Indolecarboxamide derivatives and pharmaceutical compositions containing the same

Abstract

The present invention relates to an indolecarboxamide derivative having excellent activity and suppressing the production of PGE2 by suppressing microsomal prostaglandin E2 synthase-1 (mPGES-1) and a pharmaceutical composition comprising the indolecarboxamide derivative as an active ingredient. The indolecarboxamide derivative according to the present invention can be effectively used to treat or prevent inflammation, arthritis, high fever, pain, cancer and brain diseases such as stroke or Alzheimer's disease.

Description

Technical Field

[0001] The present invention relates to an indolecarboxamide derivative and a pharmaceutical composition containing the same, and more particularly, to an indolecarboxamide derivative that blocks the production of prostaglandin E2 (PGE2, a factor that induces inflammation) by inhibiting microsomal prostaglandin E synthase-1 (mPGES-1) and a pharmaceutical composition containing the same as an active ingredient. Background Art

[0002] Prostaglandins are endocrine substances involved in various physiological processes, and one of them, prostaglandin E2 (PGE2), is known to be involved in inducing inflammation.

[0003] As a therapeutic agent for this inflammation, COX-2 inhibitors that selectively inhibit only cyclooxygenase-2 (COX-2) have been developed. As a representative COX-2 inhibitor, Celebrex (Celecoxib) from Pfizer TM ), Valdecoxib (Bextra TM ) and rofecoxib (Vioxx from Merck TM ) are known. They have been widely used for arthritis, severe pain, rheumatism, etc.

[0004] However, although COX-2 inhibitors reduce gastrointestinal dysfunction (the biggest side effect of nonsteroidal anti-inflammatory drugs (NSAIDs)), they have been removed from the pharmaceutical market due to cardiovascular side effects, with the exception of celecoxib. These cardiovascular side effects are reported to occur because the production of the intermediate PGH2 (prostaglandin H2) is inhibited, thereby inhibiting not only the production of PGE2, but also the production of PGI2 (prostacyclin) and TXA2 (thromboxane).

[0005] Therefore, inhibitors of microsomal prostaglandin E synthase-1 (mPGES-1) that selectively inhibit PGE2 production by acting on the final stage of PGH2 are considered to be new drug candidates that utilize the advantages of COX-2 inhibitors and make up for the disadvantages, and research on mPGES-1 is underway.

[0006] Specifically, inhibition of mPGES-1 has been shown in animal model studies of pain and inflammation to be as effective as treatment with nonsteroidal anti-inflammatory drugs and is expected to be effective in the treatment of inflammation, arthritis, high fever, pain, cancer, stroke, and brain diseases such as Alzheimer's disease.

[0007] For example, pyridopyrimidine derivatives having the following formula (I) have been proposed as inhibitors of mPGES-1 (Bioorgnic & Medicinal Chemistry Letters, 2014, 24, 4838-4844).

[0008]

[0009] However, the development of new mPGES-1 inhibitors that are more effective and without side effects is needed. Summary of the Invention

[0010] Technical issues

[0011] An object of the present invention is to provide an indolecarboxamide derivative having the following formula (II) or a pharmaceutically acceptable salt thereof, which strongly inhibits the production of PGE2.

[0012] Another object of the present invention is to provide a pharmaceutical composition for inhibiting mPGES-1, which comprises an indolecarboxamide derivative having the following formula (II) or a pharmaceutically acceptable salt thereof.

[0013] Technical Solution

[0014] One embodiment of the present invention relates to an indolecarboxamide derivative having the following formula (II) or a pharmaceutically acceptable salt thereof.

[0015]

[0016] in,

[0017] R 1 is an aryl group;

[0018] L is absent or is a C1-C6 alkylene group;

[0019] R 2 is hydrogen; or

[0020] L and R 2 bonded to each other to form a 4- to 7-membered heterohydrocarbon ring;

[0021] Y 1 and Y 2 are each independently C═O or CH 2 ; and

[0022] R 3 is hydrogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group or a C2-C 12 Alkoxyalkyl group.

[0023] As used herein, the term "aryl group" includes aromatic and heteroaromatic groups and partially reduced derivatives thereof. An aromatic group is a 5- to 15-membered monocyclic or condensed ring, and a heteroaromatic group refers to an aromatic group containing at least one oxygen, sulfur, or nitrogen. Examples of representative aryl groups include phenyl, naphthyl, pyridyl, furyl, thiophenyl, indolyl, quinolyl, imidazolinyl, oxazolyl, thiazolyl, and tetrahydronaphthyl, but are not limited thereto.

[0024] As used herein, the term "C1-C6 alkylene group" refers to a linear or branched divalent hydrocarbon consisting of 1 to 6 carbon atoms, and includes, for example, methylene, ethylene, propylene, butylene, etc., but is not limited thereto.

[0025] As used herein, the term "4- to 7-membered heterohydrocarbon ring" refers to a functional group in which at least one of the ring carbons of the 4- to 7-membered hydrocarbon ring is substituted with oxygen, sulfur or nitrogen, and includes, for example, piperidine, morpholine, pyrimidine, oxolein, oxane, thiazolidine and the like, but is not limited thereto.

[0026] As used herein, the term "C1-C6 alkyl group" refers to a straight or branched monovalent hydrocarbon consisting of 1 to 6 carbon atoms, and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, etc., but is not limited thereto.

[0027] As used herein, the term "C1-C6 haloalkyl group" refers to a straight or branched hydrocarbon having 1 to 6 carbon atoms substituted by one or more halogens selected from the group consisting of fluorine, chlorine, bromine and iodine, and includes, for example, trifluoromethyl, trichloromethyl, trifluoroethyl and the like, but is not limited thereto.

[0028] As used herein, the term "C2-C 12 The “alkoxyalkyl group” refers to a composite group formed by substituting a C1-C6 alkoxy group on the carbon of a C1-C6 alkyl group, and includes, for example, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, propoxymethyl, propoxyethyl, propoxypropyl and the like, but is not limited thereto.

[0029] Aryl groups, C1-C6 alkylene groups, 4- to 7-membered heterohydrocarbon rings, C1-C6 alkyl groups, C1-C5 haloalkyl groups, and C2-C 12 One or more hydrogen atoms of the alkoxyalkyl group may be replaced by C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 alkyl, C4-C6 alkyl, C6-C6 alkyl, C7-C6 alkyl, C8-C6 alkyl, C9-C6 alkyl, C1-C6 alkyl, C2 ...3-C 10 Cycloalkyl, C3-C 10 Heterocycloalkyl, C3-C 10The alkyl radicals may be substituted by heterocycloalkyloxy, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 thioalkoxy, aryl, acyl, hydroxy, thio, halogen, amino, alkoxycarbonyl, carboxyl, carbamoyl, cyano, nitro, or the like.

[0030] In one embodiment of the present invention, the indolecarboxamide derivative may be an indolecarboxamide derivative or a pharmaceutically acceptable salt thereof, which is a compound having the following formula (II-1).

[0031]

[0032] in,

[0033] R 1 is an aryl group;

[0034] L is absent or is a C1-C6 alkylene group;

[0035] R 2 is hydrogen; or

[0036] L and R 2 bonded to each other to form a 4- to 7-membered heterohydrocarbon ring;

[0037] Y 1 and Y 2 are each independently C═O or CH 2 ; and

[0038] R 3 is hydrogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group or a C2-C 12 Alkoxyalkyl group.

[0039] In one embodiment of the present invention, the indolecarboxamide derivative may be an indolecarboxamide derivative or a pharmaceutically acceptable salt thereof, which is a compound having the following formula (II-2).

[0040]

[0041] in,

[0042] R 1 is an aryl group;

[0043] L is absent or is a C1-C6 alkylene group;

[0044] R 2 is hydrogen; or

[0045] L and R 2 bonded to each other to form a 4- to 7-membered heterohydrocarbon ring;

[0046] Y 1 and Y 2are each independently C═O or CH 2 ; and

[0047] R 3 is hydrogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group or a C2-C 12 Alkoxyalkyl group.

[0048] In one embodiment of the present invention, the indolecarboxamide derivative is a compound wherein R 1 is an aryl group which is substituted or unsubstituted by one or more substituents selected from the group consisting of halogen, C1-C6 alkyl group, C1-C6 haloalkyl group, C1-C6 alkoxy group, C1-C6 haloalkoxy group, nitro, aryl group, C3-C 10 Cycloalkyl groups, C3-C 10 heterocycloalkyl group, cyano group, C1-C6 alkoxycarbonyl group and carboxyl group.

[0049] In one embodiment of the present invention, the indolecarboxamide derivative is a compound wherein R 1 is phenyl, pyridyl, pyrazolyl, pyrimidinyl, naphthyl, benzodioxolyl or tetrahydronaphthyl, which may be substituted or unsubstituted by one or more substituents selected from the group consisting of fluoro, chloro, bromo, methyl, tert-butyl, trifluoromethyl, methoxy, trifluoromethoxy, nitro, phenyl, trifluoromethylphenyl, cyclohexyl, morpholinyl, cyano, methoxycarbonyl and carboxyl.

[0050] In one embodiment of the present invention, the indolecarboxamide derivative is wherein Y 1 or Y 2 A compound wherein at least one of the compounds is C=O.

[0051] In one embodiment of the present invention, the indolecarboxamide derivative is a compound wherein R 1 is phenyl, pyridyl, pyrazolyl, pyrimidinyl, naphthyl, benzodioxolyl or tetrahydronaphthyl, which may be substituted or unsubstituted by one or more substituents selected from the group consisting of fluoro, chloro, bromo, methyl, tert-butyl, trifluoromethyl, methoxy, trifluoromethoxy, nitro, phenyl, trifluoromethylphenyl, cyclohexyl, morpholinyl, cyano, methoxycarbonyl and carboxyl; L is absent or is methylene or ethylene; R 2 is hydrogen; or L and R 2 bonded to each other to form piperazine; Y 1 and Y 2 are each independently C═O or CH 2 ; and R 3is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, trifluoromethyl, difluoroethyl, trifluoroethyl, methoxymethyl, methoxyethyl, methoxypropyl or ethoxymethyl.

[0052] In one embodiment of the present invention, the indolecarboxamide derivative is a compound wherein R 1 is a phenyl group substituted with a C1-C6 haloalkoxy group; L is absent; R 2 is hydrogen; Y 1 and Y 2 is C=O; and R 3 It is a C1-C6 alkyl group.

[0053] The pharmaceutically acceptable salts of the present invention include both non-toxic inorganic salts and organic salts, and may be acid addition salts or base addition salts. Examples of acid addition salts include hydrochlorides, sulfates, nitrates, phosphates, acetates, adipates, aspartates, benzoates, benzenesulfonates, citrates, camphorates, camphorsulfonates, diphosphates, ethanesulfonates, fumarates, glutamates, malates, lactates, methanesulfonates, succinates, tartrates, picrates, toluenesulfonates, and the like. Examples of base addition salts include salts of alkali metals or alkaline earth metals such as lithium, sodium, potassium, magnesium, and calcium; ammonium salts, quaternary ammonium salts such as tetramethylammonium; and amine salts such as methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine.

[0054] Representative compounds according to the present invention are selected from the following group.

[0055] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-fluorophenyl)-1-methyl-1H-indole-2-carboxamide (Compound 1);

[0056] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-fluorophenyl)-1-methyl-1H-indole-2-carboxamide (Compound 2);

[0057] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-chlorophenyl)-1-methyl-1H-indole-2-carboxamide (Compound 3);

[0058] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-1-methyl-1H-indole-2-carboxamide (Compound 4);

[0059] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-chloro-5-fluorophenyl)-1-methyl-1H-indole-2-carboxamide (Compound 5);

[0060] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3,5-difluorophenyl)-1-methyl-1H-indole-2-carboxamide (Compound 6);

[0061] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-N-(3-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide (Compound 7);

[0062] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-N-(4-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide (Compound 8);

[0063] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-N-(4-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (Compound 9);

[0064] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(2-fluorophenyl)-1-methyl-1H-indole-2-carboxamide (Compound 10);

[0065] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-chlorophenyl)-1-methyl-1H-indole-2-carboxamide (Compound 11);

[0066] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-N-(4′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)-1H-indole-2-carboxamide (Compound 12);

[0067] N-(4-bromophenyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-1H-indole-2-carboxamide (Compound 13);

[0068] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-N-(o-tolyl)-1H-indole-2-carboxamide (Compound 14);

[0069] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-N-(2-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (Compound 15);

[0070] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-N-(4′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-1H-indole-2-carboxamide (Compound 16);

[0071] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-fluoro-5-(trifluoromethyl)phenyl)-1-methyl-1H-indole-2-carboxamide (Compound 17);

[0072] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-N-(6-(trifluoromethyl)pyridin-3-yl)-1H-indole-2-carboxamide (Compound 18);

[0073] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-N-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazol-5-yl)-1H-indole-2-carboxamide (Compound 19);

[0074] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-N-(4-methyl-3-(4-(trifluoromethyl)phenyl)-1H-pyrazol-5-yl)-1H-indole-2-carboxamide (Compound 20);

[0075] 2-chloro-5-(isobutyrylaminomethyl)-N-(1-methyl-2-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)-1H-indol-5-yl)benzamide (Compound 21);

[0076] N-(4-chloro-2-methylphenyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-1H-indole-2-carboxamide (Compound 22);

[0077] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-fluoro-2-methylphenyl)-1-methyl-1H-indole-2-carboxamide (Compound 23);

[0078] (S)-N-(1-(4-bromophenyl)ethyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-1H-indole-2-carboxamide (Compound 24);

[0079] (S)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-N-(1-(4-nitrophenyl)ethyl)-1H-indole-2-carboxamide (Compound 25);

[0080] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-N-(2-methylbenzyl)-1H-indole-2-carboxamide (Compound 26);

[0081] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(1-(4-fluorophenyl)ethyl)-1-methyl-1H-indole-2-carboxamide (Compound 27);

[0082] (S)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-N-(1-phenylethyl)-1H-indole-2-carboxamide (Compound 28);

[0083] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-methoxybenzyl)-1-methyl-1H-indole-2-carboxamide (Compound 29);

[0084] N-([1,1′-biphenyl]-4-ylmethyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-1H-indole-2-carboxamide (Compound 30);

[0085] (S)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-N-(1-(naphthalen-2-yl)ethyl)-1H-indole-2-carboxamide (Compound 31);

[0086] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-fluorobenzyl)-1-methyl-1H-indole-2-carboxamide (Compound 32);

[0087] N-(4-(tert-Butyl)benzyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-1H-indole-2-carboxamide (Compound 33);

[0088] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-N-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxamide (Compound 34);

[0089] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-N-(2-(trifluoromethyl)benzyl)-1H-indole-2-carboxamide (Compound 35);

[0090] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-fluorobenzyl)-1-methyl-1H-indole-2-carboxamide (Compound 36);

[0091] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(2-fluorobenzyl)-1-methyl-1H-indole-2-carboxamide (Compound 37);

[0092] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3,4-difluorobenzyl)-1-methyl-1H-indole-2-carboxamide (Compound 38);

[0093] N-(4-chloro-3-fluorobenzyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-1H-indole-2-carboxamide (Compound 39);

[0094] (R)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-N-(1-phenylethyl)-1H-indole-2-carboxamide (Compound 40);

[0095] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-N-(3-(trifluoromethyl)benzyl)-1H-indole-2-carboxamide (Compound 41);

[0096] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-fluoro-5-(trifluoromethyl)benzyl)-1-methyl-1H-indole-2-carboxamide (Compound 42);

[0097] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-chlorobenzyl)-1-methyl-1H-indole-2-carboxamide (Compound 43);

[0098] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(2-chlorobenzyl)-1-methyl-1H-indole-2-carboxamide (Compound 44);

[0099] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-N-(4-nitrobenzyl)-1H-indole-2-carboxamide (Compound 45);

[0100] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-bromobenzyl)-1-methyl-1H-indole-2-carboxamide (Compound 46);

[0101] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-N-(1-(4-(trifluoromethyl)phenyl)ethyl)-1H-indole-2-carboxamide (Compound 47);

[0102] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-bromobenzyl)-1-methyl-1H-indole-2-carboxamide (Compound 48);

[0103] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-chlorobenzyl)-1-methyl-1H-indole-2-carboxamide (Compound 49);

[0104] N-(Benzo[d][1,3]dioxol-5-ylmethyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-1H-indole-2-carboxamide (Compound 50);

[0105] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3,5-difluorobenzyl)-1-methyl-1H-indole-2-carboxamide (Compound 51);

[0106] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-N-(4-(trifluoromethoxy)benzyl)-1H-indole-2-carboxamide (Compound 52);

[0107] N-(4-bromo-2-fluorobenzyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-1H-indole-2-carboxamide (Compound 53);

[0108] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(2,6-difluorobenzyl)-1-methyl-1H-indole-2-carboxamide (Compound 54);

[0109] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(2,6-dichlorobenzyl)-1-methyl-1H-indole-2-carboxamide (Compound 55);

[0110] N-(3-chloro-4-fluorobenzyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-1H-indole-2-carboxamide (Compound 56);

[0111] N-(2-chloro-3-(trifluoromethyl)benzyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-1H-indole-2-carboxamide (Compound 57);

[0112] (R)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-N-(1-(4-(trifluoromethyl)phenyl)ethyl)-1H-indole-2-carboxamide (Compound 58);

[0113] (R)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)-1H-indole-2-carboxamide (Compound 59);

[0114] (S)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-N-(1-(4-(trifluoromethyl)phenyl)ethyl)-1H-indole-2-carboxamide (Compound 60);

[0115] (S)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)-1H-indole-2-carboxamide (Compound 61);

[0116] N-(4-(tert-Butyl)benzyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2,2,2-trifluoroethyl)-1H-indole-2-carboxamide (Compound 62);

[0117] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2,2,2-trifluoroethyl)-N-(2-(trifluoromethyl)benzyl)-1H-indole-2-carboxamide (Compound 63);

[0118] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2,2,2-trifluoroethyl)-N-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxamide (Compound 64);

[0119] (S)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(1-(naphthalen-2-yl)ethyl)-1-(2,2,2-trifluoroethyl)-1H-indole-2-carboxamide (Compound 65);

[0120] (S)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(1-(4-nitrophenyl)ethyl)-1-(2,2,2-trifluoroethyl)-1H-indole-2-carboxamide (Compound 66);

[0121] (S)-N-(1-(4-bromophenyl)ethyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2,2,2-trifluoroethyl)-1H-indole-2-carboxamide (Compound 67);

[0122] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-fluorobenzyl)-1-(2,2,2-trifluoroethyl)-1H-indole-2-carboxamide (Compound 68);

[0123] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-fluoro-5-(trifluoromethyl)benzyl)-1-(2,2,2-trifluoroethyl)-1H-indole-2-carboxamide (Compound 69);

[0124] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2,2,2-trifluoroethyl)-N-(3-(trifluoromethyl)benzyl)-1H-indole-2-carboxamide (Compound 70);

[0125] N-(4-chloro-3-fluorobenzyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2,2,2-trifluoroethyl)-1H-indole-2-carboxamide (Compound 71);

[0126] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2,2,2-trifluoroethyl)-N-(4-(trifluoromethoxy)benzyl)-1H-indole-2-carboxamide (Compound 72);

[0127] 5-((2-chloro-5-(isobutyrylaminomethyl)benzyl)amino)-1-methyl-N-(4-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (Compound 73);

[0128] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (Compound 74);

[0129] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide (Compound 75);

[0130] 2-chloro-5-(isobutyrylaminomethyl)-N-(1-methyl-2-(((4-(trifluoromethoxy)phenyl)amino)methyl)-1H-indol-5-yl)benzamide (Compound 76);

[0131] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(methoxymethyl)-N-(4-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (Compound 77);

[0132] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(methoxymethyl)-N-(4-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide (Compound 78);

[0133] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-chlorophenyl)-1-(methoxymethyl)-1H-indole-2-carboxamide (Compound 79);

[0134] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(methoxymethyl)-N-(6-(trifluoromethyl)pyridin-3-yl)-1H-indole-2-carboxamide (Compound 80);

[0135] N-(4-chloro-2-methylphenyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(methoxymethyl)-1H-indole-2-carboxamide (Compound 81);

[0136] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-cyclohexylphenyl)-1-(methoxymethyl)-1H-indole-2-carboxamide (Compound 82);

[0137] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(2,4-difluorophenyl)-1-(methoxymethyl)-1H-indole-2-carboxamide (Compound 83);

[0138] N-(4-(tert-Butyl)phenyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(methoxymethyl)-1H-indole-2-carboxamide (Compound 84);

[0139] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-fluorophenyl)-1-(methoxymethyl)-1H-indole-2-carboxamide (Compound 85);

[0140] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-chlorophenyl)-1-(methoxymethyl)-1H-indole-2-carboxamide (Compound 86);

[0141] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(methoxymethyl)-N-(3-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide (Compound 87);

[0142] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-fluorophenyl)-1-(methoxymethyl)-1H-indole-2-carboxamide (Compound 88);

[0143] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(methoxymethyl)-N-(3-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (Compound 89);

[0144] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-chloro-5-fluorophenyl)-1-(methoxymethyl)-1H-indole-2-carboxamide (Compound 90);

[0145] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(methoxymethyl)-N-(5,6,7,8-tetrahydronaphthalen-1-yl)-1H-indole-2-carboxamide (Compound 91);

[0146] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(3-methoxypropyl)-N-(4-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (Compound 92);

[0147] N-(4-(tert-Butyl)phenyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(3-methoxypropyl)-1H-indole-2-carboxamide (Compound 93);

[0148] N-(4-chloro-2-methylphenyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(3-methoxypropyl)-1H-indole-2-carboxamide (Compound 94);

[0149] N-(3-chloro-4-fluorophenyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(3-methoxypropyl)-1H-indole-2-carboxamide (Compound 95);

[0150] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-chlorophenyl)-1-(3-methoxypropyl)-1H-indole-2-carboxamide (Compound 96);

[0151] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-fluoro-2-methylphenyl)-1-(3-methoxypropyl)-1H-indole-2-carboxamide (Compound 97);

[0152] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-fluoro-4-morpholinophenyl)-1-(3-methoxypropyl)-1H-indole-2-carboxamide (Compound 98);

[0153] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(3-methoxypropyl)-N-(3-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (Compound 99);

[0154] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(3-methoxypropyl)-N-(3-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide (Compound 100);

[0155] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(3-methoxypropyl)-N-(4-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide (Compound 101);

[0156] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-fluorophenyl)-1-(3-methoxypropyl)-1H-indole-2-carboxamide (Compound 102);

[0157] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-chlorophenyl)-1-(3-methoxypropyl)-1H-indole-2-carboxamide (Compound 103);

[0158] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(2-chlorophenyl)-1-(3-methoxypropyl)-1H-indole-2-carboxamide (Compound 104);

[0159] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-cyclohexylphenyl)-1-(3-methoxypropyl)-1H-indole-2-carboxamide (Compound 105);

[0160] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(2,4-difluorophenyl)-1-(3-methoxypropyl)-1H-indole-2-carboxamide (Compound 106);

[0161] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(2-fluorophenyl)-1-(3-methoxypropyl)-1H-indole-2-carboxamide (Compound 107);

[0162] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-fluorophenyl)-1-(3-methoxypropyl)-1H-indole-2-carboxamide (Compound 108);

[0163] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3,5-difluorophenyl)-1-(3-methoxypropyl)-1H-indole-2-carboxamide (Compound 109);

[0164] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(ethoxymethyl)-N-(4-fluorophenyl)-1H-indole-2-carboxamide (Compound 110)

[0165] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(ethoxymethyl)-N-(4-chlorophenyl)-1H-indole-2-carboxamide (Compound 111);

[0166] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-(trifluoromethoxy)phenyl)-1-(ethoxymethyl)-1H-indole-2-carboxamide (Compound 112);

[0167] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(ethoxymethyl)-N-(4-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide (Compound 113);

[0168] N-(3-chlorophenyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(ethoxymethyl)-1H-indole-2-carboxamide (Compound 114);

[0169] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-chloro-4-fluorophenyl)-1-(ethoxymethyl)-1H-indole-2-carboxamide (Compound 115);

[0170] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-fluorophenyl)-1-(2-methoxyethyl)-1H-indole-2-carboxamide (Compound 116);

[0171] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-chlorophenyl)-1-(2-methoxyethyl)-1H-indole-2-carboxamide (Compound 117);

[0172] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2-methoxyethyl)-N-(4-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (Compound 118);

[0173] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2-methoxyethyl)-N-(3-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (Compound 119);

[0174] N-(2-chloro-4-fluorophenyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2-methoxyethyl)-1H-indole-2-carboxamide (Compound 120);

[0175] N-(4-chloro-2-fluorophenyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2-methoxyethyl)-1H-indole-2-carboxamide (Compound 121);

[0176] N-(4-chloro-3-fluorophenyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2-methoxyethyl)-1H-indole-2-carboxamide (Compound 122);

[0177] N-(3-chloro-4-fluorophenyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2-methoxyethyl)-1H-indole-2-carboxamide (Compound 123);

[0178] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-chloro-5-fluorophenyl)-1-(2-methoxyethyl)-1H-indole-2-carboxamide (Compound 124);

[0179] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-chlorophenyl)-1-(2-methoxyethyl)-1H-indole-2-carboxamide (Compound 125);

[0180] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-trifluoromethylphenyl)-1-(2-methoxyethyl)-1H-indole-2-carboxamide (Compound 126);

[0181] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-trifluoromethylphenyl)-1-(2-methoxyethyl)-1H-indole-2-carboxamide (Compound 127);

[0182] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-fluorophenyl)-1-(2-methoxyethyl)-1H-indole-2-carboxamide (Compound 128);

[0183] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-fluoro-5-trifluoromethylphenyl)-1-(2-methoxyethyl)-1H-indole-2-carboxamide (Compound 129);

[0184] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3,4-dichlorophenyl)-1-(2-methoxyethyl)-1H-indole-2-carboxamide (Compound 130);

[0185] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(2,4-dichlorophenyl)-1-(2-methoxyethyl)-1H-indole-2-carboxamide (Compound 131);

[0186] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3,5-dichlorophenyl)-1-(2-methoxyethyl)-1H-indole-2-carboxamide (Compound 132);

[0187] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3,4-difluorophenyl)-1-(2-methoxyethyl)-1H-indole-2-carboxamide (Compound 133);

[0188] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-ethyl-N-(4-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (Compound 134);

[0189] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-ethyl-N-(4-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide (Compound 135);

[0190] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-ethyl-N-(3-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide (Compound 136);

[0191] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-ethyl-N-(4-fluorophenyl)-1H-indole-2-carboxamide (Compound 137);

[0192] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-chlorophenyl)-1-ethyl-1H-indole-2-carboxamide (Compound 138);

[0193] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-ethyl-N-(3-fluorophenyl)-1H-indole-2-carboxamide (Compound 139);

[0194] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-ethyl-N-(3-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (Compound 140);

[0195] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-chlorophenyl)-1-ethyl-1H-indole-2-carboxamide (Compound 141);

[0196] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(2,4-difluorophenyl)-1-ethyl-1H-indole-2-carboxamide (Compound 142);

[0197] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-ethyl-N-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide (Compound 143);

[0198] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-ethyl-N-(2-fluorophenyl)-1H-indole-2-carboxamide (Compound 144);

[0199] N-(3-chloro-4-fluorophenyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-ethyl-1H-indole-2-carboxamide (Compound 145);

[0200] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-ethyl-N-(3-fluoro-5-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide (Compound 146);

[0201] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-cyanophenyl)-1-ethyl-1H-indole-2-carboxamide (Compound 147);

[0202] N-(4-chloro-2-methylphenyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-ethyl-1H-indole-2-carboxamide (Compound 148);

[0203] N-(4-Fluoro-2-methylphenyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-ethyl-1H-indole-2-carboxamide (Compound 149);

[0204] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3,5-difluorophenyl)-1-ethyl-1H-indole-2-carboxamide (Compound 150);

[0205] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-chloro-5-fluorophenyl)-1-ethyl-1H-indole-2-carboxamide (Compound 151);

[0206] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-ethyl-N-(2-fluoro-4-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide (Compound 152);

[0207] N-(4-chloro-3-fluorophenyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-ethyl-1H-indole-2-carboxamide (Compound 153);

[0208] N-(4-chloro-2-fluorophenyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-ethyl-1H-indole-2-carboxamide (Compound 154);

[0209] N-(2-chloro-4-fluorophenyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-ethyl-1H-indole-2-carboxamide (Compound 155);

[0210] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-cyclohexylphenyl)-1-ethyl-1H-indole-2-carboxamide (Compound 156);

[0211] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-propyl-N-(4-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (Compound 157);

[0212] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-propyl-N-(3-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (Compound 158);

[0213] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-propyl-N-(4-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide (Compound 159);

[0214] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-propyl-N-(3-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide (Compound 160);

[0215] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-chlorophenyl)-1-propyl-1H-indole-2-carboxamide (Compound 161);

[0216] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-chlorophenyl)-1-propyl-1H-indole-2-carboxamide (Compound 162);

[0217] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-chloro-5-fluorophenyl)-1-propyl-1H-indole-2-carboxamide (Compound 163);

[0218] N-(3-chloro-4-fluorophenyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-propyl-1H-indole-2-carboxamide (Compound 164);

[0219] N-(4-chloro-3-fluorophenyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-propyl-1H-indole-2-carboxamide (Compound 165);

[0220] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-fluorophenyl)-1-propyl-1H-indole-2-carboxamide (Compound 166);

[0221] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-fluorophenyl)-1-propyl-1H-indole-2-carboxamide (Compound 167);

[0222] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-cyclohexylphenyl)-1-propyl-1H-indole-2-carboxamide (Compound 168);

[0223] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-fluoro-5-(trifluoromethyl)phenyl)-1-propyl-1H-indole-2-carboxamide (Compound 169);

[0224] 1-Butyl-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-fluorophenyl)-1H-indole-2-carboxamide (Compound 170);

[0225] 1-Butyl-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-chlorophenyl)-1H-indole-2-carboxamide (Compound 171);

[0226] 1-Butyl-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (Compound 172);

[0227] 1-Butyl-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (Compound 173);

[0228] 1-Butyl-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide (Compound 174);

[0229] 1-Butyl-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide (Compound 175);

[0230] 1-Butyl-N-(4-chloro-3-fluorophenyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1H-indole-2-carboxamide (Compound 176);

[0231] 1-Butyl-N-(3-chloro-4-fluorophenyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1H-indole-2-carboxamide (Compound 177);

[0232] 1-Butyl-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3,4-dichlorophenyl)-1H-indole-2-carboxamide (Compound 178);

[0233] 1-Butyl-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3,4-difluorophenyl)-1H-indole-2-carboxamide (Compound 179);

[0234] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-isopropyl-N-(4-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (Compound 180);

[0235] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-isopropyl-N-(3-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (Compound 181);

[0236] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-fluorophenyl)-1-isopropyl-1H-indole-2-carboxamide (Compound 182);

[0237] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-chlorophenyl)-1-isopropyl-1H-indole-2-carboxamide (Compound 183);

[0238] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-chlorophenyl)-1-isopropyl-1H-indole-2-carboxamide (Compound 184);

[0239] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-isopropyl-N-(4-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide (Compound 185);

[0240] N-(3-chloro-4-fluorophenyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-isopropyl-1H-indole-2-carboxamide (Compound 186);

[0241] N-(4-chloro-3-fluorophenyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-isopropyl-1H-indole-2-carboxamide (Compound 187);

[0242] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-isopropyl-N-(3-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide (Compound 188);

[0243] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(2-chlorophenyl)-1-isopropyl-1H-indole-2-carboxamide (Compound 189);

[0244] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3,4-dichlorophenyl)-1-isopropyl-1H-indole-2-carboxamide (Compound 190);

[0245] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3,5-dichlorophenyl)-1-isopropyl-1H-indole-2-carboxamide (Compound 191);

[0246] N-(4-bromophenyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-isopropyl-1H-indole-2-carboxamide (Compound 192);

[0247] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-cyclohexylphenyl)-1-isopropyl-1H-indole-2-carboxamide (Compound 193);

[0248] N-(4-(tert-Butyl)phenyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-isopropyl-1H-indole-2-carboxamide (Compound 194);

[0249] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-chloro-5-fluorophenyl)-1-isopropyl-1H-indole-2-carboxamide (Compound 195);

[0250] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3,5-difluorophenyl)-1-isopropyl-1H-indole-2-carboxamide (Compound 196);

[0251] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-isopropyl-N-(4-methoxyphenyl)-1H-indole-2-carboxamide (Compound 197);

[0252] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-isopropyl-N-(6-(trifluoromethyl)pyridin-3-yl)-1H-indole-2-carboxamide (Compound 198);

[0253] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-cyanophenyl)-1-isopropyl-1H-indole-2-carboxamide (Compound 199);

[0254] N-(4-chloro-2-methylphenyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-isopropyl-1H-indole-2-carboxamide (Compound 200);

[0255] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-isopropyl-N-(5,6,7,8-tetrahydronaphthalen-1-yl)-1H-indole-2-carboxamide (Compound 201);

[0256] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(2,4-difluorophenyl)-1-isopropyl-1H-indole-2-carboxamide (Compound 202);

[0257] Methyl 4-(5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-isopropyl-1H-indole-2-carboxamido)benzoate (Compound 203);

[0258] 4-(5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-isopropyl-1H-indole-2-carboxamido)benzoic acid (Compound 204);

[0259] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-fluorophenyl)-1-(2,2,2-trifluoroethyl)-1H-indole-2-carboxamide (Compound 205);

[0260] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-chlorophenyl)-1-(2,2,2-trifluoroethyl)-1H-indole-2-carboxamide (Compound 206);

[0261] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2,2,2-trifluoroethyl)-N-(4-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide (Compound 207);

[0262] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2,2,2-trifluoroethyl)-N-(3-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide (Compound 208);

[0263] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2,2,2-trifluoroethyl)-N-(4-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (Compound 209);

[0264] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2,2,2-trifluoroethyl)-N-(3-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (Compound 210);

[0265] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-chlorophenyl)-1-(2,2,2-trifluoroethyl)-1H-indole-2-carboxamide (Compound 211);

[0266] N-(3-chloro-4-fluorophenyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2,2,2-trifluoroethyl)-1H-indole-2-carboxamide (Compound 212);

[0267] N-(4-chloro-3-fluorophenyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2,2,2-trifluoroethyl)-1H-indole-2-carboxamide (Compound 213);

[0268] N-(4-chloro-2-fluorophenyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2,2,2-trifluoroethyl)-1H-indole-2-carboxamide (Compound 214);

[0269] N-(3-chloro-5-fluorophenyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2,2,2-trifluoroethyl)-1H-indole-2-carboxamide (Compound 215);

[0270] N-(3-Fluoro-5-trifluoromethylphenyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2,2,2-trifluoroethyl)-1H-indole-2-carboxamide (Compound 216);

[0271] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-fluorophenyl)-1-(2,2-difluoroethyl)-1H-indole-2-carboxamide (Compound 217);

[0272] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-chlorophenyl)-1-(2,2-difluoroethyl)-1H-indole-2-carboxamide (Compound 218);

[0273] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2,2-difluoroethyl)-N-(4-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (Compound 219);

[0274] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2,2-difluoroethyl)-N-(4-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide (Compound 220);

[0275] N-(2-chloro-4-fluorophenyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2,2-difluoroethyl)-1H-indole-2-carboxamide (Compound 221);

[0276] N-(4-chloro-2-fluorophenyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2,2-difluoroethyl)-1H-indole-2-carboxamide (Compound 222);

[0277] N-(4-chloro-3-fluorophenyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2,2-difluoroethyl)-1H-indole-2-carboxamide (Compound 223);

[0278] N-(3-chloro-4-fluorophenyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2,2-difluoroethyl)-1H-indole-2-carboxamide (Compound 224);

[0279] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3,4-dichlorophenyl)-1-(2,2-difluoroethyl)-1H-indole-2-carboxamide (Compound 225);

[0280] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2,2-difluoroethyl)-N-(2-fluoro-4-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide (Compound 226);

[0281] Methyl 4-(5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-1H-indole-2-carboxamido)benzoate (Compound 227);

[0282] 4-(5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-1H-indole-2-carboxamido)benzoic acid (Compound 228);

[0283] Sodium 4-(5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-1H-indole-2-carboxamido)benzoate (Compound 229);

[0284] Methyl 5-(5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-1H-indole-2-carboxamido)-2-fluorobenzoate (Compound 230);

[0285] 5-(5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-1H-indole-2-carboxamido)-2-fluorobenzoic acid (Compound 231);

[0286] 6-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (Compound 232);

[0287] 6-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide (Compound 233);

[0288] 6-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-fluorophenyl)-1H-indole-2-carboxamide (Compound 234);

[0289] 6-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (Compound 235);

[0290] 6-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide (Compound 236);

[0291] 6-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-chlorophenyl)-1H-indole-2-carboxamide (Compound 237);

[0292] 6-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-chlorophenyl)-1H-indole-2-carboxamide (Compound 238);

[0293] 6-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-N-(4-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (Compound 239);

[0294] 6-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-N-(4-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide (Compound 240);

[0295] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(3-methoxypropyl)-N-(4-(trifluoromethoxy)benzyl)-1H-indole-2-carboxamide (Compound 241);

[0296] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-fluoro-3-(trifluoromethyl)benzyl)-1-(3-methoxypropyl)-1H-indole-2-carboxamide (Compound 243); and

[0297] 5-(2-Chloro-5-(isobutyrylaminomethyl)benzamido)-N-(2-fluoro-4-(trifluoromethyl)benzyl)-1-(3-methoxypropyl)-1H-indole-2-carboxamide (Compound 244).

[0298] Methods for preparing indolecarboxamide derivatives of formula (II) according to the present invention are depicted in the following reaction schemes 1 to 4. However, those shown in the following reaction schemes represent examples of representative methods used in the present invention. Reagents, reaction conditions, etc. can be varied without limitation.

[0299] [Reaction Scheme 1]

[0300]

[0301] In Reaction Scheme 1, R 1 , L, R 2 and R 3 As defined in Formula II, and R 4 It is a C1-C6 alkyl group.

[0302] As shown in Reaction Scheme 1, a compound having formula (IIa) wherein Y 1 and Y 2Indolecarboxamide derivatives that are C=O can be prepared by the following: a compound of formula (IIIa) is subjected to an amide coupling reaction with a compound of formula (IV) to obtain a compound of formula (Va), and the ester group of the compound of formula (Va) is hydrolyzed to obtain a compound having a carboxylic acid group of formula (VIa), and then the compound of formula (VIa) is subjected to an amide coupling reaction with a compound of formula (VII).

[0303] At this time, the amide coupling reaction can be carried out using a conventional amide coupling agent. For example, it can be carried out by adding hydroxybenzotriazole (HOBT) and 4-dimethylaminopyridine (DMAP) and reacting them, and then adding 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and optionally triethylamine (TEA) to react, or it can be carried out by adding azabenzotriazole tetramethyluronium hexafluorophosphate (HATU) and N,N-diisopropylethylamine (DIPEA) and reacting them.

[0304] In addition, the hydrolysis reaction of the carboxylate group can be carried out in the presence of a base catalyst. For example, LiOH, NaOH, KOH, etc. can be used as the base.

[0305] [Reaction Scheme 2]

[0306]

[0307] In Reaction Scheme 2, R 1 , L, R 2 and R 3 As defined in formula (II), and R 4 It is a C1-C6 alkyl group.

[0308] As shown in Reaction Scheme 2, wherein Y 1 Is C=O and Y 2 An indolecarboxamide derivative of formula (IIb) which is CH2 can be prepared by subjecting a compound of formula (IIIa) to a reductive amination reaction with a compound of formula (VIII) to obtain a compound of formula (Vb), and hydrolyzing the ester group of the compound of formula (Vb) to obtain a compound of formula (VIb) having a carboxylic acid group, and then subjecting the compound of formula (VIb) to an amide coupling reaction with a compound of formula (VII).

[0309] In this case, the reductive amination reaction can be carried out in the presence of sodium triacetoxyborohydride (NaBH(OAc) 3 ) and acetic acid.

[0310] The amide coupling reaction can be carried out using a conventional amide coupling agent. For example, it can be carried out using the amide coupling agent used in the above reaction scheme 1.

[0311] In addition, the hydrolysis reaction of the carboxylate group can be carried out in the presence of a base catalyst. For example, LiOH, NaOH, KOH, etc. can be used as the base.

[0312] [Reaction Scheme 3]

[0313]

[0314] In Reaction Scheme 3, R 1 , L, R 2 and R 3 As defined in formula (II), and R 4 It is a C1-C6 alkyl group.

[0315] As shown in Reaction Scheme 3, wherein Y 1 is CH2 and Y 2 An indolecarboxamide derivative of formula (IIc) wherein C=O can be prepared by reducing the ester group of a compound having formula (IIIa) to obtain a compound having a hydroxyl group of formula (IIIb), and subjecting the compound of formula (IIIb) to an amide coupling reaction with a compound of formula (IV) to obtain a compound of formula (VIc), and then subjecting the compound of formula (VIc) to a Mitsunobu coupling reaction with a compound of formula (VII).

[0316] At this time, the reduction reaction can be performed using a reducing agent such as lithium aluminum hydride (LAH).

[0317] The amide coupling reaction can be carried out using a conventional amide coupling agent. For example, it can be carried out using the amide coupling agent used in the above reaction scheme 1.

[0318] Alternatively, the Mitsunobu coupling reaction can be performed using an azodicarboxylate such as diisopropyl azodicarboxylate (DIAD) or diethyl azodicarboxylate (DEAD) and triphenylphosphine (PPh 3 ).

[0319] [Reaction Scheme 4]

[0320]

[0321] In Reaction Scheme 4, R 1 , L, R 2 and R 3 As defined in formula (II).

[0322] As shown in Reaction Scheme 4, wherein Y 1 and Y 2 Indolecarboxamide derivatives of formula (IId) where C=O can be prepared by amide coupling reaction of a compound of formula (IX) with a compound of formula (IV).

[0323] The amide coupling reaction can be carried out using a conventional amide coupling agent. For example, it can be carried out using the amide coupling agent used in the above reaction scheme 1.

[0324] The compound of formula (II) or a pharmaceutically acceptable salt thereof according to the present invention exhibits excellent inhibitory activity on PGE2 production by inhibiting microsomal prostaglandin E2 synthase-1 (mPGES-1) (see Experimental Example 1).

[0325] Therefore, the present invention relates to a pharmaceutical composition for inhibiting microsomal prostaglandin E2 synthase-1 (mPGES-1), which comprises a compound of formula (II) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, and specifically relates to a pharmaceutical composition for treating or preventing inflammation, arthritis, high fever, pain, cancer, stroke or brain diseases such as Alzheimer's disease.

[0326] The pharmaceutical composition according to the present invention can be administered orally, such as by ingestion or inhalation; or parenteral administration, such as injection, deposition, implantation or suppository. Injection can be, for example, intravenous injection, subcutaneous injection, intramuscular injection or intraperitoneal injection. Depending on the route of administration, the pharmaceutical composition of the present invention can be formulated as tablets, capsules, granules, fine tablets (finesubtilae), powders, sublingual tablets, suppositories, ointments, injection solutions, emulsions, suspensions, syrups, aerosols, etc. The above various forms of the pharmaceutical composition of the present invention can be prepared in a manner well known in the art using one or more pharmaceutically acceptable carriers commonly used in each form. The example of a pharmaceutically acceptable carrier includes excipients, binders, disintegrants, lubricants, preservatives, antioxidants, isotonic agents, buffers, coating agents, sweeteners, solubilizers, alkalis, dispersants, wetting agents, suspending agents, stabilizers, coloring agents, etc.

[0327] Depending on its form, the pharmaceutical composition according to the present invention contains about 0.01 wt% to 95 wt% of the compound of the present invention or a pharmaceutically acceptable salt thereof.

[0328] The specific dosage of the pharmaceutical composition of the present invention may vary depending on the mammalian species, including humans, body weight, sex, severity of the disease, physician's judgment, etc. Preferably, for oral use, 0.01 mg to 50 mg of the active ingredient is administered per kg body weight per day, while for parenteral use, 0.01 mg to 10 mg of the active ingredient is administered per kg body weight per day. The total daily dose may be administered once or several times depending on the severity of the disease, physician's judgment, etc.

