Benzimidazolone cinnamamide derivatives as TRPV1 antagonists and pharmaceutical compositions containing the same as active ingredients for treating or preventing pain

Abstract

The present invention relates to a benzimidazolone cinnamamide derivative as a TRPV1 antagonist and a pharmaceutical composition for treating or preventing pain comprising the same as an active ingredient. The embodiment compound provided in one aspect of the present invention blocks the activation of TRPV1 caused by capsaicin, a TRPV1 receptor activator, but induces appropriate inhibition at a pH of about 20% to 80%, so that the compound has the effect of alleviating pain and effectively reducing side effects such as abnormal body temperature.

Description

Background Art

[0001] Field of the Invention

[0002] The present invention relates to a benzimidazolone cinnamic amide derivative as a TRPV1 antagonist and a pharmaceutical composition containing the same as an active ingredient for treating or preventing pain.

[0003] Description of Related Technology

[0004] Transient receptor potential vanilloid 1 (TRPV1) is one of the subfamily of TRP (transient receptor potential) channels (a cation channel protein found in various tissues of animals), and is a non-selective cation channel expressed mainly in primary sensory neurons. In addition, TRPV1 plays an important role in pain transmission as a pain receptor and pain sensor involved in transduction, the first step of the pain pathway (the process of receiving pain). TRPV1 also maintains the inflammatory state that occurs after tissue damage caused by trauma, infection, surgery, burns, and disease, and is involved in inflammatory temperature hypersensitivity.

[0005] In other words, TRPV1 is the "pain pathway" that recognizes and transmits pain in the human body, and by inhibiting TRPV1 function, it can selectively block inappropriate pain sensations while maintaining normal sensations. Therefore, TRPV1 has attracted much attention as a target for the development of analgesics.

[0006] Research on the development of analgesics targeting TRPV1 is mainly divided into two mechanisms: agonists and antagonists. For agonists, like ligands, they bind to receptors and deliver pain, and show analgesic effects through desensitization after the threshold. Therefore, agonists have side effects such as initial pain, burning pain, and discomfort, so they are only developed as transdermal analgesics. In contrast, TRPV1 antagonists competitively bind to TRPV1 receptors with ligands and inhibit pain transmission itself through TRPV1. Therefore, TRPV1 antagonists have no side effects such as agonist-induced burning sensation and initial pain, and there is no strong stimulation, so they can be developed as oral preparations.

[0007] Specifically, TRPV1 antagonists have attracted attention as targets for the development of novel non-opioid analgesics that can be applied to neuropathic pain, inflammatory pain, and cancer pain, which require the development of specialized therapeutic agents due to low efficacy and side effects. In fact, many multinational pharmaceutical companies, including Abbott and Amgen, have developed TRPV1 antagonists. As a result of evaluating the efficacy of low-molecular TRPV1 antagonists in nonclinical animal experiments, the efficacy of TRPV1 antagonists showing selective and strong antagonistic effects was confirmed.

[0008] However, it has been reported that the first-generation TRPV1 antagonist ABT-102 is a strong TRPV1 antagonist that has been shown to increase body temperature in rodents for more than 2 days. For AMG 517 developed by Amgen, it shows excellent analgesic effects as an antagonist, but it is known that in clinical trials, the body temperature of subjects rose to 40.2°C and lasted for 1-5 days, resulting in very fatal side effects. In addition, some TRPV1 antagonists, including Amgen's AMG7905 and AMG8562, have been confirmed to cause hypothermia even in the absence of partial agonism. Therefore, in the development of TRPV1 antagonists, the resolution of abnormal body temperature is an important issue.

[0009] The side effect of increasing body temperature of most first-generation TRPV1 antagonists developed so far is believed to be due to antagonism of all activators of TRPV1 receptors (capsaicin, heat, pH, NADA, etc.). In particular, when ingested, capsaicin, one of the alkaloids, stimulates TRPV1 (one of the receptor activation channels) and does not actually increase temperature, but induces high fever.

[0010] In addition, it has been reported that blocking 100% of pH in TRPV1 receptor agonists causes an increase in body temperature, and blocking 20% ​​or less causes activation of high concentrations of protons, leading to a decrease in body temperature. That is, in the development of TRPV1 antagonists, when blocking TRPV1 activation caused by capsaicin and heat, the most important task is to overcome the abnormal body temperature phenomenon by obtaining a selective key strategy of moderate inhibition of pH (20%-80%).

[0011] Referring to the prior art, Patent Document 1 (WO 2011 / 120604A1) discloses a TRPV1 antagonist compound and a pharmaceutical composition comprising the same as an active ingredient, the compound inhibiting the vanilloid receptor TRPV1, thereby relieving pain and treating diseases such as dry eye.

[0012] On the other hand, the compound of the present invention inhibits the activation of TRPV1 caused by capsaicin, but exhibits a TRPV1 inhibitory activity of 20% to 80% relative to pH, thereby having an analgesic effect, having no side effect of body temperature change, and having an excellent absorption rate in the body. Therefore, the compound of the present invention has the following differences from the content of the above-mentioned Patent Document 1 (WO 2011 / 120604A1).

[0013] First, in the compound of the present invention, the A segment is a 4-amino-1,3-dihydro-2H-benzo[d]imidazol-2-one derivative, the B segment (linking portion) is acrylamide, propionamide or cyclopropane-1-carboxamide, and the C segment is phenyl, pyridine, pyrazole or thiazole. On the other hand, in the compound disclosed in Patent Document 1 (WO 2011 / 120604A1), the A segment is generally a benzoheterocyclic olefin, the B segment is urea or amide, and other substituents including the C segment are different. Therefore, the compound has a chemical structure different from that of the compound of the present invention as a whole.

[0014] In addition, the compounds of the present invention block the activation of TRPV1 caused by capsaicin and heat, but show a TRPV1 inhibitory activity of 20%-80% relative to pH, so an analgesic having an analgesic effect but no abnormal body temperature effect and excellent absorption rate in the body can be prepared. On the other hand, the above-mentioned patent document 1 (WO2011 / 120604A1) only discloses the inhibitory effect on the activation of TRPV1 caused by capsaicin in the experimental examples, but does not disclose the TRPV1 inhibitory activity in a specific pH range, the side effects of body temperature changes, and the absorption rate of the compound. Therefore, there is a difference between the compounds of the present invention and the compounds of patent document 1 in terms of the effectiveness of the invention.

[0015] That is, the compound of the present invention inhibits the activation of TRPV1 caused by capsaicin, but exhibits a TRPV1 inhibitory activity of 20%-80% relative to pH, so it has an analgesic effect, has no side effect of body temperature change, and has an excellent in vivo absorption rate. Therefore, the inventors have completed the present invention by demonstrating that the compound can be effectively used as an analgesic. Summary of the invention

[0016] An object of the present invention is to provide a benzimidazolone-based cinnamamide derivative compound that blocks TRPV1 activation caused by capsaicin (an activator of TRPV1 receptor) but induces an appropriate inhibition of pH by 20% to 80% to relieve pain and effectively reduce side effects such as abnormal body temperature.

[0017] Another object of the present invention is to provide a pharmaceutical composition for preventing or treating pain, comprising the above compound as an active ingredient.

[0018] Another object of the present invention is to provide a method for treating pain, which comprises the step of administering the above compound to a subject in need thereof.

[0019] Another object of the present invention is to provide the above compound for use in preventing or treating pain.

[0020] Another object of the present invention is to provide a use of the above compound in preparing a medicament for preventing or treating pain.

[0021] To achieve the above object, in one aspect of the present invention, the present invention provides a compound represented by Formula 1 as described herein, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

[0022] In another aspect of the present invention, the present invention provides a pharmaceutical composition for preventing or treating pain, comprising the above compound as an active ingredient.

[0023] In another aspect of the present invention, the present invention provides a method for treating pain, comprising the step of administering the above compound to a subject in need thereof.

[0024] In another aspect of the present invention, the present invention provides the above compound for use in preventing or treating pain.

[0025] In another aspect of the present invention, the present invention provides a use of the above compound in preparing a medicament for preventing or treating pain.

[0026] Beneficial Effects

[0027] The example compounds provided in one aspect of the present invention block TRPV1 activation caused by capsaicin (TRPV1 receptor activator) but induce a moderate inhibition of pH of about 20% to 80%, and therefore, the compounds have the effects of alleviating pain and effectively reducing side effects such as abnormal body temperature. DETAILED DESCRIPTION

[0028] Hereinafter, the present invention is described in detail.

[0029] The embodiments of the present invention may be modified in various other forms, and the scope of the present invention is not limited to the embodiments described below. It should be understood by those skilled in the art that the embodiments of the present invention are given to explain the present invention more accurately.

[0030] In addition, unless particularly stated otherwise, an element “comprising” throughout the specification does not exclude other elements but may include other elements.

[0031] In one aspect of the present invention, the present invention provides a compound represented by the following Formula 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

[0032] [Formula 1]

[0033]

[0034] In the above formula 1,

[0035] X 1 and X 2 are independently hydrogen, or

[0036] by bonding to the carbon atoms to which they are attached to form a C=C double bond, or

[0037] By connecting to the carbon atoms to which they are attached, they form a 3-6 membered cycloalkylene group; and

[0038] is an unsubstituted or substituted 5-10 membered heteroaryl group containing at least one heteroatom selected from N, O and S, or an unsubstituted or substituted C 6-10 Aryl,

[0039] wherein the substituted 5-10 membered heteroaryl and C 6-10 Aryl is independently a 5-10 membered heteroaryl group substituted with at least one substituent selected from 6-10 Aryl: unsubstituted or substituted by at least one halogen or hydroxyl group C 1-12 Straight or branched alkyl, C 1-12 Straight-chain or branched alkynyl, unsubstituted or substituted with at least one C 1-5 Straight-chain or branched alkyl substituted C 3-10 Cycloalkyl, unsubstituted or substituted with at least one C containing at least one heteroatom selected from N and O 1-5 5-8 membered heterocycloalkyl substituted with straight or branched alkyl, -NR 1 R 2 、-OR 3 、-SR 4 , unsubstituted or substituted by at least one halogen or C 1-5 Straight-chain or branched alkyl substituted C 6-10 aryl, and a 5-8 membered heteroaryl containing at least one heteroatom selected from N, O and S, R 1 and R 2 Independently for C 1-10 Straight or branched alkyl group,

[0040] R 3 is unsubstituted or substituted by at least one halogen 1-10 Straight or branched alkyl, C 3-10 Cycloalkyl, or unsubstituted or substituted by at least one methyl group C 3-10 Cycloalkyl C 1-5 Straight or branched alkyl group,

[0041] R 4 is unsubstituted or substituted by at least one halogen 1-10 Straight or branched alkyl, C 3-10 Cycloalkyl, or unsubstituted or substituted by at least one methyl group C 3-10 Cycloalkyl C 1-5 Straight chain or branched chain alkyl.

[0042] On the other hand,

[0043] X 1 and X 2 are independently hydrogen, or

[0044] by bonding to the carbon atoms to which they are attached to form a C=C double bond, or

[0045] By connecting to the carbon atoms to which they are attached, they form a 3-5 membered cycloalkylene group; and

[0046] is an unsubstituted or substituted 5-8 membered heteroaryl group containing at least one heteroatom selected from N, O and S, or an unsubstituted or substituted C 6-8 Aryl,

[0047] wherein the substituted 5-8 membered heteroaryl and C 6-8 Aryl is independently a 5-8 membered heteroaryl group substituted with at least one substituent selected from 6-8 Aryl: unsubstituted or substituted by at least one halogen or hydroxyl group C 1-10 Straight or branched alkyl, C 1-10 Straight-chain or branched alkynyl, unsubstituted or substituted with at least one C 1-5 Straight-chain or branched alkyl substituted C 3-8 Cycloalkyl, unsubstituted or substituted with at least one C containing at least one heteroatom selected from N and O 1-5 5-6 membered heterocycloalkyl substituted with straight or branched alkyl, -NR 1 R 2 、-OR 3 、-SR 4 , unsubstituted or substituted by at least one halogen or C 1-5 Straight-chain or branched alkyl substituted C 6-8 aryl and a 5-6 membered heteroaryl containing at least one heteroatom selected from N, O and S, R 1 and R 2 Independently for C 1-8 Straight or branched alkyl group,

[0048] R 3 is unsubstituted or substituted by at least one halogen 1-8 Straight or branched alkyl, C 3-8 Cycloalkyl, or unsubstituted or substituted by at least one methyl group C 3-8 Cycloalkyl C 1-5 Straight or branched alkyl group,

[0049] R 4 is unsubstituted or substituted by at least one halogen 1-8 Straight or branched alkyl, C 3-8Cycloalkyl, or unsubstituted or substituted by at least one methyl group C 3-8 Cycloalkyl C 1-5 Straight chain or branched chain alkyl.

[0050] On the other hand,

[0051] X 1 and X 2 are independently hydrogen, or

[0052] by bonding to the carbon atoms to which they are attached to form a C=C double bond, or

[0053] By connecting to the carbon atoms to which they are attached, they form a 3-4 membered cycloalkylene group; and

[0054] is an unsubstituted or substituted 5-6 membered heteroaryl group containing at least one heteroatom selected from N and S, or an unsubstituted or substituted C6 aryl group,

[0055] wherein the substituted 5-6 membered heteroaryl and C6 aryl are independently substituted by at least one substituent selected from the group consisting of: unsubstituted or C6 substituted by at least one halogen or hydroxyl group; 1-7 Straight or branched alkyl, C 1-7 Straight-chain or branched alkynyl, unsubstituted or substituted with at least one C 1-5 Straight-chain or branched alkyl substituted C 3-6 Cycloalkyl, unsubstituted or substituted with at least one C containing at least one heteroatom selected from N and O 1-5 5-6 membered heterocyclic alkyl substituted with straight chain or branched chain alkyl, NR 1 R 2 、-OR 3 、-SR 4 , unsubstituted or substituted by at least one halogen or C 1-5 a C6 aryl group substituted with a straight or branched alkyl group and a 5-membered heteroaryl group containing at least one heteroatom selected from N, O and S,

[0056] R 1 and R 2 Independently for C 1-5 Straight or branched alkyl group,

[0057] R 3 is unsubstituted or substituted by at least one halogen 1-7 Straight or branched alkyl, C 3-6 Cycloalkyl, or unsubstituted or substituted by at least one methyl group C 3-6 Cycloalkyl C 1-5 Straight or branched alkyl group,

[0058] R 4is unsubstituted or substituted by at least one halogen 1-7 Straight or branched alkyl, C 3-6 Cycloalkyl, or unsubstituted or substituted by at least one methyl group C 3-6 Cycloalkyl C 1-5 Straight chain or branched chain alkyl.

[0059] On the other hand,

[0060] X 1 and X 2 are independently hydrogen, or

[0061] by bonding to the carbon atoms to which they are attached to form a C=C double bond, or

[0062] Forming cyclocyclopropylene by linking to the carbon atom to which they are attached; and

[0063] yes

[0064]

[0065] The compound represented by Formula 1 may be any one compound selected from the following compounds.

