Novel compound and use thereof for treating psoriasis

Abstract

The present invention relates to a novel compound and a use thereof for treating psoriasis. The novel compound of the present invention exhibits inhibitory activity against chemokine like receptor 1 (CMKLR1), thereby having excellent effects of preventing and treating psoriasis.

Description

Novel compounds and their use in the treatment of psoriasis

[0001] The present invention relates to a novel compound and its use in the treatment of psoriasis.

[0002]

[0003] Psoriasis is a chronic immune disease characterized by skin erythema and scaling. Its causes include genetics, environmental factors, and irritation. While not life-threatening, it is considered a serious skin condition due to its potential for relapse and the risk of secondary conditions such as arthritis, metabolic syndrome, and depression. Current treatment options for symptom relief include topical treatments such as steroid ointments and immunomodulators, as well as oral retinoids and methotrexate. However, these treatments are incomplete and only provide symptom relief. Therefore, the development of safe psoriasis treatments with novel targets is urgently needed.

[0004]

[0005] The purpose of the present invention is to provide a novel compound having an excellent CMKLR1 (Chemokine like receptor 1) inhibitory effect.

[0006] The purpose of the present invention is to provide a pharmaceutical composition having an excellent effect in preventing or treating psoriasis by inhibiting CMKLR1.

[0007]

[0008] 1. A compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof:

[0009] [Chemical Formula 1]

[0010]

[0011] (In the formula, A is a substituted or unsubstituted 5-10 membered aryl or heteroaryl, R1 is C1 to C4 alkyl, C3 to C6 cycloalkyl, acetyl, benzyl or methyl substituted with C3 to C6 cycloalkyl; R2 is C1 to C4 alkyl or C3 to C6 cycloalkyl; R8 is hydrogen or halogen; Ra and Rb are each independently hydrogen or methyl; Rc is hydrogen or C1 to C4 alkyl, X is carbon or nitrogen, and R 10 is absent, hydrogen; halogen; or methyl substituted or unsubstituted with halogen).

[0012] 2. In the above 1, A is a compound or a pharmaceutically acceptable salt thereof, which is substituted or unsubstituted phenyl, pyridine, benzo[b]thiophene or 1H-tetrazol.

[0013] 3. In the above 1, the substituent of A is C1 to C3 alkyl, C1 to C5 alkoxy, -OH, -CF3, -CN, -CH2OH, -NH2, -CH=NOH, halogen, phenyl, -NO2, -0CH2CH=CHC(=O)OH, -OCH2CH=CH 2, -C(=O)OH, -NHC(=O)R9 or dioxane, and R9 is alkyl or alkenyl having C2 to C4, or a pharmaceutically acceptable salt thereof.

[0014] 4. In the above 1, A is substituted or unsubstituted phenyl, and the substitution is C1 to C3 alkyl, C1 to C5 alkoxy, -OH, -CF3, -CN, -CH2OH, -NH2, -CH=NOH, halogen, phenyl, -NO2, -0CH2CH=CHC(=O)OH, -OCH2CH=CH 2, -C(=O)OH, A compound or a pharmaceutically acceptable salt thereof, comprising -NHC(=O)R9 (R-9 is alkyl or alkenyl of C2 to C4) or dioxane.

[0015] 5. In the above 1, the compound represented by the chemical formula 1 is any one selected from the group consisting of the following compounds, or a pharmaceutically acceptable salt thereof:

[0016]

[0017]

[0018]

[0019]

[0020]

[0021]

[0022]

[0023]

[0024]

[0025]

[0026]

[0027]

[0028]

[0029]

[0030]

[0031]

[0032]

[0033] 6. A pharmaceutical composition for preventing or treating psoriasis, comprising any one of the compounds 1 to 5 above or a pharmaceutically acceptable salt thereof.

[0034]

[0035] The compound of the present invention has an excellent CMKLR1 inhibitory effect.

[0036] The pharmaceutical composition of the present invention has an excellent effect in preventing or treating psoriasis.