[0329] One embodiment of the present invention relates to a method for inhibiting microsomal prostaglandin E2 synthase-1 (mPGES-1), comprising administering to a subject in need thereof a composition comprising an effective amount of an indolecarboxamide derivative or a pharmaceutically acceptable salt thereof.

[0330] One embodiment of the present invention relates to a method for treating or preventing inflammation, arthritis, high fever, pain, cancer, stroke or Alzheimer's disease, comprising administering to a subject in need thereof a composition comprising an effective amount of an indolecarboxamide derivative or a pharmaceutically acceptable salt thereof.

[0331] One embodiment of the present invention relates to the use of an indolecarboxamide derivative or a pharmaceutically acceptable salt thereof for inhibiting microsomal prostaglandin E2 synthase-1 (mPGES-1).

[0332] One embodiment of the present invention relates to use of an indolecarboxamide derivative or a pharmaceutically acceptable salt thereof for preventing or treating inflammation, arthritis, high fever, pain, cancer, stroke or Alzheimer's disease.

[0333] Beneficial effects

[0334] Compound of the present invention shows the excellent inhibitory activity for PGE2 production by suppressing microsomal prostaglandin E2 synthetase-1 (mPGES-1).Therefore, compound of the present invention can be effectively used in pharmaceutical composition to be used for the treatment or prevention of inflammation, arthritis, high fever, pain, cancer, apoplexy or such as Alzheimer's brain disease. BRIEF DESCRIPTION OF THE DRAWINGS

[0335] Figure 1 This is a graph showing the results of a hindlimb disability test conducted on Compound 9 of the present invention in an osteoarthritis animal model.

[0336] Figure 2 This is a graph showing the results of evaluating the inflammatory factor PGE2 in the blood of Compound 9 of the present invention in an osteoarthritis animal model.

[0337] Figure 3 This is a graph showing the results of evaluating the inflammatory factor IL-1β in the blood of Compound 9 of the present invention in an osteoarthritis animal model.

[0338] Figure 4 This is a graph showing the results of evaluating the inflammatory factor TNF-α in the blood of Compound 9 of the present invention in an osteoarthritis animal model.

[0339] Figure 5 This is a graph showing the results of the evaluation of the analgesic effect of Compound 9 of the present invention in a pain animal model. DETAILED DESCRIPTION

[0340] The present invention is further described by the following examples, which are not to be construed as limiting the scope of the invention.

[0341]

[0342] Example 1: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-fluorophenyl)-1-methyl-1H-indole-2-carboxamide (Compound 1)

[0343] Example 1-1: Synthesis of ethyl 1-methyl-5-nitro-1H-indole-2-carboxylate

[0344] 5-nitro-1H-indole-2-carboxylic acid ethyl ester (2.5g, 10.67mmol) and MeI (2.27g, 16.01mmol) are added in a 100mL flask and dissolved in DMF (25ml). KCO (2.95g, 21.34mmol) is added thereto and stirred at room temperature for 12 hours. After the reaction is complete, organic material is extracted with ethyl acetate / HO. The organic layer is dried and distilled under reduced pressure to remove the solvent. Residue is subjected to column chromatography (ethyl acetate: normal hexane=1:3) to obtain 1-methyl-5-nitro-1H-indole-2-carboxylic acid ethyl ester (2.38g, 9.58mmol, 90%, white solid).

[0345] 1H NMR (300MHz, CDCl3)8.66-8.65(m,1H),8.25-8.22(m,1H),7.46-7.43(m,2H),4.45-4.42(m,2H),4.14(s,3H),1.45-1.41(m,3H).

[0346] Example 1-2: Synthesis of 5-amino-1-methyl-1H-indole-2-carboxylic acid ethyl ester

[0347] 1-methyl-5-nitro-1H-indole-2-carboxylic acid, ethyl ester (2.38g, 9.58mmol) is added in 100mL flask and is dissolved in MeOH (50ml).Add 10%Pd / C (2.3g) and at room temperature under H2(g) stir 12 hours.After carrying out diatomite filtration when reaction is complete, under reduced pressure by distillation removal solvent.Residue is subjected to column chromatography (ethyl acetate: normal hexane=1:3) to obtain 5-amino-1-methyl-1H-indole-2-carboxylic acid, ethyl ester (1.66g, 7.60mmol, 77%).

[0348] 1H NMR(300MHz, CDCl3)7.52(s,1H),7.21-7.18(m,1H),7.09(s,1H),6.92-6.91(m,1H),6 .85-6.82(m,1H),4.38-4.31(m,2H),4.01(s,3H),3.55(br,NH,2H),1.42-1.37(m,3H).

[0349] Example 1-3: Synthesis of ethyl 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-1H-indole-2-carboxylate

[0350] 5-amino-1-methyl-1H-indole-2-carboxylic acid, ethyl ester (660mg, 3.02mmol) and 2-chloro-5-(isobutyrylaminomethyl) benzoic acid (927mg, 3.624mmol) are added in a 100mL flask and dissolved in CH Cl (20ml). HOBT (612mg, 4.53mmol) and DMAP (369mg, 3.02mmol) are added thereto and reacted 10 minutes. Then, EDC (1.74g, 9.06mmol) and TEA (917mg, 9.06mmol) are added and stirred 12 hours under reflux. After the reaction is complete, CH Cl / H O is used to extract the organic material. With the organic layer through MgSO Dry and distill under reduced pressure to remove solvent. The residue was subjected to column chromatography (ethyl acetate:n-hexane=3:1) to obtain ethyl 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-1H-indole-2-carboxylate (900 mg, 1.97 mmol, 66%, white solid).

[0351] 1H NMR(300MHz,DMSO-d6)10.46(br,NH,1H),8.39-8.35(m,NH,1H),8.18(m,1H),7.59-7.49(m,3H),7.43(m,1H),7.35- 7.33(m,1H),7.25(m,1H),4.36-4.28(m,4H),4.01(s,3H),2.50-2.38(m,1H),1.36-1.31(m,3H),1.04-1.02(m,6H).

[0352] Example 1-4: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-1H-indole-2-carboxylic acid

[0353] 5-(2-chloro-5-(isobutyrylamino methyl) benzamido)-1-methyl isophthalic acidH-indole-2-carboxylic acid, ethyl ester (900mg, 1.97mmol) is added in the 500mL flask and is dissolved in THF (100ml) and MeOH (100ml).To be dissolved in H2O (70ml) in LiOH (413mg, 9.85mmol) add wherein and stir 12 hours.After concentrating when reaction is complete, with 2N-HCl, pH is adjusted to 2, and the solid of gained is filtered to obtain 5-(2-chloro-5-(isobutyrylamino methyl) benzamido)-1-methyl isophthalic acidH-indole-2-carboxylic acid (812mg, 1.89mmol, 96%, white solid).

[0354] 1H NMR(300MHz,DMSO-d6)10.45(br,NH,1H),8.39-8.35(m,NH,1H),8.18(m,1H),7.57-7.49(m,3H),7.43(m,1 H),7.35-7.33(m,1H),7.21(m,1H),4.30-4.28(m,2H),4.01(s,3H),2.50-2.38(m,1H),1.04-1.02(m,6H).

[0355] Example 1-5: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-fluorophenyl)-1-methyl-1H-indole-2-carboxamide (Compound 1)

[0356] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-1H-indole-2-carboxylic acid (100 mg, 0.23 mmol) and 3-fluoroaniline (38 mg, 0.345 mmol) were added to a 25 mL flask and dissolved in CH Cl (5 ml). HOBT (46 mg, 0.345 mmol) and DMAP (28 mg, 0.23 mmol) were added thereto and reacted for 10 minutes. Then, EDC (132 mg, 0.69 mmol) and TEA (96 μl, 0.69 mmol) were added and stirred under reflux for 12 hours. After the reaction was complete, the organic material was extracted with CH Cl / H O. The organic layer was dried over MgSO and distilled under reduced pressure to remove the solvent. The residue was subjected to column chromatography (ethyl acetate:n-hexane=3:1) to obtain 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-fluorophenyl)-1-methyl-1H-indole-2-carboxamide (50 mg, 0.095 mmol, 41%, white solid).

[0357] 1H NMR(300MHz,DMSO-d6)10.50(br,NH,1H),10.47(br,NH,1H),8.37(m,NH,1H),8.19(m,1H),7.78-7.74(m,1H),7.59-7. 50(m,4H),7.44-7.31(m,4H),6.97-6.91(m,1H),4.31-4.29(m,2H),4.00(s,3H),2.50-2.39(m,1H),1.04-1.02(m,6H).

[0358] Example 2: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-fluorophenyl)-1-methyl-1H-indole-2-carboxamide (Compound 2)

[0359] The title compound was obtained according to the same procedure as in Example 1, except using 4-fluoroaniline instead of 3-fluoroaniline.

[0360] 1H NMR(300MHz,DMSO-d6)10.46(br,NH,1H),10.38(br,NH,1H),8.39-8.36(m,NH,1H),8.18(m,1H),7.82-7.77(m,2H),7.58-7.50( m,3H),7.44(m,1H),7.36-7.33(m,1H),7.28-7.18(m,3H),4.31-4.29(m,2H),4.00(s,3H),2.50-2.39(m,1H),1.04-1.02(m,6H).

[0361] Example 3: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-chlorophenyl)-1-methyl-1H-indole-2-carboxamide (Compound 3)

[0362] The title compound was obtained according to the same procedure as in Example 1, except using 3-chloroaniline instead of 3-fluoroaniline.

[0363] 1H NMR(300MHz,DMSO-d6)10.47(br,NH,2H),8.39-8.36(m,NH,1H),8.19(m,1H),7.99(m,1H),7.72-7.70(m,1H),7.59-7. 50(m,3H),7.44-7.32(m,4H),7.18-7.15(m,1H),4.31-4.29(m,2H),4.00(s,3H),2.50-2.39(m,1H),1.04-1.02(m,6H).

[0364] Example 4: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-1-methyl-1H-indole-2-carboxamide (Compound 4)

[0365] The title compound was obtained according to the same procedure as in Example 1, except using 4-fluoro-3-(trifluoromethyl)aniline instead of 3-fluoroaniline.

[0366] 1H NMR(300MHz,DMSO-d6)10.62(br,NH,1H),10.45(br,NH,1H),8.35(m,NH,1H),8.29-8.27(m,1H),8.20(m,1H),8.07(m,1H) ,7.59-7.52(m,4H),7.44(m,1H),7.36-7.34(m,2H),4.31-4.29(m,2H),4.01(s,3H),2.50-2.39(m,1H),1.04-1.02(m,6H).

[0367] Example 5: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-chloro-5-fluorophenyl)-1-methyl-1H-indole-2-carboxamide (Compound 5)

[0368] The title compound was obtained according to the same procedure as in Example 1, except using 3-chloro-5-fluoroaniline instead of 3-fluoroaniline.

[0369] 1H NMR(300MHz,DMSO-d6)10.61(br,NH,1H),10.46(br,NH,1H),8.38(m,NH,1H),8.20(m,1H),7.77(m,1H),7.71-7.67(m,1H),7.59-7. 50(m,3H),7.44(m,1H),7.36-7.33(m,2H),7.18-7.15(m,1H),4.31-4.29(m,2H),4.00(s,3H),2.50-2.39(m,1H),1.04-1.02(m,6H).

[0370] Example 6: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3,5-difluorophenyl)-1-methyl-1H-indole-2-carboxamide (Compound 6)

[0371] The title compound was obtained according to the same procedure as in Example 1, except using 3,5-difluoroaniline instead of 3-fluoroaniline.

[0372] 1H NMR(300MHz,DMSO-d6)10.62(br,NH,1H),10.45(br,NH,1H),8.35(m,NH,1H),8.19(m,1H),7.59-7.50(m,5H),7.44( m,1H),7.35-7.32(m,2H),6.99-6.93(m,1H),4.31-4.29(m,2H),4.00(s,3H),2.50-2.39(m,1H),1.04-1.02(m,6H).

[0373] Example 7: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-N-(3-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide (Compound 7)

[0374] The title compound was obtained according to the same procedure as in Example 1, except using 3-(trifluoromethyl)aniline instead of 3-fluoroaniline.

[0375] 1H NMR(300MHz,DMSO-d6)10.60(br,NH,1H),10.45(br,NH,1H),8.38-8.34(m,NH,1H),8.27(m,1H),8.20(m,1H),8.06-8. 03(m,1H),7.64-7.44(m,6H),7.35-7.33(m,2H),4.31-4.29(m,2H),4.02(s,3H),2.50-2.39(m,1H),1.04-1.02(m,6H).

[0376] Example 8: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-N-(4-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide (Compound 8)

[0377] The title compound was obtained according to the same procedure as in Example 1, except using 4-(trifluoromethyl)aniline instead of 3-fluoroaniline.

[0378] 1H NMR(300MHz,DMSO-d6)10.63(br,NH,1H),10.46(br,NH,1H),8.38-8.34(m,NH,1H),8.20(m,1H),8.02-8.01(m,2H),7.75-7.72( m,2H),7.59-7.50(m,3H),7.44(m,1H),7.36-7.33(m,2H),4.31-4.29(m,2H),4.01(s,3H),2.50-2.39(m,1H),1.04-1.02(m,6H).

[0379] Example 9: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-N-(4-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (Compound 9)

[0380] The title compound was obtained according to the same procedure as in Example 1, except using 4-(trifluoromethoxy)aniline instead of 3-fluoroaniline.

[0381] 1H NMR(300MHz,DMSO-d6)10.50(br,NH,1H),10.46(br,NH,1H),8.37(m,NH,1H),8.19(m,1H),7.91-7.88(m,2H) ,7.58-7.50(m,3H),7.45-7.31(m,5H),4.31-4.29(m,2H),4.00(s,3H),2.50-2.39(m,1H),1.04-1.02(m,6H).

[0382] Example 10: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(2-fluorophenyl)-1-methyl-1H-indole-2-carboxamide (Compound 10)

[0383] The title compound was obtained according to the same procedure as in Example 1, except using 2-fluoroaniline instead of 3-fluoroaniline.

[0384] 1H NMR(300MHz,DMSO-d6)10.45(br,NH,1H),10.13(br,NH,1H),8.36(m,NH,1H),8.19(m,1H),7.64-7.50(m,4 H),7.44(m,1H),7.35-7.23(m,5H),4.31-4.29(m,2H),4.00(s,3H),2.50-2.39(m,1H),1.04-1.02(m,6H).

[0385] Example 11: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-chlorophenyl)-1-methyl-1H-indole-2-carboxamide (Compound 11)

[0386] The title compound was obtained according to the same procedure as in Example 1, except using 4-chloroaniline instead of 3-fluoroaniline.

[0387] 1H NMR(300MHz,DMSO-d6)10.45(br,NH,1H),10.43(br,NH,1H),8.36(m,NH,1H),8.18(m,1H),7.83-7.81(m,2H),7.58-7. 50(m,3H),7.44-7.40(m,3H),7.36-7.30(m,2H),4.31-4.29(m,2H),4.00(s,3H),2.50-2.39(m,1H),1.04-1.02(m,6H).

[0388] Example 12: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-N-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-1H-indole-2-carboxamide (Compound 12)

[0389] The title compound was obtained according to the same procedure as in Example 1, except using 4′-(trifluoromethyl)-[1,1′-biphenyl]-4-amine instead of 3-fluoroaniline.

[0390] 1H NMR(300MHz,DMSO-d6)10.49(br,NH,1H),10.47(br,NH,1H),8.41-8.37(m,NH,1H),8.20(m,1H),7.96-7.91(m,4H),7.82-7.77( m,4H),7.59-7.50(m,4H),7.45(m,1H),7.36-7.34(m,2H),4.31-4.29(m,2H),4.03(s,3H),2.50-2.39(m,1H),1.04-1.02(m,6H).

[0391] Example 13: Synthesis of N-(4-bromophenyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-1H-indole-2-carboxamide (Compound 13)

[0392] The title compound was obtained according to the same procedure as in Example 1, except using 4-bromoaniline instead of 3-fluoroaniline.

[0393] 1H NMR(300MHz,DMSO-d6)10.45-10.43(br,NH,2H),8.39-8.35(m,NH,1H),8.18(m,1H),7.78-7.76(m,2H),7.56-7. 50(m,5H),7.44(m,1H),7.36-7.30(m,2H),4.31-4.29(m,2H),4.00(s,3H),2.50-2.39(m,1H),1.04-1.02(m,6H).

[0394] Example 14: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-N-(o-tolyl)-1H-indole-2-carboxamide (Compound 14)

[0395] The title compound was obtained according to the same procedure as in Example 1, except using o-toluidine instead of 3-fluoroaniline.

[0396] 1H NMR(300MHz,DMSO-d6)10.45(br,NH,1H),9.90(br,NH,1H),8.39-8.35(m,NH,1H),8.17(m,1H),7.57-7.50(m,3H),7.44(m,1H), 7.39-7.36(m,2H),7.33-7.28(m,2H),7.23-7.18(m,2H),4.31-4.29(m,2H),4.00(s,3H),2.50-2.39(m,1H),1.04-1.02(m,6H).

[0397] Example 15: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-N-(2-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (Compound 15)

[0398] The title compound was obtained according to the same procedure as in Example 1, except using 2-(trifluoromethoxy)aniline instead of 3-fluoroaniline.

[0399] 1H NMR(300MHz,DMSO-d6)10.47(br,NH,1H),10.22(br,NH,1H),8.38(m,NH,1H),8.19(m,1H),7.70-7. 68(m,1H),7.55-7.29(m,9H),4.31-4.29(m,2H),3.99(s,3H),2.50-2.39(m,1H),1.04-1.02(m,6H).

[0400] Example 16: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-N-(4'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)-1H-indole-2-carboxamide (Compound 16)

[0401] The title compound was obtained according to the same procedure as in Example 1, except using 4′-(trifluoromethyl)-[1,1′-biphenyl]-3-amine instead of 3-fluoroaniline.

[0402] 1H NMR(300MHz,DMSO-d6)10.47(br,NH,2H),8.38(m,NH,1H),8.20(m,2H),7.88-7.85(m,5H),7.59-7. 45(m,6H),7.35-7.33(m,2H),4.31-4.29(m,2H),4.03(s,3H),2.50-2.39(m,1H),1.04-1.02(m,6H).

[0403] Example 17: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-fluoro-5-(trifluoromethyl)phenyl)-1-methyl-1H-indole-2-carboxamide (Compound 17)

[0404] The title compound was obtained according to the same procedure as in Example 1, except using 3-fluoro-5-(trifluoromethyl)aniline instead of 3-fluoroaniline.

[0405] 1H NMR(300MHz,DMSO-d6)10.77(br,NH,1H),10.48(br,NH,1H),8.37(m,NH,1H),8.21(m,1H),8.07(m,1H),8.03-7.99( m,1H),7.60-7.50(m,3H),7.44-7.33(m,4H),4.31-4.29(m,2H),4.02(s,3H),2.50-2.39(m,1H),1.04-1.02(m,6H).

[0406] Example 18: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-N-(6-(trifluoromethyl)pyridin-3-yl)-1H-indole-2-carboxamide (Compound 18)

[0407] The title compound was obtained according to the same procedure as in Example 1, except using 6-(trifluoromethyl)pyridin-3-amine instead of 3-fluoroaniline.

[0408] 1H NMR(300MHz,DMSO-d6)10.86(br,NH,1H),10.49(br,NH,1H),9.12(m,1H),8.51-8.48(m,1H),8.40-8.36(m,NH,1H),8.23(m,1H),7.95-7. 92(m,1H),7.61-7.50(m,3H),7.45-7.42(m,2H),7.36-7.33(m,1H),4 .31-4.29(m,2H),4.03(s,3H),2.50-2.39(m,1H),1.04-1.02(m,6H).

[0409] Example 19: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-N-(3-(4-(trifluoromethyl)phenyl)-1H-pyrazol-5-yl)-1H-indole-2-carboxamide (Compound 19)

[0410] The title compound was obtained according to the same procedure as in Example 1, except using 3-(4-(trifluoromethyl)phenyl)-1H-pyrazol-5-amine instead of 3-fluoroaniline.

[0411] 1H NMR(300MHz,DMSO-d6)10.49(br,NH,1H),8.35-8.32(m,2H),8.07(m,2H),7.83-7.81(m,3H),7.66-7.61(m,1H),7.56-7.48(m,2H) ,7.44(m,1H),7.36-7.34(m,1H),6.92(m,2H),6.01-5.99(m,1H),4.29(m,2H),4.03(m,3H),2.49-2.41(m,1H),1.04-1.02(m,6H).

[0412] Example 20: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-N-(4-methyl-3-(4-(trifluoromethyl)phenyl)-1H-pyrazol-5-yl)-1H-indole-2-carboxamide (Compound 20)

[0413] The title compound was obtained according to the same procedure as in Example 1, except using 4-methyl-3-(4-(trifluoromethyl)phenyl)-1H-pyrazol-5-amine instead of 3-fluoroaniline.

[0414] 1H NMR(300MHz,DMSO-d6)10.49(br,NH,1H),8.36(br,NH,1H),8.27(m,1H),7.98-7.96(m,2H),7.86-7.83(m,2H),7.76(m,1H),7.63-7.60(m, 1H),7.55-7.50(m,2H),7.44(m,1H),7.35-7.32(m,1H),4.30-4.28(m ,2H),4.01(s,3H),2.50-2.41(m,1H),2.08(s,3H),1.04-1.02(m,6H).

[0415] Example 21: Synthesis of 2-chloro-5-(isobutyrylaminomethyl)-N-(1-methyl-2-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)-1H-indol-5-yl)benzamide (Compound 21)

[0416] The title compound was obtained according to the same procedure as in Example 1, except using 2-(piperazin-1-yl)pyrimidine instead of 3-fluoroaniline.

[0417] 1H NMR(300MHz,DMSO-d6)10.40(br,NH,1H),8.40-8.39(m,3H),8.11(m,1H),7.52-7.43(m,4H),7.35-7.33(m, 1H),6.72-6.66(m,2H),4.28(m,2H),3.83(m,4H),3.77-3.73(m,7H),2.49-2.39(m,1H),1.04-1.02(m,6H).

[0418] Example 22: Synthesis of N-(4-chloro-2-methylphenyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-1H-indole-2-carboxamide (Compound 22)

[0419] The title compound was obtained according to the same procedure as in Example 1, except using 4-chloro-2-methylaniline instead of 3-fluoroaniline.

[0420] 1H NMR(300MHz,DMSO-d6)10.46(br,NH,1H),9.94(br,NH,1H),8.37(m,NH,1H),8.18(m,1H),7.57-7.50(m,3H),7.44- 7.36(m,4H),7.33-7.28(m,2H),4.31-4.29(m,2H),4.00(s,3H),2.50-2.41(m,1H),2.28(s,3H),1.05-1.02(m,6H).

[0421] Example 23: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-fluoro-2-methylphenyl)-1-methyl-1H-indole-2-carboxamide (Compound 23)

[0422] The title compound was obtained according to the same procedure as in Example 1, except using 4-fluoro-2-methylaniline instead of 3-fluoroaniline.

[0423] 1H NMR(300MHz,DMSO-d6)10.45(br,NH,1H),9.92(br,NH,1H),8.37(m,NH,1H),8.18(m,1H),7.57-7.50(m,3H),7.45(m,1H),7.40-7.3 0(m,3H),7.18-7.15(m,1H),7.10-7.04(m,1H),4.31-4.29(m,2H),4.00(s,3H),2.50-2.41(m,1H),2.28(s,3H),1.05-1.02(m,6H).

[0424]

[0425] Example 24: Synthesis of (S)-N-(1-(4-bromophenyl)ethyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-1H-indole-2-carboxamide (Compound 24)

[0426] Example 24-1: Synthesis of ethyl 1-methyl-5-nitro-1H-indole-2-carboxylate

[0427] 5-nitro-1H-indole-2-carboxylic acid ethyl ester (2.5g, 10.67mmol) and MeI (2.27g, 16.01mmol) are added in a 100mL flask and dissolved in DMF (25ml). Add K CO (2.95g, 21.34mmol) and stir at room temperature for 12 hours. After the reaction is complete, use ethyl acetate / H O extraction organic material. The organic layer is dried over MgSO and distilled under reduced pressure to remove the solvent. Residue is subjected to column chromatography (ethyl acetate: normal hexane=1:3) to obtain 1-methyl-5-nitro-1H-indole-2-carboxylic acid ethyl ester (2.38g, 9.58mmol, 90%, white solid).

[0428] 1H NMR (300MHz, CDCl3)8.66-8.65(m,1H),8.25-8.22(m,1H),7.46-7.43(m,2H),4.45-4.42(m,2H),4.14(s,3H),1.45-1.41(m,3H).

[0429] Example 24-2: Synthesis of 5-amino-1-methyl-1H-indole-2-carboxylic acid ethyl ester

[0430] 1-methyl-5-nitro-1H-indole-2-carboxylic acid, ethyl ester (2.38g, 9.58mmol) is added in 100mL flask and is dissolved in MeOH (50ml).10%Pd / C (2.3g) is added thereto and at room temperature under H2(g) stirs 12 hours.After carrying out diatomite filtration when reaction is complete, under reduced pressure, remove solvent by distillation.Resistates is subjected to column chromatography (ethyl acetate: normal hexane=1:3) to obtain 5-amino-1-methyl-1H-indole-2-carboxylic acid, ethyl ester (1.66g, 7.60mmol, 77%).

[0431] 1H NMR(300MHz, CDCl3)7.52(s,1H),7.21-7.18(m,1H),7.09(s,1H),6.92-6.91(m,1H),6 .85-6.82(m,1H),4.38-4.31(m,2H),4.01(s,3H),3.55(br,NH,2H),1.42-1.37(m,3H).

[0432] Example 24-3: Synthesis of ethyl 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-1H-indole-2-carboxylate

[0433] 5-amino-1-methyl-1H-indole-2-carboxylic acid, ethyl ester (660mg, 3.02mmol) and 2-chloro-5-(isobutyrylaminomethyl) benzoic acid (927mg, 3.624mmol) are added in a 100mL flask and dissolved in CH Cl (20ml). HOBT (612mg, 4.53mmol) and DMAP (369mg, 3.02mmol) are added thereto and reacted 10 minutes. Then, EDC (1.74g, 9.06mmol) and TEA (917mg, 9.06mmol) are added and stirred 12 hours under reflux. After the reaction is complete, CH Cl / H O is used to extract the organic material. With the organic layer through MgSO Dry and distill under reduced pressure to remove solvent. The residue was subjected to column chromatography (ethyl acetate:n-hexane=3:1) to obtain ethyl 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-1H-indole-2-carboxylate (900 mg, 1.97 mmol, 66%, white solid).

[0434] 1H NMR(300MHz,DMSO-d6)10.46(br,NH,1H),8.39-8.35(m,NH,1H),8.18(m,1H),7.59-7.49(m,3H),7.43(m,1H),7.35- 7.33(m,1H),7.25(m,1H),4.36-4.28(m,4H),4.01(s,3H),2.50-2.38(m,1H),1.36-1.31(m,3H),1.04-1.02(m,6H).

[0435] Example 24-4: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-1H-indole-2-carboxylic acid

[0436] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-1H-indole-2-carboxylic acid, ethyl ester (900mg, 1.97mmol) is added in a 500mL flask and dissolved in THF (100ml) and MeOH (100ml).Add and be dissolved in H2LiOH (413mg, 9.85mmol) in O (70ml) and stirred 12 hours.After concentrating when the reaction is complete, pH is adjusted to 2 with 2N-HCl.The solid of gained is filtered to obtain 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-1H-indole-2-carboxylic acid (812mg, 1.89mmol, 96%, white solid).

[0437] 1H NMR(300MHz,DMSO-d6)10.45(br,NH,1H),8.39-8.35(m,NH,1H),8.18(m,1H),7.57-7.49(m,3H),7.43(m,1 H),7.35-7.33(m,1H),7.21(m,1H),4.30-4.28(m,2H),4.01(s,3H),2.50-2.38(m,1H),1.04-1.02(m,6H).

[0438] Example 24-5: Synthesis of (S)-N-(1-(4-bromophenyl)ethyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-1H-indole-2-carboxamide (Compound 24)

[0439] 5-(2-Chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-1H-indole-2-carboxylic acid (100 mg, 0.23 mmol) and (S)-1-(4-bromophenyl)ethanamine (69 mg, 0.345 mmol) were added to a 25 mL flask and dissolved in DMF (2 ml). HATU (131 mg, 0.345 mmol) and DIPEA (60 mg, 0.46 mmol) were added thereto and stirred at room temperature for 12 hours. After the reaction was complete, the organic material was extracted with ethyl acetate / H2O. The organic layer was dried over MgSO4 and distilled under reduced pressure to remove the solvent. The residue was subjected to column chromatography (ethyl acetate:n-hexane=3:1) to obtain (S)-N-(1-(4-bromophenyl)ethyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-1H-indole-2-carboxamide (87 mg, 0.142 mmol, 62%, white solid).

[0440] 1H NMR(300MHz,DMSO-d6)10.41(br,NH,1H),8.88-8.85(m,NH,1H),8.35(m,NH,1H),8.11(m,1H),7.54-7.49(m,5H),7.43(m,1H),7.39-7 .32(m,3H),7.19(m,1H),5.15-5.10(m,1H),4.30-4.28(m,2H),3.92(s,3H),2.50-2.39(m,1H),1.49-1.46(m,3H),1.04-1.02(m,6H).

[0441] Example 25: Synthesis of (S)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-N-(1-(4-nitrophenyl)ethyl)-1H-indole-2-carboxamide (Compound 25)

[0442] The title compound was obtained according to the same procedure as in Example 24, except using (S)-1-(4-nitrophenyl)ethanamine instead of (S)-1-(4-bromophenyl)ethanamine.

[0443] 1H NMR(300MHz,DMSO-d6)10.42(br,NH,1H),9.02-8.99(m,NH,1H),8.38-8.34(m ,NH,1H),8.24-8.21(m,2H),8.13(m,1H),7.70-7.67(m,2H),7.52-7.50(m,3H ),7.44(m,1H),7.35-7.33(m,1H),7.24(m,1H),5.27-5.23(m,1H),4.30-4.28 (m,2H),3.92(s,3H),2.50-2.39(m,1H),1.53-1.51(m,3H),1.04-1.02(m,6H).

[0444] Example 26: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-N-(2-methylbenzyl)-1H-indole-2-carboxamide (Compound 26)

[0445] The title compound was obtained according to the same procedure as in Example 24, except using o-tolylmethanamine instead of (S)-1-(4-bromophenyl)ethylamine.

[0446] 1H NMR(300MHz,DMSO-d6)10.41(br,NH,1H),8.94(m,NH,1H),8.35(m,NH,1H),8.12(m,1H),7.52-7.43(m,4H),7.35-7 .16(m,6H),4.47-4.45(m,2H),4.30-4.28(m,2H),3.98(s,3H),2.50-2.39(m,1H),2.34(s,3H),1.04-1.02(m,6H).

[0447] Example 27: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(1-(4-fluorophenyl)ethyl)-1-methyl-1H-indole-2-carboxamide (Compound 27)

[0448] The title compound was obtained according to the same procedure as in Example 24, except using 1-(4-fluorophenyl)ethanamine instead of (S)-1-(4-bromophenyl)ethanamine.

[0449] 1H NMR(300MHz,DMSO-d6)10.40(br,NH,1H),8.85-8.82(m,NH,1H),8.37-8.33(m,NH,1H),8.11(m,1H),7.52-7.43(m,6H),7.35-7.32(m ,1H),7.19-7.13(m,3H),5.19-5.14(m,1H),4.30-4.28(m,2H),3.93(s,3H),2.50-2.38(m,1H),1.49-1.47(m,3H),1.04-1.02(m,6H).

[0450] Example 28: Synthesis of (S)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-N-(1-phenylethyl)-1H-indole-2-carboxamide (Compound 28)

[0451] The title compound was obtained according to the same procedure as in Example 24, except using (S)-1-phenylethylamine instead of (S)-1-(4-bromophenyl)ethylamine.

[0452] 1H NMR(300MHz,DMSO-d6)10.40(br,NH,1H),8.85-8.83(m,NH,1H),8.37-8.33(m,NH,1H),8.11(m,1H),7.52-7.49(m,3H),7.43-7.41(m,3H),7.3 6-7.31(m,3H),7.25-7.20(m,2H),5.19-5.14(m,1H),4.30-4.28(m,2H) ,3.93(s,3H),2.50-2.39(m,1H),1.50-1.48(m,3H),1.04-1.02(m,6H).

[0453] Example 29: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-methoxybenzyl)-1-methyl-1H-indole-2-carboxamide (Compound 29)

[0454] The title compound was obtained according to the same procedure as in Example 24, except using (4-methoxyphenyl)methanamine instead of (S)-1-(4-bromophenyl)ethylamine.

[0455] 1H NMR(300MHz,DMSO-d6)10.40(br,NH,1H),9.00-8.96(m,NH,1H),8.37-8.33(m,NH,1H),8.11(m,1H),7.51-7.43(m,4H),7.35-7.26(m,3H),7.10(m ,1H),6.91-6.88(m,2H),4.41-4.39(m,2H),4.30-4.28(m,2H),3.98(s,3 H),3.73(s,3H),2.50-2.38(m,1H),1.49-1.47(m,3H),1.04-1.02(m,6H).

[0456] Example 30: Synthesis of N-([1,1'-biphenyl]-4-ylmethyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-1H-indole-2-carboxamide (Compound 30)

[0457] The title compound was obtained according to the same procedure as in Example 24, except using [1,1′-biphenyl]-4-ylmethanamine instead of (S)-1-(4-bromophenyl)ethylamine.

[0458] 1H NMR(300MHz,DMSO-d6)10.41(br,NH,1H),9.12-9.07(m,NH,1H),8.37-8.33(m,NH,1H),7.94(m,1H),7.66-7.63(m,4H),7.51-7.43(m,8H),7.37-7 .32(m,2H),7.16(m,1H),4.53-4.51(m,2H),4.30-4.28(m,2H),4.00(s,3 H),3.73(s,3H),2.50-2.38(m,1H),1.49-1.47(m,3H),1.04-1.02(m,6H).

[0459] Example 31: Synthesis of (S)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-N-(1-(naphthalen-2-yl)ethyl)-1H-indole-2-carboxamide (Compound 31)

[0460] The title compound was obtained according to the same procedure as in Example 24, except using (S)-1-(naphthalen-2-yl)ethanamine instead of (S)-1-(4-bromophenyl)ethanamine.

[0461] 1H NMR(300MHz,DMSO-d6)10.42(br,NH,1H),8.98-8.95(m,NH,1H),8.38-8.34(m,NH,1H),8.13(m,1H),7.92-7.89(m,4H),7.63-7.60(m,1H),7.52-7.44 (m,6H),7.35-7.32(m,1H),7.24(m,1H),5.36-5.31(m,1H),4.30-4.28(m, 2H),3.93(s,3H),2.50-2.38(m,1H),1.60-1.58(m,3H),1.04-1.02(m,6H).

[0462] Example 32: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-fluorobenzyl)-1-methyl-1H-indole-2-carboxamide (Compound 32)

[0463] The title compound was obtained according to the same procedure as in Example 24, except using (4-fluorophenyl)methanamine instead of (S)-1-(4-bromophenyl)ethylamine.

[0464] 1H NMR(300MHz,DMSO-d6)10.41(br,NH,1H),9.08-9.04(m,NH,1H),8.35(m,NH,1H),8.12(m,1H),7.52-7.32(m,7H ),7.19-7.13(m,3H),4.45-4.44(m,2H),4.30-4.28(m,2H),3.98(s,3H),2.50-2.38(m,1H),1.04-1.02(m,6H).

[0465] Example 33: Synthesis of N-(4-(tert-butyl)benzyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-1H-indole-2-carboxamide (Compound 33)

[0466] The title compound was obtained according to the same procedure as in Example 24, except using (4-(tert-butyl)phenyl)methanamine instead of (S)-1-(4-bromophenyl)ethylamine.

[0467] 1H NMR(300MHz,DMSO-d6)10.41(br,NH,1H),9.03-8.99(m,NH,1H),8.38-8.34(m,NH,1H),8.12(m,1H),7.52-7.43(m,4H),7.37-7.32(m,3H ),7.28-7.25(m,2H),7.12(m,1H),4.44-4.42(m,2H),4.30-4.28(m,2H),3.98(s,3H),2.50-2.38(m,1H),1.26(s,9H),1.04-1.02(m,6H).

[0468] Example 34: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-N-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxamide (Compound 34)

[0469] The title compound was obtained according to the same procedure as in Example 24, except using (4-(trifluoromethyl)phenyl)methanamine instead of (S)-1-(4-bromophenyl)ethanamine.

[0470] 1H NMR(300MHz,DMSO-d6)10.42(br,NH,1H),9.16(m,NH,1H),8.36(m,NH,1H),8.14(m,1H),7.73-7.70(m,2H),7.58-7.43(m,6H ),7.35-7.32(m,1H),7.16(m,1H),4.57-4.55(m,2H),4.30-4.28(m,2H),3.98(s,3H),2.50-2.38(m,1H),1.04-1.02(m,6H).

[0471] Example 35: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzylamino)-1-methyl-N-(2-(trifluoromethyl)benzyl)-1H-indole-2-carboxamide (Compound 35)

[0472] The title compound was obtained according to the same procedure as in Example 24, except using (2-(trifluoromethyl)phenyl)methanamine instead of (S)-1-(4-bromophenyl)ethylamine.

[0473] 1H NMR(300MHz,DMSO-d6)10.43(br,NH,1H),9.17-9.13(m,NH,1H),8.37(m,NH,1H),8.16(m,1H),7.76-7.66(m,2H),7.60-7.43(m ,6H),7.35-7.33(m,2H),7.23(m,1H),4.68-4.66(m,2H),4.30-4.28(m,2H),3.98(s,3H),2.50-2.38(m,1H),1.04-1.02(m,6H).

[0474] Example 36: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-fluorobenzyl)-1-methyl-1H-indole-2-carboxamide (Compound 36)

[0475] The title compound was obtained according to the same procedure as in Example 24, except using (3-fluorophenyl)methanamine instead of (S)-1-(4-bromophenyl)ethylamine.

[0476] 1H NMR(300MHz,DMSO-d6)10.41(br,NH,1H),9.09(m,NH,1H),8.35(m,NH,1H),8.13(m,1H),7.50-7.32(m,6H), 7.21-7.08(m,4H),4.50-4.48(m,2H),4.30-4.28(m,2H),3.98(s,3H),2.50-2.38(m,1H),1.04-1.02(m,6H).

[0477] Example 37: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(2-fluorobenzyl)-1-methyl-1H-indole-2-carboxamide (Compound 37)

[0478] The title compound was obtained according to the same procedure as in Example 24, except using (2-fluorophenyl)methanamine instead of (S)-1-(4-bromophenyl)ethylamine.

[0479] 1H NMR(300MHz,DMSO-d6)10.42(br,NH,1H),9.05(m,NH,1H),8.36(m,NH,1H),8.13(m,1H),7.52-7.43(m,5H),7.35-7.3 2(m,2H),7.23-7.16(m,3H),4.53-4.51(m,2H),4.30-4.28(m,2H),3.98(s,3H),2.50-2.38(m,1H),1.04-1.02(m,6H).

[0480] Example 38: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3,4-difluorobenzyl)-1-methyl-1H-indole-2-carboxamide (Compound 38)

[0481] The title compound was obtained according to the same procedure as in Example 24, except using (3,4-difluorophenyl)methanamine instead of (S)-1-(4-bromophenyl)ethylamine.

[0482] 1H NMR(300MHz,DMSO-d6)10.42(br,NH,1H),9.09(m,NH,1H),8.36(m,NH,1H),8.13(m,1H),7.53-7.32(m,7H), 7.21-7.14(m,2H),4.46-4.44(m,2H),4.30-4.28(m,2H),3.98(s,3H),2.50-2.38(m,1H),1.04-1.02(m,6H).

[0483] Example 39: Synthesis of N-(4-chloro-3-fluorobenzyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-1H-indole-2-carboxamide (Compound 39)

[0484] The title compound was obtained according to the same procedure as in Example 24, except using (4-chloro-3-fluorophenyl)methanamine instead of (S)-1-(4-bromophenyl)ethylamine.

[0485] 1H NMR(300MHz,DMSO-d6)10.42(br,NH,1H),9.13-9.09(m,NH,1H),8.36(m,NH,1H),8.14(m,1H),7.58-7.33(m,7H),7.24-7 .21(m,1H),7.17-7.15(m,1H),4.48-4.47(m,2H),4.30-4.28(m,2H),3.98(s,3H),2.50-2.38(m,1H),1.04-1.02(m,6H).

[0486] Example 40: Synthesis of (R)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-N-(1-phenylethyl)-1H-indole-2-carboxamide (Compound 40)

[0487] The title compound was obtained according to the same procedure as in Example 24, except using (R)-1-phenylethylamine instead of (S)-1-(4-bromophenyl)ethylamine.

[0488] 1H NMR(300MHz,DMSO-d6)10.40(br,NH,1H),8.85-8.83(m,NH,1H),8.37-8.33(m,NH,1H),8.11(m,1H),7.52-7.49(m,3H),7.43-7.40(m,3H),7.3 6-7.31(m,3H),7.25-7.20(m,2H),5.19-5.14(m,1H),4.30-4.28(m,2H) ,3.93(s,3H),2.50-2.38(m,1H),1.50-1.48(m,3H),1.04-1.02(m,6H).

[0489] Example 41: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-N-(3-(trifluoromethyl)benzyl)-1H-indole-2-carboxamide (Compound 41)

[0490] The title compound was obtained according to the same procedure as in Example 24, except using (3-(trifluoromethyl)phenyl)methanamine instead of (S)-1-(4-bromophenyl)ethanamine.

[0491] 1H NMR(300MHz,DMSO-d6)10.42(br,NH,1H),9.16(m,NH,1H),8.36(m,NH,1H),8.14(m,1H),7.69-7.59(m,4H),7.51-7.43(m,4H ),7.35-7.32(m,1H),7.15(m,1H),4.57-4.55(m,2H),4.30-4.28(m,2H),3.98(s,3H),2.50-2.38(m,1H),1.04-1.02(m,6H).

[0492] Example 42: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzylamino)-N-(3-fluoro-5-(trifluoromethyl)benzyl)-1-methyl-1H-indole-2-carboxamide (Compound 42)

[0493] The title compound was obtained according to the same procedure as in Example 24, except using (3-fluoro-5-(trifluoromethyl)phenyl)methanamine instead of (S)-1-(4-bromophenyl)ethanamine.

[0494] 1H NMR(300MHz,DMSO-d6)10.42(br,NH,1H),9.17(m,NH,1H),8.36(m,NH,1H),8.14(m,1H),7.58-7.43(m,7H),7.35-7 .32(m,1H),7.16(m,1H),4.58-4.56(m,2H),4.30-4.28(m,2H),3.97(s,3H),2.50-2.38(m,1H),1.04-1.02(m,6H).

[0495] Example 43: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-chlorobenzyl)-1-methyl-1H-indole-2-carboxamide (Compound 43)

[0496] The title compound was obtained according to the same procedure as in Example 24, except using (3-chlorophenyl)methanamine instead of (S)-1-(4-bromophenyl)ethylamine.

[0497] 1H NMR(300MHz,DMSO-d6)10.43(br,NH,1H),9.11(m,NH,1H),8.37(m,NH,1H),8.14(m,1H),7.52-7.49(m,3H),7.44-7 .33(m,6H),7.15(m,1H),4.49-4.47(m,2H),4.30-4.29(m,2H),3.98(s,3H),2.50-2.38(m,1H),1.04-1.02(m,6H).

[0498] Example 44: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(2-chlorobenzyl)-1-methyl-1H-indole-2-carboxamide (Compound 44)

[0499] The title compound was obtained according to the same procedure as in Example 24, except using (2-chlorophenyl)methanamine instead of (S)-1-(4-bromophenyl)ethylamine.