[0066] (1) (E)-3-(2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide;

[0067] (2) (E)-3-(2-(4-ethylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide;

[0068] (3) (E)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-3-(2-(pyrrolidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)acrylamide;

[0069] (4) (E)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-3-(2-(piperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)acrylamide;

[0070] (5) (E)-3-(2-morpholino-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide;

[0071] (6) (E)-3-(2-(diethylamino)-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide;

[0072] (7) (E)-3-(2-(dipropylamino)-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide;

[0073] (8) (E)-3-(2-butoxy-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide;

[0074] (9) (E)-3-(2-(hexyloxy)-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide;

[0075] (10) (E)-3-(2-isobutoxy-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide;

[0076] (11) (E)-3-(2-cyclobutyloxy-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide;

[0077] (12) (E)-3-(2-(cyclopentyloxy)-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide;

[0078] (13) (E)-3-(2-(cyclopropylmethoxy)-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide;

[0079] (14) (E)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-3-(2-(2,2,2-trifluoroethoxy)-6-(trifluoromethyl)pyridin-3-yl)acrylamide;

[0080] (15) (E)-3-(2-(neopentyloxy)-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide;

[0081] (16) (E)-3-(2-((2-methylcyclopropyl)methoxy)-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide;

[0082] (17) (E)-3-(6-(chlorodifluoromethyl)-2-(cyclopropylmethoxy)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide;

[0083] (18) (E)-3-(6-cyclopropyl-2-(cyclopropylmethoxy)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide;

[0084] (19) (E)-3-(2-(cyclopropylmethoxy)-6-isopropylpyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide;

[0085] (20) (E)-3-(2-(cyclopropylmethoxy)-6-(1-methylcyclopropyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide;

[0086] (21) (E)-3-(2-(cyclopropylmethoxy)-6-(difluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide;

[0087] (22) (E)-3-(2-(cyclopropylmethoxy)-6-(1,1-difluoroethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide;

[0088] (23) (E)-3-(6-(tert-butyl)-2-(cyclopropylmethoxy)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide;

[0089] (24) (E)-3-(2-(cyclopropylmethoxy)-6-(2-hydroxypropan-2-yl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide;

[0090] (25) (E)-3-(2-(cyclobutylmethoxy)-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide;

[0091] (26) (E)-3-(2-(cyclopentylmethoxy)-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide;

[0092] (27) (E)-3-(2-(isobutylthio)-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide;

[0093] (28) (E)-3-(2-((cyclopropylmethyl)thio)-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide;

[0094] (29) (E)-3-(2-(cyclohexylthio)-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide;

[0095] (30) (E)-3-(2-(3-fluorophenyl)-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide;

[0096] (31) (E)-3-(2-(3-chlorophenyl)-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide;

[0097] (32) (E)-3-(2-(3-isopropylphenyl)-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide;

[0098] (33) (E)-3-(2-(3-chloro-4-fluorophenyl)-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide;

[0099] (34) (E)-3-(2-(4-fluorophenyl)-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide;

[0100] (35) (E)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-3-(2-(thiophen-2-yl)-6-(trifluoromethyl)pyridin-3-yl)acrylamide;

[0101] (36) (E)-3-(2-(furan-2-yl)-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide;

[0102] (37) (E)-3-(2-(oxazol-2-yl)-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide;

[0103] (38) (E)-3-(2-(oxazol-5-yl)-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide;

[0104] (39) (E)-3-(2-(3,3-dimethyl-1-butyn-1-yl)-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide;

[0105] (40) (E)-3-(2-(3,3-dimethylbutyl)-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide;

[0106] (41) (E)-3-(2-cyclopentyl-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide;

[0107] (42) (E)-3-(2-isobutoxy-4-(trifluoromethyl)phenyl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide;

[0108] (43) (E)-3-(2-(cyclopropylmethoxy)-4-(trifluoromethyl)phenyl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide;

[0109] (44) (E)-3-(2-(cyclopropylmethoxy)-4-(2-hydroxypropan-2-yl)phenyl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide;

[0110] (45) (E)-3-(4-(tert-butyl)-2-(cyclopropylmethoxy)phenyl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide;

[0111] (46) (E)-3-(4-cyclopropyl-2-(cyclopropylmethoxy)phenyl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide;

[0112] (47) (E)-3-(1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide;

[0113] (48) (E)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-3-(1-(m-tolyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)acrylamide;

[0114] (49) (E)-3-(1-(3-chloro-4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide;

[0115] (50) (E)-3-(1-(3-isopropylphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide;

[0116] (51) (E)-3-(1-(3-chlorophenyl)-3-isopropyl-1H-pyrazol-5-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide;

[0117] (52) (E)-3-(1-(3-chlorophenyl)-3-(1-methylcyclopropyl)-1H-pyrazol-5-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide;

[0118] (53) (E)-3-(3-(tert-butyl)-1-(3-chlorophenyl)-1H-pyrazol-5-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide;

[0119] (54) (E)-3-(4-(3-chlorophenyl)-2-(trifluoromethyl)thiazol-5-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide;

[0120] (55) (E)-3-(4-(3-chlorophenyl)-2-isopropylthiazol-5-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide;

[0121] (56) (E)-3-(4-(3-chlorophenyl)-2-cyclopropylthiazol-5-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide;

[0122] (57) (E)-3-(4-(3-chlorophenyl)-2-(1-methylcyclopropyl)thiazol-5-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide;

[0123] (58) (E)-3-(2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide;

[0124] (59) 3-(2-isobutoxy-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)propanamide;

[0125] (60) 3-(2-(cyclopropylmethoxy)-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)propaneimide;

[0126] (61) 2-(2-isobutoxy-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)cyclopropane-1-carboxamide;

[0127] (62) 2-(2-(cyclopropylmethoxy)-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)cyclopropane-1-carboxamide;

[0128] (63) 2-(1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)cyclopropane-1-carboxamide;

[0129] (64) 2-(1-(3-chlorophenyl)-3-(1,1-difluoroethyl)-1H-pyrazol-5-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)cyclopropane-1-carboxamide;

[0130] (65) 2-(1-(3-chlorophenyl)-3-isopropyl-1H-pyrazol-5-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)cyclopropane-1-carboxamide;

[0131] (66) 2-(1-(3-chlorophenyl)-3-cyclopropyl-1H-pyrazol-5-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)cyclopropane-1-carboxamide;

[0132] (67) 2-(1-(3-chlorophenyl)-3-(1-methylcyclopropyl)-1H-pyrazol-5-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)cyclopropane-1-carboxamide; and

[0133] (68) 2-(3-(tert-Butyl)-1-(3-chlorophenyl)-1H-pyrazol-5-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)cyclopropane-1-carboxamide.

[0134] On the other hand,

[0135] is an unsubstituted or substituted 5-6 membered heteroaryl group containing at least one heteroatom selected from N and S,

[0136] wherein the substituted 5-6 membered heteroaryl is a 5-6 membered heteroaryl substituted by two substituents selected from the group consisting of: unsubstituted or substituted by at least one halogen or hydroxyl group; 1-7 Straight or branched alkyl, C 1-7 Straight-chain or branched alkynyl, unsubstituted or substituted with at least one C 1-5 Straight-chain or branched alkyl substituted C 3-6 Cycloalkyl, unsubstituted or substituted with at least one C containing at least one heteroatom selected from N and O 1-5 5-6 membered heterocyclic alkyl substituted with straight chain or branched chain alkyl, NR 1 R 2 、-OR 3 、-SR 4 , unsubstituted or substituted by at least one halogen or C 1-5 a C6 aryl group substituted with a straight or branched alkyl group and a 5-membered heteroaryl group containing at least one heteroatom selected from N, O and S,

[0137] R 1 and R 2 Independently for C 1-5 Straight or branched alkyl group,

[0138] R 3 is unsubstituted or substituted by at least one halogen 1-7 Straight or branched alkyl, C 3-6 Cycloalkyl, or unsubstituted or substituted by at least one methyl group C 3-6 Cycloalkyl C 1-5 Straight or branched alkyl group,

[0139] R 4 is unsubstituted or substituted by at least one halogen 1-7 Straight or branched alkyl, C 3-6 Cycloalkyl, or unsubstituted or substituted by at least one methyl group C 3-6 Cycloalkyl C 1-5 Straight chain or branched chain alkyl.

[0140] On the other hand,

[0141] is unsubstituted or substituted pyridine,

[0142] Wherein the substituted pyridine is pyridine substituted by two substituents selected from the group consisting of: unsubstituted or substituted by at least one halogen or hydroxyl group; 1-7 Straight or branched alkyl, C 1-7 Straight-chain or branched alkynyl, unsubstituted or substituted with at least one C 1-5 Straight-chain or branched alkyl substituted C 3-6 Cycloalkyl, unsubstituted or substituted with at least one C containing at least one heteroatom selected from N and O 1-5 5-6 membered heterocyclic alkyl substituted with straight chain or branched chain alkyl, NR 1 R 2 、-OR 3 、-SR 4 , unsubstituted or substituted by at least one halogen or C 1-5 a C6 aryl group substituted with a straight or branched alkyl group and a 5-membered heteroaryl group containing at least one heteroatom selected from N, O and S,

[0143] R 1 and R 2 Independently for C 1-5 Straight or branched alkyl group,

[0144] R 3 is unsubstituted or substituted by at least one halogen 1-7 Straight or branched alkyl, C 3-6 Cycloalkyl, or unsubstituted or substituted by at least one methyl group C 3-6 Cycloalkyl C 1-5 Straight or branched alkyl group,

[0145] R 4 is unsubstituted or substituted by at least one halogen 1-7 Straight or branched alkyl, C 3-6 Cycloalkyl, or unsubstituted or substituted by at least one methyl group C 3-6 Cycloalkyl C 1-5 Straight chain or branched chain alkyl.

[0146] The compound represented by Formula 1 of the present invention can be used in the form of a pharmaceutically acceptable salt, wherein the salt is preferably an acid addition salt formed by a pharmaceutically acceptable free acid. The acid addition salt herein can be obtained from an inorganic acid such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid and phosphorous acid; non-toxic organic acids such as aliphatic mono / dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids and aliphatic / aromatic sulfonic acids; or organic acids such as trifluoroacetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid and fumaric acid. Pharmaceutically nontoxic salts are, for example, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, fluorides, acetates, propionates, decanoates, octanoates, acrylates, formates, isobutyrates, decanoates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, carbarates, fumarates, malates, butyne-1,4-dioic acid salt, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, and mandelate.

[0147] The acid addition salt according to the present invention can be prepared by conventional methods known to those skilled in the art. For example, the derivative shown in Formula 1 is dissolved in an organic solvent such as methanol, ethanol, acetone, dichloromethane and acetonitrile, and an organic acid or an inorganic acid is added thereto to induce precipitation. Then, the precipitate is filtered and dried to obtain a salt. Alternatively, the solvent and excess acid are distilled under reduced pressure and dried to obtain a salt. Alternatively, the precipitate is crystallized in an organic solvent to obtain.

[0148] Pharmaceutically acceptable metal salts can be prepared by using a base. Alkali metal or alkaline earth metal salts are obtained by the following method: dissolving the compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution; filtering the insoluble complex salt; evaporating the remaining solution and drying. In this case, the metal salt is preferably prepared in the form of a pharmaceutically suitable sodium, potassium or calcium salt. The corresponding salt is prepared by reacting an alkali metal or alkaline earth metal salt with an appropriate silver salt (e.g., silver nitrate).

[0149] Furthermore, the present invention includes not only the compound represented by Formula 1, but also pharmaceutically acceptable salts thereof, and solvates, optical isomers or hydrates that may be generated therefrom.

[0150] The term "hydrate" refers to a compound of the present invention or a salt thereof containing a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. The hydrate of the compound represented by Formula 1 of the present invention may contain a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. The hydrate may contain 1 equivalent or more of water, preferably 1-5 equivalents of water. The hydrate may be prepared by crystallizing the compound represented by Formula 1, its isomer, or a pharmaceutically acceptable salt thereof from water or an aqueous solvent.

[0151] The term "solvate" refers to a compound of the invention or a salt thereof containing a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Thus, preferred solvents include those that are volatile, non-toxic and / or suitable for human administration.

[0152] The term "isomer" refers to a compound of the present invention or a salt thereof having the same chemical formula or molecular formula but different in structure or space. Such isomers include structural isomers such as tautomers, R or S isomers with asymmetric carbon centers, stereoisomers such as geometric isomers (trans, cis) and optical isomers (enantiomers). All of these isomers and mixtures thereof are also included within the scope of the present invention.

[0153] In another aspect of the present invention, the present invention provides a pharmaceutical composition for preventing or treating pain, comprising a compound shown in Formula 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. At this time, the compound can exhibit preventive or therapeutic activity against pain by inhibiting TRPV1 (transient receptor potential vanilloid subtype 1) receptor activator. Preferably, the compound prevents or treats pain by inhibiting capsaicin, a TRPV1 (transient receptor potential vanilloid subtype 1) receptor activator, and suppresses the pH in the range of 20% to 80% to reduce side effects such as abnormal body temperature.

[0154] The compound represented by Formula 1 of the present invention or its pharmaceutically acceptable salt can be administered orally or parenterally, and can be used in the general form of pharmaceutical preparations. That is, the compound or its pharmaceutically acceptable salt can be prepared for oral or parenteral administration by mixing with commonly used diluents or excipients such as fillers, fillers, adhesives, wetting agents, disintegrants and surfactants. Solid preparations for oral administration are tablets, pills, powders, granules and capsules. These solid preparations are prepared by mixing one or more compounds with one or more suitable excipients such as starch, calcium carbonate, sucrose or lactose, gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate, talc, etc. can be used. Liquid preparations for oral administration are suspensions, solutions, emulsions and syrups, and the above-mentioned preparations can also contain various excipients such as wetting agents, sweeteners, aromatics and preservatives in addition to commonly used simple diluents such as water and liquid paraffin. Preparations for parenteral administration are sterile aqueous solutions, water-insoluble excipients, suspensions and emulsions. In addition to the active compound, water-insoluble excipients and suspensions may contain propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate, and the like.

[0155] The pharmaceutical composition comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient can be administered parenterally, and parenteral administration includes subcutaneous injection, intravenous injection, intramuscular injection or intrathoracic injection.

[0156] At this time, in order to prepare the compound shown in Formula 1 or its pharmaceutically acceptable salt as a preparation for parenteral administration, the compound shown in Formula 1 or its pharmaceutically acceptable salt is mixed with a stabilizer or a buffer in water to prepare a solution or suspension, which is then formulated into an ampoule or a vial. The composition herein may be sterile and additionally contain a preservative, a stabilizer, a wettable powder or an emulsifier, a salt for adjusting the osmotic pressure and / or a buffer and other therapeutically useful materials, and the composition may be formulated by conventional mixing, granulation or coating methods.

[0157] Examples of preparations for oral administration include tablets, pills, hard / soft capsules, solutions, suspensions, emulsions, syrups, granules, elixirs and lozenges. In addition to active ingredients, these preparations may also include diluents (e.g., lactose, glucose, sucrose, mannitol, sorbitol, cellulose and / or glycine) and lubricants (e.g., silicon dioxide, talc, stearates and their magnesium or calcium salts and / or polyethylene glycol). Tablets may include binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinyl pyrrolidone, and if necessary, may also include disintegrants such as starch, agarose, alginic acid or its sodium salt or azeotropic mixture and / or absorbents, colorants, flavors and sweeteners.

[0158] In another aspect of the present invention, the present invention provides an analgesic composition for treating or relieving pain, which contains a compound shown in Formula 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. At this time, the compound can exhibit activity in treating or relieving pain by inhibiting TRPV1 (transient receptor potential vanilloid subtype 1) receptor activators. Preferably, the compound treats or relieves pain by inhibiting capsaicin, a TRPV1 (transient receptor potential vanilloid subtype 1) receptor activator, and suppresses the pH in the range of 20% to 80% to reduce side effects such as abnormal body temperature.

[0159] At this time, the compound can show the activity of preventing or improving pain by inhibiting TRPV1 (transient receptor potential vanilloid subtype 1) receptor activator. Preferably, the compound prevents or improves pain by inhibiting capsaicin, a TRPV1 (transient receptor potential vanilloid subtype 1) receptor activator, and suppresses pH in the range of 20% to 80% to reduce side effects such as abnormal body temperature.

[0160] In addition to the above ingredients, the compound represented by Formula 1 according to the present invention may include various nutrients, vitamins, minerals (electrolytes), flavors (including natural flavors and synthetic flavors), colorants and fillers (cheese, chocolate, etc.), pectin acid and its salts, alginic acid and its salts, organic acids, protective colloid thickeners, pH regulators, stabilizers, preservatives, glycerol, alcohol, carbonates for adding to soda, etc. The compound represented by Formula 1 of the present invention may also include pulp that can be added to natural fruit juices, fruit drinks, and vegetable drinks.

[0161] In another aspect of the present invention, the present invention provides a drug kit for preventing or treating pain, comprising a first component and a second component, wherein the first component contains a compound represented by Formula 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof or a pharmaceutically acceptable salt thereof as an active ingredient; and the second component contains an analgesic as an active ingredient.

[0162] At this moment, analgesic can be used without restriction, as long as it is known analgesic.Analgesic can be anti-inflammatory analgesic (NSAID, such as COX inhibitor) or opioid analgesic.Some examples of analgesic can be acetaminophen, aspirin, ibuprofen, ketoprofen, meloxicam, diclofenac potassium, etodolac, sulindac, indomethacin, celecoxib, valdecoxib, rofecoxib, celecoxib, hydrocodone, oxymorphone, buprenorphine, fentanyl, hydromorphone, tramadol etc., or its combination.

[0163] In another aspect of the present invention, the present invention provides a method for treating pain, comprising the step of administering the above-mentioned compound to a subject in need thereof. In another aspect of the present invention, the present invention provides the above-mentioned compound for use in preventing or treating pain. In another aspect of the present invention, the present invention provides the use of the above-mentioned compound in the preparation of a medicament for preventing or treating pain.

