 1 is a hydrogen atom or a fluorine atom, R 2 is methyl, ethyl, propyl, isopropyl, 1-methyl-1-methoxyethyl, cyclopropyl, cyclopentyl, tert-butyl, fluoromethyl, difluoromethyl or trifluoromethyl, R 3 is a fluorine atom, R 4 is trifluoromethyl, L 1 For -CO-, X is a 4- to 6-membered saturated hydrocarbon group which may have a substituent or a 4- to 6-membered saturated heterocyclic group which may have a substituent and contains one nitrogen atom constituting the ring, L 2 is a single bond, -O- or -O-CH2-, Y is a hydrogen atom, a phenyl group which may have a substituent, a naphthyl group which may have a substituent, a pyridyl group which may have a substituent, or a quinolyl group which may have a substituent.

9. The compound or salt thereof according to claim 1, wherein R 1 is a hydrogen atom or a fluorine atom, R 2 is methyl, ethyl, propyl, isopropyl, 1-methyl-1-methoxyethyl, cyclopropyl, cyclopentyl, tert-butyl, fluoromethyl, difluoromethyl or trifluoromethyl, R 3 is a fluorine atom, R 4 is trifluoromethyl, L 1 For -CO-, X is cyclobutanediyl, cyclopentanediyl, cyclohexanediyl, azetidinediyl, pyrrolidinediyl or piperidinediyl, L 2 is a single bond or -O-CH2-, Y is a hydrogen atom, a phenyl group, a naphthyl group, a pyridyl group or a quinolyl group, wherein the phenyl group, the naphthyl group, the pyridyl group or the quinolyl group may be selected from the following group: 1-6 Alkyl, C 1-6 Alkoxy, halogen atom, C substituted with 1 or 2 or more fluorine atoms 1-6 Alkyl, C substituted by 1 or 2 or more fluorine atoms 1-6 One or more substituents in the alkoxy group and the cyano group.

10. The compound or salt thereof according to claim 1, wherein R 1 is a hydrogen atom or a fluorine atom, R 2 is methyl, ethyl, propyl, isopropyl, 1-methyl-1-methoxyethyl, cyclopropyl, cyclopentyl, tert-butyl, fluoromethyl, difluoromethyl or trifluoromethyl, R 3 is a fluorine atom, R 4 is trifluoromethyl, L 1 For -CO-, X is 1,3-cyclobutanediyl, 1,4-cyclohexanediyl, 1,3-azetidinediyl or 1,4-piperidinediyl, L 2 is a single bond or -O-CH2-, Y is a hydrogen atom, a phenyl group, a naphthyl group, a pyridyl group or a quinolyl group, wherein the phenyl group, the naphthyl group, the pyridyl group or the quinolyl group optionally has one or more substituents selected from the following group: a methyl group, an ethyl group, a methoxy group, an ethoxy group, a fluorine atom, a chlorine atom, a difluoromethyl group, a trifluoromethyl group, a difluoromethoxy group, a trifluoromethoxy group and a cyano group.

11. An mPGES-1 inhibitor comprising the compound represented by the general formula (I) according to claim 1 or a salt thereof.

12. A PGE2 biosynthesis inhibitor comprising the compound represented by the general formula (I) according to claim 1 or a salt thereof.

13. A medicine comprising the compound represented by the general formula (I) as claimed in claim 1 or a physiologically acceptable salt thereof as an active ingredient.

14. A drug comprising a compound represented by the general formula (I) according to claim 1 or a physiologically acceptable salt thereof as an active ingredient, for preventing and / or treating inflammation, pain, rheumatism, osteoarthritis, fever, Alzheimer's disease, multiple sclerosis, arteriosclerosis, ocular hypertension, ischemic retinal disease, systemic sclerosis, malignant tumors, overactive bladder, urinary dysfunction associated with prostatic hypertrophy, nocturnal urinary frequency, urinary incontinence, neurogenic bladder, interstitial cystitis, bladder pain syndrome, urinary tract stones, prostatic hypertrophy or diseases in which inhibition of PGE2 production is effective.

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