Title of the invention: sphingosine-1-phosphate receptor agonist, method for preparing the same, and pharmaceutical composition containing the same as an active ingredient
technical field
[One]
Cross Citation with Related Applications
[2]
This application claims the benefit of priority based on Korean Patent Application No. 10-2019-0159309 dated December 3, 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 novel compound serving as a sphingosine-1-phosphate receptor agonist useful for the treatment of autoimmune disorders such as multiple sclerosis, a method for preparing the same, and a pharmaceutical composition containing the same as an active ingredient.
background
[5]
S1P (sphingosine-1-phosphate) is generated through the intracellular ceramide pathway, and ceramide, the starting material of this synthesis pathway, has two production pathways, namely, the de novo biosynthesis pathway and sphingomyelene, a component of the cell membrane. (sphingomyelin) is produced in the cell through the degradation (degradation). S1P level in each tissue is regulated by two biosynthetic sphingosine kinases (SphKs) and two biodegradable S1P phosphatases (S1P lyase and lysophospholipid phosphatases). The produced substance S1P mediates various cellular responses such as cell proliferation, cytoskeletal organization and migration, adhesion- and tight junction assembly, and morphogenesis. it is known They are present in high concentrations (100-1000 nM) in plasma bound to albumin and other plasma proteins, whereas in tissues, they are present in low concentrations.
[6]
S1P binds to the S1P receptor, a G-protein coupled receptor, and exhibits various biological functions. There are five known subtypes of S1P receptors, S1P1 to S1P5, each of which is an endothelial differentiation gene (EDG) receptor. ) receptor) 1, 5, 3, 6 and 8. These S1P receptors are responsible for leukocyte recirculation, neural cell proliferation, morphological changes, migration, endothelial function, vasoregulation and cardiovascular development ( It is known to be involved in various biological functions such as cardiovascular development.
[7]
A number of recent studies have revealed that S1P signaling through these receptors plays an important role in a series of responses related to multiple sclerosis, including inflammatory responses and repair processes. In fact, nonselective S1P1 agonists have recently It is approved for the treatment of multiple sclerosis. S1P receptors are equally widely expressed in many cells involved in the induction of multiple sclerosis. In particular, S1P1 receptors play a very important role in the immune system. The S1P1 receptor is mainly expressed on the surface of lymphocytes such as T cells and B cells, and reacts with S1P to participate in lymphocyte recycling. In the normal state, the S1P concentration is higher in body fluid than in lymphoid tissue, so that lymphocytes leave the lymphoid tissue according to the difference in S1P concentration and circulate along the efferent lymph. However, when the S1P1 receptor of lymphocytes is down-regulated by the S1P1 agonist, the egress of lymphocytes from the lymphoid tissue does not occur, and eventually autoaggressive causing inflammation and tissue damage to the CNS. The infiltration of lymphocytes is reduced, and the therapeutic effect appears in multiple sclerosis. In the case of fingolimod, a nonselective S1P1 agonist licensed as an oral multiple sclerosis treatment, when activated by binding to the S1P1 receptor, paradoxically, the receptor is internalized or degraded from the lymphocyte surface, resulting in functional S1P1 antagonism. it will work
[8]
[Prior art literature]
[9]
[Patent Literature]
[10]
International Patent Publication No. 2010-064707 (published on June 10, 2010)
DETAILED DESCRIPTION OF THE INVENTION
technical challenge
[11]
Specifically, the present invention is to provide a novel compound, a pharmaceutically acceptable salt, isomer, or solvate thereof having excellent action and efficacy on the sphingosine-1-phosphate (hereinafter, sometimes abbreviated as S1P) receptor. The purpose.
[12]
Another object of the present invention is to provide a method for preparing the novel compound.
[13]
The present invention also provides a sphingosine-1-phosphate receptor agonist composition comprising the novel compound, a pharmaceutically acceptable salt, isomer or solvate thereof as an active ingredient together with a pharmaceutically acceptable carrier. aims to provide
[14]
In particular, the composition according to the present invention exhibits excellent effects in preventing and treating autoimmune disorders such as multiple sclerosis.
means of solving the problem
[15]
In order to achieve the above object, the present invention provides a compound represented by the following formula (1), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:
[16]
[Formula 1]
[17]

[18]
In Formula 1,
[19]
R 1 is hydrogen or alkyl, alkenyl or alkynyl substituted or unsubstituted with a substituent,
[20]
R 2 is hydrogen, alkyl, halogen, CN, CF 3 or COCF 3 substituted or unsubstituted with a substituent ,
[21]
R 3 and R 4 are each independently hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl or halogen,
[22]
R 5 A and R 5 B are each independently hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, or —R 6 (COOH), wherein R 6 is a single bond, substituted or unsubstituted with a substituent alkylene, alkenylene or alkynylene, wherein any one of R 5 A and R 5 B is —R 6 (COOH),
[23]
The R 5 A and R 5 B may be bonded to each other to form a ring, wherein the ring is a ring substituted with -R 6 (COOH).
[24]
Further, according to one embodiment of the present invention, there is provided a compound, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof for use in the treatment of an autoimmune disorder including multiple sclerosis.
[25]
Further, according to another embodiment of the present invention, there is provided a compound that is a sphingosine-1-phosphate receptor agonist, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.
[26]
In addition, according to another aspect of the present invention, there is provided a pharmaceutical composition for the treatment of autoimmune disorders, comprising the compound represented by Formula 1, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.
[27]
In addition, according to another aspect of the present invention, systemic lupus erythematosus, chronic rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis comprising the compound represented by Formula 1, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof as an active ingredient , Amyotrophic lateral sclerosis (ALS), arteriosclerosis, atherosclerosis, scleroderma and provides a pharmaceutical composition for the treatment or prevention of an autoimmune or chronic inflammatory disease selected from the group consisting of autoimmune hepatitis.
Effects of the Invention
[28]
The compound of Formula 1 according to the present invention acts as a sphingosine-1-phosphate receptor agonist, and is effective in a wide range of autoimmune and chronic inflammatory diseases including relapsing-remitting multiple sclerosis, and treats or prevents immune modulation abnormalities can also be used for
Modes for carrying out the invention
[29]
Hereinafter, the present invention will be described in detail with reference to the drawings. 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.
[30]
[31]
Hereinafter, unless otherwise indicated for convenience, the compound of Formula 1 refers to both the compound of Formula 1 and a pharmaceutically acceptable salt or isomer and solvate thereof.
[32]
In defining the compound of Formula 1 throughout this specification, the concepts defined as follows are used. The following definitions also apply to terms used individually or as part of a larger group throughout this specification, unless specifically indicated otherwise.
[33]
In the formula, the vertical wavy indicates a position where it is bound to the parent nucleus of the compound.
[34]
The term "alkyl" when used alone or in combination as "heteroalkyl" means a hydrocarbon radical in the form of a straight chain, branched chain or ring (cycloalkyl), respectively, preferably straight chain or having from 1 to 10 carbon atoms or branched saturated hydrocarbon radicals; or a cyclic saturated hydrocarbon radical having 3 to 10 carbon atoms; or a cyclic saturated hydrocarbon radical having 3 to 10 carbon atoms bonded to a straight-chain and/or branched saturated hydrocarbon radical having 1 to 10 carbon atoms.
[35]
The term "alkenyl" refers to an unsaturated hydrocarbon radical containing one or more double bonds, and when used alone or in combination such as "heteroalkenyl", a straight-chain, branched-chain or ring (cycloalkenyl) hydrocarbon radical, respectively. means radical. straight-chain or branched-chain unsaturated hydrocarbon radicals, preferably having 1 to 10 carbon atoms and comprising at least one double bond; or a cyclic unsaturated hydrocarbon radical having 3 to 10 carbon atoms and comprising at least one double bond; or a cyclic unsaturated hydrocarbon radical having from 3 to 10 carbon atoms and comprising at least one double bond, having 1 to 10 carbon atoms and bonded to a straight and/or branched chain unsaturated hydrocarbon radical comprising at least one double bond.
[36]
The term "halogeno-alkyl" means that at least one of the hydrogen atoms of the alkyl is replaced by a halogen.
[37]
The term "alkynyl" means an unsaturated hydrocarbon radical containing one or more triple bonds, and when used alone or in combination such as "heteroalkynyl", is a straight-chain, branched-chain or ring (cycloalkanyl) hydrocarbon radical, respectively. means radical.
[38]
The term "alkoxy" refers to -O-alkyl, wherein alkyl is as defined above.
[39]
The term “halo(gen)” refers to a substituent selected from the group fluoro, chloro, bromo and iodo. In addition, terms and abbreviations used herein have their original meanings unless otherwise defined.
[40]
The term "substituent" refers to an atom or group of atoms that replaces one or more hydrogen atoms on the parent chain, such as halogen, cyano, hydroxy, alkyloxy having 1 to 10 carbon atoms, oxo (=O) and alkyl. It may be at least one selected from the group consisting of substituted or unsubstituted sulfonyl. In addition, when substituted with a substituent in the present invention, one or more hydrogen atoms may be substituted.
[41]
Further, the alkyl, alkenyl, alkynyl, alkyloxy having 1 to 10 carbon atoms may preferably have 1 to 6 carbon atoms.
[42]
In addition, the cycloalkyl, cycloalkenyl, and cycloalkynyl having 3 to 10 carbon atoms, the cycloalkyloxy may preferably have 3 to 6 carbon atoms.
[43]
The compounds according to the invention may also form pharmaceutically acceptable salts. Examples of such pharmaceutically acceptable salts include acids that form non-toxic acid addition salts containing pharmaceutically acceptable anions, such as inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, tartaric acid, formic acid, and the like. , organic carboxylic acids such as citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, etc., sulfonic acid such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or naphthalenesulfonic acid acid addition salts formed with phonic acid or the like, particularly preferably acid addition salts formed with sulfuric acid, methanesulfonic acid or hydrohalic acid or the like. The compound of formula (1) according to the present invention can be converted into a salt thereof by a conventional method.
[44]
On the other hand, since the compounds according to the present invention may have an asymmetric carbon center, they may exist as R or S isomers, racemics, diastereomeric mixtures and individual diastereomers, and all these isomers and mixtures are included within the scope of the present invention. . That is, when the asymmetric carbon(s) is included in the structure of Formula 1, it is understood that all stereoisomers are included unless the direction is otherwise specified.
[45]
[46]
According to one aspect of the present invention, the present invention provides a compound represented by the following formula (1), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:
[47]
[Formula 1]
[48]

[49]
In Formula 1,
[50]
R 1 may be hydrogen or substituted or unsubstituted alkyl, alkenyl or alkynyl, R 2 may be hydrogen, substituted or unsubstituted alkyl, halogen, CN, CF 3 or COCF 3 , R 3 and R 4 may be each independently hydrogen, alkyl, alkenyl, alkynyl, or halogen substituted or unsubstituted with a substituent, R 5 A and R 5 B are each independently hydrogen, substituted or unsubstituted with a substituent may be alkyl, alkenyl, alkynyl or -R 6 (COOH), wherein R 6 may be a single bond, substituted or unsubstituted alkylene, alkenylene or alkynylene, wherein R 5 A and Any one of R 5 B may be -R 6 (COOH), wherein R 5 A and R 5B may combine with each other to form a ring, and the ring may be a ring substituted with -R 6 (COOH).
[51]
Specifically, in Formula 1, R 1 may be hydrogen or alkyl substituted or unsubstituted with a substituent, R 2 may be hydrogen, alkyl substituted or unsubstituted with a substituent, halogen or CF 3 , R 3 and R 4 may each independently be hydrogen, unsubstituted alkyl or halogen, and R 5 A and R 5 B may each independently be alkyl or —R 6 (COOH) substituted or unsubstituted with a substituent , where R 6 may be a single bond or an alkylene group unsubstituted or substituted with a single bond, any one of R 5 A and R 5 B may be —R 6 (COOH), and R 5 A and R 5 B are each other may combine to form a ring, wherein the ring is -R 6(COOH) may be a substituted ring.
[52]
In addition, in Formula 1, when R 5 A and R 5 B are combined with each other to form a ring, the ring is additionally selected from the group consisting of halogen, alkyl and halogeno-alkyl in addition to substituted -R 6 (COOH). More than one kind of substituent may be further substituted.
[53]
In addition, in Formula 1, when R 5 A and R 5 B are bonded to each other to form a ring, the ring may be a ring represented by Formula 1-1.
[54]
[Formula 1-1]
[55]

[56]
In Formula 1-1, N is the same N as N bonded to R 5 A and R 5 B in Formula 1, and R 7 to R 11 are each independently hydrogen, alkyl substituted or unsubstituted with a substituent, It may be halogen or halogeno-alkyl, and m and n may each independently be an integer of 0 to 6, and m+n≥1.
[57]
Specifically, the ring represented by Formula 1-1 may be a ring represented by Formula 1-2 below.
[58]
[Formula 1-2]
[59]