[0164] The example compounds provided in one aspect of the present invention block the activation of TRPV1 caused by capsaicin, a TRPV1 receptor activator, but induce a moderate inhibition of pH of about 20% to 80%, and thus the compounds have the effects of alleviating pain and effectively reducing side effects such as abnormal body temperature. These are directly supported by the examples and experimental examples described below.

[0165] Hereinafter, the present invention will be described in detail through embodiments and experimental examples.

[0166] However, the following embodiments and experimental examples are only used to illustrate the present invention, and the contents of the present invention are not limited thereto.

[0167] synthesis

[0168] 1. Synthesis of compounds

[0169] 1-1. Synthesis of Region A

[0170] [Reaction Scheme 1] Synthesis of Region A (4-amino-1,3-dihydro-2H-benzo[d]imidazol-2-one derivative)

[0171]

[0172] Synthesis of 1-1-1.4-Nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0173]

[0174] 3-Nitrobenzene-1,2-diamine (1 equivalent) is dissolved in acetonitrile, triphosgene (1.2 equivalent) is added dropwise at 0°C for 3-5 minutes, and then stirred at room temperature for 30 minutes, preferably 1 hour. The reaction mixture is diluted by slowly adding water at 0°C, and when no more gas is generated and a dark yellow-green solid begins to form, the reaction mixture is stirred at room temperature for 30 minutes, preferably 1 hour. Then, the generated yellow-green solid is filtered and washed with water to obtain the target product 4-nitro-1,3-dihydro-2H-benzo[d]imidazole-2-one. (Yield: 80-89%)

[0175] 1-1-2. Synthesis of 4-amino-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0176]

[0177] The 4-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (1 equivalent) obtained in the above reaction is hydrogenated with a reducing agent (such as 10% palladium-activated carbon (Pd-C) dissolved in a lower alcohol such as methanol), filtered, and the filtrate is dried under reduced pressure. The reactant is purified by flash column chromatography filled with silica gel, using a mixed solvent of dichloromethane and methanol as an elution solvent to obtain the target compound 4-amino-1,3-dihydro-2H-benzo[d]imidazol-2-one. (Yield 80-85%)

[0178] 1-2. Synthesis of Region C

[0179] [Reaction 2] Synthesis of pyridine C-region

[0180]

[0181]

[0182] 1-2-1. Synthesis of R2-pyridine / phenyl

[0183]

[0184] [Method 1A] NR / OR

[0185] Pyridine or phenyl (wherein R1 is CF3 or C(CH3)3, Y is CN or Br, and Z is OH, Cl, F or SH) is used as a raw material and dissolved in THF or DMF, to which DBU (2 equivalents), NaH (2 equivalents) or K2CO3 (2 equivalents) are added at 0°C, and then stirred for 5 to 10 minutes. The corresponding NR, OR, haloalkyl and SR (2 equivalents) are dissolved in THF or DMF and added to the stirred mixture, which is then stirred at room temperature for 16 hours. The reaction is terminated by adding water, and the reactant is extracted with ethyl acetate or dichloromethane. The obtained organic layer is washed with brine, dried over magnesium sulfate, and then concentrated in vacuo. The obtained residue is purified by flash column chromatography filled with silica gel, using a mixed solvent of ethyl acetate, hexane or dichloromethane and methanol as an eluting solvent to obtain the target compound. (Yield: 85%-92%)

[0186] [Method 1B] CC

[0187] The raw material 2-chloro-6-(trifluoromethyl)nicotinonitrile (2-chloro-6-(trifluoromethyl)nicotinonitrile) (1 equivalent) was dissolved in toluene and stirred, and Na2CO3 (24 equivalents) dissolved in water was added thereto, followed by stirring for 5-10 minutes. Then, Pd(PPh3)4 (0.2 equivalents) was added. After the mixture was refluxed for 30 minutes or 3 hours, the reactor temperature was lowered to room temperature. The corresponding boronic acid (2 equivalents) was dissolved in toluene or 1,4-dioxane and added dropwise thereto, and the mixture was refluxed and stirred for 15 hours. After the reaction was completed, the temperature of the reactor was lowered to room temperature, and the reactants were filtered through a diatomaceous earth pad filter and concentrated under reduced pressure. The obtained mixture was dissolved in ethyl acetate, washed with brine and water, dried over magnesium sulfate, and concentrated in vacuo. The obtained residue was purified by flash column chromatography filled with silica gel, using ethyl acetate, hexane or a mixed solvent of dichloromethane and methanol as the eluting solvent to obtain the target compound. (Yield: 72%-85%)

[0188] [Method 1C] CC

[0189] The raw material 2-chloro-6-(trifluoromethyl)nicotinonitrile (2-chloro-6-(trifluoromethyl)nicotinonitrile) (1 equivalent) was dissolved in toluene and stirred, and the corresponding alkyne (2 equivalents), Pd(PPh3)4 (0.2 equivalents), copper (I) iodide (0.2 equivalents) and TEA (2 equivalents) were added thereto, and the mixture was refluxed and stirred for 15 hours. After the reaction was completed, the temperature of the reactor was lowered to room temperature, and the reactants were filtered through a diatomaceous earth pad filter and concentrated under reduced pressure. The obtained mixture was dissolved in EtOAc, washed with brine and water, dried over magnesium sulfate, and concentrated in vacuo. The obtained residue was purified by flash column chromatography filled with silica gel using a mixed solvent of ethyl acetate and hexane as an eluting solvent to obtain the target compound. (Yield: 65%-73%)

[0190] 1-2-2. Synthesis of pyridine / benzaldehyde

[0191]

[0192] The pyridine / benzonitrile (1 equivalent) obtained in the above reaction was dissolved in toluene and filled with nitrogen, and DIBAL-H (1M in toluene, 2 equivalents) was slowly added dropwise at -78°C, and then stirred at the same temperature for 2 hours. The reaction was terminated by adding NH4Cl aqueous solution, and the organic matter was extracted with EtOAc. The resulting mixture was washed with brine and water, dried over magnesium sulfate, and concentrated in vacuo. The resulting residue was purified by flash column chromatography filled with silica gel, using a mixed solvent of ethyl acetate and hexane as the eluting solvent to obtain the target compound. (Yield 61%-75%)

[0193] 1-2-3. Synthesis of E-methyl / ethyl acetate

[0194]

[0195] [Method 2A]

[0196] The aldehyde (1 equivalent) obtained in the above reaction was dissolved in toluene, and (triphenylphosphine) methyl acetate or (triphenylphosphine) ethyl acetate (2 equivalents) was added thereto, and then stirred at room temperature for 24 hours. After the reaction was completed, the toluene was removed by concentration under reduced pressure, and the obtained residue was purified by flash column chromatography filled with silica gel, using a mixed solvent of ethyl acetate and hexane as an elution solvent to obtain the target compound. (Yield: 50%-65%)

[0197] [Method 2B] Synthesis of (E)-methyl 3-(2-(cyclopropylmethoxy)-6-(2-hydroxypropan-2-yl)pyridin-3-yl)acrylate

[0198]

[0199] In the case of 2-(5-bromo-6-(cyclopropylmethoxy)pyridin-2-yl)propan-2-ol containing bromine in Y, 2-(5-bromo-6-(cyclopropylmethoxy)pyridin-2-yl)propan-2-ol (1 eq.) was dissolved in anhydrous DMF, methyl acrylate (4 eq.), P(o-tol)3 (0.3 eq.) and triethylamine (10 eq.) were added thereto, and then bubbled with inert gases (nitrogen and argon) for at least 5 minutes. The reaction mixture was stirred at room temperature for 10 to 30 minutes. Pd(OAc)2 (3 mol%) was added thereto, and then bubbled with inert gases (nitrogen and argon) for 5-10 minutes. The reaction mixture was then stirred at 100°C for 24 hours. After the reaction was complete, the temperature of the reactor was lowered to room temperature. The reactant was diluted with EtOAc, washed with water and brine, dried over magnesium sulfate, and concentrated in vacuo. The obtained residue was purified by flash column chromatography filled with silica gel using a mixed solvent of ethyl acetate and hexane as the elution solvent to obtain the target compound. (Yield: 65%)

[0200] 1-2-4. Synthesis of trifluoromethylpyridine cyclopropane-1-carboxylate

[0201]

[0202] Trimethylsulfoxide iodide (2 equivalents) is dissolved in DMSO, NaH (2 equivalents) is added thereto at 0°C, and then stirred at room temperature for 1-2 hours, preferably until a clear mixture is formed. The raw material pyridine acrylate (1 equivalent) obtained in the above reaction is dissolved in a small amount of DMSO, slowly added dropwise thereto, and the mixture is stirred at room temperature for 2-4 hours. The reaction is terminated by adding water, and the organic matter is extracted with ethyl acetate. The reaction mixture is washed with water and brine, and the obtained filtrate is dried over magnesium sulfate and concentrated in vacuo. The obtained residue is purified by flash column chromatography filled with silica gel, using ethyl acetate, hexane or a mixed solvent of dichloromethane and methanol as the eluting solvent to obtain the target compound. (Yield: 80%-90%)

[0203] 1-2-5. Synthesis of pyridine / phenyl acrylic acid and cyclopropanecarboxylic acid

[0204]

[0205] The pyridine or phenyl acrylate or pyridine cyclopropane carboxylate (1 equivalent) obtained in the above reaction is dissolved in THF, LiOH·H2O (2-3 equivalents) and the same amount of water are added, and then stirred at room temperature for 2-5 hours. After the reaction is completed, 1N HCl is added at 0°C to adjust the pH of the reactant to 2-3, the organic matter is extracted with EtOAc, washed with water and brine, and the obtained filtrate is dried over magnesium sulfate and concentrated in vacuo. The obtained residue is purified by flash column chromatography filled with silica gel, using ethyl acetate, hexane or a mixed solvent of dichloromethane and methanol as the elution solvent to obtain the target compound. (Yield: 85%-98%)

[0206] 1-3. Synthesis of raw materials in zone C

[0207] [Reaction 3]

[0208]

[0209] 1-3-1.2, Synthesis of 2-difluoropropionic anhydride

[0210]

[0211] 2,2-Difluoropropionic acid (1 equivalent) was dissolved in dichloromethane at -10°C with stirring, oxalyl chloride (1.2 equivalent) was added dropwise thereto, and the mixture was stirred at room temperature for 4 hours. The crude product was then used as a raw material for the next reaction.

[0212] Synthesis method of 1-3-2.4-ethoxydifluorobutenone

[0213]

[0214] The 2,2-difluoropropionic anhydride obtained in the above reaction of the raw material or the commercially available 2,2-difluoroacetic anhydride and 2-chloro-2,2-difluoroacetic anhydride (1 equivalent) are dissolved in chloroform, the temperature of the reactor is lowered to 0°C, and then stirred. Ethyl vinyl ether (1.3 equivalents) and pyridine (1.3 equivalents) are added to the reaction mixture, and then stirred at room temperature for 4 hours. 1N HCl is added to terminate the reaction, the organic matter is extracted with dichloromethane, washed with water and brine, and concentrated under reduced pressure at 30°C. The obtained residue is purified by flash column chromatography filled with silica gel, using a mixed solvent of ethyl acetate and hexane as the elution solvent to obtain the target compound. (Yield 89-95%)

[0215] Synthesis of 1-3-3.2-Hydroxynicotinonitrile

[0216]

[0217] 2-Cyanoacetamide (1 equivalent) was dissolved in ethanol, and an ethanol solution of 21% NaOEt (1.5 equivalents) was added dropwise thereto, and then stirred at room temperature for 10-20 minutes. After the temperature of the reactor was reduced to 0°C, the raw material (1 equivalent) obtained in the above reaction was added dropwise to the reaction mixture. The reactor temperature was raised and the reaction mixture was reacted under reflux for 5 hours. After the reaction was completed, the reactor temperature was reduced to room temperature, the reactant was acidified with 4N HCl, extracted with EtOAc, and washed with water and brine. The resulting mixture was dried over magnesium sulfate and concentrated in vacuo. The obtained residue was purified by flash column chromatography filled with silica gel, using a mixed solvent of ethyl acetate and hexane as an eluting solvent to obtain the target compound. (Yield: 60%-75%)

[0218] Synthesis of 1-3-4.2-Chloronicotinonitrile

[0219]

[0220] The raw material (1 equivalent) obtained in the above reaction was dissolved in phenylphosphoryl dichloride, and stirred for 3 hours at 170 ℃ in a sealed tube. After the reaction was completed, the reactor temperature was cooled to room temperature, the reactant was extracted with EtOAc or ether, and washed with water and brine. The resulting mixture was dried over magnesium sulfate and concentrated in vacuo. The obtained residue was purified by rapid column chromatography filled with silica gel to obtain the target compound.

[0221] (Yield 71%-82%)

[0222] [Reaction 4]

[0223]

[0224] 1-4-1. Synthesis of (Z)-3-cyclopropyl-3-oxoprop-1-en-1-ol ester

[0225]

[0226] Add NaH (1 equivalent) to the reaction vessel, pass nitrogen, add toluene and ethanol, and stir. Add cyclopropyl methyl ketone (1 equivalent) and ethyl formate (1 equivalent) dissolved in toluene to the mixture, and then react at room temperature for 15 hours. After the reaction is completed, add excess toluene to the reactant, filter and concentrate under reduced pressure to obtain the target product. (Yield: 81%)

[0227] Synthesis of 1-4-2.6-cyclopropyl-2-hydroxynicotinonitrile

[0228]

[0229] The (Z)-3-cyclopropyl-3-oxoprop-1-ene-1-ol ester (1 equivalent) obtained in the above reaction is dissolved in 1,4-dioxane, 2-cyanoacetamide (1 equivalent) is added thereto, and then reflux reaction is 21 hours. After the reaction is completed, the temperature of the reactor is reduced to room temperature, and the reactant is filtered. AcOH is added to the obtained filtrate, and then stirred for 10-30 minutes. Then, the reaction mixture is extracted with EtOAc, washed with water and salt water, and the mixture obtained is dried over magnesium sulfate, and concentrated in vacuo to obtain the target product.

[0230] (Yield: 60%-70%)

[0231] Synthesis of 1-4-3.2-Chloro-6-cyclopropylnicotinonitrile

[0232]

[0233] The 6-cyclopropyl-2-hydroxynicotinonitrile (1 equivalent) obtained in the above reaction was dissolved in phenylphosphite dichloride and stirred at 170°C in a sealed tube for 3 hours. After the reaction was completed, the reactor temperature was lowered to room temperature, the reactants were extracted with EtOAc or ether, and washed with water and brine. The resulting mixture was dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by flash column chromatography filled with silica gel to obtain the target compound. (Yield 71%-82%)

[0234] [Reaction 5]

[0235]

[0236] 1-5-1. Synthesis of dimethylaminopropene / butene-1-one

[0237]

[0238] In a sealed test tube, the raw material 3-methylbutane-2-one or 1-(1-methylcyclopropyl)ethane-1-one or 3,3-dimethylbutane-2-one is dissolved in an excess of dimethylformamide dimethyl acetal and stirred at 110°C for 5 hours. After the reaction is completed, the reactor temperature is lowered to room temperature, and the organic layer is extracted with dichloromethane and washed with water and brine. The resulting mixture is dried over magnesium sulfate and concentrated under reduced pressure at 30°C. The resulting residue is purified by flash column chromatography filled with silica gel to obtain the target compound.

