Title of Invention: Method for preparing indole or indazole compound
technical field
[One]
Cross Citation with Related Applications
[2]
This application claims the benefit of priority based on Korean Patent Application No. 10-2019-0073019 dated June 19, 2019, and all contents disclosed in the literature of the Korean patent application are incorporated as a part of this specification.
[3]
technical field
[4]
The present invention relates to a method for preparing an indole or indazole compound containing an amine group as an intermediate structure necessary for synthesizing a pharmaceutically useful indole or indazole compound.
background
[5]
Numerous research results have been reported on compounds having an indole structure as the parent nucleus. For example, patent WO2006/112549 reporting activity against glucokinase, and patent WO1995/007276 reporting useful as an antitumor and cardiovascular inhibitory agent. , and patent WO2004/018428, which reports that it can be used as an antibiotic, are representative.
[6]
Among them, the present invention relates to a method for preparing an indole or indazole compound containing an amine group as an intermediate structure necessary to obtain an indole or indazole compound exhibiting a preventive or therapeutic and ameliorating effect on cell necrosis and related diseases. .
[7]
Conventionally, a method for preparing an indole or indazole compound containing an amine group as the intermediate structure from an indole or indazole compound containing a nitro group using an iron (Fe) catalyst has been used.
[8]
However, in this case, when the particle size of iron (Fe) is varied, stirring is not smooth during the reaction, or the reaction time is long, problems such as a decrease in yield due to impurities generated in the reaction occurred. In addition, the reactor was coated with iron oxide produced after the reaction, and there was a difficulty due to the cost and time required to wash it.
[9]
Accordingly, there is a need for development of a new method capable of resolving problems caused by using a conventional iron (Fe) catalyst and producing an indole or indazole compound containing an amine group economically in terms of cost.
DETAILED DESCRIPTION OF THE INVENTION
technical challenge
[10]
The present invention is a method for producing an indole or indazole compound containing an amine group from an indole or indazole compound containing a nitro group, solving the problems of the conventional method using an iron (Fe) catalyst, and economically in terms of cost An object of the present invention is to provide a method for preparing an indole or indazole compound containing an amine group.
means of solving the problem
[11]
One aspect of the present invention provides a method for preparing a compound represented by the following formula (1), comprising reducing the compound represented by the following formula (2) in the presence of iron (III) chloride hydrate:
[12]
[Formula 1]
[13]

[14]
In Formula 1,
[15]
n is an integer from 1 to 3,
[16]
m is 0 or 1,
[17]
A represents C 3 -C 8 -cycloalkyl, phenyl or 5 to 6 membered heteroaryl or heterocycle comprising 1 or 2 heteroatoms each selected from N, O and S atoms,
[18]
X represents C or N, with the proviso that when X is N, m is 0 and when X is C, m is 1,
[19]
R 1 represents hydrogen, C 1 -C 6 -alkyl or —(CH 2 ) r NR 9 R 10 , wherein r is an integer from 2 to 5, and R 9 and R 10 are each independently hydrogen or C 1 -C 3 -alkyl, with the proviso that when X is N R 1 is hydrogen,
[20]
R 2 represents hydrogen, halogen or C 1 -C 6 -alkoxy, or -(CH 2 ) p C(O) 2 R 9 , -(CH 2 ) p OR 9 , -(CH 2 ) p NR 9 R 10 , -NHR 11 , -N(H)S(O) 2 R 9 or -NHC(O) 2 R 11 , or the heterocycle moiety represents 1 or 2 heteroatoms selected from N, O and S atoms A 5- to 6-membered ring comprising -(CH 2 ) Represents p -heterocycle- R 11 , wherein p is an integer from 0 to 3, R 9 and R 10 are as defined above, R 11 is hydrogen, oxo, C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -alkoxy or C 1 -C 6 -alkyl or 5 to 6 membered heterocycle comprising 1 or 2 nitrogen atoms as heteroatoms,
[21]
R 3 represents hydrogen, halogen, C 1 -C 6 -alkyl or phenyl, or -(CH 2 ) q - wherein the heterocycle contains 1 or 2 heteroatoms selected from N and O atoms and is a 5 to 6 membered ring heterocycle, wherein q is an integer from 1 to 3 with the proviso that when X is N R 3 is hydrogen or phenyl,
[22]
R 4 represents -Y 1 R 12 , wherein Y 1 is a direct bond or represents -(CR 9 R 10 ) s Y 2 -, where s is an integer from 0 to 3, R 9 and R 10 are As defined, Y 2 is selected from the group consisting of -O-, -C(O)- and -C(O)O-,
[23]
R 12 is selected from the group consisting of hydrogen, halogen, C 1 -C 6 -alkyl and —(CH 2 ) t B 1 -R 13 , t is an integer from 0 to 3, and B 1 is N, O and S It contains 1 or 2 heteroatoms selected from atoms and represents a 5 to 6 membered heterocycle or C 6 -C 10 -aryl, R 13 is hydrogen, cyano, halogen, hydroxy, oxo, thiol, carboxy or carboxy -C 1 -C 6 -alkyl, with the proviso that when X is N then R 4 represents hydrogen or C 1 -C 6 -alkyl,
[24]
wherein alkyl, alkoxy, aryl, cycloalkyl, heterocycle and heteroaryl may be optionally substituted, the substituents being hydroxy, C 1 -C 6 -alkylamino, di(C 1 -C 6 -alkyl)amino, at least one selected from the group consisting of carboxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, carboxy-C 1 -C 6 -alkyl and oxo.
[25]
[Formula 2]
[26]

[27]
In Formula 2,
[28]
k is an integer from 1 to 3,
[29]
j is 0 or 1,
[30]
A' represents C 3 -C 8 -cycloalkyl, phenyl or 5 to 6 membered heteroaryl or heterocycle comprising 1 or 2 heteroatoms each selected from N, O and S atoms,
[31]
X' represents C or N, with the proviso that when X' is N, j is 0 and when X' is C, j is 1,
[32]
R 5 represents hydrogen, C 1 -C 6 -alkyl or —(CH 2 ) e NR 14 R 15 , wherein e is an integer from 2 to 5, and R 14 and R 15 are each independently hydrogen or C 1 -C 3 -alkyl, with the proviso that when X' is N R 5 is hydrogen,
[33]
R 6 represents hydrogen, halogen or C 1 -C 6 -alkoxy, or -(CH 2 ) f C(O) 2 R 14 , -(CH 2 ) f OR 14 , -(CH 2 ) f NR 14 R 15 , -NHR 16 , -N(H)S(O) 2 R 14 or -NHC(O) 2 R 16 , or the heterocycle moiety is selected from N, O and S atoms 1 or 2 heteroatoms A 5- to 6-membered ring comprising -(CH 2 ) Represents f -heterocycle- R 16 , wherein f is an integer from 0 to 3, R 14 and R 15 are as defined above, R 16 is hydrogen, oxo, C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -alkoxy or C 1 -C 6 -alkyl or 5 to 6 membered heterocycle comprising 1 or 2 nitrogen atoms as heteroatoms,
[34]
R 7 represents hydrogen, halogen, C 1 -C 6 -alkyl or phenyl, or the heterocycle contains 1 or 2 heteroatoms selected from N and O atoms and is a 5 to 6 membered ring -(CH 2 ) g - heterocycle, wherein g is an integer from 1 to 3 with the proviso that when X' is N R 7 is hydrogen or phenyl,
[35]
R 8 represents -Y 3 R 17 , where Y 3 is a direct bond or represents -(CR 14 R 15 ) h Y 4 -, where h is an integer from 0 to 3, and R 14 and R 15 are As defined, Y 4 is selected from the group consisting of -O-, -C(O)- and -C(O)O-,
[36]
R 17 is selected from the group consisting of hydrogen, halogen, C 1 -C 6 -alkyl and —(CH 2 ) i B 2 -R 18 , i is an integer from 0 to 3, and B 2 is N, O and S Represents a 5-6 membered heterocycle containing 1 or 2 heteroatoms selected from atoms or represents C 6 -C 10 -aryl, R 18 is hydrogen, cyano, halogen, hydroxy, oxo, thiol, carboxy or carboxy -C 1 -C 6 -alkyl, with the proviso that when X′ is N R 8 represents hydrogen or C 1 -C 6 -alkyl,
[37]
wherein alkyl, alkoxy, aryl, cycloalkyl, heterocycle and heteroaryl may be optionally substituted, the substituents being hydroxy, C 1 -C 6 -alkylamino, di(C 1 -C 6 -alkyl)amino, at least one selected from the group consisting of carboxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, carboxy-C 1 -C 6 -alkyl and oxo.