[60]
In Formula 1-2, R 7 may be hydrogen, alkyl substituted or unsubstituted with a substituent, or halogeno-alkyl, and N, n and m are as defined in claim 4.
[61]
In addition, when R 5 A and R 5 B in Formula 1 form a ring, the ring is specifically any one of azetidine, pyrrolidine, piperidine, or azepaine in which -R 6 (COOH) is substituted. may be, and the ring may be an additionally substituted or unsubstituted substituent in addition to -R 6 (COOH).
[62]
In addition, according to an embodiment of the present invention, in Formula 1, any one or more of R 3 and R 4 may be hydrogen, for example, both R 3 and R 4 may be hydrogen.
[63]
More specifically, the compound represented by Formula 1 may include a compound selected from the following group.
[64]
{[7-(3-Chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-methyl-amino}-acetic acid ({[7-(3- chloro-1-isopropyl-1H-indazol-5-yl methoxy)-2H-chromene-3-ylmethoxy]-methyl-amino}-acetic acid);
[65]
1-[7-(3-Chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-azetidine-3-carboxylic acid (1-[7 -(3-chloro-1-isopropyl-1H-indazol-5-yl methoxy)-2H-chromene-3-ylmethyl]-azetidin-3-carboxylic acid);
[66]
1-[7-(3-Chloro-2-propyl-2H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-azetidine-3-carboxylic acid (1-[7- (3-chloro-2-propyl-2H-indazol-5-yl methoxy)-2H-chromene-3-ylmethyl]-azetidin-3-carboxylic acid);
[67]
1-[7-(3-Chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-piperidine-4-carboxylic acid (1-[ 7-(3-chloro-1-isopropyl-1H-indazol-5-yl methoxy)-2H-chromene-3-ylmethyl]-piperidine-4-carboxylic acid);
[68]
(R)-1-[7-(3-Chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-piperidine-3-carboxylic acid ((R)-1-[7-(3-chloro-1-isopropyl-1H-indazol-5-yl methoxy)-2H-chromene-3-ylmethyl]-piperidine-3-carboxylic acid);
[69]
(S)-1-[7-(3-Chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-piperidine-3-carboxylic acid ((S)-1-[7-(3-chloro-1-isopropyl-1H-indazol-5-yl methoxy)-2H-chromene-3-ylmethyl]-piperidine-3-carboxylic acid);
[70]
(S)-1-[7-(3-Chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-pyrrolidine-3-carboxylic acid ((S)-1-[7-(3-chloro-1-isopropyl-1H-indazol-5-yl methoxy)-2H-chromene-3-ylmethyl]-pyrrolidine-3-carboxylic acid);
[71]
1-[7-(3-Chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-3-chloromethyl-azetidine-3-carboxylic acid (1-[7-(3-chloro-1-isopropyl-1H-indazol-5-yl methoxy)-2H-chromene-3-ylmethyl]-3-chloromethyl-azetidine-3-carboxylic acid);
[72]
(R)-1-[7-(3-Chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-pyrrolidine-3-carboxylic acid ((R)-1-[7-(3-chloro-1-isopropyl-1H-indazol-5-yl methoxy)-2H-chromene-3-ylmethyl]-pyrrolidine-3-carboxylic acid);
[73]
1-[7-(3-Chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-4-methyl-2H-chromin-3-ylmethyl]-piperidine-4-carboxylic acid (1-[7-(3-chloro-1-isopropyl-1H-indazol-5-yl methoxy)-4-methyl-2H-chromene-3-ylmethyl]-piperidine-4-carboxylic acid);
[74]
1-[4-Chloro-7-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-piperidine-4-carboxylic acid (1-[4-chloro-7-(3-chloro-1-isopropyl-1H-indazol-5-yl methoxy)-2H-chromene-3-ylmethyl]-piperidine-4-carboxylic acid);
[75]
1-[7-(3-Chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-5-fluoro-2H-chromin-3-ylmethyl]-piperidine-4-carboxyl acid (1-[7-(3-chloro-1-isopropyl-1H-indazol-5-yl methoxy)-5-fluoro-2H-chromene-3-ylmethyl]-piperidine-4-carboxylic acid);
[76]
1-[7-(1-Isopropyl-3-trifluoromethyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-piperidine-4-carboxylic acid ( 1-[7-(1-isopropyl-3-trifluoromethyl-1H-indazol-5-yl methoxy)-2H-chromene-3-ylmethyl]-piperidine-4-carboxylic acid);
[77]
1-[7-(1-Isopropyl-3-ethyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-piperidine-4-carboxylic acid (1-[ 7-(1-isopropyl-3-ethyl-1H-indazol-5-yl methoxy)-2H-chromene-3-ylmethyl]-piperidine-4-carboxylic acid);
[78]
1-[7-(3-Chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-azepaine-4-carboxylic acid (1-[7 -(3-chloro-1-isopropyl-1H-indazol-5-yl methoxy)-2H-chromene-3-ylmethyl]-azepane-4-carboxylic acid);
[79]
1-[7-(3-Chloro-1-propyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-azetidine-3-carboxylic acid (1-[7- (3-chloro-1-propyl-1H-indazol-5-yl methoxy)-2H-chromene-3-ylmethyl]-azetidine-3-carboxylic acid);
[80]
1-[7-(3-Chloro-1-propyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-piperidine-4-carboxylic acid (1-[7 -(3-chloro-1-propyl-1H-indazol-5-yl methoxy)-2H-chromene-3-ylmethyl]-piperidine-4-carboxylic acid);
[81]
1-[7-(3-Chloro-1-cyclopropylmethyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-piperidine-4-carboxylic acid (1- [7-(3-chloro-1-cyclopropylmethyl-1H-indazol-5-yl methoxy)-2H-chromene-3-ylmethyl]-piperidine-4-carboxylic acid);
[82]
1-[7-(3-Chloro-1-cyclopentyl-1H-indazol-5-ylmethoxy)-5-fluoro-2H-chromin-3-ylmethyl]-piperidine-4-carboxyl acid (1-[7-(3-chloro-1-cyclopentyl-1H-indazol-5-yl methoxy)-5-fluoro-2H-chromene-3-ylmethyl]-piperidine-4-carboxylic acid);
[83]
1-[7-(3-Chloro-1-isobutyl-1H-indazol-5-ylmethoxy)-5-fluoro-2H-chromin-3-ylmethyl]-piperidine-4-carboxyl acid (1-[7-(3-chloro-1-isobutyl-1H-indazol-5-yl methoxy)-5-fluoro-2H-chromene-3-ylmethyl]-piperidine-4-carboxylic acid);
[84]
1-[7-(3-Chloro-1-isobutyl-1H-indazol-5-ylmethoxy)-5-fluoro-2H-chromin-3-ylmethyl]-azepaine-4-carboxylic acid (1-[7-(3-chloro-1-isobutyl-1H-indazol-5-yl methoxy)-5-fluoro-2H-chromene-3-ylmethyl]-azepane-4-carboxylic acid); and
[85]
2-{1-[7-(1-Isopropyl-3-trifluoromethyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-piperidin-4-yl }Acetic acid (2-{1-[7-(1-isopropyl-3-trifluoromethyl-1H-indazol-5-yl methoxy)-2H-chromene-3-ylmethyl]-piperidine-4-yl}acetic acid).
[86]
[87]
The compound of formula (1), a pharmaceutically acceptable salt, isomer or solvate thereof according to the present invention is suitable for the treatment or prevention of sphingosine-1-phosphate receptor-related diseases.
[88]
The present invention also provides a sphingosine-1-phosphate receptor agonist comprising an effective amount of a compound of formula (1), a pharmaceutically acceptable salt, isomer or solvate thereof and a pharmaceutically acceptable carrier. A pharmaceutical composition is provided.
[89]
The pharmaceutical composition according to the present invention can also be used for the treatment or prevention of diseases caused by undesirable lymphocyte infiltration involving sphingosine-1-phosphate.
[90]
Diseases for which the pharmaceutical composition according to the present invention exhibits therapeutic efficacy include a wide range of autoimmune and chronic inflammatory diseases including relapsing-remitting multiple sclerosis.
[91]
In addition, the pharmaceutical composition according to the present invention can be used for the treatment or prevention of immune modulation disorders, wherein the immune modulation disorders include systemic lupus erythematosus, chronic rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, and amyotrophic lateral sclerosis (ALS). , arteriosclerosis, atherosclerosis, scleroderma and autoimmune hepatitis.
[92]
Further, the present invention relates to relapsing-remitting multiple sclerosis comprising the step of mixing a compound of formula (1), a pharmaceutically acceptable salt, isomer or solvate thereof as an active ingredient, with a pharmaceutically acceptable carrier. It provides a method for preparing a composition for the prevention or treatment of a wide range of autoimmune and chronic inflammatory diseases, including.
[93]
[94]
The "pharmaceutical composition" may include a compound of the present invention and other chemical components such as diluents and carriers. Accordingly, the pharmaceutical composition may include a pharmaceutically acceptable carrier, diluent, or excipient, or a combination thereof, as needed. The pharmaceutical composition facilitates administration of the compound into an organism. Various techniques for administering a compound exist, including, but not limited to, oral, injection, aerosol, parenteral, and topical administration.
[95]
The term “carrier” refers to a compound that facilitates the addition of the compound into a cell or tissue. For example, dimethylsulfoxide (DMSO) is a commonly used carrier that facilitates the introduction of many organic compounds into cells or tissues of living organisms.
[96]
The "diluent" is defined as a compound that not only stabilizes the biologically active form of the target compound, but is diluted in water to dissolve the compound. Salts dissolved in buffer solutions are used as diluents in the art. A commonly used buffer solution is phosphate buffered saline, which mimics the salt form of human solutions. Because buffer salts can control the pH of a solution at low concentrations, buffer diluents rarely modify the biological activity of a compound.
[97]
The "pharmaceutically acceptable" is defined as a carrier, diluent, etc. that does not impair the biological activity and properties of the compound.
[98]
The compounds of the present invention may be formulated into various pharmaceutical dosage forms as desired. In preparing the pharmaceutical composition according to the present invention, the active ingredient, specifically, the compound of formula (1), or a pharmaceutically acceptable salt, isomer, or solvate thereof may be selected according to the formulation to be prepared. mixed with various pharmaceutically acceptable carriers. For example, the pharmaceutical composition according to the present invention may be formulated as an injectable preparation, an oral preparation, etc. as desired.
[99]
The compounds of the present invention may be formulated by known methods using known pharmaceutical carriers and excipients and incorporated in unit dosage form or multi-dose containers. The form of the preparation may be in the form of a solution, suspension or emulsion in oil or aqueous medium, and may contain customary dispersing, suspending or stabilizing agents. In addition, for example, it may be in the form of a dry powder that is used by dissolving it in sterile, pyrogen-free water before use. The compounds of the present invention may also be formulated in the form of suppositories using conventional suppository bases such as cocoa butter or other glycerides. A solid dosage form for oral administration can be capsules, tablets, pills, powders and granules, and capsules and tablets are particularly useful. Tablets and pills are preferably prepared with an enteric coating. Solid dosage forms can be prepared by mixing a compound of the present invention with one or more inert diluents such as sucrose, lactose, starch, and the like, and carriers such as lubricants, disintegrants, binders, and the like, such as magnesium stearate.
[100]
If necessary, the compound according to the present invention or a pharmaceutical composition containing the same may be administered in combination with other agents, for example, other immunotherapeutic agents.
[101]
The dosage of the compound of formula (1) according to the present invention is determined according to a doctor's prescription in consideration of factors such as the patient's sex, weight, age, and the specific nature and severity of the disease. However, the dosage required for adult treatment is usually in the range of about 0.1 to 500 mg per day, depending on the frequency and intensity of administration. When administered intramuscularly or intravenously to adults, a total dose of about 0.1 to 300 mg per day, usually divided into single doses, will suffice, although higher daily doses may be desirable for some patients.
[102]
The "treatment" means stopping or delaying the progression of a disease when used in a subject showing symptoms of onset, and the term "prevention" means stopping or delaying symptoms of an onset when used in a subject showing no symptoms but at high risk means to do
[103]
[104]
Hereinafter, the present invention will be described in more detail through Preparation Examples and Examples, but the scope of the present invention is not limited thereto. When preparing the compound of the present invention, the reaction sequence can be appropriately changed. That is, an arbitrary process may be performed first or an arbitrary substituent change process may be inserted, and any other reagent other than the exemplified reagent may be used if necessary. The compound obtained in each process may be separated or purified by conventional methods such as recrystallization, distillation, and silica gel column. In addition, the following process may be performed without isolating or purifying the compound obtained in each process.
[105]
In the structural formulas below, unless otherwise indicated, all substituents are as defined above. Reagents and starting materials are readily commercially available. Others can be prepared by the synthesis methods described in the following Preparation Examples and Examples, including methods for synthesizing known structurally similar compounds. Unless the preparation method is specifically described, the compound used as a starting material is a known compound, or a compound that can be synthesized from a known compound by a known synthesis method or a method similar thereto.
[106]
In the following formula, M means molar concentration, N means normal concentration, and "room temperature" means a temperature of 1 to 40 ℃.
[107]
[108]
Preparation 1-1: Synthesis of 7-hydroxy-2H-chromine-3-carbaldehyde
[109]
The title compound was obtained by the method described in International Patent Publication No. 2010-064707.
[110]
NMR: 1 H-NMR (400 Hz, CDCl 3 ); δ 9.51 (s, 1H), 7.40 (m, 5H), 7.19 (s, 1H), 7.11 (d, 1H), 6.60 (dd, 1H), 6.49 (d, 1H), 5.10 (s, 2H), 5.00(s, 2H)
[111]
[112]
Preparation 1-2: (3-chloro-1-isopropyl-1H-indazol-5-yl) -synthesis of methanol
[113]
The title compound was obtained by the method described in Korean Patent Publication No. 10-1939657.
[114]
NMR: 1 H-NMR (400 HMz, CDCl 3 ); δ 7.64 (s, 1H), 7.43 (m, 2H), 4.79 (m, 3H), 1.83 (br s, 1H), 1.56 (d, 6H)
[115]
[116]
Preparation 1-3: Synthesis of 7-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-2H-chromine-3-carbaldehyde
[117]
(3-chloro-1-isopropyl-1H-indazol-5-yl)-methanol (383 mg, 1.70 mmol) obtained in Preparation Example 1-2 and 7-hydroxy-2H- obtained in Preparation Example 1-1 After dissolving chromine-3-carbaldehyde (300 mg, 1.70 mmol) in toluene (10 ml), tributylphosphine (BuP 3 , 291 mg, 1.44 mmol) and 1,1'-(azodicarbonyl) ) Dipiperidine (ADD, 363 mg, 1.44 mmol) was added dropwise. After stirring at room temperature for 18 hours, an excess of hexane was added. After filtration, the mixture was distilled under reduced pressure, and the residue was purified by column chromatography to obtain the title compound (320 mg, 49%).
[118]
NMR: 1 H-NMR (400 Hz, CDCl 3 ); δ 9.52 (s, 1H), 7.71 (s, 1H), 7.47 (dd, J = 1.6 Hz, 1H), 7.44 (d, 1H), 7.21 (s, 1H), 7.14 (d, 1H), 6.62 ( dd, J = 2.4 Hz, 1H), 6.52 (d, 1H), 5.16 (s, 2H), 5.03 (s, 2H), 4.83-4.76 (m, 1H), 1.57 (d, 6H)
[119]
[120]
Preparation 1-4: {[7-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-methyl-amino}-acetic acid ethyl ester synthesis of
[121]
7-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-2H-chromine-3-carbaldehyde obtained in Preparation Example 1-3 (160 mg, 0.42 mmol) and sarcosine Ethyl ester hydrochloride (129 mg, 0.84 mmol) was dissolved in dichloroethane (10 ml), sodium triacetoxyborohydride (46 mg, 0.22 mmol) was added, and the mixture was stirred at room temperature for 5 hours. After completion of the reaction, water was added to the reaction product, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the filtered filtrate was distilled under reduced pressure. The residue was separated by column chromatography to obtain the title compound (90 mg, 45%).
[122]
NMR: 1 H-NMR (400 Hz, CDCl 3 ); δ 7.74 (s, 1H), 7.52 (d, 1H), 7.46 (d, 1H), 6.92 (d, 1H), 6.56 (dd, J = 2.4 Hz, 1H), 6.53 (d, 1H), 6.32 ( s, 1H), 5.16 (s, 2H), 4.87-4.80 (m, 3H), 4.21 (q, 2H), 3.29 (s, 2H), 3.24 (s, 2H), 2.42 (s, 3H), 1.62 (d, 6H), 1.30 (t, 3H)
[123]
[124]
Example 1: Synthesis of {[7-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-methyl-amino}-acetic acid
[125]

[126]
{[7-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-methyl-amino}-ethyl acetate obtained in Preparation Example 1-4 The ester (90 mg, 0.19 mmol) was dissolved in a mixture of tetrahydrofuran and methanol (2/1, 20 mL), and 6N aqueous sodium hydroxide solution (1 mL, 6.32 mmol) was slowly added dropwise. After stirring at room temperature for 3 hours, 1N hydrochloric acid solution was added and extraction was performed with ethyl acetate. After washing with brine and drying over anhydrous magnesium sulfate, the filtered filtrate was distilled under reduced pressure to obtain the title compound (40 mg, 46%).
[127]
NMR: 1 H-NMR (400 MHz, CDCl3) δ 7.68 (s, 1H), 7.43 (q, 2H), 6.93 (d, 1H), 6.53 (d, 1H), 6.48 (d, 2H), 5.10 ( s, 2H), 4.82 (s, 2H), 4.80-4.76 (m, 1H), 3.56 (s, 2H), 3.49 (s, 2H), 2.67 (s, 3H), 1.56 (d, 6H)
[128]
[129]
Preparation 2: 1-[7-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-azetidine-3-carboxylic acid methyl synthesis of esters
[130]
According to the method described in Preparation Example 1-4, 7-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-2H-chromine-3-carbal obtained in Preparation Example 1-3 Dehyde (160 mg, 0.42 mmol) and azetidine-3-carboxylic acid methyl ester hydrochloride (127 mg, 0.84 mmol) were used to obtain the title compound (120 mg, 60%).
[131]
NMR: 1 H-NMR (400 Hz, CDCl 3 ); δ 7.69 (s, 1H), 7.47 (dd, 1H), 7.41 (d, 1H), 6.87 (d, 1H), 6.51 (dd, 1H), 6.46 (d, 1H), 6.25 (s, 1H), 5.11(s, 2H), 4.76(m, 1H), 4.68(s, 2H), 3.71(s, 3H), 3.55(m, 2H), 3.32(m, 3H), 3.11(s, 2H), 1.57 (d, 6H)
[132]
[133]
Example 2: of 1-[7-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-azetidine-3-carboxylic acid synthesis
[134]