[0500] 1H NMR(300MHz,DMSO-d6)10.43(br,NH,1H),9.10-9.06(m,NH,1H),8.39-8.35(m,NH,1H),8.15(m,1H),7.54-7.41(m,6H),7 .37-7.28(m,3H),7.20(m,1H),4.56-4.54(m,2H),4.31-4.29(m,2H),3.98(s,3H),2.50-2.38(m,1H),1.04-1.02(m,6H).

[0501] Example 45: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-N-(4-nitrobenzyl)-1H-indole-2-carboxamide (Compound 45)

[0502] The title compound was obtained according to the same procedure as in Example 24, except using (4-nitrophenyl)methanamine instead of (S)-1-(4-bromophenyl)ethylamine.

[0503] 1H NMR(300MHz,DMSO-d6)10.43(br,NH,1H),9.23-9.20(m,NH,1H),8.36(m,NH,1H),8.24-8.21(m,2H),8.15(m,1H),7.63-7.60(m,2H),7.5 4-7.43(m,4H),7.35-7.32(m,1H),7.18(m,1H),4.61-4.59(m,2H),4.30-4.28(m,2H),3.98(s,3H),2.50-2.38(m,1H),1.04-1.02(m,6H).

[0504] Example 46: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-bromobenzyl)-1-methyl-1H-indole-2-carboxamide (Compound 46)

[0505] The title compound was obtained according to the same procedure as in Example 24, except using (3-bromophenyl)methanamine instead of (S)-1-(4-bromophenyl)ethylamine.

[0506] 1H NMR(300MHz,DMSO-d6)10.43(br,NH,1H),9.13-9.09(m,NH,1H),8.37(m,NH,1H),8.14(m,1H),7.54-7.44(m,6H),7.3 8-7.31(m,3H),7.15(m,1H),4.48-4.46(m,2H),4.30-4.28(m,2H),3.98(s,3H),2.50-2.38(m,1H),1.04-1.02(m,6H).

[0507] Example 47: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-N-(1-(4-(trifluoromethyl)phenyl)ethyl)-1H-indole-2-carboxamide (Compound 47)

[0508] The title compound was obtained according to the same procedure as in Example 24, except using 1-(4-(trifluoromethyl)phenyl)ethanamine instead of (S)-1-(4-bromophenyl)ethanamine.

[0509] 1H NMR(300MHz,DMSO-d6)10.42(br,NH,1H),8.98-8.95(m,NH,1H),8.37(m,NH, 1H),8.12(m,1H),7.73-7.70(m,2H),7.65-7.62(m,2H),7.52-7.49(m,3H),7 .43(m,1H),7.35-7.32(m,1H),7.23(m,1H),5.24-5.19(m,1H),4.30-4.28(m ,2H),3.92(s,3H),2.50-2.38(m,1H),1.52-1.50(m,3H),1.04-1.02(m,6H).

[0510] Example 48: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-bromobenzyl)-1-methyl-1H-indole-2-carboxamide (Compound 48)

[0511] The title compound was obtained according to the same procedure as in Example 24, except using (4-bromophenyl)methanamine instead of (S)-1-(4-bromophenyl)ethylamine.

[0512] 1H NMR(300MHz,DMSO-d6)10.42(br,NH,1H),9.09(m,NH,1H),8.38-8.34(m,NH,1H),8.13(m,1H),7.55-7.43(m,6H),7.3 5-7.30(m,3H),7.13(m,1H),4.45-4.43(m,2H),4.30-4.28(m,2H),3.98(s,3H),2.50-2.38(m,1H),1.04-1.02(m,6H).

[0513] Example 49: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-chlorobenzyl)-1-methyl-1H-indole-2-carboxamide (Compound 49)

[0514] The title compound was obtained according to the same procedure as in Example 24, except using (4-chlorophenyl)methanamine instead of (S)-1-(4-bromophenyl)ethylamine.

[0515] 1H NMR(300MHz,DMSO-d6)10.42(br,NH,1H),9.11-9.07(m,NH,1H),8.38-8.34(m,NH,1H),8.13(m,1H),7.52-7.32 (m,9H),7.13(m,1H),4.47-4.45(m,2H),4.30-4.28(m,2H),3.98(s,3H),2.50-2.38(m,1H),1.04-1.02(m,6H).

[0516] Example 50: Synthesis of N-(Benzo[d][1,3]dioxol-5-ylmethyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-1H-indole-2-carboxamide (Compound 50)

[0517] The title compound was obtained according to the same procedure as in Example 24, except using benzo[d][1,3]dioxol-5-ylmethanamine instead of (S)-1-(4-bromophenyl)ethylamine.

[0518] 1H NMR(300MHz,DMSO-d6)10.41(br,NH,1H),8.99(m,NH,1H),8.36(m,NH,1H),8.11(m,1H),7.52-7.43(m,4H),7.35-7.32(m,1H ),7.11(m,1H),6.91-6.80(m,3H),4.38-4.36(m,2H),4.30-4.28(m,2H),3.98(s,3H),2.50-2.38(m,1H),1.04-1.02(m,6H).

[0519] Example 51: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3,5-difluorobenzyl)-1-methyl-1H-indole-2-carboxamide (Compound 51)

[0520] The title compound was obtained according to the same procedure as in Example 24, except using (3,5-difluorophenyl)methanamine instead of (S)-1-(4-bromophenyl)ethylamine.

[0521] 1H NMR(300MHz,DMSO-d6)10.43(br,NH,1H),9.14-9.10(m,NH,1H),8.39-8.35(m,NH,1H),8.15(m,1H),7.54-7.44(m,4H),7.3 5-7.33(m,1H),7.17-7.05(m,4H),4.50-4.48(m,2H),4.30-4.28(m,2H),3.98(s,3H),2.50-2.38(m,1H),1.04-1.02(m,6H).

[0522] Example 52: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-N-(4-(trifluoromethoxy)benzyl)-1H-indole-2-carboxamide (Compound 52)

[0523] The title compound was obtained according to the same procedure as in Example 24, except using (4-(trifluoromethoxy)phenyl)methanamine instead of (S)-1-(4-bromophenyl)ethylamine.

[0524] 1H NMR(300MHz,DMSO-d6)10.41(br,NH,1H),9.12-9.08(m,NH,1H),8.36(m,NH,1H),8.13(m,1H),7.52-7.43(m,6H),7.3 5-7.33(m,3H),7.14(m,1H),4.51-4.49(m,2H),4.30-4.28(m,2H),3.98(s,3H),2.50-2.38(m,1H),1.04-1.02(m,6H).

[0525] Example 53: Synthesis of N-(4-bromo-2-fluorobenzyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-1H-indole-2-carboxamide (Compound 53)

[0526] The title compound was obtained according to the same procedure as in Example 24, except using (4-bromo-2-fluorophenyl)methanamine instead of (S)-1-(4-bromophenyl)ethylamine.

[0527] 1H NMR(300MHz,DMSO-d6)10.43(br,NH,1H),9.06(m,NH,1H),8.37(m,NH,1H),8.13(m,1H),7.56-7.32(m,8H ),7.15(m,1H),4.47-4.45(m,2H),4.30-4.28(m,2H),3.97(s,3H),2.50-2.40(m,1H),1.04-1.02(m,6H).

[0528] Example 54: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(2,6-difluorobenzyl)-1-methyl-1H-indole-2-carboxamide (Compound 54)

[0529] The title compound was obtained according to the same procedure as in Example 24, except using (2,6-difluorophenyl)methanamine instead of (S)-1-(4-bromophenyl)ethylamine.

[0530] 1H NMR(300MHz,DMSO-d6)10.41(br,NH,1H),8.91(m,NH,1H),8.36(m,NH,1H),8.08(m,1H),7.51-7.32(m,6H), 7.13-7.07(m,3H),4.52-4.51(m,2H),4.29-4.27(m,2H),3.96(s,3H),2.50-2.38(m,1H),1.03-1.01(m,6H).

[0531] Example 55: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(2,6-dichlorobenzyl)-1-methyl-1H-indole-2-carboxamide (Compound 55)

[0532] The title compound was obtained according to the same procedure as in Example 24, except using (2,6-dichlorophenyl)methanamine instead of (S)-1-(4-bromophenyl)ethylamine.

[0533] 1H NMR(300MHz,DMSO-d6)10.40(br,NH,1H),8.72(m,NH,1H),8.36(m,NH,1H),8.06(m,1H),7.52-7.49(m,5H),7.42-7 .31(m,3H),7.07(m,1H),4.71-4.69(m,2H),4.29-4.27(m,2H),3.97(s,3H),2.50-2.38(m,1H),1.03-1.01(m,6H).

[0534] Example 56: Synthesis of N-(3-chloro-4-fluorobenzyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-1H-indole-2-carboxamide (Compound 56)

[0535] The title compound was obtained according to the same procedure as in Example 24, except using (3-chloro-4-fluorophenyl)methanamine instead of (S)-1-(4-bromophenyl)ethylamine.

[0536] 1H NMR(300MHz,DMSO-d6)10.43(br,NH,1H),9.10(m,NH,1H),8.38(m,NH,1H),8.14(m,1H),7.56-7.32(m,8H ),7.14(m,1H),4.46-4.44(m,2H),4.30-4.28(m,2H),3.98(s,3H),2.50-2.40(m,1H),1.04-1.02(m,6H).

[0537] Example 57: Synthesis of N-(2-chloro-3-(trifluoromethyl)benzyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-1H-indole-2-carboxamide (Compound 57)

[0538] The title compound was obtained according to the same procedure as in Example 24, except using (2-chloro-3-(trifluoromethyl)phenyl)methanamine instead of (S)-1-(4-bromophenyl)ethanamine.

[0539] 1H NMR(300MHz,DMSO-d6)10.44(br,NH,1H),9.18(m,NH,1H),8.38(m,NH,1H),8.15(m,1H),7.81-7.79(m,1H),7.74-7.72(m,1H),7.60-7 .436(m,5H),7.35-7.32(m,1H),7.22(m,1H),4.62-4.61(m,2H),4.30-4.28(m,2H),3.98(s,3H),2.50-2.38(m,1H),1.04-1.02(m,6H).

[0540] Example 58: Synthesis of (R)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-N-(1-(4-(trifluoromethyl)phenyl)ethyl)-1H-indole-2-carboxamide (Compound 58)

[0541] The title compound was obtained according to the same procedure as in Example 24, except using (R)-1-(4-(trifluoromethyl)phenyl)ethanamine hydrochloride instead of (S)-1-(4-bromophenyl)ethanamine.

[0542] 1H NMR(300MHz,DMSO-d6)10.43(br,NH,1H),8.91-8.96(m,NH,1H),8.39-8.36(m ,NH,1H),8.13(m,1H),7.73-7.70(m,2H),7.65-7.62(m,2H),7.52-7.49(m,3H ),7.44(m,1H),7.35-7.33(m,1H),7.23(m,1H),5.24-5.19(m,1H),4.30-4.28 (m,2H),3.92(s,3H),2.50-2.39(m,1H),1.52-1.50(m,3H),1.04-1.02(m,6H).

[0543] Example 59: Synthesis of (R)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)-1H-indole-2-carboxamide (Compound 59)

[0544] The title compound was obtained according to the same procedure as in Example 24, except using (R)-1-(4-(trifluoromethoxy)phenyl)ethanamine hydrochloride instead of (S)-1-(4-bromophenyl)ethanamine.

[0545] 1H NMR(300MHz,DMSO-d6)10.42(br,NH,1H),8.92-8.89(m,NH,1H),8.38-8.34(m,NH,1H),8.11(m,1H),7.55-7.49(m,5H),7.43(m,1H),7.3 5-7.32(m,3H),7.21(m,1H),5.21-5.16(m,1H),4.30-4.28(m,2H),3.93(s,3H),2.50-2.38(m,1H),1.51-1.48(m,3H),1.04-1.02(m,6H).

[0546] Example 60: Synthesis of (S)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-N-(1-(4-(trifluoromethyl)phenyl)ethyl)-1H-indole-2-carboxamide (Compound 60)

[0547] The title compound was obtained according to the same procedure as in Example 24, except using (S)-1-(4-(trifluoromethyl)phenyl)ethanamine hydrochloride instead of (S)-1-(4-bromophenyl)ethanamine.

[0548] 1H NMR(300MHz,DMSO-d6)10.41(br,NH,1H),8.96-8.94(m,NH,1H),8.35(m,NH, 1H),8.12(m,1H),7.72-7.70(m,2H),7.64-7.62(m,2H),7.51-7.49(m,3H),7 .43(m,1H),7.35-7.32(m,1H),7.23(m,1H),5.24-5.19(m,1H),4.30-4.28(m ,2H),3.92(s,3H),2.50-2.38(m,1H),1.52-1.50(m,3H),1.04-1.02(m,6H).

[0549] Example 61: Synthesis of (S)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)-1H-indole-2-carboxamide (Compound 61)

[0550] The title compound was obtained according to the same procedure as in Example 24, except using (S)-1-(4-(trifluoromethoxy)phenyl)ethanamine hydrochloride instead of (S)-1-(4-bromophenyl)ethanamine.

[0551] 1H NMR(300MHz,DMSO-d6)10.40(br,NH,1H),8.90-8.88(m,NH,1H),8.35(m,NH,1H),8.11(m,1H),7.55-7.49(m,5H),7.43(m,1H),7.35-7 .32(m,3H),7.20(m,1H),5.21-5.16(m,1H),4.30-4.28(m,2H),3.93(s,3H),2.49-2.39(m,1H),1.51-1.48(m,3H),1.04-1.02(m,6H).

[0552]

[0553] Example 62: Synthesis of N-(4-(tert-butyl)benzyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2,2,2-trifluoroethyl)-1H-indole-2-carboxamide (Compound 62)

[0554] Example 62-1: Synthesis of ethyl 5-nitro-1-(2,2,2-trifluoroethyl)-1H-indole-2-carboxylate

[0555] 5-nitro-1H-indole-2-carboxylic acid ethyl ester (3g, 12.81mmol) and 1,1,1-trifluoro-2-iodoethane (4.03g, 19.21mmol) are added into a 100mL flask and dissolved in DMF (50ml). KCO (3.54g, 25.62mmol) is added thereto and stirred under reflux for 12 hours. After the reaction is complete, the organic material is extracted with ethyl acetate / HO. The organic layer is dried over MgSO and distilled under reduced pressure to remove the solvent. Residue is subjected to column chromatography (ethyl acetate: normal hexane=1:3) to obtain 5-nitro-1-(2,2,2-trifluoroethyl)-1H-indole-2-carboxylic acid ethyl ester (3.4g, 10.75mmol, 84%, white solid).

[0556] 1H NMR(300MHz, DMSO-d6)8.79(m,1H),8.29-8.26(m,1H),8.03-8.00(m,1H),7.71(m,1H),5.75-5.66(m,2H),4.41-4.34(m,2H),1.37-1.32(m,3H).

[0557] Example 62-2: Synthesis of ethyl 5-amino-1-(2,2,2-trifluoroethyl)-1H-indole-2-carboxylate

[0558] 5-nitro-1-(2,2,2-trifluoroethyl)-1H-indole-2-carboxylic acid ethyl ester (3.4g, 10.75mmol) is added in 100mL flask and dissolved in EtOH (60ml).10%Pd / C (1.7g) is added thereto and stirred 12 hours under H2(g) at room temperature.After diatomite filtration is carried out when the reaction is complete, solvent is removed by distillation under reduced pressure.Residue is subjected to column chromatography (ethyl acetate: normal hexane=1:3) to obtain 5-amino-1-(2,2,2-trifluoroethyl)-1H-indole-2-carboxylic acid ethyl ester (2.8g, 9.78mmol, 90%).

[0559] 1H NMR(300MHz,DMSO-d6)7.42-7.39(m,1H),7.12(m,1H),6.81-6.78(m,1H),6.74(m ,1H),5.49-5.40(m,2H),4.84(br,NH,2H),4.33-4.26(m,2H),1.33-1.28(m,3H).

[0560] Example 62-3: Synthesis of ethyl 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2,2,2-trifluoroethyl)-1H-indole-2-carboxylate

[0561] 5-Amino-1-(2,2,2-trifluoroethyl)-1H-indole-2-carboxylic acid ethyl ester (2.8g, 9.78mmol) and 2-chloro-5-(isobutyrylaminomethyl) benzoic acid (3.0g, 11.736mmol) are added to a 100mL flask and dissolved in CH Cl (60ml). HOBT (1.98g, 14.67mmol) and DMAP (1.194g, 9.78mmol) are added thereto and reacted for 10 minutes. Then, EDC (5.624g, 29.34mmol) and TEA (4.09ml, 29.34mmol) are added and stirred under reflux for 12 hours. After the reaction is complete, the organic material is extracted with CH Cl / H O. The organic layer is dried over MgSO and distilled under reduced pressure to remove the solvent. The residue was subjected to column chromatography (ethyl acetate:n-hexane=3:1) to obtain ethyl 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2,2,2-trifluoroethyl)-1H-indole-2-carboxylate (3.54 g, 6.75 mmol, 69%, white solid).

[0562] 1H NMR(300MHz,DMSO-d6)10.53(br,NH,1H),8.39-8.35(m,NH,1H),8.23(m,1H),7.75-7.72(m,1H),7.59-7.56(m,1H),7.52-7.50(m,1 H),7.43(m,2H),7.36-7.33(m,1H),5.62-5.53(m,2H),4.38-4.28(m,4H),2.50-2.38(m,1H),1.36-1.31(m,3H),1.04-1.02(m,6H).

[0563] Example 62-4: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2,2,2-trifluoroethyl)-1H-indole-2-carboxylic acid

[0564] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2,2,2-trifluoroethyl)-1H-indole-2-carboxylic acid, ethyl ester (3.54g, 6.75mmol) is added to a 500mL flask and dissolved in THF (40ml) and MeOH (40ml).Add LiOH (1.416g, 33.75mmol) dissolved in H2O (40ml) and stir for 12 hours.After concentrating when the reaction is complete, pH is adjusted to 2 with 2N-HCl.The solid gained is filtered to obtain 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2,2,2-trifluoroethyl)-1H-indole-2-carboxylic acid (2.94g, 5.92mmol, 88%, white solid).

[0565] 1H NMR(300MHz,DMSO-d6)10.51(br,NH,1H),8.37(m,NH,1H),8.22(m,1H),7.72-7.69(m,1H),7.56-7.50(m,H), 7.43(m,1H),7.37-7.33(m,2H),5.61-5.59(m,2H),4.30-4.29(m,2H),2.50-2.38(m,1H),1.04-1.02(m,6H).

[0566] Example 62-5: Synthesis of N-(4-(tert-butyl)benzyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2,2,2-trifluoroethyl)-1H-indole-2-carboxamide (Compound 62)

[0567] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2,2,2-trifluoroethyl)-1H-indole-2-carboxylic acid (100 mg, 0.2 mmol) and (4-(tert-butyl)phenyl)methanamine (49 mg, 0.3 mmol) were added to a 25 mL flask and dissolved in DMF (2 ml). HATU (114 mg, 0.3 mmol) and DIPEA (52 mg, 0.4 mmol) were added thereto and stirred at room temperature for 12 hours. After the reaction was complete, the organic material was extracted with ethyl acetate / H2O. The organic layer was dried over MgSO4 and distilled under reduced pressure to remove the solvent. The residue was subjected to column chromatography (ethyl acetate:n-hexane=3:1) to obtain N-(4-(tert-butyl)benzyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2,2,2-trifluoroethyl)-1H-indole-2-carboxamide (94 mg, 0.146 mmol, 73%, white solid).

[0568] 1H NMR(300MHz,DMSO-d6)10.47(br,NH,1H),9.17(m,NH,1H),8.35(m,NH,1H),8.15(m,1H),7.69-7.66(m,1H),7.53-7.50(m,2H),7.43(m,1H),7.3 7-7.34(m,3H),7.28-7.24(m,3H),5.69-5.66(m,2H),4.46-4.45(m,2H) ,4.30-4.29(m,2H),2.50-2.39(m,1H),1.27(s,9H),1.04-1.02(m,6H).

[0569] Example 63: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2,2,2-trifluoroethyl)-N-(2-(trifluoromethyl)benzyl)-1H-indole-2-carboxamide (Compound 63)

[0570] The title compound was obtained according to the same procedure as in Example 62, except using (2-(trifluoromethyl)phenyl)methanamine instead of (4-(tert-butyl)phenyl)methanamine.

[0571] 1H NMR(300MHz,DMSO-d6)10.51(br,NH,1H),9.33(m,NH,1H),8.37(m,NH,1H),8.19(m,1H),7.77-7.65(m,3H),7.56-7.4 4(m,5H),7.37-7.33(m,2H),5.67-5.64(m,2H),4.68(m,2H),4.31-4.29(m,2H),2.50-2.39(m,1H),1.04-1.02(m,6H).

[0572] Example 64: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2,2,2-trifluoroethyl)-N-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxamide (Compound 64)

[0573] The title compound was obtained according to the same procedure as in Example 62, except using (4-(trifluoromethyl)phenyl)methanamine instead of (4-(tert-butyl)phenyl)methanamine.

[0574] 1H NMR(300MHz,DMSO-d6)10.48(br,NH,1H),9.32(m,NH,1H),8.35(m,NH,1H),8.17(m,1H),7.73-7.67(m,3H),7.56-7.50(m,4H), 7.43(m,1H),7.36-7.31(m,2H),5.66-5.64(m,2H),4.58-4.57(m,2H),4.30-4.29(m,2H),2.50-2.39(m,1H),1.04-1.02(m,6H).

[0575] Example 65: Synthesis of (S)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(1-(naphthalen-2-yl)ethyl)-1-(2,2,2-trifluoroethyl)-1H-indole-2-carboxamide (Compound 65)

[0576] The title compound was obtained according to the same procedure as in Example 62, except using (S)-1-(naphthalen-2-yl)ethylamine instead of (4-(tert-butyl)phenyl)methanamine.

[0577] 1H NMR(300MHz,DMSO-d6)10.49(br,NH,1H),9.17-9.14(m,NH,1H),8.37(m,NH,1H),8.16(m,1H),7.91-7.86(m,4H),7.68-7.65(m,1H),7.60-7.4 4(m,6H),7.37-7.33(m,2H),5.60-5.58(m,2H),5.35-5.30(m,1H),4.30 -4.29(m,2H),2.50-2.39(m,1H),1.60-1.57(m,3H),1.04-1.02(m,6H).

[0578] Example 66: Synthesis of (S)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(1-(4-nitrophenyl)ethyl)-1-(2,2,2-trifluoroethyl)-1H-indole-2-carboxamide (Compound 66)

[0579] The title compound was obtained according to the same procedure as in Example 62, except using (S)-1-(4-nitrophenyl)ethylamine instead of (4-(tert-butyl)phenyl)methanamine.

[0580] 1H NMR(300MHz,DMSO-d6)10.50(br,NH,1H),9.21-9.19(m,NH,1H),8.37(m,NH,1H),8.23-8.17(m,3H),7.69-7.66(m,3H),7.55-7.50(m,2H),7.4 4(m,1H),7.38-7.33(m,2H),5.60-5.64(m,2H),5.27-5.23(m,1H),4.31 -4.29(m,2H),2.50-2.39(m,1H),1.53-1.51(m,3H),1.04-1.02(m,6H).

[0581] Example 67: Synthesis of (S)-N-(1-(4-bromophenyl)ethyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2,2,2-trifluoroethyl)-1H-indole-2-carboxamide (Compound 67)

[0582] The title compound was obtained according to the same procedure as in Example 62, except using (S)-1-(4-bromophenyl)ethylamine instead of (4-(tert-butyl)phenyl)methanamine.

[0583] 1H NMR(300MHz,DMSO-d6)10.48(br,NH,1H),9.06-9.04(m,NH,1H),8.36(m,NH,1H),8.14(m,1H),7.68-7.65(m,1H),7.54-7.50(m,4H),7.43(m ,1H),7.37-7.33(m,4H),5.61-5.56(m,2H),5.15-5.10(m,1H),4.30- 4.28(m,2H),2.50-2.39(m,1H),1.48-1.46(m,3H),1.04-1.02(m,6H).

[0584] Example 68: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-fluorobenzyl)-1-(2,2,2-trifluoroethyl)-1H-indole-2-carboxamide (Compound 68)

[0585] The title compound was obtained according to the same procedure as in Example 62, except using (4-fluorophenyl)methanamine instead of (4-(tert-butyl)phenyl)methanamine.

[0586] 1H NMR(300MHz,DMSO-d6)10.49(br,NH,1H),9.26-9.22(m,NH,1H),8.37(m,NH,1H),8.16(m,1H),7.69-7.66(m,1H),7.52-7.50(m,2H),7.43-7 .34(m,4H),7.28(m,1H),7.20-7.14(m,2H),5.67-5.64(m,2H),4.48- 4.46(m,2H),4.30-4.28(m,2H),2.50-2.39(m,1H),1.04-1.02(m,6H).

[0587] Example 69: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzylamino)-N-(3-fluoro-5-(trifluoromethyl)benzyl)-1-(2,2,2-trifluoroethyl)-1H-indole-2-carboxamide (Compound 69)

[0588] The title compound was obtained according to the same procedure as in Example 62, except using (3-fluoro-5-(trifluoromethyl)phenyl)methanamine instead of (4-(tert-butyl)phenyl)methanamine.

[0589] 1H NMR(300MHz,DMSO-d6)10.51(br,NH,1H),9.38(m,NH,1H),8.38(m,NH,1H),8.19(m,1H),7.71-7.68(m,1H),7.60-7.44(m ,6H),7.36-7.30(m,2H),5.66-5.63(m,2H),4.59-4.58(m,2H),4.31-4.29(m,2H),2.50-2.39(m,1H),1.04-1.02(m,6H).

[0590] Example 70: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2,2,2-trifluoroethyl)-N-(3-(trifluoromethyl)benzyl)-1H-indole-2-carboxamide (Compound 70)

[0591] The title compound was obtained according to the same procedure as in Example 62, except using (3-(trifluoromethyl)phenyl)methanamine instead of (4-(tert-butyl)phenyl)methanamine.

[0592] 1H NMR(300MHz,DMSO-d6)10.50(br,NH,1H),9.35(m,NH,1H),8.37(m,NH,1H),8.18(m,1H),7.71-7.58(m,5H),7.53-7.50(m,2H),7.43(m ,1H),7.36-7.33(m,1H),7.29(m,1H),5.67-5.61(m,2H),4.59-4.57(m,2H),4.31-4.29(m,2H),2.50-2.41(m,1H),1.04-1.02(m,6H).

[0593] Example 71: Synthesis of N-(4-chloro-3-fluorobenzyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2,2,2-trifluoroethyl)-1H-indole-2-carboxamide (Compound 71)

[0594] The title compound was obtained according to the same procedure as in Example 62, except using (4-chloro-3-fluorophenyl)methanamine instead of (4-(tert-butyl)phenyl)methanamine.

[0595] 1H NMR(300MHz,DMSO-d6)10.50(br,NH,1H),9.30(m,NH,1H),8.37(m,NH,1H),8.18(m,1H),7.70-7.67(m,1H),7.59-7.50(m,3H),7.43(m,1 H),7.36-7.30(m,3H),7.21-7.19(m,1H),5.66-5.63(m,2H),4.50-4.48(m,2H),4.30-4.28(m,2H),2.50-2.41(m,1H),1.04-1.02(m,6H).

[0596] Example 72: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2,2,2-trifluoroethyl)-N-(4-(trifluoromethoxy)benzyl)-1H-indole-2-carboxamide (Compound 72)

[0597] The title compound was obtained according to the same procedure as in Example 62, except using (4-(trifluoromethoxy)phenyl)methanamine instead of (4-(tert-butyl)phenyl)methanamine.

[0598] 1H NMR(300MHz,DMSO-d6)10.50(br,NH,1H),9.29(m,NH,1H),8.37(m,NH,1H),8.17(m,1H),7.70-7.67(m,1H),7.53-7.44(m ,5H),7.36-7.30(m,4H),5.67-5.64(m,2H),4.52-4.50(m,2H),4.30-4.28(m,2H),2.50-2.38(m,1H),1.04-1.02(m,6H).

[0599]

[0600] Example 73: Synthesis of 5-((2-chloro-5-(isobutyrylaminomethyl)benzyl)amino)-1-methyl-N-(4-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (Compound 73)

[0601] Example 73-1: Synthesis of ethyl 5-((2-chloro-5-(isobutyrylaminomethyl)benzyl)amino)-1-methyl-1H-indole-2-carboxylate

[0602] 5-amino-1-methyl-1H-indole-2-carboxylic acid ethyl ester (300mg, 1.37mmol) and N-(4-chloro-3-formylbenzyl) isobutyramide (328mg, 1.37mmol) are added into a 25mL flask and dissolved in DCE (10ml). AcOH (2 drops) and NaBH (OAc) (580mg, 2.74mmol) are added thereto at 0°C and stirred at room temperature for 12 hours. After the reaction is complete, the organic material is extracted with CH Cl / NaHCO (aqueous solution). The organic layer is dried over MgSO and distilled under reduced pressure to remove the solvent. Residue is subjected to column chromatography (ethyl acetate: normal hexane=1:1) to obtain 5-((2-chloro-5-(isobutyrylaminomethyl)benzyl)amino)-1-methyl-1H-indole-2-carboxylic acid ethyl ester (420mg, 0.95mmol, 69%, solid).

[0603] 1H NMR(300MHz,DMSO-d6)8.19(br,NH,1H),7.41-7.38(m,1H),7.35-7.32(m,2H),7.12-7.10(m,1H),6.95(m,1H),6.89-6.86(m,1H),6.5 0(m,1H),5.98(m,NH,1H),4.31-4.23(m,4H),4.15-4.14(m,2H),3.92(s,3H),2.34-2.25(m,1H),1.32-1.27(m,3H),0.92-0.90(m,6H).

[0604] Example 73-2: Synthesis of 5-((2-chloro-5-(isobutyrylaminomethyl)benzyl)amino)-1-methyl-1H-indole-2-carboxylic acid

[0605] 5-((2-chloro-5-(isobutyrylaminomethyl)benzyl)amino)-1-methyl-1H-indole-2-carboxylic acid, ethyl ester (420mg, 0.95mmol) is added in a 500mL flask and dissolved in THF (5ml) and MeOH (5ml).Add H and be dissolved in LiOH (199mg, 4.75mmol) in O (5ml) and stir for 12 hours.After concentrating when the reaction is complete, pH is adjusted to 2 with 2N-HCl.The solid gained is filtered to obtain 5-((2-chloro-5-(isobutyrylaminomethyl)benzyl)amino)-1-methyl-1H-indole-2-carboxylic acid (260mg, 0.628mmol, 66%, solid).

[0606] 1H NMR(300MHz,Cd3Od)7.67-7.64(m,2H),7.50-7.47(m,1H),7.42(m,1H),7.37-7.30(m,3 H),4.72(m,1H),4.32-4.31(m,2H),4.10(s,3H),2.47-2.38(m,1H),1.10-1.07(m,6H).

[0607] Example 73-3: Synthesis of 5-((2-chloro-5-(isobutyrylaminomethyl)benzyl)amino)-1-methyl-N-(4-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (Compound 73)

[0608] 5-((2-chloro-5-(isobutyrylaminomethyl)benzyl)amino)-1-methyl-1H-indole-2-carboxylic acid (150 mg, 0.362 mmol) and 4-(trifluoromethoxy)aniline (117 mg, 0.724 mmol) were added to a 25 mL flask and dissolved in CH2Cl2 (5 ml) and DMF (1 ml). HOBT (98 mg, 0.724 mmol) and DMAP (85 mg, 0.724 mmol) were added thereto and reacted for 10 minutes. EDC (139 mg, 0.724 mmol) and TEA (100 μl, 0.724 mmol) were added and heated at reflux temperature for 12 hours. After the reaction was complete, the organic material was extracted with CH2Cl2 / H2O. The organic layer was dried over MgSO4 and distilled under reduced pressure to remove the solvent. The residue was subjected to column chromatography (ethyl acetate:n-hexane=3:1) to obtain 5-((2-chloro-5-(isobutyrylaminomethyl)benzyl)amino)-1-methyl-N-(4)-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (65 mg, 0.116 mmol, 32%, white solid).

[0609] 1H NMR(300MHz,DMSO-d6)10.27(br,NH,1H),8.21(br,NH,1H),7.88-7.85(m,2H),7.42-7.31(m,5H),7.12-7.09(m,1H),7.04(m,1H),6.8 5-6.82(m,1H),6.51(m,1H),6.00(m,NH,1H),4.33-4.32(m,2H),4.16-4.14(m,2H),3.92(s,3H),2.34-2.29(m,1H),0.95-0.92(m,6H).

[0610]

[0611] Example 74: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (Compound 74)

[0612] Example 74-1: Synthesis of 5-amino-1H-indole-2-carboxylic acid ethyl ester

[0613] 5-nitro-1H-indole-2-carboxylic acid, ethyl ester (3.0g, 12.81mmol) is added in 100mL flask and is dissolved in MeOH (60ml).10%Pd / C (3.0g) is added thereto and at room temperature under H2(g) stirs 6 hours.After carrying out diatomite filtration when reaction is complete, solvent is removed by distillation under reduced pressure.Resistates is subjected to column chromatography (ethyl acetate: normal hexane=1:3) to obtain 5-amino-1H-indole-2-carboxylic acid, ethyl ester (2.46g, 12.04mmol, 94%).

[0614] 1H NMR(300MHz DMSO-d6)11.37(br,NH,1H),7.13(m,1H),6.82-6.80(m,1H),6.68-6.67(m,1H),4.63(br,NH,2H),4.32-4.25(m,2H),1.33-1.26(m,3H).

[0615] Example 74-2: Synthesis of ethyl 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1H-indole-2-carboxylate

[0616] 5-amino-1H-indole-2-carboxylic acid, ethyl ester (1.0g, 4.89mmol) and 2-chloro-5-(isobutyrylaminomethyl) benzoic acid (1.37g, 5.379mmol) are added in a 100mL flask and dissolved in CH Cl (20ml). HOBT (1.32g, 9.78mmol) and DMAP (1.2g, 9.78mmol) are added thereto and reacted 10 minutes. Then, EDC (1.87g, 9.78mmol) and TEA (989mg, 9.78mmol) are added and at room temperature stirred 12 hours. After the reaction is complete, CH Cl / H O is used to extract the organic material. With the organic layer through MgSO Dry and distill under reduced pressure to remove solvent. The residue was subjected to column chromatography (ethyl acetate:n-hexane=3:1) to obtain ethyl 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1H-indole-2-carboxylate (1.6 g, 3.62 mmol, 74%, white solid).

[0617] 1H NMR(300MHz,DMSO-d6)11.85(br,NH,1H),10.41(br,NH,1H),8.37-8.34(m,NH,1H),8.15(m,1H),7.51- 7.32(m,5H),7.14(m,1H),4.37-4.28(m,4H),2.50-2.38(m,1H),1.36-1.32(m,3H),1.04-1.02(m,6H).

[0618] Example 74-3: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1H-indole-2-carboxylic acid

[0619] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1H-indole-2-carboxylic acid, ethyl ester (1.6g, 3.62mmol) is added in a 250mL flask and dissolved in THF (20ml) and MeOH (20ml).Add and be dissolved in H2LiOH (760mg, 18.1mmol) in O (20ml) and at room temperature stirred 12 hours.After concentrating when the reaction is complete, pH is adjusted to 2 with 2N-HCl.The solid of gained is filtered to obtain 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1H-indole-2-carboxylic acid (1.3g, 3.14mmol, 86%, white solid).

[0620] 1H NMR(300MHz,DMSO-d6)12.91(br,OH,1H),11.70(br,NH,1H),10.38(br,NH,1H),8.37-8.33(m,NH,1H),8.12(m,1 H),7.51-7.48(m,1H),7.44-7.32(m,4H),7.06(m,1H),4.30-4.28(m,2H),2.50-2.38(m,1H),1.04-1.02(m,6H).

[0621] Example 74-4: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (Compound 74)

[0622] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1H-indole-2-carboxylic acid (150 mg, 0.362 mmol) and 4-(trifluoromethoxy)aniline (117 mg, 0.724 mmol) were added to a 25 mL flask and dissolved in CH Cl (5 ml) and DMF (1 ml). HOBT (98 mg, 0.724 mmol) and DMAP (85 mg, 0.724 mmol) were added thereto and reacted for 10 minutes. Then, EDC (139 mg, 0.724 mmol) and TEA (100 μl, 0.724 mmol) were added and heated at reflux temperature for 12 hours. After completion of the reaction, the organic material was extracted with CH Cl / H O. The organic layer was dried over MgSO and distilled under reduced pressure to remove the solvent. The residue was subjected to column chromatography (ethyl acetate:n-hexane=3:1) to obtain 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (65 mg, 0.116 mmol, 32%, white solid).

[0623] 1H NMR(300MHz,DMSO-d6)11.82(br,NH,1H),10.53(br,NH,1H),10.41(br,NH,1H),8.36(m,NH,1H),8.17(m,1H),8.06-8.03(m,2H) ,7.76-7.74(m,2H),7.52-7.50(m,1H),7.44(m,4H),7.36-7.33(m,1H),4.31-4.29(m,2H),2.50-2.39(m,1H),1.05-1.02(m,6H).

[0624] Example 75: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide (Compound 75)

[0625] The title compound was obtained according to the same procedure as in Example 74, except using 4-(trifluoromethyl)aniline instead of 4-(trifluoromethoxy)aniline.

[0626] 1H NMR(300MHz,DMSO-d6)11.80(br,NH,1H),10.42-10.40(br,NH,2H),8.39-8.36(m,NH,1H),8.17(m,1H),7.94 -7.91(m,2H),7.53-7.50(m,1H),7.43-7.33(m,7H),4.31-4.29(m,2H),2.50-2.41(m,1H),1.05-1.02(m,6H).

[0627]

[0628] Example 76: Synthesis of 2-chloro-5-(isobutyrylaminomethyl)-N-(1-methyl-2-(((4-(trifluoromethoxy)phenyl)amino)methyl)-1H-indol-5-yl)benzamide (Compound 76)

[0629] Example 76-1: Synthesis of (5-amino-1-methyl-1H-indol-2-yl)methanol

[0630] LAH (1.13g, 29.783mmol) is added in 250mL flask and is dissolved in THF (60ml).5-amino-1-methyl-1H-indole-2-carboxylic acid ethyl ester (5g, 22.91mmol) is added thereto and at room temperature stirred 3 hours.After the reaction is complete, sodium sulfate (20g) / H o (10ml) is added and stirred 30 minutes.After diatomite filtration, solvent is removed by distillation under reduced pressure.Residue is subjected to column chromatography (ethyl acetate: normal hexane=1:1) to obtain (5-amino-1-methyl-1H-indole-2-yl) methanol (3.3g, 18.72mmol, 81%, white solid).

[0631] 1H NMR(300MHz,DMSO-d6)7.09-7.06(m,1H),6.63(m,1H),6.52-6.49(m,1H),6 .05(m,1H),5.09(br,OH,1H),4.55-4.53(m,2H),4.44(m,2H),3.62(s,3H).

[0632] Example 76-2: Synthesis of 2-chloro-N-(2-(hydroxymethyl)-1-methyl-1H-indol-5-yl)-5-(isobutyrylaminomethyl)benzamide

[0633] Ethyl (5-amino-1-methyl-1H-indol-2-yl) methanol (2 g, 11.35 mmol) and 2-chloro-5-(isobutyrylaminomethyl) benzoic acid (3.2 g, 12.485 mmol) were added to a 100 mL flask and dissolved in CH Cl (50 ml). HOBT (3.07 g, 22.7 mmol) and DMAP (2.78 g, 22.7 mmol) were added thereto and reacted for 10 minutes. Then, EDC (4.35 g, 22.7 mmol) was added and stirred at room temperature for 12 hours. After the reaction was complete, the organic material was extracted with CH Cl / H O. The organic layer was dried over MgSO and distilled under reduced pressure to remove the solvent. The residue was subjected to column chromatography (ethyl acetate:n-hexane=5:1) to obtain 2-chloro-N-(2-(hydroxymethyl)-1-methyl-1H-indol-5-yl)-5-(isobutyrylaminomethyl)benzamide (900 mg, 2.17 mmol, 19%, white solid).

[0634] 1H NMR(300MHz,DMSO-d6)10.28(br,NH,1H),8.35(br,NH,1H),7.95(m,1H),7.50-7.48(m,H),7.41(m,1H),7.34-7.31(m,3H) ,6.34(m,1H),5.23(br,OH,1H),4.62-4.61(m,2H),4.29-4.27(m,2H),3.72(s,3H),2.49-2.40(m,1H),1.04-1.02(m,6H).

[0635] Example 76-3: Synthesis of 2-chloro-5-(isobutyrylaminomethyl)-N-(1-methyl-2-(((4-(trifluoromethoxy)phenyl)amino)methyl)-1H-indol-5-yl)benzamide (Compound 76)

[0636] Triphenylphosphine (253 mg, 0.966 mmol), diisopropyl azodicarboxylate (195 mg, 0.966 mmol) and THF (5 ml) were added to a 25 mL flask and stirred at 0° C. for 10 minutes. Then, 2-chloro-N-(2-(hydroxymethyl)-1-methyl-1H-indol-5-yl)-5-(isobutyrylaminomethyl)benzamide (200 mg, 0.483 mmol) and 4-(trifluoromethoxy)aniline (94 mg, 0.531 mmol) dissolved in THF (5 ml) were added and stirred at room temperature for 12 hours. After the reaction was complete, the organic material was extracted with EA / H O. The organic layer was dried over MgSO and distilled under reduced pressure to remove the solvent. The residue was subjected to column chromatography (ethyl acetate:n-hexane=3:1) to obtain 2-chloro-5-(isobutyrylaminomethyl)-N-(1-methyl-2-(((4-(trifluoromethoxy)phenyl)amino)methyl)-1H-indol-5-yl)benzamide (28 mg, 0.048 mmol, 10%, solid).

[0637] 1H NMR(300MHz,DMSO-d6)10.29(br,NH,1H),8.35(m,2H),7.92(m,1H),7.50-7.47(m,1H),7.41-7.31(m,4H),7.08-7.05(m,2H),6 .75-6.72(m,2H),6.42-6.40(m,2H),4.43-4.42(m,2H),4.29-4.28(m,2H),3.75(s,3H),2.49-2.38(m,1H),1.04-1.01(m,6H).

[0638]

[0639] Example 77: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(methoxymethyl)-N-(4-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (Compound 77)

[0640] Example 77-1: Synthesis of ethyl 1-(methoxymethyl)-5-nitro-1H-indole-2-carboxylate

[0641] 5-nitro-1H-indole-2-carboxylic acid, ethyl ester (5g, 21.35mmol) and chloro(methoxy)methane (3.4g, 42.7mmol) are added in a 100mL flask and dissolved in DMF (50ml). By CsCO(13.9g, 42.7mmol) is added thereto and at room temperature stirred for 6 hours. After the reaction is complete, organic material is extracted with ethyl acetate / HO. By organic layer through MgSO4 drying and distillation under reduced pressure to remove solvent. Residue is subjected to column chromatography (ethyl acetate: normal hexane=1:3) to obtain 1-(methoxymethyl)-5-nitro-1H-indole-2-carboxylic acid, ethyl ester (3.0g, 10.78mmol, 50%, white solid).

[0642] 1H NMR(300MHz,DMSO-d6)8.77(m,1H),8.23-8.20(m,1H),7.95-7.92(m,1H),7 .63(m,1H),5.99(s,2H),4.40-4.33(m,2H),3.18(s,3H),1.38-1.33(m,3H).

[0643] Example 77-2: Synthesis of ethyl 5-amino-1-(methoxymethyl)-1H-indole-2-carboxylate

[0644] 1-(methoxymethyl)-5-nitro-1H-indole-2-carboxylic acid, ethyl ester (3.0g, 10.78mmol) is added in 100mL flask and is dissolved in MeOH (60ml).10%Pd / C (1.0g) is added thereto and at room temperature under H2(g) stirs 12 hours.After carrying out diatomite filtration when the reaction is complete, solvent is removed by distillation under reduced pressure.Resistates is subjected to column chromatography (ethyl acetate: normal hexane=1:3) to obtain 5-amino-1-(methoxymethyl)-1H-indole-2-carboxylic acid, ethyl ester (2.4g, 9.67mmol, 89%).