Effects of the Invention
[38]
The method for producing an indole or indazole compound of the present invention can produce a desired indole or indazole compound in a consistently excellent yield by solving the problems of the conventional iron (Fe) catalyst, and is much better than iron (Fe). Since it uses cheap iron(III) chloride hydrate, it is economical in terms of cost.
Best mode for carrying out the invention
[39]
Hereinafter, the present invention will be described in more detail to help the understanding of the present invention.
[40]
The terms or words used in the present specification and claims should not be construed as being limited to their ordinary or dictionary meanings, and the inventor may properly define the concept of the term in order to best describe his invention. Based on the principle that there is, it should be interpreted as meaning and concept consistent with the technical idea of ​​the present invention.
[41]
In the definition of the substituent of the compound of formula (1) according to the present invention, the term 'alkyl' means an aliphatic hydrocarbon radical. Alkyl may be "saturated alkyl" containing no alkenyl or alkynyl moieties, or "unsaturated alkyl" containing at least one alkenyl or alkynyl moiety. "Alkenyl" refers to a group containing at least one carbon-carbon double bond, and "alkynyl" refers to a group containing at least one carbon-carbon triple bond. Alkyl, when used alone or in combination with alkoxy, may be branched or straight-chain, respectively.
[42]
Alkyl groups may have from 1 to 20 carbon atoms unless otherwise defined. The alkyl group may be a medium sized alkyl having from 1 to 10 carbon atoms. The alkyl group may be a lower alkyl having 1 to 6 carbon atoms. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, and the like. For example, C 1 -C 4 -alkyl has 1 to 4 carbon atoms in the alkyl chain and consists of methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and t-butyl. selected from the group.
[43]
The term 'alkoxy', unless otherwise defined, means alkyloxy having 1 to 10 carbon atoms.
[44]
The term 'cycloalkyl' means a saturated aliphatic 3-10 membered ring, unless otherwise defined. Typical cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
[45]
The term 'aryl' includes at least one ring having a shared pi electron system, for example monocyclic or fused-ring polycyclic (i.e., rings that share adjacent pairs of carbon atoms) groups. . That is, in the present specification, unless otherwise defined, aryl means a 4-10 membered, preferably 6-10 membered aromatic monocyclic or multicyclic ring including phenyl, naphthyl, and the like.
[46]
Unless otherwise defined, the term 'heteroaryl' includes 1 to 3 heteroatoms selected from the group consisting of N, O and S, and 3 to 10 membered aromatic that may be fused with benzo or C 3 -C 8 cycloalkyl. ring, preferably a 4 to 8 membered ring, more preferably a 5 to 6 membered ring. Examples of monocyclic heteroaryl include thiazole, oxazole, thiophene, furan, pyrrole, imidazole, isoxazole, isothiazole, pyrazole, triazole, triazine, thiadiazole, tetrazole, oxadia sol, pyridine, pyridazine, pyrimidine, pyrazine and the like. Examples of bicyclic heteroaryls include indole, indoline, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzisoxazole, benzthiazole, benzthiadiazole, benztriazole, quinoline, isoquinoline, purine. , puropyridine and a group similar thereto, but are not limited thereto.
[47]
The term 'heterocycle', unless otherwise defined, contains 1 to 3 heteroatoms selected from the group consisting of N, O and S, may be fused with benzo or C 3 -C 8 cycloalkyl, may be saturated or 1 or It means a 3-10 membered ring containing two double bonds, preferably a 4-8 membered ring, more preferably a 5-6 membered ring. Examples of heterocycles include pyrroline, pyrrolidine, imidazoline, imidazolidine, pyrazoline, pyrazolidine, pyran, piperidine, morpholine, thiomorpholine, piperazine, hydrofuran, and the like. However, it is not limited only to these.
[48]
Other terms and abbreviations used in this specification may be interpreted as meanings commonly understood by those skilled in the art to which the present invention belongs, unless otherwise defined.
[49]
[50]
The present invention relates to a method for preparing an indole or indazole compound containing an amine group, which is an intermediate structure necessary for synthesizing a pharmaceutically useful indole or indazole compound, in the presence of iron(III) chloride hydrate, Formula 2 Including the step of reducing the compound represented by, characterized in that to prepare a compound represented by the formula (1).
[51]
[52]
In the present invention, iron(III) chloride hydrate may be referred to as ferric chloride hexahydrate, ferric trichloride hexahydrate, Iron(III) chloride hexahydrate or ferric chloride hexahydrate, etc., and is represented by FeCl 3 6H 2 O do.
[53]
In the present invention, the yield and reproducibility of the reaction can be improved by using iron (III) chloride hydrate instead of the conventional iron (Fe) catalyst, and problems caused by products such as iron oxide coating the reactor can be solved. there is.
[54]
The reducing step in the present invention may be performed at a temperature of 0 to 65 ℃. Specifically, the reducing step may be performed at 5 to 30 °C, or 10 to 25 °C, and more specifically, at 20 to 25 °C.
[55]
The reducing step may be performed by further including a reducing agent. Specifically, the reducing agent may be at least one selected from the group consisting of NaBH 4 , N 2 H 4 , 9-borabicyclo[3.3.1]nonane (9-BBN), BH 3 SMe 2 , and LiBH 4 . .
[56]
[57]
In addition, the preparation method of the present invention may further include the step of purifying the compound obtained after the reducing step, wherein the purification may be performed by a solid purification method.
[58]
Specifically, the solid purification may include the steps of filtering and washing the synthesized compound in any order, and in this case, water, a polar organic solvent, or a mixture thereof may be used for filtration and washing.
[59]
The polar organic solvent may specifically include at least one of alcohol and dichloromethane, and specifically, the alcohol may include at least one of methanol, ethanol, propanol, and butanol.
[60]
In addition, the filtering step is not particularly limited and may be performed in a conventional manner. For example, the filtering may be filtering using a silica or celite filter.
[61]
Hereinafter, Chemical Formulas 1 and 2 and related contents will be described in detail.