[135]
1-[7-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl] obtained in Preparation Example 2 according to the method described in Example 1 -azetidine-3-carboxylic acid methyl ester (120 mg, 0.25 mmol) was used to obtain the title compound (70 mg, 60%).
[136]
NMR: 1 H-NMR (400 MHz, CDCl3) δ 7.71 (s, 1H), 7.44 (q, 2H), 6.98 (d, 1H), 6.63 (s, 1H), 6.578 (d, 1H), 6.50 ( s, 1H), 5.12 (s, 2H), 4.87 (s, 2H), 4.84-4.80 (m, 1H), 4.27 (br, s, 2H), 4.18 (br, s, 2H), 3.76 (s, 2H), 3.67 (br, s, 1H), 1.60 (d, 6H)
[137]
[138]
Preparation Example 3-1: Synthesis of 1H-indazole-5-carboxylic acid methyl ester
[139]
After dissolving 4-amino-3-methyl-benzoic acid methyl ester (2.0 g, 12.03 mmol) in chloroform (25 mL), acetic anhydride (2.12 g, 30.07 mmol) was slowly added dropwise at 0°C. After stirring at room temperature for 1 hour, potassium acetate (250 mg, 3.61 mmol) and isoamyl nitrite (2.23 mL, 24.06 mmol) were added. After stirring under reflux at 70° C. for 18 hours, an excess of dichloromethane was added. It was washed with a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and the filtered filtrate was distilled under reduced pressure. The residue was separated by column chromatography to obtain an intermediate acetyl indazole (1.2 g, 5.50 mmol).
[140]
Acetyl indazole (1.2 g, 5.50 mmol) was dissolved in a mixture of tetrahydrofuran and methanol (1/1, 20 mL), and then 6N aqueous sodium hydroxide solution (1.8 mL) was added dropwise. After stirring at room temperature for 10 minutes, it was acidified with a 6N aqueous hydrochloric acid solution. After extraction with dichloromethane, drying over anhydrous magnesium sulfate, and distillation under reduced pressure, the title compound (1.0 g, 47%) was obtained.
[141]
NMR: 1 H-NMR (400 Hz, CDCl 3 ); δ 9.72 (br, s, 1H), 8.59 (s, 1H), 8.27 (s, 1H), 8.14 (dd, J = 1.2 Hz, 1H), 7.60 (d, 1H), 3.97 (s, 3H)
[142]
[143]
Preparation 3-2: Synthesis of 1-propyl-1H-indazole-5-carboxylic acid methyl ester and 2-propyl-2H-indazole-5-carboxylic acid methyl ester
[144]
Dissolved in 1H-indazole-5-carboxylic acid methyl ester (1.0 g, 5.68 mmol) and dimethylformamide (20 mL) obtained in Preparation Example 3-1, and propylbromide (0.6 mL, 6.23 mmol) at 0 ° C. Sodium hydride (205 mg, 8.56 mmol) was slowly added dropwise, followed by stirring at 50° C. for 8 hours. After that, 1N hydrochloric acid solution was added and extracted with ethyl acetate. After washing with brine, drying over anhydrous magnesium sulfate, the filtered filtrate was distilled under reduced pressure. The residue was separated by column chromatography, and 1-propyl-1H-indazole-5-carboxylic acid methyl ester (680 mg, 55%) and 2-propyl-2H-indazole- 5-carboxylic acid methyl ester (330 mg, 26%) was obtained.
[145]
NMR: 1 H-NMR (500 HMz, CDCl 3 ); δ 8.31 (s, 1H), 7.96 (d, 1H), 7.29 (d, 1H), 4.20 (t, 2H), 3.86 (s, 3H), 1.87 (q, 2H), 0.84 (t, 3H) ( 1-propyl-1H-indazole-5-carboxylic acid methyl ester NMR data)
[146]
NMR: 1 H-NMR (500 HMz, CDCl 3 ); δ 8.49 (s, 1H), 8.05 (s, 1H), 7.89 (dd, J = 1.8 Hz, 1H), 7.70 (d, 1H), 4.39 (t, 2H), 3.93 (s, 3H), 2.06 ( q, 2H), 0.96 (t, 3H) (2-propyl-2H-indazole-5-carboxylic acid methyl ester NMR data)
[147]
[148]
Preparation 3-3: Synthesis of 3-chloro-2-propyl-2H-indazole-5-carboxylic acid methyl ester
[149]
1-propyl-1H-indazole-5-carboxylic acid methyl ester obtained in Preparation Example 3-1 and 2-propyl-2H-indazole-5-carboxylic acid methyl ester (330 mg, 1.51 mmol) were mixed with dimethylform It was dissolved in amide, and N-chlorosuccinimide (NCS, 253 mg, 1.90 mmol) was added dropwise, followed by stirring at room temperature for 18 hours. Thereafter, water was added and extraction was performed with ethyl acetate. After washing with brine, drying over anhydrous magnesium sulfate, the filtered filtrate was distilled under reduced pressure. The residue was separated by column chromatography to obtain the title compound (180 mg, 47%).
[150]
NMR: 1 H-NMR (400 Hz, CDCl 3 ); δ 8.45 (s, 1H), 7.96 (dd, J = 1.6 Hz, 1H), 7.69 (dd, J = 1.2 Hz, 1H), 4.47 (t, 2H), 3.99 (s, 3H), 2.08 (q, 2H), 1.03 (t, 3H)
[151]
[152]
Preparation 3-4: (3-chloro-2-propyl-2H-indazol-5-yl) -synthesis of methanol
[153]
After dissolving 3-chloro-2-propyl-2H-indazole-5-carboxylic acid methyl ester (180 mg, 0.71 mmol) obtained in Preparation Example 3-3 in tetrahydrofuran, lithium aluminum borohydride (8 mg, 0.20 mmol) was added dropwise. After stirring at room temperature for 1 hour, water (1 mL), 6N aqueous sodium hydroxide solution (1 mL) and water (3 mL) were sequentially added. Celite was added dropwise, and the filtered filtrate was distilled under reduced pressure. The residue was separated by column chromatography to obtain the title compound (159 mg, 100%).
[154]
[155]
Preparation 3-5: Synthesis of 7-(3-chloro-2-propyl-2H-indazol-5-ylmethoxy)-2H-chromine-3-carbaldehyde
[156]
According to the method described in Preparation Example 1-3, (3-chloro-2-propyl-2H-indazol-5-yl)-methanol (159 mg, 0.71 mmol) obtained in Preparation Example 3-4 and Preparation Example 1- 7-hydroxy-2H-chromine-3-carbaldehyde (125 mg, 0.71 mmol) obtained in step 1 was used to obtain the title compound (130 mg, 48%).
[157]
NMR: 1 H-NMR (500 HMz, CDCl 3 ); δ 9.49 (s, 1H), 7.66 (d, 1H), 7.59 (s, 1H), 7.32 (dd, J = 1.85, 1.25, 1H), 7.21 (s, 1H), 7.13 (d, 1H), 6.61 (dd, J = 2.45 Hz, 1H), 6.51 (d, 1H), 5.12 (s, 2H), 5.02 (s, 2H), 4.41 (t, 2H), 2.01 (q, 2H), 0.96 (t, 3H)
[158]
[159]
Preparation 3-6: 1-[7-(3-chloro-2-propyl-2H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-azetidine-3-carboxylic acid Synthesis of methyl esters
[160]
According to the method described in Preparation Example 1-4, 7-(3-chloro-2-propyl-2H-indazol-5-ylmethoxy)-2H-chromine-3-carbaldehyde obtained in Preparation Example 3-5 (130 mg, 0.34 mmol) and azetidine-3-carboxylic acid methyl ester hydrochloride (103 mg, 0.68 mmol) were used to obtain the title compound (100 mg, 62%).
[161]
NMR: 1 H-NMR (400 Hz, CDCl 3 ); δ 7.65 (d, 1H), 7.59 (s, 1H), 7.33 (d, 1H), 6.87 (d, 1H), 6.52 (dd, J = 2.4 Hz, 1H), 6.47 (d, J = 2.4 Hz, 1H), 6.25 (s, 1H), 5.07 (S, 2H), 4.69 (s, 2H), 4.41 (t, 2H), 3.71 (s, 3H), 3.52 (t, 2H), 3.33-3.27 (m) , 3H), 3.10 (s, 2H), 2.01 (q, 2H), 0.97 (t, 3H)
[162]
[163]
Example 3: Synthesis of 1-[7-(3-chloro-2-propyl-2H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-azetidine-3-carboxylic acid
[164]

[165]
1-[7-(3-chloro-2-propyl-2H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl obtained in Preparation Example 3-6 according to the method described in Example 1 ]-azetidine-3-carboxylic acid methyl ester (100 mg, 0.33 mmol) was used to obtain the title compound (30 mg, 19%).
[166]
NMR: 1 H-NMR (500 MHz, CDCl3) δ 7.61 (d, 1H), 7.53 (d, 1H), 7.27 (br, s, 1H), 6.90 (d, 1H), 6.50 (br, s, 2H) ), 6.43 (s, 1H), 4.98 (s, 2H), 4.74 (s, 2H), 4.38 (t, 2H), 4.19-4.02 (m, 4H), 3.64 (br, s, 2H), 3.47 ( br, s, 1H). 1.97 (q, 2H), 0.93 (t, 3H)
[167]
[168]
Preparation 4-1: 1-[7-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-piperidine-4-car Synthesis of acid ethyl ester
[169]
According to the method described in Preparation Example 1-4, 7- (3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-2H-chromine-3-carbal obtained in Preparation Example 1-3 Dehydride (178 mg, 0.46 mmol) and piperidine-4-carboxylic acid ethyl ester hydrochloride (110 mg, 0.69 mmol) were used to obtain the title compound (100 mg, 41%).
[170]
NMR: 1 H-NMR (400 Hz, CDCl 3 ); δ 7.66 (s, 1H), 7.43 (d, 1H), 7.37 (d, 1H), 6.82 (d, 1H), 6.45 (m, 2H), 6.20 (s, 1H), 5.05 (s, 2H), 4.73(m, 3H), 4.10(m, 1H), 2.95(s, 2H), 2.81(m, 2H), 2.23(m, 1H), 1.94(t, 2H), 1.84(m, 2H), 1.71 (m, 2H), 1.52 (d, 6H), 1.21 (t, 3H)
[171]
[172]
Example 4: 1-[7-(3-Chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-piperidine-4-carboxylic acid synthesis of
[173]

[174]
According to the method described in Example 1, Preparation Example 1- [7- (3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy) -2H-chromin-3 obtained in Preparation Example 4-1 -ylmethyl]-piperidine-4-carboxylic acid ethyl ester (100 mg, 0.19 mmol) was used to obtain the title compound (48 mg, 51%).
[175]
NMR: 1 H-NMR (400 Hz, CDCl 3 ); δ 7.73(s, 1H), 7.48(m, 2H), 6.92(d, 1H), 6.54(m, 2H), 6.36(s, 1H), 5.14(s, 2H), 4.83(m, 3H), 3.27(s, 2H), 3.17(m, 2H), 2.32(m, 1H), 2.21(m, 2H), 2.03(m, 2H), 1.87(m, 2H), 1.61(d, 6H)
[176]
[177]
Preparation 5-1: (R)-1-[7-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-piperidine Synthesis of -3-carboxylic acid ethyl ester
[178]
According to the method described in Preparation Example 1-4, 7- (3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-2H-chromine-3-carbal obtained in Preparation Example 1-3 Dehyde (143 mg, 0.37 mmol) and (R)-piperidine-3-carboxylic acid ethyl ester hydrochloride (88 mg, 0.56 mmol) were used to obtain the title compound (105 mg, 53%).
[179]
NMR: 1 H-NMR (400 Hz, CDCl 3 ); δ 7.70 (s, 1H), 7.47 (d, 1H), 7.41 (d, 1H), 6.87 (d, 1H), 6.50 (dd, J = 2.4 Hz, 1H), 6.47 (d, 1H), 6.24 ( s, 1H), 5.11 (s, 2H), 4.83-4.75 (m, 1H), 4.73 (s, 2H), 4.13 (q, 2H), 3.00 (q. 2H), 2.87 (d, 1H), 2.67 (d, 1H), 2.53 (br, s, 1H), 2.22 (br, s, 1H), 2.01 (br, s, 1H), 1.88 (br, s, 1H), 1.71 (br, s, 1H) , 1.57 (d, 6H), 1.24 (t, 3H)
[180]
[181]
Example 5: (R)-1-[7-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-piperidin-3 -Synthesis of carboxylic acids
[182]

[183]
According to the method described in Example 1, (R)-1-[7-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-2H-chromine obtained in Preparation Example 5-1 Using -3-ylmethyl]-piperidine-3-carboxylic acid ethyl ester (105 mg, 0.20 mmol), the title compound (66 mg, 66%) was obtained.
[184]
NMR: 1 H-NMR (400 Hz, DMSO d6 ); δ 7.80 (d, 1H), 7.72 (s, 1H), 7.54 (dd, J = 1.2 Hz, 1H), 7.08 (d, 1H), 6.70 (s, 1H), 6.62 (dd, J = 2.4, 2.0) Hz, 1H), 6.54 (s, 1H), 5.22 (s, 2H), 5.04-4.97 (m, 1H), 4.89 (s, 2H), 3.81 (br, s, 2H), 3.51 (br, s, 1H), 3.36 (br, s, 2H), 3.00-2.80 (m, 3H), 2.02 (br, s, 1H), 1.87 (br, s, 2H), 1.46 (d, 6H)
[185]
[186]
Preparation 6-1: (S)-1-[7-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-piperidine Synthesis of -3-carboxylic acid ethyl ester
[187]
According to the method described in Preparation Example 1-4, 7- (3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-2H-chromine-3-carbal obtained in Preparation Example 1-3 Dehydride (126 mg, 0.33 mmol) and (S)-piperidine-3-carboxylic acid ethyl ester hydrochloride (77 mg, 0.49 mmol) were used to obtain the title compound (92 mg, 54%).
[188]
NMR: 1 H-NMR (400 Hz, CDCl 3 ); δ 7.70 (s, 1H), 7.47 (d, 1H), 7.41 (d, 1H), 6.86 (d, 1H), 6.50 (dd, J = 2.4 Hz, 1H), 6.47 (s, 1H), 6.24 ( s, 1H), 5.10 (s, 2H), 4.81-4.73 (m, 1H), 4.69 (s, 2H), 4.14-4.08 (m, 2H), 3.00 (q, 2H), 2.86 (d, 1H) , 2.67 (d, 1H), 2.53 (br, s, 1H), 2.23 (br, s, 1H), 2.03 (br, s, 1H), 1.88 (br, s, 1H), 1.71 (br, s, 1H), 1.56 (d, 6H), 1.24 (t, 3H)
[189]
[190]
Example 6: (S)-1-[7-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-piperidin-3 -Synthesis of carboxylic acids
[191]