[0239] (Yield: 20%-50%)

[0240] Synthesis of 1-5-2.2-Hydroxynicotinonitrile

[0241]

[0242] The raw material (1 equivalent) and cyanide acetamide (1.3 equivalents) obtained in the above reaction were added to a mixture of AcOH and piperidine (1:1.3), and then refluxed and stirred for 24 hours. After the reaction was completed, the reactor temperature was lowered to room temperature, the reactant was acidified with 4N HCl, extracted with EtOAc, and washed with water and brine. The resulting mixture was dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by flash column chromatography filled with silica gel, using a mixed solvent of ethyl acetate and hexane as the eluting solvent to obtain the target compound. (Yield: 60%-75%)

[0243] 1-5-3. Synthesis of Chloronicotinonitrile

[0244]

[0245] The raw material (1 equivalent) obtained in the above reaction was dissolved in phenyl dichlorophosphate and stirred at 170°C in a sealed tube for 3 hours. After the reaction was completed, the reactor temperature was lowered to room temperature, the reactants were extracted with EtOAc or ether, and washed with water and brine. The resulting mixture was dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by flash column chromatography filled with silica gel to obtain the target compound. (Yield 71%-82%)

[0246] [Reaction 6]

[0247]

[0248] Synthesis of 1-6-1.5-bromo-2-(methoxycarbonyl)pyridine-1-oxide

[0249]

[0250] The raw material 5-bromopicolinic acid methyl ester (1.0 equivalent) was dissolved in dichloromethane, m-CPBA (2.0 equivalent) was added thereto, and stirred for 20 hours under reflux conditions. The temperature of the reactor was cooled to room temperature, and the reaction was terminated by adding Na2SO3 aqueous solution (saturated Na2SO3). The organic matter was extracted with dichloromethane and washed with water and brine. The resulting mixture was dried over magnesium sulfate and concentrated in vacuo. The obtained residue was purified by flash column chromatography filled with silica gel to obtain the target compound. (Yield: 76%-85%)

[0251] Synthesis of 1-6-2.5-bromo-6-chloropicolinic acid methyl ester

[0252]

[0253] An excess of POCl3 was added to 5-bromo-2-(methoxycarbonyl)pyridine 1-oxide) (1 equivalent) obtained in the above reaction at 0°C, and the mixture was stirred at 95°C for 1 hour. The reaction was terminated by adding water. The organic material was extracted with EtOAc and washed with water and brine. The resulting mixture was dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by flash column chromatography filled with silica gel to obtain the target compound. (Yield: 68%-90%)

[0254] 1-6-3. Synthesis of 2-(5-bromo-6-chloropyridin-2-yl)propan-2-ol

[0255]

[0256] The methyl 5-bromo-6-chloropicolinate (1 equivalent) obtained in the above reaction was dissolved in THF, and a 3M CH3MgBr ether solution (4.0 equivalents) was added dropwise thereto in a nitrogen-filled reactor at 0°C, and then stirred at room temperature for 1 hour. The reaction was terminated by adding an aqueous NH4Cl solution. The organic layer was extracted with EtOAc, washed with water and brine. The resulting mixture was dried over magnesium sulfate and concentrated in vacuo to obtain the target compound. (Yield: 70%-85%)

[0257] [Reaction 7]

[0258]

[0259] Synthesis of 1-7-1.2-Mercapto-6-(trifluoromethyl)nicotinonitrile

[0260]

[0261] The raw material 2-chloro-6-(trifluoromethyl)nicotinonitrile (1 equivalent) was dissolved in tert-butyl alcohol, to which Na2S (1 equivalent) was added, and then stirred at 150°C in a microwave for 20 minutes. The reaction was terminated by adding 1N HCl. The organic layer was extracted with EtOAc, washed with water and brine. The resulting mixture was dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by flash column chromatography filled with silica gel to obtain the target compound. (Yield: 60%-65%)

[0262] [Reaction formula 8] Synthesis of 4-cyclopropyl-2-fluorobenzonitrile

[0263]

[0264] Synthesis of 1-8-1.4-Cyclopropyl-2-fluorobenzonitrile

[0265]

[0266] The raw material 4-bromo-2-fluorobenzonitrile (1 equivalent) was dissolved in toluene, stirred, and Na2CO3 (24 equivalents) dissolved in water was added thereto, followed by stirring for 5 to 10 minutes. Then, Pd(PPh3)4 (0.2 equivalents) was added to the reaction mixture. After the mixture was stirred under reflux for 2 hours, the reactor temperature was lowered to room temperature, and the corresponding boronic acid (2 equivalents) dissolved in 1,4-dioxane (1,4-dioxane) was added dropwise thereto, followed by stirring under reflux for 15 hours. After the reaction was completed, the temperature of the reactor was lowered to room temperature, and the reactants were filtered through a diatomaceous earth pad filter and concentrated under reduced pressure. The obtained mixture was dissolved in ethyl acetate, washed with brine and water, dried over magnesium sulfate, and concentrated in vacuo. The obtained residue was purified by flash column chromatography filled with silica gel, using a mixed solvent of ethyl acetate, hexane or dichloromethane and methanol as an eluting solvent to obtain the target compound. (Yield: 85%)

[0267] [Reaction Scheme 9] Synthesis of the C-region of pyrazole

[0268]

[0269] 1-9-1. Synthesis of NR pyrazole-5-carboxylate

[0270]

[0271] The raw material 1H-pyrazole-5-carboxylate (1 equivalent) synthesized in reaction formulas 10 to 11 is dissolved in dichloromethane, stirred, and appropriate acid (2 equivalents), Cu(OAc)2 (1.5 equivalents) and pyridine (2 equivalents) are added thereto, and then reacted at room temperature for 24 hours. After the reaction is completed, the reactant is filtered through a diatomaceous earth pad filter, and the filtrate is concentrated under reduced pressure. Using ethyl acetate, hexane or a mixed solvent of dichloromethane and methanol as an elution solvent, the residue is purified by rapid column chromatography filled with silica gel to obtain the target compound.

[0272] (Yield: 80%-90%)

[0273] 1-9-2.1 Synthesis of H-pyrazolylmethanol

[0274]

[0275] LAH (2 equivalents) was dissolved in THF in a reaction vessel and filled with nitrogen, and the raw material (1 equivalent) obtained in the above reaction dissolved in THF was added dropwise thereto at 0°C, followed by stirring at room temperature for 30 minutes to 1 hour. After the reaction was completed, the temperature of the reactor was lowered to 0°C, and the reaction was terminated by slowly adding an aqueous solution of NaHCO3. The reactant was filtered through a diatomaceous earth pad filter, and the filtrate was concentrated under reduced pressure. A mixed solvent of dichloromethane and methanol was used as an eluting solvent, and the residue was purified by flash column chromatography filled with silica gel to obtain the target compound. (Yield: 90%-98%)

[0276] 1-9-3. Synthesis of 1H-pyrazole acrylate

[0277]

[0278] The raw material (1 equivalent) obtained by the above reaction is dissolved in toluene, MnO2 (1 equivalent) is added thereto, and then stirred at room temperature for 30 minutes to 1 hour. Methyl (triphenylphosphoranylidene) acetate (3.5 equivalents) is added to the mixture, and then reacted under reflux conditions for 24 hours. After the reaction is completed, the reactant is filtered through a diatomaceous earth pad filter. The organic matter is extracted with EtOAc, washed with brine and water, and the filtrate is dried over magnesium sulfate and concentrated in vacuo. Using ethyl acetate, hexane or a mixed solvent of dichloromethane and methanol as an eluting solvent, the obtained residue is purified by flash column chromatography filled with silica gel to obtain the target compound. (Yield: 75%-90%)

[0279] 1-9-4. Synthesis of 1H-pyrazolylcyclopropane-1-carboxylate

[0280]

[0281] Trimethylsulfoxide iodide (2 equivalents) is dissolved in DMSO, NaH (2 equivalents) is added thereto at 0°C, and then stirred at room temperature for 1-2 hours, preferably until a clear mixture is formed. The raw material 1H-pyrazolyl acrylate (1 equivalent) obtained in the above reaction is dissolved in a small amount of DMSO, slowly added dropwise to the mixture, and then stirred at room temperature for 2 to 4 hours. The reaction is terminated by adding water, and the organic matter is extracted with ethyl acetate. The mixture is washed with water and brine, and the obtained filtrate is dried over magnesium sulfate and concentrated in vacuo. Using ethyl acetate, hexane or a mixed solvent of dichloromethane and methanol as an eluting solvent, the obtained residue is purified by flash column chromatography filled with silica gel to obtain the target compound. (Yield: 80%-90%)

[0282] 1-9-5. Synthesis of carboxylic acid

[0283]

[0284] The acrylic acid ester or cyclic carboxylic acid ester (1 equivalent) obtained in the above reaction is dissolved in THF, LiOH·H2O (2-3 equivalents) and the same amount of water are added thereto, and then stirred at room temperature for 2-5 hours. After the reaction is completed, 1N HCl is added at 0°C to adjust the pH of the reactant to 2-3. The organic matter is extracted with ethyl acetate, washed with water and brine, and the resulting filtrate is dried over magnesium sulfate and concentrated in vacuo. Using ethyl acetate, hexane or a mixed solvent of dichloromethane and methanol as an elution solvent, the resulting residue is purified by flash column chromatography filled with silica gel to obtain the target compound. (Yield: 85%-98%)

[0285] [Reaction Scheme 10] Synthesis of 1H-pyrazole-5-carboxylate

[0286] [Method A]

[0287]

[0288] 1-10-1. Synthesis of 3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid methyl ester

[0289]

[0290] The raw material methyl propionate (1 equivalent) was dissolved in dichloromethane, to which NaNO2 (3 equivalents) dissolved in water was slowly added dropwise, and then stirred for 10-20 minutes. The reactor temperature was reduced to 0°C, and 3,3,3-trifluoroaniline (3 equivalents) was added dropwise to the reaction mixture, followed by stirring at 0°C for 1 to 2 hours. The reaction mixture was stirred at room temperature for 30 minutes, and the reaction was terminated by adding water. The organic matter was extracted with dichloromethane, washed with water and brine, and the obtained filtrate was dried over magnesium sulfate and concentrated in vacuo. Using ethyl acetate, hexane or a mixed solvent of dichloromethane and methanol as the eluting solvent, the obtained residue was purified by rapid column chromatography filled with silica gel to obtain the target compound. (yield: 65%-88%)

[0291] [Method B]

[0292]

[0293] 1-10-2. Synthesis of 1H-pyrazole-5-carboxylate

[0294]

[0295] Methyl-1-methylcyclopropyl ketone, isopropyl methyl ketone or pinacolone (1 equivalent) is added to a mixture of t-BuOK (1.5 equivalents) dissolved in THF at 0°C, diethyl oxalate (1 equivalent) dissolved in THF is added dropwise thereto, and then stirred at room temperature for 15 hours. AcOH (0.15 ml / mmol) is added to the mixture, hydrazine monohydrate (1.1 equivalents) is added dropwise thereto, and then stirred under reflux conditions for 3 hours. After the reaction is completed, the reactant is concentrated under reduced pressure, water is added to the obtained solid, and then stirred for 3 to 6 hours. The obtained solid is filtered under reduced pressure and dried to obtain the target product. (Yield: 80%-91%)

[0296] [Reaction Scheme 11] Synthesis of Thiazole C-region

[0297]

[0298] 1-11-1. Synthesis of methyl 3-(3-chlorophenyl)-3-oxopropanoate

[0299]

[0300] NaH (3 eq.) was dissolved in THF by stirring in a reaction vessel filled with nitrogen. The reactor temperature was lowered to 0°C, and the raw materials 1-(3-chlorophenyl)ethan-1-one (1 eq.) and dimethyl carbonate (3 eq.) were slowly added dropwise, followed by stirring at room temperature for 10 to 30 minutes. The reactor temperature was raised to 50°C, and the reactants were stirred for 15 hours. The reaction was terminated by adding 1N HCl at 0°C. The organic material was extracted with ethyl acetate, washed with water and brine, and the obtained filtrate was dried over magnesium sulfate and concentrated in vacuo. The obtained residue was purified by flash column chromatography filled with silica gel using a mixed solvent of ethyl acetate and hexane as the eluting solvent to obtain the target compound. (Yield: 65%-88%)

[0301] 1-11-2. Synthesis of methyl 2-chloro-3-(3-chlorophenyl)-3-oxopropanoate

[0302]

[0303] The 3-(3-chlorophenyl)-3-oxopropionic acid methyl ester (1 equivalent) obtained in the above reaction was dissolved in chloroform, and then the reactor was filled with nitrogen, and sulfonyl chloride (1.1 equivalent) was added dropwise thereto at 0°C, and then stirred under reflux for 15 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. Using a mixed solvent of ethyl acetate and hexane as an elution solvent, the obtained residue was purified by rapid column chromatography filled with silica gel to obtain the target compound. (Yield: 75%-88%)

[0304] 1-11-3. Synthesis of R-carboxamide

[0305]

[0306] In a nitrogen-filled reaction vessel, 1-methylcyclopropane-1-carboxylic acid or pivalic acid (1 equivalent) was dissolved in toluene, thionyl chloride (1.1 equivalent) was added dropwise at 0°C, and then stirred at room temperature for 5 hours. An excess of NH4OH aqueous solution was slowly added dropwise at sub-zero temperature, and then stirred at room temperature for 15 hours. The reaction was terminated by adding water. The organic matter was extracted with EtOAc, washed with water and brine, and the obtained filtrate was dried over magnesium sulfate and concentrated in vacuo to obtain the target compound. (Yield 71%-89%)

[0307] 1-11-4. Synthesis of R-thioamide

[0308]

[0309] Using 1-methylcyclopropane-1-carboxamide and pivalamide obtained in the above reaction, or commercially available isobutylamide and 2,2,2-trifluoroacetamide as raw materials, they are dissolved in THF or toluene, Lawesson's reagent (0.6 equivalent) is added thereto, and then stirred at room temperature for 15-30 minutes. Then, the reaction mixture is stirred under reflux conditions for 2 hours, preferably 4 hours. After the reaction is completed, the reaction mixture is concentrated under reduced pressure. Using a mixed solvent of dichloromethane and methanol as an eluting solvent, the obtained residue is purified by rapid column chromatography filled with silica gel to obtain the target compound. (Yield: 45%-68%)

[0310] 1-11-5. Synthesis method of thiazole-5-carboxylate

[0311]

[0312] The methyl 2-chloro-3-(3-chlorophenyl)-3-oxopropanoate (1 equivalent) obtained in the above reaction is dissolved in a mixed solution of MeOH or i-PrOH:n-BuOH (1:1), and the thiocarboxamide (1.32 equivalents) obtained in 1-11-4 dissolved in the same solvent is added dropwise thereto, and then stirred at room temperature for 10-30 minutes. Then, the reaction mixture is stirred under reflux conditions for 15 hours. The reaction is terminated by adding water. The organic matter is extracted with ethyl acetate. The organic matter is extracted with ethyl acetate, washed with water and brine, and the obtained filtrate is dried over magnesium sulfate and concentrated in vacuo. Using a mixed solvent of ethyl acetate and hexane as an eluting solvent, the obtained residue is purified by flash column chromatography filled with silica gel to obtain the target compound.

[0313] (yield: 65%-88%)

[0314] 1-11-6. Synthesis of R-(3-chlorophenyl)thiazol-5-ylmethanol

[0315]

[0316] LAH (2 equivalents) was dissolved in THF in a reaction vessel and filled with nitrogen, and the raw material thiazole-5-carboxylate (1 equivalent) dissolved in THF obtained in the above reaction was added dropwise thereto at 0°C, followed by stirring at room temperature for 30 minutes to 1 hour. The temperature of the reactor was lowered to 0°C, and the reaction was terminated by slowly adding an aqueous solution of NaHCO3. The reactants were filtered through a diatomaceous earth pad filter, and the filtrate was concentrated under reduced pressure. A mixed solvent of dichloromethane and methanol was used as an eluting solvent, and the obtained residue was purified by rapid column chromatography filled with silica gel to obtain the target compound. (Yield: 90%-98%)

[0317] 1-11-7. Synthesis of R-(3-chlorophenyl)thiazol-5-yl)methyl acrylate

[0318]

[0319] The raw material obtained in 1-11-6 (1 equivalent) is dissolved in toluene, MnO2 (1 equivalent) is added thereto, and then stirred at room temperature for 30 minutes to 1 hour. (Triphenylphosphoranylidene) methyl acetate) or (triphenylphosphoranylidene) ethyl acetate) (3.5 equivalents) is added to the mixture, and then stirred for 24 hours under reflux conditions. After the reaction is completed, the reactant is filtered with a diatomaceous earth pad filter, and the organic matter is extracted with ethyl acetate and washed with water and brine. The obtained filtrate is dried over magnesium sulfate and concentrated in vacuo. Using ethyl acetate, hexane or a mixed solvent of dichloromethane and methanol as an elution solvent, the obtained residue is purified by flash column chromatography filled with silica gel to obtain the target compound. (Yield: 75%-90%)

[0320] 1-11-8. Synthesis of (E)-R-(3-chlorophenyl)thiazolyl-acrylic acid

[0321]

[0322] The acrylate (1 equivalent) obtained in 11-7 is dissolved in THF, LiOH·H2O (2-3 equivalents) and the same amount of water are added thereto, and then stirred at room temperature for 2-5 hours. After the reaction is completed, 1N HCl is added at 0°C to adjust the pH of the reactant to 2-3. The organic matter is extracted with EtOAc, washed with water and brine, and the resulting filtrate is dried over magnesium sulfate and concentrated in vacuo. Using ethyl acetate, hexane or a mixed solvent of dichloromethane and methanol as an elution solvent, the resulting residue is purified by flash column chromatography filled with silica gel to obtain the target compound. (Yield: 85%-98%)

[0323] 1-3. Synthesis of Region B

[0324] [Reaction 12] EDC coupling

[0325]

[0326] 1-12-1. EDC coupling

[0327] The acrylic acid or cyclopropane-1-carboxylic acid obtained in the above reaction is dissolved in DMA, EDC·HCl (1.5 equivalents) and DMAP (1.5 equivalents) are added thereto, and then stirred at room temperature for 10-20 minutes. After adding the 4-amino-benzo[d]imidazole-2-one (4-amino-benzo[d]imidazole-2-one) derivative (2 equivalents) obtained in reaction formulas 1A and 1B, the mixture is stirred at room temperature for 3 hours, preferably 5 hours. The reaction is terminated by adding water. The organic layer is extracted with ethyl acetate or dichloromethane and concentrated under reduced pressure. The obtained residue is purified by column chromatography to obtain the target compound. (Yield: 60-88%)

[0328] [Reaction 13]

[0329]

[0330] 1-13-1. Synthesis of 6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)propanamide (6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)propanamide

[0331] The (E)-3-(2-isobutoxy-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide obtained in 1-12-1 or (E)-3-(2-(cyclopropylmethoxy)-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide (E)-3-(2-(cyclopropylmethoxy)-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide) (1 equivalent) is hydrogenated with a reducing agent such as 10% palladium-activated carbon (Pd-c) dissolved in a lower alcohol such as methanol, filtered through a diatomaceous earth pad, and the filtrate is dried under reduced pressure. The reactant is purified by flash column chromatography filled with silica gel using a mixed solvent of dichloromethane and methanol as an elution solvent to obtain the target compound. (Yield: 90%-98%)

[0332] The compounds of Examples 1 to 68 were synthesized via Reaction Schemes 1 to 13, and the NMR data of the compounds of each Example are as follows.