[62]
[Formula 1]
[63]

[64]
In Formula 1,
[65]
n is an integer from 1 to 3,
[66]
m is 0 or 1,
[67]
A represents C 3 -C 8 -cycloalkyl, phenyl or 5 to 6 membered heteroaryl or heterocycle comprising 1 or 2 heteroatoms each selected from N, O and S atoms,
[68]
X represents C or N, with the proviso that when X is N, m is 0 and when X is C, m is 1,
[69]
R 1 represents hydrogen, C 1 -C 6 -alkyl or —(CH 2 ) r NR 9 R 10 , wherein r is an integer from 2 to 5, and R 9 and R 10 are each independently hydrogen or C 1 -C 3 -alkyl, with the proviso that when X is N R 1 is hydrogen,
[70]
R 2 represents hydrogen, halogen or C 1 -C 6 -alkoxy, or -(CH 2 ) p C(O) 2 R 9 , -(CH 2 ) p OR 9 , -(CH 2 ) p NR 9 R 10 , -NHR 11 , -N(H)S(O) 2 R 9 or -NHC(O) 2 R 11 , or the heterocycle moiety represents 1 or 2 heteroatoms selected from N, O and S atoms A 5- to 6-membered ring comprising -(CH 2 ) Represents p -heterocycle- R 11 , wherein p is an integer from 0 to 3, R 9 and R 10 are as defined above, R 11 is hydrogen, oxo, C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -alkoxy or C 1 -C 6 -alkyl or 5 to 6 membered heterocycle comprising 1 or 2 nitrogen atoms as heteroatoms,
[71]
R 3 represents hydrogen, halogen, C 1 -C 6 -alkyl or phenyl, or -(CH 2 ) q - wherein the heterocycle contains 1 or 2 heteroatoms selected from N and O atoms and is a 5 to 6 membered ring heterocycle, wherein q is an integer from 1 to 3 with the proviso that when X is N R 3 is hydrogen or phenyl,
[72]
R 4 represents -Y 1 R 12 , wherein Y 1 is a direct bond or represents -(CR 9 R 10 ) s Y 2 -, where s is an integer from 0 to 3, R 9 and R 10 are As defined, Y 2 is selected from the group consisting of -O-, -C(O)- and -C(O)O-,
[73]
R 12 is selected from the group consisting of hydrogen, halogen, C 1 -C 6 -alkyl and —(CH 2 ) t B 1 -R 13 , t is an integer from 0 to 3, and B 1 is N, O and S It contains 1 or 2 heteroatoms selected from atoms and represents a 5 to 6 membered heterocycle or C 6 -C 10 -aryl, R 13 is hydrogen, cyano, halogen, hydroxy, oxo, thiol, carboxy or carboxy -C 1 -C 6 -alkyl, with the proviso that when X is N then R 4 represents hydrogen or C 1 -C 6 -alkyl,
[74]
wherein alkyl, alkoxy, aryl, cycloalkyl, heterocycle and heteroaryl may be optionally substituted, the substituents being hydroxy, C 1 -C 6 -alkylamino, di(C 1 -C 6 -alkyl)amino, at least one selected from the group consisting of carboxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, carboxy-C 1 -C 6 -alkyl and oxo.
[75]
[Formula 2]
[76]

[77]
In Formula 2,
[78]
k is an integer from 1 to 3,
[79]
j is 0 or 1,
[80]
A' represents C 3 -C 8 -cycloalkyl, phenyl or 5 to 6 membered heteroaryl or heterocycle comprising 1 or 2 heteroatoms each selected from N, O and S atoms,
[81]
X' represents C or N, with the proviso that when X' is N, j is 0 and when X' is C, j is 1,
[82]
R 5 represents hydrogen, C 1 -C 6 -alkyl or —(CH 2 ) e NR 14 R 15 , wherein e is an integer from 2 to 5, and R 14 and R 15 are each independently hydrogen or C 1 -C 3 -alkyl, with the proviso that when X' is N R 5 is hydrogen,
[83]
R 6 represents hydrogen, halogen or C 1 -C 6 -alkoxy, or -(CH 2 ) f C(O) 2 R 14 , -(CH 2 ) f OR 14 , -(CH 2 ) f NR 14 R 15 , -NHR 16 , -N(H)S(O) 2 R 14 or -NHC(O) 2 R 16 , or the heterocycle moiety is selected from N, O and S atoms 1 or 2 heteroatoms A 5- to 6-membered ring comprising -(CH 2 ) Represents f -heterocycle- R 16 , wherein f is an integer from 0 to 3, R 14 and R 15 are as defined above, R 16 is hydrogen, oxo, C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -alkoxy or C 1 -C 6 -alkyl or 5 to 6 membered heterocycle comprising 1 or 2 nitrogen atoms as heteroatoms,
[84]
R 7 represents hydrogen, halogen, C 1 -C 6 -alkyl or phenyl, or the heterocycle contains 1 or 2 heteroatoms selected from N and O atoms and is a 5 to 6 membered ring -(CH 2 ) g - heterocycle, wherein g is an integer from 1 to 3 with the proviso that when X' is N R 7 is hydrogen or phenyl,
[85]
R 8 represents -Y 3 R 17 , where Y 3 is a direct bond or represents -(CR 14 R 15 ) h Y 4 -, where h is an integer from 0 to 3, and R 14 and R 15 are As defined, Y 4 is selected from the group consisting of -O-, -C(O)- and -C(O)O-,
[86]
R 17 is selected from the group consisting of hydrogen, halogen, C 1 -C 6 -alkyl and —(CH 2 ) i B 2 -R 18 , i is an integer from 0 to 3, and B 2 is N, O and S Represents a 5-6 membered heterocycle containing 1 or 2 heteroatoms selected from atoms or represents C 6 -C 10 -aryl, R 18 is hydrogen, cyano, halogen, hydroxy, oxo, thiol, carboxy or carboxy -C 1 -C 6 -alkyl, with the proviso that when X′ is N R 8 represents hydrogen or C 1 -C 6 -alkyl,
[87]
wherein alkyl, alkoxy, aryl, cycloalkyl, heterocycle and heteroaryl may be optionally substituted, the substituents being hydroxy, C 1 -C 6 -alkylamino, di(C 1 -C 6 -alkyl)amino, at least one selected from the group consisting of carboxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, carboxy-C 1 -C 6 -alkyl and oxo.
[88]
[89]
Specifically, in Formula 1, R 1 may be hydrogen, C 1 -C 6 -alkyl, or di(C 1 -C 3 -alkyl)amino-C 2 -C 3 -alkyl.
[90]
In addition, the R 2 is hydrogen, halogen, carboxy, carboxy -C 1 -C 3 -alkyl, C 1 -C 3 -alkoxycarbonyl, C 1 -C 3 -alkoxycarbonyl-C 1 -C 3 -alkyl, hydroxy-C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy, -(CH 2 ) p NR 9 R 10 , -NHR 11 , -N(H)S ( O) 2 R 9　or -NHC(O) 2It may represent R 11 or -(CH 2 ) p -heterocycle-R 11 , wherein heterocycle, p, R 9 , R 10　and R 11 are as described above.
[91]
Furthermore, R 3 represents hydrogen, methyl or halogen, or represents phenyl optionally substituted by C 1 -C 3 -alkoxy, or the heterocycle comprises 1 or 2 heteroatoms selected from N and O atoms and 1 or heterocyclyl-C 1 -C 3 -alkylene, which is a 5 to 6 membered ring optionally substituted by two oxo groups.
[92]
In addition, Y 1 may be selected from the group consisting of a direct bond, -O-, -C(O)-, and -CH 2 C(O)-.
[93]
In addition, R 12 is hydrogen, methyl, ethyl, phenyl, fluoro, chloro, 2-carboxy-pyrrolidin-1-yl, pyrrolidin-1-yl, 4-acetic acid-1,3-thiazoline- 2-yl, -CH 2 -(1,1-dioxo-thiomorpholin-4-yl) and -CH 2 -(2-oxopiperazin-4-yl).
[94]
[95]
In addition, in Formula 2, R 5 may be hydrogen, C 1 -C 6 -alkyl, or di(C 1 -C 3 -alkyl)amino-C 2 -C 3 -alkyl.
[96]
In addition, R 6 is hydrogen, halogen, carboxy, carboxy -C 1 -C 3 -alkyl, C 1 -C 3 -alkoxycarbonyl, C 1 -C 3 -alkoxycarbonyl-C 1 -C 3 -alkyl, hydroxy-C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy, -(CH 2 ) f NR 14 R 15 , -NHR 16 , -N(H)S( O) 2 R 14 or -NHC(O) 2It may represent R 16 or -(CH 2 ) f -heterocycle-R 16 , wherein heterocycle, f, R 14 , R 15　and R 16 are as described above.