[192]
According to the method described in Example 1, (S)-1-[7-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-2H-chromine obtained in Preparation Example 6-1 -3-ylmethyl]-piperidine-3-carboxylic acid ethyl ester (92 mg, 0.20 mmol) was used to obtain the title compound (78 mg, 89%).
[193]
NMR: 1 H-NMR (400 Hz, DMSO d6 ); δ 7.80 (d, 1H), 7.72 (s, 1H), 7.54 (d, 1H), 7.08 (d, 1H), 6.70 (s, 1H), 6.62 (dd, J = 2.4 Hz, 1H), 6.54 ( d, J = 2.4 Hz, 1H), 5.22 (s, 2H), 5.04-4.97 (m, 1H), 4.88 (s, 2H), 3.81 (br, s, 2H), 3.51 (br, s, 1H) , 3.35 (br, s, 2H), 2.99-2.80 (m, 3H), 2.04 (br, s, 1H), 1.87 (br, s, 2H), 1.46 (d, 6H)
[194]
[195]
Preparation 7-1: (S)-1-[7-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-pyrrolidine Synthesis of -3-carboxylic acid methyl ester
[196]
According to the method described in Preparation Example 1-4, 7- (3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-2H-chromine-3-carbal obtained in Preparation Example 1-3 Dehyde (137 mg, 0.36 mmol) and (S)-pyrrolidine-3-carboxylic acid methyl ester hydrochloride (90 mg, 0.54 mmol) were used to obtain the title compound (127 mg, 71%).
[197]
NMR: 1 H-NMR (400 Hz, CDCl 3 ); δ 7.69 (s, 1H), 7.46 (dd, J = 1.2 Hz, 1H), 7.41 (d, 1H), 6.86 (d, 1H), 6.52-6.47 (m, 2H), 6.26 (s, 1H), 5.10 (s, 2H), 4.83-4.76 (m, 1H), 4.74 (s, 2H), 3.68 (s, 3H), 3.12 (q, 2H), 3.01 (q, 1H), 2.85 (t, 1H) , 2.65-2.62 (m, 2H), 2.52 (q, 1H), 2.08-2.02 (m, 2H), 1.56 (d, 6H)
[198]
[199]
Example 7: (S)-1-[7-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-pyrrolidin-3 -Synthesis of carboxylic acids
[200]

[201]
According to the method described in Example 1, (S)-1-[7-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-2H-chromine obtained in Preparation 7-1 -3-ylmethyl]-pyrrolidine-3-carboxylic acid methyl ester (127 mg, 0.26 mmol) was used to obtain the title compound (97 mg, 79%).
[202]
NMR: 1 H-NMR (400 Hz, DMSO d6 ); δ 7.80 (d, 1H), 7.72 (s, 1H), 7.54 (d, 1H), 7.06 (d, 1H), 6.71 (s, 1H), 6.61 (dd, J = 2.0 Hz, 1H), 6.54 ( s, 1H), 5.22 (s, 2H), 5.04-4.98 (m, 1H), 4.86 (s, 2H), 3.87 (s, 2H), 3.32 (br, s. 5H), 2.22 (d, 2H) , 1.46 (d, 6H)
[203]
[204]
Preparation 8-1: 1-[7-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-3-chloromethyl-azetidine Synthesis of -3-carboxylic acid ethyl ester
[205]
According to the method described in Preparation Example 1-4, 7- (3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-2H-chromine-3-carbal obtained in Preparation Example 1-3 Dehydrate (93 mg, 0.24 mmol) and chloromethyl-azetidine-3-carboxylic acid ethyl ester hydrochloride (78 mg, 0.36 mmol) were used to obtain the title compound (53 mg, 41%).
[206]
NMR: 1 H-NMR (400 Hz, CDCl 3 ); δ 7.70 (s, 1H), 7.47 (dd, J = 1.2 Hz, 1H), 7.42 (d, 1H), 6.87 (d, 1H), 6.51 (d, 1H), 6.51 (dd, J = 2.4 Hz, 1H), 6.46 (d, 1H), 6.24 (s, 1H), 5.11 (s, 2H), 4.84-4.75 (m, 1H), 4.68 (s, 2H), 4.23 (q, 2H), 4.03 (s) , 2H), 3.38 (d, 2H), 3.30 (d, 2H), 3.12 (s, 2H), 1.57 (d, 6H), 1.29 (t, 3H)
[207]
[208]
Example 8: 1-[7-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-chloromethyl-azetidine-3-car synthesis of acids
[209]

[210]
1-[7-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-yl obtained in Preparation Example 8-1 according to the method described in Example 1 Methyl]-3-chloromethyl-azetidine-3-carboxylic acid ethyl ester (53 mg, 0.10 mmol) was used to give the title compound (42 mg, 83%).
[211]
NMR: 1 H-NMR (400 Hz, DMSO d6 ); δ 7.80 (d, 1H), 7.72 (s, 1H), 7.54 (d, 1H), 7.04 (d, 1H), 6.70 (s, 1H), 6.60 (d, 1H), 6.51 (s, 1H), 5.21 (s, 2H), 5.02-4.97 (m, 1H), 4.76 (s, 2H), 4.26 (br, s, 4H), 4.03 (d, 2H), 3.88 (s, 2H), 1.46 (d, 6H)
[212]
[213]
Preparation 9-1: (R)-1-[7-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-pyrrolidine Synthesis of -3-carboxylic acid methyl ester
[214]
According to the method described in Preparation Example 1-4, 7- (3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-2H-chromine-3-carbal obtained in Preparation Example 1-3 Dehyde (120 mg, 0.32 mmol) and (R)-pyrrolidine-3-carboxylic acid methyl ester hydrochloride (177 mg, 1.07 mmol) were used to obtain the title compound (121 mg, 78%).
[215]
NMR: 1 H-NMR (400 Hz, CDCl 3 ); δ 7.69 (s, 1H), 7.46 (dd, J = 1.2 Hz, 1H), 7.41 (d, 1H), 6.86 (d, 1H), 6.52-6.47 (m, 2H), 6.26 (s, 1H), 5.10 (s, 2H), 4.83-4.76 (m, 1H), 4.74 (s, 2H), 3.68 (s, 3H), 3.12 (q, 2H), 3.01 (q, 1H), 2.85 (t, 1H) , 2.65-2.62 (m, 2H), 2.52 (q, 1H), 2.08-2.02 (m, 2H), 1.56 (d, 6H)
[216]
[217]
Example 9: (R)-1-[7-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-pyrrolidin-3 -Synthesis of carboxylic acids
[218]

[219]
According to the method described in Example 1, (R)-1-[7-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-2H-chromine obtained in Preparation Example 9-1 -3-ylmethyl]-pyrrolidine-3-carboxylic acid methyl ester (121 mg, 0.24 mmol) was used to obtain the title compound (101 mg, 86%).
[220]
NMR: 1 H-NMR (400 Hz, DMSO d6 ); δ 7.80 (d, 1H), 7.73 (s, 1H), 7.54 (d, 1H), 7.06 (d, 1H), 6.72 (s, 1H), 6.61 (dd, J = 2.0 Hz, 1H), 6.53 ( d, J = 2.0 Hz, 1H), 5.22 (s, 2H), 5.04-4.97 (m, 1H), 4.87 (s, 2H), 3.87 (s, 2H), 3.31 (br, s, 3H), 2.51 (t, 2H), 2.22 (br, s, 1H), 2.16 (br, s, 1H), 1.46 (d, 6H)
[221]
[222]
Preparation 10-1: Synthesis of 7-hydroxy-4-methyl-2H-chromine-3-carbaldehyde
[223]
The title compound was obtained by the method described in International Patent Application Laid-Open No. 2010-064707.
[224]
NMR: 1 H-NMR (400 Hz, CDCl 3 ); δ 10.08 (s, 1H), 7.32 (d, 1H), 6.51 (dd, 1H), 6.38 (d, 1H), 4.88 (s, 2H), 2.45 (s, 3H)
[225]
[226]
Preparation 10-2: Synthesis of 7-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-4-methyl-2H-chromine-3-carbaldehyde
[227]
According to the method described in Preparation Example 1-3, (3-chloro-1-isopropyl-1H-indazol-5-yl)-methanol (193 mg, 0.86 mmol) obtained in Preparation Example 1-2 and Preparation 10 7-hydroxy-4-methyl-2H-chromine-3-carbaldehyde (136 mg, 0.72 mmol) obtained in -1 was used to obtain the title compound (104 mg, 30%).
[228]
NMR: 1 H-NMR (400 Hz, CDCl 3 ); δ 10.10 (s, 1H), 7.71 (s, 1H), 7.46-7.41 (m, 3H), 7.38 (d, 1H), 6.67 (dd, 1H), 6.54 (d, 1H), 5.16 (s, 2H) ), 4.90 (s, 2H), 4.81-4.72 (m, 1H), 2.44 (s, 3H), 1.57 (d, 6H)
[229]
[230]
Preparation 10-3: 1-[7-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-4-methyl-2H-chromin-3-ylmethyl]-piperidine Synthesis of -4-carboxylic acid ethyl ester
[231]
According to the method described in Preparation Example 1-4, 7-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-4-methyl-2H-chromine- obtained in Preparation 10-2 Using 3-carbaldehyde (104 mg, 0.26 mmol) and piperidine-4-carboxylic acid ethyl ester hydrochloride (62 mg, 0.39 mmol), the title compound (101 mg, 72%) was obtained.
[232]
NMR: 1 H-NMR (400 Hz, CDCl 3 ); δ 7.70 (s, 1H), 7.46 (d, 1H), 7.41 (d, 1H), 7.10 (d, 1H), 6.57 (dd, J = 2.4, 2.8 Hz, 1H), 6.50 (d, 1H), 5.12 (s, 2H), 4.83-4.74 (m, 1H), 4.65 (s, 2H), .81-4.72 (m, 1H), 4.12 (q, 2H), 3.07 (s, 2H), 2.83 (d , 2H), 2.28-2.22 (m, 1H), 1.99 (s, 3H), 1.98 (t, 2H), 1.85 (d, 2H), 1.75-1.66 (m, 2H), 1.57 (d, 6H), 1.25 (t, 3H)
[233]
[234]
Example 10: 1-[7-(3-Chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-4-methyl-2H-chromin-3-ylmethyl]-piperidin-4 -Synthesis of carboxylic acids
[235]

[236]
According to the method described in Example 1, 1-[7-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-4-methyl-2H-chromine obtained in Preparation 10-3 Using -3-ylmethyl]-piperidine-4-carboxylic acid ethyl ester (101 mg, 0.19 mmol), the title compound (34 mg, 35%) was obtained.
[237]
NMR: 1 H-NMR (400 Hz, DMSO d6 ); δ 7.79 (d, 1H), 7.72 (s, 1H), 7.54 (d, 1H), 7.19 (br, s, 1H), 6.63 (d, 1H), 6.51 (s, 1H), 5.21 (s, 2H) ), 5.02-4.98 (m, 1H), 4.60 (br, s, 2H), 3.33 (br, s, 4H), 3.17 (br, s, 2H), 2.80 (br, s, 2H), 2.22 (br) , s, 1H), 1.98 (s, 3H), 1.83 (br, s, 2H), 1.46 (d, 6H)
[238]
[239]
Preparation 11-1: Synthesis of 4-chloro-7-hydroxy-2H-chromine-3-carbaldehyde
[240]
The title compound was obtained by the method described in International Patent Application Laid-Open No. 2010-064707.
[241]
NMR: 1 H-NMR (400 Hz, CDCl 3 ); δ 10.09 (s, 1H), 7.57 (d, 1H), 6.54 (dd, 1H), 6.38 (d, 1H), 4.99 (s, 2H), 1.46 (s, 9H)
[242]
[243]
Preparation 11-2: Synthesis of 4-chloro-7- (3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-2H-chromine-3-carbaldehyde
[244]
According to the method described in Preparation Example 1-3, (3-chloro-1-isopropyl-1H-indazol-5-yl)-methanol (87 mg, 0.39 mmol) obtained in Preparation Example 1-2 and Preparation Example 11 The title compound (18 mg, 15%) was obtained using 4-chloro-7-hydroxy-2H-chromine-3-carbaldehyde (60 mg, 0.29 mmol) obtained in -1.
[245]
NMR: 1 H-NMR (400 Hz, CDCl 3 ); δ 10.11 (s, 1H), 7.71 (s, 1H), 7.63 (d, 1H), 7.46 (d, 1H), 6.71 (dd, 1H), 6.54 (d, 1H), 5.18 (s, 2H), 5.01 (s, 2H), 4.85-4.77 (m, 1H), 1.58 (d, 6H)
[246]
[247]
Preparation 11-3: 1- [4-chloro-7- (3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy) -2H-chromin-3-ylmethyl] -piperidine Synthesis of -4-carboxylic acid ethyl ester
[248]
According to the method described in Preparation Example 1-4, 4-chloro-7- (3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-2H-chromine- obtained in Preparation Example 11-2 Using 3-carbaldehyde (18 mg, 0.04 mmol) and piperidine-4-carboxylic acid ethyl ester hydrochloride (10 mg, 0.07 mmol), the title compound (12 mg, 50%) was obtained.
[249]
NMR: 1 H-NMR (500 HMz, CDCl 3 ); δ 7.70 (s, 1H), 7.47 (d, 1H), 7.42 (d, 1H), 7.36 (d, 1H), 6.59 (dd, J = 2.45 Hz, 1H), 6.49 (d, 1H), 5.12 ( s, 2H), 4.91-4.76 (m, 3H), 4.12 (q, 2H), 3.25 (s, 2H), 2.82 (d, 2H), 2.27-2.24 (m, 1H), 2.06 (t, 1H) , 1.86 (d, 2H), 1.73-1.67 (m, 2H), 1.57 (d, 6H), 1.24 (t, 3H)
[250]
[251]
Example 11: 1-[4-chloro-7-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-piperidin-4 -Synthesis of carboxylic acids
[252]

[253]
According to the method described in Example 1, 1- [4-chloro-7- (3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy) -2H-chromine obtained in Preparation Example 11-3 Using -3-ylmethyl]-piperidine-4-carboxylic acid ethyl ester (12 mg, 0.02 mmol), the title compound (10 mg, 86%) was obtained.
[254]
NMR: 1 H-NMR (500 HMz, DMSO d6 ); δ 7.77 (d, 1H), 7.70 (s, 1H), 7.51 (d, 1H), 7.36 (d, 1H), 6.72 (d, 1H), 6.62 (s, 1H), 5.23 (s, 2H), 4.98-4.91 (m, 3H), 3.30 (br, s, 4H), 3.03 (br, s, 1H), 2.46 (br, s, 3H), 1.99 (br, s, 2H), 1.80 (br, s) , 1H), 1.42 (d, 6H)
[255]
[256]
Preparation 12-1: Synthesis of 5-fluoro-7-hydroxy-2H-chromine-3-carbaldehyde
[257]
The title compound was obtained by the method described in International Patent Publication No. 2010-064707.
[258]
NMR: 1 H-NMR (400 Hz, CDCl 3 ); δ 9.54 (s, 1H), 7.44 (s, 1H), 6.22 (dd, 1H), 6.18 (d, 1H), 5.59 (s, 1H), 5.01 (d, 2H)
[259]
[260]
Preparation 12-2: Synthesis of 3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-5-fluoro-2H-chromine-3-carbaldehyde
[261]
According to the method described in Preparation Example 1-3, (3-chloro-1-isopropyl-1H-indazol-5-yl)-methanol (80 mg, 0.35 mmol) obtained in Preparation Example 1-2 and Preparation Example 12 5-fluoro-7-hydroxy-2H-chromine-3-carbaldehyde (57 mg, 0.30 mmol) obtained in -1 was used to obtain the title compound (19 mg, 14%).
[262]
NMR: 1 H-NMR (500 HMz, CDCl 3 ); δ 9.53 (s, 1H), 7.69 (s, 1H), 7.44 (s, 1H), 7.43 (d, 1H), 6.35 (d, 1H), 6.32 (s, 1H), 5.16 (s, 2H), 5.01 (s, 2H), 4.82-4.76 (m, 1H), 1.58 (d, 6H)
[263]
[264]
Preparation 12-3: 1-[7-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-5-fluoro-2H-chromin-3-ylmethyl]-piperid Synthesis of din-4-carboxylic acid ethyl ester
[265]
According to the method described in Preparation Example 1-4, 7- (3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-5-fluoro-2H-chromine obtained in Preparation Example 12-2 Using -3-carbaldehyde (19 mg, 0.05 mmol) and piperidine-4-carboxylic acid ethyl ester hydrochloride (11 mg, 0.07 mmol), the title compound (15 mg, 58%) was obtained.
[266]
NMR: 1 H-NMR (500 HMz, CDCl 3 ); δ 7.68 (s, 1H), 7.46-7.41 (m, 2H), 6.42 (s, 1H), 6.27-6.25 (m, 2H), 5.08 (s, 2H), 4.80-4.76 (m, 1H), 4.72 (s, 2H), 4.12 (q, 2H), 3.01 (s, 2H), 2.83 (d, 2H), 2.26-2.23 (m, 1H), 1.96 (t, 2H), 1.86 (d, 2H), 1.72 (t, 2H), 1.57 (d, 6H), 1.24 (t, 3H)
[267]
[268]
Example 12: 1-[7-(3-Chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-5-fluoro-2H-chromin-3-ylmethyl]-piperidine- Synthesis of 4-carboxylic acid
[269]