[0333] Representatively, the compound of Example 1 is prepared by using a compound in which R1 is CF3, X is N, and R2 is methylpiperidine in Reaction Formula 2 as a starting material in Reaction Formula 12 and reacting with the A-region.

[0334] Example 1 (E) -3- (2- (4-methylpiperidin-1-yl) -6- (trifluoromethyl) pyridin-3-yl) -N- (2-oxo-2,3-dihydro-1H-benzo [d] imidazole-4-yl) acrylamide

[0335]

[0336] Yellow solid, yield 72%; 1 H NMR (500MHz, DMSO) δ10.72(s,1H),10.15(s,1H),9.96(s,1H),8.05(d,J=7.65Hz,1H).7.70(m,1H),7.59(d, J=10.20Hz,1H),7.42(d,J=7.75Hz,1H),7.24(d,J=8.05Hz,1H),6.93(t,J=7.90Hz,1H),6.86(d,J=15.70Hz ,1H),6.78(d,J=7.70Hz,1H),4.20(m,1H),3.63(d,J=12.55Hz,2H),2.86(t,J=12.15Hz,2H),1.96(m,1H),1 .72(d,J=11.45Hz,2H),1.58(m,1H),1.31-1.26(m,2H),1.25(s,4H),0.95(d,J=6.45Hz,3H); Mass(FAB)m / z 446[M+H] +

[0337] Example 2 (E) -3- (2- (4-ethylpiperidin-1-yl) -6- (trifluoromethyl) pyridin-3-yl) -N- (2-oxo-2,3-dihydro-1H-benzo [d] imidazole-4-yl) acrylamide

[0338]

[0339] White solid, yield 88%; 1H-NMR (400MHz, DMSO) δ10.69(s,1H),10.09(s,1H),9.88(s,1H),8.01(d,J=7.6H z,1H),7.51(d,J=15.6Hz,1H),7.39(d,J=8.0Hz,1H),7.20(d,J=8.4Hz,1H),6.8 9(t,J=8.0Hz,1H),6.81(d,J=15.6Hz,1H),6.74(d,J=7.2Hz,1H),3.62(d,J=14. 2Hz,2H),2.81(t,J=11.6Hz,2H),1.74(d,J=10.4Hz,2H),1.27-1.19(m,4H),1.15 -1.13(t,J=7.6Hz,1H),0.84(m,3H); Mass(FAB)m / z 460[M+H] +

[0340] Example 3 (E) -N- (2-oxo-2,3-dihydro-1H-benzo [d] imidazole-4-yl) -3- (2- (pyrrolidin-1-yl) -6- (trifluoromethyl) pyridin-3-yl) acrylamide

[0341]

[0342] White solid, yield 65%; 1 H-NMR (400MHz, DMSO) δ10.67(s,1H),10.08(s,1H),9.08(s,1H),7.83(d,J=7.2Hz,1H),7.78(d,J=15.6Hz,1H),7.20(d,J=8.0Hz,1H),7.1 1(d,J=8.0Hz,1H),6.88(t,J=8.0Hz,1H),6.72(d,J=7.6Hz,1H),6.50(d,J=15.2Hz,1H),3.49(m,4H),1.85(m,4H); Mass(FAB)m / z418[M+H] +

[0343] Example 4 (E) -N- (2-oxo-2,3-dihydro-1H-benzo [d] imidazole-4-yl) -3- (2- (piperidin-1-yl) -6- (trifluoromethyl) pyridin-3-yl) acrylamide

[0344]

[0345] Yellow solid, yield 61%; 1H NMR (300MHz, DMSO) δ10.73(s,1H),10.14(s,1H),9.92(s,1H),8.06(d,J=7.71Hz,1H),7.56(d,J=15.39Hz,1H),7.44(d,J =7.68Hz,1H),7.23(d,J=7.89Hz,1H),6.95-6.84(m,2H),6.77(d,J=7.86Hz,1H),3.24(m,4H),1.66(m,8H); Mass(ESI)m / z 432[M+H] +

[0346] <Example 5> (E) -3- (2-morpholinyl-6- (trifluoromethyl) pyridin-3-yl) -N- (2-oxo-2,3-dihydro-1H-benzo [d] imidazole-4-yl) acrylamide

[0347]

[0348] Yellow solid, yield 82%; 1 H NMR (300MHz, CD3OD) δ8.06(d,J=7.9Hz,1H),7.84(d,J=15.8Hz,1H),7.38(d,J=7.9Hz,1H),7.05(s ,1H),7.04(d,J=2.4Hz,1H),6.93-6.87(m,2H),3.86(m,4H),3.33(m,4H); Mass(ESI)m / z434[M+H] +

[0349] Example 6 (E)-3-(2-(diethylamino)-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide

[0350]

[0351] Yellow solid, yield 80%; 1H NMR (500MHz, DMSO) δ10.72(s,1H),10.12(s,1H),9.90(s,1H),7.99(d,J=7.60Hz,1H),7.59(d,J=15.55Hz,1H),7.33(d,J=7.75Hz,1H), 7.25(d,J=8.10Hz,1H),6.92(t,J=7.95Hz,1H),6.78(d,J=11.76Hz,1H),6.76(s,1H),2.94(m,4H)1.14(t,J=6.90Hz,6H); Mass(FAB)m / z 420[M+H] +

[0352] Example 7 (E)-3-(2-(dipropylamino)-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide

[0353]

[0354] Yellow solid, yield 82%; 1 H NMR(500MHz,DMSO)δ10.72(s,1H),10.10(s,1H),9.91(s,1H),7.97(d,J=7.6 0Hz,1H),7.59(d,J=15.55Hz,1H),7.31(d,J=7.70Hz,1H),7.25(d,J=8.10Hz, 1H),6.93(t,J=7.90Hz,1H),6.75-6.78(dd,J=3.35Hz,7.95Hz,2H),3.28(t, J=7.50Hz, 4H), 1.60 (q, J=7.25Hz, 4H), 0.81 (t, J=7.35Hz, 6H); Mass (FAB) m / z 448[M+H] +

[0355] <Example 8> (E) -3- (2-butoxy-6- (trifluoromethyl) pyridin-3-yl) -N- (2-oxo-2,3-dihydro-1H-benzo [d] imidazole-4-yl) acrylamide

[0356]

[0357] White solid, yield 63%; 1H-NMR (300MHz, DMSO) δ10.71 (s, 1H), 10.15 (s, 1H), 9.95 (s, 1H), 8.24 (d, J = 7. 5Hz,1H),7.71(d,J=15.8Hz,1H),7.57(d,J=7.9Hz,1H),7.20(d,J=8.2Hz,1H), 7.05(d,J=15.8Hz,1H),6.93(t,J=7.5Hz,1H),6.78(d,J=7.7Hz,1H),4.44(t, J=6.6Hz,2H),1.81(m,2H),1.46(m,2H),0.96(t,J=7.32Hz,3H); Mass(FAB)m / z 421[M+H] +

[0358] Example 9 (E)-3-(2-(hexyloxy)-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide

[0359]

[0360] White solid, yield 73%; 1 H NMR (300MHz, DMSO) δ10.71(s,1H),10.15(s,1H),9.95(s,1H),8.24(d,J=7.71 Hz,1H),7.70(d,J=15.75Hz,1H),7.56(d,J=7.68Hz,1H),7.21(d,J=8.25Hz,1 H),7.05(d,J=15.75Hz,1H),6.93(t,1H),6.77(d,J=7.89Hz,1H),4.43(t,J=6 .57Hz,2H),1.82(m,2H),1.43-1.23(m,7H),0.88-0.86(m,3H); Mass(FAB)m / z 449[M+H] +

[0361] Example 10 (E)-3-(2-isobutoxy-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide

[0362]

[0363] White solid, yield 73%; 1H NMR (300MHz, DMSO) δ10.72 (s, 1H), 10.16 (s, 1H), 7.95 (s, 1H), 8.25 (d, J = 7.71Hz, 1H),7.74(d,J=15.75Hz,1H),7.57(d,J=7.69Hz,1H),7.19(d,J=7.71Hz,1H),7.04 (d,J=15.72Hz,1H),6.93(t,J=8.04Hz,1H),6.78(d,J=7.68Hz,1H),4.21(d,J=6. 78Hz,1H),2.17(p,J=6.57Hz,1H),1.02(d,J=6.78Hz,6H); Mass(ESI)m / z421[M+H] +

[0364] Example 11 (E)-3-(2-cyclobutyloxy-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide

[0365]

[0366] White solid, yield 82%; 1 H-NMR (300MHz, DMSO) δ10.71(s,1H),10.14(s,1H),9.98(s,1H),8.23(d,J=7.7Hz,1H),7.68(d,J=15.6Hz,1H),7.56(d,J=7.5Hz,1H),7.18(d,J=7 .9Hz,1H),7.09(d,J=7.5Hz,1H),6.93(t,J=7.9Hz,1H),6.78(d,J=7.9Hz,1H),5.26(m,1H),2.50(m,2H),2.22(m,2H),1.78(m,2H); Mass(ESI)m / z 419[M+H] +

[0367] Example 12 (E)-3-(2-(cyclopentyloxy)-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide

[0368]

[0369] White solid, yield 62%; 1H-NMR (400MHz, DMSO-D6) δ10.66(s,1H),10.09(s,1H),9.90(s,1H),8.18(d,J=7.8H z,1H),7.63(d,J=16.1Hz,1H),7.50(d,J=7.4Hz,1H),7.13(d,J=8.3Hz,1H),6.99(d ,J=16.1Hz,1H),6.89(t,J=7.8Hz,1H),6.74(d,J=7.8Hz,1H),5.45(s,1H),2.01(t, J=6.4Hz,3H),1.92(s,2H),1.69-1.79(m,4H),1.59(d,J=8.3Hz,3H); Mass(ESI)m / z 433[M+H] +

[0370] Example 13 (E)-3-(2-(cyclopropylmethoxy)-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide

[0371]

[0372] Light yellow solid, yield 82%; 1 H NMR(600MHz,DMSO)δ10.70(s,1H),10.14(s,1H),9.95(s,1H),8.24(d,J=7.80Hz,1 H),7.73(d,J=16.02Hz,1H),7.57(d,J=7.38Hz,1H),7.20(d,J=8.28Hz,1H),7.07( d,J=16.02Hz,1H),6.93(t,J=8.28Hz,1H),6.77(d,J=7.80Hz,1H),4.29(d,J=6.84 Hz,2H),1.35(m,1H),0.60(q,J=6.42Hz,2H),0.42(q,J=5.04Hz,2H); Mass(ESI)m / z 419[M+H] +

[0373] Example 14 (E) -N- (2-oxo-2,3-dihydro-1H-benzo [d] imidazole-4-yl) -3- (2- (2,2,2-trifluoroethoxy) -6- (trifluoromethyl) pyridin-3-yl) acrylamide

[0374]

[0375] Light yellow solid, yield 62%; 1H-NMR (400MHz, DMSO) δ10.68(s,1H),10.14(s,1H),9.98(s.1H),8.33(d,J=7.2Hz,1H),7.69(m,2H),7.14(d,J=7.6Hz,1 H),6.96(d,J=15.6Hz,1H),6.89(t,J=8.0Hz,1H),6.74(d,J=8.8Hz,1H),5.11(q,J=8.8Hz,2H); Mass(FAB)m / z447[M+H] +

[0376] Example 15 (E)-3-(2-(neopentyloxy)-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide

[0377]

[0378] Yellow solid, yield 52%; 1 H-NMR (400MHz, DMSO) δ10.68(s,1H),10.13(s,1H),9.91(s.1H),8.22(d,J=7.6Hz,1H),7.74(d,J=16.0Hz,1H),7.75(d,J=0.80Hz,1H ),7.15(d,J=8.4Hz,1H),6.95(d,J=8.4Hz,1H),6.88(t,J=8.4Hz,1H),6.73(d,J=7.6Hz,1H),4.60(s,2H),1.02(s,9H); Mass(FAB)m / z 435[M+H] +

[0379] Example 16 (E)-3-(2-((2-methylcyclopropyl)methoxy)-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide

[0380]

[0381] Yellow solid, yield 63%; 1H-NMR (400MHz, DMSO) δ10.69 (s, 1H), 10.15 (s, 1H), 9.94 (s, 1H), 8.20 (d, J = 7.6Hz, 1H),7.72-7.66(m,1H),7.52(d,J=8.0Hz,1H),7.16(d,J=7.6Hz,1H),7.03(d,J=16. 0Hz,1H),6.89(t,J=8.0Hz,1H),6.74(d,J=7.2Hz,1H),4.32-4.18(m,2H),0.99(d, J=6.0Hz,3H),0.81-0.80(m,2H),0.54(m,1H),0.32(m,1H); Mass(FAB)m / z433[M+H] +

[0382] Example 17 (E)-3-(6-(chlorodifluoromethyl)-2-(cyclopropylmethoxy)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide

[0383]

[0384] White solid, yield 71%; 1 H NMR (400MHz, DMSO) δ10.67(s,1H),10.23(s,1H),10.02(s,1H),8.20(d,J=8.0Hz ,1H),7.68(d,J=16.0Hz,1H),7.46(d,J=7.6Hz,1H),7.19(d,J=8.0Hz,1H),7.05 (d,J=16.0Hz,1H),6.88(t,J=8.4Hz,1H),6.73(d,J=7.6Hz,1H),4.26(d,J=7.2H z,2H),1.33(m,1H),0.55(d,J=8.0Hz,2H),0.38(d,J=5.2Hz,2H); Mass(ESI)m / z 435[M+H] +

[0385] Example 18 (E)-3-(6-cyclopropyl-2-(cyclopropylmethoxy)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide

[0386]

[0387] White solid, yield 82%; 1H NMR (400MHz, DMSO) δ10.66 (s, 1H), 10.09 (s, 1H), 9.75 (s, 1H), 7.80 (d, J = 7.8Hz, 1H), 7. 64(d,J=16.0Hz,1H),7.19(t,J=8.0Hz,1H),6.96(d,J=7.8Hz,1H),6.79-6.90(m,2H),6. 71(d,J=7.3Hz,1H),4.14(d,J=6.9Hz,2H),1.99-2.05(m,1H),0.93(d,J=6.4Hz,4H),0.8 1(t,J=6.9Hz,1H),0.53(d,J=6.9Hz,2H),0.31(d,J=4.6Hz,2H); Mass(FAB)m / z391[M+H] +

[0388] Example 19 (E)-3-(2-(cyclopropylmethoxy)-6-isopropylpyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide

[0389]

[0390] White solid, yield 52%; 1 H NMR (400MHz, DMSO) δ10.67(s,1H),10.10(s,1H),9.77(s,1H),7.87(d,J=7.6 Hz,1H),7.67(d,J=16.0Hz,1H),7.20(d,J=8.0Hz,1H),6.92-6.83(m,3H),6.7 2(d,J=7.2Hz,1H),4.23(d,J=6.8Hz,2H),2.94-2.87(m,1H),1.36-1.27(m,1H ),1.19(d,J=6.8Hz,6H),0.56-0.51(m,2H),0.35-0.33(m,2H); Mass(FAB)m / z 393[M+H] +