[0645] 1H NMR(300MHz,DMSO-d6)7.38-7.35(m,1H),7.06(m,1H),6.79-6.76(m,1H),6.74(m,1H ),5.80(s,2H),4.80(br,NH,2H),4.32-4.25(m,2H),3.12(s,3H),1.33-1.29(m,3H).

[0646] Example 77-3: Synthesis of ethyl 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(methoxymethyl)-1H-indole-2-carboxylate

[0647] 5-amino-1-(methoxymethyl)-1H-indole-2-carboxylic acid, ethyl ester (2.4g, 9.67mmol) and 2-chloro-5-(isobutyrylaminomethyl) benzoic acid (2.97g, 11.604mmol) are added in a 100mL flask and dissolved in CH Cl (50ml). HOBT (3.92g, 29.01mmol) and DMAP (3.54g, 29.01mmol) are added thereto and reacted 10 minutes. Then, EDC (5.56g, 29.01mmol) and TEA (4.0ml, 29.01mmol) are added and stirred under reflux for 12 hours. After the reaction is complete, CH Cl / H O is used to extract the organic material. With the organic layer through MgSO Dry and distill under reduced pressure to remove the solvent. The residue was subjected to column chromatography (ethyl acetate:n-hexane=2:1) ​​to obtain ethyl 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(methoxymethyl)-1H-indole-2-carboxylate (4.1 g, 8.43 mmol, 89%, white solid).

[0648] 1H NMR(300MHz,DMSO-d6)10.50(br,NH,1H),8.36(m,NH,1H),8.20(m,1H),7.70-7.67(m,1H),7.57-7.49(m,2H),7.43( m,1H),7.36-7.33(m,2H),4.37-4.28(m,4H),3.14(s.3H),2.50-2.38(m,1H),1.36-1.31(m,3H),1.04-1.02(m,6H).

[0649] Example 77-4: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(methoxymethyl)-1H-indole-2-carboxylic acid

[0650] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(methoxymethyl)-1H-indole-2-carboxylic acid, ethyl ester (4.1g, 8.43mmol) is added in a 500mL flask and dissolved in THF (50ml) and MeOH (50ml).Add and be dissolved in H2LiOH (1.77g, 42.15mmol) in O (50ml) and stirred 12 hours.After concentrating when the reaction is complete, pH is adjusted to 2 with 2N-HCl.The solid of gained is filtered to obtain 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(methoxymethyl)-1H-indole-2-carboxylic acid (3.4g, 7.42mmol, 88%, white solid).

[0651] 1H NMR(300MHz,DMSO-d6)10.47(br,NH,1H),8.36(m,NH,1H),8.18(m,1H),7.65-7.63(m,1H),7.53-7.49(m,2H),7.43(m,1 H),7.35-7.33(m,1H),7.28(m,1H),5.94(s,2H),4.30-4.28(m,2H),3.14(s.3H),2.50-2.38(m,1H),1.04-1.02(m,6H).

[0652] Example 77-5: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(methoxymethyl)-N-(4-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (Compound 77)

[0653] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(methoxymethyl)-1H-indole-2-carboxylic acid (300 mg, 0.65 mmol) and 4-(trifluoromethoxy)aniline (232 mg, 1.31 mmol) were added to a 25 mL flask and dissolved in CH2Cl2 (10 ml) and DMF (1 ml). HOBT (265 mg, 1.965 mmol) and DMAP (240 mg, 1.965 mmol) were added thereto and reacted for 10 minutes. EDC (377 mg, 1.965 mmol) and TEA (273 μl, 1.965 mmol) were added and stirred at reflux for 12 hours. After the reaction was complete, the organic material was extracted with ethyl acetate / H2O. The organic layer was dried over MgSO4 and distilled under reduced pressure to remove the solvent. The residue was subjected to column chromatography (ethyl acetate:n-hexane=3:1) to obtain 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(methoxymethyl)-N-(4-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (230 mg, 0.37 mmol, 57%, white solid).

[0654] 1H NMR(300MHz,DMSO-d6)10.60(br,NH,1H),10.49(br,NH,1H),8.38-8.34(m,NH,1H),8.21(m,1H),7.91-7.88(m,2H),7.69-7.66( m,1H),7.56-7.50(m,2H),7.44-7.33(m,5H),5.92(s,2H),4.31-4.29(m,2H),3.18(s,3H),2.50-2.39(m,1H),1.04-1.02(m,6H).

[0655] Example 78: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(methoxymethyl)-N-(4-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide (Compound 78)

[0656] The title compound was obtained according to the same procedure as in Example 77, except using 4-(trifluoromethyl)aniline instead of 4-(trifluoromethoxy)aniline.

[0657] 1H NMR(300MHz,DMSO-d6)10.74(br,NH,1H),10.50(br,NH,1H),8.38-8.34(m,NH,1H),8.20(m,1H),8.03-8.00(m,2H),7.75-7.68(m,3H),7. 58-7.50(m,3H),7.44-7.43(m,2H),7.37-7.34(m,1H),5.93(s,2H),4 .31-4.29(m,2H),3.15(s,3H),2.50-2.39(m,1H),1.05-1.02(m,6H).

[0658] Example 79: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-chlorophenyl)-1-(methoxymethyl)-1H-indole-2-carboxamide (Compound 79)

[0659] The title compound was obtained according to the same procedure as in Example 77, except using 4-chloroaniline instead of 4-(trifluoromethoxy)aniline.

[0660] 1H NMR(300MHz,DMSO-d6)10.54(br,NH,1H),10.49(br,NH,1H),8.38-8.34(m,NH,1H),8.20(m,1H),7.83-7.80(m,2H),7.69-7.66(m,1H),7. 55-7.50(m,2H),7.44-7.41(m,3H),7.37-7.33(m,2H),5.92(s,2H),4 .31-4.29(m,2H),3.14(s,3H),2.50-2.36(m,1H),1.04-1.02(m,6H).

[0661] Example 80: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(methoxymethyl)-N-(6-(trifluoromethyl)pyridin-3-yl)-1H-indole-2-carboxamide (Compound 80)

[0662] The title compound was obtained according to the same procedure as in Example 77, except using 6-(trifluoromethyl)pyridin-3-amine instead of 4-(trifluoromethoxy)aniline.

[0663] 1H NMR(300MHz,DMSO-d6)10.96(br,NH,1H),10.52(br,NH,1H),9.03(m,NH,1H),8.51-8.48(m,1H),8.37(m,1H),8.24(m,1H),7.94-7.92(m,1H) ,7.72-7.69(m,1H),7.59-7.45(m,4H),7.37-7.34(m,1H),5.95(s,2H) ,4.31-4.29(m,2H),3.16(s,3H),2.50-2.36(m,1H),1.05-1.02(m,6H).

[0664] Example 81: Synthesis of N-(4-chloro-2-methylphenyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(methoxymethyl)-1H-indole-2-carboxamide (Compound 81)

[0665] The title compound was obtained according to the same procedure as in Example 77, except using 4-chloro-2-methylaniline instead of 4-(trifluoromethoxy)aniline.

[0666] 1H NMR(300MHz,DMSO-d6)10.50(br,NH,1H),10.06(br,NH,1H),8.36(m,NH,1H),8.21(s,1H),7.70-7.64(m,1H),7.55-7.51(m,2H),7.45- 7.38(m,5H),7.37-7.28(m,1H),5.94(m,2H),4.32-4.29(m,2H),3.20-3.16(m,3H),2.50-2.29(m,1H),2.29(m,3H),1.06-1.02(m,6H).

[0667] Example 82: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-cyclohexylphenyl)-1-(methoxymethyl)-1H-indole-2-carboxamide (Compound 82)

[0668] The title compound was obtained according to the same procedure as in Example 77, except using 4-cyclohexylaniline instead of 4-(trifluoromethoxy)aniline.

[0669] 1H NMR(300MHz,DMSO-d6)10.54(br,NH,1H),10.49(br,NH,1H),8.38-8.34(m,NH,1H),8.20(m,1H),7.83-7.80(m,2H),7.69-7.66(m,1H),7.55- 7.50(m,2H),7.44-7.41(m,3H),7.37-7.33(m,2H),5.92(s,2H),4.31- 4.29(m,2H),3.15-3.14(m,3H),2.50-2.36(m,1H),1.04-1.02(m,6H).

[0670] Example 83: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(2,4-difluorophenyl)-1-(methoxymethyl)-1H-indole-2-carboxamide (Compound 83)

[0671] The title compound was obtained according to the same procedure as in Example 77, except using 2,4-difluoroaniline instead of 4-(trifluoromethoxy)aniline.

[0672] 1H NMR(300MHz,DMSO-d6)10.54(br,NH,1H),10.49(br,NH,1H),8.38-8.34(m,NH,1H),8.20(m,1H),7.83-7.80(m,2H),7.69-7.66(m,1H),7.55- 7.50(m,2H),7.44-7.41(m,3H),7.37-7.33(m,2H),5.92(s,2H),4.31- 4.29(m,2H),3.15-3.14(m,3H),2.50-2.36(m,1H),1.04-1.02(m,6H).

[0673] Example 84: Synthesis of N-(4-(tert-butyl)phenyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(methoxymethyl)-1H-indole-2-carboxamide (Compound 84)

[0674] The title compound was obtained according to the same procedure as in Example 77, except using 4-(tert-butyl)aniline instead of 4-(trifluoromethoxy)aniline.

[0675] 1H NMR(300MHz,DMSO-d6)10.48(br,NH,1H),10.35(br,NH,1H),8.36(m,NH,1H),8.20(m,1H),7.70-7.58(m,3H),7.58-7.48(m,2 H),7.45(m,1H),7.40-7.33(m,4H),5.93(s,2H),4.31-4.29(m,2H),3.15-3.14(m,3H),2.50-2.36(m,1H),1.05-1.03(m,6H).

[0676] Example 85: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-fluorophenyl)-1-(methoxymethyl)-1H-indole-2-carboxamide (Compound 85)

[0677] The title compound was obtained according to the same procedure as in Example 77, except using 4-fluoroaniline instead of 4-(trifluoromethoxy)aniline.

[0678] 1H NMR(300MHz,DMSO-d6)10.50(br,NH,1H),8.39(br,NH,1H),8.20(m,NH,1H),7.79-7.77(m,2H),7.70-7.66(m,1H),7.55-7.50(m,2H),7.4 4(m,1H),7.37-7.33(m,2H),7.22-7.19(m,2H),5.92(s,2H),4.31-4.29(m,2H),3.15-3.14(m,3H),2.50-2.36(m,1H),1.05-1.02(m,6H).

[0679] Example 86: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-chlorophenyl)-1-(methoxymethyl)-1H-indole-2-carboxamide (Compound 86)

[0680] The title compound was obtained according to the same procedure as in Example 77, except using 3-chloroaniline instead of 4-(trifluoromethoxy)aniline.

[0681] 1H NMR(300MHz,DMSO-d6)10.60(br,NH,1H),10.52(br,NH,1H),8.40-8.38(m,NH,1H),8.22(m,1H),7.97(m,1H),7.59-7.48(m,2H) ,7.45-7.30(m,4H),7.20-7.15(m,1H),5.92(s,2H),4.31-4.29(m,2H),3.15-3.14(m,3H),2.50-2.36(m,1H),1.04-1.02(m,6H).

[0682] Example 87: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(methoxymethyl)-N-(3-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide (Compound 87)

[0683] The title compound was obtained according to the same procedure as in Example 77, except using 3-(trifluoromethyl)aniline instead of 4-(trifluoromethoxy)aniline.

[0684] 1H NMR(300MHz,DMSO-d6)10.73(br,NH,1H),10.52(br,NH,1H),8.38(m,NH,1H),8.26-8.22(m,2H),8.05-8.02(m,1H),7.75-7.68(m,1H),7.65- 7.45(m,4H),7.45-7.42(m,2H),7.36-7.34(m,1H),5.94(s,2H),4.31- 4.29(m,2H),3.15-3.14(m,3H),2.50-2.41(m,1H),1.05-1.02(m,6H).

[0685] Example 88: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-fluorophenyl)-1-(methoxymethyl)-1H-indole-2-carboxamide (Compound 88)

[0686] The title compound was obtained according to the same procedure as in Example 77, except using 3-fluoroaniline instead of 4-(trifluoromethoxy)aniline.

[0687] 1H NMR(300MHz,DMSO-d6)10.63(br,NH,1H),10.52(br,NH,1H),8.41-8.38(m,NH,1H),8.20(m,1H),7.77-7.66(m,2H),7.60-7.51(m,3 H),7.45-7.34(m,4H),6.99-6.32(m,1H),5.92(s,2H),4.31-4.29(m,2H),3.15-3.14(m,3H),2.50-2.36(m,1H),1.05-1.02(m,6H).

[0688] Example 89: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(methoxymethyl)-N-(3-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (Compound 89)

[0689] The title compound was obtained according to the same procedure as in Example 77, except using 3-(trifluoromethoxy)aniline instead of 4-(trifluoromethoxy)aniline.

[0690] 1H NMR(300MHz,DMSO-d6)10.70(br,NH,1H),10.53(br,NH,1H),8.41-8.38(m,NH,1H),8.22(m,1H),7.93(s,1H),7.79-7.76(m,1H),7.71-7.68(m,1H) ,7.56-7.48(m,3H),7.48-7.34(m,3H),7.13-7.10(m,1H),5.92(s,2H),4. 31-4.29(m,2H),3.15-3.14(m,3H),2.50-2.36(m,1H),1.05-1.02(m,6H).

[0691] Example 90: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-chloro-5-fluorophenyl)-1-(methoxymethyl)-1H-indole-2-carboxamide (Compound 90)

[0692] The title compound was obtained according to the same procedure as in Example 77, except using 3-chloro-5-fluoroaniline instead of 4-(trifluoromethoxy)aniline.

[0693] 1H NMR(300MHz,DMSO-d6)10.78(br,NH,1H),10.53(br,NH,1H),8.40-8.38(m,NH,1H),8.23(s,1H),7.77(s,1H),7.71-7.67(m,2H),7.58-7. 51(m,2H),7.45-7.34(m,3H),7.20-7.18(m,1H),5.92(s,2H),4.31-4 .29(m,2H),3.15-3.14(m,3H),2.50-2.36(m,1H),1.05-1.03(m,6H).

[0694] Example 91: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(methoxymethyl)-N-(5,6,7,8-tetrahydronaphthalen-1-yl)-1H-indole-2-carboxamide (Compound 91)

[0695] The title compound was obtained according to the same procedure as in Example 77, except using 5,6,7,8-tetrahydronaphthalen-1-amine instead of 4-(trifluoromethoxy)aniline.

[0696] 1H NMR(300MHz,DMSO-d6)10.51(br,NH,1H),9.87(br,NH,1H),8.39(m,NH,1H),8 .20(m,1H),7.67-7.63(m,1H),7.54-7.51(m,2H),7.45(m,1H),7.35-7.33(m,2 H),7.20-7.10(m,2H),7.03-7.00(m,1H),5.93(s,2H),4.31-4.29(m,2H),3.14 (s,3H),2.78-2.69(m,4H),2.50-2.36(m,1H),1.73(s,4H),1.05-1.02(m,6H).

[0697]

[0698] Example 92: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(3-methoxypropyl)-N-(4-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (Compound 92)

[0699] Example 92-1: Synthesis of ethyl 1-(3-methoxypropyl)-5-nitro-1H-indole-2-carboxylate

[0700] 5-nitro-1H-indole-2-carboxylic acid ethyl ester (3g, 12.8mmol) and 1-chloro-3-methoxypropane (2.78g, 25.6mmol) are added in a 100mL flask and dissolved in DMF (30ml).NaH (768mg, 19.2mmol) is added thereto and stirred at 90 ℃ for 12 hours.After the reaction is complete, ethyl acetate / H o is used to extract the organic material.The organic layer is dried and distilled under reduced pressure to remove the solvent.Resistates is subjected to column chromatography (ethyl acetate: normal hexane=1:3) to obtain 1-(3-methoxypropyl)-5-nitro-1H-indole-2-carboxylic acid ethyl ester (1.8g, 5.88mmol, 46%, oily matter).

[0701] 1H NMR(300MHz,DMSO-d6)8.74(m,1H),8.20-8.17(m,1H),7.80-7.77(m,1H),7.56(m,1H),4.68-4.64 (m,2H),4.39-4.32(m,2H),3.23-3.21(m,2H),3.14(s,3H),1.97-1.93(m,2H),1.37-1.33(m,3H).

[0702] Example 92-2: Synthesis of ethyl 5-amino-1-(3-methoxypropyl)-1H-indole-2-carboxylate

[0703] 1-(3-methoxypropyl)-5-nitro-1H-indole-2-carboxylic acid, ethyl ester (1.8g, 5.88mmol) is added in 100mL flask and is dissolved in EtOH (40ml).Add 10%Pd / C (360mg) and at room temperature under H2(g) stir 12 hours.After carrying out diatomite filtration when the reaction is complete, solvent is removed by distillation under reduced pressure.Residue is subjected to column chromatography (ethyl acetate: normal hexane=1:1) to obtain 5-amino-1-(3-methoxypropyl)-1H-indole-2-carboxylic acid, ethyl ester (1.42g, 5.14mmol, 87%).

[0704] 1H NMR(300MHz,DMSO-d6)7.27-7.24(m,1H),6.96(m,1H),6.78-6.72(m,2H),4.73(br,NH,2H),4 .50-4.45(m,2H),4.31-4.24(m,2H),3.23-3.19(m,5H),1.89-1.85(m,2H),1.33-1.29(m,3H).

[0705] Example 92-3: Synthesis of ethyl 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(3-methoxypropyl)-1H-indole-2-carboxylate

[0706] 5-amino-1-(3-methoxypropyl)-1H-indole-2-carboxylic acid, ethyl ester (1.42g, 5.14mmol) and 2-chloro-5-(isobutyrylaminomethyl) benzoic acid (1.58g, 6.168mmol) are added in a 100mL flask and dissolved in CH Cl (30ml). HOBT (2.08g, 15.42mmol) and DMAP (1.88g, 15.42mmol) are added thereto and reacted 10 minutes. Then, EDC (2.96g, 15.42mmol) and TEA (2.15ml, 15.42mmol) are added and stirred under reflux for 12 hours. After the reaction is complete, CH Cl / H O is used to extract the organic material. With the organic layer through MgSO Dry and distill under reduced pressure to remove the solvent. The residue was subjected to column chromatography (ethyl acetate:n-hexane=2:1) ​​to obtain ethyl 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(3-methoxypropyl)-1H-indole-2-carboxylate (2.1 g, 4.09 mmol, 79%, white solid).

[0707] 1H NMR(300MHz,DMSO-d6)10.48(br,NH,1H),8.38(m,NH,1H),8.18(m,1H),7.54-7.50(m,3H),7.43(m,1H),7.36-7.33(m,1H),7.28(m, 1H),4.59(m,2H),4.36-4.29(m,4H),3.23-3.19(m.5H),2.50-2.38(m,1H),1.95-1.91(m,2H),1.36-1.32(m,3H),1.04-1.02(m,6H).

[0708] Example 92-4: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(3-methoxypropyl)-1H-indole-2-carboxylic acid

[0709] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(3-methoxypropyl)-1H-indole-2-carboxylic acid, ethyl ester (2.1g, 4.09mmol) is added in a 500mL flask and dissolved in THF (30ml) and MeOH (30ml).Add and be dissolved in H2LiOH (858mg, 20.45mmol) in O (30ml) and stir 12 hours.After concentrating when the reaction is complete, pH is adjusted to 2 with 2N-HCl.The solid of gained is filtered to obtain 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(3-methoxypropyl)-1H-indole-2-carboxylic acid (1.79g, 3.68mmol, 89%, white solid).

[0710] 1H NMR(300MHz,DMSO-d6)12.90(br,OH,1H),10.45(br,NH,1H),8.37(m,NH,1H),8.16(m,1H),7.51-7.49(m,3H),7.42(m,1H),7.35-7.32( m,1H),7.22(m,1H),4.59-4.57(m,2H),4.30-4.28(m,2H),3.24-3.19(m,5H),2.50-2.38(m,1H),1.94-1.90(m,2H),1.04-1.02(m,6H).

[0711] Example 92-5: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(3-methoxypropyl)-N-(4-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (Compound 92)

[0712] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(3-methoxypropyl)-1H-indole-2-carboxylic acid (200 mg, 0.411 mmol) and 4-(trifluoromethoxy)aniline (146 mg, 0.822 mmol) were added to a 10 mL flask and dissolved in CH Cl (5 ml) and DMF (1 ml). HOBT (167 mg, 1.233 mmol) and DMAP (151 mg, 1.233 mmol) were added thereto and reacted for 10 minutes. Then, EDC (236 mg, 1.233 mmol) and TEA (172 μl, 1.233 mmol) were added and stirred at reflux for 12 hours. After the reaction was complete, the organic material was extracted with ethyl acetate / H O. The organic layer was dried over MgSO and distilled under reduced pressure to remove the solvent. The residue was subjected to column chromatography (ethyl acetate:n-hexane=3:1) to obtain 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(3-methoxypropyl)-N-(4-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (212 mg, 0.32 mmol, 80%, white solid).

[0713] 1H NMR(300MHz,DMSO-d6)10.52(br,NH,1H),10.46(br,NH,1H),8.37(m,NH,1H),8.18(m,1H),7.91-7.88(m,2H),7.53-7.50(m,3H),7.44-7. 39(m,2H),7.36-7.31(m,3H),4.59(m,2H),4.31-4.29(m,2H),3.24-3 .17(m,5H),2.50-2.39(m,1H),1.99-1.93(m,2H),1.04-1.02(m,6H).

[0714] Example 93: Synthesis of N-(4-(tert-butyl)phenyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(3-methoxypropyl)-1H-indole-2-carboxamide (Compound 93)

[0715] The title compound was obtained according to the same procedure as in Example 92, except using 4-(tert-butyl)aniline instead of 4-(trifluoromethoxy)aniline.

[0716] 1H NMR(300MHz,DMSO-d6)10.45(br,NH,1H),10.26(br,NH,1H),8.37(m,NH,1H),8.16(s,1H),7.70-7.67(m,2H),7.53-7.50(m,3H),7.44(m,1H),7.39- 7.33(m,3H),7.27(m,1H),4.59(m,2H),4.31-4.29(m,2H),3.25-3.21(m,2 H),3.18(s,3H),2.50-2.41(m,1H),1.97-1.95(m,2H),1.05-1.03(m,6H).

[0717] Example 94: Synthesis of N-(4-chloro-2-methylphenyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(3-methoxypropyl)-1H-indole-2-carboxamide (Compound 94)

[0718] The title compound was obtained according to the same procedure as in Example 92, except using 4-chloro-2-methylaniline instead of 4-(trifluoromethoxy)aniline.

[0719] 1H NMR(300MHz,DMSO-d6)10.46(br,NH,1H),9.96(br,NH,1H),8.37-8.35(m,NH, 1H),8.17(s,1H),7.60-7.50(m,3H),7.44(m,1H),7.41-7.39(m,1H),7.36(m,1 H),7.31-7.28(m,3H),4.58(m,2H),4.32-4.29(m,2H),3.25-3.21(m,2H),3.19 (s,3H),2.50-2.34(m,1H),2.28(s,3H),1.96-1.92(m,2H),1.04-1.02(m,6H).

[0720] Example 95: Synthesis of N-(3-chloro-4-fluorophenyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(3-methoxypropyl)-1H-indole-2-carboxamide (Compound 95)

[0721] The title compound was obtained according to the same procedure as in Example 92, except using 3-chloro-4-fluoroaniline instead of 4-(trifluoromethoxy)aniline.

[0722] 1H NMR(300MHz,DMSO-d6)10.51(br,NH,1H),10.46(br,NH,1H),8.37(m,NH,1H) ,8.19(s,1H),8.12-8.08(m,1H),7.74-7.71(m,2H),7.53-7.50(m,3H),7.46- 7.40(m,2H),7.36-7.31(m,2H),4.59(m,2H),4.31-4.29(m,2H),3.25-3.20( m,2H),3.18(s,3H),2.50-2.39(m,1H),1.97-1.95(m,2H),1.05-1.03(m,6H).

[0723] Example 96: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-chlorophenyl)-1-(3-methoxypropyl)-1H-indole-2-carboxamide (Compound 96)

[0724] The title compound was obtained according to the same procedure as in Example 92, except using 4-chloroaniline instead of 4-(trifluoromethoxy)aniline.

[0725] 1H NMR(300MHz,DMSO-d6)10.46(br,NH,2H),8.38-8.34(m,NH,1H),8.18(m,1H),7.83-7.81(m,2H),7.53-7.50(m,3H),7.43-7.41(m,3H),7. 37-7.33(m,2H),4.59(m,2H),4.31-4.29(m,2H),3.25-3.20(m,2H),3 .17(s,3H),2.50-2.39(m,1H),1.97-1.95(m,2H),1.04-1.02(m,6H).

[0726] Example 97: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-fluoro-2-methylphenyl)-1-(3-methoxypropyl)-1H-indole-2-carboxamide (Compound 97)

[0727] The title compound was obtained according to the same procedure as in Example 92, except using 4-fluoro-2-methylaniline instead of 4-(trifluoromethoxy)aniline.

[0728] 1H NMR(300MHz,DMSO-d6)10.45(br,NH,1H),9.93(br,NH,1H),8.37(m,NH,1H),8.17 (s,1H),7.52-7.50(m,3H),7.44(m,1H),7.39-7.33(m,2H),7.30(m,1H),7.18-7.1 4(m,1H),7.10-7.04(m,1H),4.58(m,2H),4.32-4.29(m,2H),3.26-3.22(m,2H),3 .19(s,3H),2.50-2.39(m,1H),2.27(s,3H),1.96-1.92(m,2H),1.05-1.02(m,6H).

[0729] Example 98: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-fluoro-4-morpholinophenyl)-1-(3-methoxypropyl)-1H-indole-2-carboxamide (Compound 98)

[0730] The title compound was obtained according to the same procedure as in Example 92, except using 3-fluoro-4-morpholinoaniline instead of 4-(trifluoromethoxy)aniline.

[0731] 1H NMR(300MHz,DMSO-d6)10.45(br,NH,1H),10.36(br,NH,1H),8.37(m,NH,1H),8.1 7(m,1H),7.73-7.67(m,1H),7.53-7.44(m,5H),7.36-7.33(m,1H),7.26(s,1H),7. 08-7.01(m,1H),4.58(m,2H),4.32-4.29(m,2H),3.75(s,4H),3.24-3.20(m,2H),3 .17(s,3H),2.98(s,4H),2.50-2.41(m,1H),1.96-1.92(m,2H),1.05-1.02(m,6H).

[0732] Example 99: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(3-methoxypropyl)-N-(3-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (Compound 99)

[0733] The title compound was obtained according to the same procedure as in Example 92, except using 3-(trifluoromethoxy)aniline instead of 4-(trifluoromethoxy)aniline.

[0734] 1H NMR(300MHz,DMSO-d6)10.58(br,NH,1H),10.47(br,NH,1H),8.39-8.35(m,NH,1H ),8.19(m,1H),7.93(m,1H),7.80-7.77(m,1H),7.54-7.49(m,4H),7.47-7.44(m, 1H),7.36-7.33(m,2H),7.11-7.08(m,1H),4.60(m,2H),4.31-4.29(m,2H),3.24- 3.20(m,3H),3.17(s,3H)2.50-2.41(m,1H),1.98-1.93(m,2H),1.05-1.02(m,6H).

[0735] Example 100: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(3-methoxypropyl)-N-(3-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide (Compound 100)

[0736] The title compound was obtained according to the same procedure as in Example 92, except using 3-(trifluoromethyl)aniline instead of 4-(trifluoromethoxy)aniline.

[0737] 1H NMR(300MHz,DMSO-d6)10.62(br,NH,1H),10.47(br,NH,1H),8.39-8.35(m,NH,1H),8.26-8.19(m,2H),8.07-8.04(m,1H),7.64-7.58(m,1H),7.54- 7.45(m,5H),7.36(m,2H),4.61(m,2H),4.31-4.29(m,2H),3.24-3.21(m,3 H),3.17(s,3H),2.50-2.42(m,1H),1.98-1.96(m,2H),1.05-1.02(m,6H).

[0738] Example 101: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(3-methoxypropyl)-N-(4-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide (Compound 101)

[0739] The title compound was obtained according to the same procedure as in Example 92, except using 4-(trifluoromethyl)aniline instead of 4-(trifluoromethoxy)aniline.

[0740] 1H NMR(300MHz,DMSO-d6)10.65(br,NH,1H),10.47(br,NH,1H),8.39-8.35(m,N H,1H),8.19(m,1H),8.03-8.01(m,2H),7.75-7.72(m,2H),7.55-7.53(m,3H), 7.44(m,1H),7.36-7.33(m,2H),4.62(m,2H),4.31-4.29(m,2H),3.33-3.21( m,2H),3.17(s,3H),2.50-2.41(m,1H),1.98-1.94(m,2H),1.05-1.02(m,6H).

[0741] Example 102: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-fluorophenyl)-1-(3-methoxypropyl)-1H-indole-2-carboxamide (Compound 102)

[0742] The title compound was obtained according to the same procedure as in Example 92, except using 4-fluoroaniline instead of 4-(trifluoromethoxy)aniline.

[0743] 1H NMR(300MHz,DMSO-d6)10.45(br,NH,1H),10.39(br,NH,1H),8.39-8.35(m,NH,1 H),8.17(m,1H),7.82-7.77(m,2H),7.55-7.50(m,3H),7.44(m,1H),7.36-7.33( m,2H),7.28(m,1H),7.23-7.18(m,2H),4.59(m,2H),4.31-4.29(m,2H),3.24-3. 21(m,2H),3.17(s,3H),2.50-2.41(m,1H),1.98-1.93(m,2H),1.05-1.02(m,6H).

[0744] Example 103: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-chlorophenyl)-1-(3-methoxypropyl)-1H-indole-2-carboxamide (Compound 103)

[0745] The title compound was obtained according to the same procedure as in Example 92, except using 3-chloroaniline instead of 4-(trifluoromethoxy)aniline.

[0746] 1H NMR(300MHz,DMSO-d6)10.48(br,NH,1H),10.46(br,NH,1H),8.39-8.35(m,N H,1H),8.18(m,1H),7.98(m,1H),7.72-7.69(m,1H),7.54-7.50(m,3H),7.44- 7.32(m,4H),7.18-7.15(m,1H),4.59(m,2H),4.31-4.29(m,2H),3.24-3.21( m,2H),3.17(s,3H),2.50-2.41(m,1H),1.98-1.93(m,2H),1.05-1.02(m,6H).

[0747] Example 104: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(2-chlorophenyl)-1-(3-methoxypropyl)-1H-indole-2-carboxamide (Compound 104)

[0748] The title compound was obtained according to the same procedure as in Example 92, except using 2-chloroaniline instead of 4-(trifluoromethoxy)aniline.

[0749] 1H NMR(300MHz,DMSO-d6)10.46(br,NH,1H),10.06(br,NH,1H),8.39-8.35(m,NH,1H),8.18(m,1H),7.66-7.59(m,2H),7.57-7.50(m,3H),7.44-7.38( m,2H),7.36-7.31(m,3H),4.59(m,2H),4.31-4.29(m,2H),3.26-3.19(m,2 H),3.13(s,3H),2.50-2.41(m,1H),1.97-1.93(m,2H),1.05-1.02(m,6H).

[0750] Example 105: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-cyclohexylphenyl)-1-(3-methoxypropyl)-1H-indole-2-carboxamide (Compound 105)

[0751] The title compound was obtained according to the same procedure as in Example 92, except using 4-cyclohexylaniline instead of 4-(trifluoromethoxy)aniline.

[0752] 1H NMR(300MHz,DMSO-d6)10.46(br,NH,1H),10.27(br,NH,1H),8.41(m,NH,1H),8.17(s,1H) ,7.69-7.65(m,2H),7.52-7.50(m,3H),7.44(s,1H),7.36-7.33(m,1H),7.26(s,1H),7.21 -7.18(m,2H),4.59-4.59(m,2H),4.32-4.29(m,2H),3.24-3.20(m,2H),3.17(s,3H),2.50 -2.39(m,1H),1.99-1.92(m,2H),1.80-1.69(m,5H),1.39-1.20(m,6H),1.05-1.02(m,6H).

[0753] Example 106: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(2,4-difluorophenyl)-1-(3-methoxypropyl)-1H-indole-2-carboxamide (Compound 106)

[0754] The title compound was obtained according to the same procedure as in Example 92, except using 2,4-difluoroaniline instead of 4-(trifluoromethoxy)aniline.

[0755] 1H NMR(300MHz,DMSO-d6)10.47(br,NH,1H),10.18(br,NH,1H),8.38-8.34(m,N H,1H),8.19(s,1H),7.64-7.55(m,1H),7.55-7.51(m,3H),7.44(m,1H),7.36- 7.34(m,3H),7.17-7.10(m,1H),4.58(s,2H),4.31-4.29(m,2H),3.25-3.19( m,2H),3.18(s,3H),2.50-2.38(m,1H),1.96-1.93(m,2H),1.04-1.02(m,6H).

[0756] Example 107: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(2-fluorophenyl)-1-(3-methoxypropyl)-1H-indole-2-carboxamide (Compound 107)

[0757] The title compound was obtained according to the same procedure as in Example 92, except using 2-fluoroaniline instead of 4-(trifluoromethoxy)aniline.

[0758] 1H NMR(300MHz,DMSO-d6)10.48(br,NH,1H),10.16(br,NH,1H),8.39(m,NH,1H),8. 18(s,1H),7.62-7.56(m,1H),7.54-7.50(m,2H),7.44(m,1H),7.36-7.32(m,2H) ,7.30-7.24(m,3H),4.58(s,2H),4.31-4.29(m,2H),3.24-3.19(m,2H),3.18(s, 3H),2.50-2.38(m,1H),2.00-1.93(m,3H),1.96-1.93(m,2H),1.05-1.02(m,6H).

[0759] Example 108: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-fluorophenyl)-1-(3-methoxypropyl)-1H-indole-2-carboxamide (Compound 108)

[0760] The title compound was obtained according to the same procedure as in Example 92, except using 3-fluoroaniline instead of 4-(trifluoromethoxy)aniline.

[0761] 1H NMR(300MHz,DMSO-d6)10.53(br,NH,1H),10.48(br,NH,1H),8.38-8.34(m,NH,1H),8.19(s,1H),7.77-7.73(m,1H),7.60-7.51(m,4H),7.44-7.31( m,4H),6.97-6.91(m,1H),4.59(s,2H),4.31-4.29(m,2H),3.25-3.20(m,2 H),3.17(s,3H),2.50-2.37(m,1H),2.00-1.95(m,2H),1.05-1.02(m,6H).

[0762] Example 109: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3,5-difluorophenyl)-1-(3-methoxypropyl)-1H-indole-2-carboxamide (Compound 109)

[0763] The title compound was obtained according to the same procedure as in Example 92, except using 3,5-difluoroaniline instead of 4-(trifluoromethoxy)aniline.

[0764] 1H NMR(300MHz,DMSO-d6)10.67(br,NH,1H),10.49(br,NH,1H),8.40-8.38(m,NH,1H),8.20(s,1H),7.58-7.51(m,5H),7.44(m,1H),7.36-7.32(m,2 H),7.00-6.90(m,1H),4.59(s,2H),4.31-4.29(m,2H),3.22-3.18(m,2H ),3.17(s,3H),2.50-2.38(m,1H),1.96-1.93(m,2H),1.04-1.02(m,6H).

[0765]

[0766] Example 110: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(ethoxymethyl)-N-(4-fluorophenyl)-1H-indole-2-carboxamide (Compound 110)

[0767] Example 110-1: Synthesis of ethyl 1-(ethoxymethyl)-5-nitro-1H-indole-2-carboxylate

[0768] 5-nitro-1H-indole-2-carboxylic acid, ethyl ester (5g, 21.35mmol) and chloromethoxyethane (7.91mL, 85.4mmol) are added in the 100mL flask and are dissolved among the DMF (50ml).With Cs CO (20.9g, 64.0mmol) add wherein and at room temperature stirred 38 hours.After reaction is completed, use ethyl acetate / H O extraction organic material.With organic layer through MgSO Dry and distill under reduced pressure to remove solvent.Concentrated solution is handled with ethyl acetate and ether to collect solid, and then filter to obtain 1-(ethoxymethyl)-5-nitro-1H-indole-2-carboxylic acid, ethyl ester (4.5g, 15.4mmol, 72%, white solid).

[0769] 1H NMR(300MHz,DMSO-d6)8.77(d,1H),8.25-8.21(d,1H),7.95-7.92(d,1H),7.63(br,1 H),5.99(s,2H),4.40-4.33(q,2H),3.39(q,2H),1.38-1.33(t,3H),1.05-1.0(t,3H).

[0770] Example 110-2: Synthesis of ethyl 5-amino-1-(ethoxymethyl)-1H-indole-2-carboxylate

[0771] 1-(ethoxymethyl)-5-nitro-1H-indole-2-carboxylic acid, ethyl ester (4.5g, 17.16mmol) is added in the 250mL flask and is dissolved in MeOH (90ml).10%Pd / C (450mg) is added wherein and at room temperature under H2(g) stirred 12 hours down.After carrying out diatomite filtration when reaction is finished, under reduced pressure, remove solvent by distillation.Obtain the solid 5-amino-1-(ethoxymethyl)-1H-indole-2-carboxylic acid, ethyl ester (4.15g, 15.8mmol, 92%) of gained.

[0772] 1H NMR(300MHz,DMSO-d6)7.38-7.35(d,1H),7.06(s,1H),6.79-6.76(m,1H),6.74(m,1H),5.80(s,2 H),4.80(br,NH,2H),4.32-4.25(q,2H),3.39-3.32(m,2H),1.33-1.29(t,3H),1.08-0.98(t,3H).

[0773] Example 110-3: Synthesis of ethyl 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(ethoxymethyl)-1H-indole-2-carboxylate

[0774] 5-amino-1-(ethoxymethyl)-1H-indole-2-carboxylic acid, ethyl ester (1.0g, 3.81mmol) and 2-chloro-5-(isobutyrylaminomethyl) benzoic acid (1.17g, 4.575mmol) are added in a 100mL flask and dissolved in CH Cl (25ml). HOBT (77.3mg, 5.72mmol) and DMAP (0.14g, 1.14mmol) are added thereto and reacted 10 minutes. Then, EDC (1.10g, 5.72mmol) and TEA (1.33ml, 9.53mmol) are added and stirred under reflux for 12 hours. After the reaction is complete, CH Cl / H O is used to extract the organic material. With the organic layer through MgSO Dry and distill under reduced pressure to remove the solvent. The residue was subjected to column chromatography (ethyl acetate:n-hexane=2:1) ​​to obtain ethyl 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(ethoxymethyl)-1H-indole-2-carboxylate (1.52 g, 3.04 mmol, 80%, white solid).

[0775] 1H NMR(300MHz,DMSO-d6)10.52(br,NH,1H),8.36(m,NH,1H),8.20(m,1H),7.70-7.67(m,1H),7.57-7.49(m,2H),7.43(m,1H),7. 36-7.33(m,2H),5.96(s,2H),4.37-4.29(m,4H),3.39-3.32(m,2H),2.50-2.38(m,1H),1.36-1.32(t,3H),1.05-0.99(m,9H).

[0776] Example 110-4: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(ethoxymethyl)-1H-indole-2-carboxylic acid

[0777] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(ethoxymethyl)-1H-indole-2-carboxylic acid, ethyl ester (1.5g, 3.00mmol) is added in a 250mL flask and dissolved in THF (15ml) and MeOH (15ml).Add and be dissolved in H2LiOH (0.63g, 15.00mmol) in O (12ml) and stirred 12 hours.After concentrating when the reaction is complete, pH is adjusted to 2 with 2N-HCl.The solid of gained is filtered to obtain 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(ethoxymethyl)-1H-indole-2-carboxylic acid (1.10g, 2.33mmol, 77.6%, white solid).

[0778] 1H NMR(300MHz,DMSO-d6)13.07(br,OH,1H),10.51(br,NH,1H),8.41-8.36(m,NH,1H),8.20(br,1H),7.67-7.64(d,1H),7.53-7.50( d,2H),7.43(m,1H),7.36-7.30(m,2H),5.98(s,2H),4.31-4.29(d,2H),3.41-3.35(m.2H),2.50-2.38(m,1H),1.04-1.02(m,9H).

[0779] Example 110-5: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(ethoxymethyl)-N-(4-fluorophenyl)-1H-indole-2-carboxamide (Compound 110)

[0780] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(ethoxymethyl)-1H-indole-2-carboxylic acid (150 mg, 0.32 mmol) and 4-fluoroaniline (36 μl, 0.38 mmol) were added to a 10 mL flask and dissolved in CH Cl (2.1 ml) and DMF (0.5 ml). HOBT (64.4 mg, 0.477 mmol) and DMAP (11.6 mg, 0.095 mmol) were added thereto and reacted for 10 minutes. Then, EDC (91.4 mg, 0.477 mmol) and TEA (130 μl, 0.953 mmol) were added and stirred under reflux for 12 hours. After the reaction was complete, the organic material was extracted with ethyl acetate / H O. The organic layer was dried over MgSO and distilled under reduced pressure to remove the solvent. The residue was subjected to column chromatography (ethyl acetate:n-hexane=3:1) to obtain 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(ethoxymethyl)-N-(4-fluorophenyl)-1H-indole-2-carboxamide (79.6 mg, 0.141 mmol, 44.3%, white solid).

[0781] 1H NMR(300MHz,DMSO-d6)10.48(br,NH,2H),8.37-8.35(m,NH,1H),8.19(br,1H),7.81-7.77(m,2H),7.68-7.65(m,1H),7.54-7.51(m,2H),7. 44(m,1H),7.36-7.33(m,2H),7.24-7.19(m,2H),5.97(s,2H),4.31-4 .29(d,2H),3.42-3.30(m.2H),2.50-2.41(m,1H),1.05-0.98(m,9H).

[0782] Example 111: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(ethoxymethyl)-N-(4-chlorophenyl)-1H-indole-2-carboxamide (Compound 111)

[0783] The title compound was obtained according to the same procedure as in Example 110, except using 4-chloroaniline instead of 4-fluoroaniline.

[0784] 1H NMR(300MHz,DMSO-d6)10.54(br,NH,1H),10.49(br,NH,1H),8.37-8.34(m,NH,1H),8.19(br,1H),7.83-7.80(m,2H),7.68-7.65(m,1H),7. 56-7.48(m,2H),7.45-7.41(m,3H),7.34(m,2H),5.96(s,2H),4.31-4 .29(d,2H),3.41-3.30(m,2H),2.50-2.39(m,1H),1.05-0.96(m,9H).

[0785] Example 112: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-(trifluoromethoxy)phenyl)-1-(ethoxymethyl)-1H-indole-2-carboxamide (Compound 112)

[0786] The title compound was obtained according to the same procedure as in Example 110, except using 3-(trifluoromethoxy)aniline instead of 4-fluoroaniline.

[0787] 1H NMR(300MHz,DMSO-d6)10.67(br,NH,1H),10.50(br,NH,1H),8.38(m,NH,1H),8.20(br,1H),7.92(br,1H),7.79-7.76(d,1H),7.70-7.67(d,1H),7 .56-7.44(m,4H),7.38-7.34(m,2H),7.12-7.09(d,1H),5.96(s,2H),4.3 1-4.29(d,2H),3.14-3.32(m,2H),2.50-2.39(m,1H),1.05-0.98(m,9H).

[0788] Example 113: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(ethoxymethyl)-N-(4-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide (Compound 113)

[0789] The title compound was obtained according to the same procedure as in Example 110, except using 4-(trifluoromethyl)aniline instead of 4-fluoroaniline.

[0790] 1H NMR(300MHz,DMSO-d6)10.75(br,NH,1H),10.50(br,NH,1H),8.37(m,NH,1H),8.21(m,1H),8.02-8.00(d,2H),7.75-7.67(m,3H),7.57-7. 51(t,2H),7.44-7.41(d,2H),7.36-7.34(m,1H),5.97(s,2H),4.31-4 .29(d,2H),3.41-3.32(m,2H),2.50-2.41(m,1H),1.05-0.98(m,9H).