[270]
1-[7-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-5-fluoro-2H-chloro obtained in Preparation Example 12-3 according to the method described in Example 1 Min-3-ylmethyl]-piperidine-4-carboxylic acid ethyl ester (15 mg, 0.03 mmol) was used to obtain the title compound (12 mg, 81%).
[271]
NMR: 1 H-NMR (500 HMz, DMSO d6 ); δ 7.76 (d, 1H), 7.69 (s, 1H), 7.49 (d, 1H), 6.78 (br, s, 1H), 6.53 (d, 1H), 6.39 (s, 1H), 5.18 (s, 2H) ), 4.98-4.94 (m, 1H), 4.81 (br, s, 2H), 3.31 (br, s, 4H), 2.86 (br, s, 1H), 2.46 (br, s, 3H), 1.95 (br) , s, 2H), 1.79 (br, s, 1H), 1.42 (d, 6H)
[272]
[273]
Preparation 13-1: Synthesis of 5-bromo-3-trifluoromethyl-1H-indazole
[274]
The title compound was obtained by the method described in International Patent Publication No. 2008-086404.
[275]
NMR: 1 H-NMR (400 Hz, CDCl 3 ); δ 10.9(s, 1H), 8.02(s, 1H), 7.58(dd, 1H), 7.46(d, 1H)
[276]
[277]
Preparation 13-2: Synthesis of 5-bromo-1-isopropyl-3-trifluoromethyl-1H-indazole
[278]
According to the method described in Preparation Example 3-2, 5-bromo-3-trifluoromethyl-1H-indazole (540 mg, 2.04 mmol) and isopropyl iodide (0.41 mL) obtained in Preparation Example 13-1 , 4.08 mmol) to give the title compound (310 mg, 50%).
[279]
NMR: 1 H-NMR (400 Hz, CDCl 3 ); δ 7.98 (s, 1H), 7.52 (dd, 1H), 7.39 (d, 1H), 4.86 (m, 1H), 1.62 (d, 6H)
[280]
[281]
Preparation 13-3: Synthesis of 1-isopropyl-3-trifluoromethyl-1H-indazole-5-carbonitrile
[282]
After dissolving 5-bromo-1-isopropyl-3-trifluoromethyl-1H-indazole (310 mg, 1.01 mmol) obtained in Preparation Example 13-2 in N-methylpyrrolidone, zinc cyanide ( ZnCN 2 , 1.9 g, 14.16 mmol) and palladium tetrakitriphenylphosphine ([Pd(Ph 3 P) 4 ], 1.0 g, 0.71 mmol) were added dropwise. After stirring at 100° C. for 4 hours, water was added and the mixture was extracted with ethyl acetate. After washing with brine and drying over anhydrous magnesium sulfate, the filtered filtrate was distilled under reduced pressure. The residue was separated by column chromatography to obtain the title compound (100 mg, 39%).
[283]
NMR: 1 H-NMR (400 Hz, CDCl 3 ); δ 8.23 ​​(s, 1H), 7.62 (m, 2H), 4.89 (m, 1H), 1.64 (d, 6H)
[284]
[285]
Preparation 13-4: Synthesis of 1-isopropyl-3-trifluoromethyl-1H-indazole-5-carboxylic acid
[286]
After dissolving 1-isopropyl-3-trifluoromethyl-1H-indazole-5-carbonitrile (100 mg, 0.39 mmol) obtained in Preparation Example 13-3 in ethanol (100 ml), 6N aqueous sodium hydroxide solution ( 6.7 mL, 40.20 mmol) was added dropwise. After stirring under reflux for 18 hours, the solvent was removed under reduced pressure. A 1N aqueous hydrochloric acid solution was added, followed by extraction with ethyl acetate. It was washed with brine, dried over anhydrous magnesium sulfate, and the filtered filtrate was distilled under reduced pressure to obtain the title compound (69 mg, 65%).
[287]
[288]
Preparation 13-5: Synthesis of 1-isopropyl-3-trifluoromethyl-1H-indazole-5-carboxylic acid methyl ester
[289]
After dissolving 1-isopropyl-3-trifluoromethyl-1H-indazole-5-carboxylic acid (69 mg, 0.25 mmol) obtained in Preparation Example 13-4 in tetrahydrofuran (10 ml), 0.25 M A solution of diazomethane diethyl ether (1.2 mL, 0.3 mmol) was slowly added dropwise. After stirring at room temperature for 30 minutes, distillation under reduced pressure gave the title compound (53 mg, 75%).
[290]
NMR: 1 H-NMR (400 Hz, CDCl 3 ); δ 8.58 (s, 1H), 8.11 (dd, 1H), 7.52 (d, 1H), 4.91 (m, 1H), 3.96 (s, 3H), 1.62 (d, 6H)
[291]
[292]
Preparation 13-6: (1-isopropyl-3-trifluoromethyl-1H-indazol-5-yl) -synthesis of methanol
[293]
According to the method described in Preparation Example 3-4, 1-isopropyl-3-trifluoromethyl-1H-indazole-5-carboxylic acid methyl ester (53 mg, 0.19 mmol) obtained in Preparation Example 13-5 was prepared was used to give the title compound (30 mg, 61%).
[294]
[295]
Preparation 13-7: Synthesis of 7-(1-isopropyl-3-trifluoromethyl-1H-indazol-5-ylmethoxy)-2H-chromine-3-carbaldehyde
[296]
According to the method described in Preparation Example 1-3, (1-isopropyl-3-trifluoromethyl-1H-indazol-5-yl)-methanol (30 mg, 0.12 mmol) obtained in Preparation Example 13-6 and 7-hydroxy-2H-chromine-3-carbaldehyde (25 mg, 0.14 mmol) obtained in Preparation Example 1-1 was used to obtain the title compound (23 mg, 48%).
[297]
NMR: 1 H-NMR (400 Hz, CDCl 3 ); 9.53(s, 1H), 7.87(s, 1H), 7.52(m, 2H), 7.22(s, 1H), 7.14(d, 1H), 6.62(dd, 1H), 6.51(d, 1H), 5.17 (s, 2H), 5.03 (s, 2H), 4.90 (m, 1H), 1.62 (d, 6H)
[298]
[299]
Preparation 13-8: 1-[7-(1-isopropyl-3-trifluoromethyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-piperidin- Synthesis of 4-carboxylic acid ethyl ester
[300]
According to the method described in Preparation Example 1-4, 7-(1-isopropyl-3-trifluoromethyl-1H-indazol-5-ylmethoxy)-2H-chromin-3 obtained in Preparation Example 13-7 -carbaldehyde (23 mg, 0.06 mmol) and piperidine-4-carboxylic acid ethyl ester hydrochloride (12 mg, 0.08 mmol) were used to obtain the title compound (21 mg, 68%).
[301]
NMR: 1 H-NMR (500 HMz, CDCl 3 ); δ7.85(s, 1H), 7.52(s, 2H), 6.86(d, 1H), 6.49(m, 2H), 6.24(s, 1H), 5.12(s, 2H), 4.90(m, 1H) , 4.73(s, 2H), 4.13(q, 2H), 2.99(s, 2H), 2.84(m, 2H), 2.26(m, 1H), 1.85(m, 6H), 1.62(d, 6H), 1.25 (t, 3H)
[302]
[303]
Example 13: 1-[7-(1-Isopropyl-3-trifluoromethyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-piperidin-4- Synthesis of carboxylic acids
[304]

[305]
1-[7-(1-isopropyl-3-trifluoromethyl-1H-indazol-5-ylmethoxy)-2H-chromine- obtained in Preparation Example 13-8 according to the method described in Example 1 3-ylmethyl]-piperidine-4-carboxylic acid ethyl ester (21 mg, 0.04 mmol) was used to obtain the title compound (3 mg, 15%).
[306]
NMR: 1 H-NMR (500 HMz, DMSO d6 ); δ 7.89(s, 1H), 7.55(s, 2H), 6.92(d, 1H), 6.54(m, 2H), 6.36(s, 1H), 5.16(s, 2H), 4.92(m, 1H), 4.80(s, 2H), 3.23(s,2H), 3.09(m, 4H), 2.37(m, 1H), 1.89(m, 4H), 1.65(d, 6H)
[307]
[308]
Preparation 14-1: Synthesis of 5-bromo-3-ethyl-1H-indazole
[309]
The title compound was obtained by the method described in International Patent Publication No. 2005-085227.
[310]
NMR: 1 H-NMR (400 Hz, CDCl 3 ); δ 10.20 (s, 1H), 7.83 (d, 1H), 7.48 (dd, 1H), 7.32 (d, 1H), 2.57 (s, 3H)
[311]
[312]
Preparation 14-2: Synthesis of 5-bromo-1-isopropyl-3-ethyl-1H-indazole
[313]
According to the method described in Preparation Example 3-2, 5-bromo-3-ethyl-1H-indazole (740 mg, 3.29 mmol) and isopropyl iodide (0.65 mL, 6.58 mmol) obtained in Preparation Example 14-1 ) to give the title compound (680 mg, 77%).
[314]
NMR: 1 H-NMR (400 Hz, CDCl 3 ); δ 7.81(s, 1H), 7.40(dd, 1H), 7.26(d, 1H), 4.73(m, 1H), 2.96(q, 2H), 1.35(t, 3H)
[315]
[316]
Preparation 14-3: Synthesis of 1-isopropyl-3-ethyl-1H-indazole-5-carbonitrile
[317]
According to the method described in Preparation Example 13-3, the title compound (190) using 5-bromo-1-isopropyl-3-ethyl-1H-indazole (680 mg, 2.55 mmol) obtained in Preparation 14-2 mg, 35%) was obtained.
[318]
[319]
Preparation 14-4: Synthesis of 1-isopropyl-3-ethyl-1H-indazole-5-carboxylic acid
[320]
According to the method described in Preparation Example 13-4, the title compound (85) using 1-isopropyl-3-ethyl-1H-indazole-5-carbonitrile (190 mg, 0.89 mmol) obtained in Preparation 14-3 mg, 41%) was obtained.
[321]
[322]
Preparation 14-5: Synthesis of 1-isopropyl-3-ethyl-1H-indazole-5-carboxylic acid methyl ester
[323]
After dissolving 1-isopropyl-3-ethyl-1H-indazole-5-carboxylic acid (85 mg, 0.36 mmol) obtained in Preparation Example 14-4 in tetrahydrofuran (10 ml), 0.25M diazomethane Diethyl ether solution (1.73 mL, 0.43 mmol) was slowly added dropwise. After stirring at room temperature for 30 minutes, it was distilled under reduced pressure to obtain the title compound (69 mg, 78%).
[324]
[325]
Preparation 14-6: (1-isopropyl-3-ethyl-1H-indazol-5-yl) -synthesis of methanol
[326]
According to the method described in Preparation Example 3-4, using 1-isopropyl-3-ethyl-1H-indazole-5-carboxylic acid methyl ester (69 mg, 0.28 mmol) obtained in Preparation Example 14-5, the title The compound (40 mg, 65%) was obtained.
[327]
[328]
Preparation 14-7: Synthesis of 7-(1-isopropyl-3-ethyl-1H-indazol-5-ylmethoxy)-2H-chromine-3-carbaldehyde
[329]
According to the method described in Preparation Example 1-3, (1-isopropyl-3-ethyl-1H-indazol-5-yl)-methanol (40 mg, 0.18 mmol) obtained in Preparation Example 14-6 and Preparation Example 145 7-hydroxy-2H-chromine-3-carbaldehyde (38 mg, 0.22 mmol) obtained in -1 was used to obtain the title compound (29 mg, 43%).
[330]
[331]
Preparation 14-8: 1-[7-(1-isopropyl-3-ethyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-piperidine-4-car Synthesis of acid ethyl ester
[332]
According to the method described in Preparation Example 1-4, 7-(1-isopropyl-3-ethyl-1H-indazol-5-ylmethoxy)-2H-chromine-3-carbal obtained in Preparation Example 14-7 Dehydride (29 mg, 0.08 mmol) and piperidine-4-carboxylic acid ethyl ester hydrochloride (19 mg, 0.12 mmol) were used to obtain the title compound (20 mg, 48%).
[333]
NMR: 1 H-NMR (500 HMz, CDCl 3 ); δ 7.70(s, 1H), 7.38(s, 2H), 6.85(d, 1H), 6.48(m, 2H), 6.23(s, 1H), 5.08(s, 2H), 4.78(m, 1H), 4.72(s, 2H), 4.12(q, 2H), 2.99(m, 4H), 2.82(m, 2H), 2.25(m, 1H), 1.83(m, 6H), 1.55(d, 6H), 1.37 (t, 3H), 1.25 (t, 3H)
[334]
[335]
Example 14: 1-[7-(1-Isopropyl-3-ethyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-piperidine-4-carboxylic acid synthesis of
[336]

[337]
1-[7-(1-isopropyl-3-ethyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-yl obtained in Preparation Example 14-8 according to the method described in Example 1 Methyl]-piperidine-4-carboxylic acid ethyl ester (20 mg, 0.04 mmol) was used to give the title compound (10 mg, 51%).
[338]
NMR: 1 H-NMR (500 HMz, DMSO d6 ); δ 7.69(s, 1H), 7.37(s, 2H), 6.86(d, 1H), 6.49(m, 2H), 6.29(s, 1H), 5.06(s, 2H), 4.76(m, 3H), 3.16(s, 2H), 3.05(m, 3H), 2.27(m, 1H), 2.03(m, 6H), 1.54(d, 6H), 1.36(t, 3H)
[339]
[340]
Preparation 15-1: Synthesis of azepaine-4-carboxylic acid ethyl ester, hydrochloride
[341]
The title compound was obtained by the method described in US Patent Publication No. 2007-0225275.
[342]
NMR: 1 H-NMR (500 HMz, CDCl 3 ); δ 9.55 (br, s, 2H), 4.09 (m, 2H), 3.41-2.95 (m, 4H), 2.68 (br, s, 1H), 2.41-1.73 (m, 6H), 1.22-1.10 (m, 3H)
[343]
[344]
Preparation 15-2: 1-[7-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-azepaine-4-carboxyl Synthesis of acid ethyl esters
[345]
According to the method described in Preparation Example 1-4, 7- (3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-2H-chromine-3-carbal obtained in Preparation Example 1-3 Dehydrate (204 mg, 0.53 mmol), azepaine-4-carboxylic acid ethyl ester, and hydrochloride (166 mg, 0.80 mmol) were used to obtain the title compound (229 mg, 79%).
[346]
NMR: 1 H-NMR (500 HMz, CDCl 3 ); δ 7.69(s, 1H), 7.48-7.44(m, 1H), 7.41-7.39(m, 1H), 6.88-6.84(m, 1H), 6.51-6.45(m, 2H), 6.21(s, 1H) , 5.10(s, 2H), 4.78-4.73(m, 1H), 4.73(s, 2H), 4.14-4.08(m, 2H), 3.10(s, 2H), 2.70-2.63(m, 1H), 2.62 -2.50(m, 4H), 1.99-1.88(m, 2H), 1.87-1.71(m, 3H), 1.62-1.51(m, 7H), 1.27-1.20(m, 3H)
[347]
[348]
Example 15: of 1-[7-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-azepaine-4-carboxylic acid synthesis
[349]