[0391] Example 20 (E) -3- (2- (cyclopropylmethoxy) -6- (1-methylcyclopropyl) pyridin-3-yl) -N- (2-oxo-2,3-dihydro-1H-benzo [d] imidazole-4-yl) acrylamide

[0392]

[0393] Yellow solid, yield 61%; 1H NMR (400MHz, DMSO) δ10.65 (s, 1H), 10.23 (s, 1H), 9.87 (s, 1H), 7.86 (d, J = 8.4Hz, 1H), 7.65(d,J=16.0Hz,1H),7.23(d,J=8.0Hz,1H),6.98(d,J=8.0Hz,1H),6.89-6.84(m,2H ),6.70(d,J=8.0Hz,1H),4.13(d,J=6.8Hz,2H),1.42(s,3H),1.27-1.25(m,1H),1.18 -1.17(m,2H),0.81-0.78(m,2H),0.55-0.52(m,2H),0.32-0.31(m,2H); Mass(FAB)m / z 405[M+H] +

[0394] Example 21 (E)-3-(2-(cyclopropylmethoxy)-6-(difluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide

[0395]

[0396] Yellow solid, yield 70%; 1 H NMR (DMSO, 400MHz) δ10.68(s,1H),10.21(s,1H),9.97(s,1H),8.14(d,J=7.2Hz,1H),7.69(d,J=16.0Hz,1H),7.32(d,J=7.2Hz,1H),7. 18(d,J=8.0Hz,1H),7.02-6.72(m,4H),4.23(d,J=6.8Hz,2H),1.33-1.28(m,1H),0.57-0.53(m,2H),0.38-0.34(m,2H); Mass(FAB)m / z 401[M+H] +

[0397] Example 22 (E)-3-(2-(cyclopropylmethoxy)-6-(1,1-difluoroethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide

[0398]

[0399] Yellow solid, yield 59%; 1H NMR(DMSO,400MHz)δ10.67(s,1H),10.20(s,1H),9.97(s,1H),8.12(d,J=8.0Hz,1H), 7.69(d,J=16.0Hz,1H),7.32(d,J=7.6Hz,1H),7.19(d,J=8.4Hz,1H),6.99(d,J=16.0H z,1H),6.89(t,J=8.0Hz,1H),6.73(d,J=7.6Hz,1H),4.25(d,J=6.8Hz,2H),1.95(t,J =18.8Hz,3H),1.35-1.30(m,1H),0.58-0.53(m,2H),0.38-0.35(m,2H); Mass(FAB)m / z 415[M+H] +

[0400] Example 23 (E)-3-(6-(tert-butyl)-2-(cyclopropylmethoxy)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide

[0401]

[0402] Yellow solid, yield 59%; 1 H NMR (DMSO, 400MHz) δ10.66 (s, 1H), 10.17 (s, 1H), 9.84 (s, 1H), 7.88 (d, J = 8. 0Hz,1H),7.66(d,J=15.6Hz,1H),7.21(d,J=8.0Hz,1H),7.02(d,J=7.6Hz,1H ),6.89-6.85(m,2H),6.71(d,J=8.0Hz,1H),4.23(d,J=6.8Hz,2H),1.36-1. 30(m,1H),1.26(s,9H),0.56-0.51(m,2H),0.35-0.33(m,2H); Mass(FAB)m / z 407[M+H] +

[0403] Example 24 (E) -3- (2- (cyclopropylmethoxy) -6- (2-hydroxypropane-2-yl) pyridin-3-yl) -N- (2-oxo-2,3-dihydro-1H-benzo [d] imidazole-4-yl) acrylamide

[0404]

[0405] Yellow solid, yield 63%; 1H NMR(DMSO,400MHz)δ10.65(s,1H),10.33(s,1H),9.98(s,1H),7.95(d,J=7.6Hz,1H),7.68(d,J=16.0Hz,1H),7.25(d,J=7.6Hz,1H),6.93-6.86(m ,2H),6.71(d,J=7.6Hz),5.12(s,1H),4.22(d,J=7.2Hz,2H),1.39(s,6H) ,1.34-1.27(m,1H),0.56-0.51(m,2H),0.36-0.32(m,2H); Mass(FAB)m / z 409[M+H] +

[0406] Example 25 (E)-3-(2-(cyclobutylmethoxy)-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide

[0407]

[0408] Yellow solid, yield 83%; 1 H NMR(300MHz,DMSO)δ10.72(s,1H),10.10(s,1H),9.91(s,1H),7.97(d,J=7 .60Hz,1H),7.69(d,J=15.36Hz,1H),7.55(d,J=7.68Hz,1H),7.15(d,J=7.9 5Hz,1H),7.01(d,J=15.93Hz,1H),6.92(m,1H),6.78(d,J=7.95Hz,1H),4. 40(d,J=6.96Hz,2H),2.01(m,2H),1.89(m,3H),1.21(m,2H); Mass(FAB)m / z 433[M+H] +

[0409] Example 26 (E)-3-(2-(cyclopentylmethoxy)-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide

[0410]

[0411] Yellow solid, yield 63%; 1H NMR (300MHz, DMSO) δ10.72(s,1H),10.16(s,1H),9.94(s,1H),8.24(d,J=7.71Hz,1 H),7.72(d,J=15.75Hz,1H),7.57(d,J=7.68Hz,1H),7.19(d,J=7.89Hz,1H),7.04(d ,J=15.75Hz,1H),6.93(t,J=7.86Hz,1H),6.78(d,J=7.71Hz,1H),4.31(d,J=7.14H z,2H),2.46(m,1H),1.80(m,2H),1.61(m,4H),1.37(m,2H); Mass(FAB)m / z447[M+H] +

[0412] Example 27 (E)-3-(2-(isobutylthio)-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide

[0413]

[0414] White solid, yield 55%; 1 H NMR (400MHz, DMSO) δ10.73(s,1H),10.22(s,1H),10.08(s,1H),8.15(d,J=8.43Hz,1H),7.22(d,J=8.43Hz,1H),7.73(d,J=16.11Hz,1H),7.71(m,1H) ,6.96(d,J=15.93Hz,1H),6.92(d,J=7.89Hz,1H),6.78(d,J=7.86Hz,1H), 3.17(d,J=6.24Hz,2H),1.94(m,1H),1.00(d,J=6.42Hz,6H); Mass(FAB)m / z 437[M+H] +

[0415] Example 28 (E)-3-(2-((cyclopropylmethyl)thio)-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide

[0416]

[0417] White solid, yield 55%; 1H NMR (400MHz, DMSO) δ10.67(s,1H),10.11(s,1H),9.98(s,1H),8.14(d,J=7.88Hz,1H ),7.70(d,J=7.88Hz,1H),7.72(d,J=15.56Hz,1H),7.22(d,J=8.12Hz,1H),6.94(d, J=8.24Hz,1H),6.62(d,J=7.64Hz,1H),6.78(d,J=7.68Hz,1H),6.93(d,J=15.88Hz, 1H),3.21(d,J=7.20Hz,2H),1.16(m,1H),0.55(m,2H),0.3469(m,2H); Mass(FAB)m / z 435[M+H] +

[0418] Example 29 (E)-3-(2-(cyclohexylthio)-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide

[0419]

[0420] White solid, yield 59%; 1 H NMR (400MHz, DMSO) δ10.72(s,1H),10.19(s,1H),10.04(s,1H),8.14(d,J= 8.07Hz, 1H), 7.70 (d, J = 8.04Hz, 1H), 7.67 (d, J = 15.36Hz, 1H), 7.22 (d, J = 8. 07Hz,1H),6.94(d,J=7.32Hz,1H),6.93(d,J=15.75Hz,1H),6.78(d,J=7.68 Hz,1H),3.91(m,1H),2.03(m,2H),1.72(m,2H),1.51(m,6H); Mass(FAB)m / z 463[M+H] +

[0421] Example 30 (E)-3-(2-(3-fluorophenyl)-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide

[0422]

[0423] White solid, yield 75%; 1H NMR (400MHz, DMSO) δ10.72(s,1H),10.13(s,1H),9.99(s,1H),8.45(d,J=8.43Hz,1H),8.07(d,J=8.58Hz, 1H),7.55(m,2H),7.43(m,3H),7.20(d,J=8.25Hz,1H),6.93(m,2H),6.76(d,J=7.86Hz,1H); Mass(FAB)m / z 443[M+H] +

[0424] Example 31 (E)-3-(2-(3-chlorophenyl)-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide

[0425]

[0426] White solid, yield 62%; 1 H NMR (300MHz, DMSO) δ10.72(s,1H),10.11(s,1H),9.98(s,1H),8.45(d,J=8.2Hz,1H),8.07(d,J=8.3Hz, 1H),7.51-7.65(m,5H),7.20(d,J=8.3Hz,1H),6.89-6.98(m,2),6.71(d,J=7.50Hz,1H); Mass(ESI)m / z 459[M+H] +

[0427] Example 32 (E)-3-(2-(3-isopropylphenyl)-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide

[0428]

[0429] White solid, yield 82%; 1H NMR (300MHz, DMSO) δ10.71(s,1H),10.05(s,1H),9.95(s,1H),8.42(d,J=7.7Hz,1H),8.02(d,J=8.1Hz,1H),7.59(d,J=15.8Hz,1H),7.39- 7.51(m,4H),7.20(d,J=8.4Hz,1H),6.89-6.97(m,2H),6.76(d,J=7.7Hz,1H),2.98(m,1H),1.24(d,J=6.8Hz,6H); Mass(FAB)m / z467[M+H] +

[0430] Example 33 (E) -3- (2- (3-chloro-4-fluorophenyl) -6- (trifluoromethyl) pyridin-3-yl) -N- (2-oxo-2,3-dihydro-1H-benzo [d] imidazole-4-yl) acrylamide

[0431]

[0432] White solid, yield 82%; 1 H NMR (300MHz, DMSO) δ10.72(s,1H),10.10(s,1H),9.98(s,1H),8.44(d,J=6.1Hz,1H),8.07(d,J=8.2Hz,1H),7.81(dd,J=1.8,7.1Hz ,1H),7.59-7.66(m,2H),7.53(d,J=15.4Hz,1H),7.21(d,J=8.3Hz,1H),.6.89-6.97(m,2H),6.77(d,J=7.50Hz,1H); Mass(FAB)m / z 477[M+H] +

[0433] Example 34 (E)-3-(2-(4-fluorophenyl)-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide

[0434]

[0435] White solid, yield 69%; 1H NMR (400MHz, DMSO) δ10.71(s,1H),10.13(s,1H),10.00(s,1H),8.41(d,J=8.07Hz,1H),8.01(d,J=8.25Hz,1H),7.63(m ,2H),7.53(d,J=15.54Hz,1H),7.39(m,2H),7.20(d,J=8.22Hz,1H),6.93(m,2H),6.75(d,J=7.68Hz,1H); Mass(FAB)m / z 443[M+H] +

[0436] Example 35 (E)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-3-(2-(thiophen-2-yl)-6-(trifluoromethyl)pyridin-3-yl)acrylamide

[0437]

[0438] Yellow solid, yield 71%; 1 H NMR (400MHz, DMSO) δ10.70(s,1H),10.14(s,1H),10.01(s,1H),8.27(d,J=7.8Hz,1H),7.83-7.91(m,3H),7.48-7.48 (m,1H),7.25(dd,J=5.3,3.9Hz,1H),7.17(d,J=8.3Hz,1H),6.85-6.92(m,2H),6.75(d,J=7.8Hz,1H); Mass(FAB)m / z 431[M+H] +

[0439] Example 36 (E)-3-(2-(Furan-2-yl)-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide

[0440]

[0441] Light brown solid, yield 61%; 1H NMR (400MHz, DMSO) δ10.69(s,1H),10.12(s,1H),9.97(s,1H),8.29(d,J=8.0Hz,1H),8.00-8.07(m,2H),7.89(d,J=8. 2Hz,1H),7.19(d,J=8.2Hz,1H),7.08(d,J=3.7Hz,1H),6.83-6.92(m,2H),6.73-6.76(m,2H); Mass(FAB)m / z415[M+H] +

[0442] Example 37 (E)-3-(2-(oxazol-2-yl)-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide

[0443]

[0444] Light brown solid, yield 58%; 1 H NMR (300MHz, DMSO) δ10.69(s,1H),10.12(s,1H),9.97(s,1H),8.29(d,J=8.0Hz,1H),7.75(d,J=8. 2Hz,1H),7.60(d,J=8.2Hz,1H),7.15(m,2H),6.83-6.92(m,2H),6.73-6.76(m,2H); Mass(FAB)m / z 416[M+H] +

[0445] Example 38 (E)-3-(2-(oxazol-5-yl)-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide

[0446]

[0447] Light brown solid, yield 51%; 1 H NMR (400MHz, DMSO) δ10.69(s,1H),10.12(s,1H),9.97(s,1H),8.29(s,1H),7.75(d,J=8.2Hz, 1H),7.60(d,J=8.2Hz,1H),7.09(m,2H),6.83-6.92(m,2H),6.73-6.76(m,2H); Mass(FAB)m / z 416[M+H] +

[0448] Example 39 (E) -3- (2- (3,3-dimethyl-1-butyn-1-yl) -6- (trifluoromethyl) pyridin-3-yl) -N- (2-oxo-2,3-dihydro-1H-benzo [d] imidazole-4-yl) acrylamide

[0449]

[0450] Yellow solid, yield 67%; 1 H-NMR (400MHz, DMSO) δ10.70(s,1H),10.16(s,1H),9.99(s,1H),8.35(d,J=8.0Hz,1H),7.95(d,J=16.0Hz,1H),7.16(d, J=8.0Hz,1H),7.02(d,J=16.0Hz,1H),6.89(t,J=8.0Hz,1H),6.75(d,J=8.0Hz,1H),1.35(s,9H); Mass(FAB)m / z429[M+H] +

[0451] Example 40 (E)-3-(2-(3,3-dimethylbutyl)-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide

[0452]

[0453] Yellow solid, yield 82%; 1 H-NMR (400MHz, DMSO) δ10.70 (s, 1H), 10.14 (s, 1H), 9.97 (s, 1H), 8.20 (d, J = 8.0Hz, 1H), 7.80 (m, 2H), 7. 19(d,J=8.0Hz,1H),6.87-6.91(m,2H),6.72(d,J=8.0Hz,1H),2.88(m,2H),1.47(m,2H); Mass(FAB)m / z 433[M+H] +

[0454] Example 41 (E)-3-(2-cyclopentyl-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide

[0455]

[0456] Yellow solid, yield 82%; 1H-NMR (400MHz, DMSO) δ10.69(s,1H),10.13(s,1H),9.95(s,1H),8.14(d,J=8.0Hz,1H),7.87(d,J=15.6Hz,1H),7.76(d,J=8.0Hz,1H),7.16 (d,J=7.6Hz,1H),6.89(t,J=7.6Hz,1H),6.80-6.73(m,2H),3.62-3.54(m,1H),1.95(m,2H),1.85-1.76(m,4H),1.65(m,2H); Mass(FAB)m / z 417[M+H] +

[0457] Example 42 (E)-3-(2-isobutoxy-4-(trifluoromethyl)phenyl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide

[0458]

[0459] Yellow solid, yield 71%; 1 H NMR (300MHz, DMSO) δ10.69(s,1H),10.10(s,1H),9.85(s,1H),7.89(d,J=15.2Hz,1H),7.80(d,J=7.9Hz,1H),7.36(m,2H),7.20(d,J=8.2H z,1H),6.88-6.93(m,2H),6.75(d,J=7.7Hz,1H),3.95(d,J=6.2Hz,2H),1.97-2.12(m,1H),1.02(d,J=6.6Hz,6H); Mass(ESI)m / z420[M+H] +

[0460] Example 43 (E)-3-(2-(cyclopropylmethoxy)-4-(trifluoromethyl)phenyl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide

[0461]

[0462] Yellow solid, yield 65%; 1H NMR (300MHz, DMSO) δ10.70(s,1H),10.12(s,1H),9.88,(s,1H),7.89(d,J=15.8Hz,1H),7.81(d,J=7.7Hz,1H),7.34-7.38(m,2H),7.22(d, J=8.8Hz,1H),6.90-6.96(m,2H),6.76(d,J=7.7Hz,1H),4.03(d,J=7.1Hz,2H),1.31-1.16(m,1H),0.62(m,2H),0.38(m,2H); Mass(FAB)m / z 418[M+H] +