[97]
Furthermore, R 7 represents hydrogen, methyl or halogen, or phenyl optionally substituted by C 1 -C 3 -alkoxy, or the heterocycle comprises 1 or 2 heteroatoms selected from N and O atoms and 1 or heterocyclyl-C 1 -C 3 -alkylene, which is a 5 to 6 membered ring optionally substituted by two oxo groups.
[98]
In addition, Y 3 may be selected from the group consisting of a direct bond, -O-, -C(O)-, and -CH 2 C(O)-.
[99]
In addition, R 17 is hydrogen, methyl, ethyl, phenyl, fluoro, chloro, 2-carboxy-pyrrolidin-1-yl, pyrrolidin-1-yl, 4-acetic acid-1,3-thiazoline- 2-yl, -CH 2 -(1,1-dioxo-thiomorpholin-4-yl) and -CH 2 -(2-oxopiperazin-4-yl).
[100]
[101]
In addition, the compound represented by Formula 1 may be represented by the following Formula (1a) or (1b):
[102]
[Formula 1a]
[103]

[104]
[Formula 1b]
[105]

[106]
In the above formula, n, A, R 1 , R 2 , R 3 and R 4 are as defined above.
[107]
[108]
In addition, the compound represented by Formula 2 may be represented by the following Formula (2a) or (2b):
[109]
[Formula 2a]
[110]

[111]
[Formula 2b]
[112]

[113]
In the above formula, k, A', R 5 , R 6 , R 7 and R 8 are as defined above.
[114]
[115]
As an example, the compound represented by Formula 1 or Formula 1a is (4-((7-amino-2-phenyl-1H-indol-5-yl)methyl)thiomorpholine 1,1-dioxide, 2 or the compound represented by Formula 2a may be (4-((7-nitro-2-phenyl-1H-indol-5-yl)methyl)thiomorpholine 1,1-dioxide.
[116]
[117]
In addition, in the present invention, the compound of Formula 2 may be prepared using a conventionally known method.
[118]
In the case of an indole compound in which X is C, a compound having a simple substituent (7-nitro-indole, 2,3-dimethyl-7-nitro-indole, etc.) can be purchased commercially, and most of the compounds are compounds of Scheme 1 below ( It can be synthesized by cyclizing the acetylene intermediate as in 8). In addition, compound (8) can be synthesized from a halobenzene compound (6) and an acetylene compound (7) through a linking reaction.
[119]
[Scheme 1]
[120]

[121]
In Scheme 1 above
[122]
R 6* represents (R 6 )kA′-, and k, A′, R 6 and R 8 are as defined above,
[123]
Q represents iodine or bromine.
[124]
In order to obtain the compound of Formula 2 having a preferred R 8 functional group, additional steps for substituting the R 8 functional group in the compound (2-1) with the preferred R 8 functional group may be performed, which is a conventionally known method. Or it may be a novel method, and is not particularly limited thereto.
[125]
The compound (2-1) can be prepared by cyclization of the acetylene compound (8) in the presence of a base such as KOBut, K 2 CO 3 , DBU, or a metal catalyst such as CuI and Pd(II).
[126]
The preparation of the acetylene compound (8) can be performed by adding a base in the presence of a metal catalyst, and Pd(II), Cu(I), etc. are used as the metal catalyst, and Et 3 N, Et 2 N (iPr ) are used as the base. ), DBU, N-methyl-morpholine, methyl-pyrrolidine, K 2 CO 3 and the like are used.
[127]
The acetylene compound (7) is commercially available, or the literature [Synthesis, 2004 59-61; Bioorganic & Medicinal Chemistry, 13, 2005, 197-209; Journal of Organic Chemistry, 71, 2006, 167-175] can be prepared through a coupling reaction of Pd(II) or Cu(I) with acetylene in the presence of a base according to a known method. Acetylene used is trimethylsilylacetylene or 2-methyl-3-butyn-2-ol, and the base used is diethylamine, triethylamine, diisopropylethyl amines, etc.
[128]
The halobenzene compound (6) can be synthesized using iodine or bromine from the nitroaniline compound (13) as shown in Scheme 2 below.
[129]
[Scheme 2]
[130]

[131]
In Scheme 2, R 8 is as defined above.
[132]
The nitroaniline compound (13) is commercially available, or can be synthesized from commercially available nitro compound (11) or aniline compound (12) through acetylation, nitration and deacetylation reactions. The aniline compound (12), which is difficult to obtain commercially, can be synthesized from the nitro compound (11). Likewise, the nitro compound (11) is also commercially available or can be synthesized from the 4-fluoro-nitrobenzene compound (9). there is. Compound (10) of formula R 8 -H in Scheme 2 refers to commercially available alcohols and amines.
[133]
The halogenated material for preparing compound (6) may be selected from iodine, bromine, iodine monobromide and iodine monochloride, and silver ions, for example, silver nitrate (AgNO 3 ), silver carbonate (AgCO 3 ), Silver sulfate (Ag 2 SO 4 ) and the like may be used together.
[134]
Conventional acetylation and nitration reactions can be used to obtain compound (13) from compound (12). The nitration reaction may be performed using nitric acid as a stock solution at a low temperature (-15 to 0° C.), or may be used together with various solvents, for example, dichloroethane or dichloromethane. In addition, the reduction reaction of the nitro group can be carried out using an acid catalyst and a metal, or by using a metal catalyst in the presence of hydrogen gas. As the metal, iron, zinc, lithium, sodium, and tin (usually, tin chloride) may be used, and as the acid catalyst, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and the like; organic carboxylic acids such as acetic acid and trifluoroacetic acid; Or ammonium chloride may be used. In addition, as a metal catalyst usable in a reduction reaction using a metal catalyst in the presence of hydrogen gas, palladium, nickel, platinum, ruthenium, rhodium, etc. may be mentioned, and in this case, the pressure of hydrogen gas is usually 1 to 3 atmospheres.