[350]
1-[7-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-yl obtained in Preparation Example 15-2 according to the method described in Example 1 Methyl]-azepaine-4-carboxylic acid ethyl ester (229 mg, 0.43 mmol) was used to give the title compound (170 mg, 78%).
[351]
NMR: 1 H-NMR (500 HMz, DMSO d6 ); δ 7.75(d, 1H), 7.68(s, 1H), 7.49(d, 1H), 7.01(d, 1H), 6.67(s, 1H), 6.56(d, 1H), 6.49(s, 1H), 5.18(s, 2H), 5.02-4.92(m, 1H), 4.82(s, 2H), 3.76(s, 2H), 3.33-2.88(m, 4H), 2.59(br, s, 1H), 2.19- 1.73(m, 6H), 1.49-1.35(m, 7H)
[352]
[353]
Preparation 16-1: Synthesis of 3-chloro-1-propyl-1H-indazole-5-carboxylic acid methyl ester
[354]
According to the method described in Preparation Example 3-3, the title compound (643 mg, using 1-propyl-1H-indazole-5-carboxylic acid methyl ester (598 mg, 2.74 mmol) obtained in Preparation Example 3-2 93%) was obtained.
[355]
NMR: 1 H-NMR (500 HMz, CDCl 3 ); δ 8.31(s, 1H), 7.99-7.95(dd, 1H), 7.29(d, 1H), 4.20(t, 2H), 3.86(s, 3H), 1.89-1.83(m, 2H), 0.84(t) , 3H)
[356]
[357]
Preparation 16-2: Synthesis of (3-chloro-1-propyl-1H-indazol-5-yl)-methanol
[358]
According to the method described in Preparation Example 3-4, the title compound using 3-chloro-1-propyl-1H-indazole-5-carboxylic acid methyl ester (256 mg, 1.01 mmol) obtained in Preparation 16-1 (212 mg, 93%) was obtained.
[359]
NMR: 1 H-NMR (500 HMz, CDCl 3 ); δ 7.58(s, 1H), 7.41-7.38(dd, 1H), 7.31(d, 1H), 4.74(s, 2H), 4.22(t, 2H), 2.61(br, s, 1H), 1.92-1.84 (m, 2H), 0.87 (t, 3H)
[360]
[361]
Preparation 16-3: Synthesis of 7-(3-chloro-1-propyl-1H-indazol-5-ylmethoxy)-2H-chromine-3-carbaldehyde
[362]
According to the method described in Preparation Example 3-5, (3-chloro-1-propyl-1H-indazol-5-yl)-methanol (97 mg, 0.43 mmol) obtained in Preparation Example 16-2 and Preparation Example 1- 7-hydroxy-2H-chromine-3-carbaldehyde (76 mg, 0.43 mmol) obtained in Step 1 was used to obtain the title compound (63 mg, 38%).
[363]
NMR: 1 H-NMR (500 HMz, CDCl 3 ); δ 9.52(s, 1H), 7.71(s, 1H), 7.48-7.36(m, 3H), 7.15-7.12(m, 1H), 6.62-6.60(m, 1H), 6.50(m, 1H), 5.15 (s, 2H), 5.02 (s, 2H), 4.30-4.24 (m, 2H), 1.98-1.89 (m, 2H), 0.94-0.86 (m, 3H)
[364]
[365]
Preparation 16-4: 1-[7-(3-chloro-1-propyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-azetidine-3-carboxylic acid Synthesis of methyl esters
[366]
According to the method described in Preparation Example 1-4, 7-(3-chloro-1-propyl-1H-indazol-5-ylmethoxy)-2H-chromine-3-carbaldehyde obtained in Preparation Example 16-3 (65 mg, 0.17 mmol) and azetidine-3-carboxylic acid methyl ester hydrochloride (51 mg, 0.34 mmol) were used to obtain the title compound (50 mg, 62%).
[367]
NMR: 1 H-NMR (500 HMz, CDCl 3 ); δ 7.69(s, 1H), 7.46(d, 1H), 7.37(d, 1H), 6.86(d, 1H), 6.50(d, 1H), 6.45(d, 1H), 6.23(s, 1H), 5.09(s, 2H), 4.68(s, 2H), 4.26(t, 2H), 3.70(s, 3H), 3.51(t, 2H), 3.28(m, 3H), 3.09(s, 2H), 1.92 (m, 2H), 0.90 (t, 3H)
[368]
[369]
Example 16: Synthesis of 1-[7-(3-chloro-1-propyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-azetidine-3-carboxylic acid
[370]

[371]
1-[7-(3-chloro-1-propyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl obtained in Preparation Example 16-4 according to the method described in Example 1 ]-azetidine-3-carboxylic acid methyl ester (50 mg, 0.16 mmol) was used to obtain the title compound (15 mg, 19%).
[372]
NMR: 1 H-NMR (500 MHz, CDCl 3 ); δ 7.69(s, 1H), 7.46(d, 1H), 7.37(d, 1H), 6.86(d, 1H), 6.50(d, 1H), 6.45(d, 1H), 6.23(s, 1H), 5.09(s, 2H), 4.68(s, 2H), 4.26(t, 2H), 3.70(s, 3H), 3.51(t, 2H), 3.27(m, 1H), 3.09(s, 2H), 1.92 (m, 2H)
[373]
[374]
Preparation 17-1: 1-[7-(3-chloro-1-propyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-piperidine-4-carboxyl Synthesis of acid ethyl ester
[375]
According to the method described in Preparation Example 1-4, 7-(3-chloro-1-propyl-1H-indazol-5-ylmethoxy)-2H-chromine-3-carbaldehyde obtained in Preparation Example 16-3 (63 mg, 0.17 mmol) and piperidine-4-carboxylic acid ethyl ester hydrochloride (39 mg, 0.25 mmol) were used to obtain the title compound (22 mg, 25%).
[376]
NMR: 1 H-NMR (500 HMz, CDCl 3 ); δ 7.69(s, 1H), 7.46(d, 1H), 7.37(m, 1H), 6.85(d, 1H), 6.53-6.45(m, 2H), 6.23(s, 1H), 5.10(s, 2H) ), 4.72(s, 2H), 4.27(t, 2H), 4.14-4.09(m, 2H), 2.98(s, 2H), 2.83(d, 2H), 2.25(m, 1H), 2.01-1.87( m, 6H), 1.71-1.68 (m, 2H), 1.24 (t, 3H), 0.91 (t, 3H)
[377]
[378]
Example 17: 1-[7-(3-chloro-1-propyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-piperidine-4-carboxylic acid synthesis
[379]

[380]
1-[7-(3-chloro-1-propyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl obtained in Preparation Example 17-1 according to the method described in Example 1 ]-piperidine-4-carboxylic acid ethyl ester (22 mg, 0.04 mmol) was used to obtain the title compound (16 mg, 80%).
[381]
NMR: 1 H-NMR (500 MHz, DMSO d6 ); δ 7.75(d, 1H), 7.69(s, 1H), 7.50(dd, 1H), 7.04(m, 1H), 6.68-6.54(m, 2H), 6.50(s, 1H), 5.20(s, 2H) ), 4.72(s, 2H), 4.33-4.22(m, 4H), 2.15-1.91(m, 2H), 1.87-1.65(m, 6H), 1.46-1.04(m, 4H), 0.80-0.71(m) , 3H)
[382]
[383]
Preparation 18-1: Synthesis of 1-cyclopropylmethyl-1H-indazole-5-carboxylic acid methyl ester
[384]
According to the method described in Preparation Example 3-2, 1H-indazole-5-carboxylic acid methyl ester (200 mg, 1.13 mmol) and cyclopropylmethyl bromide (0.12 mL, 1.25 mmol) obtained in Preparation Example 3-1 were prepared. 1-cyclopropylmethyl-1H-indazole-5-carboxylic acid methyl ester (116 mg, 55%) was obtained.
[385]
[386]
Preparation 18-2: Synthesis of 3-chloro-1-cyclopropylmethyl-1H-indazole-5-carboxylic acid methyl ester
[387]
According to the method described in Preparation Example 3-3, the title compound (128) using 1-cyclopropylmethyl-1H-indazole-5-carboxylic acid methyl ester (116 mg, 0.55 mmol) obtained in Preparation 18-1 mg, 93%) was obtained.
[388]
NMR: 1 H-NMR (500 HMz, CDCl 3 ); δ 8.42 (s, 1H), 8.06 (dd, 1H), 7.38 (d, 1H), 4.19 (d, 2H), 3.94 (s, 3H), 1.32 (m, 1H), 0.59 (m, 2H), 0.40 (m, 2H)
[389]
[390]
Preparation 18-3: Synthesis of (3-chloro-1-cyclopropylmethyl-1H-indazol-5-yl)-methanol
[391]
According to the method described in Preparation Example 3-4, using 3-chloro-1-cyclopropylmethyl-1H-indazole-5-carboxylic acid methyl ester (128 mg, 0.51 mmol) obtained in Preparation Example 18-2 The title compound (106 mg, 93%) was obtained.
[392]
[393]
Preparation 18-4: Synthesis of 7-(3-chloro-1-cyclopropylmethyl-1H-indazol-5-ylmethoxy)-2H-chromine-3-carbaldehyde
[394]
According to the method described in Preparation Example 3-5, (3-chloro-1-cyclopropylmethyl-1H-indazol-5-yl)-methanol (48 mg, 0.22 mmol) obtained in Preparation 18-3 and Preparation Example 7-hydroxy-2H-chromine-3-carbaldehyde (38 mg, 0.22 mmol) obtained in 1-1 was used to obtain the title compound (31 mg, 38%).
[395]
[396]
Preparation 18-5: 1-[7-(3-chloro-1-cyclopropylmethyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-piperidin-4- Synthesis of carboxylic acid ethyl ester
[397]
According to the method described in Preparation Example 1-4, 7- (3-chloro-1-cyclopropylmethyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-car obtained in Preparation Example 18-4 Valdehyde (31 mg, 0.08 mmol) and piperidine-4-carboxylic acid ethyl ester hydrochloride (20 mg, 0.13 mmol) were used to obtain the title compound (11 mg, 25%).
[398]
NMR: 1 H-NMR (500 HMz, CDCl 3 ); δ 7.70(s, 1H), 7.46(d, 1H), 7.40(d, 1H), 6.85(d, 1H), 6.48(m, 2H), 6.23(s, 1H), 5.10(s, 2H), 4.72(s, 2H), 4.20(d, 2H), 4.14(q, 2H), 2.98(s, 2H), 2.83(m, 2H), 2.26(m, 1H), 1.95(m, 2H), 1.86 (m, 2H), 1.72 (m, 2H), 1.25 (m, 1H), 1.23 (t, 3H), 0.57 (m, 2H), 0.40 (m, 2H)
[399]
[400]
Example 18: 1-[7-(3-chloro-1-cyclopropylmethyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-piperidine-4-carboxyl synthesis of acids
[401]

[402]
1-[7-(3-chloro-1-cyclopropylmethyl-1H-indazol-5-ylmethoxy)-2H-chromin-3- obtained in Preparation Example 18-5 according to the method described in Example 1 Using ethyl]-piperidine-4-carboxylic acid ethyl ester (11 mg, 0.02 mmol), the title compound (8 mg, 80%) was obtained.
[403]
NMR: 1 H-NMR (500 MHz, DMSO d6 ); δ 7.67(s, 1H), 7.43(d, 1H), 7.37(d, 1H), 6.88(d, 1H), 6.50(d, 1H), 6.44(s, 1H), 6.39(s, 1H), 5.07(s, 2H), 4.79(s, 2H), 4.16(d, 2H), 3.35(s, 2H), 3.19(m, 2H), 2.34(m, 3H), 2.03(m, 2H), 1.91 (m, 2H), 1.25 (m, 1H), 0.56 (m, 2H), 0.38 (m, 2H)
[404]
[405]
Preparation 19-1: Synthesis of 1-cyclopentyl-1H-indazole-5-carboxylic acid methyl ester
[406]
According to the method described in Preparation Example 3-2, 1H-indazole-5-carboxylic acid methyl ester (600 mg, 3.41 mmol) and cyclopentyl bromide (1.1 mL, 10.23 mmol) obtained in Preparation Example 3-1 were used. Thus, 1-cyclopentyl-1H-indazole-5-carboxylic acid methyl ester (450 mg, 53%) was obtained.
[407]
NMR: 1 H-NMR (500 HMz, CDCl 3 ); δ 8.49(s, 1H), 8.08(s, 1H), 8.02(d, 1H), 7.44(d, 1H), 4.99(m, 1H), 3.93(s, 3H), 2.18(m, 4H), 1.97 (m, 2H), 1.75 (m, 2H)
[408]
[409]
Preparation 19-2: Synthesis of 3-chloro-1-cyclopentyl-1H-indazole-5-carboxylic acid methyl ester
[410]
According to the method described in Preparation Example 3-3, the title compound (135 mg) using 1-cyclopentyl-1H-indazole-5-carboxylic acid methyl ester (134 mg, 0.55 mmol) obtained in Preparation Example 19-1 , 93%) was obtained.
[411]
[412]
Preparation 19-3: Synthesis of (3-chloro-1-cyclopentyl-1H-indazol-5-yl)-methanol
[413]
According to the method described in Preparation Example 3-4, using the 3-chloro-1-cyclopentyl-1H-indazole-5-carboxylic acid methyl ester (135 mg, 0.51 mmol) obtained in Preparation Example 19-2, the title The compound (112 mg, 93%) was obtained.
[414]
[415]
Preparation 19-4: Synthesis of 7-(3-chloro-1-cyclopentyl-1H-indazol-5-ylmethoxy)-5-fluoro-2H-chromine-3-carbaldehyde
[416]
According to the method described in Preparation Example 3-5, (3-chloro-1-cyclopentyl-1H-indazol-5-yl)-methanol (88 mg, 0.35 mmol) obtained in Preparation Example 19-3 and Preparation Example 12 5-fluoro-7-hydroxy-2H-chromine-3-carbaldehyde (57 mg, 0.30 mmol) obtained in -1 was used to obtain the title compound (52 mg, 35%).
[417]
[418]
Preparation 19-5: 1-[7-(3-chloro-1-cyclopentyl-1H-indazol-5-ylmethoxy)-5-fluoro-2H-chromin-3-ylmethyl]-piperid Synthesis of din-4-carboxylic acid ethyl ester
[419]
According to the method described in Preparation Example 1-4, 7- (3-chloro-1-cyclopentyl-1H-indazol-5-ylmethoxy)-5-fluoro-2H-chromine obtained in Preparation Example 19-4 Using -3-carbaldehyde (52 mg, 0.12 mmol) and piperidine-4-carboxylic acid ethyl ester hydrochloride (38 mg, 0.24 mmol), the title compound (40 mg, 58%) was obtained.
[420]
NMR: 1 H-NMR (500 HMz, CDCl 3 ); δ 7.66(s, 1H), 7.42(m, 2H), 6.41(s, 1H), 6.25(m, 2H), 5.06(s, 2H), 4.90(m, 1H), 4.72(s, 2H), 4.11(q, 2H), 3.00(s, 2H), 2.82(m, 2H), 2.15(m, 1H), 2.13(m, 4H), 1.97(m, 4H), 1.86(m, 2H), 1.72 (m, 4H), 1.24 (t, 3H)
[421]
[422]
Example 19: 1-[7-(3-Chloro-1-cyclopentyl-1H-indazol-5-ylmethoxy)-5-fluoro-2H-chromin-3-ylmethyl]-piperidine- Synthesis of 4-carboxylic acid
[423]