[0791] Example 114: Synthesis of N-(3-chlorophenyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(ethoxymethyl)-1H-indole-2-carboxamide (Compound 114)

[0792] The title compound was obtained according to the same procedure as in Example 110, except using 3-chloroaniline instead of 4-fluoroaniline.

[0793] 1H NMR(300MHz,DMSO-d6)10.58(br,NH,1H),10.50(br,NH,1H),8.39-8.35(m,NH,1H),8.20(s,1H),7.97(s,2H),7.71-7.66(m,2H),7.56-7. 50(m,2H),7.44-7.34(m,4H),7.19-7.16(d,1H),5.96(s,2H),4.31-4 .29(m,2H),3.41-3.32(m,2H),2.50-2.41(m,1H),1.05-0.98(m,9H).

[0794] Example 115: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-chloro-4-fluorophenyl)-1-(ethoxymethyl)-1H-indole-2-carboxamide (Compound 115)

[0795] The title compound was obtained according to the same procedure as in Example 110, except using 3-chloro-4-fluoroaniline instead of 4-fluoroaniline.

[0796] 1H NMR(300MHz,DMSO-d6)10.61(br,NH,1H),10.49(br,NH,1H),8.38-8.35(m,NH,1H),8.20(s,1H),8.09-8.06(dd,1H),7.73-7.66(m,2H),7. 55-7.50(m,2H),7.47-7.41(m,2H),7.35(m,2H),5.96(s,2H),4.31-4 .29(m,2H),3.41-3.32(m,2H),2.50-2.39(m,1H),1.05-0.98(m,9H).

[0797]

[0798] Example 116: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-fluorophenyl)-1-(2-methoxyethyl)-1H-indole-2-carboxamide (Compound 116)

[0799] Example 116-1: Synthesis of ethyl 1-(2-methoxyethyl)-5-nitro-1H-indole-2-carboxylate

[0800] 5-nitro-1H-indole-2-carboxylic acid ethyl ester (5g, 21.35mmol) and 1-chloro-2-methoxyethane (4.04g, 42.7mmol) are added in a 100mL flask and dissolved in DMF (50ml). By CsCO(13.9g, 42.7mmol) is added thereto and stirred at 90 ℃ for 12 hours.After the reaction is complete, organic material is extracted with ethyl acetate / HO.Organic layer is dried and distilled under reduced pressure to remove solvent.Resistates is subjected to column chromatography (ethyl acetate: normal hexane=1:3) to obtain 1-(2-methoxyethyl)-5-nitro-1H-indole-2-carboxylic acid ethyl ester (4g, 13.68mmol, 64%, white solid).

[0801] 1H NMR(300MHz,DMSO-d6)8.73-8.72(m,1H),8.18-8.14(m,1H),7.84-7.81(m,1H),7.55(m,1H ),4.81-4.78(m,2H),4.39-4.32(m,2H),3.66-3.63(m,2H),3.15(s,3H),1.37-1.32(m,6H).

[0802] Example 116-2: Synthesis of ethyl 5-amino-1-(2-methoxyethyl)-1H-indole-2-carboxylate

[0803] 1-(2-methoxyethyl)-5-nitro-1H-indole-2-carboxylic acid ethyl ester (4g, 13.68mmol) is added in 100mL flask and is dissolved in MeOH (100ml).Add 10%Pd / C (after 2.0g) and at room temperature under H2(g) stir 12 hours.After carrying out diatomite filtration when the reaction is complete, solvent is removed by distillation under reduced pressure.Residue is subjected to column chromatography (ethyl acetate: normal hexane=1:1) to obtain 5-amino-1-(2-methoxyethyl)-1H-indole-2-carboxylic acid ethyl ester (3.38g, 12.88mmol, 94%).

[0804] 1H NMR(300MHz,DMSO-d6)7.30-7.27(m,1H),6.96(m,1H),6.76-6.70(m,2H),4.72(br,NH,2H) ,4.61-4.58(m,2H),4.30-4.23(m,2H),3.58-3.54(m,2H),3.16(s,3H),1.33-1.29(m,3H).

[0805] Example 116-3: Synthesis of ethyl 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2-methoxyethyl)-1H-indole-2-carboxylate

[0806] 5-amino-1-(2-methoxyethyl)-1H-indole-2-carboxylic acid, ethyl ester (1.5g, 5.72mmol) and 2-chloro-5-(isobutyrylaminomethyl) benzoic acid (1.755g, 6.864mmol) are added in a 100mL flask and dissolved in CH Cl (30ml) and DMF (5ml). HOBT (1.545g, 11.44mmol) and DMAP (1.4g, 11.44mmol) are added thereto and reacted 10 minutes. Then, EDC (2.2g, 11.44mmol) and TEA (1.6ml, 11.44mmol) are added and stirred under reflux for 12 hours. After the reaction is complete, the organic material is extracted with ethyl acetate / H O. The organic layer is dried and distilled under reduced pressure to remove the solvent. The residue was subjected to column chromatography (ethyl acetate:n-hexane=3:1) to obtain ethyl 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2-methoxyethyl)-1H-indole-2-carboxylate (2.4 g, 4.8 mmol, 84%, white solid).

[0807] 1H NMR(300MHz,DMSO-d6)10.45(br,NH,1H),8.37(m,NH,1H),8.16(m,1H),7.60-7.57(m,1H),7.52-7.49(m,2H),7.42(m,1H),7.36-7.33(m,1H) ,7.27(m,1H),4.71-4.69(m,2H),4.36-4.28(m,4H),3.63-3.59(m,2H) ,3.16(s,3H),2.50-2.38(m,1H),1.36-1.31(m,3H),1.04-1.02(m,6H).

[0808] Example 116-4: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2-methoxyethyl)-1H-indole-2-carboxylic acid

[0809] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2-methoxyethyl)-1H-indole-2-carboxylic acid, ethyl ester (2.4g, 4.8mmol) is added in a 500mL flask and dissolved in THF (50ml) and MeOH (50ml).Add and be dissolved in H2LiOH (1.0g, 24.0mmol) in O (40ml) and stirred 12 hours.After concentrating when the reaction is complete, pH is adjusted to 2 with 2N-HCl.The solid of gained is filtered to obtain 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2-methoxyethyl)-1H-indole-2-carboxylic acid (2.1g, 4.45mmol, 93%, white solid).

[0810] 1H NMR(300MHz,DMSO-d6)12.92(br,OH,1H),10.43(br,NH,1H),8.36(m,NH,1H),8.14(m,1H),7.658-7.45(m,3H),7.42(m,1H),7.36-7. 33(m,1H),7.21(m,1H),4.73-4.70(m,2H),4.30-4.28(m,2H),3.63-3.60(m,2H),3.16(s,3H),2.50-2.38(m,1H),1.04-1.02(m,6H).

[0811] Example 116-5: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-fluorophenyl)-1-(2-methoxyethyl)-1H-indole-2-carboxamide (Compound 116)

[0812] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2-methoxyethyl)-1H-indole-2-carboxylic acid (150 mg, 0.33 mmol) and 4-fluoroaniline (87 mg, 0.495 mmol) were added to a 10 mL flask and dissolved in CH Cl (5 ml) and DMF (1 ml). HOBT (89 mg, 0.66 mmol) and DMAP (80 mg, 0.66 mmol) were added thereto and reacted for 10 minutes. EDC (126 mg, 0.66 mmol) and TEA (91 μl, 0.66 mmol) were added and stirred at reflux for 12 hours. After the reaction was complete, the organic material was extracted with ethyl acetate / H O. The organic layer was dried over MgSO and distilled under reduced pressure to remove the solvent. The residue was subjected to column chromatography (ethyl acetate:n-hexane=3:1) to obtain 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-fluorophenyl)-1-(2-methoxyethyl)-1H-indole-2-carboxamide (140 mg, 0.227 mmol, 69%, white solid).

[0813] 1H NMR(300MHz,DMSO-d6)10.43-10.40(m,NH,2H),8.39-8.34(m,NH,1H),8.15( s,1H),7.82-7.77(m,2H),7.60-7.56(m,1H),7.53-7.48(m,2H),7.44(s,1H), 7.37-7.33(m,1H),7.26(s,1H),7.24-7.17(m,2H),4.72(m,2H),4.32-4.29( m,2H),3.65-3.61(m,2H),3.16(s,3H),2.51-2.35(m,1H),1.05-1.02(m,6H).

[0814] Example 117: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-chlorophenyl)-1-(2-methoxyethyl)-1H-indole-2-carboxamide (Compound 117)

[0815] The title compound was obtained according to the same procedure as in Example 116, except using 4-chloroaniline instead of 4-fluoroaniline.

[0816] 1H NMR(300MHz,DMSO-d6)10.47-10.44(m,NH,2H),8.39-8.34(m,NH,1H),8.15(s,1H),7.84-7.80(m,2H),7.60-7.56(m,1H),7.53-7.48(m,2H),7.44- 7.40(m,3H),7.37-7.33(m,1H),7.28(s,1H),4.72(m,2H),4.32-4.29(m,2 H),3.65-3.60(m,2H),3.16(s,3H),2.51-2.35(m,1H),1.05-1.02(m,6H).

[0817] Example 118: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2-methoxyethyl)-N-(4-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (Compound 118)

[0818] The title compound was obtained according to the same procedure as in Example 116, except using 4-(trifluoromethoxy)aniline instead of 4-fluoroaniline.

[0819] 1H NMR(300MHz,DMSO-d6)10.60-10.44(m,NH,2H),8.39-8.34(m,NH,1H),8.15(s,1H),7.91-7.88(m,2H),7.61-7.57(m,1H),7.53-7.50(m,2H),7.4 4(s,1H),7.40-7.33(m,3H),7.29(s,1H),4.72(m,2H),4.32-4.29(m,2H ),3.65-3.60(m,2H),3.16(s,3H),2.51-2.35(m,1H),1.05-1.02(m,6H).

[0820] Example 119: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2-methoxyethyl)-N-(3-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (Compound 119)

[0821] The title compound was obtained according to the same procedure as in Example 116, except using 3-(trifluoromethoxy)aniline instead of 4-fluoroaniline.

[0822] 1H NMR(300MHz,DMSO-d6)10.60-10.44(m,NH,2H),8.39-8.34(m,NH,1H),8.17(s ,1H),7.93(m,1H),7.80-7.77(m,1H),7.61-7.58(m,1H),7.52-7.50(m,3H),7. 47-7.44(m,1H),7.37-7.31(m,2H),7.12-7.08(m,1H),4.72(m,2H),4.32-4.29 (m,2H),3.65-3.60(m,2H),3.16(s,3H),2.51-2.35(m,1H),1.05-1.02(m,6H).

[0823] Example 120: Synthesis of N-(2-chloro-4-fluorophenyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2-methoxyethyl)-1H-indole-2-carboxamide (Compound 120)

[0824] The title compound was obtained according to the same procedure as in Example 116, except using 2-chloro-4-fluoroaniline instead of 4-fluoroaniline.

[0825] 1H NMR(300MHz,DMSO-d6)10.44(m,NH,1H),10.11(s,NH,1H),8.39-8.34(m,NH,1H),8.16(s,1H),7.65-7.57(m,3H),7.53-7.50(m,2H),7.4 7-7.44(m,1H),7.37-7.27(m,3H),4.71(m,2H),4.32-4.29(m,2H),3.64-3.60(m,2H),3.17(s,3H),2.51-2.35(m,1H),1.05-1.02(m,6H).

[0826] Example 121: Synthesis of N-(4-chloro-2-fluorophenyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2-methoxyethyl)-1H-indole-2-carboxamide (Compound 121)

[0827] The title compound was obtained according to the same procedure as in Example 116, except using 4-chloro-2-fluoroaniline instead of 4-fluoroaniline.

[0828] 1H NMR(300MHz,DMSO-d6)10.44(m,NH,1H),10.23(s,NH,1H),8.39-8.34(m,NH,1H),8.16(s,1H),7.69-7.63(m,1H),7.60-7.57(m,2H),7.54-7.50(m ,2H),7.47-7.43(m,1H),7.36-7.33(m,3H),4.71(m,2H),4.32-4.29(m,2 H),3.64-3.60(m,2H),3.17(s,3H),2.51-2.35(m,1H),1.05-1.02(m,6H).

[0829] Example 122: Synthesis of N-(4-chloro-3-fluorophenyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2-methoxyethyl)-1H-indole-2-carboxamide (Compound 122)

[0830] The title compound was obtained according to the same procedure as in Example 116, except using 4-chloro-3-fluoroaniline instead of 4-fluoroaniline.

[0831] 1H NMR(300MHz,DMSO-d6)10.64(m,NH,1H),10.44(s,NH,1H),8.39-8.34(m,N H,1H),8.17(s,1H),7.97-7.92(m,1H),7.64-7.58(m,3H),7.53-7.50(m,2H ),7.44(s,1H),7.37-7.33(m,1H),7.30(s,1H),4.71(m,2H),4.32-4.29(m, 2H),3.64-3.60(m,2H),3.17(s,3H),2.51-2.35(m,1H),1.05-1.02(m,6H).

[0832] Example 123: Synthesis of N-(3-chloro-4-fluorophenyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2-methoxyethyl)-1H-indole-2-carboxamide (Compound 123)

[0833] The title compound was obtained according to the same procedure as in Example 116, except using 3-chloro-4-fluoroaniline instead of 4-fluoroaniline.

[0834] 1H NMR(300MHz,DMSO-d6)10.53(m,NH,1H),10.44(s,NH,1H),8.38-8.34(m,NH,1H), 8.16(s,1H),8.11-8.08(m,1H),7.75-7.71(m,1H),7.61-7.57(m,1H),7.53-7.48 (m,2H),7.47-7.43(m,2H),7.40-7.33(m,1H),7.28(s,1H),4.71(m,2H),4.32-4. 29(m,2H),3.64-3.60(m,2H),3.16(s,3H),2.51-2.35(m,1H),1.05-1.02(m,6H).

[0835] Example 124: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-chloro-5-fluorophenyl)-1-(2-methoxyethyl)-1H-indole-2-carboxamide (Compound 124)

[0836] The title compound was obtained according to the same procedure as in Example 116, except using 3-chloro-5-fluoroaniline instead of 4-fluoroaniline.

[0837] 1H NMR(300MHz,DMSO-d6)10.65(m,NH,1H),10.45(s,NH,1H),8.39-8.34(m,NH,1H ),8.17(s,1H),7.78(s,1H),7.71-7.67(m,1H),7.62-7.58(m,1H),7.53-7.50(m ,2H),7.44(s,1H),7.36-7.30(m,2H),7.18-7.15(m,1H),4.72(m,2H),4.32-4.2 9(m,2H),3.64-3.60(m,2H),3.15(s,3H),2.51-2.35(m,1H),1.05-1.02(m,6H).

[0838] Example 125: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-chlorophenyl)-1-(2-methoxyethyl)-1H-indole-2-carboxamide (Compound 125)

[0839] The title compound was obtained according to the same procedure as in Example 116, except using 3-chloroaniline instead of 4-fluoroaniline.

[0840] 1H NMR(300MHz,DMSO-d6)10.50-10.45(m,NH,2H),8.39-8.34(m,NH,1H),8.16(s,1 H),7.98(s,1H),7.73-7.69(m,1H),7.61-7.58(m,1H),7.53-7.50(m,2H),7.44( s,1H),7.42-7.33(m,2H),7.29(s,1H),7.18-7.15(m,1H),4.71(m,2H),4.32-4. 29(m,2H),3.64-3.60(m,2H),3.17(s,3H),2.51-2.35(m,1H),1.05-1.02(m,6H).

[0841] Example 126: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-trifluoromethylphenyl)-1-(2-methoxyethyl)-1H-indole-2-carboxamide (Compound 126)

[0842] The title compound was obtained according to the same procedure as in Example 116, except using 4-trifluoromethylaniline instead of 4-fluoroaniline.

[0843] 1H NMR(300MHz,DMSO-d6)10.69-10.46(m,NH,2H),8.39-8.34(m,NH,1H),8.18(s,1H),8.04-8.01(m,2H),7.76-7.72(m,2H),7.63-7.59(m,1H),7.5 3-7.50(m,2H),7.44(s,1H),7.37-7.33(m,2H),4.73(m,2H),4.32-4.29 (m,2H),3.63(m,2H),3.15(s,3H),2.51-2.35(m,1H),1.05-1.02(m,6H).

[0844] Example 127: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-trifluoromethylphenyl)-1-(2-methoxyethyl)-1H-indole-2-carboxamide (Compound 127)

[0845] The title compound was obtained according to the same procedure as in Example 116, except using 3-trifluoromethylaniline instead of 4-fluoroaniline.

[0846] 1H NMR(300MHz,DMSO-d6)10.66(br,NH,1H),10.46(br,NH,1H),8.40-8.35(m,NH,1H),8.27(s,1H),8.17(s,1H),8.06-8.03(m,1H),7.64-7.58(m,2H),7. 53-7.47(m,2H),7.44(s,2H),7.37-7.33(m,2H),4.73(m,2H),4.32-4.29(m ,2H),3.66-3.62(m,2H),3.15(s,3H),2.51-2.35(m,1H),1.05-1.02(m,6H).

[0847] Example 128: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-fluorophenyl)-1-(2-methoxyethyl)-1H-indole-2-carboxamide (Compound 128)

[0848] The title compound was obtained according to the same procedure as in Example 116, except using 3-fluoroaniline instead of 4-fluoroaniline.

[0849] 1H NMR(300MHz,DMSO-d6)10.54(br,NH,1H),10.46(br,NH,1H),8.40-8.35(m,NH,1H ),8.17(s,1H),7.78-7.73(m,1H),7.61-7.56(m,2H),7.53-7.50(m,2H),7.43-7.4 1(m,2H),7.39-7.33(m,1H),7.28(s,1H),6.97-6.94(m,1H),4.72(m,2H),4.32-4 .29(m,2H),3.66-3.62(m,2H),3.15(s,3H),2.51-2.35(m,1H),1.05-1.02(m,6H).

[0850] Example 129: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-fluoro-5-trifluoromethylphenyl)-1-(2-methoxyethyl)-1H-indole-2-carboxamide (Compound 129)

[0851] The title compound was obtained according to the same procedure as in Example 116, except using 3-fluoro-5-trifluoromethylaniline instead of 4-fluoroaniline.

[0852] 1H NMR(300MHz,DMSO-d6)10.81(br,NH,1H),10.47(br,NH,1H),8.40-8.35(m, NH,1H),8.19(s,1H),8.07(s,1H),8.07-7.99(m,1H),7.63-7.60(m,1H),7.5 4-7.50(m,2H),7.45-7.40(m,2H),7.35(m,21H),4.72(m,2H),4.32-4.29(m ,2H),3.66-3.62(m,2H),3.15(s,3H),2.51-2.35(m,1H),1.05-1.02(m,6H).

[0853] Example 130: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3,4-dichlorophenyl)-1-(2-methoxyethyl)-1H-indole-2-carboxamide (Compound 130)

[0854] The title compound was obtained according to the same procedure as in Example 116, except using 3,4-dichloroaniline instead of 4-fluoroaniline.

[0855] 1H NMR(300MHz,DMSO-d6)10.61(br,NH,1H),10.46(br,NH,1H),8.40-8.35(m,NH,1H),8.18-8.16(s,2H),7.78-7.74(m,1H),7.65-7.58(m,2H),7.53-7 .48(m,2H),7.44(m,1H),7.36-7.30(m,21H),4.72(m,2H),4.32-4.29(m,2 H),3.65-3.60(m,2H),3.15(s,3H),2.51-2.35(m,1H),1.05-1.02(m,6H).

[0856] Example 131: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(2,4-dichlorophenyl)-1-(2-methoxyethyl)-1H-indole-2-carboxamide (Compound 131)

[0857] The title compound was obtained according to the same procedure as in Example 116, except using 2,4-dichloroaniline instead of 4-fluoroaniline.

[0858] 1H NMR(300MHz,DMSO-d6)10.46(br,NH,1H),10.14(br,NH,1H),8.40-8.35(m,NH,1H),8.16(s,1H),7.76(m,1H),7.67-7.64(m,1H),7.61-7.57(m,1H), 7.54-7.48(m,3H),7.44(s,1H),7.35(m,2H),4.71(m,2H),4.32-4.29(m,2 H),3.65-3.60(m,2H),3.17(s,3H),2.51-2.35(m,1H),1.05-1.02(m,6H).

[0859] Example 132: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3,5-dichlorophenyl)-1-(2-methoxyethyl)-1H-indole-2-carboxamide (Compound 132)

[0860] The title compound was obtained according to the same procedure as in Example 116, except using 3,5-dichloroaniline instead of 4-fluoroaniline.

[0861] 1H NMR(300MHz,DMSO-d6)10.61(br,NH,1H),10.46(br,NH,1H),8.40-8.35(m,NH,1H),8.17(s,2H),7.78-7.74(m,1H),7.65-7.58(m,2H),7.53-7.4 8(m,2H),7.44(m,1H),7.37-7.30(m,2H),4.72(m,2H),4.32-4.29(m,2H ),3.65-3.60(m,2H),3.15(s,3H),2.51-2.35(m,1H),1.05-1.02(m,6H).

[0862] Example 133: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3,4-difluorophenyl)-1-(2-methoxyethyl)-1H-indole-2-carboxamide (Compound 133)

[0863] The title compound was obtained according to the same procedure as in Example 116, except using 3,4-difluoroaniline instead of 4-fluoroaniline.

[0864] 1H NMR(300MHz,DMSO-d6)10.56(br,NH,1H),10.46(br,NH,1H),8.40-8.35(m,NH,1H),8.18-8.16(s,2H),7.98-7.90(m,1H),7.61-7.39(m,6 H),7.37-7.33(m,1H),7.27(s,1H),4.72(m,2H),4.32-4.29(m,2H),3.65-3.60(m,2H),3.15(s,3H),2.51-2.35(m,1H),1.05-1.02(m,6H).

[0865]

[0866] Example 134: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-ethyl-N-(4-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (Compound 134)

[0867] Example 134-1: Synthesis of 1-ethyl-5-nitro-1H-indole-2-carboxylic acid ethyl ester

[0868] 5-nitro-1H-indole-2-carboxylic acid, ethyl ester (3g, 12.8mmol) and iodoethane (4g, 25.6mmol) are added in a 100mL flask and dissolved in DMF (40ml). By K CO (5.3g, 38.4mmol) is added thereto and at room temperature stirred for 12 hours. After the reaction is complete, organic material is extracted with ethyl acetate / H O. By organic layer through MgSO drying and distilled under reduced pressure to remove solvent. Residue is subjected to column chromatography (ethyl acetate: normal hexane=1:3) to obtain 1-ethyl-5-nitro-1H-indole-2-carboxylic acid, ethyl ester (3.1g, 11.82mmol, 92%, white solid).

[0869] 1H NMR(300MHz,DMSO-d6)8.73(m,1H),8.17-8.15(m,1H),7.86-7.84(m,1H),7 .55-7.54(m,1H),4.65-4.64(m,2H),4.38-4.34(m,2H),1.35-1.30(m,6H).

[0870] Example 134-2: Synthesis of 5-amino-1-ethyl-1H-indole-2-carboxylic acid ethyl ester

[0871] 1-ethyl-5-nitro-1H-indole-2-carboxylic acid, ethyl ester (3.1g, 11.82mmol) is added in 100mL flask and is dissolved in MeOH (50ml).10%Pd / C (1.5g) is added thereto and at room temperature under H2(g) is stirred 12 hours.After carrying out diatomite filtration when the reaction is complete, solvent is removed by distillation under reduced pressure.Resistates is subjected to column chromatography (ethyl acetate: normal hexane=1:3) to obtain 5-amino-1-ethyl-1H-indole-2-carboxylic acid, ethyl ester (2.5g, 10.76mmol, 91%).

[0872] 1H NMR(300MHz,DMSO-d6)7.29-7.27(m,1H),6.95-6.93(m,1H),6.77-6.70(m,2H),4.7 1(Br,NH,2H),4.47-4.46(m,2H),4.29-4.25(m,2H),1.33-1.29(m,3H),1.23(m,3H).

[0873] Example 134-3: Synthesis of ethyl 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-ethyl-1H-indole-2-carboxylate

[0874] 5-amino-1-ethyl-1H-indole-2-carboxylic acid, ethyl ester (1g, 4.3mmol) and 2-chloro-5-(isobutyrylaminomethyl) benzoic acid (1.32g, 5.16mmol) are added in a 100mL flask and dissolved in CH Cl (20ml) and DMF (4ml). HOBT (1.16g, 8.6mmol) and DMAP (1.05g, 8.6mmol) are added thereto and reacted 10 minutes. Then, EDC (1.64g, 8.6mmol) and TEA (1.2ml, 8.6mmol) are added and stirred 12 hours under reflux. After the reaction is complete, CH Cl / H O is used to extract the organic material. With the organic layer through MgSO Dry and distill under reduced pressure to remove solvent. The residue was subjected to column chromatography (ethyl acetate:n-hexane=3:1) to obtain ethyl 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-ethyl-1H-indole-2-carboxylate (1.68 g, 3.57 mmol, 83%, white solid).

[0875] 1H NMR(300MHz,DMSO-d6)10.46(br,NH,1H),8.37(m,NH,1H),8.17(m,1H),7.61-7.50(m,3H),7.43(m,1H),7.35-7.33( m,1H),7.26(m,1H),4.59-4.57(m,2H),4.36-4.29(m,4H),2.50-2.38(m,1H),1.36-1.26(m,6H),1.04-1.02(m,6H).

[0876] Example 134-4: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-ethyl-1H-indole-2-carboxylic acid

[0877] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-ethyl-1H-indole-2-carboxylic acid, ethyl ester (1.68g, 3.57mmol) is added in a 500mL flask and dissolved in THF (30ml) and MeOH (30ml).Add and be dissolved in H2LiOH (749mg, 17.85mmol) in O (30ml) and stirred 12 hours.After concentrating when the reaction is complete, pH is adjusted to 2 with 2N-HCl.The solid of gained is filtered to obtain 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-ethyl-1H-indole-2-carboxylic acid (1.48g, 3.35mmol, 94%, white solid).

[0878] 1H NMR(300MHz,DMSO-d6)12.90(br,OH,1H),10.44(br,NH,1H),8.38-8.34(m,NH,1H),8.16(m,1H),7.59-7.49(m,3H),7.43(m,1H) ,7.36-7.33(m,1H),7.21(m,1H),4.60-4.57(m,2H),4.30-4.29(m,2H),2.50-2.38(m,1H),1.29-1.25(m,3H),1.04-1.02(m,6H).

[0879] Example 134-5: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-ethyl-N-(4-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (Compound 134)

[0880] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-ethyl-1H-indole-2-carboxylic acid (150 mg, 0.34 mmol) and 4-(trifluoromethoxy)aniline (90 mg, 0.51 mmol) were added to a 10 mL flask and dissolved in CH Cl (5 ml) and DMF (1 ml). HOBT (91 mg, 0.68 mmol) and DMAP (83 mg, 0.68 mmol) were added thereto and reacted for 10 minutes. EDC (130 mg, 0.68 mmol) and TEA (95 μl, 0.68 mmol) were added and stirred at reflux for 12 hours. After the reaction was complete, the organic material was extracted with ethyl acetate / H O. The organic layer was dried over MgSO and distilled under reduced pressure to remove the solvent. The residue was subjected to column chromatography (ethyl acetate:n-hexane=3:1) to obtain 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-ethyl-N-(4-trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (100 mg, 0.166 mmol, 49%, white solid).

[0881] 1H NMR(300MHz,DMSO-d6)10.49(br,NH,1H),10.44(br,NH,1H),8.36(m,NH,1H),8.18(m,1H),7.92-7.89(m,2H),7.60-7.57(m,1H),7.53-7. 50(m,2H),7.44(m,1H),7.39-7.32(m,4H),4.58-4.56(m,2H),4.31-4 .29(m,2H),2.50-2.39(m,1H),1.33-1.29(m,3H),1.05-1.02(m,6H).

[0882] Example 135: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-ethyl-N-(4-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide (Compound 135)

[0883] The title compound was obtained according to the same procedure as in Example 134, except using 4-(trifluoromethyl)aniline instead of 4-(trifluoromethoxy)aniline.

[0884] 1H NMR(300MHz,DMSO-d6)10.63(br,NH,1H),10.46(br,NH,1H),8.36(m,NH,1H),8.19(m,1H),8.04-8.01(m,2H),7.74-7.72(m,2H),7.61-7.58(m,1H) ,7.54-7.50(m,2H),7.44(m,1H),7.37-7.32(m,2H),4.59-4.57(m,2H),4. 31-4.29(m,2H),2.50-2.39(m,1H),1.34-1.29(m,3H),1.05-1.02(m,6H).

[0885] Example 136: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-ethyl-N-(3-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide (Compound 136)

[0886] The title compound was obtained according to the same procedure as in Example 134, except using 3-(trifluoromethyl)aniline instead of 4-(trifluoromethoxy)aniline.

[0887] 1H NMR(300MHz,DMSO-d6)10.62(br,NH,1H),10.47(br,NH,1H),8.38(m,NH,1H),8.28(m,1H),8.20(m,1H),8.06-8.04(m,1H),7.64-7.59(m,2H),7.53 -7.51(m,2H),7.48-7.45(m,2H),7.36-7.34(m,2H),4.59-4.57(m,2H),4. 31-4.29(m,2H),2.50-2.39(m,1H),1.34-1.30(m,3H),1.05-1.02(m,6H).

[0888] Example 137: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-ethyl-N-(4-fluorophenyl)-1H-indole-2-carboxamide (Compound 137)

[0889] The title compound was obtained according to the same procedure as in Example 134, except using 4-fluoroaniline instead of 4-(trifluoromethoxy)aniline.

[0890] 1H NMR(300MHz,DMSO-d6)10.44(br,NH,1H),10.37(br,NH,1H),8.36(m,NH,1H) ,8.17(m,1H),7.82-7.78(m,2H),7.60-7.57(m,1H),7.53-7.50(m,2H),7.44( m,1H),7.36-7.33(m,1H),7.28(m,1H),7.23-7.17(m,2H),4.58-4.56(m,2H) ,4.31-4.29(m,2H),2.50-2.39(m,1H),1.33-1.28(m,3H),1.05-1.02(m,6H).

[0891] Example 138: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-chlorophenyl)-1-ethyl-1H-indole-2-carboxamide (Compound 138)

[0892] The title compound was obtained according to the same procedure as in Example 134, except using 4-chloroaniline instead of 4-(trifluoromethoxy)aniline.

[0893] 1H NMR(300MHz,DMSO-d6)10.46(br,NH,1H),10.45(br,NH,1H),8.38(m,NH,1H),8.18(m,1H),7.84-7.81(m,2H),7.60-7.57(m,1H),7.53-7.50( m,2H),7.44-7.41(m,3H),7.36-7.30(m,2H),4.58-4.56(m,2H),4.31- 4.29(m,2H),2.50-2.39(m,1H),1.33-1.28(m,3H),1.04-1.02(m,6H).

[0894] Example 139: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-ethyl-N-(3-fluorophenyl)-1H-indole-2-carboxamide (Compound 139)

[0895] The title compound was obtained according to the same procedure as in Example 134, except using 3-fluoroaniline instead of 4-(trifluoromethoxy)aniline.

[0896] 1H NMR(300MHz,DMSO-d6)10.50(br,NH,1H),10.47(br,NH,1H),8.38(m,NH,1H),8.18(m,1H),7.78-7.74(m,2H),7.61-7.50(m,4H),7. 44-7.32(m,4H),6.96-6.91(m,1H),4.58-4.56(m,2H),4.31-4.29(m,2H),2.50-2.39(m,1H),1.33-1.29(m,3H),1.05-1.02(m,6H).

[0897] Example 140: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-ethyl-N-(3-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (Compound 140)

[0898] The title compound was obtained according to the same procedure as in Example 134, except using 3-(trifluoromethoxy)aniline instead of 4-(trifluoromethoxy)aniline.

[0899] 1H NMR(300MHz,DMSO-d6)10.57(br,NH,1H),10.47(br,NH,1H),8.38(m,NH,1H) ,8.19(m,1H),7.94(m,1H),7.80-7.77(m,1H),7.62-7.59(m,1H),7.53-7.47 (m,3H),7.44(m,1H),7.36-7.34(m,H),7.11-7.09(m,1H),4.58-4.56(m,2H) ,4.31-4.29(m,2H),2.50-2.39(m,1H),1.34-1.29(m,3H),1.05-1.02(m,6H).

[0900] Example 141: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-chlorophenyl)-1-ethyl-1H-indole-2-carboxamide (Compound 141)

[0901] The title compound was obtained according to the same procedure as in Example 134, except using 3-chloroaniline instead of 4-(trifluoromethoxy)aniline.

[0902] 1H NMR(300MHz,DMSO-d6)10.47(br,NH,2H),8.38(m,NH,1H),8.18(m,1H),7.99(m,1H),7.72-7.70(m,1H),7.61-7.58(m,1H),7.53-7.50(m,2H),7. 44(m,1H),7.42-7.32(m,3H),7.18-7.15(m,1H),4.58-4.56(m,2H),4.3 1-4.29(m,2H),2.50-2.39(m,1H),1.33-1.29(m,3H),1.04-1.02(m,6H).

[0903] Example 142: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(2,4-difluorophenyl)-1-ethyl-1H-indole-2-carboxamide (Compound 142)

[0904] The title compound was obtained according to the same procedure as in Example 134, except using 2,4-difluoroaniline instead of 4-(trifluoromethoxy)aniline.

[0905] 1H NMR(300MHz,DMSO-d6)10.47(br,NH,1H),10.16(br,NH,1H),8.39(m,NH,1H),8.19(m,1H),7.65-7.57(m,2H),7.53-7.48(m,2H),7.44(m, 1H),7.39-7.33(m,3H),7.17-7.11(m,1H),4.58-4.56(m,2H),4.31-4 .29(m,2H),2.50-2.39(m,1H),1.30-1.26(m,3H),1.05-1.02(m,6H).

[0906] Example 143: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-ethyl-N-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide (Compound 143)

[0907] The title compound was obtained according to the same procedure as in Example 134, except using 4-fluoro-3-(trifluoromethyl)aniline instead of 4-(trifluoromethoxy)aniline.

[0908] 1H NMR(300MHz,DMSO-d6)10.64(br,NH,1H),10.47(br,NH,1H),8.38(m,NH,1H),8.29-8.27(m,1H),8.20(m,1H),8.11-7.08(m,1H),7.63-7.59(m,1 H),7.53-7.50(m,3H),7.44(m,1H),7.34(m,2H),4.59-4.57(m,2H),4.3 1-4.29(m,2H),2.50-2.39(m,1H),1.34-1.29(m,3H),1.05-1.02(m,6H).

[0909] Example 144: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-ethyl-N-(2-fluorophenyl)-1H-indole-2-carboxamide (Compound 144)

[0910] The title compound was obtained according to the same procedure as in Example 134, except using 2-fluoroaniline instead of 4-(trifluoromethoxy)aniline.

[0911] 1H NMR(300MHz,DMSO-d6)10.46(br,NH,1H),10.14(br,NH,1H),8.38(m,NH,1H),8.18(m,1H),7.64-7.57(m,2H),7.53-7.49(m,2H) ,7.44(m,1H),7.35-7.24(m,5H),4.58-4.56(m,2H),4.31-4.29(m,2H),2.50-2.39(m,1H),1.31-1.26(m,3H),1.05-1.02(m,6H).

[0912] Example 145: Synthesis of N-(3-chloro-4-fluorophenyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-ethyl-1H-indole-2-carboxamide (Compound 145)

[0913] The title compound was obtained according to the same procedure as in Example 134, except using 3-chloro-4-fluoroaniline instead of 4-(trifluoromethoxy)aniline.

[0914] 1H NMR(300MHz,DMSO-d6)10.451(br,NH,1H),10.47(br,NH,1H),8.38(m,NH,1H),8.19(m,1H),8.12-8.09(m,1H),7.75-7.71(m,1H),7.61-7.58(m,1H),7 .53-7.50(m,2H),7.46-7.40(m,2H),7.36-7.31(m,2H),4.58-4.56(m,2H), 4.31-4.29(m,2H),2.50-2.39(m,1H),1.33-1.29(m,3H),1.04-1.02(m,6H).

[0915] Example 146: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-ethyl-N-(3-fluoro-5-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide (Compound 146)

[0916] The title compound was obtained according to the same procedure as in Example 134, except using 3-fluoro-5-(trifluoromethyl)aniline instead of 4-(trifluoromethoxy)aniline.

[0917] 1H NMR(300MHz,DMSO-d6)10.77(br,NH,1H),10.48(br,NH,1H),8.38(m,NH,1H),8.21(m,1H),8.07(m,1H),8.03-8.00(m,1H),7.63-7.60(m,1H),7. 55-7.50(m,2H),7.44(m,1H),7.44-7.34(m,3H),4.59-4.57(m,2H),4.3 1-4.29(m,2H),2.50-2.39(m,1H),1.34-1.30(m,3H),1.05-1.02(m,6H).

[0918] Example 147: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-cyanophenyl)-1-ethyl-1H-indole-2-carboxamide (Compound 147)

[0919] The title compound was obtained according to the same procedure as in Example 134, except using 4-aminobenzonitrile instead of 4-(trifluoromethoxy)aniline.

[0920] 1H NMR(300MHz,DMSO-d6)10.71(br,NH,1H),10.48(br,NH,1H),8.38(m,NH,1H),8.20(m,1H),8.02-7.99(m,2H),7.85-7.82(m,2H),7.62-7.59(m,1H) ,7.54-7.50(m,2H),7.44(m,1H),7.37-7.33(m,2H),4.58-4.56(m,2H),4. 31-4.29(m,2H),2.50-2.39(m,1H),1.34-1.29(m,3H),1.05-1.02(m,6H).

[0921] Example 148: Synthesis of N-(4-chloro-2-methylphenyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-ethyl-1H-indole-2-carboxamide (Compound 148)

[0922] The title compound was obtained according to the same procedure as in Example 134, except using 4-chloro-2-methylaniline instead of 4-(trifluoromethoxy)aniline.

[0923] 1H NMR(300MHz,DMSO-d6)10.46(br,NH,1H),9.95(br,NH,1H),8.38(m,NH,1H),8.17(m,1H),7.60-7.57(m,1H),7.53-7.50(m,2H),7.44-7.3 9(m,3H),7.36-7.29(m,3H),4.58-4.56(m,2H),4.31-4.29(m,2H),2.50-2.39(m,1H),2.28(s,3H),1.31-1.27(m,3H),1.05-1.02(m,6H).

[0924] Example 149: Synthesis of N-(4-fluoro-2-methylphenyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-ethyl-1H-indole-2-carboxamide (Compound 149)

[0925] The title compound was obtained according to the same procedure as in Example 134, except using 4-fluoro-2-methylaniline instead of 4-(trifluoromethoxy)aniline.

[0926] 1H NMR(300MHz,DMSO-d6)10.46(br,NH,1H),9.93(br,NH,1H),8.38(m,NH,1H),8.17(m,1H),7.659-7.49(m,3H),7.44(m,1H),7.40-7.29(m,3H),7. 18-7.15(m,1H),7.10-7.05(m,1H),4.58-4.56(m,2H),4.31-4.29(m,2H ),2.50-2.39(m,1H),2.27(s,3H),1.31-1.27(m,3H),1.05-1.02(m,6H).

[0927] Example 150: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3,5-difluorophenyl)-1-ethyl-1H-indole-2-carboxamide (Compound 150)

[0928] The title compound was obtained according to the same procedure as in Example 134, except using 3,5-difluoroaniline instead of 4-(trifluoromethoxy)aniline.

[0929] 1H NMR(300MHz,DMSO-d6)10.64(br,NH,1H),10.47(br,NH,1H),8.38(m,NH,1H),8.19(m,1H),7.62-7.50(m,5H),7.44(m,1H),7.36 -7.33(m,2H),7.00-6.94(m,1H),4.57-4.55(m,2H),4.31-4.29(m,2H),2.50-2.39(m,1H),1.33-1.29(m,3H),1.05-1.02(m,6H).

[0930] Example 151: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-chloro-5-fluorophenyl)-1-ethyl-1H-indole-2-carboxamide (Compound 151)

[0931] The title compound was obtained according to the same procedure as in Example 134, except using 3-chloro-5-fluoroaniline instead of 4-(trifluoromethoxy)aniline.

[0932] 1H NMR(300MHz,DMSO-d6)10.62(br,NH,1H),10.48(br,NH,1H),8.38(m,NH,1H) ,8.20(m,1H),7.78(m,1H),7.71-7.67(m,1H),7.62-7.59(m,1H),7.54-7.50( m,2H),7.44(m,1H),7.36-7.34(m,2H),7.18-7.15(m,1H),4.58-4.56(m,2H) ,4.31-4.29(m,2H),2.50-2.39(m,1H),1.33-1.29(m,3H),1.04-1.02(m,6H).

[0933] Example 152: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-ethyl-N-(2-fluoro-4-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide (Compound 152)

[0934] The title compound was obtained according to the same procedure as in Example 134, except using 2-fluoro-4-(trifluoromethyl)aniline instead of 4-(trifluoromethoxy)aniline.

[0935] 1H NMR(300MHz,DMSO-d6)10.48(br,NH,1H),10.41(br,NH,1H),8.38(m,NH,1H),8.20(m,1H),7.99-7.94(m,1H),7.83-7.79(m,1H),7.65-7.59(m,2H) ,7.53-7.50(m,2H),7.44(m,1H),7.40-7.34(m,2H),4.59-4.57(m,2H),4. 31-4.29(m,2H),2.50-2.39(m,1H),1.32-1.28(m,3H),1.05-1.02(m,6H).

[0936] Example 153: Synthesis of N-(4-chloro-3-fluorophenyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-ethyl-1H-indole-2-carboxamide (Compound 153)

[0937] The title compound was obtained according to the same procedure as in Example 134, except using 4-chloro-3-fluoroaniline instead of 4-(trifluoromethoxy)aniline.

[0938] 1H NMR(300MHz,DMSO-d6)10.60(br,NH,1H),10.46(br,NH,1H),8.37(m,NH,1H),8.19(m,1H),7.97-7.93(m,1H),7.64-7.57(m,3H),7.54-7. 50(m,2H),7.44(m,1H),7.36-7.33(m,2H),4.58-4.56(m,2H),4.31-4 .29(m,2H),2.50-2.39(m,1H),1.33-1.29(m,3H),1.05-1.02(m,6H).

[0939] Example 154: Synthesis of N-(4-chloro-2-fluorophenyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-ethyl-1H-indole-2-carboxamide (Compound 154)

[0940] The title compound was obtained according to the same procedure as in Example 134, except using 4-chloro-2-fluoroaniline instead of 4-(trifluoromethoxy)aniline.

[0941] 1H NMR(300MHz,DMSO-d6)10.45(br,NH,1H),10.21(br,NH,1H),8.37(m,NH,1H),8.18(m,1H),7.69-7.64(m,1H),7.60-7.50(m,4 H),7.44(m,1H),7.34(m,3H),4.58-4.55(m,2H),4.31-4.29(m,2H),2.50-2.39(m,1H),1.31-1.26(m,3H),1.05-1.02(m,6H).

[0942] Example 155: Synthesis of N-(2-chloro-4-fluorophenyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-ethyl-1H-indole-2-carboxamide (Compound 155)

[0943] The title compound was obtained according to the same procedure as in Example 134, except using 2-chloro-4-fluoroaniline instead of 4-(trifluoromethoxy)aniline.

[0944] 1H NMR(300MHz,DMSO-d6)10.45(br,NH,1H),10.10(br,NH,1H),8.36(m,NH,1H),8.18(m,1H),7.65-7.57(m,3H),7.53-7.50(m,2H) ,7.44(m,1H),7.36-7.27(m,3H),4.58-4.56(m,2H),4.31-4.29(m,2H),2.50-2.39(m,1H),1.31-1.26(m,3H),1.05-1.02(m,6H).