[135]
[136]
Furthermore, the present invention relates to a method for preparing a compound represented by the following formula (3), comprising reacting the compound represented by the formula (1) with a ketone or an aldehyde:
[137]
[Formula 3]
[138]

[139]
In Formula 3,
[140]
n' is an integer from 1 to 3,
[141]
m' is 0 or 1,
[142]
A" represents C 3 -C 8 -cycloalkyl, phenyl or 5 to 6 membered heteroaryl or heterocycle comprising 1 or 2 heteroatoms each selected from N, O and S atoms,
[143]
X" represents C or N, with the proviso that when X" is N, m' is 0 and when X" is C, m' is 1,
[144]
R 19 represents hydrogen, C 1 -C 6 -alkyl or —(CH 2 ) u NR 25 R 26 , wherein u is an integer from 2 to 5, and R 25 and R 26 are each independently hydrogen or C 1 -C 3 -alkyl, with the proviso that when X" is N R 19 is hydrogen,
[145]
R 20 represents hydrogen, halogen or C 1 -C 6 -alkoxy, or -(CH 2 ) v C(O) 2 R 25 , -(CH 2 ) v OR 25 , -(CH 2 ) v NR 25 R 26 , -NHR 27 , -N(H)S(O) 2 R 25 or -NHC(O) 2 R 27 , or the heterocycle moiety represents 1 or 2 heteroatoms selected from N, O and S atoms A 5- to 6-membered ring comprising -(CH 2 ) v -heterocycle-R 27 , wherein v is an integer from 0 to 3, R 25 and R 26 are as defined above, R 27 is hydrogen, oxo, C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -alkoxy or C 1 -C 6 -alkyl or 5 to 6 membered heterocycle comprising 1 or 2 nitrogen atoms as heteroatoms,
[146]
R 21 represents hydrogen, halogen, C 1 -C 6 -alkyl or phenyl, or -(CH 2 ) w - wherein the heterocycle contains 1 or 2 heteroatoms selected from N and O atoms and is a 5 to 6 membered ring heterocycle, wherein w is an integer from 1 to 3 with the proviso that when X" is N then R 21 is hydrogen or phenyl;
[147]
R 22 represents -Y 5 R 28 , wherein Y 5 is a direct bond or represents -(CR 25 R 26 ) x Y 6 -, where x is an integer from 0 to 3, R 25 and R 26 are As defined, Y 6 is selected from the group consisting of -O-, -C(O)- and -C(O)O-,
[148]
R 28 is selected from the group consisting of hydrogen, halogen, C 1 -C 6 -alkyl and —(CH 2 ) y B 3 -R 29 , y is an integer from 0 to 3, and B 3 is N, O and S It contains 1 or 2 heteroatoms selected from atoms and represents a 5 to 6 membered heterocycle or C 6 -C 10 -aryl, R 29 is hydrogen, cyano, halogen, hydroxy, oxo, thiol, carboxy or carboxy -C 1 -C 6 -alkyl, with the proviso that when X″ is N then R 22 represents hydrogen or C 1 -C 6 -alkyl,
[149]
R 23 represents hydrogen, C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, heterocycle or heterocyclyl-C 1 -C 6 -alkyl, wherein the heterocycle is selected from N and O atoms a 3 to 8 membered ring containing 1 to 3 heteroatoms, with the proviso that when X" is N, R 23 is hydrogen,
[150]
R 24 represents -(CR 25 R 26 ) o -ZDWR 30 , Z represents a direct bond or is selected from the group consisting of -C(O)- and -C(O)O-, and D represents a direct bond or represents C 4 -C 6 -cycloalkyl or 5 to 6 membered heteroaryl comprising 1 or 2 N atoms or contains 1 or 2 heteroatoms selected from N, O and S atoms represents a 5 to 6 membered heterocycle, W represents a direct bond or -NR 25 -, -C(O)-, -C(O)O-, -C(O)NR 31 - or -S(O ) ) z -, R 31 is hydrogen, C 1 -C 3 -alkyl or C 6 -C 10-aryl, z is an integer of 1 or 2, o is an integer of 0 to 3, R 25 and R 26 are as defined above, R 30 is hydrogen, hydroxy, C 1 -C 6 -alkyl, 5 to 6 membered heterocycle comprising 1 to 3 heteroatoms selected from N, O and S atoms, or C 6 -C 10 -ar-C 1 -C 6 -alkyl,
[151]
with the proviso that when X" is N, R 24 represents C 4 -C 6 -cycloalkyl or a 5 to 6 membered heterocycle comprising 1 or 2 heteroatoms selected from N, O and S atoms,
[152]
wherein alkyl, alkoxy, aryl, cycloalkyl, heterocycle and heteroaryl may be optionally substituted, the substituents being hydroxy, C 1 -C 6 -alkylamino, di(C 1 -C 6 -alkyl)amino, at least one selected from the group consisting of carboxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, carboxy-C 1 -C 6 -alkyl and oxo.
[153]
[154]
It should be understood that the compound of Formula 3 includes pharmaceutically acceptable salts and isomers thereof. For convenience of explanation, in the present specification, these are simply expressed as a compound of Formula 3.
[155]
As used herein, "pharmaceutically acceptable salt" refers to acids that form non-toxic acid addition salts containing pharmaceutically acceptable anions, for example, inorganic acids such as sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, and the like; organic carboxylic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicylic acid and the like; and acid addition salts formed with sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid and the like. Also, pharmaceutically acceptable base addition salts such as alkali metal or alkaline earth metal salts formed with lithium, sodium, potassium, calcium, magnesium and the like; amino acid salts such as lysine, arginine, and guanidine; organic salts such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, diethanolamine, choline, triethylamine, and the like. The compound of Formula 3 according to the present invention can be converted into a salt thereof by a conventional method, and the preparation of the salt can be easily performed by those skilled in the art based on the structure of Formula 3 without a separate explanation.
[156]
In addition, as used herein, the term 'isomer' refers to a compound having the same chemical formula or molecular formula, but optically or sterically different, or a salt thereof. Since the compound of Formula 3 according to the present invention may have an asymmetric carbon center, it may exist as an optical isomer (R or S isomer), a racemate, a diastereomer mixture, an individual diastereomer, etc., and if it has a double bond , geometric isomers (trans, cis isomers) may also exist. All these isomers and mixtures thereof are also included within the scope of the present invention.
Modes for carrying out the invention
[157]
Hereinafter, the present invention will be described in more detail by way of Examples. However, the following examples are provided to illustrate the present invention, and the scope of the present invention is not limited thereto.
[158]
Example
[159]
Preparation Example 1
[160]
Synthesis of (4-((7-nitro-2-phenyl-1H-indol-5-yl)methyl)thiomorpholine 1,1-dioxide)
[161]
1) Synthesis of (4-amino-3-iodo-5-nitrobenzoic acid)
[162]
Commercially purchased (4-amino-3-nitrobenzoic acid) (Sinochem Ningbo Corporation) (5.0 kg), NIS (N-Iodosuccinimide, 9.3 kg), H 2 SO 4 (0.50 kg) and THF (25.0 L) were prepared at room temperature. After input and stirring in the reactor, the temperature of the reactor was heated to 80 °C, and then stirred for 2 hours. Thereafter, the reaction was terminated when the result of analyzing the reaction solution by HPLC was 5.0% or less of the peak of (4-amino-3-nitrobenzoic acid).
[163]
After confirming the completion of the reaction, the temperature of the reactor was cooled to room temperature, and DCM (Dichloromethane, 50.0 L) was added to the concentrated solution obtained by distillation under reduced pressure to form a solid. The formed solid was stirred at room temperature for 1 hour, followed by filtration and washing [1st: DCM (40.0 L), 2nd: H 2 O (30.0 L), 3rd: EtOH/H 2 O= 3/7, 30.0 L] It was dried under N 2 pressure for 16 hours to synthesize (4-amino-3-iodo-5-nitrobenzoic acid) (7.6 kg, Yield: 89.8%, Purity: 96.4%).
[164]
1 H NMR (500 MHz, DMSO-d 6 ) δ 13.1 (br s, 1H), 8.52 (d, J=1.8 Hz, 1H) 8.36 (d, J=1.8 Hz, 1H), 7.50 (s, 2H).
[165]
[166]
2) Synthesis of (7-nitro-2-phenyl-1H-indole-5-carboxylic acid)
[167]
(4-amino-3-iodo-5-nitrobenzoic acid) (7.6 kg), TEA (Triethylamine, 7.5 kg), Phenylacetylene (3.0 kg) and 1,4-Dioxane (76.0 L) were put into the reactor at room temperature, After stirring, CuI [Copper(I) Iodide, 47.0 g] as a reaction catalyst and Pd(PPh 3 ) 2 Cl 2 (173.0 g) were added and the temperature of the reactor was heated to 60°C. The reaction mixture was stirred for 2 hours. After that, the reaction was terminated when the result of analyzing the reaction solution by HPLC was 1.0% or less of the peak of (4-amino-3-iodo-5-nitrobenzoic acid).
[168]
Thereafter, DBU (1,8-Diazabicyclo[5.4.0]undec-7-ene, 22.5 kg) was added to the reaction mixture, the temperature of the reactor was heated to 110° C., and the reaction was terminated after stirring for 18 hours. After the reaction mixture was cooled to room temperature, the pH was adjusted to 3 using a 3N-HCl aqueous solution (114.0 L), H 2 O (38.0 L) was added, and the mixture was stirred for 2 hours, followed by filtration and washing [1st: H 2 O (38.0 L), 2nd: EtOH/H 2 O= 3/7, 23.0 L] and dried under N 2 pressure for 16 hours (7-nitro-2-phenyl-1H-indole-5-carboxylic acid) ( 6.1 Kg, Yield: 87.4%, Purity: 98.0%) was synthesized.