[0463] Example 44 (E)-3-(2-(cyclopropylmethoxy)-4-(2-hydroxypropane-2-yl)phenyl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide

[0464]

[0465] Yellow solid, yield 60%; 1 H NMR (400MHz, DMSO) δ10.66(s,1H),10.07(s,1H),9.70(s,1H),7.85(d,J=15.6Hz,1H),7.50(d,J=7.8Hz,1H),7.22(d,J=8.2Hz,1H),6.99-7.01( m,2H),6.88(t,J=8.0Hz,1H),6.70-6.75(m,2H),3.91(d,J=6.9Hz,2H),1.24(s,6H),0.57(t,J=6.2Hz,2H),0.34(t,J=5.0Hz,2H); Mass(FAB)m / z 408[M+H] +

[0466] Example 45 (E)-3-(4-(tert-butyl)-2-(cyclopropylmethoxy)phenyl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide

[0467]

[0468] Yellow solid, yield 70%; 1H NMR (400MHz, DMSO) δ10.66(s,1H),10.07(s,1H),9.70(s,1H),7.85(d,J=15.6Hz,1H),7.50(d,J=7.8Hz,1H),7.22(d,J=8.2Hz,1H),6.99-7.01(m ,2H),6.88(t,J=8.0Hz,1H),6.70-6.76(m,2H),3.92(d,J=6.9Hz,2H),1.25(s,10H),0.57(t,J=6.2Hz,2H),0.34(t,J=5.0Hz,2H); Mass(FAB)m / z 406[M+H] +

[0469] Example 46 (E)-3-(4-cyclopropyl-2-(cyclopropylmethoxy)phenyl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide

[0470]

[0471] White solid, yield 82%; 1 H-NMR (400MHz, DMSO) δ10.66(s,1H),10.05(s,1H),9.66(s,1H),7.82(d,J=15.6Hz, 1H),7.43(d,J=7.8Hz,1H),7.21(d,J=7.8Hz,1H),6.87(t,J=8.0Hz,1H),6.66-6.72 (m,4H),3.88(d,J=6.9Hz,2H),1.87-1.95(m,1H),1.25(m,1H),0.95(t,J=6.4Hz,2H ),0.71(d,J=4.6Hz,2H),0.57(d,J=7.8Hz,2H),0.32(d,J=4.6Hz,2H); Mass(FAB)m / z 390[M+H] +

[0472] Example 47 (E)-3-(1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide

[0473]

[0474] White solid, yield 82%; 1H NMR (300MHz, DMSO) δ10.73(s,1H),10.14(s,1H),10.02(s,1H),7.78(m,1H),7.67(m,2H),7.60(m,1H),7.50(s,1H),7.26(d,J =15.54Hz, 1H), 7.15 (d, J = 7.86Hz, 1H), 6.91 (t, J = 8.04Hz, 1H), 6.88 (d, J = 15.6Hz, 1H), 6.76 (d, J = 7.68Hz, 1H); Mass (FAB) m / z 448[M+H] +

[0475] Example 48 (E) -N- (2-oxo-2,3-dihydro-1H-benzo [d] imidazole-4-yl) -3- (1- (m-tolyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) acrylamide

[0476]

[0477] White solid, yield 60%; 1 H NMR (300MHz, DMSO) δ10.69(s,1H),10.11(s,1H),9.99,(s,1H),7.42-7.55(m,4H),7.35(d,J=7.9Hz,1H),7.26 (d,J=15.7Hz,1H),7.15(d,J=7.9Hz,1H),6.86-6.93(m,2H),6.76(d,J=7.7Hz,1H),2.42(s,3H); Mass(FAB)m / z 428[M+H] +

[0478] Example 49 (E) -3- (1- (3-chloro-4-fluorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) -N- (2-oxo-2,3-dihydro-1H-benzo [d] imidazole-4-yl) acrylamide

[0479]

[0480] Pale yellow solid, yield 73%; 1H NMR (300MHz, DMSO) δ10.70(s,1H),10.10(s,1H),9.99,(s,1H),7.99(dd,J=6.78,2.55Hz,1H),7.69-7.74(m,2H),7.48(s,1H),7 .24(d,J=15.8Hz,1H),7.15(d,J=8.1Hz,1H),6.92(d,J=8.0Hz,1H),6.85(d,J=16.3Hz,1H),6.76(d,J=7.9Hz,1H); Mass(FAB)m / z 466[M+H] +

[0481] Example 50 (E) -3- (1- (3-isopropylphenyl) -3- (trifluoromethyl) -1H- pyrazol-5-yl) -N- (2-oxo-2,3-dihydro -1H- benzo [d] imidazole-4-yl) acrylamide

[0482]

[0483] Pale yellow solid, yield 66%; 1 H NMR (300MHz, DMSO) δ10.70(s,1H),10.09(s,1H),9.98(s,1H),7.58-7.44(m,4H),7.37(m,1H),7.28(d,J=15.75Hz,1H), 7.15(d,J=8.25Hz,1H),6.93-6.80(m,2H),6.76(d,J=7.5Hz,1H),3.02(m,1H),1.26(s,3H),1.24(s,3H); Mass(FAB)m / z 456[M+H] +

[0484] Example 51 (E)-3-(1-(3-chlorophenyl)-3-isopropyl-1H-pyrazol-5-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide

[0485]

[0486] Yellow solid, yield 46%; 1H NMR (300MHz, DMSO) δ10.70(s,1H),10.10(s,1H),9.90(s,1H),7.59(m,3H),7.46(m,1H),7.31(d,J=15 .39Hz,1H),7.19(m,1H),6.90(m,1H),6.81(m,3H),3.0(m,1H),1.28(d,J=6.96Hz,4H); Mass(FAB)m / z 422[M+H] +

[0487] Example 52 (E) -3- (1- (3-chlorophenyl) -3- (1-methylcyclopropyl) -1H- pyrazol-5-yl) -N- (2-oxo-2,3-dihydro-1H-benzo [d] imidazole-4-yl) acrylamide

[0488]

[0489] Yellow solid, yield 87%; 1 H NMR(300MHz,DMSO)δ10.70(s,1H),10.10(s,1H),9.90(s,1H),7.61-7.58(m,3H),7.44(m,1H),7.28(d,J=15.39Hz,1H),7 .20(d,J=8.25Hz,1H),6.90(m,1H),6.78-6.71(m,3H),1.45(s,3H),1.23(s,1H),0.99(m,2H),0.80(m,2H); Mass(FAB)m / z 434[M+H] +

[0490] Example 53 (E)-3-(3-(tert-butyl)-1-(3-chlorophenyl)-1H-pyrazol-5-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide

[0491]

[0492] Yellow solid, yield 88%; 1H NMR(300MHz,DMSO-D6)δ10.73(s,1H),10.09(s,1H),9.87,(s,1H),7.57-7.64(m,3H),7.44-7.47(m,1H),7.3 2(d,J=15.4Hz,1H),7.20(d,J=8.0Hz,1H),6.86-6.93(m,2H),6.74-6.79(m,2H),1.33(s,9H); Mass(FAB)m / z 436[M+H] +

[0493] Example 54 (E)-3-(4-(3-chlorophenyl)-2-(trifluoromethyl)thiazol-5-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide

[0494]

[0495] Light brown solid, yield 77%; 1 H-NMR (400MHz, DMSO) δ10.70(s,1H),10.08(s,1H),10.02(s,1H),7.66(d,J=10.8Hz,1H),7.59(m,4H),7 .12(d,J=8.0Hz,1H),6.88(t,J=8.4Hz,1H),6.80(d,J=15.6Hz,1H),6.74(d,J=8.0Hz,1H); Mass(FAB)m / z 465[M+H] +

[0496] Example 55 (E)-3-(4-(3-chlorophenyl)-2-isopropylthiazol-5-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide

[0497]

[0498] Light yellow solid, yield 78%; 1H NMR (400MHz, DMSO) δ10.69(s,1H),10.05(s,1H),9.85(s,1H),7.63(d,J=15.2Hz,1H),7.63(s,1H),7.56-7.52(m,3H),7.17(d,J=8 .4Hz,1H),6.88(t,J=8.0Hz,1H),6.73(d,J=7.6Hz,1H),6.56(d,J=15.6Hz,1H),3.35(m,1H),1.37(d,J=6.8Hz,6H); Mass(FAB)m / z 439[M+H] +

[0499] Example 56 (E)-3-(4-(3-chlorophenyl)-2-cyclopropylthiazol-5-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide

[0500]

[0501] Light yellow solid, yield 78%; 1 H NMR (400MHz, DMSO) δ10.69(s,1H),10.05(s,1H),9.84(s,1H),7.61(s,1H),7.60(d,J=15.6Hz,1H),7.56 -7.53(m,3H),7.17(d,J=8.0Hz,1H),6.88(t,J=8.4Hz,1H),6.73(d,J=7.2Hz,1H),6.50(d,J=15.6Hz,1H),1.21(m,3H),1.10(m,2H); Mass(FAB)m / z 437[M+H] +

[0502] Example 57 (E) -3- (4- (3-chlorophenyl) -2- (1-methylcyclopropyl) thiazol-5-yl) -N- (2-oxo-2,3-dihydro-1H-benzo [d] imidazole-4-yl) acrylamide

[0503]

[0504] Light brown solid, yield 66%; 1H NMR (400MHz, DMSO) δ10.68(s,1H),10.03(s,1H),9.81(s,1H),7.59(m,1H),7.58(d,J=15.2Hz,1H),7.54 -7.49(m,3H),7.15(d,J=8.4Hz,1H),6.86(t,J=8.0Hz,1H),6.71(d,J=7.2Hz,1H ),6.51(d,J=15.2Hz,1H),1.55(s,3H),1.31(m,2H),1.08(m,2H); Mass(FAB)m / z 451[M+H] +

[0505] Example 58 (E)-3-(2-(tert-butyl)-4-(3-chlorophenyl)thiazol-5-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide

[0506]

[0507] Light brown solid, yield 66%; 1 H NMR (400MHz, DMSO) δ10.66(s,1H),10.01(s,1H),9.82(s,1H),7.67(d,J=15.2Hz,1H),7.66(m,1H),7.58(m,3H),7.21 (d,J=8.12Hz,1H),6.91(t,J=7.96Hz,1H),6.75(d,J=7.72Hz,1H),6.60(d,J=15.2Hz,1H),1.46(s,9H); Mass(FAB)m / z 453[M+H] +

[0508] <Example 59> 3-(2-isobutoxy-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)propanamide

[0509]

[0510] Light yellow solid, yield 86%; 1H NMR (500MHz, CDCl3) δ9.14 (s, 1H), 8.16 (s, 1H), 7.58 (d, J = 7.35Hz, 1H), 7.27 (s, 1H),7.16(d,J=7.40Hz,1H),6.93(t,J=7.90Hz,1H),6.81(d,J=7.75Hz,1H),6.58 (d,J=8.05Hz,1H),4.16(d,J=6.45Hz,2H),3.05(t,J=7.25Hz,2H),2.74(t,J=7.2 5Hz,2H),2.11(p,J=6.70Hz,1H),1.03(d,J=6.65Hz,6H); Mass(FAB)m / z423[M+H] +

[0511] <Example 60> 3-(2-(cyclopropylmethoxy)-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)propanamide

[0512]

[0513] White solid, yield 77%; 1 H NMR (300MHz, DMSO) δ10.66 (s, 1H), 10.08 (s, 1H), 9.53 (s, 1H), 7.80 (d, J = 7.50Hz, 1H),7.41(d,J=6.00Hz,1H),7.07(d,J=8.25Hz,1H),6.87(t,J=7.86Hz,1H),6.72( d,J=7.86Hz,1H),4.20(d,J=6.96Hz,2H),2.96(t,J=7.14Hz.2H),2.70(t,J=7.50H z,2H),1.28(m,1H),0.55(q,J=5.70Hz,2H),0.40(q,J=5.70Hz,2H); Mass(FAB)m / z 421[M+H] +

[0514] <Example 61> 2-(2-isobutoxy-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)cyclopropane-1-carboxamide

[0515]

[0516] Light yellow solid, yield 72%; 1H NMR (500MHz, CDCl3) δ9.14 (s, 1H), 8.16 (s, 1H), 7.58 (d, J = 7.35Hz, 1H), 7.27 (s, 1 H),7.16(d,J=7.40Hz,1H),6.93(t,J=7.90Hz,1H),6.81(d,J=7.75Hz,1H),6.58(d ,J=8.05Hz,1H),4.16(d,J=6.45Hz,2H),3.11(s,1H),2.89(s,1H),2.11(p,J=6.70 Hz,1H),1.23(m,2H),1.03(d,J=6.65Hz,6H),0.89(m,1H); Mass(FAB)m / z435[M+H] +

[0517] <Example 62> 2-(2-(cyclopropylmethoxy)-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)cyclopropane-1-carboxamide

[0518]

[0519] White solid, yield 65%; 1 H NMR(300MHz,DMSO)δ10.66(s,1H),10.08(s,1H),9.53(s,1H),7.80(d,J=7.50Hz,1H) ,7.41(d,J=6.00Hz,1H),7.07(d,J=8.25Hz,1H),6.87(t,J=7.86Hz,1H),6.72(d,J=7. 86Hz,1H),4.20(d,J=6.96Hz,2H),2.96(t,J=7.14Hz.2H),2.70(t,J=7.50Hz,2H),1. 28(m,3H),0.80(m,1H),0.55(q,J=5.70Hz,2H),0.40(q,J=5.70Hz,2H); Mass(FAB)m / z 433[M+H] +

[0520] <Example 63> 2-(1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)cyclopropane-1-carboxamide

[0521]

[0522] White solid, yield 78%; 1H NMR (400MHz, DMSO) δ10.67(s,1H),9.95(s,1H),9.85(s,1H),7.75(s,1H),7.66-7.64(t,J=5.88Hz,1H),7.57(s,2H),7.07(d,J=6.52Hz,1H), 6.90(d,1H),6.87(s,1H),6.74(d,J=6.16Hz,1H),2.35(m,1H),2.18(m,1H),1.53(t,J=5.92Hz,2H),1.23(s,2H),0.80(m,1H); Mass(FAB)m / z 462[M+H] +

[0523] <Example 64> 2-(1-(3-chlorophenyl)-3-(1,1-difluoroethyl)-1H-pyrazol-5-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)cyclopropane-1-carboxamide

[0524]

[0525] Yellow solid, yield 65%; 1 H NMR (300MHz, DMSO) δ10.67(s,1H),9.95(s,1H),9.87(s,1H),7.63(s,1H),7.56(m,1H),7.46(t,J=8.22Hz,1H),7.41(s,1H),7.10(d ,J=7.89Hz,1H),6.88(t,J=7.68Hz,1H),6.73(d,J=8.07Hz,1H),6.05(s,1H),1.23(m,1H),0.91(m,1H),0.67(m,3H); Mass(FAB)m / z 458[M+H] +

[0526] <Example 65> 2-(1-(3-chlorophenyl)-3-isopropyl-1H-pyrazol-5-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)cyclopropane-1-carboxamide

[0527]

[0528] Light brown solid, yield 60%; 1H NMR(300MHz,DMSO)δ10.67(s,1H),9.98(s,1H),9.89(s,1H),7.64(s,1H),7.5 9(d,J=7.68Hz,1H),7.48(t,J=8.25Hz,1H),7.42(m,1H),7.16(d,J=8.04Hz,1 H),6.88(t,J=7.53Hz,1H),6.72(d,J=7.62Hz,1H),6.21(s,1H),2.30(m,1H), 2.19(m,1H),1.74(s,2H),1.51(m,1H),1.23(d,J=6.78Hz,6H); Mass(FAB)m / z 436[M+H] +

[0529] <Example 66> 2-(1-(3-chlorophenyl)-3-cyclopropyl-1H-pyrazol-5-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)cyclopropane-1-carboxamide

[0530]

[0531] Yellow solid, yield 82%; 1 H NMR(300MHz,DMSO)δ10.67(s,1H),9.98(s,1H),9.89(s,1H),7.64(s,1H),7 .57(m,2H),7.49(t,J=8.25Hz,2H),7.42(m,2H),7.10(d,J=7.86Hz,1H),6. 88(t,J=7.68Hz,1H),6.73(d,J=7.68Hz,1H),6.05(s,1H),2.32(m,1H),2.0 8(m,1H),1.95(m,2H),1.51(m,1H),0.89(m,2H),0.67(m,2H); Mass(FAB)m / z 434[M+H] +

[0532] <Example 67> 2-(1-(3-chlorophenyl)-3-(1-methylcyclopropyl)-1H-pyrazol-5-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)cyclopropane-1-carboxamide

[0533]

[0534] Yellow solid, yield 73%; 1H NMR (300MHz, DMSO) δ10.68(s,1H),9.96(s,1H),9.87(s,1H),7.64(s,1H),7.57(m,1H),7.49(t,J=8.25Hz,1H),7.42(m,1H),7.10(d ,J=7.86Hz,1H),6.88(t,J=7.68Hz,1H),6.73(d,J=7.68Hz,1H),6.12(s,1H),1.40(s,3H),0.91(s,2H),0.74(s,2H); Mass(FAB)m / z 448[M+H] +

[0535] <Example 68> 2-(3-(tert-butyl)-1-(3-chlorophenyl)-1H-pyrazol-5-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)cyclopropane-1-carboxamide

[0536]

[0537] Yellow solid, yield 82%; 1 H NMR(400MHz,DMSO)δ10.67(s,1H),9.93(s,1H),9.85(s,1H),7.64(s,1H),7.6 0(d,J=6.92Hz,1H),7.51(t,J=8.00Hz,1H),7.44(d,J=6.92Hz,1H),7.11(d,J =8.08Hz,1H),6.89(t,J=7.96Hz,1H),6.74(d,J=7.76Hz,1H),6.22(s,1H),2. 32(m,1H),2.13(m,1H),1.53(m,1H),1.42(m,1H),1.27(s,9H); Mass(FAB)m / z 450[M+H] +

[0538] The chemical formulas of the compounds prepared in Examples 1-68 are summarized and shown in Table 1 below.