[424]
1-[7-(3-chloro-1-cyclopentyl-1H-indazol-5-ylmethoxy)-5-fluoro-2H-chloro obtained in Preparation Example 19-5 according to the method described in Example 1 Min-3-ylmethyl]-piperidine-4-carboxylic acid ethyl ester (40 mg, 0.07 mmol) was used to obtain the title compound (31 mg, 81%).
[425]
NMR: 1 H-NMR (500 HMz, DMSO d6 ); δ 7.66(s, 1H), 7.42(m, 2H), 6.52(s, 1H), 6.26(m, 2H), 5.06(s, 2H), 4.91(m, 1H), 4.78(s, 2H), 3.25(s, 2H), 3.09(m, 2H), 2.30(m, 2H), 2.15(m, 5H), 1.96(m, 4H), 1.86(m, 2H), 1.71(m, 2H)
[426]
[427]
Preparation 20-1: Synthesis of 1-isobutyl-1H-indazole-5-carboxylic acid methyl ester
[428]
According to the method described in Preparation Example 3-2, 1H-indazole-5-carboxylic acid methyl ester (1.9 g, 11.24 mmol) and isobutyl iodide (2.6 mL, 22.48 mmol) obtained in Preparation Example 3-1 was used to obtain 1-isobutyl-1H-indazole-5-carboxylic acid methyl ester (1.2 g, 45%).
[429]
[430]
Preparation 20-2: Synthesis of 3-chloro-1-isobutyl-1H-indazole-5-carboxylic acid methyl ester
[431]
According to the method described in Preparation Example 3-3, the title compound (1.02 g) using 1-isobutyl-1H-indazole-5-carboxylic acid methyl ester (1.2 g, 5.1 mmol) obtained in Preparation Example 20-1. , 75%) was obtained.
[432]
NMR: 1 H-NMR (500 HMz, CDCl 3 ); δ 8.36(br, s, 1H), 8.02-8.00(m, 1H), 7.32(d, 1H), 4.06(d, 2H), 3.89(s, 3H), 2.31-2.24(m, 1H), 0.87 (d, 6H)
[433]
[434]
Preparation 20-3: Synthesis of (3-chloro-1-isobutyl-1H-indazol-5-yl)-methanol
[435]
According to the method described in Preparation Example 3-4, using the 3-chloro-1-isobutyl-1H-indazole-5-carboxylic acid methyl ester (691 mg, 2.59 mmol) obtained in Preparation 20-2, the title The compound (560 mg, 91%) was obtained.
[436]
NMR: 1 H-NMR (500 HMz, CDCl 3 ); δ 7.55(br, s, 1H), 7.37-7.34(m, 1H), 7.27(d, 1H), 4.71(s, 2H), 4.02(d, 2H), 3.15(s, 1H), 2.27-2.21 (m, 1H), 0.85 (d, 6H)
[437]
[438]
Preparation 20-4: Synthesis of 7-(3-chloro-1-isobutyl-1H-indazol-5-ylmethoxy)-5-fluoro-2H-chromine-3-carbaldehyde
[439]
According to the method described in Preparation Example 3-5, (3-chloro-1-isobutyl-1H-indazol-5-yl)-methanol (152 mg, 0.64 mmol) obtained in Preparation Example 20-3 and Preparation Example 12 5-fluoro-7-hydroxy-2H-chromine-3-carbaldehyde (124 mg, 0.64 mmol) obtained in -1 was used to obtain the title compound (84 mg, 32%).
[440]
NMR: 1 H-NMR (500 HMz, CDCl 3 ); δ 9.52 (m, 1H), 7.69 (br, s, 1H), 7.45-7.35 (m, 3H), 6.36-6.31 (m, 2H), 5.12 (s, 2H), 5.00 (m, 2H), 4.10 (m, 2H), 2.34-2.29 (m, 1H), 0.90 (d, 6H)
[441]
[442]
Preparation 20-5: 1-[7-(3-chloro-1-isobutyl-1H-indazol-5-ylmethoxy)-5-fluoro-2H-chromin-3-ylmethyl]-piperid Synthesis of din-4-carboxylic acid ethyl ester
[443]
According to the method described in Preparation Example 1-4, 7- (3-chloro-1-isobutyl-1H-indazol-5-ylmethoxy)-5-fluoro-2H-chromine obtained in Preparation Example 20-4 Using -3-carbaldehyde (53 mg, 0.13 mmol) and piperidine-4-carboxylic acid ethyl ester hydrochloride (30 mg, 0.19 mmol), the title compound (23 mg, 33%) was obtained.
[444]
NMR: 1 H-NMR (500 HMz, CDCl 3 ); δ 7.68(s, 1H), 7.46-7.43(m, 1H), 7.37(d, 1H), 6.43(s, 1H), 6.28-6.25(m, 2H), 5.07(s, 2H), 4.73(s) , 2H), 4.15-4.05 (m, 4H), 3.01 (s, 2H), 2.82 (d, 2H), 2.36-2.22 (m, 2H), 1.96 (t, 2H), 1.86 (d, 2H), 1.75-1.68 (m, 2H), 1.28-1.19 (m, 3H), 0.91 (d, 6H)
[445]
[446]
Example 20: 1-[7-(3-Chloro-1-isobutyl-1H-indazol-5-ylmethoxy)-5-fluoro-2H-chromin-3-ylmethyl]-piperidine- Synthesis of 4-carboxylic acid
[447]

[448]
1-[7-(3-chloro-1-isobutyl-1H-indazol-5-ylmethoxy)-5-fluoro-2H-chloro obtained in Preparation Example 20-5 according to the method described in Example 1 Min-3-ylmethyl]-piperidine-4-carboxylic acid ethyl ester (23 mg, 0.04 mmol) was used to obtain the title compound (21 mg, 93%).
[449]
NMR: 1 H-NMR (500 HMz, DMSO d6 ); δ 7.76(d, 1H), 7.71(s, 1H), 7.50(d, 1H), 6.80(s, 1H), 6.58-6.46(m, 1H), 6.41(s, 1H), 5.21-5.09(m) , 2H), 4.81(s, 2H), 4.19-4.08(m, 2H), 3.88-3.71(m, 2H), 3.48-3.30(m, 2H), 2.87(m, 1H), 2.19-1.71(m) , 6H), 1.20-1.15 (m, 2H), 0.83-0.71 (m, 6H)
[450]
[451]
Preparation 21-1: 1-[7-(3-chloro-1-isobutyl-1H-indazol-5-ylmethoxy)-5-fluoro-2H-chromin-3-ylmethyl]-azepaine Synthesis of -4-carboxylic acid ethyl ester
[452]
According to the method described in Preparation Example 1-4, 7- (3-chloro-1-isobutyl-1H-indazol-5-ylmethoxy)-5-fluoro-2H-chromine obtained in Preparation Example 20-4 -3-carbaldehyde (47 mg, 0.11 mmol) and azepaine-4-carboxylic acid ethyl ester hydrochloride (35 mg, 0.17 mmol) were used to obtain the title compound (40 mg, 62%).
[453]
NMR: 1 H-NMR (500 HMz, CDCl 3 ); δ 7.68(s, 1H), 7.46-7.43(m, 1H), 7.37(d, 1H), 6.42(s, 1H), 6.28-6.24(m, 2H), 5.07(s, 2H), 4.74(s) , 2H), 4.13-4.05 (m, 5H), 3.14 (s, 2H), 2.75-2.48 (m, 4H), 2.35-2.28 (m, 1H), 2.03-1.71 (m, 5H), 1.58 (br , s, 1H), 1.24 (t, 3H), 0.91 (d, 6H)
[454]
[455]
Example 21: 1-[7-(3-Chloro-1-isobutyl-1H-indazol-5-ylmethoxy)-5-fluoro-2H-chromin-3-ylmethyl]-azepain-4 -Synthesis of carboxylic acids
[456]

[457]
1-[7-(3-chloro-1-isobutyl-1H-indazol-5-ylmethoxy)-5-fluoro-2H-chloro obtained in Preparation Example 21-1 according to the method described in Example 1 Min-3-ylmethyl]-azepaine-4-carboxylic acid ethyl ester (40 mg, 0.07 mmol) was used to obtain the title compound (31 mg, 82%).
[458]
NMR: 1 H-NMR (500 HMz, DMSO d6 ); δ 7.76(d, 1H), 7.71(s, 1H), 7.50(d, 1H), 6.83(s, 1H), 6.58-6.52(m, 1H), 6.40(s, 1H), 5.18(s, 2H) ), 4.84(s, 2H), 4.18-4.12(m, 2H), 3.83(s, 2H), 3.33-2.82(m, 4H), 2.59(br, s, 1H), 2.16-1.65(m, 6H) ), 1.31-1.05 (m, 2H), 0.81 (d, 6H)
[459]
[460]
Experimental Example: Evaluation of Ca2+ Inducing Ability of Test Compounds Using Human Sphingosine-1-phosphate Expression Cell Lines
[461]
(1) Test method: EC 50
[462]
This is a functional experimental method to confirm the treatment effect of an agonist by increasing calcium in CHO (Chinese hamster ovary) cells overexpressing the human S1P1 receptor (S1P1 receptor) that reacts with sphingosine-1 phosphate (S1P). S1P is a G-protein coupled receptor (GPCR) linked to the Gi protein that increases the intracellular calcium concentration by reacting with the S1P1 receptor. CHO-K1 cells to create a stable cell line are cells that do not change the calcium concentration due to S1P, and are transfected with human S1P receptors for each subtype and show signals by these receptors.
[463]
To create human S1P1-S1P5 overexpressing CHO cells, purchase human clones for each subtype with HA attached to the N-terminal residue from the Missouri S&T cDNA Resource Center (S1P1: EDG010TN00, S1P2: EDG020TN00, S1P3: EDG030TN00, S1P4: EDG S1P5: EDG080TN00) and co-tansfection into G-protein alpha subunit (G-alpha-16) and CHO-K1 cells. Next, cells separated by FACS (Fluorescence-activated cell sorting, LK BioScience, JSAN) using HA-antibody (MACS, Anti-HA-PE) were treated with 10% FBS (Gibco, USA), 0.5 mg/ml Geneticin ( Gibco), 0.2 mg/ml Hygromycin B F12 (Gibco) was selectively cultured to obtain cells.
[464]
Efficacy material selection was performed using a calcium measurement kit (Calcium 5 assay kit, Molecular devices). The principle of calcium measurement is to measure the calcium sensitive dye enters the cytoplasm of the cell during incubation after hitting the dye, and when the ligand binds to a specific receptor and calcium is released in the cytoplasm, it binds and induces fluorescence. On the other hand, it is a test method that can only sensitively measure changes in intracellular calcium because changes outside the cells are masked by a masking dye.
[465]
As for the experimental method, the day before calcium measurement, hS1P1-hS1P5 overexpressing CHO cells were spread in a 96-well plate (bottom clear black well) at 3×10 4 per well and cultured at 37° C. under the condition of 5% carbon dioxide for one day. After that, 100 μl of calcium dye mixed with Assay Buffer (1 X HBSS, 20 mM HEPES, 2.5 mM probenecid, pH 7.4) was put into each well of the culture medium, and incubated at 37° C. for 1 hour. The test substance was dissolved in 100% DMSO, made 1 μl for each concentration, and mixed with 199 μl Assay Buffer so that the concentrations were 50, 5, 0.5, 0.05, 0.005, 0.0005 μM. Put the plate incubated with calcium dye into FlaxstationII (Molecular Devices) and program to automatically dispense 50 μl of the prepared test substance (final test substance concentration: 10, 1, 0.1, 0.01, 0.001, 0.0001 μM) for a total of 90 seconds. relative fluorescence unit) values ​​were measured. For the measured value, the reference (S1P material 1 μM) value minus the blank value was set to 100%, and the EC 50 value of the test material was calculated as a prism.
[466]
[467]
(2) Results
[468]
The results are shown in Table 1 below as EC 50 (nM).
[469]
[Table 1]
division EC 50 (nM)
Example 1 4.07
Example 2 2.09
Example 3 70.79
Example 4 9.12
Example 5 10.96
Example 6 12.88
Example 7 5.75
Example 8 6.31
Example 9 14.45
Example 10 2.75
Example 11 8.32
Example 12 14.45
Example 13 17.38
Example 14 12.02
Example 15 6.31
Example 16 43.65
Example 17 20.89
Example 18 64.57
Example 19 70.79
Example 20 5.13
Example 21 14.45
[470]
As shown in Table 1 above, the S1P receptor agonist compound according to the present invention exhibited excellent activity.
Claims
[Claim 1]
A compound represented by the following formula (1), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof: [Formula 1] A compound represented by the following formula (1), a pharmaceutically acceptable salt or a stereoisomer thereof: [Formula 1 ] In 1, R 1 is hydrogen or substituted or unsubstituted alkyl, alkenyl or alkynyl, R 2 is hydrogen, substituted or unsubstituted alkyl, halogen, CN, CF 3 or COCF 3 , R 3 and R 4 are each independently hydrogen, alkyl, alkenyl, alkynyl, or halogen substituted or unsubstituted with a substituent, R 5 A and R 5 B are each independently hydrogen, alkyl substituted or unsubstituted with a substituent, alkenyl, alkynyl or -R 6 (COOH), wherein R 6 is a single bond, substituted or unsubstituted alkylene, alkenylene or alkynylene, wherein R 5 A and R 5Any one of B is -R 6 (COOH), and R 5 A and R 5 B may be bonded to each other to form a ring, wherein the ring is a ring substituted with -R 6 (COOH).
[Claim 2]
The method of claim 1, wherein in Formula 1, R 1 is hydrogen or alkyl substituted or unsubstituted with a substituent, R 2 is hydrogen, alkyl substituted or unsubstituted with a substituent, halogen or CF3, R 3 and R 4 are each independently hydrogen, unsubstituted alkyl or halogen, R 5 A and R 5 B are each independently substituted or unsubstituted alkyl or —R 6 (COOH) with a substituent, R 6 is a single bond or a substituent substituted or unsubstituted alkylene, wherein any one of R 5 A and R 5 B is —R 6 (COOH), and R 5 A and R 5 B may be bonded to each other to form a ring, the ring is a compound in which -R 6 (COOH) is a substituted ring, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.
[Claim 3]
According to claim 1, wherein in Formula 1, when R 5 A and R 5 B are combined with each other to form a ring, the ring further comprises one or more substituents selected from the group consisting of halogen, alkyl and halogeno-alkyl. A substituted compound, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.
[Claim 4]
The compound according to claim 1, wherein in Formula 1, when R 5 A and R 5 B are bonded to each other to form a ring, the ring is a ring represented by the following Formula 1-1, and a pharmaceutically thereof Acceptable salts or stereoisomers thereof: [Formula 1-1]
[Claim 5]
The compound according to claim 4, wherein the ring represented by Formula 1-1 is a ring represented by Formula 1-2, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof: [Formula 1-2 ] In Formula 1-2, R 7 is hydrogen, alkyl or halogeno-alkyl substituted or unsubstituted with a substituent, and N, n and m are as defined in claim 4.
[Claim 6]
The compound according to claim 1, wherein in Formula 1, at least one of R 3 and R 4 is hydrogen, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.
[Claim 7]
The compound according to claim 1, wherein the compound represented by Formula 1 is a compound selected from the following group, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof: {[7-(3-chloro-1-isopropyl- 1H-Indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-methyl-amino}-acetic acid ({[7-(3-chloro-1-isopropyl-1H-indazol-5-yl methoxy) )-2H-chromene-3-ylmethoxy]-methyl-amino}-acetic acid); 1-[7-(3-Chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-azetidine-3-carboxylic acid (1-[7 -(3-chloro-1-isopropyl-1H-indazol-5-yl methoxy)-2H-chromene-3-ylmethyl]-azetidin-3-carboxylic acid); 1-[7-(3-Chloro-2-propyl-2H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-azetidine-3-carboxylic acid (1-[7- (3-chloro-2-propyl-2H-indazol-5-yl methoxy)-2H-chromene-3-ylmethyl]-azetidin-3-carboxylic acid); 1-[7-(3-Chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-piperidine-4-carboxylic acid (1-[ 7-(3-chloro-1-isopropyl-1H-indazol-5-yl methoxy)-2H-chromene-3-ylmethyl]-piperidine-4-carboxylic acid); (R)-1-[7-(3-Chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-piperidine-3-carboxylic acid ((R)-1-[7-(3-chloro-1-isopropyl-1H-indazol-5-yl methoxy)-2H-chromene-3-ylmethyl]-piperidine-3-carboxylic acid); (S)-1-[7-(3-Chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-piperidine-3-carboxylic acid ((S)-1-[7-(3-chloro-1-isopropyl-1H-indazol-5-yl methoxy)-2H-chromene-3-ylmethyl]-piperidine-3-carboxylic acid); (S)-1-[7-(3-Chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-pyrrolidine-3-carboxylic acid ((S)-1-[7-(3-chloro-1-isopropyl-1H-indazol-5-yl methoxy)-2H-chromene-3-ylmethyl]-pyrrolidine-3-carboxylic acid); 1-[7-(3-Chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-3-chloromethyl-azetidine-3-carboxylic acid (1-[7-(3-chloro-1-isopropyl-1H-indazol-5-yl methoxy)-2H-chromene-3-ylmethyl]-3-chloromethyl-azetidine-3-carboxylic acid); (R)-1-[7-(3-Chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-pyrrolidine-3-carboxylic acid ((R)-1-[7-(3-chloro-1-isopropyl-1H-indazol-5-yl methoxy)-2H-chromene-3-ylmethyl]-pyrrolidine-3-carboxylic acid); 1-[7-(3-Chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-4-methyl-2H-chromin-3-ylmethyl]-piperidine-4-carboxylic acid (1-[7-(3-chloro-1-isopropyl-1H-indazol-5-yl methoxy)-4-methyl-2H-chromene-3-ylmethyl]-piperidine-4-carboxylic acid); 1-[4-Chloro-7-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-piperidine-4-carboxylic acid (1-[4-chloro-7-(3-chloro-1-isopropyl-1H-indazol-5-yl methoxy)-2H-chromene-3-ylmethyl]-piperidine-4-carboxylic acid); 1-[7-(3-Chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-5-fluoro-2H-chromin-3-ylmethyl]-piperidine-4-carboxyl acid (1-[7-(3-chloro-1-isopropyl-1H-indazol-5-yl methoxy)-5-fluoro-2H-chromene-3-ylmethyl]-piperidine-4-carboxylic acid); 1-[7-(1-Isopropyl-3-trifluoromethyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-piperidine-4-carboxylic acid ( 1-[7-(1-isopropyl-3-trifluoromethyl-1H-indazol-5-yl methoxy)-2H-chromene-3-ylmethyl]-piperidine-4-carboxylic acid); 1-[7-(1-Isopropyl-3-ethyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-piperidine-4-carboxylic acid (1-[ 7-(1-isopropyl-3-ethyl-1H-indazol-5-yl methoxy)-2H-chromene-3-ylmethyl]-piperidine-4-carboxylic acid); 1-[7-(3-Chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-azepaine-4-carboxylic acid (1-[7 -(3-chloro-1-isopropyl-1H-indazol-5-yl methoxy)-2H-chromene-3-ylmethyl]-azepane-4-carboxylic acid); 1-[7-(3-Chloro-1-propyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-azetidine-3-carboxylic acid (1-[7- (3-chloro-1-propyl-1H-indazol-5-yl methoxy)-2H-chromene-3-ylmethyl]-azetidine-3-carboxylic acid); 1-[7-(3-Chloro-1-propyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-piperidine-4-carboxylic acid (1-[7 -(3-chloro-1-propyl-1H-indazol-5-yl methoxy)-2H-chromene-3-ylmethyl]-piperidine-4-carboxylic acid); 1-[7-(3-Chloro-1-cyclopropylmethyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-piperidine-4-carboxylic acid (1- [7-(3-chloro-1-cyclopropylmethyl-1H-indazol-5-yl methoxy)-2H-chromene-3-ylmethyl]-piperidine-4-carboxylic acid); 1-[7-(3-Chloro-1-cyclopentyl-1H-indazol-5-ylmethoxy)-5-fluoro-2H-chromin-3-ylmethyl]-piperidine-4-carboxyl acid (1-[7-(3-chloro-1-cyclopentyl-1H-indazol-5-yl methoxy)-5-fluoro-2H-chromene-3-ylmethyl]-piperidine-4-carboxylic acid); 1-[7-(3-Chloro-1-isobutyl-1H-indazol-5-ylmethoxy)-5-fluoro-2H-chromin-3-ylmethyl]-piperidine-4-carboxyl acid (1-[7-(3-chloro-1-isobutyl-1H-indazol-5-yl methoxy)-5-fluoro-2H-chromene-3-ylmethyl]-piperidine-4-carboxylic acid); 1-[7-(3-Chloro-1-isobutyl-1H-indazol-5-ylmethoxy)-5-fluoro-2H-chromin-3-ylmethyl]-azepaine-4-carboxylic acid (1-[7-(3-chloro-1-isobutyl-1H-indazol-5-yl methoxy)-5-fluoro-2H-chromene-3-ylmethyl]-azepane-4-carboxylic acid);
[Claim 8]
The compound according to claim 1, wherein the compound represented by Formula 1 is for use in the treatment of an autoimmune disorder including multiple sclerosis, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.
[Claim 9]
The compound according to claim 1, wherein the compound represented by Formula 1 is a sphingosine-1-phosphate receptor agonist, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.
[Claim 10]
A pharmaceutical composition for the treatment of autoimmune disorders, comprising the compound according to claim 1, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.
[Claim 11]
Systemic lupus erythematosus, chronic rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, amyotrophic lateral sclerosis (ALS), arterial comprising the compound according to claim 1, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof as an active ingredient. A pharmaceutical composition for the treatment or prevention of autoimmune or chronic inflammatory diseases selected from the group consisting of sclerosis, atherosclerosis, scleroderma and autoimmune hepatitis.
Amendment of Claims (Article 19 of the Treaty)
[ International Secretariat filing date: March 29, 2021 (29.03.2021)]
[One]
[Correction]　
A compound represented by the following Chemical Formula 1, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:
[Formula 1] In