[0945] Example 156: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-cyclohexylphenyl)-1-ethyl-1H-indole-2-carboxamide (Compound 156)

[0946] The title compound was obtained according to the same procedure as in Example 134, except using 4-cyclohexylaniline instead of 4-(trifluoromethoxy)aniline.

[0947] 1H NMR(300MHz,DMSO-d6)10.45(br,NH,1H),10.24(br,NH,1H),8.38(m,NH,1H) ,8.16(m,1H),7.69-7.66(m,2H),7.59-7.50(m,3H),7.44(m,1H),7.36-7.33( m,1H),7.26(m,1H),7.21-7.19(m,2H),4.58-4.55(m,2H),4.31-4.29(m,2H) ,2.50-2.39(m,1H),1.80-1.69(m,5H),1.42-1.15(m,9H),1.05-1.02(m,6H).

[0948]

[0949] Example 157: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-propyl-N-(4-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (Compound 157)

[0950] Example 157-1: Synthesis of 5-nitro-1-propyl-1H-indole-2-carboxylic acid ethyl ester

[0951] 5-nitro-1H-indole-2-carboxylic acid, ethyl ester (5g, 21.34mmol) and 1-iodopropane (6.24ml, 64.02mmol) are added in a 100mL flask and dissolved in DMF (50ml). By Cs CO (20.86g, 64.02mmol) is added thereto and stirred at 90 ℃ for 12 hours. After the reaction is complete, organic material is extracted with ethyl acetate / H O. By organic layer through MgSO dry and distill under reduced pressure to remove solvent. Residue is subjected to column chromatography (ethyl acetate: normal hexane=1:3) to obtain 5-nitro-1-propyl group-1H-indole-2-carboxylic acid, ethyl ester (5.2g, 18.82mmol, 88%, solid).

[0952] 1H NMR(300MHz,DMSO-d6)8.75-8.74(m,1H),8.18-8.14(m,1H),7.89-7.86(m,1H),7.57(m,1H),4 .61-4.56(m,2H),4.39-4.32(m,2H),1.77-1.70(m,2H),1.37-1.33(m,3H),0.90-0.81(m,3H).

[0953] Example 157-2: Synthesis of 5-amino-1-propyl-1H-indole-2-carboxylic acid ethyl ester

[0954] 5-nitro-1-propyl group-1H-indole-2-carboxylic acid, ethyl ester (5.2g, 18.82mmol) is added in 100mL flask and is dissolved in MeOH (150ml).Add 10%Pd / C (2.5g) and the mixture is at room temperature under H2(g) and stirred 12 hours.After carrying out diatomite filtration when the reaction is complete, under reduced pressure, remove solvent by distillation.Resistates is subjected to column chromatography (ethyl acetate: normal hexane=1:3) to obtain 5-amino-1-propyl group-1H-indole-2-carboxylic acid, ethyl ester (4.3g, 17.45mmol, 92.8%).

[0955] 1H NMR (300MHz, DMSO-d6)7.31-7.28(m,1H),6.95(m,1H),6.77-6.73(m,1H),6.71-6.70(m,1H),4.72(br, NH,2H),4.42-4.38(m,2H),4.31-4.23(m,2H),1.69-1.61(m,2H),1.33-1.28(m,3H),0.83-0.78(m,3H).

[0956] Example 157-3: Synthesis of ethyl 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-propyl-1H-indole-2-carboxylate

[0957] 5-amino-1-propyl-1H-indole-2-carboxylic acid, ethyl ester (1.5g, 6.09mmol) and 2-chloro-5-(isobutyrylaminomethyl) benzoic acid (1.87g, 7.308mmol) are added in a 100mL flask and dissolved in CH Cl (30ml) and DMF (3ml). HOBT (1.65g, 12.18mmol) and DMAP (1.49g, 12.18mmol) are added thereto and reacted 10 minutes. Add EDC (2.33g, 12.18mmol) and TEA (1.7ml, 12.18mmol) and stir 12 hours under reflux. After the reaction is complete, use ethyl acetate / H O extraction organic material. With organic layer through MgSO Dry and distill under reduced pressure to remove solvent. The residue was subjected to column chromatography (ethyl acetate:n-hexane=3:1) to obtain ethyl 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-propyl-1H-indole-2-carboxylate (2.34 g, 4.83 mmol, 79%, white solid).

[0958] 1H NMR(300MHz,DMSO-d6)10.46(br,NH,1H),8.38(m,NH,1H),8.17(m,1H),7.63-7.60(m,1H),7.52-7.49(m,2H),7.43(m,1H),7.36-7.33(m,1H),7. 27(m,1H),4.53-4.49(m,2H),4.36-4.29(m,4H),2.50-2.39(m,1H),1.7 5-1.68(m,2H),1.36-1.31(m,3H),1.04-1.02(m,6H),0.85-0.82(m,3H).

[0959] Example 157-4: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-propyl-1H-indole-2-carboxylic acid

[0960] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-propyl group-1H-indole-2-carboxylic acid, ethyl ester (2.34g, 4.83mmol) is added in a 500mL flask and dissolved in THF (30ml) and MeOH (30ml).Add and be dissolved in H2LiOH (1.01g, 24.15mmol) in O (30ml) and stirred 12 hours.After concentrating when the reaction is complete, pH is adjusted to 2 with 2N-HCl.The solid of gained is filtered to obtain 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-propyl group-1H-indole-2-carboxylic acid (1.98g, 4.34mmol, 90%, white solid).

[0961] 1H NMR(300MHz,DMSO-d6)12.88(br,OH,1H),10.43(br,NH,1H),8.36(m,NH,1H),8.15(m,1H),7.59-7.56(m,1H),7.52-7.47(m,2H),7.42(m,1H),7. 35-7.33(m,1H),7.20(m,1H),4.55-4.50(m,2H),4.30-4.28(m,2H),2.5 0-2.38(m,1H),1.74-1.67(m,2H),1.04-1.02(m,6H),0.86-0.78(m,3H).

[0962] Example 157-5: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-propyl-N-(4-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (Compound 157)

[0963] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-propyl-1H-indole-2-carboxylic acid (150 mg, 0.33 mmol) and 4-(trifluoromethoxy)aniline (87 mg, 0.495 mmol) were added to a 10 mL flask and dissolved in CH Cl (5 ml) and DMF (1 ml). HOBT (89 mg, 0.66 mmol) and DMAP (80 mg, 0.66 mmol) were added thereto and reacted for 10 minutes. EDC (126 mg, 0.66 mmol) and TEA (91 μl, 0.66 mmol) were added and stirred at reflux for 12 hours. After the reaction was complete, the organic material was extracted with ethyl acetate / H O. The organic layer was dried over MgSO and distilled under reduced pressure to remove the solvent. The residue was subjected to column chromatography (ethyl acetate:n-hexane=3:1) to obtain 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-propyl-N-(4-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (140 mg, 0.227 mmol, 69%, white solid).

[0964] 1H NMR(300MHz,DMSO-d6)10.52(br,NH,1H),10.45(br,NH,1H),8.38(m,NH,1H),8.17(m,1H),7.91-7.88(m,2H),7.62-7.59(m,1H),7.53-7.40(m,2H) ,7.44(m,1H),7.39-7.31(m,4H),4.54-4.50(m,2H),4.31-4.29(m,2H),2. 50-2.39(m,1H),1.76-1.69(m,2H),1.05-1.02(m,6H),0.84-0.79(m,3H).

[0965] Example 158: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-propyl-N-(3-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (Compound 158)

[0966] The title compound was obtained according to the same procedure as in Example 157, except using 3-(trifluoromethoxy)aniline instead of 4-(trifluoromethoxy)aniline.

[0967] 1H NMR(300MHz,DMSO-d6)10.58(br,NH,1H),10.46(br,NH,1H),8.37(m,NH,1H), 8.18(m,1H),7.92(m,1H),7.80-7.78(m,1H),7.62-7.59(m,1H),7.53-7.44(m, 4H),7.36-7.33(m,2H),7.11-7.08(m,1H),4.54-4.50(m,2H),4.31-4.29(m,2H ),2.50-2.39(m,1H),1.77-1.70(m,2H),1.05-1.02(m,6H),0.84-0.79(m,3H).

[0968] Example 159: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-propyl-N-(4-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide (Compound 159)

[0969] The title compound was obtained according to the same procedure as in Example 157, except using 4-(trifluoromethyl)aniline instead of 4-(trifluoromethoxy)aniline.

[0970] 1H NMR(300MHz,DMSO-d6)10.66(br,NH,1H),10.46(br,NH,1H),8.37(m,NH,1H), 8.19(m,1H),8.03-8.01(m,2H),7.75-7.72(m,1H),7.63-7.60(m,1H),7.53-7. 50(m,2H),7.44(m,1H),7.36-7.34(m,2H),4.55-4.50(m,2H),4.31-4.29(m,2H ),2.50-2.39(m,1H),1.77-1.70(m,2H),1.05-1.02(m,6H),0.85-0.80(m,3H).

[0971] Example 160: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-propyl-N-(3-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide (Compound 160)

[0972] The title compound was obtained according to the same procedure as in Example 157, except using 3-(trifluoromethyl)aniline instead of 4-(trifluoromethoxy)aniline.

[0973] 1H NMR(300MHz,DMSO-d6)10.63(br,NH,1H),10.46(br,NH,1H),8.37(m,NH,1H),8.25(m,1H),8.19(m,1H),8.07-8.04(m,1H),7.63-7.60(m,2H),7.53 -7.44(m,4H),7.35-7.34(m,2H),4.55-4.51(m,2H),4.31-4.29(m,2H),2. 50-2.41(m,1H),1.78-1.70(m,2H),1.05-1.02(m,6H),0.85-0.80(m,3H).

[0974] Example 161: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-chlorophenyl)-1-propyl-1H-indole-2-carboxamide (Compound 161)

[0975] The title compound was obtained according to the same procedure as in Example 157, except using 4-chloroaniline instead of 4-(trifluoromethoxy)aniline.

[0976] 1H NMR(300MHz,DMSO-d6)10.45(br,NH,2H),8.37(m,NH,1H),8.17(m,1H),7.84-7.81(m,2H),7.61-7.58(m,1H),7.53-7.50(m,2H),7.43-7.40( m,3H),7.36-7.30(m,2H),4.54-4.49(m,2H),4.31-4.29(m,2H),2.50- 2.39(m,1H),1.76-1.69(m,2H),1.05-1.02(m,6H),0.84-0.79(m,3H).

[0977] Example 162: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-chlorophenyl)-1-propyl-1H-indole-2-carboxamide (Compound 162)

[0978] The title compound was obtained according to the same procedure as in Example 157, except using 3-chloroaniline instead of 4-(trifluoromethoxy)aniline.

[0979] 1H NMR(300MHz,DMSO-d6)10.48(br,NH,1H),10.45(br,NH,1H),8.36(m,NH,1H),8.18 (m,1H),7.98(m,1H),7.72-7.69(m,1H),7.62-7.59(m,1H),7.53-7.50(m,2H),7.44 -7.42(m,1H),7.39-7.31(m,3H),7.18-7.16(m,1H),4.54-4.50(m,2H),4.31-4.29( m,2H),2.50-2.39(m,1H),1.77-1.70(m,2H),1.05-1.02(m,6H),0.85-0.80(m,3H).

[0980] Example 163: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-chloro-5-fluorophenyl)-1-propyl-1H-indole-2-carboxamide (Compound 163)

[0981] The title compound was obtained according to the same procedure as in Example 157, except using 3-chloro-5-fluoroaniline instead of 4-(trifluoromethoxy)aniline.

[0982] 1H NMR(300MHz,DMSO-d6)10.63(br,NH,1H),10.46(br,NH,1H),8.37(m,NH,1H),8.1 9(m,1H),7.77(m,1H),7.70-7.66(m,1H),7.63-7.60(m,1H),7.53-7.50(m,2H),7. 44(m,1H),7.36-7.33(m,2H),7.18-7.15(m,1H),4.53-4.49(m,2H),4.31-4.29(m ,2H),2.50-2.39(m,1H),1.76-1.69(m,2H),1.05-1.02(m,6H),0.84-0.80(m,3H).

[0983] Example 164: Synthesis of N-(3-chloro-4-fluorophenyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-propyl-1H-indole-2-carboxamide (Compound 164)

[0984] The title compound was obtained according to the same procedure as in Example 157, except using 3-chloro-4-fluoroaniline instead of 4-(trifluoromethoxy)aniline.

[0985] 1H NMR(300MHz,DMSO-d6)10.51(br,NH,1H),10.44(br,NH,1H),8.36(m,NH,1H),8. 18(m,1H),8.10-8.08(m,1H),7.74-7.71(m,1H),7.62-7.59(m,2H),7.53-7.50( m,2H),7.46-7.40(m,2H),7.36-7.30(m,2H),4.54-4.49(m,2H),4.31-4.29(m,2 H),2.50-2.39(m,1H),1.76-1.69(m,2H),1.05-1.02(m,6H),0.84-0.79(m,3H).

[0986] Example 165: Synthesis of N-(4-chloro-3-fluorophenyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-propyl-1H-indole-2-carboxamide (Compound 165)

[0987] The title compound was obtained according to the same procedure as in Example 157, except using 4-chloro-3-fluoroaniline instead of 4-(trifluoromethoxy)aniline.

[0988] 1H NMR(300MHz,DMSO-d6)10.61(br,NH,1H),10.45(br,NH,1H),8.36(m,NH,1H),8.18(m,1H),7.96-7.92(m,1H),7.60-7.57(m,3H),7.53-7.50(m,2H) ,7.44(m,1H),7.36-7.32(m,2H),4.54-4.49(m,2H),4.31-4.29(m,2H),2. 50-2.39(m,1H),1.76-1.69(m,2H),1.05-1.02(m,6H),0.84-0.79(m,3H).

[0989] Example 166: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-fluorophenyl)-1-propyl-1H-indole-2-carboxamide (Compound 166)

[0990] The title compound was obtained according to the same procedure as in Example 157, except using 4-fluoroaniline instead of 4-(trifluoromethoxy)aniline.

[0991] 1H NMR(300MHz,DMSO-d6)10.43(br,NH,1H),10.38(br,NH,1H),8.36(m,NH,1H),8.1 6(m,1H),7.81-7.77(m,2H),7.60-7.57(m,1H),7.52-7.50(m,2H),7.43(m,1H),7. 36-7.33(m,1H),7.27(m,1H),7.23-7.17(m,2H),4.54-4.49(m,2H),4.31-4.29(m ,2H),2.50-2.39(m,1H),1.76-1.69(m,2H),1.05-1.02(m,6H),0.85-0.79(m,3H).

[0992] Example 167: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-fluorophenyl)-1-propyl-1H-indole-2-carboxamide (Compound 167)

[0993] The title compound was obtained according to the same procedure as in Example 157, except using 3-fluoroaniline instead of 4-(trifluoromethoxy)aniline.

[0994] 1H NMR(300MHz,DMSO-d6)10.50(br,NH,1H),10.44(br,NH,1H),8.36(m,NH,1H),8.17(m,1H),7.76-7.72(m,1H),7.61-7.50(m,4H),7.43-7.30( m,4H),6.96-6.91(m,1H),4.54-4.49(m,2H),4.31-4.29(m,2H),2.50- 2.39(m,1H),1.76-1.69(m,2H),1.05-1.02(m,6H),0.84-0.79(m,3H).

[0995] Example 168: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-cyclohexylphenyl)-1-propyl-1H-indole-2-carboxamide (Compound 168)

[0996] The title compound was obtained according to the same procedure as in Example 157, except using 4-cyclohexylaniline instead of 4-(trifluoromethoxy)aniline.

[0997] 1H NMR(300MHz,DMSO-d6)10.42(br,NH,1H),10.24(br,NH,1H),8.36(m,NH,1H),8.15 (m,1H),7.68-7.65(m,2H),7.60-7.56(m,1H),7.52-7.48(m,2H),7.43(m,1H),7.36 -7.33(m,1H),7.25-7.18(m,3H),4.54-4.49(m,2H),4.31-4.29(m,2H),2.50-2.39( m,1H),1.80-1.68(m,7H),1.38-1.17(m,6H),1.05-1.02(m,6H),0.84-0.79(m,3H).

[0998] Example 169: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-fluoro-5-(trifluoromethyl)phenyl)-1-propyl-1H-indole-2-carboxamide (Compound 169)

[0999] The title compound was obtained according to the same procedure as in Example 157, except using 3-fluoro-5-(trifluoromethyl)aniline instead of 4-(trifluoromethoxy)aniline.

[1000] 1H NMR(300MHz,DMSO-d6)10.77(br,NH,1H),10.45(br,NH,1H),8.36(m,NH,1H),8.19(m,1H),8.05-7.99(m,2H),7.63-7.60(m,1H),7.54-7.50( m,2H),7.44-7.33(m,4H),4.55-4.51(m,2H),4.31-4.29(m,2H),2.50- 2.39(m,1H),1.77-1.70(m,2H),1.05-1.02(m,6H),0.85-0.80(m,3H).

[1001]

[1002] Example 170: Synthesis of 1-butyl-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-fluorophenyl)-1H-indole-2-carboxamide (Compound 170)

[1003] Example 170-1: Synthesis of 1-butyl-5-nitro-1H-indole-2-carboxylic acid ethyl ester

[1004] 5-nitro-1H-indole-2-carboxylic acid, ethyl ester (5g, 21.35mmol) and iodine butyl ester (4.86mL, 42.70mmol) are added in the 100mL flask and are dissolved in DMF (50ml).By Cs CO (20.89g, 64.04mmol) is added wherein and at room temperature stirred 22 hours.After reaction is completed, use ethyl acetate / H O extraction organic material.With organic layer through MgSO dry and under reduced pressure distillation to obtain 1-butyl-5-nitro-1H-indole-2-carboxylic acid, ethyl ester (6.19g, 21.35mmol, quantitative, white solid).

[1005] 1H NMR(300MHz,DMSO-d6)8.75(s,1H),8.19-8.15(d,1H),7.88-7.84(d,1H),7.57(s,1H),4.65-4.60(t, 2H),4.40-4.33(dd,2H),1.72-1.67(m,2H),1.37-1.33(t,3H),1.30-1.24(m,2H),0.91-0.85(t,3H).

[1006] Example 170-2: Synthesis of 5-amino-1-butyl-1H-indole-2-carboxylic acid ethyl ester

[1007] 1-butyl-5-nitro-1H-indole-2-carboxylic acid, ethyl ester (6.19g, 21.35mmol) is added in the 250mL flask and is dissolved in MeOH (124ml).Add 10%Pd / C (619mg) and at room temperature under H2(g) stirred 12 hours.After carrying out diatomite filtration when reaction is complete, under reduced pressure, remove solvent by distillation to obtain the solid 5-amino-1-butyl-1H-indole-2-carboxylic acid, ethyl ester (5.34g, 20.52mmol, 96%) of gained.

[1008] 1H NMR(300MHz,DMSO-d6)7.30-7.26(d,1H),6.95(s,1H),6.77-6.73(d,1H),6.70(s,1H),4.72(br,NH,2H),4.46 -4.41(t,2H),4.31-4.23(dd,2H),1.64-1.59(m,2H),1.33-1.28(t,3H),1.25-1.20(m,2H),0.89-0.84(t,3H).

[1009] Example 170-3: Synthesis of ethyl 1-butyl-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1H-indole-2-carboxylate

[1010] 5-amino-1-butyl-1H-indole-2-carboxylic acid, ethyl ester (1.5g, 5.76mmol) and 2-chloro-5-(isobutyrylaminomethyl) benzoic acid (1.77g, 6.91mmol) are added in a 100mL flask and dissolved in CH Cl (38ml). HOBT (1.17g, 8.64mmol) and DMAP (0.21g, 1.73mmol) are added thereto and reacted 10 minutes. Add EDC (1.65g, 8.64mmol) and TEA (2.01ml, 14.40mmol) and stir 12 hours under reflux. After the reaction is complete, use CH Cl / H O extracts organic material. With organic layer through MgSO Dry and distill under reduced pressure to remove solvent. The residue was subjected to column chromatography (ethyl acetate:n-hexane=2:1) ​​to obtain ethyl 1-butyl-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1H-indole-2-carboxylate (2.09 g, 4.20 mmol, 73%, white solid).

[1011] 1H NMR(300MHz,DMSO-d6)10.47(br,NH,1H),8.40-8.36(m,NH,1H),8.18(s,1H), 7.62-7.59(m,1H),7.53-7.50(m,2H),7.43(s,1H),7.36-7.33(m,1H),7.27(s, 1H),4.57-4.52(m,2H),4.37-4.29(m,4H),2.50-2.38(m,1H),1.70-1.61(m,2H ),1.36-1.31(m,3H),1.30-1.19(m,2H),1.04-1.02(m,6H),0.90-0.85(m,3H).

[1012] Example 170-4: Synthesis of 1-butyl-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1H-indole-2-carboxylic acid

[1013] 1-butyl-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1H-indole-2-carboxylic acid, ethyl ester (1.5g, 3.00mmol) is added in a 250mL flask and dissolved in THF (15ml) and MeOH (15ml).Add and be dissolved in H2LiOH (0.63g, 15.00mmol) in O (12ml) and stirred 12 hours.After concentrating when the reaction is complete, pH is adjusted to 2 with 2N-HCl.The solid of gained is filtered to obtain 1-butyl-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1H-indole-2-carboxylic acid (1.94g, 4.13mmol, 98.3%, white solid).

[1014] 1H NMR(300MHz,DMSO-d6)12.88(br,OH,1H),10.45(br,NH,1H),8.40-8.35(m,NH ,1H),8.16(s,1H),7.59-7.56(m,1H),7.53-7.47(m,2H),7.43(s,1H),7.36-7. 33(m,1H),7.22(s,1H),4.59-4.54(s,2H),4.30-4.28(m,2H),2.50-2.38(m,1H ),1.69-1.63(m,2H),1.30-1.16(m,2H),1.04-1.02(m,6H),0.90-0.84(m,3H).

[1015] Example 170-5: Synthesis of 1-butyl-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-fluorophenyl)-1H-indole-2-carboxamide (Compound 170)

[1016] 1-Butyl-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1H-indole-2-carboxylic acid (150 mg, 0.32 mmol) and 4-fluoroaniline (36 μl, 0.38 mmol) were added to a 10 mL flask and dissolved in CH Cl (2.1 ml) and DMF (0.5 ml). HOBT (64.4 mg, 0.477 mmol) and DMAP (11.6 mg, 0.095 mmol) were added thereto and reacted for 10 minutes. EDC (91.4 mg, 0.477 mmol) and TEA (130 μl, 0.953 mmol) were added and stirred at reflux for 12 hours. After the reaction was complete, the organic material was extracted with ethyl acetate / H O. The organic layer was dried over MgSO and distilled under reduced pressure to remove the solvent. The residue was subjected to column chromatography (ethyl acetate:n-hexane=3:1) to obtain 1-butyl-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-fluorophenyl)-1H-indole-2-carboxamide (55.6 mg, 0.099 mmol, 46.4%, white solid).

[1017] 1H NMR(300MHz,DMSO-d6)10.45(br,NH,1H),10.40(br,NH,1H),8.38-8.34(m,NH,1H),8.1 7(s,1H),7.82-7.77(m,2H),7.60-7.56(m,1H),7.54-7.48(m,2H),7.44(s,1H),7.37-7. 33(m,1H),7.27(s,1H),7.24-7.18(m,2H),4.59-4.54(m,2H),4.32-4.29(m,2H),2.50-2 .38(m,1H),1.69-1.63(m,2H),1.30-1.17(m,2H),1.05-1.02(m,6H),0.90-0.83(m,3H).

[1018] Example 171: Synthesis of 1-butyl-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-chlorophenyl)-1H-indole-2-carboxamide (Compound 171)

[1019] The title compound was obtained according to the same procedure as in Example 170, except using 4-chloroaniline instead of 4-fluoroaniline.

[1020] 1H NMR(300MHz,DMSO-d6)10.45(br,NH,2H),8.38-8.34(m,NH,1H),8.17(s,1H),7. 84-7.80(m,2H),7.60-7.57(m,1H),7.52-7.50(m,2H),7.44-7.41(m,3H),7.37- 7.33(m,1H),7.29(s,1H),4.59-4.54(m,2H),4.32-4.29(m,2H),2.50-2.38(m,1 H),1.69-1.63(m,2H),1.30-1.17(m,2H),1.05-1.02(m,6H),0.90-0.83(m,3H).

[1021] Example 172: Synthesis of 1-butyl-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (Compound 172)

[1022] The title compound was obtained according to the same procedure as in Example 170, except using 4-(trifluoromethoxy)aniline instead of 4-fluoroaniline.

[1023] 1H NMR(300MHz,DMSO-d6)10.52(br,NH,1H),10.46(br,NH,1H),8.40-8.35(m,NH,1 H),8.17(s,1H),7.92-7.88(m,2H),7.61-7.57(m,1H),7.53-7.50(m,2H),7.44( s,1H),7.40-7.30(m,4H),4.59-4.53(m,2H),4.32-4.29(m,2H),2.50-2.38(m,1 H),1.71-1.63(m,2H),1.30-1.20(m,2H),1.05-1.02(m,6H),0.90-0.83(m,3H).

[1024] Example 173: Synthesis of 1-butyl-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (Compound 173)

[1025] The title compound was obtained according to the same procedure as in Example 170, except using 3-(trifluoromethoxy)aniline instead of 4-fluoroaniline.

[1026] 1H NMR(300MHz,DMSO-d6)10.59(br,NH,1H),10.46(br,NH,1H),8.40-8.35(m,NH,1H),8.18( s,1H),7.92(s,1H),7.81-7.78(m,1H),7.61-7.58(m,1H),7.54-7.50(m,3H),7.48-7.44( m,1H),7.37-7.32(m,2H),7.12-7.09(m,1H),4.59-4.53(m,2H),4.32-4.29(m,2H),2.50- 2.38(m,1H),1.71-1.63(m,2H),1.28-1.20(m,2H),1.05-1.02(m,6H),0.90-0.83(m,3H).

[1027] Example 174: Synthesis of 1-butyl-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide (Compound 174)

[1028] The title compound was obtained according to the same procedure as in Example 170, except using 4-(trifluoromethyl)aniline instead of 4-fluoroaniline.

[1029] 1H NMR(300MHz,DMSO-d6)10.66(br,NH,1H),10.47(br,NH,1H),8.40-8.35(m,NH,1H),8 .19(s,1H),8.04-8.00(m,2H),7.76-7.71(m,2H),7.62-7.58(m,1H),7.54-7.50(m,2 H),7.44(s,1H),7.36-7.33(m,2H),4.57-4.54(m,2H),4.32-4.29(m,2H),2.50-2.35 (m,1H),1.71-1.63(m,2H),1.29-1.20(m,2H),1.05-1.02(m,6H),0.90-0.83(m,3H).

[1030] Example 175: Synthesis of 1-butyl-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide (Compound 175)

[1031] The title compound was obtained according to the same procedure as in Example 170, except using 3-(trifluoromethyl)aniline instead of 4-fluoroaniline.

[1032] 1H NMR(300MHz,DMSO-d6)10.62(br,NH,1H),10.46(br,NH,1H),8.40-8.35(m,NH ,1H),8.25(s,1H),8.18(s,1H),8.10-8.04(m,1H),7.64-7.58(m,2H),7.54-7. 44(m,4H),7.34(m,2H),4.59-4.53(m,2H),4.32-4.29(m,2H),2.50-2.38(m,1H ),1.72-1.63(m,2H),1.28-1.20(m,2H),1.05-1.01(m,6H),0.90-0.83(m,3H).

[1033] Example 176: Synthesis of 1-butyl-N-(4-chloro-3-fluorophenyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1H-indole-2-carboxamide (Compound 176)

[1034] The title compound was obtained according to the same procedure as in Example 170, except using 4-chloro-3-fluoroaniline instead of 4-fluoroaniline.

[1035] 1H NMR(300MHz,DMSO-d6)10.62(br,NH,1H),10.46(br,NH,1H),8.40-8.35(m,NH,1H),8.18(s,1H),7.97-7.92(m,1H),7.65-7.58(m,3H),7.54-7.50( m,2H),7.44(s,1H),4.55(m,2H),4.32-4.29(m,2H),2.50-2.38(m,1H),1. 72-1.66(m,2H),1.28-1.20(m,2H),1.05-1.01(m,6H),0.90-0.83(m,3H).

[1036] Example 177: Synthesis of 1-butyl-N-(3-chloro-4-fluorophenyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1H-indole-2-carboxamide (Compound 177)

[1037] The title compound was obtained according to the same procedure as in Example 170, except using 3-chloro-4-fluoroaniline instead of 4-fluoroaniline.

[1038] 1H NMR(300MHz,DMSO-d6)10.52(br,NH,1H),10.46(br,NH,1H),8.40-8.35(m,NH,1H) ,8.18(s,1H),8.10-8.70(m,1H),7.72(m,1H),7.41-7.58(m,1H),7.54-7.50(m,2H) ,7.47-7.40(m,2H),7.37-7.29(m,2H),4.55(m,2H),4.32-4.29(m,2H),2.50-2.38( m,1H),1.72-1.66(m,2H),1.28-1.20(m,2H),1.05-1.01(m,6H),0.90-0.83(m,3H).

[1039] Example 178: Synthesis of 1-butyl-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3,4-dichlorophenyl)-1H-indole-2-carboxamide (Compound 178)

[1040] The title compound was obtained according to the same procedure as in Example 170, except using 3,4-dichloroaniline instead of 4-fluoroaniline.

[1041] 1H NMR(300MHz,DMSO-d6)10.58(br,NH,1H),10.46(br,NH,1H),8.40-8.35(m,NH,1 H),8.19-8.16(m,2H),7.79-7.75(m,1H),7.65-7.58(m,2H),7.54-7.50(m,2H), 7.44(s,1H),7.37-7.32(m,2H),4.55(m,2H),4.32-4.29(m,2H),2.50-2.38(m,1 H),1.72-1.66(m,2H),1.28-1.20(m,2H),1.05-1.01(m,6H),0.90-0.83(m,3H).

[1042] Example 179: Synthesis of 1-butyl-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3,4-difluorophenyl)-1H-indole-2-carboxamide (Compound 179)

[1043] The title compound was obtained according to the same procedure as in Example 170, except using 3,4-difluoroaniline instead of 4-fluoroaniline.

[1044] 1H NMR(300MHz,DMSO-d6)10.54(br,NH,1H),10.46(br,NH,1H),8.40-8.35(m,NH,1 H),8.18(s,1H),7.97-7.90(m,1H),7.61-7.57(m,1H),7.53-7.50(m,3H),7.47- 7.39(m,2H),7.37-7.29(m,2H),4.55(m,2H),4.32-4.29(m,2H),2.50-2.36(m,1 H),1.72-1.65(m,2H),1.28-1.20(m,2H),1.05-1.01(m,6H),0.90-0.83(m,3H).

[1045]

[1046] Example 180: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-isopropyl-N-(4-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (Compound 180)

[1047] Example 180-1: Synthesis of ethyl 1-isopropyl-5-nitro-1H-indole-2-carboxylate

[1048] 5-nitro-1H-indole-2-carboxylic acid ethyl ester (5g, 21.34mmol) and 2-iodopropane (8.53ml, 85.36mmol) are added in 100mL flask and dissolved in DMF (50ml).By K CO (8.85g, 64.02mmol) is added thereto and stirred at 100 ℃ for 12 hours.After the reaction is complete, use ethyl acetate / H O extraction organic material.With organic layer through MgSO Dry and distill under reduced pressure to remove solvent.Residue is subjected to column chromatography (ethyl acetate: normal hexane=1:3) to obtain 1-isopropyl-5-nitro-1H-indole-2-carboxylic acid ethyl ester (3.76g, 13.6mmol, 63%, white solid).

[1049] 1H NMR(300MHz,DMSO-d6)8.74(m,1H),8.12-8.10(m,1H),8.02-7.99(m,1H),7.53(m ,1H),5.74-5.65(m,1H),4.39-4.32(m,2H),1.62-1.60(m,6H),1.37-1.33(m,6H).

[1050] Example 180-2: Synthesis of 5-amino-1-isopropyl-1H-indole-2-carboxylic acid ethyl ester

[1051] 1-isopropyl-5-nitro-1H-indole-2-carboxylic acid, ethyl ester (3.76g, 13.6mmol) is added in 100mL flask and is dissolved in MeOH (50ml).Add 10%Pd / C (2.0g) and at room temperature under H2(g) stir 12 hours.After carrying out diatomite filtration when the reaction is complete, under reduced pressure by distillation removal solvent.Residue is subjected to column chromatography (ethyl acetate: normal hexane=1:3) to obtain 5-amino-1-isopropyl-1H-indole-2-carboxylic acid, ethyl ester (3.0g, 12.18mmol, 89%).

[1052] 1H NMR(300MHz,DMSO-d6)7.45-7.42(m,1H),6.93(m,1H),6.72-6.70(m,2H),5.64-5.5 5(m,1H),4.72(br,NH,2H),4.29-4.22(m,2H),1.53-1.50(m,6H),1.33-1.29(m,3H).

[1053] Example 180-3: Synthesis of ethyl 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-isopropyl-1H-indole-2-carboxylate

[1054] 5-amino-1-isopropyl-1H-indole-2-carboxylic acid, ethyl ester (1.5g, 6.09mmol) and 2-chloro-5-(isobutyrylaminomethyl) benzoic acid (1.87g, 7.308mmol) are added in a 100mL flask and dissolved in CH Cl (30ml) and DMF (3ml). HOBT (1.65g, 12.18mmol) and DMAP (1.05g, 12.18mmol) are added thereto and reacted 10 minutes. Add EDC (1.64g, 12.18mmol) and TEA (1.2ml, 12.18mmol) and stir 12 hours under reflux. After the reaction is complete, use ethyl acetate / H O extraction organic material. With organic layer through MgSO Dry and distill under reduced pressure to remove solvent. The residue was subjected to column chromatography (ethyl acetate:n-hexane=3:1) to obtain ethyl 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-isopropyl-1H-indole-2-carboxylate (2.4 g, 4.96 mmol, 81%, white solid).

[1055] 1H NMR(300MHz,DMSO-d6)10.47(br,NH,1H),8.39(m,NH,1H),8.17(m,1H),7.76-7.74(m,1H),7.52-7.46(m,2H),7.42(m,1H),7.36-7.33( m,1H),7.23(m,1H),5.69-5.62(m,1H),4.34-4.28(m,4H),2.50-2.38(m,1H),1.59-1.56(m,6H),1.36-1.31(m,3H),1.04-1.02(m,6H).

[1056] Example 180-4: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-isopropyl-1H-indole-2-carboxylic acid

[1057] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-sec.-propyl-1H-indole-2-carboxylic acid, ethyl ester (2.4g, 4.96mmol) is added in a 500mL flask and dissolved in THF (30ml) and MeOH (30ml).Addition is dissolved in H2LiOH (1.04g, 24.8mmol) in O (30ml) and stirred 12 hours.After concentrating when the reaction is complete, pH is adjusted to 2 with 2N-HCl.The solid of gained is filtered to obtain 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-sec.-propyl-1H-indole-2-carboxylic acid (1.85g, 4.05mmol, 82%, white solid).

[1058] 1H NMR(300MHz,DMSO-d6)12.92(br,OH,1H),10.45(br,NH,1H),8.38(m,NH,1H),8.16(m,1H),7.75-7.72(m,1H),7.52-7.50(m,1H),7.46-7. 42(m,2H),7.36-7.33(m,1H),7.18(m,1H),5.82-5.73(m,1H),4.30-4 .29(m,2H),2.50-2.38(m,1H),1.58-1.56(m,6H),1.04-1.02(m,6H).

[1059] Example 180-5: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-isopropyl-N-(4-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (Compound 180)

[1060] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-isopropyl-1H-indole-2-carboxylic acid (150 mg, 0.33 mmol) and 4-(trifluoromethoxy)aniline (87 mg, 0.495 mmol) were added to a 10 mL flask and dissolved in CH2Cl2 (5 ml) and DMF (1 ml). HOBT (89 mg, 0.66 mmol) and DMAP (80 mg, 0.66 mmol) were added thereto and reacted for 10 minutes. EDC (126 mg, 0.66 mmol) and TEA (91 μl, 0.66 mmol) were added and stirred at reflux for 12 hours. After the reaction was complete, the organic material was extracted with ethyl acetate / H2O. The organic layer was dried over MgSO4 and distilled under reduced pressure to remove the solvent. The residue was subjected to column chromatography (ethyl acetate:n-hexane=3:1) to obtain 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-isopropyl-N-(4-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (140 mg, 0.227 mmol, 69%, white solid).

[1061] 1H NMR(300MHz,DMSO-d6)10.66(br,NH,1H),10.45(br,NH,1H),8.38(m,NH,1H),8.17(m,1H),7.91-7.88(m,2H),7.74-7.71(m,1H),7.53-7. 43(m,3H),7.39-7.33(m,3H),7.10(m,1H),5.38-5.31(m,1H),4.31-4 .29(m,2H),2.50-2.39(m,1H),1.60-1.58(m,6H),1.04-1.02(m,6H).

[1062] Example 181: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-isopropyl-N-(3-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (Compound 181)

[1063] The title compound was obtained according to the same procedure as in Example 180, except using 3-(trifluoromethoxy)aniline instead of 4-(trifluoromethoxy)aniline.

[1064] 1H NMR(300MHz,DMSO-d6)10.73(br,NH,1H),10.45(br,NH,1H),8.38(m,NH,1H),8.17(m,1H),7.95(m,1H),7.77-7.72(m,2H),7.53-7.43(m, 4H),7.36-7.33(m,1H),7.13-7.09(m,2H),5.42-5.32(m,1H),4.31-4 .29(m,2H),2.50-2.39(m,1H),1.61-1.58(m,6H),1.05-1.02(m,6H).

[1065] Example 182: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-fluorophenyl)-1-isopropyl-1H-indole-2-carboxamide (Compound 182)

[1066] The title compound was obtained according to the same procedure as in Example 180, except using 4-fluoroaniline instead of 4-(trifluoromethoxy)aniline.

[1067] 1H NMR(300MHz,DMSO-d6)10.54(br,NH,1H),10.45(br,NH,1H),8.39(m,NH,1H),8.16(m,1H),7.82-7.78(m,2H),7.73-7.70(m,1H),7.53-7.43(m,3H) ,7.36-7.33(m,1H),7.23-7.18(m,2H),7.07(m,1H),5.40-5.31(m,1H),4. 31-4.29(m,2H),2.50-2.39(m,1H),1.60-1.58(m,6H),1.04-1.02(m,6H).

[1068] Example 183: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-chlorophenyl)-1-isopropyl-1H-indole-2-carboxamide (Compound 183)

[1069] The title compound was obtained according to the same procedure as in Example 180, except using 4-chloroaniline instead of 4-(trifluoromethoxy)aniline.

[1070] 1H NMR(300MHz,DMSO-d6)10.60(br,NH,1H),10.45(br,NH,1H),8.38(m,NH,1H),8.16(m,1H),7.84-7.81(m,2H),7.73-7.70(m,1H),7.53-7.50(m,1H) ,7.47-7.40(m,4H),7.36-7.33(m,1H),7.10(m,1H),5.39-5.31(m,1H),4. 31-4.29(m,2H),2.50-2.39(m,1H),1.60-1.58(m,6H),1.04-1.02(m,6H).

[1071] Example 184: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-chlorophenyl)-1-isopropyl-1H-indole-2-carboxamide (Compound 184)

[1072] The title compound was obtained according to the same procedure as in Example 180, except using 3-chloroaniline instead of 4-(trifluoromethoxy)aniline.

[1073] 1H NMR(300MHz,DMSO-d6)10.64(br,NH,1H),10.45(br,NH,1H),8.38(m,NH,1H), 8.17-8.16(m,1H),7.98(m,1H),7.74-7.68(m,2H),7.53-7.50(m,1H),7.49-7. 42(m,2H),7.39-7.33(m,2H),7.18-7.16(m,1H),7.1(m,1H),5.40-5.31(m,1H ),4.31-4.29(m,2H),2.50-2.39(m,1H),1.60-1.58(m,6H),1.04-1.02(m,6H).

[1074] Example 185: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-isopropyl-N-(4-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide (Compound 185)

[1075] The title compound was obtained according to the same procedure as in Example 180, except using 4-(trifluoromethyl)aniline instead of 4-(trifluoromethoxy)aniline.

[1076] 1H NMR(300MHz,DMSO-d6)10.81(br,NH,1H),10.46(br,NH,1H),8.38(m,NH,1H),8.18(m,1H),8.03-8.00(m,2H),7.75-7.72(m,3H),7.53-7. 43(m,3H),7.36-7.33(m,1H),7.15(m,1H),5.41-5.32(m,1H),4.31-4 .29(m,2H),2.50-2.39(m,1H),1.61-1.59(m,6H),1.05-1.02(m,6H).

[1077] Example 186: Synthesis of N-(3-chloro-4-fluorophenyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-isopropyl-1H-indole-2-carboxamide (Compound 186)

[1078] The title compound was obtained according to the same procedure as in Example 180, except using 3-chloro-4-fluoroaniline instead of 4-(trifluoromethoxy)aniline.

[1079] 1H NMR(300MHz,DMSO-d6)10.65(br,NH,1H),10.45(br,NH,1H),8.37(m,NH,1H),8.17(m,1H),8.11-8.08(m,1H),7.74-7.71(m,2H),7.5-7.4 0(m,4H),7.36-7.34(m,1H),7.11(m,1H),5.41-5.32(m,1H),4.31-4.29(m,2H),2.50-2.39(m,1H),1.60-1.58(m,6H),1.05-1.03(m,6H).

[1080] Example 187: Synthesis of N-(4-chloro-3-fluorophenyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-isopropyl-1H-indole-2-carboxamide (Compound 187)

[1081] The title compound was obtained according to the same procedure as in Example 180, except using 4-chloro-3-fluoroaniline instead of 4-(trifluoromethoxy)aniline.

[1082] 1H NMR(300MHz,DMSO-d6)10.76(br,NH,1H),10.44(br,NH,1H),8.36(m,NH,1H),8.17-8.16(m,1H),7.97-7.92(m,1H),7.74-7.71(m,1H),7.58-7.57(m,2 H),7.54-7.43(m,3H),7.36-7.33(m,1H),7.12(m,1H),5.38-5.31(m,1H),4 .31-4.29(m,2H),2.50-2.39(m,1H),1.60-1.58(m,6H),1.04-1.02(m,6H).

[1083] Example 188: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-isopropyl-N-(3-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide (Compound 188)

[1084] The title compound was obtained according to the same procedure as in Example 180, except using 3-(trifluoromethyl)aniline instead of 4-(trifluoromethoxy)aniline.

[1085] 1H NMR(300MHz,DMSO-d6)10.77(br,NH,1H),10.45(br,NH,1H),8.40-8.35(m,NH ,1H),8.28(s,1H),8.18(s,1H),8.04-8.01(m,1H),7.76-7.72(m,1H),7.64-7. 58(m,1H),7.54-7.44(m,4H),7.37-7.33(m,1H),7.16(m,1H),5.42-5.37(m,1H ),4.31-4.29(m,2H),2.50-2.39(m,1H),1.60-1.58(m,6H),1.04-1.02(m,6H).

[1086] Example 189: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(2-chlorophenyl)-1-isopropyl-1H-indole-2-carboxamide (Compound 189)

[1087] The title compound was obtained according to the same procedure as in Example 180, except using 2-chloroaniline instead of 4-(trifluoromethoxy)aniline.

[1088] 1H NMR(300MHz,DMSO-d6)10.45(br,NH,1H),10.10(br,NH,1H),8.40-8.35(m,NH,1 H),8.16(s,1H),7.75-7.65(m,2H),7.59-7.56(m,1H),7.54-7.48(m,1H),7.44- 7.40(m,2H),7.38-7.28(m,3H),7.17(m,1H),5.42-5.35(m,1H),4.31-4.29(m,2 H),3.79-3.71(m,3H),2.50-2.39(m,1H),1.60-1.58(m,6H),1.04-1.02(m,6H).