[0539] [Table 1]

[0540]

[0541]

[0542]

[0543]

[0544]

[0545]

[0546]

[0547] <Comparative Example 1> Preparation of 1-(2-oxo-1,3-dihydrobenzimidazol-4-yl)-3-[[2-pyrrolidin-1-yl-6-(trifluoromethyl)-3-pyridyl]methyl]urea

[0548]

[0549] As a compound of Comparative Example 1, the compound of Example 39 disclosed in Korean Patent Publication No. 10-2013-0065636 (WO 2011 / 120604A1) was prepared.

[0550] <Comparative Example 2> Preparation of 1-[[2-isopropoxy-6-(trifluoromethyl)-3-pyridyl]methyl]-3-(2-oxo-1,3-dihydrobenzimidazol-4-yl)urea

[0551]

[0552] As a compound of Comparative Example 2, the compound of Example 68 disclosed in Korean Patent Publication No. 10-2013-0065634 (WO 2011 / 120604 A1) was prepared.

[0553] <Comparative Example 3> Preparation of 1-(2-oxo-1,3-dihydrobenzimidazol-4-yl)-3-[[2-(1-piperidinyl)-6-(trifluoromethyl)-3-pyridinyl]methyl]urea

[0554]

[0555] As a compound of Comparative Example 3, the compound of Example 71 disclosed in Korean Patent Publication No. 10-2013-0065634 (WO 2011 / 120604 A1) was prepared.

[0556] <Experimental Example 1> Evaluation of the antagonistic effect of TRPV1 (transient receptor potential vanilloid subtype 1) receptor activators (in vitro)

[0557] As described above, the side effect of increasing body temperature of the first generation TRPV1 antagonists developed so far has been reported to be due to the antagonism of all TRPV1 receptor activators (capsaicin, heat, pH, NADA). In particular, it has been reported that blocking 100% of pH in TRPV1 receptor activators causes excessive increase in body temperature, and blocking 20% ​​or less causes proton activation at high concentrations, thereby causing excessive decrease in body temperature. That is, in the development of TRPV1 antagonists, when TRPV1 activation caused by capsaicin and heat is blocked, but appropriate inhibition of pH of about 20% to 80% is induced, which may lead to the effect of not only alleviating pain but also reducing side effects such as abnormal body temperature.

[0558] Hereinafter, it was evaluated whether the example compounds provided in one aspect of the present invention can block capsaicin-induced TRPV1 activation but induce a moderate inhibition of pH of about 20%-80%, thereby alleviating pain and reducing side effects such as abnormal body temperature.

[0559] Antagonism of capsaicin and pH, hTRPV1 receptor activators, was studied and the target was set at IC50(CAP) < 15 nM (efficacy), 80% inhibition at pH = 6 (non-hyperthermia). This is because in our own experiments, the IC50(CAP) of the control clinical drug Mavatrep was studied as 13.8 nM, and when pH antagonism is below 80% inhibition, it is considered non-hyperthermia.

[0560] Ca 2+ Influx assay

[0561] PrecisIONTM hTRPV1-HEK recombinant cells (CYL3063) were purchased from Millipore and used as cells for human TRPV1 (hTRPV1) antagonist assay. DME / F-12 (HyClone) (10% FBS, 1% NEAA, 1% penicillin-streptomycin) was used as culture medium, and Fluo4-NW (Molecular Probes, F-36206) was used as ELISA kit. After culturing the above cells at 37°C and 5% CO2, the cells were plated at 5×10 4 The density of cells / well was inoculated in a 96-well plate and then cultured for 16 hours. Then, the culture medium was removed and 100 μL of staining solution was added to each well, followed by culture at 37°C, 5% CO2 for 30 minutes. Then, the cells were acclimated at room temperature for 15 minutes, and the test substances (example compounds of the present invention and comparative example compounds) were added to each well and then cultured at room temperature for 15 minutes. After diluting capsaicin (Sigma, M2028) to a concentration of 10 nM, it was added to each well of the plate and fluorescence (ex485 / em535) was measured. In the above experiment, BCTC was used as a representative TRPV1 antagonist to evaluate the efficacy of the drug.

[0562] Evaluation of human pH inhibitory activity

[0563] PrecisIONTM hTRPV1-HEK recombinant cells (CYL3063) were purchased from Millipore and used. After culturing the above cells at 37°C and 5% CO2, the cells were plated at 5×10 4 The cells / well were seeded in a 96-well plate at a density of 1:1 and then cultured for 16 hours. The culture medium was then removed, and 100 μL of staining solution was added to each well and cultured for 30 minutes at 37°C and 5% CO2. After 30 minutes, all existing staining solutions were removed and replaced with 100 μL of HBSS. The cells were then acclimated at room temperature for 15 minutes, and the test substances (example compounds of the present invention and comparative example compounds) were added to each well and then cultured at room temperature for 15 minutes. The final pH was then adjusted to 6.0 with MES, and fluorescence (ex485 / em535) was measured. In the pH test, BCTC was used as a TRPV1 antagonist to evaluate the efficacy of the drug.

[0564] The in vitro test results of <Experimental Example 1> and the in vivo test results of <Experimental Example 2> were combined, as shown in Table 2 below.

[0565] <Experimental Example 2> Evaluation of bioavailability (BA)

[0566] Efficacy, ADME and toxicity properties are important for new drug candidates, and as pharmacokinetic properties, they should have a blood concentration profile above a certain level, based on which it is very important to check whether the PK-PD correlation is good. Using the PK parameters of new drug candidates obtained from experimental animals such as rats or mice, the blood concentration and drug efficacy in humans can be predicted by allometric scaling or PK-PD prediction. For this purpose, it is important to measure Cl and Vss, which will determine the dose and dosing interval to obtain PK parameters such as Cmax, tmax, and tmax during oral administration. 1 / 2 and AUCall. In addition, basic information related to the metabolic enzymes, transporters, and tissue distribution of candidate substances can be obtained, and inappropriate physical properties can be estimated. The information obtained through this analysis can provide important decision criteria for obtaining the best candidates and contribute to the molecular design and development of more effective drugs.

[0567] Test Method

[0568] SD rats (Coatec, Hana Trading Co., Ltd., 7-8 weeks old, male, n=4, 250-300g) were used in the experiment. The rats were raised in a small animal breeding room (experimental animal center) at a temperature of 22±2°C, a relative humidity of 50±5%, a light exposure time of 12 hours (08:00-20:00), and a light intensity of 150-300lux. The rats were free to eat and drink RO water during the entire test period. The rats were fasted for 16 hours before oral administration of the test substances (the example compounds of the present invention and the comparative example compounds).

[0569] The dosage of the example compounds of the present invention and the comparative example compounds was 5 mg / kg for intravenous administration and 10 mg / kg for oral administration. For intravenous administration, a clear solution of 10% DMSO, 10% Cremophor EL and 80% PEG400 was used. For oral administration, a solution or suspension of 10% DMSO and 10% Cremophor EL dissolved in 80% DDW was used.

[0570] After intravenous or oral administration, blood was collected at 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours and 8 hours, and the concentration of the test substance (the example compounds of the present invention and the comparative example compounds) in plasma was measured by LC-MS / MS.

[0571] After adding 80 μl of acetonitrile (including internal standard) to 20 μl of plasma, centrifugation was carried out at 15,000 rpm for 5 minutes at 4°C by vortexing. The supernatant obtained after centrifugation was analyzed by LC-MS / MS. For HPLC, a Nexera XR system (Shimadzu, Japan) was used, and for mass spectrometry, a TSQ vantage triple quadruple (Thermo, USA) was used.

[0572] ①HPLC conditions

[0573]

[0574]

[0575] PK parameters were calculated using Phoenix WinNonlin version 6.4 (Pharsight, USA) program using a non-compartmental analysis model.

[0576] The AUC (area under the plasma concentration-time curve) for up to 8 hours was calculated from the measured plasma concentrations by the trapezoidal rule, and the oral absorption rate (F%) was calculated based on the ratio of the AUC when the same dose was administered intravenously. The AUC was calculated using the linear trapezoidal rule during the rising plasma level phase and the logarithmic trapezoidal rule during the falling plasma level phase.

[0577] The results are shown in Table 2 below.

[0578] [Table 2]

[0579]

[0580]

[0581]

[0582]

[0583] *NT = Not Tested

[0584] As shown in Table 2, the example compounds provided by the present invention on one hand block the activation of TRPV1 caused by capsaicin, but induce a proper inhibition of pH of about 20%-80%, so the compounds have the effect of alleviating pain and reducing side effects such as abnormal body temperature. In addition, it is confirmed that the compounds of the present invention have a high PK value, so the example compounds are easily absorbed by the human body, and thus also maintain thermoneutrality.

[0585] On the other hand, the compounds of Comparative Examples 1 to 3 blocked the activation of TRPV1 caused by capsaicin, but inhibited the pH to be lower or higher than required, i.e., outside the appropriate range of 20% to 80%. In addition, it was confirmed that the compounds of the comparative examples had low PK values, and therefore, the compounds were not easily absorbed by the human body, and there was a problem that it was difficult to use them as practical analgesics.

[0586] <Production Example 1> Preparation of powder

[0587] The derivative shown in formula 1 2g

[0588] Lactose 1g

[0589] Powder is prepared by mixing all the above ingredients and filled in sealed packages.

[0590] <Manufacturing Example 2> Preparation of tablets

[0591]

[0592] Tablets are prepared by mixing all the above ingredients by a conventional tablet preparation method.

[0593] <Manufacturing Example 3> Preparation of capsules

[0594]

[0595]

[0596] Capsules are prepared by mixing all the above ingredients, and filled into gelatin capsules according to a conventional method for preparing capsules.

[0597] <Manufacturing Example 4> Preparation of injection

[0598]

[0599] The injection solution is prepared by including all the above-mentioned components in the amounts shown according to the conventional method for preparing injection solutions.

[0600] Industrial Applicability

[0601] The example compounds provided in one aspect of the present invention block TRPV1 activation caused by capsaicin and heat, but exhibit 20%-80% TRPV2 inhibitory activity relative to pH, and thus can not only improve pain but also effectively reduce side effects such as abnormal body temperature effects.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the following compounds: (1) (E)-3-(2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide; (2) (E)-3-(2-(4-ethylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide; (3) (E)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-3-(2-(pyrrolidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)acrylamide; (4) (E)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-3-(2-(piperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)acrylamide; (5) (E)-3-(2-morpholino-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide; (6) (E)-3-(2-(diethylamino)-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide; (7) (E)-3-(2-(dipropylamino)-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide; (8) (E)-3-(2-butoxy-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide; (9) (E)-3-(2-(hexyloxy)-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide; (10) (E)-3-(2-isobutoxy-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide; (11) (E)-3-(2-cyclobutyloxy-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide; (12) (E)-3-(2-(cyclopentyloxy)-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide; (13) (E)-3-(2-(cyclopropylmethoxy)-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide; (14) (E)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-3-(2-(2,2,2-trifluoroethoxy)-6-(trifluoromethyl)pyridin-3-yl)acrylamide; (15) (E)-3-(2-(neopentyloxy)-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide; (16) (E)-3-(2-((2-methylcyclopropyl)methoxy)-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide; (17) (E)-3-(6-(chlorodifluoromethyl)-2-(cyclopropylmethoxy)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide; (18) (E)-3-(6-cyclopropyl-2-(cyclopropylmethoxy)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide; (19) (E)-3-(2-(cyclopropylmethoxy)-6-isopropylpyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide; (20) (E)-3-(2-(cyclopropylmethoxy)-6-(1-methylcyclopropyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide; (21) (E)-3-(2-(cyclopropylmethoxy)-6-(difluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide; (22) (E)-3-(2-(cyclopropylmethoxy)-6-(1,1-difluoroethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide; (23) (E)-3-(6-(tert-butyl)-2-(cyclopropylmethoxy)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide; (25) (E)-3-(2-(cyclobutylmethoxy)-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide; (26) (E)-3-(2-(cyclopentylmethoxy)-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide; (27) (E)-3-(2-(isobutylthio)-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide; (28) (E)-3-(2-((cyclopropylmethyl)thio)-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide; (29) (E)-3-(2-(cyclohexylthio)-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide; (30) (E)-3-(2-(3-fluorophenyl)-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide; (31) (E)-3-(2-(3-chlorophenyl)-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide; (32) (E)-3-(2-(3-isopropylphenyl)-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide; (33) (E)-3-(2-(3-chloro-4-fluorophenyl)-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide; (34) (E)-3-(2-(4-fluorophenyl)-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide; (35) (E)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-3-(2-(thiophen-2-yl)-6-(trifluoromethyl)pyridin-3-yl)acrylamide; (36) (E)-3-(2-(furan-2-yl)-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide; (39) (E)-3-(2-(3,3-dimethyl-1-butyn-1-yl)-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide; (40) (E)-3-(2-(3,3-dimethylbutyl)-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide; (41) (E)-3-(2-cyclopentyl-6-(trifluoromethyl)pyridin-3-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide; (42) (E)-3-(2-isobutoxy-4-(trifluoromethyl)phenyl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide; (43) (E)-3-(2-(cyclopropylmethoxy)-4-(trifluoromethyl)phenyl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide; (45) (E)-3-(4-(tert-butyl)-2-(cyclopropylmethoxy)phenyl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide; (46) (E)-3-(4-cyclopropyl-2-(cyclopropylmethoxy)phenyl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide; (47) (E)-3-(1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide; (48) (E)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-3-(1-(m-tolyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)acrylamide; (49) (E)-3-(1-(3-chloro-4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide; (50) (E)-3-(1-(3-isopropylphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide; (51) (E)-3-(1-(3-chlorophenyl)-3-isopropyl-1H-pyrazol-5-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide; (52) (E)-3-(1-(3-chlorophenyl)-3-(1-methylcyclopropyl)-1H-pyrazol-5-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide; (53) (E)-3-(3-(tert-butyl)-1-(3-chlorophenyl)-1H-pyrazol-5-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide; (54) (E)-3-(4-(3-chlorophenyl)-2-(trifluoromethyl)thiazol-5-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide; (55) (E)-3-(4-(3-chlorophenyl)-2-isopropylthiazol-5-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide; (56) (E)-3-(4-(3-chlorophenyl)-2-cyclopropylthiazol-5-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide; (57) (E)-3-(4-(3-chlorophenyl)-2-(1-methylcyclopropyl)thiazol-5-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide; and (58) (E)-3-(2-(tert-Butyl)-4-(3-chlorophenyl)thiazol-5-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acrylamide.

2. A pharmaceutical composition for preventing or treating pain, comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

3. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating pain by inhibiting TRPV1 (transient receptor potential vanilloid type 1) receptor activators.

4. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof in the preparation of analgesics.

5. A pharmaceutical kit for preventing or treating pain, comprising a first component and a second component, wherein the first component comprises the compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient; and the second component comprises an analgesic as an active ingredient.

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