Chemical Formula 1,
R 1 is hydrogen or alkyl, alkenyl or alkyl unsubstituted or substituted with hydrogen or a substituent nyl ,
R 2 is hydrogen, alkyl substituted or unsubstituted with a substituent, halogen, CN, CF 3 or COCF 3 ,
R 3 and R 4 are each independently hydrogen, substituted or unsubstituted alkyl, alkenyl , alkynyl or halogen,
R 5 A and R 5 B are each independently hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, or —R 6 (COOH), wherein R 6 is a single bond , alkylene, alkenylene or alkynylene substituted or unsubstituted with a substituent, wherein R 5Any one of A and R 5 B is -R 6 (COOH),
wherein R 5 A and R 5 B may be bonded to each other to form a ring, wherein the ring is a ring substituted with -R 6 (COOH) .
[2]
The method of claim 1, wherein in Formula 1, R 1 is hydrogen or alkyl substituted or unsubstituted with a substituent, R 2 is hydrogen, alkyl substituted or unsubstituted with a substituent, halogen or CF3, R 3 and R 4 are each independently hydrogen, unsubstituted alkyl or halogen, R 5 A and R 5 B are each independently substituted or unsubstituted alkyl or —R 6 (COOH) with a substituent, R 6 is a single bond or a substituent substituted or unsubstituted alkylene, wherein any one of R 5 A and R 5 B is —R 6 (COOH), and R 5 A and R 5 B may be bonded to each other to form a ring, the ring is a compound in which -R 6 (COOH) is a substituted ring, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.
[3]
According to claim 1, wherein in Formula 1, when R 5 A and R 5 B are combined with each other to form a ring, the ring further comprises one or more substituents selected from the group consisting of halogen, alkyl and halogeno-alkyl. A substituted compound, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.
[4]
[Correction]　
The compound of claim 1,
wherein in Formula 1, when
R 5 A and R 5 B are combined with each other to form a ring, the ring is a ring represented by the following Formula 1-1; A pharmaceutically acceptable salt or a stereoisomer thereof:
[Formula 1-1]

In Formula 1-1,
N is the same N as N bonded to R 5 A and R 5
B in Formula 1, and R 7 to R 11 is each independently hydrogen, alkyl, halogen or halogeno-alkyl substituted or unsubstituted with a substituent, m and n are each independently an integer of 0 to 6, and m+n≥1.

[5]
[Correction]　
The compound of claim 4, wherein
the ring represented by Formula 1-1 is a ring represented by Formula 1-2, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:
[Formula 1- 2]

In Formula 1-2,
R 7 is hydrogen, alkyl or halogeno-alkyl substituted or unsubstituted with a substituent, and
N, n and m are as defined in claim 4.
[6]
The compound according to claim 1, wherein in Formula 1, at least one of R 3 and R 4 is hydrogen, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.
[7]
The compound according to claim 1, wherein the compound represented by Formula 1 is a compound selected from the following group, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof: {[7-(3-chloro-1-isopropyl- 1H-Indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-methyl-amino}-acetic acid ({[7-(3-chloro-1-isopropyl-1H-indazol-5-yl methoxy) )-2H-chromene-3-ylmethoxy]-methyl-amino}-acetic acid); 1-[7-(3-Chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-azetidine-3-carboxylic acid (1-[7 -(3-chloro-1-isopropyl-1H-indazol-5-yl methoxy)-2H-chromene-3-ylmethyl]-azetidin-3-carboxylic acid); 1-[7-(3-Chloro-2-propyl-2H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-azetidine-3-carboxylic acid (1-[7- (3-chloro-2-propyl-2H-indazol-5-yl methoxy)-2H-chromene-3-ylmethyl]-azetidin-3-carboxylic acid); 1-[7-(3-Chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-piperidine-4-carboxylic acid (1-[ 7-(3-chloro-1-isopropyl-1H-indazol-5-yl methoxy)-2H-chromene-3-ylmethyl]-piperidine-4-carboxylic acid); (R)-1-[7-(3-Chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-piperidine-3-carboxylic acid ((R)-1-[7-(3-chloro-1-isopropyl-1H-indazol-5-yl methoxy)-2H-chromene-3-ylmethyl]-piperidine-3-carboxylic acid); (S)-1-[7-(3-Chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-piperidine-3-carboxylic acid ((S)-1-[7-(3-chloro-1-isopropyl-1H-indazol-5-yl methoxy)-2H-chromene-3-ylmethyl]-piperidine-3-carboxylic acid); (S)-1-[7-(3-Chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-pyrrolidine-3-carboxylic acid ((S)-1-[7-(3-chloro-1-isopropyl-1H-indazol-5-yl methoxy)-2H-chromene-3-ylmethyl]-pyrrolidine-3-carboxylic acid); 1-[7-(3-Chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-3-chloromethyl-azetidine-3-carboxylic acid (1-[7-(3-chloro-1-isopropyl-1H-indazol-5-yl methoxy)-2H-chromene-3-ylmethyl]-3-chloromethyl-azetidine-3-carboxylic acid); (R)-1-[7-(3-Chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-pyrrolidine-3-carboxylic acid ((R)-1-[7-(3-chloro-1-isopropyl-1H-indazol-5-yl methoxy)-2H-chromene-3-ylmethyl]-pyrrolidine-3-carboxylic acid); 1-[7-(3-Chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-4-methyl-2H-chromin-3-ylmethyl]-piperidine-4-carboxylic acid (1-[7-(3-chloro-1-isopropyl-1H-indazol-5-yl methoxy)-4-methyl-2H-chromene-3-ylmethyl]-piperidine-4-carboxylic acid); 1-[4-Chloro-7-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-piperidine-4-carboxylic acid (1-[4-chloro-7-(3-chloro-1-isopropyl-1H-indazol-5-yl methoxy)-2H-chromene-3-ylmethyl]-piperidine-4-carboxylic acid); 1-[7-(3-Chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-5-fluoro-2H-chromin-3-ylmethyl]-piperidine-4-carboxyl acid (1-[7-(3-chloro-1-isopropyl-1H-indazol-5-yl methoxy)-5-fluoro-2H-chromene-3-ylmethyl]-piperidine-4-carboxylic acid); 1-[7-(1-Isopropyl-3-trifluoromethyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-piperidine-4-carboxylic acid ( 1-[7-(1-isopropyl-3-trifluoromethyl-1H-indazol-5-yl methoxy)-2H-chromene-3-ylmethyl]-piperidine-4-carboxylic acid); 1-[7-(1-Isopropyl-3-ethyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-piperidine-4-carboxylic acid (1-[ 7-(1-isopropyl-3-ethyl-1H-indazol-5-yl methoxy)-2H-chromene-3-ylmethyl]-piperidine-4-carboxylic acid); 1-[7-(3-Chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-azepaine-4-carboxylic acid (1-[7 -(3-chloro-1-isopropyl-1H-indazol-5-yl methoxy)-2H-chromene-3-ylmethyl]-azepane-4-carboxylic acid); 1-[7-(3-Chloro-1-propyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-azetidine-3-carboxylic acid (1-[7- (3-chloro-1-propyl-1H-indazol-5-yl methoxy)-2H-chromene-3-ylmethyl]-azetidine-3-carboxylic acid); 1-[7-(3-Chloro-1-propyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-piperidine-4-carboxylic acid (1-[7 -(3-chloro-1-propyl-1H-indazol-5-yl methoxy)-2H-chromene-3-ylmethyl]-piperidine-4-carboxylic acid); 1-[7-(3-Chloro-1-cyclopropylmethyl-1H-indazol-5-ylmethoxy)-2H-chromin-3-ylmethyl]-piperidine-4-carboxylic acid (1- [7-(3-chloro-1-cyclopropylmethyl-1H-indazol-5-yl methoxy)-2H-chromene-3-ylmethyl]-piperidine-4-carboxylic acid); 1-[7-(3-Chloro-1-cyclopentyl-1H-indazol-5-ylmethoxy)-5-fluoro-2H-chromin-3-ylmethyl]-piperidine-4-carboxyl acid (1-[7-(3-chloro-1-cyclopentyl-1H-indazol-5-yl methoxy)-5-fluoro-2H-chromene-3-ylmethyl]-piperidine-4-carboxylic acid); 1-[7-(3-Chloro-1-isobutyl-1H-indazol-5-ylmethoxy)-5-fluoro-2H-chromin-3-ylmethyl]-piperidine-4-carboxyl acid (1-[7-(3-chloro-1-isobutyl-1H-indazol-5-yl methoxy)-5-fluoro-2H-chromene-3-ylmethyl]-piperidine-4-carboxylic acid); 1-[7-(3-Chloro-1-isobutyl-1H-indazol-5-ylmethoxy)-5-fluoro-2H-chromin-3-ylmethyl]-azepaine-4-carboxylic acid (1-[7-(3-chloro-1-isobutyl-1H-indazol-5-yl methoxy)-5-fluoro-2H-chromene-3-ylmethyl]-azepane-4-carboxylic acid);
[8]
The compound according to claim 1, wherein the compound represented by Formula 1 is for use in the treatment of an autoimmune disorder including multiple sclerosis, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.
[9]
The compound according to claim 1, wherein the compound represented by Formula 1 is a sphingosine-1-phosphate receptor agonist, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.
[10]
A pharmaceutical composition for the treatment of autoimmune disorders, comprising the compound according to claim 1, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.
[11]
Systemic lupus erythematosus, chronic rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, amyotrophic lateral sclerosis (ALS), arterial comprising the compound according to claim 1, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof as an active ingredient. A pharmaceutical composition for the treatment or prevention of autoimmune or chronic inflammatory diseases selected from the group consisting of sclerosis, atherosclerosis, scleroderma and autoimmune hepatitis.