[1089] Example 190: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3,4-dichlorophenyl)-1-isopropyl-1H-indole-2-carboxamide (Compound 190)

[1090] The title compound was obtained according to the same procedure as in Example 180, except using 3,4-dichloroaniline instead of 4-(trifluoromethoxy)aniline.

[1091] 1H NMR(300MHz,DMSO-d6)10.72(br,NH,1H),10.45(br,NH,1H),8.37(m,NH,1H),8.17(m,2H),7.76-7.71(m,2H),7.64-7.61(m,1H),7.53-7. 43(m,3H),7.36-7.33(m,1H),7.13(m,1H),5.41-5.32(m,1H),4.31-4 .29(m,2H),2.50-2.39(m,1H),1.60-1.58(m,6H),1.04-1.02(m,6H).

[1092] Example 191: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3,5-dichlorophenyl)-1-isopropyl-1H-indole-2-carboxamide (Compound 191)

[1093] The title compound was obtained according to the same procedure as in Example 180, except using 3,5-dichloroaniline instead of 4-(trifluoromethoxy)aniline.

[1094] 1H NMR(300MHz,DMSO-d6)10.75(br,NH,1H),10.45(br,NH,1H),8.37(m,NH,1H),8.17(m,1H),7.89(m,2H),7.75-7.72(m,1H),7.53-7. 43(m,3H),7.34(m,2H),7.14(m,1H),5.40-5.31(m,1H),4.31-4.29(m,2H),2.50-2.39(m,1H),1.60-1.58(m,6H),1.04-1.02(m,6H).

[1095] Example 192: Synthesis of N-(4-bromophenyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-isopropyl-1H-indole-2-carboxamide (Compound 192)

[1096] The title compound was obtained according to the same procedure as in Example 180, except using 4-bromoaniline instead of 4-(trifluoromethoxy)aniline.

[1097] 1H NMR(300MHz,DMSO-d6)10.58(br,NH,1H),10.44(br,NH,1H),8.37(m,NH,1H),8.16(m,1H),7.78-7.70(m,3H),7.56-7.36(m,5H) ,7.36-7.33(m,1H),7.09(m,1H),5.39-5.31(m,1H),4.31-4.29(m,2H),2.50-2.39(m,1H),1.60-1.58(m,6H),1.04-1.02(m,6H).

[1098] Example 193: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-cyclohexylphenyl)-1-isopropyl-1H-indole-2-carboxamide (Compound 193)

[1099] The title compound was obtained according to the same procedure as in Example 180, except using 4-cyclohexylaniline instead of 4-(trifluoromethoxy)aniline.

[1100] 1H NMR(300MHz,DMSO-d6)10.43(br,NH,1H),10.38(br,NH,1H),8.37(m,NH,1H),8. 15-8.14(m,1H),7.72-7.66(m,3H),7.53-7.44(m,3H),7.36-7.33(m,1H),7.21- 7.18(m,2H),7.04(m,1H),5.40-5.31(m,1H),4.31-4.29(m,2H),2.50-2.39(m,1 H),1.80-1.68(m,5H),1.60-1.58(m,6H),1.42-1.24(m,6H),1.05-1.02(m,6H).

[1101] Example 194: Synthesis of N-(4-(tert-butyl)phenyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-isopropyl-1H-indole-2-carboxamide (Compound 194)

[1102] The title compound was obtained according to the same procedure as in Example 180, except using 4-(tert-butyl)aniline instead of 4-(trifluoromethoxy)aniline.

[1103] 1H NMR(300MHz,DMSO-d6)10.43(br,NH,1H),10.38(br,NH,1H),8.37(m,NH,1H),8.14(m,1H),7.72-7.68(m,3H),7.53-7.50(m,1H),7.47-7.44(m,2 H),7.38-7.33(m,3H),7.05(m,1H),5.41-5.31(m,1H),4.31-4.29(m,2H ),2.50-2.39(m,1H),1.60-1.58(m,6H),1.29(s,9H),1.04-1.02(m,6H).

[1104] Example 195: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-chloro-5-fluorophenyl)-1-isopropyl-1H-indole-2-carboxamide (Compound 195)

[1105] The title compound was obtained according to the same procedure as in Example 180, except using 3-chloro-5-fluoroaniline instead of 4-(trifluoromethoxy)aniline.

[1106] 1H NMR(300MHz,DMSO-d6)10.78(br,NH,1H),10.45(br,NH,1H),8.37(m,NH,1H),8.18-8.17(m,1H),7.76-7.66(m,3H),7.53-7.43(m,3H) ,7.36-7.34(m,1H),7.18-7.14(m,2H),5.40-5.31(m,1H),4.31-4.29(m,2H),2.50-2.39(m,1H),1.60-1.58(m,6H),1.05-1.02(m,6H).

[1107] Example 196: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3,5-difluorophenyl)-1-isopropyl-1H-indole-2-carboxamide (Compound 196)

[1108] The title compound was obtained according to the same procedure as in Example 180, except using 3,5-difluoroaniline instead of 4-(trifluoromethoxy)aniline.

[1109] 1H NMR(300MHz,DMSO-d6)10.81(br,NH,1H),10.46(br,NH,1H),8.37(m,NH,1H),8.17(m,1H),7.75-7.72(m,1H),7.56-7.43(m,5H),7.36-7. 33(m,1H),7.13(m,1H),7.01-6.94(m,1H),5.38-5.31(m,1H),4.31-4 .29(m,2H),2.50-2.39(m,1H),1.60-1.58(m,6H),1.05-1.02(m,6H).

[1110] Example 197: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-isopropyl-N-(4-methoxyphenyl)-1H-indole-2-carboxamide (Compound 197)

[1111] The title compound was obtained according to the same procedure as in Example 180, except using 4-methoxyaniline instead of 4-(trifluoromethoxy)aniline.

[1112] 1H NMR(300MHz,DMSO-d6)10.43(br,NH,1H),10.33(br,NH,1H),8.37(m,NH,1H), 8.14(m,1H),7.75-7.67(m,3H),7.53-7.50(m,1H),7.47-7.43(m,2H),7.36-7. 33(m,1H),7.03(s,1H),6.95-6.91(m,2H),5.40-5.35(m,1H),4.31-4.29(m,2H ),3.79-3.71(m,3H),2.50-2.39(m,1H),1.61-1.57(m,6H),1.05-1.02(m,6H).

[1113] Example 198: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-isopropyl-N-(6-(trifluoromethyl)pyridin-3-yl)-1H-indole-2-carboxamide (Compound 198)

[1114] The title compound was obtained according to the same procedure as in Example 180, except using 6-(trifluoromethyl)pyridin-3-amine instead of 4-(trifluoromethoxy)aniline.

[1115] 1H NMR(300MHz,DMSO-d6)10.99(br,NH,1H),10.47(br,NH,1H),9.11(m,NH,1H),8. 51-8.47(m,1H),8.37(m,1H),8.19(s,1H),7.95-7.91(m,1H),7.78-7.74(m,1H) ,7.53-7.48(m,2H),7.44(s,1H),7.37-7.33(m,1H),7.24(s,1H),5.45-5.39(m, 1H),4.32-4.29(m,2H),2.50-2.39(m,1H),1.62-1.59(m,6H),1.05-1.02(m,6H).

[1116] Example 199: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-cyanophenyl)-1-isopropyl-1H-indole-2-carboxamide (Compound 199)

[1117] The title compound was obtained according to the same procedure as in Example 180, except using 4-aminobenzonitrile instead of 4-(trifluoromethoxy)aniline.

[1118] 1H NMR(300MHz,DMSO-d6)10.87(br,NH,1H),10.46(br,NH,1H),8.40-8.35(m,NH ,1H),8.18(m,1H),8.00-7.98(m,1H),7.85-7.82(m,2H),7.76-7.72(m,1H),7. 56-7.47(m,2H),7.44(m,2H),7.37-7.33(m,1H),7.16(s,1H),5.41-5.33(m,1H ),4.32-4.29(m,2H),2.50-2.39(m,1H),1.62-1.59(m,6H),1.05-1.02(m,6H).

[1119] Example 200: Synthesis of N-(4-chloro-2-methylphenyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-isopropyl-1H-indole-2-carboxamide (Compound 200)

[1120] The title compound was obtained according to the same procedure as in Example 180, except using 4-chloro-2-methylaniline instead of 4-(trifluoromethoxy)aniline.

[1121] 1H NMR(300MHz,DMSO-d6)10.44(br,NH,1H),10.00(br,NH,1H),8.37(m,NH,1H),8.15(s,1H),7.73-7.70(m,1H),7.53-7.45(m,4H),7.39-7.36(m,2 H),7.34-7.27(m,1H),7.13(s,1H),5.44-5.39(m,1H),4.31-4.29(m,2H ),2.50-2.39(m,1H),2.29(s,3H),1.60-1.58(m,6H),1.05-1.02(m,6H).

[1122] Example 201: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-isopropyl-N-(5,6,7,8-tetrahydronaphthalen-1-yl)-1H-indole-2-carboxamide (Compound 201)

[1123] The title compound was obtained according to the same procedure as in Example 180, except using 5,6,7,8-tetrahydronaphthalen-1-amine instead of 4-(trifluoromethoxy)aniline.

[1124] 1H NMR(300MHz,DMSO-d6)10.43(br,NH,1H),9.81(br,NH,1H),8.37(m,NH,1H),8.14( m,1H),7.73-7.69(m,1H),7.53-7.44(m,3H),7.37-7.33(m,1H),7.24-7.21(m,1H), 7.15-7.10(m,2H),7.02-6.99(m,1H),5.45-5.39(m,1H),4.32-4.29(m,2H),2.78- 2.71(m,4H),2.50-2.39(m,1H),1.74(m,4H),1.60-1.58(m,6H),1.05-1.02(m,6H).

[1125] Example 202: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(2,4-difluorophenyl)-1-isopropyl-1H-indole-2-carboxamide (Compound 202)

[1126] The title compound was obtained according to the same procedure as in Example 180, except using 2,4-difluoroaniline instead of 4-(trifluoromethoxy)aniline.

[1127] 1H NMR(300MHz,DMSO-d6)10.45(br,NH,1H),10.22(br,NH,1H),8.39(m,NH,1H),8.17(m,1H),7.74-7.70(m,1H),7.68-7.60(m,1H),7.53-7.50(m,1H),7. 48-7.40(m,2H),7.37-7.33(m,2H),7.15-7.10(m,2H),5.47-5.42(m,1H),4 .32-4.29(m,2H),2.50-2.39(m,1H),1.60-1.58(m,6H),1.05-1.02(m,6H).

[1128] Example 203: Synthesis of methyl 4-(5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-isopropyl-1H-indole-2-carboxamido)benzoate (Compound 203)

[1129] The title compound was obtained according to the same procedure as in Example 180, except using methyl 4-aminobenzoate instead of 4-(trifluoromethoxy)aniline.

[1130] 1H NMR(300MHz,DMSO-d6)10.79(br,NH,1H),10.45(br,NH,1H),8.37(m,NH,1H) ,8.17(m,1H),8.03-7.88(m,3H),7.75-7.71(m,1H),7.53-7.49(m,2H),7.47- 7.43(m,2H),7.36-7.33(m,1H),7.15(s,1H),5.40-5.34(m,1H),4.31-4.29( m,2H),3.85(s,3H),2.50-2.40(m,1H),1.62-1.59(m,6H),1.05-1.02(m,6H).

[1131] Example 204: Synthesis of 4-(5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-isopropyl-1H-indole-2-carboxamido)benzoic acid (Compound 204)

[1132] Methyl 4-(5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-isopropyl-1H-indole-2-formamido)benzoate (25 mg, 0.042 mmol) was added to a 10 mL flask and dissolved in THF (0.5 ml) and MeOH (0.5 ml). LiOH (8.9 mg, 0.212 mmol) dissolved in H O (0.3 ml) was added and stirred for 12 hours. After concentrating when the reaction was complete, the pH was adjusted to 2 with 2N-HCl. The resulting solid was filtered to obtain 4-(5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-isopropyl-1H-indole-2-formamido)benzoic acid (15 mg, 0.026 mmol, 61%, white solid).

[1133] 1H NMR(300MHz,DMSO-d6)13.80(br,OH,1H),10.75(br,NH,1H),10.45(br,NH,1H),8.37(m,NH,1H),8.17-8.13(m,1H),7.97-7.89(m,3H),7.75-7.71(m,1 H),7.53-7.43(m,3H),7.36-7.33(m,2H),7.14(s,1H),5.40-5.34(m,1H),4 .31-4.29(m,2H),2.50-2.40(m,1H),1.62-1.59(m,6H),1.05-1.02(m,6H).

[1134]

[1135] Example 205: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-fluorophenyl)-1-(2,2,2-trifluoroethyl)-1H-indole-2-carboxamide (Compound 205)

[1136] Example 205-1: Synthesis of ethyl 5-nitro-1-(2,2,2-trifluoroethyl)-1H-indole-2-carboxylate

[1137] 5-nitro-1H-indole-2-carboxylic acid ethyl ester (3g, 12.81mmol) and 1,1,1-trifluoro-2-iodoethane (4.03g, 19.21mmol) are added into a 100mL flask and dissolved in DMF (50ml). KCO (3.54g, 25.62mmol) is added thereto and stirred under reflux for 12 hours. After the reaction is complete, the organic material is extracted with ethyl acetate / HO. The organic layer is dried over MgSO and distilled under reduced pressure to remove the solvent. Residue is subjected to column chromatography (ethyl acetate: normal hexane=1:3) to obtain 5-nitro-1-(2,2,2-trifluoroethyl)-1H-indole-2-carboxylic acid ethyl ester (3.4g, 10.75mmol, 84%, white solid).

[1138] 1H NMR(300MHz, DMSO-d6)8.79(m,1H),8.29-8.26(m,1H),8.03-8.00(m,1H),7.71(m,1H),5.75-5.66(m,2H),4.41-4.34(m,2H),1.37-1.32(m,3H).

[1139] Example 205-2: Synthesis of ethyl 5-amino-1-(2,2,2-trifluoroethyl)-1H-indole-2-carboxylate

[1140] 5-nitro-1-(2,2,2-trifluoroethyl)-1H-indole-2-carboxylic acid ethyl ester (3.4g, 10.75mmol) is added in 100mL flask and dissolved in EtOH (60ml).Add 10%Pd / C (1.7g) and stir 12 hours under H2(g) at room temperature.After diatomite filtration when the reaction is complete, solvent is removed by distillation under reduced pressure.Residue is subjected to column chromatography (ethyl acetate: normal hexane=1:3) to obtain 5-amino-1-(2,2,2-trifluoroethyl)-1H-indole-2-carboxylic acid ethyl ester (2.8g, 9.78mmol, 90%).

[1141] 1H NMR(300MHz,DMSO-d6)7.42-7.39(m,1H),7.12(m,1H),6.81-6.78(m,1H),6.74(m ,1H),5.49-5.40(m,2H),4.84(br,NH,2H),4.33-4.26(m,2H),1.33-1.28(m,3H).

[1142] Example 205-3: Synthesis of ethyl 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2,2,2-trifluoroethyl)-1H-indole-2-carboxylate

[1143] 5-Amino-1-(2,2,2-trifluoroethyl)-1H-indole-2-carboxylic acid ethyl ester (2.8g, 9.78mmol) and 2-chloro-5-(isobutyrylaminomethyl) benzoic acid (3.0g, 11.736mmol) are added to a 100mL flask and dissolved in CH Cl (60ml). HOBT (1.98g, 14.67mmol) and DMAP (1.194g, 9.78mmol) are added thereto and reacted for 10 minutes. EDC (5.624g, 29.34mmol) and TEA (4.09ml, 29.34mmol) are added and stirred under reflux for 12 hours. After the reaction is complete, the organic material is extracted with CH Cl / H O. The organic layer is dried over MgSO and distilled under reduced pressure to remove the solvent. The residue was subjected to column chromatography (ethyl acetate:n-hexane=3:1) to obtain ethyl 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2,2,2-trifluoroethyl)-1H-indole-2-carboxylate (3.54 g, 6.75 mmol, 69%, white solid).

[1144] 1H NMR(300MHz,DMSO-d6)10.53(br,NH,1H),8.39-8.35(m,NH,1H),8.23(m,1H),7.75-7.72(m,1H),7.59-7.56(m,1H),7.52-7.50(m,1 H),7.43(m,2H),7.36-7.33(m,1H),5.62-5.53(m,2H),4.38-4.28(m,4H),2.50-2.38(m,1H),1.36-1.31(m,3H),1.04-1.02(m,6H).

[1145] Example 205-4: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2,2,2-trifluoroethyl)-1H-indole-2-carboxylic acid

[1146] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2,2,2-trifluoroethyl)-1H-indole-2-carboxylic acid, ethyl ester (3.54g, 6.75mmol) is added to a 500mL flask and dissolved in THF (40ml) and MeOH (40ml).Add LiOH (1.416g, 33.75mmol) dissolved in H2O (40ml) and stir for 12 hours.After concentrating when the reaction is complete, pH is adjusted to 2 with 2N-HCl.The solid gained is filtered to obtain 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2,2,2-trifluoroethyl)-1H-indole-2-carboxylic acid (2.94g, 5.92mmol, 88%, white solid).

[1147] 1H NMR(300MHz,DMSO-d6)10.51(br,NH,1H),8.37(m,NH,1H),8.22(m,1H),7.72-7.69(m,1H),7.56-7.50(m,H), 7.43(m,1H),7.37-7.33(m,2H),5.61-5.59(m,2H),4.30-4.29(m,2H),2.50-2.38(m,1H),1.04-1.02(m,6H).

[1148] Example 205-5: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-fluorophenyl)-1-(2,2,2-trifluoroethyl)-1H-indole-2-carboxamide (Compound 205)

[1149] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2,2,2-trifluoroethyl)-1H-indole-2-carboxylic acid (100 mg, 0.2 mmol) and 4-fluoroaniline (87 mg, 0.495 mmol) were added to a 10 mL flask and dissolved in CH2Cl2 (5 ml) and DMF (1 ml). HOBT (89 mg, 0.66 mmol) and DMAP (80 mg, 0.66 mmol) were added thereto and reacted for 10 minutes. EDC (126 mg, 0.66 mmol) and TEA (91 μl, 0.66 mmol) were added and stirred at reflux for 12 hours. After the reaction was complete, the organic material was extracted with ethyl acetate / H2O. The organic layer was dried over MgSO4 and distilled under reduced pressure to remove the solvent. The residue was subjected to column chromatography (ethyl acetate:n-hexane=3:1) to obtain 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-fluorophenyl)-1-(2,2,2-trifluoroethyl)-1H-indole-2-carboxamide (140 mg, 0.227 mmol, 69%, white solid).

[1150] 1H NMR (300MHz, DMSO-d6)10.54-10.52(m,NH,2H),8.39-8.35(m,NH,1H),8.22(s,1H),7.81-7.72(m,3H),7.58-7.44(m,2H),7. 45(s,2H),7.36-7.34(m,2H),7.26-7.19(m,2H),5.70-5.61(m,2H),4.31-4.29(m,2H),2.51-2.39(m,1H),1.05-1.02(m,6H).

[1151] Example 206: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-chlorophenyl)-1-(2,2,2-trifluoroethyl)-1H-indole-2-carboxamide (Compound 206)

[1152] The title compound was obtained according to the same procedure as in Example 205, except using 4-chloroaniline instead of 4-fluoroaniline.

[1153] 1H NMR(300MHz,DMSO-d6)10.60(s,NH,1H),10.52(s,NH,1H),8.39-8.35(m,NH,1H),8.22(s,1H),7.82-7.79(m,2H),7.75-7.72(m,1H), 7.59-7.51(m,2H),7.47-7.42(m,4H),7.37-7.34(m,1H),5.70-5.60(m,2H),4.31-4.29(m,2H),2.51-2.39(m,1H),1.05-1.02(m,6H).

[1154] Example 207: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2,2,2-trifluoroethyl)-N-(4-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide (Compound 207)

[1155] The title compound was obtained according to the same procedure as in Example 205, except using 4-(trifluoromethyl)aniline instead of 4-fluoroaniline.

[1156] 1H NMR(300MHz,DMSO-d6)10.80(s,NH,1H),10.54(s,NH,1H),8.39-8.35(m,NH,1H),8.24(s,1H),8.03-7.99(m,2H),7.77-7.74(m,3H),7.60-7 .57(m,1H),7.54-7.51(m,2H),7.44(s,1H),7.38-7.34(m,1H),5.68- 5.61(m,2H),4.31-4.29(m,2H),2.51-2.39(m,1H),1.05-1.02(m,6H).

[1157] Example 208: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2,2,2-trifluoroethyl)-N-(3-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide (Compound 208)

[1158] The title compound was obtained according to the same procedure as in Example 205, except using 3-(trifluoromethyl)aniline instead of 4-fluoroaniline.

[1159] 1H NMR(300MHz,DMSO-d6)10.77(s,NH,1H),10.54(s,NH,1H),8.39-8.35(m,NH ,1H),8.24(s,2H),8.06-8.02(m,1H),7.78-7.74(m,1H),7.66-7.57(m,2H), 7.54-7.51(m,2H),7.52-7.45(m,2H),7.38-7.34(m,1H),7.38-7.34(m,1H), 5.69-5.65(m,2H),4.32-4.29(m,2H),2.51-2.39(m,1H),1.05-1.02(m,6H).

[1160] Example 209: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2,2,2-trifluoroethyl)-N-(4-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (Compound 209)

[1161] The title compound was obtained according to the same procedure as in Example 205, except using 4-(trifluoromethoxy)aniline instead of 4-fluoroaniline.

[1162] 1H NMR(300MHz,DMSO-d6)10.67(s,NH,1H),10.53(s,NH,1H),8.39-8.35(m,NH,1H),8.23(s,2H),7.91-7.87(m,2H),7.76-7.73(m,1H), 7.59-7.51(m,2H),7.48-7.44(m,2H),7.41-7.34(m,3H),5.68-5.64(m,2H),4.32-4.29(m,2H),2.51-2.35(m,1H),1.05-1.02(m,6H).

[1163] Example 210: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2,2,2-trifluoroethyl)-N-(3-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (Compound 210)

[1164] The title compound was obtained according to the same procedure as in Example 205, except using 3-(trifluoromethoxy)aniline instead of 4-fluoroaniline.

[1165] 1H NMR(300MHz,DMSO-d6)10.72(s,NH,1H),10.53(s,NH,1H),8.39-8.35(m,NH,1H),8.23(s,1H),7.90(s,1H),7.80-7.73(m,2H),7.60-7.53(m ,2H),7.52-7.44(m,3H),7.38-7.34(m,1H),7.14-7.11(m,1H),5.68- 5.64(m,2H),4.32-4.29(m,2H),2.51-2.35(m,1H),1.05-1.02(m,6H).

[1166] Example 211: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-chlorophenyl)-1-(2,2,2-trifluoroethyl)-1H-indole-2-carboxamide (Compound 211)

[1167] The title compound was obtained according to the same procedure as in Example 205, except using 3-chloroaniline instead of 4-fluoroaniline.

[1168] 1H NMR(300MHz,DMSO-d6)10.64(s,NH,1H),10.53(s,NH,1H),8.39-8.35(m,NH,1H),8.23(s,1H),7.96(s,1H),7.77-7.68(m,2H),7.60-7.51(m ,2H),7.48-7.44(m,2H),7.42-7.34(m,2H),7.22-7.18(m,1H),5.67- 5.63(m,2H),4.32-4.29(m,2H),2.51-2.35(m,1H),1.05-1.02(m,6H).

[1169] Example 212: Synthesis of N-(3-chloro-4-fluorophenyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2,2,2-trifluoroethyl)-1H-indole-2-carboxamide (Compound 212)

[1170] The title compound was obtained according to the same procedure as in Example 205, except using 3-chloro-4-fluoroaniline instead of 4-fluoroaniline.

[1171] 1H NMR(300MHz,DMSO-d6)10.67(s,NH,1H),10.53(s,NH,1H),8.39-8.35(m,NH,1H),8.23(s,1H),8.08-8.05(m,1H),7.76-7.68(m,2H), 7.60-7.51(m,2H),7.48-7.42(m,3H),7.38-7.34(m,1H),5.67-5.63(m,2H),4.32-4.29(m,2H),2.51-2.35(m,1H),1.05-1.02(m,6H).

[1172] Example 213: Synthesis of N-(4-chloro-3-fluorophenyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2,2,2-trifluoroethyl)-1H-indole-2-carboxamide (Compound 213)

[1173] The title compound was obtained according to the same procedure as in Example 205, except using 4-chloro-3-fluoroaniline instead of 4-fluoroaniline.

[1174] 1H NMR(300MHz,DMSO-d6)10.77(s,NH,1H),10.53(s,NH,1H),8.39-8.35(m,NH,1H),8.23(s,1H),7.94-7.90(m,1H),7.77-7.73(m,1H), 7.60-7.56(m,3H),7.54-7.44(m,3H),7.38-7.34(m,1H),5.67-5.60(m,2H),4.32-4.29(m,2H),2.51-2.35(m,1H),1.05-1.02(m,6H).

[1175] Example 214: Synthesis of N-(4-chloro-2-fluorophenyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2,2,2-trifluoroethyl)-1H-indole-2-carboxamide (Compound 214)

[1176] The title compound was obtained according to the same procedure as in Example 205, except using 4-chloro-2-fluoroaniline instead of 4-fluoroaniline.

[1177] 1H NMR(300MHz,DMSO-d6)10.53(s,NH,1H),10.42(s,NH,1H),8.39-8.35(m,NH,1H),8.23(s,1H),7.75-7.72(m,1H),7.70-7.52(m,4H ),7.50(s,1H),7.45-7.44(s,1H),7.38-7.33(m,2H),5.67-5.60(m,2H),4.32-4.29(m,2H),2.51-2.35(m,1H),1.05-1.02(m,6H).

[1178] Example 215: Synthesis of N-(3-chloro-5-fluorophenyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2,2,2-trifluoroethyl)-1H-indole-2-carboxamide (Compound 215)

[1179] The title compound was obtained according to the same procedure as in Example 205, except using 3-chloro-5-fluoroaniline instead of 4-fluoroaniline.

[1180] 1H NMR(300MHz,DMSO-d6)10.78(s,NH,1H),10.54(s,NH,1H),8.40-8.35(m,N H,1H),8.24(s,1H),7.77-7.74(m,2H),7.69-7.64(m,1H),7.61-7.57(m,1H ),7.55-7.50(m,2H),7.45(s,1H),7.38-7.34(m,1H),7.22-7.18(m,1H),5 .69-5.60(m,2H),4.32-4.29(m,2H),2.51-2.35(m,1H),1.05-1.02(m,6H).

[1181] Example 216: Synthesis of N-(3-fluoro-5-trifluoromethylphenyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2,2,2-trifluoroethyl)-1H-indole-2-carboxamide (Compound 216)

[1182] The title compound was obtained according to the same procedure as in Example 205, except using 3-fluoro-5-trifluoromethylaniline instead of 4-fluoroaniline.

[1183] 1H NMR(300MHz,DMSO-d6)10.93(s,NH,1H),10.55(s,NH,1H),8.40-8.35(m,NH,1H),8.25(s,1H),8.05-7.96(m,2H),7.79-7.75(m,1H),7.61-7 .57(m,1H),7.54-7.50(m,2H),7.45(s,2H),7.38-7.34(m,1H),5.69- 5.60(m,2H),4.32-4.29(m,2H),2.51-2.35(m,1H),1.05-1.02(m,6H).

[1184]

[1185] Example 217: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-fluorophenyl)-1-(2,2-difluoroethyl)-1H-indole-2-carboxamide (Compound 217)

[1186] Example 217-1: Synthesis of ethyl 5-nitro-1-(2,2-difluoroethyl)-1H-indole-2-carboxylate

[1187] 5-nitro-1H-indole-2-carboxylic acid, ethyl ester (5g, 21.35mmol) and 1,1-difluoro-2-iodoethane (8.19g, 42.70mmol) are added in a 250mL flask and dissolved in DMF (50ml). By CsCO(20.87g, 64.04mmol) is added thereto and stirred 12 hours under reflux.After the reaction is complete, organic material is extracted with ethyl acetate / HO.By organic layer through MgSO4 drying and distillation under reduced pressure to remove solvent.Resistates is recrystallized with hexane to obtain 5-nitro-1-(2,2-difluoroethyl)-1H-indole-2-carboxylic acid, ethyl ester (5.05g, 16.93mmol, 79%, white solid).

[1188] 1H NMR(300MHz,DMSO-d6)8.78(s,1H),8.25-8.21(m,1H),7.95-7.91(m,1H),7.65(s ,1H),6.62-6.23(m,1H),5.22-5.12(m,2H),4.41-4.34(m,2H),1.38-1.32(m,3H).

[1189] Example 217-2: Synthesis of ethyl 5-amino-1-(2,2-difluoroethyl)-1H-indole-2-carboxylate

[1190] 5-nitro-1-(2,2-difluoroethyl)-1H-indole-2-carboxylic acid ethyl ester (5.05g, 16.93mmol) is added in 250mL flask and dissolved in MeOH (100ml).Add 10%Pd / C (505mg) and stir 12 hours under H2(g) at room temperature.After diatomite filtration when the reaction is complete, solvent is removed by distillation under reduced pressure.Residue is subjected to column chromatography (ethyl acetate: normal hexane=1:3) to obtain 5-amino-1-(2,2-difluoroethyl)-1H-indole-2-carboxylic acid ethyl ester (4.08g, 15.22mmol, 89.9%).

[1191] 1H NMR(300MHz,DMSO-d6)7.37-7.33(m,1H),7.05(s,1H),6.80-6.73(m,1H),6.47-6.0 9(m,1H),4.97-4.85(m,2H),4.80(br,NH,2H),4.33-4.25(m,2H),1.33-1.28(m,3H).

[1192] Example 217-3: Synthesis of ethyl 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2,2-difluoroethyl)-1H-indole-2-carboxylate

[1193] 5-Amino-1-(2,2-difluoroethyl)-1H-indole-2-carboxylic acid ethyl ester (1.5g, 5.59mmol) and 2-chloro-5-(isobutyrylaminomethyl) benzoic acid (1.71g, 6.71mmol) are added to a 100mL flask and dissolved in CH Cl (38ml). HOBT (1.13g, 8.39mmol) and DMAP (205mg, 1.68mmol) are added thereto and reacted for 10 minutes. EDC (1.61g, 8.39mmol) and TEA (1.95ml, 13.98mmol) are added and stirred under reflux for 12 hours. After the reaction is complete, the organic material is extracted with CH Cl / H O. The organic layer is dried over MgSO and distilled under reduced pressure to remove the solvent. The residue was recrystallized from dichloromethane to give ethyl 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2,2-difluoroethyl)-1H-indole-2-carboxylate (2.16 g, 4.26 mmol, 76.2%, white solid).

[1194] 1H NMR(300MHz,DMSO-d6)10.50(br,NH,1H),8.39-8.34(m,NH,1H),8.21(m,1H),7.68-7.64(m,1H),7.57-7.50(m,2H),7.43(s,1H),7. 37-7.33(m,2H),6.55-6.17(m,1H),5.09-5.00(m,2H),4.38-4.28(m,4H),2.51-2.37(m,1H),1.37-1.32(m,3H),1.05-1.02(m,6H).

[1195] Example 217-4: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2,2-difluoroethyl)-1H-indole-2-carboxylic acid

[1196] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2,2-difluoroethyl)-1H-indole-2-carboxylic acid, ethyl ester (2.1g, 4.15mmol) is added into a 500mL flask and dissolved in THF (21ml) and MeOH (21ml).Add LiOH (0.87g, 20.75mmol) dissolved in H o (17ml) and stir for 12 hours.After concentrating when the reaction is complete, pH is adjusted to 2 with 2N-HCl.The solid gained is filtered to obtain 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2,2-difluoroethyl)-1H-indole-2-carboxylic acid (1.96g, 4.11mmol, 99%, white solid).

[1197] 1H NMR(300MHz,DMSO-d6)13.14(br,OH,1H),10.48(br,NH,1H),8.37(m,NH,1H),8.20(s,NH,1H),7.66-7.62(m,1H),7.54-7.50(m,2H ),7.43(m,1H),7.37-7.33(m,2H),6.53-6.15(m,1H),5.10-5.00(m,2H),4.31-4.29(m,2H),2.50-2.38(m,1H),1.04-1.02(m,6H).

[1198] Example 217-5: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-fluorophenyl)-1-(2,2-difluoroethyl)-1H-indole-2-carboxamide (Compound 217)

[1199] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2,2-difluoroethyl)-1H-indole-2-carboxylic acid (120 mg, 0.25 mmol) and 4-fluoroaniline (33.4 mg, 0.30 mmol) were added to a 10 mL flask and dissolved in CH2Cl2 (1.7 ml). HOBT (50.8 mg, 0.38 mmol) and DMAP (9.2 mg, 0.07 mmol) were added thereto and reacted for 10 minutes. EDC (72.1 mg, 0.38 mmol) and TEA (0.11 ml, 0.75 mmol) were added and stirred at reflux for 12 hours. After the reaction was complete, the organic material was extracted with ethyl acetate / H2O. The organic layer was dried over MgSO4 and distilled under reduced pressure to remove the solvent. The residue was subjected to column chromatography (ethyl acetate:n-hexane=2:1) ​​to obtain 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-fluorophenyl)-1-(2,2-difluoroethyl)-1H-indole-2-carboxamide (124.7 mg, 0.22 mmol, 87.1%, white solid).

[1200] 1H NMR(300MHz,DMSO-d6)10.52-10.50(m,NH,2H),8.43-8.39(m,NH,1H),8.20(s,1H),7.83-7.78(m,2H),7.67-7.63(m,1H),7.56-7.50(m,2H),7.45- 7.42(m,2H),7.37-7.34(m,1H),7.25-7.18(m,2H),6.59-6.21(m,1H),5. 10-5.00(m,2H),4.31-4.29(m,2H),2.51-2.39(m,1H),1.05-1.02(m,6H).

[1201] Example 218: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-chlorophenyl)-1-(2,2-difluoroethyl)-1H-indole-2-carboxamide (Compound 218)

[1202] The title compound was obtained according to the same procedure as in Example 217, except using 4-chloroaniline instead of 4-fluoroaniline.

[1203] 1H NMR(300MHz,DMSO-d6)10.55-10.49(m,NH,2H),8.40-8.35(m,NH,1H),8.20(s,1H),7.84-7.80(m,2H),7.67-7.63(m,1H),7.56-7.50(m,2 H),7.45-7.41(m,4H),7.37-7.33(m,1H),6.59-6.21(m,1H),5.10-5.00(m,2H),4.31-4.29(m,2H),2.51-2.39(m,1H),1.05-1.02(m,6H).

[1204] Example 219: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2,2-difluoroethyl)-N-(4-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (Compound 219)

[1205] The title compound was obtained according to the same procedure as in Example 217, except using 4-(trifluoromethoxy)aniline instead of 4-fluoroaniline.

[1206] 1H NMR(300MHz,DMSO-d6)10.62-10.49(m,NH,2H),8.40-8.35(m,NH,1H),8.21(s,1H),7.92-7.88(m,2H),7.68-7.64(m,1H),7.56- 7.50(m,2H),7.45-7.34(m,5H),6.59-6.21(m,1H),5.10-5.00(m,2H),4.32-4.29(m,2H),2.51-2.39(m,1H),1.05-1.02(m,6H).

[1207] Example 220: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2,2-difluoroethyl)-N-(4-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide (Compound 220)

[1208] The title compound was obtained according to the same procedure as in Example 217, except using 4-(trifluoromethyl)aniline instead of 4-fluoroaniline.

[1209] 1H NMR(300MHz,DMSO-d6)10.75(br,NH,1H),10.51(br,NH,1H),8.40-8.35(m,N H,1H),8.22(s,1H),8.04-8.01(m,2H),7.67-7.73(m,2H),7.69-7.65(m,1H) ,7.57-7.51(m,2H),7.48-7.45(m,2H),7.37-7.34(m,1H),6.61-6.21(m,1H) ,5.10-5.00(m,2H),4.32-4.28(m,2H),2.51-2.39(m,1H),1.05-1.02(m,6H).

[1210] Example 221: Synthesis of N-(2-chloro-4-fluorophenyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2,2-difluoroethyl)-1H-indole-2-carboxamide (Compound 221)

[1211] The title compound was obtained according to the same procedure as in Example 217, except using 2-chloro-4-fluoroaniline instead of 4-fluoroaniline.

[1212] 1H NMR(300MHz,DMSO-d6)10.51(br,NH,1H),10.25(br,NH,1H),8.40-8.35(m,NH,1H),8.21(s,1H),7.68-7.58(m,3H),7.54-7.51(m,2H) ,7.47-7.45(m,2H),7.37-7.27(m,2H),6.54-6.16(m,1H),5.08-4.98(m,2H),4.32-4.28(m,2H),2.51-2.39(m,1H),1.05-1.02(m,6H).

[1213] Example 222: Synthesis of N-(4-chloro-2-fluorophenyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2,2-difluoroethyl)-1H-indole-2-carboxamide (Compound 222)

[1214] The title compound was obtained according to the same procedure as in Example 217, except using 4-chloro-2-fluoroaniline instead of 4-fluoroaniline.

[1215] 1H NMR(300MHz,DMSO-d6)10.50(br,NH,1H),10.35(br,NH,1H),8.40-8.35(m,NH,1H),8.22(s,1H),7.69-7.62(m,2H),7.60-7.50(m,3H) ,7.47-7.44(m,2H),7.37-7.33(m,2H),6.61-6.17(m,1H),5.09-4.99(m,2H),4.32-4.29(m,2H),2.51-2.39(m,1H),1.05-1.02(m,6H).

[1216] Example 223: Synthesis of N-(4-chloro-3-fluorophenyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2,2-difluoroethyl)-1H-indole-2-carboxamide (Compound 223)

[1217] The title compound was obtained according to the same procedure as in Example 217, except using 4-chloro-3-fluoroaniline instead of 4-fluoroaniline.

[1218] 1H NMR(300MHz,DMSO-d6)10.72(br,NH,1H),10.51(br,NH,1H),8.40-8.35(m,NH,1H),8.22(s,1H),7.97-7.91(m,1H),7.68-7.50(m,5 H),7.43(m,2H),7.37-7.34(m,1H),6.60-6.21(m,1H),5.10-5.00(m,2H),4.32-4.29(m,2H),2.51-2.39(m,1H),1.05-1.02(m,6H).

[1219] Example 224: Synthesis of N-(3-chloro-4-fluorophenyl)-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2,2-difluoroethyl)-1H-indole-2-carboxamide (Compound 224)

[1220] The title compound was obtained according to the same procedure as in Example 217, except using 3-chloro-4-fluoroaniline instead of 4-fluoroaniline.

[1221] 1H NMR(300MHz,DMSO-d6)10.61(br,NH,1H),10.50(br,NH,1H),8.40-8.35(m,N H,1H),8.22(s,1H),8.11-8.07(m,1H),7.75-7.69(m,1H),7.68-7.64(m,1H) ,7.55-7.50(m,2H),7.48-7.41(m,3H),7.37-7.34(m,1H),6.60-6.22(m,1H) ,5.10-5.00(m,2H),4.32-4.28(m,2H),2.51-2.39(m,1H),1.05-1.02(m,6H).

[1222] Example 225: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3,4-dichlorophenyl)-1-(2,2-difluoroethyl)-1H-indole-2-carboxamide (Compound 225)

[1223] The title compound was obtained according to the same procedure as in Example 217, except using 3,4-dichloroaniline instead of 4-fluoroaniline.

[1224] 1H NMR(300MHz,DMSO-d6)10.67(br,NH,1H),10.51(br,NH,1H),8.40-8.35(m,NH,1H),8.22-8.17(m,2H),7.78-7.74(m,1H),7.69-7.62(m,2H),7. 57-7.50(m,2H),7.44(s,2H),7.37-7.34(m,1H),6.60-6.22(m,1H),5.1 0-5.00(m,2H),4.32-4.29(m,2H),2.51-2.39(m,1H),1.05-1.02(m,6H).

[1225] Example 226: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(2,2-difluoroethyl)-N-(2-fluoro-4-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide (Compound 226)

[1226] The title compound was obtained according to the same procedure as in Example 217, except using 2-fluoro-4-(trifluoromethyl)aniline instead of 4-fluoroaniline.

[1227] 1H NMR(300MHz,DMSO-d6)10.54-10.51(br,NH,2H),8.40-8.35(m,NH,1H),8.22(m,1H),7.98-7.92(m,1H),7.84-7.80(m,1H),7.69-7.65(m,2H),7. 56-7.51(m,3H),7.44(s,1H),7.39-7.33(m,1H),6.57-6.19(m,1H),5.1 0-5.00(m,2H),4.32-4.29(m,2H),2.51-2.39(m,1H),1.05-1.02(m,6H).

[1228]

[1229] Example 227: Synthesis of methyl 4-(5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-1H-indole-2-carboxamido)benzoate (Compound 227)

[1230] Example 227-1: Synthesis of ethyl 1-methyl-5-nitro-1H-indole-2-carboxylate

[1231] 5-nitro-1H-indole-2-carboxylic acid, ethyl ester (2.5g, 10.67mmol) and iodomethane (2.27g, 16.01mmol) are added in a 100mL flask and dissolved in DMF (25ml). By K CO (2.95g, 21.34mmol) is added thereto and at room temperature stirred for 12 hours. After the reaction is complete, organic material is extracted with ethyl acetate / H O. By organic layer through MgSO drying and distilled under reduced pressure to remove solvent. Residue is subjected to column chromatography (ethyl acetate: normal hexane=1:3) to obtain 1-methyl-5-nitro-1H-indole-2-carboxylic acid, ethyl ester (2.38g, 9.58mmol, 90%, white solid).

[1232] 1H NMR (300MHz, CDCl3)8.66-8.65(m,1H),8.25-8.22(m,1H),7.46-7.43(m,2H),4.45-4.42(m,2H),4.14(s,3H),1.45-1.41(m,3H).

[1233] Example 227-2: Synthesis of 5-amino-1-methyl-1H-indole-2-carboxylic acid ethyl ester

[1234] 1-methyl-5-nitro-1H-indole-2-carboxylic acid, ethyl ester (2.38g, 9.58mmol) is added in 100mL flask and is dissolved in MeOH (50ml).Add 10%Pd / C (2.3g) and at room temperature under H2(g) stir 12 hours.After carrying out diatomite filtration when reaction is complete, under reduced pressure by distillation removal solvent.Residue is subjected to column chromatography (ethyl acetate: normal hexane=1:3) to obtain 5-amino-1-methyl-1H-indole-2-carboxylic acid, ethyl ester (1.66g, 7.60mmol, 77%).

[1235] 1H NMR(300MHz, CDCl3)7.52(s,1H),7.21-7.18(m,1H),7.09(s,1H),6.92-6.91(m,1H),6 .85-6.82(m,1H),4.38-4.31(m,2H),4.01(s,3H),3.55(br,NH,2H),1.42-1.37(m,3H).

[1236] Example 227-3: Synthesis of ethyl 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-1H-indole-2-carboxylate

[1237] 5-amino-1-methyl-1H-indole-2-carboxylic acid, ethyl ester (660mg, 3.02mmol) and 2-chloro-5-(isobutyrylaminomethyl) benzoic acid (927mg, 3.624mmol) are added in a 100mL flask and dissolved in CH Cl (20ml). HOBT (612mg, 4.53mmol) and DMAP (369mg, 3.02mmol) are added thereto and reacted 10 minutes. Add EDC (1.74g, 9.06mmol) and TEA (917mg, 9.06mmol) and stir under reflux for 12 hours. After the reaction is complete, use CH Cl / H O extracts organic material. With the organic layer through MgSO Dry and distill under reduced pressure to remove solvent. The residue was subjected to column chromatography (ethyl acetate:n-hexane=3:1) to obtain ethyl 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-1H-indole-2-carboxylate (900 mg, 1.97 mmol, 66%, white solid).

[1238] 1H NMR(300MHz,DMSO-d6)10.46(br,NH,1H),8.39-8.35(m,NH,1H),8.18(m,1H),7.59-7.49(m,3H),7.43(m,1H),7.35- 7.33(m,1H),7.25(m,1H),4.36-4.28(m,4H),4.01(s,3H),2.50-2.38(m,1H),1.36-1.31(m,3H),1.04-1.02(m,6H).