[169]
1 H NMR (500 MHz, DMSO-d 6 ) δ 11.6 (s, 1H), 8.03 (s, 1H), 7.96 (m, 3H), 7.46 (t, J= 7.7 Hz, 2H) 7.36 (d, J= 7.3 Hz, 1H), 7.10 (s, 1H)
[170]
[171]
3) Synthesis of (7-nitro-2-phenyl-1H-indol-5-yl_methanol)
[172]
(7-Nitro-2-phenyl-1H-indole-5-carboxylic acid) (5.8 kg) and THF (61 L) were put into a reactor at room temperature, stirred, and then the reaction mixture was cooled to 12±2 ° C. 5 M BH 3 -DMS (12.3 L) was slowly added dropwise so that the internal temperature did not exceed 40°C. After the dropwise addition was completed and the temperature of the reactor was heated to 40° C., the reaction mixture was stirred for 2 hours. Thereafter, the reaction was terminated when the result of analyzing the reaction solution by HPLC was 1.0% or less of the peak of (7-nitro-2-phenyl-1H-indole-5-carboxylic acid).
[173]
After confirming the completion of the reaction, H 2 O (55 L) was slowly added dropwise to the reaction mixture, the layers were separated to store the organic layer, and the water layer was extracted with EtOAc (29 L), mixed with the stored organic layer, and distilled under reduced pressure. EtOH/H 2 O (6.1 L/12.2 L) was added to the obtained concentrate, stirred for 2 hours, and then filtered. After washing with a washing solution (EtOH/H 2 O = 1/3, 9.0 L), it was dried under N2 pressure for 16 hours (7-nitro-2-phenyl-1H-indol-5-yl methanol) (4.6 kg, Yield: 83.5%, Purity: 98.4%) was synthesized.
[174]
1 H NMR (500 MHz, DMSO-d 6 ) δ 11.6 (s, 1H), 8.07 (s, 1H), 8.00 (m, 3H), 7.49 (t, J= 7.7 Hz, 2H) 7.40 (d, J= 7.3 Hz, 1H), 7.14 (s, 1H), 5.42 (t, J= 6.7 Hz, 1H), 4.66 (d, J= 6.7 Hz, 2H).
[175]
[176]
4) Synthesis of 4-((7-nitro-2-phenyl-1H-indol-5-yl)methyl)thiomorpholine 1,1-dioxide
[177]
At room temperature, 7-nitro-2-phenyl-1H-indol-5-yl_methanol (4.6 kg) and THF (46 L) were added to the reactor and stirred, and after cooling the temperature of the reactor to 0° C., PBr 3 ( 2.8 kg) was added while the internal temperature of the reaction did not exceed 20 °C. After completion of the input, the temperature of the reactor was raised to 25° C., stirred for 1 hour, and sampled and analyzed when the result was 1.0% or less of the peak of 5-(hydroxymethyl)-7-nitro-2-phenyl-1H-indole. was terminated.
[178]
After confirming the completion of the reaction, the reaction mixture was cooled to 0 ° C, and 1,1-dioxothiomorpholine HCl (4.4 kg) and N,N-diisopropylethylamine (DIPEA) 8.0 kg) were added while the internal temperature of the reaction did not exceed 20 ° C. was put in. After completion of the input, the temperature of the reactor was raised to 50° C., stirred for 4 hours, and sampled. When the peak of 5-(bromomethyl)-7-nitro-2-phenyl-1H-indole was 1.0% or less, the reaction was terminated.
[179]
After confirming the completion of the reaction, the temperature of the reactor was cooled to 0° C., water (46.0 L) was added, followed by stirring, and the organic solvent was distilled under reduced pressure. After distillation under reduced pressure, ethyl acetate (EtOAc) (48.0 L) was further added, and the organic solvent was distilled again under reduced pressure, followed by 4-((7-nitro-2-phenyl-1H-indol-5-yl)methyl)thiomorpholine 1, 1-dioxide was obtained as a solid and then filtered. After washing with water (26.0 L) and ethanol (26.0 L), the crude 4-((7-nitro-2-phenyl-1H-indol-5-yl)methyl)thiomol was dried under N 2 pressure for 16 hours. Porin 1,1-dioxide (6.4 kg, Purity: 92.9%) was synthesized.
[180]
For purification, the above crude 4-((7-nitro-2-phenyl-1H-indol-5-yl)methyl)thiomorpholine 1,1-dioxide was added to a mixture of DMF (6.0 L) and toluene (60.0 L). After adding and stirring, the mixture was heated to 120° C. and stirred for 2 hours, then lowered to room temperature and stirred for an additional 2 hours. Toluene (60.0 L) was additionally added and stirred for an additional 2 hours, then the solid in the solution was filtered, washed with toluene (20.0 L), and 4-((7-nitro-2-phenyl-1H-indol-5-yl) Methyl) thiomorpholine 1,1-dioxide (5.1 kg, Yield: 77.0% overall, Purity: 98.4%) was synthesized.
[181]
1 H NMR (500 MHz, DMSO-d 6 ) δ 11.63 (s, 1H), 8.07 (s, 1H), 8.04 (m, 3H), 7.49 (t, J= 7.7 Hz, 2H) 7.38 (d, J= 7.3 Hz, 1H), 7.14 (s, 1H), 3.79 (s, 2H), 3.12 (m, 4H), 2.84 (m, 4H).
[182]
[183]
Example 1
[184]
Synthesis of (4-((7-amino-2-phenyl-1H-indol-5-yl)methyl)thiomorpholine 1,1-dioxide)
[185]
(4-((7-nitro-2-phenyl-1H-indol-5-yl)methyl)thiomorpholine 1,1-dioxide) of Preparation Example 1 (0.345 kg), THF/MeOH (2:1, 5.18 L) and FeCl 3 ·6H 2 O (2.4 g) were added to the reactor at room temperature, stirred for 30 minutes, and then cooled to 0 to 5°C. NaBH 4 (0.1 kg) was slowly added for 30 minutes, the temperature of the reactor was heated to 20 to 25 ℃, stirred for 2 hours, and the analysis result (4-((7-nitro-2-phenyl-1H-indole- The reaction was terminated at a time point below 0.5% PAR of the peak of 5-yl)methyl)thiomorpholine 1,1-dioxide).
[186]
After confirming the completion of the reaction, THF (1.73 L) and H 2 O (1.73 L) were added to the reaction mixture, stirred for 30 minutes, filtered through Celite, and washed with THF/H 2 O (1:1, 1.0 L). The filtrate was reduced pressure and THF was distilled to form a solid, and then the reaction mixture was stirred at room temperature for 2 hours. Filtration, washing with a washing solution [1st H 2 O: 1.73 L, 2nd EtOH/H 2 O= 1/3, 1.73 L], and drying under N 2 pressure for 16 hours, the title compound [0.31 kg (Yield: 97.53) %, Purity: 97.64% PAR)] was obtained.
[187]
1 H NMR (500 MHz, DMSO-d 6 ) δ 10.89 (s, 1H), 7.80 (m, 2H), 7.48 (t, J= 7.7 Hz, 2H) 7.30 (d, J= 7.3 Hz, 1H), 6.74 (m, 2H), 6.34 (s, 1H), 5.15 (s, 2H), 3.07 (m, 4H), 2.87 (m, 4H).
[188]
[189]
Comparative Example 1
[190]
Synthesis of (4-((7-amino-2-phenyl-1H-indol-5-yl)methyl)thiomorpholine 1,1-dioxide)
[191]
(4-((7-nitro-2-phenyl-1H-indol-5-yl)methyl)thiomorpholine 1,1-dioxide) of Preparation Example 1 (0.60 kg), THF/MeOH/H 2 O ( 1:1:1, 3.0 L) and NH 4 Cl (124 g) were added to the reactor at room temperature, and after stirring, Fe (480 g) was added. The temperature of the reactor was heated to 60 °C, stirred for 1 hour, and sampled and analyzed as a result of analysis (4-((7-nitro-2-phenyl-1H-indol-5-yl)methyl)thiomorpholine 1,1 -dioxide), the reaction was terminated at a point below 0.5% PAR of the peak.