[1239] Example 227-4: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-1H-indole-2-carboxylic acid

[1240] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-1H-indole-2-carboxylic acid, ethyl ester (900mg, 1.97mmol) is added in a 500mL flask and dissolved in THF (100ml) and MeOH (100ml).Add and be dissolved in H2LiOH (413mg, 9.85mmol) in O (70ml) and stirred 12 hours.After concentrating when the reaction is complete, pH is adjusted to 2 with 2N-HCl.The solid of gained is filtered to obtain 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-1H-indole-2-carboxylic acid (812mg, 1.89mmol, 96%, white solid).

[1241] 1H NMR(300MHz,DMSO-d6)10.45(br,NH,1H),8.39-8.35(m,NH,1H),8.18(m,1H),7.57-7.49(m,3H),7.43(m,1 H),7.35-7.33(m,1H),7.21(m,1H),4.30-4.28(m,2H),4.01(s,3H),2.50-2.38(m,1H),1.04-1.02(m,6H).

[1242] Example 227-5: Synthesis of methyl 4-(5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-1H-indole-2-carboxamido)benzoate (Compound 227)

[1243] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-1H-indole-2-carboxylic acid (500mg, 1.17mmol) and methyl 4-aminobenzoate (265mg, 0.345mmol) are added in a 25mL flask and dissolved in CH Cl (10ml) and DMF (2ml).HOBT (474mg, 3.51mmol) and DMAP (429mg, 3.51mmol) are added thereto and stirred for 10 minutes.EDC (673mg, 3.51mmol) and TEA (490 μl, 3.51mmol) are added and stirred under reflux for 12 hours.After the reaction is complete, CH Cl / H O is used to extract the organic material.The organic layer is dried over MgSO and distilled under reduced pressure to remove the solvent. The residue was subjected to column chromatography (ethyl acetate:n-hexane=3:1) to obtain methyl 4-(5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-1H-indole-2-carboxamido)benzoate (420 mg, 0.748 mmol, 64%, white solid).

[1244] 1H NMR(300MHz,DMSO-d6)10.63(br,NH,1H),10.47(br,NH,1H),8.37(m,NH,1H),8.20(m,1H),7.97(m,4H),7.60-7.50( m,3H),7.45(m,1H),7.36-7.34(m,2H),4.31(m,2H),4.01(m,3H),3.84(s,3H),2.50-2.39(m,1H),1.06-1.02(m,6H).

[1245] Example 228: Synthesis of 4-(5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-1H-indole-2-carboxamido)benzoic acid (Compound 228)

[1246] Methyl 4-(5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-1H-indole-2-formamido)benzoate (420 mg, 0.748 mmol) was added to a 100 mL flask and dissolved in THF (15 ml) and MeOH (15 ml). LiOH (156 mg, 3.74 mmol) dissolved in H O (10 ml) was added and stirred for 12 hours. After concentrating when the reaction was complete, the pH was adjusted to 2 with 2N-HCl. The resulting solid was filtered to obtain 4-(5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-1H-indole-2-formamido)benzoic acid (240 mg, 0.43 mmol, 58%, white solid).

[1247] 1H NMR(300MHz,DMSO-d6)10.58(br,NH,1H),10.46(br,NH,1H),8.37(m,NH,1H),8.20(m,1H),7.93(m,4H),7.56- 7.50(m,3H),7.45(m,1H),7.36(m,2H),4.31-4.30(m,2H),4.01(s,3H),2.50-2.38(m,1H),1.05-1.02(m,6H).

[1248] Example 229: Synthesis of sodium 4-(5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-1H-indole-2-carboxamido)benzoate (Compound 229)

[1249] 4-(5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-1H-indole-2-carboxamido)benzoic acid (100 mg, 0.183 mmol) was added to a 25 mL flask and dissolved in MeOH (10 ml). NaOH (7.32 mg, 0.183 mmol) dissolved in HO (2 ml) was added and stirred for 12 hours. Upon completion of the reaction, sodium 4-(5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-1H-indole-2-carboxamido)benzoate (94 mg, 0.16 mmol, 90%, white solid) was obtained after concentration.

[1250] 1H NMR(300MHz,DMSO-d6)10.47(br,NH,1H),10.28(br,NH,1H),8.40(m,NH,1H),8.17(m,1H),7.84-7.81(m,2H),7.67-7. 64(m,2H),7.54-7.46(m,4H),7.36-7.29(m,2H),4.31-4.29(m,2H),4.01(s,3H),2.50-2.38(m,1H),1.05-1.02(m,6H).

[1251] Example 230: Synthesis of methyl 5-(5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-1H-indole-2-carboxamido)-2-fluorobenzoate (Compound 230)

[1252] The title compound was obtained according to the same procedure as in Example 227, except using methyl 5-amino-2-fluorobenzoate instead of methyl 4-aminobenzoate.

[1253] 1H NMR(300MHz,DMSO-d6)10.55(br,NH,1H),10.47(br,NH,1H),8.43-8.36(m,2H),8.20(m,1H),8.08-8.02(m,1H),7.59-7.51 (m,3H),7.45(m,1H),7.41-7.34(m,3H),4.31-4.29(m,2H),4.01(s,3H),3.88(s,3H),2.50-2.38(m,1H),1.05-1.02(m,6H).

[1254] Example 231: Synthesis of 5-(5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-1H-indole-2-carboxamido)-2-fluorobenzoic acid (Compound 231)

[1255] The title compound was obtained according to the same procedure as in Example 228, except using methyl 5-(5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-1H-indole-2-carboxamido)-2-fluorobenzoate instead of methyl 4-(5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-1H-indole-2-carboxamido)benzoate.

[1256] 1H NMR(300MHz,DMSO-d6)10.51(br,NH,1H),10.47(br,NH,1H),8.39-8.36(m,2H),8.19(m,1H),8.02-7.99(m,1H),7.59 -7.50(m,3H),7.44(m,1H),7.36-7.30(m,3H),4.31-4.29(m,2H),4.01(s,3H),2.50-2.38(m,1H),1.04-1.02(m,6H).

[1257]

[1258] Example 232: Synthesis of 6-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (Compound 232)

[1259] Example 232-1: Synthesis of (E)-3-(4-acetylaminophenyl)-2-azidoacrylate

[1260] N-(4-formylphenyl)acetamide (3 g, 18.38 mmol) was added to a 100 mL flask and dissolved in MeOH (50 ml). NaOMe (1.49 g, 27.57 mmol) and methyl 2-azidoacetate (9.52 g, 82.71 mmol) were added and stirred at room temperature for 12 hours. After the reaction was complete, the organic material was extracted with ethyl acetate / NH4Cl. The organic layer was dried over MgSO4 and distilled under reduced pressure to remove the solvent to obtain (E)-methyl 3-(4-acetamidophenyl)-2-azidoacrylate (3.8 g, 14.6 mmol, 79%).

[1261] Example 232-2: Synthesis of methyl 6-acetylamino-1H-indole-2-carboxylate

[1262] (E)-3-(4-acetylaminophenyl)-2-azidopropenoic acid methyl ester (3.8 g, 14.6 mmol) was added to a 100 mL flask, dissolved in chlorobenzene (60 ml) and stirred under reflux for 3 hours. After the reaction was complete, the organic material was extracted with ethyl acetate / H2O. The organic layer was dried over MgSO4 and distilled under reduced pressure to remove the solvent. The residue was subjected to column chromatography (ethyl acetate: n-hexane = 1:1) to obtain 6-acetylamino-1H-indole-2-carboxylic acid methyl ester (1.1 g, 4.73 mmol, 32% solid).

[1263] 1H NMR (300MHz, DMSO-d6) 11.76(br,NH,1H),9.97(br,NH,1H),8.02(m,1H),7.55-7.53(m,1H),7.13-7.08(m,2H),3.85(s,3H),2.06(s,3H).

[1264] Example 232-3: Synthesis of methyl 6-amino-1H-indole-2-carboxylate hydrochloride

[1265] 6-acetylamino-1H-indole-2-carboxylic acid methyl esters (1.54g, 6.63mmol) is added in the 100mL flask and is dissolved among the MeOH (50ml).C-HCl (10ml) is added wherein and under reflux, stirred 3 hours.After reaction is completed, under reduced pressure, remove solvent by distillation to obtain 6-amino-1H-indole-2-carboxylic acid methyl esters hydrochloride (1.44g, 5.83mmol, 96%).

[1266] 1H NMR (300MHz, DMSO-d6)12.14(br,NH,1H),10.08(br,NH,3H),7.77-7.74(m,1H),7.47(m,1H),7.20(m,1H),7.06-7.02(m,1H),3.88(s,3H).

[1267] Example 232-4: Synthesis of methyl 6-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1H-indole-2-carboxylate

[1268] 6-amino-1H-indole-2-carboxylic acid methyl ester hydrochloride (1.44g, 5.83mmol) and 2-chloro-5-(isobutyrylaminomethyl) benzoic acid (2.44g, 9.525mmol) are added in a 100mL flask and dissolved in CH Cl (30ml).HOBT (2.58g, 19.05mmol) and DMAP (2.33g, 19.05mmol) are added thereto and stirred 10 minutes.Add EDC (3.65g, 19.05mmol) and TEA (2.65ml, 19.05mmol) and at room temperature stirred 12 hours.After the reaction is complete, use CH Cl / H O extracts organic material.With organic layer through MgSO Dry and distill under reduced pressure to remove solvent. The residue was subjected to column chromatography (ethyl acetate:n-hexane=3:1) to obtain methyl 6-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1H-indole-2-carboxylate (1.33 g, 3.1 mmol, 48%).

[1269] 1H NMR(300MHz,DMSO-d6)11.87(br,NH,1H),10.55(br,NH,1H),8.35(m,NH,1H),8.17(m,1H),7.61-7.58(m,1H),7.52-7.49(m,1H),7. 43(m,1H),7.35-7.33(m,1H),7.25-7.22(m,1H),7.12(m,1H),4.30-4.28(m,2H),3.86(s,3H),2.50-2.38(m,1H),1.04-1.02(m,6H).

[1270] Example 232-5: Synthesis of 6-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1H-indole-2-carboxylic acid

[1271] 6-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1H-indole-2-carboxylic acid methyl esters (1.33g, 3.1mmol) is added in a 250mL flask and dissolved in THF (30ml) and MeOH (30ml).Add and be dissolved in H2LiOH (650mg, 15.5mmol) in O (30ml) and stir 12 hours.After concentrating when the reaction is complete, pH is adjusted to 2 with 2N-HCl.The solid of gained is filtered to obtain 6-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1H-indole-2-carboxylic acid (1.98g, 4.34mmol, 90%, white solid).

[1272] 1H NMR(300MHz,DMSO-d6)11.67(br,NH,1H),10.52(br,NH,1H),8.35(m,NH,1H),8.15(m,1H),7.58-7.55(m,1H),7.52-7.49(m,2 H),7.42(m,1H),7.35-7.32(m,1H),7.22-7.19(m,1H),7.03(m,1H),4.30-4.28(m,2H),2.50-2.38(m,1H),1.04-1.02(m,6H).

[1273] Example 232-6: Synthesis of 6-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (Compound 232)

[1274] 6-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1H-indole-2-carboxylic acid (200 mg, 0.48 mmol) and 4-(trifluoromethoxy)aniline (170 mg, 0.96 mmol) were added to a 10 mL flask and dissolved in CH Cl (5 ml) and DMF (1 ml). HOBT (195 mg, 1.44 mmol) and DMAP (176 mg, 1.44 mmol) were added thereto and stirred for 10 minutes. EDC (276 mg, 1.44 mmol) and TEA (200 μl, 1.44 mmol) were added and stirred at reflux for 12 hours. After the reaction was complete, the organic material was extracted with ethyl acetate / H O. The organic layer was dried over MgSO and distilled under reduced pressure to remove the solvent. The residue was suspended in CH2Cl2 and filtered to give 6-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (187 mg, 0.32 mmol, 68%, yellow solid).

[1275] 1H NMR(300MHz,DMSO-d6)11.73(br,NH,1H),10.49(br,NH,1H),10.32(br,NH,1H),8.32(m,NH,1H),8.14(m,1H),7.93-7.90( m,2H),7.64-7.61(m,1H),7.52-7.49(m,1H),7.43-7.33(m,5H),4.31-4.29(m,2H),2.50-2.39(m,1H),1.05-1.02(m,6H).

[1276] Example 233: Synthesis of 6-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide (Compound 233)

[1277] The title compound was obtained according to the same procedure as in Example 232, except using 4-(trifluoromethyl)aniline instead of 4-(trifluoromethoxy)aniline.

[1278] 1H NMR(300MHz,DMSO-d6)11.80(br,NH,1H),10.55(br,NH,1H),10.47(br,NH,1H),8.37(m,NH,1H),8.17(m,1H),8.05-8.02(m,2H),7.75-7.73(m,2H),7. 66-7.63(m,1H),7.53-7.50(m,1H),7.45-7.44(m,2H),7.36-7.33(m,1H),7 .28-7.25(m,1H),4.31-4.29(m,2H),2.50-2.39(m,1H),1.04-1.02(m,6H).

[1279] Example 234: Synthesis of 6-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-fluorophenyl)-1H-indole-2-carboxamide (Compound 234)

[1280] The title compound was obtained according to the same procedure as in Example 232, except using 4-fluoroaniline instead of 4-(trifluoromethoxy)aniline.

[1281] 1H NMR(300MHz,DMSO-d6)11.75(br,NH,1H),10.53(br,NH,1H),10.22(br,NH,1H),8.36(m,NH,1H),8.15(m,1H),7.82(m,2H),7.63-7.60( m,1H),7.53-7.50(m,1H),7.44(m,1H),7.37-7.33(m,2H),7.27-7.19(m,3H),4.31-4.30(m,2H),2.50-2.39(m,1H),1.04-1.02(m,6H).

[1282] Example 235: Synthesis of 6-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (Compound 235)

[1283] The title compound was obtained according to the same procedure as in Example 232, except using 3-(trifluoromethoxy)aniline instead of 4-(trifluoromethoxy)aniline.

[1284] 1H NMR(300MHz,DMSO-d6)11.78(br,NH,1H),10.55(br,NH,1H),10.41(br,NH,1H),8.37(m,NH,1H),8.17(m,1H),7.96(m,1H),7.82-7.79(m,1H),7.65 -7.62(m,1H),7.53-7.47(m,2H),7.44-7.42(m,1H),7.28-7.25(m,1H),7. 10-7.07(m,1H),4.31-4.29(m,2H),2.50-2.39(m,1H),1.05-1.02(m,6H).

[1285] Example 236: Synthesis of 6-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide (Compound 236)

[1286] The title compound was obtained according to the same procedure as in Example 232, except using 3-(trifluoromethyl)aniline instead of 4-(trifluoromethoxy)aniline.

[1287] 1H NMR(300MHz,DMSO-d6)11.79(br,NH,1H),10.55(br,NH,1H),10.46(br,NH,1H),8.36(m,NH,1H),8.25(m,1H),8.18(m,1H),8.1-8.08(m,1H),7.66- 7.59(m,2H),7.53-7.50(m,1H),7.46-7.44(m,3H),7.36-7.34(m,1H),7. 28-7.25(m,1H),4.31-4.29(m,2H),2.50-2.39(m,1H),1.05-1.02(m,6H).

[1288] Example 237: Synthesis of 6-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-chlorophenyl)-1H-indole-2-carboxamide (Compound 237)

[1289] The title compound was obtained according to the same procedure as in Example 232, except using 4-chloroaniline instead of 4-(trifluoromethoxy)aniline.

[1290] 1H NMR(300MHz,DMSO-d6)11.76(br,NH,1H),10.53(br,NH,1H),10.28(br,NH,1H),8.36(m,NH,1H),8.15(m,1H),7.86-7.83(m,2H),7.64-7.61( m,1H),7.53-7.50(m,1H),7.44-7.39(m,4H),7.36-7.33(m,1H),7.27- 7.24(m,1H),4.31-4.29(m,2H),2.50-2.39(m,1H),1.04-1.02(m,6H).

[1291] Example 238: Synthesis of 6-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-chlorophenyl)-1H-indole-2-carboxamide (Compound 238)

[1292] The title compound was obtained according to the same procedure as in Example 232, except using 3-chloroaniline instead of 4-(trifluoromethoxy)aniline.

[1293] 1H NMR(300MHz,DMSO-d6)11.76(br,NH,1H),10.54(br,NH,1H),10.30(br,NH,1H),8.36(m,NH,1H),8.16(m,1H),7.99(m,1H),7.75-.72(m,1H),7.64 -7.62(m,1H),7.5-7.50(m,1H),7.43-7.33(m,4H),7.27-7.25(m,1H),7. 17-7.14(m,1H),4.31-4.29(m,2H),2.50-2.39(m,1H),1.05-1.02(m,6H).

[1294]

[1295] Example 239: Synthesis of 6-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-N-(4-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (Compound 239)

[1296] Example 239-1: Synthesis of (E)-3-(4-acetylaminophenyl)-2-azidoacrylate

[1297] N-(4-formylphenyl)acetamide (3g, 18.38mmol) is added to a 100mL flask and dissolved in MeOH (50ml). NaOMe (1.49g, 27.57mmol) and methyl 2-azidoacetate (9.52g, 82.71mmol) are added thereto and stirred at room temperature for 12 hours. After the reaction is complete, the organic material is extracted with ethyl acetate / NH4Cl. The organic layer is dried over MgSO4 and distilled under reduced pressure to remove the solvent to obtain (E)-3-(4-acetamidophenyl)-2-azidoacrylate (3.8g, 14.6mmol, 79%).

[1298] Example 239-2: Synthesis of methyl 6-acetylamino-1H-indole-2-carboxylate

[1299] (E)-3-(4-acetylaminophenyl)-2-azidopropenoic acid methyl ester (3.8 g, 14.6 mmol) was added to a 100 mL flask, dissolved in chlorobenzene (60 ml) and stirred under reflux for 3 hours. After the reaction was complete, the organic material was extracted with ethyl acetate / H2O. The organic layer was dried over MgSO4 and distilled under reduced pressure to remove the solvent. The residue was subjected to column chromatography (ethyl acetate: n-hexane = 1:1) to obtain 6-acetylamino-1H-indole-2-carboxylic acid methyl ester (1.1 g, 4.73 mmol, 32% solid).

[1300] 1H NMR (300MHz, DMSO-d6) 11.76(br,NH,1H),9.97(br,NH,1H),8.02(m,1H),7.55-7.53(m,1H),7.13-7.08(m,2H),3.85(s,3H),2.06(s,3H).

[1301] Example 239-3: Synthesis of methyl 6-amino-1H-indole-2-carboxylate hydrochloride

[1302] 6-acetylamino-1H-indole-2-carboxylic acid methyl esters (1.54g, 6.63mmol) is added in the 100mL flask and is dissolved among the MeOH (50ml).C-HCl (10ml) is added wherein and under reflux, stirred 3 hours.After reaction is completed, under reduced pressure, remove solvent by distillation to obtain 6-amino-1H-indole-2-carboxylic acid methyl esters hydrochloride (1.44g, 5.83mmol, 96%).

[1303] 1H NMR (300MHz, DMSO-d6)12.14(br,NH,1H),10.08(br,NH,3H),7.77-7.74(m,1H),7.47(m,1H),7.20(m,1H),7.06-7.02(m,1H),3.88(s,3H).

[1304] Example 239-4: Synthesis of methyl 6-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1H-indole-2-carboxylate

[1305] 6-amino-1H-indole-2-carboxylic acid methyl ester hydrochloride (1.44g, 5.83mmol) and 2-chloro-5-(isobutyrylaminomethyl) benzoic acid (2.44g, 9.525mmol) are added in a 100mL flask and dissolved in CH Cl (30ml).HOBT (2.58g, 19.05mmol) and DMAP (2.33g, 19.05mmol) are added thereto and reacted 10 minutes.Add EDC (3.65g, 19.05mmol) and TEA (2.65ml, 19.05mmol) and at room temperature stirred 12 hours.After the reaction is complete, use CH Cl / H O extracts organic material.With organic layer through MgSO Dry and distill under reduced pressure to remove solvent. The residue was subjected to column chromatography (ethyl acetate:n-hexane=3:1) to obtain methyl 6-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1H-indole-2-carboxylate (1.33 g, 3.1 mmol, 48%).

[1306] 1H NMR(300MHz,DMSO-d6)11.87(br,NH,1H),10.55(br,NH,1H),8.35(m,NH,1H),8.17(m,1H),7.61-7.58(m,1H),7.52-7.49(m,1H),7. 43(m,1H),7.35-7.33(m,1H),7.25-7.22(m,1H),7.12(m,1H),4.30-4.28(m,2H),3.86(s,3H),2.50-2.38(m,1H),1.04-1.02(m,6H).

[1307] Example 239-5: Synthesis of methyl 6-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-1H-indole-2-carboxylate

[1308] 6-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1H-indole-2-carboxylic acid methyl ester (1.1g, 2.57mmol) and iodomethane (1.1g, 7.71mmol) are added to a 25mL flask and dissolved in DMF (15ml). KCO (1.06g, 7.71mmol) is added thereto and stirred at room temperature for 12 hours. After the reaction is complete, the organic material is extracted with ethyl acetate / HO. The organic layer is dried over MgSO and distilled under reduced pressure to remove the solvent. Residue is subjected to column chromatography (ethyl acetate: normal hexane=2:1) ​​to obtain 6-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-1H-indole-2-carboxylic acid methyl ester (200mg, 0.45mmol, 17%).

[1309] 1H NMR(300MHz,DMSO-d6)11.66(br,NH,1H),8.36(m,NH,1H),8.20(m,1H),7.65-7.62(m,1H),7.53-7.51(m,1H),7.44(m,1H) ,7.37-7.34(m,1H),7.29-7.24(m,2H),4.30-4.29(m,2H),3.99(s,3H),3.85(s,3H),2.50-2.38(m,1H),1.04-1.02(m,6H).

[1310] Example 239-6: Synthesis of 6-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-1H-indole-2-carboxylic acid

[1311] 6-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-1H-indole-2-carboxylic acid methyl ester (200mg, 0.45mmol) is added in 50mL flask and is dissolved in THF (10ml) and MeOH (10ml).Add and be dissolved in H2LiOH (94mg, 2.25mmol) in O (10ml) and at room temperature stirred 12 hours.After concentrating when reaction is complete, pH is adjusted to 2 with 2N-HCl.The solid of gained is filtered to obtain 6-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-1H-indole-2-carboxylic acid (187mg, 0.43mmol, 96%, solid).

[1312] 1H NMR(300MHz,DMSO-d6)11.63(br,NH,1H),8.36(m,NH,1H),8.18(m,1H),7.63-7.61(m,1H),7.53-7.50(m,1H),7.44( m,1H),7.36-7.34(m,1H),7.28-7.25(m,1H),7.19(m,1H),4.30-4.29(m,2H),2.50-2.38(m,1H),1.04-1.02(m,6H).

[1313] Example 239-7: Synthesis of 6-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-N-(4-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (Compound 239)

[1314] 6-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-1H-indole-2-carboxylic acid (90 mg, 0.21 mmol) and 4-(trifluoromethoxy)aniline (75 mg, 0.42 mmol) were added to a 10 mL flask and dissolved in CH Cl (5 ml) and DMF (1 ml). HOBT (85 mg, 0.63 mmol) and DMAP (77 mg, 0.63 mmol) were added thereto and reacted for 10 minutes. EDC (121 mg, 0.63 mmol) and TEA (64 μl, 0.63 mmol) were added and stirred at reflux for 12 hours. After the reaction was complete, the organic material was extracted with ethyl acetate / H O. The organic layer was dried over MgSO and distilled under reduced pressure to remove the solvent. The residue was suspended in CH2Cl2 and filtered to give 6-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-N-(4-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (95 mg, 0.16 mmol, 77%, white solid).

[1315] 1H NMR(300MHz,DMSO-d6)11.63(br,NH,1H),10.46(br,NH,1H),8.37(m,NH,1H),8.18(m,1H),7.91-7.88(m,2H),7.68-7.65(m,1 H),7.54-7.51(m,1H),7.45(m,1H),7.39-7.29(m,5H),4.31-4.29(m,2H),3.98(s,3H),2.50-2.39(m,1H),1.05-1.02(m,6H).

[1316] Example 240: Synthesis of 6-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-N-(4-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide (Compound 240)

[1317] The title compound was obtained according to the same procedure as in Example 239, except using 4-(trifluoromethyl)aniline instead of 4-(trifluoromethoxy)aniline.

[1318] 1H NMR(300MHz,DMSO-d6)11.64(br,NH,1H),10.59(br,NH,1H),8.36(m,NH,1H),8.18(m,1H),8.03-8.00(m,2H),7.74-7.66(m,3 H),7.54-7.51(m,1H),7.45(m,1H),7.37-7.30(m,3H),4.31-4.29(m,2H),3.99(s,3H),2.50-2.39(m,1H),1.05-1.02(m,6H).

[1319]

[1320] Example 241: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(3-methoxypropyl)-N-(4-(trifluoromethoxy)benzyl)-1H-indole-2-carboxamide (Compound 241)

[1321] Example 241-1: Synthesis of ethyl 1-(3-methoxypropyl)-5-nitro-1H-indole-2-carboxylate

[1322] 5-nitro-1H-indole-2-carboxylic acid ethyl ester (3g, 12.8mmol) and 1-chloro-3-methoxypropane (2.78g, 25.6mmol) are added in a 100mL flask and dissolved in DMF (30ml).NaH (768mg, 19.2mmol) is added thereto and stirred at 90 ℃ for 12 hours.After the reaction is complete, ethyl acetate / H o is used to extract the organic material.The organic layer is dried and distilled under reduced pressure to remove the solvent.Resistates is subjected to column chromatography (ethyl acetate: normal hexane=1:3) to obtain 1-(3-methoxypropyl)-5-nitro-1H-indole-2-carboxylic acid ethyl ester (1.8g, 5.88mmol, 46%, oily matter).

[1323] 1H NMR(300MHz,DMSO-d6)8.74(m,1H),8.20-8.17(m,1H),7.80-7.77(m,1H),7.56(m,1H),4.68-4.64 (m,2H),4.39-4.32(m,2H),3.23-3.21(m,2H),3.14(s,3H),1.97-1.93(m,2H),1.37-1.33(m,3H).

[1324] Example 241-2: Synthesis of ethyl 5-amino-1-(3-methoxypropyl)-1H-indole-2-carboxylate

[1325] 1-(3-methoxypropyl)-5-nitro-1H-indole-2-carboxylic acid, ethyl ester (1.8g, 5.88mmol) is added in 100mL flask and is dissolved in EtOH (40ml).Add 10%Pd / C (360mg) and at room temperature under H2(g) stir 12 hours.After carrying out diatomite filtration when the reaction is complete, solvent is removed by distillation under reduced pressure.Residue is subjected to column chromatography (ethyl acetate: normal hexane=1:1) to obtain 5-amino-1-(3-methoxypropyl)-1H-indole-2-carboxylic acid, ethyl ester (1.42g, 5.14mmol, 87%).

[1326] 1H NMR(300MHz,DMSO-d6)7.27-7.24(m,1H),6.96(m,1H),6.78-6.72(m,2H),4.73(br,NH,2H),4 .50-4.45(m,2H),4.31-4.24(m,2H),3.23-3.19(m,5H),1.89-1.85(m,2H),1.33-1.29(m,3H).

[1327] Example 241-3: Synthesis of ethyl 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(3-methoxypropyl)-1H-indole-2-carboxylate

[1328] 5-amino-1-(3-methoxypropyl)-1H-indole-2-carboxylic acid, ethyl ester (1.42g, 5.14mmol) and 2-chloro-5-(isobutyrylaminomethyl) benzoic acid (1.58g, 6.168mmol) are added in a 100mL flask and dissolved in CH Cl (30ml). HOBT (2.08g, 15.42mmol) and DMAP (1.88g, 15.42mmol) are added thereto and stirred for 10 minutes. EDC (2.96g, 15.42mmol) and TEA (2.15ml, 15.42mmol) are added and stirred under reflux for 12 hours. After the reaction is complete, CH Cl / H O is used to extract the organic material. The organic layer is dried over MgSO and distilled under reduced pressure to remove the solvent. The residue was subjected to column chromatography (ethyl acetate:n-hexane=2:1) ​​to obtain ethyl 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(3-methoxypropyl)-1H-indole-2-carboxylate (2.1 g, 4.09 mmol, 79%, white solid).

[1329] 1H NMR(300MHz,DMSO-d6)10.48(br,NH,1H),8.38(m,NH,1H),8.18(m,1H),7.54-7.50(m,3H),7.43(m,1H),7.36-7.33(m,1H),7.28(m, 1H),4.59(m,2H),4.36-4.29(m,4H),3.23-3.19(m.5H),2.50-2.38(m,1H),1.95-1.91(m,2H),1.36-1.32(m,3H),1.04-1.02(m,6H).

[1330] Example 241-4: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(3-methoxypropyl)-1H-indole-2-carboxylic acid

[1331] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(3-methoxypropyl)-1H-indole-2-carboxylic acid, ethyl ester (2.1g, 4.09mmol) is added in a 250mL flask and dissolved in THF (30ml) and MeOH (30ml).Add and be dissolved in H2LiOH (858mg, 20.45mmol) in O (30ml) and stir 12 hours.After concentrating when the reaction is complete, pH is adjusted to 2 with 2N-HCl.The solid of gained is filtered to obtain 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(3-methoxypropyl)-1H-indole-2-carboxylic acid (1.79g, 3.68mmol, 89%, white solid).

[1332] 1H NMR(300MHz,DMSO-d6)12.90(br,OH,1H),10.45(br,NH,1H),8.37(m,NH,1H),8.16(m,1H),7.51-7.49(m,3H),7.42(m,1H),7.35-7.32( m,1H),7.22(m,1H),4.59-4.57(m,2H),4.30-4.28(m,2H),3.24-3.19(m.5H),2.50-2.38(m,1H),1.94-1.90(m,2H),1.04-1.02(m,6H).

[1333] Example 241-5: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(3-methoxypropyl)-N-(4-(trifluoromethoxy)benzyl)-1H-indole-2-carboxamide (Compound 241)

[1334] 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(3-methoxypropyl)-1H-indole-2-carboxylic acid (200 mg, 0.411 mmol) and 4-(trifluoromethoxy)benzylamine (146 mg, 0.822 mmol) were added to a 10 mL flask and dissolved in DMF (1 ml). HATU (167 mg, 1.233 mmol) and DIPEA (172 μl, 1.233 mmol) were added thereto and stirred at room temperature for 12 hours. After the reaction was complete, the organic material was extracted with ethyl acetate / H2O. The organic layer was dried over MgSO4 and distilled under reduced pressure to remove the solvent. The residue was subjected to column chromatography (ethyl acetate:n-hexane=3:1) to obtain 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(3-methoxypropyl)-N-(4-(trifluoromethoxy)benzyl)-1H-indole-2-carboxamide (212 mg, 0.32 mmol, 80%, white solid).

[1335] 1H NMR(300MHz,DMSO-d6)10.42(br,NH,1H),9.12-9.10(br,NH,1H),8.37-8.36(m,NH,1H),8.12(s,1H),7.52-7.43(m,6H),7.36-7.33(m,3H),7.15(s,1 H),4.57-4.51(m,2H),4.31-4.29(m,2H),4.31-4.29(m,2H),3.32-3.20(m ,2H),3.16(s,3H)2.50-2.39(m,1H),1.92-1.88(m,2H),1.05-1.02(m,6H).

[1336] Example 242: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-(3-methoxypropyl)-N-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxamide (Compound 242)

[1337] The title compound was obtained according to the same procedure as in Example 241, except using 4-(trifluoromethyl)benzylamine instead of 4-(trifluoromethoxy)benzylamine.

[1338] 1H NMR(300MHz,DMSO-d6)10.41(br,NH,1H),9.16(br,NH,1H),8.36(m,NH,1H),8.12(s,1 H),7.72-7.71(m,2H),7.58-7.54(m,2H),7.51-7.42(m,3H),7.42(m,1H),7.35-7.31(m 1H),7.16(s,1H),4.58-4.51(m,4H),4.31-4.29(m,2H),3.20-3.17(m,2H ),3.16(s,3H),2.50-2.39(m,1H),1.92-1.88(m,2H),1.05-1.02(m,6H).

[1339] Example 243: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-fluoro-3-(trifluoromethyl)benzyl)-1-(3-methoxypropyl)-1H-indole-2-carboxamide (Compound 243)

[1340] The title compound was obtained according to the same procedure as in Example 241, except using 4-fluoro-3-(trifluoromethyl)benzylamine instead of 4-(trifluoromethoxy)benzylamine.

[1341] 1H NMR(300MHz,DMSO-d6)10.42(br,NH,1H),9.15(br,NH,1H),8.36(m,NH,1H),8.12(s,1H),7.75-7.73(m,2H),7.55-7.40(m,6H),7.35-7.30(m,1 H),7.16(m,1H),4.58-4.53(m,4H),4.31-4.29(m,2H),3.20-3.17(m,2H ),3.13(s,3H),2.50-2.39(m,1H),1.92-1.86(m,2H),1.05-1.00(m,6H).

[1342] Example 244: Synthesis of 5-(2-chloro-5-(isobutyrylaminomethyl)benzylamino)-N-(2-fluoro-4-(trifluoromethyl)benzyl)-1-(3-methoxypropyl)-1H-indole-2-carboxamide (Compound 244)

[1343] The title compound was obtained according to the same procedure as in Example 241, except using 2-fluoro-4-(trifluoromethyl)benzylamine instead of 4-(trifluoromethoxy)benzylamine.

[1344] 1H NMR(300MHz,DMSO-d6)10.43(br,NH,1H),9.15(br,NH,1H),8.36(m,NH,1H),8.14(s,1H),7.75-7.62(m,3H),7.55-7.42(m,4H),7.37-7.33(m ,1H),7.18(m,1H),4.58(m,4H),4.31-4.29(m,2H),3.20-3.17(m,2H), 3.16(s,3H),2.50-2.39(m,1H),1.92-1.86(m,2H),1.05-1.00(m,6H).

[1345] Experimental Example 1: Inhibitory activity against mPGES-1

[1346] Microsomal fraction of A549 human lung cancer cells

[1347] A549 human lung cancer cells are cultivated in an incubator at 37°C and 5% CO2 in the DMEM culture medium supplemented with 100 units / mL penicillin-streptomycin and 10% FBS. After the cells are inoculated and cultivated in an incubator at 37°C and 5% CO2, cells are processed with IL-1 β (1ng / mL). After 48 hours of incubation, the cells are washed with PBS and reacted with 2mL of trypsin / EDTA for 5 minutes. And then by adding 3mL of DMEM to separate cells, collect by centrifugation for 5 minutes at 1,000rpm, and then washed twice with PBS. The cells prepared are resuspended in homogenizing buffer (0.1M potassium phosphate buffer, pH 7.4, 2.5mM glutathione, 0.25M sucrose) and incubated on ice for 10 minutes. The cells were then sonicated (3×20 s) and centrifuged at 1,000 g for 10 minutes and 174,000 g for 1 hour at 4° C. to obtain the microsomal fraction. The microsomal fraction was resuspended in 50 μL of homogenization buffer and subjected to protein quantification by Bradford assay.

[1348] Measurement of mPGES-1 enzyme activity

[1349] Test compound or DMSO are added in protein and reaction buffer (0.1M potassium phosphate buffer, 2.5mM GSH), to obtain the cumulative volume of 100 μ L and incubated on ice 15 minutes.When adding PGH2, reaction starts and after 2 minutes, adds the stop solution (40mM FeCl2, 80mM citric acid) of 100 μ L to complete the reaction.Measure PGE2 by PGE2 ELISA test kit and produce.

[1350] Measurement of PGE2

[1351] After inoculation of A549 human lung cancer cells, add samples of different concentrations 24 hours later. After 1 hour, add the IL-1 β of 1ng / mL. Cells are cultured for 48 hours and then culture supernatants are collected. PGE2 EIA test kit is used to measure the PGE2 of the supernatant collected according to the manufacturer's instructions.

[1352] The results are shown in Tables 1 and 2 below.

[1353] [Table 1]

[1354]

[1355]

[1356]

[1357] [Table 2]

[1358]

[1359]

[1360] As can be seen in Tables 1 and 2, the indolecarboxamide derivatives according to the present invention showed an excellent inhibitory effect on PGE2 production. In addition, the compounds according to the present invention showed an inhibitory effect on the mPGES-1 enzyme that was almost equal to that of the positive control GRC27864 (compound of formula (I)).

[1361] Experimental Example 2: Efficacy experiment using a guinea pig model of osteoarthritis induced by MIA (monosodium iodoacetate)

[1362] The following experiment was performed in order to evaluate the efficacy of the compounds according to the invention on osteoarthritis induced in guinea pigs.

[1363] Specifically, male guinea pigs weighing approximately 500 g ± 20% from Coretech Co., Ltd. (Gyeonggi-do, Korea) were acclimated in the laboratory for 8 days and provided with food and water ad libitum. Temperature (23 ± 3°C), humidity (55 ± 15%), and light / dark cycle (12 h, 08:00-20:00) were automatically controlled.

[1364] Each group consisted of 10 guinea pigs. Bayer AG, Germany, 2.5mg / kg) guinea pigs were anesthetized and depilated with scissors in the area around the right knee. Using a C-arm (ARCADIS Varic, SIEMENS Co.), it was confirmed that a syringe equipped with a 26-gauge needle was positioned in the articular cavity. 50 μL of MIA at a concentration of 60mg / mL was administered into the articular cavity. One week after MIA was administered, compound 9 of the present invention was added to vehicle (DMSO (10% by weight), Tween 80 (30% by weight), HMPC (same as the amount of the drug)), dissolved in water so that the total amount was 100% by weight, and orally administered to the prepared experimental animals at 10mg / kg and 25mg / kg, respectively. In the positive control group, 12.5mg / kg of GRC27864 was orally administered using the same vehicle, and only the vehicle was orally administered to the control group. Drug administration was carried out for 4 weeks.

[1365] Hindlimb disability test was performed for behavioral assessment weekly for 4 weeks, and inflammatory factors were evaluated by measuring PGE2, IL-1β, and TNF-α in the blood after 4 weeks.

[1366] The hindlimb weight bearing ratio was obtained by placing the animal at a 60-degree inclination in a plastic space, using an incapacitator, measuring the strength applied to each hindlimb within 10 seconds and calculating the average value. The results are shown in Tables 3 and 4 below. Figure 1 The normal weight-bearing ratio is 50%, and when the disease is induced, the weight-bearing ratio is as high as nearly 30%.

[1367] [Table 3]

[1368]

[1369]

[1370] Since inflammation continued to be induced in the control group administered only with the vehicle, the weight-bearing ratio decreased to 34.57±1.49% after 4 weeks. However, it was confirmed that the weight-bearing ratios of the GRC27864-administered group and the Compound 9-administered group did not deteriorate but were maintained after MIA administration.

[1371] After 4 weeks, the concentrations of PGE2, IL-1β and TNF-α in the blood were measured using commercially available ELISA kits. The results are shown in Tables 4 and Figures 2 to 4 ***, **, and * indicate statistical significance compared to the control group, and are P < 0.001, P < 0.01, and P < 0.05 compared to the control group.

[1372] [Table 4]

[1373]

[1374] Comparison of the inhibitory ability against inflammatory factors among the control group administered with vehicle alone, the group administered with GRC27864, and the group administered with compound 9 (25 mpk) revealed that the group administered with compound 9 (25 mpk) suppressed inflammatory factors more than the group administered with GRC27864.

[1375] Experimental Example 3: Anti-pain efficacy test using acetic acid-induced abdominal contraction mouse model

[1376] In order to evaluate the antinociceptive efficacy of the compounds according to the present invention in abdominal contraction mice, the experiment was performed as follows.

[1377] Specifically, male ICR mice weighing approximately 20 to 25 g from Orient Bio Co., Ltd. (Gyeonggi-do, Korea) were acclimated in the laboratory for 7 days and provided with food and water ad libitum. Temperature (20 ± 2°C), humidity (40 ± 60%), and light / dark cycle (12 h) were automatically controlled.

[1378] Based on 10 mice / group, the control group was orally administered with vehicle (200 μL), and the positive control group was orally administered with 25 mg / kg of celecoxib. Compound 9 of the present invention was dissolved in vehicle (10% NMP (N-methyl-2-pyrrolidone), 10% ethanol, 80% polyethylene glycol 400) and orally administered to each mouse at 10 and 50 mg / kg. One hour after drug administration, 0.7% acetic acid was injected intraperitoneally at 10 mg / kg to induce pain. After acetic acid administration, the number of twisting movements was measured from 10 minutes onwards for 10 minutes. The results were as follows: Figure 5 Shown in.

[1379] In this experiment, the fewer the number of twists within 10 minutes, the stronger the anti-analgesic effect of the drug was. Statistical significance compared with the control group is expressed as **P<0.01, *P<0.05. Figure 5 As seen in the results, the celecoxib-administered group and the compound 9-administered group showed significantly fewer writhing times than the control group, and celecoxib (25 mg / kg) and compound 9 (10 mg / kg) showed similar pain inhibitory effects.

Claims

1. An indolecarboxamide derivative having formula (II) or a pharmaceutically acceptable salt thereof: in, R 1 is a phenyl group substituted with a C1-C6 haloalkoxy group; L does not exist; R 2 It is hydrogen; Y 1 and Y 2 is C=O; and R 3 It is a C1-C6 alkyl group.

2. The indolecarboxamide derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein the indolecarboxamide derivative is a compound having formula (II-1): in, R 1 is a phenyl group substituted with a C1-C6 haloalkoxy group; L does not exist; R 2 It is hydrogen; Y 1 and Y 2 is C=O; and R 3 It is a C1-C6 alkyl group.

3. The indolecarboxamide derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein the indolecarboxamide derivative is a compound having formula (II-2): in, R 1 is a phenyl group substituted with a C1-C6 haloalkoxy group; L does not exist; R 2 It is hydrogen; Y 1 and Y 2 is C=O; and R 3 It is a C1-C6 alkyl group.

4. The indolecarboxamide derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 1 It is a phenyl group substituted by a trifluoromethoxy group.

5. The indolecarboxamide derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 1 is a phenyl group substituted with a trifluoromethoxy group; L is absent; R 2 is hydrogen; Y 1 and Y 2 is C=O; and R 3 It is methyl, ethyl, n-propyl, isopropyl, and n-butyl.

6. The indolecarboxamide derivative or a pharmaceutically acceptable salt thereof according to claim 1, which is selected from the group consisting of the following compounds: 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-N-(4-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (Compound 9); 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-N-(2-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (Compound 15); 5-(2-Chloro-5-(isobutyrylaminomethyl)benzamido)-1-ethyl-N-(4-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (Compound 134); 5-(2-Chloro-5-(isobutyrylaminomethyl)benzamido)-1-ethyl-N-(3-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (Compound 140); 5-(2-Chloro-5-(isobutyrylaminomethyl)benzamido)-1-propyl-N-(4-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (Compound 157); 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-propyl-N-(3-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (Compound 158); 1-Butyl-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(4-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (Compound 172); 1-Butyl-5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-N-(3-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (Compound 173); 5-(2-Chloro-5-(isobutyrylaminomethyl)benzamido)-1-isopropyl-N-(4-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (Compound 180); 5-(2-chloro-5-(isobutyrylaminomethyl)benzamido)-1-isopropyl-N-(3-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (Compound 181); and 6-(2-Chloro-5-(isobutyrylaminomethyl)benzamido)-1-methyl-N-(4-(trifluoromethoxy)phenyl)-1H-indole-2-carboxamide (Compound 239).

7. A pharmaceutical composition for inhibiting microsomal prostaglandin E2 synthase-1 (mPGES-1), comprising the indolecarboxamide derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6 and a pharmaceutically acceptable carrier.

8. The pharmaceutical composition according to claim 7, which is used for treating or preventing inflammation, arthritis, high fever, pain, cancer, stroke or Alzheimer's disease.

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