[192]
After confirming the completion of the reaction, THF (3.0 L) was added to the reaction mixture, stirred for 10 minutes, filtered through Celite, and washed with THF/H 2 O (1:1, 3.0 L). The filtrate was reduced pressure, and THF and MeOH were distilled to form a solid, and then the reaction mixture was stirred at room temperature for 2 hours. Filtration, washing with a washing solution [1st H 2 O: 500 mL, 2nd EtOH/H 2 O= 1/3, 1.0 L], and drying under N 2 pressure for 16 hours, the title compound [0.45 kg (Yield: 81.3) %, Purity: 97.2% PAR)] was obtained.
[193]
[194]
From the above results, it can be confirmed that Example 1 of the present invention can obtain a compound of higher purity than Comparative Example 1 in excellent yield. Specifically, the indole compound of Example 1 had a yield of 97.53% and a purity of 97.64%, whereas the indole compound of Comparative Example 1 had a yield of 81.3% and a purity of 97.2%.
[195]
In addition, according to the embodiment of the present invention, there is no coating phenomenon in the reactor because there is no iron oxide generated after the reaction as described above, and the iron chloride (FeCl 3 ) hydrate used as a catalyst in the example is iron (Fe) of the comparative example. It is very economical in terms of cost because it is much cheaper than
Claims
[Claim 1]
A method for preparing a compound represented by the following formula (1) comprising reducing the compound represented by the following formula (2) in the presence of iron (III) chloride hydrate: [Formula 1] In Formula 1, n is 1 to is an integer of 3, m is 0 or 1, A represents C 3 -C 8 -cycloalkyl, phenyl, or 5 each containing 1 or 2 heteroatoms selected from N, O and S atoms to 6 membered heteroaryl or heterocycle, X represents C or N with the proviso that when X is N m is 0 and when X is C m is 1 and R 1 is hydrogen, C 1 -C 6 - alkyl or -(CH 2 ) r NR 9 R 10 , wherein r is an integer from 2 to 5, and R 9 and R 10 are each independently hydrogen or C 1 -C 3-alkyl, with the proviso that when X is N then R 1 is hydrogen and R 2 represents hydrogen, halogen or C 1 -C 6 -alkoxy, or —(CH 2 ) p C(O) 2 R 9 , — (CH 2 ) p OR 9 , -(CH 2 ) p NR 9 R 10 , -NHR 11 , -N(H)S(O) 2 R 9 or -NHC(O) 2 R 11or -(CH 2 ) p -heterocycle- R 11 , wherein the heterocycle moiety is a 5 to 6 membered ring containing 1 or 2 heteroatoms selected from N, O and S atoms , wherein p is 0 to 3, R 9 and R 10 are as defined above, and R 11 is hydrogen, oxo, C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -alkoxy or C 1 -C 6 -alkyl. represents or represents a 5 to 6 membered heterocycle comprising 1 or 2 nitrogen atoms as heteroatoms, R 3 represents hydrogen, halogen, C 1 -C 6 -alkyl or phenyl, or the heterocycle is N and O atoms -(CH) which contains 1 or 2 heteroatoms selected from and is a 5 to 6 membered ring 2 ) represents q -heterocycle, wherein q is an integer from 1 to 3, with the proviso that when X is N, R 3 is hydrogen or phenyl, R 4 represents -Y 1 R 12 , wherein Y 1 is It is a direct bond or represents -(CR 9 R 10 ) s Y 2 -, where s is an integer of 0 to 3, R 9 and R 10 are as defined above, and Y 2 is -O-, -C( O)- and -C(O)O-, R 12 is hydrogen, halogen, C 1 -C 6 -alkyl and -(CH 2 ) t B 1 -R 13 is selected from the group consisting of, t is an integer from 0 to 3, and B 1 represents a 5 to 6 membered heterocycle containing 1 or 2 heteroatoms selected from N, O and S atoms, or C 6 -C 10 -aryl, R 13 represents hydrogen, cyano, halogen, hydroxy, oxo, thiol, carboxy or carboxy -C 1 -C 6 -alkyl, with the proviso that when X is N, R 4 is hydrogen or C 1 -C 6 -alkyl, wherein alkyl, alkoxy, aryl, cycloalkyl, heterocycle and heteroaryl may be optionally substituted, the substituents being hydroxy, C 1 -C 6 -alkylamino, di(C 1 -C 6 -alkyl)amino, carboxy, C 1 -C 6-alkyl, C 1 -C 6 -alkoxy, carboxy-C 1 -C 6 -alkyl and at least one selected from the group consisting of oxo. [Formula 2] In Formula 2, k is an integer of 1 to 3, j is 0 or 1, A' represents C 3 -C 8 -cycloalkyl, phenyl, or each of N, O and represents a 5-6 membered heteroaryl or heterocycle comprising 1 or 2 heteroatoms selected from S atoms, and X' represents C or N, with the proviso that when X' is N, j is 0 and X' is C when j is 1 and R 5 represents hydrogen, C 1 -C 6 -alkyl or —(CH 2 ) e NR 14 R 15 , wherein e is an integer from 2 to 5, R 14 and R 15each independently represents hydrogen or C 1 -C 3 -alkyl, with the proviso that when X′ is N R 5 is hydrogen and R 6 represents hydrogen, halogen or C 1 -C 6 -alkoxy, or —(CH 2 ) f C(O) 2 R 14 , -(CH 2 ) f OR 14 , -(CH 2 ) f NR 14 R 15 , -NHR 16 , -N(H)S(O) 2 R 14 or -NHC (O) 2 R 16 or -(CH 2 ) f -heterocycle- R 16 , wherein the heterocycle moiety is a 5 to 6 membered ring comprising 1 or 2 heteroatoms selected from N, O and S atoms , wherein f is It is an integer from 0 to 3, R 14 and R 15 are as defined above, and R 16 is hydrogen, oxo, C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -alkoxy or C 1 -C 6 -alkyl or represents a 5 to 6 membered heterocycle containing 1 or 2 nitrogen atoms as a heteroatom, and R 7 is hydrogen, halogen, C 1 -C 6represents -alkyl or phenyl, or -(CH 2 ) g -heterocycle, wherein the heterocycle contains 1 or 2 heteroatoms selected from N and O atoms and is a 5 to 6 membered ring , wherein g is 1 to 3 an integer of, provided that when X' is N, R 7 is hydrogen or phenyl, and R 8 is -Y 3 R 17 , wherein Y 3 is a direct bond or -(CR 14 R 15 ) h Y 4 - where h is an integer from 0 to 3, R 14 and R 15 are as defined above, and Y 4 is -O-, -C(O)- and -C(O)O- from the group consisting of selected, R 17 is hydrogen, halogen, C 1 -C 6-alkyl and -(CH 2 ) i B 2 -R 18 , i is an integer from 0 to 3, B 2 contains 1 or 2 heteroatoms selected from N, O and S atoms; Represents a 5-6 membered heterocycle or C 6 -C 10 -aryl, R 18 represents hydrogen, cyano, halogen, hydroxy, oxo, thiol, carboxy or carboxy -C 1 -C 6 -alkyl, with the proviso that when X' is N, R 8 represents hydrogen or C 1 -C 6 -alkyl, wherein alkyl, alkoxy, aryl, cycloalkyl, heterocycle and heteroaryl may be optionally substituted, and the substituents are hydrogen roxy, C 1 -C 6 -alkylamino, di(C 1 -C 6 -alkyl)amino, carboxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, carboxy-C 1 -C 6 -alkyl and oxo.
[Claim 2]
The method according to claim 1, wherein the iron chloride hydrate is ferrous trichloride hexahydrate (FeCl 3 ·6H 2 O).
[Claim 3]
The method according to claim 1, wherein the reducing step is performed at a temperature of 0 to 65 °C.
[Claim 4]
The method according to claim 1, wherein the reducing step is performed by further comprising a reducing agent.
[Claim 5]
According to claim 4, wherein the reducing agent is NaBH 4 , N 2 H 4 , 9-borabicyclo [3.3.1] nonane (9-BBN), BH 3 SMe 2 , LiBH 4 One selected from the group consisting of The above manufacturing method.
[Claim 6]
According to claim 1, wherein the compound represented by Formula 1 is a preparation method represented by the following Formula (1a) or (1b): [Formula 1a] [Formula 1b] In the formula, n, A, R 1 , R 2 , R 3 and R 4 are as defined in claim 1.
[Claim 7]
The process according to claim 1, wherein R 1 represents hydrogen, C 1 -C 6 -alkyl or di(C 1 -C 3 -alkyl)amino-C 2 -C 3 -alkyl.
[Claim 8]
2. The method of claim 1, wherein R 2 is hydrogen, halogen, carboxy, carboxy -C 1 -C 3 -alkyl, C 1 -C 3 -alkoxycarbonyl, C 1 -C 3 -alkoxycarbonyl-C 1 -C 3 -alkyl, hydroxy-C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy, -(CH 2 ) p NR 9 R 10 , -NHR 11 , -N(H ) optionally substituted by one oxo group )S(O) 2 R 9　or -NHC(O) 2represents R 11 or -(CH 2 ) p -heterocycle-R 11 , wherein heterocycle, p, R 9 , R 10　and R 11 are as defined in claim 1 .
[Claim 9]
2 . The heteroatom according to claim 1 , wherein R 3 represents hydrogen, methyl or halogen, or phenyl optionally substituted by C 1 -C 3 -alkoxy, or the heterocycle is 1 or 2 heteroatoms selected from N and O atoms. A method for representing heterocyclyl-C 1 -C 3 -alkylene, which is a 5 to 6 membered ring comprising and optionally substituted with 1 or 2 oxo groups .
[Claim 10]
The method according to claim 1, wherein Y 1 is a direct bond, -O-, -C(O)-, and -CH 2 C(O)-.
[Claim 11]
2. The method of claim 1, wherein R 12 is hydrogen, methyl, ethyl, phenyl, fluoro, chloro, 2-carboxy-pyrrolidin-1-yl, pyrrolidin-1-yl, 4-acetic acid-1,3- Preparation selected from the group consisting of thiazolin-2-yl, -CH 2 -(1,1-dioxo-thiomorpholin-4-yl) and -CH 2 -(2-oxopiperazin-4-yl) method.
[Claim 12]
According to claim 1, wherein the compound represented by Formula 1 is (4-((7-amino-2-phenyl-1H-indol-5-yl)methyl)thiomorpholine 1,1-dioxide, and Formula 2 The compound represented by is (4-((7-nitro-2-phenyl-1H-indol-5-yl)methyl)thiomorpholine 1,1-dioxide.
[Claim 13]
A method for preparing a compound represented by the following formula (3) comprising reacting the compound represented by formula (1) prepared according to claim 1 with a ketone or an aldehyde: [Formula 3] In Formula 3, n' is 1 to 3 is an integer of, m' is 0 or 1, A" represents C 3 -C 8 -cycloalkyl, phenyl, or each containing 1 or 2 heteroatoms selected from N, O and S atoms 5 to 6 membered heteroaryl or heterocycle, X" represents C or N, with the proviso that when X" is N m' is 0, when X" is C m' is 1, R 19 is hydrogen, C 1 -C 6 -alkyl or —(CH 2 ) u NR 25 R 26 , wherein u is an integer from 2 to 5, and R 25 and R 26 are each independently hydrogen or C 1 -C 3-alkyl, with the proviso that when X″ is N R 19 is hydrogen and R 20 represents hydrogen, halogen or C 1 -C 6 -alkoxy, or —(CH 2 ) v C(O) 2 R 25 , -(CH 2 ) v OR 25 , -(CH 2 ) v NR 25 R 26 , -NHR 27 , -N(H)S(O) 2 R 25 or -NHC(O) 2 R 27or -(CH 2 ) v -heterocycle- R 27 , wherein the heterocycle moiety is a 5 to 6 membered ring comprising 1 or 2 heteroatoms selected from N, O and S atoms , wherein v is 0 to 3, R 25 and R 26 are as defined above, and R 27 is hydrogen, oxo, C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -alkoxy or C 1 -C 6 -alkyl. represents or represents a 5 to 6 membered heterocycle comprising 1 or 2 nitrogen atoms as heteroatoms, R 21 represents hydrogen, halogen, C 1 -C 6 -alkyl or phenyl, or the heterocycle is N and O atoms -(CH) which contains 1 or 2 heteroatoms selected from and is a 5 to 6 membered ring 2 ) represents w -heterocycle, wherein w is an integer from 1 to 3, with the proviso that when X" is N, R 21 is hydrogen or phenyl, R 22 represents -Y 5 R 28 , wherein Y 5 represents a direct bond or -(CR 25 R 26 ) x Y 6 -, wherein x is an integer of 0 to 3, R 25 and R 26 are as defined above, and Y 6 is -O-, -C (O)- and -C(O)O-, R 28 is hydrogen, halogen, C 1 -C 6 -alkyl and -(CH 2 ) y B 3 -R 29 is selected from the group consisting of, y is an integer from 0 to 3, and B 3 represents a 5 to 6 membered heterocycle containing 1 or 2 heteroatoms selected from N, O and S atoms, or C 6 -C 10 -aryl, R 29 represents hydrogen, cyano, halogen, hydroxy, oxo, thiol, carboxy or carboxy -C 1 -C 6 -alkyl, with the proviso that R 22 when X″ is N represents hydrogen or C 1 -C 6 -alkyl, R 23 is hydrogen, C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, heterocycle or heterocyclyl-C 1 -C 6-alkyl, wherein heterocycle is a 3 to 8 membered ring comprising 1 to 3 heteroatoms selected from N and O atoms, with the proviso that when X″ is N then R 23 is hydrogen and R 24 is - (CR 25 R 26 ) o represents -ZDWR 30 , Z represents a direct bond or is selected from the group consisting of -C(O)- and -C(O)O-, D represents a direct bond, or C 4 -C 6 -cycloalkyl or 5 to 6 membered heteroaryl containing 1 or 2 N atoms, or 5 to 6 containing 1 or 2 heteroatoms selected from N, O and S atoms represents a membered heterocycle, W represents a direct bond or -NR 25 -, -C(O)-, -C(O)O-, -C(O)NR 31 - or -S(O) z - Represent, R 31 is hydrogen, C 1 -C 3-alkyl or C 6 -C 10 -aryl, z is an integer of 1 or 2, o is an integer of 0 to 3, R 25 and R 26 are as defined above, R 30 is hydrogen, hydroxy, C 1 -C 6 -alkyl, 5 to 6 membered heterocycle comprising 1 to 3 heteroatoms selected from N, O and S atoms, or C 6 -C 10 -ar-C 1 -C 6 -alkyl However, when X" is N, R 24 represents C 4 -C 6 -cycloalkyl or a 5 to 6 membered heterocycle including 1 or 2 heteroatoms selected from N, O and S atoms , wherein alkyl, alkoxy, aryl, cycloalkyl, heterocycle and heteroaryl may be optionally substituted, the substituents being hydroxy, C 1-C 6 -alkylamino, di(C 1 -C 6 -alkyl)amino, carboxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, carboxy-C 1 -C 6 -alkyl and oxo One or more selected from a group.