[0037]

[0038] Figures 1 to 6 show the results of administering compound 30d (=compound 71) corresponding to chemical formula 1 of the present invention to a mouse psoriasis model induced with imiquimod.

[0039] Figure 1 shows the back images of each mouse on the 7th day after the end of the experiment.

[0040] Figure 2 shows the changes in PASI scores during the experiment.

[0041] Figure 3 shows the results of H&E staining of mouse dorsal tissue.

[0042] Figure 4 shows the epidermal thickness of each experimental group.

[0043] Figure 5 shows the change in body weight of each experimental group during the experimental period.

[0044] Figure 6 shows the back thickness and spleen weight of each experimental group.

[0045]

[0046] The present invention relates to a novel compound having excellent CMKLR1 (Chemokine like receptor 1) inhibitory ability and its use for preventing or treating psoriasis.

[0047] The present invention provides a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof:

[0048] [Chemical Formula 1]

[0049]

[0050] In the above formula, A is a substituted or unsubstituted 5- to 10-membered aryl or heteroaryl,

[0051] R1 is methyl substituted with C1 to C4 alkyl, C3 to C6 cycloalkyl, acetyl, benzyl or C3 to C6 cycloalkyl;

[0052] R2 is C1 to C4 alkyl or C3 to C6 cycloalkyl;

[0053] R8 is hydrogen or halogen;

[0054] Ra and Rb are each independently hydrogen or methyl;

[0055] Rc is hydrogen or C1 to C4 alkyl,

[0056] X is carbon or nitrogen, and R 10 is absent, hydrogen; halogen; or methyl substituted or unsubstituted with halogen.

[0057] The term "alkyl" as used herein means a straight or branched chain saturated hydrocarbon radical containing the indicated number of carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, and the like.

[0058] The term "alkenyl" as used herein means a straight or branched chain unsaturated hydrocarbon radical containing the indicated number of carbon atoms and at least one carbon-carbon double bond, such as -CH2CH=CH2 or -CH2CH2CH=CH2.

[0059] As used herein, the term "cycloalkyl" means a saturated hydrocarbon monocyclic ring containing the indicated number of ring atoms, for example, C3 to C5 cycloalkyl may include cyclopropyl, cyclobutyl and cyclopentyl.

[0060] As used herein, the term "alkoxy" means -O-(alkyl), where alkyl is as defined above. Examples of alkoxy include -OCH3, -OCH2CH3, -O(CH2)2CH3, -O(CH2)3CH3, -O(CH2)4CH3, -O(CH2)5CH3, etc.

[0061] As used herein, the term “halogen” means fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0062] As used herein, the term "acyl" refers to a substituted carbonyl radical "-C(=O)-R c " means.

[0063] As used herein, “aryl” refers to an aromatic hydrocarbon ring, which may be monocyclic or polycyclic. For example, a 5- to 10-membered aryl may include phenyl, naphthyl, or biphenyl.

[0064] The term “heteroaryl” as used herein refers to an aromatic ring containing one or more heteroatoms selected from N, O, and S as ring-forming atoms, and may be monocyclic or polycyclic. For example, a 5- to 10-membered heteroaryl may include pyridine, benzo[b]thiophene, 1H-tetrazole, and the like.

[0065] In Chemical Formula 1, A may be a substituted or unsubstituted 5- to 10-membered aryl or heteroaryl, preferably a substituted or unsubstituted phenyl, pyridine, benzo[b]thiophene or 1H-tetrazole, and more preferably a substituted or unsubstituted phenyl. The 5- to 10-membered aryl or heteroaryl may be substituted with 1 to 5 substituents, and the substituents are C1 to C3 alkyl, C1 to C5 alkoxy, -OH, -CF3, -CN, -CH2OH, -NH2, -CH=NOH, halogen, phenyl, -NO2, -0CH2CH=CHC(=O)OH, -OCH2CH=CH 2, -C(=O)OH or -NHC(=O)R9, or two substituents together can form 1,3-dioxane.

[0066] R1 may be methyl substituted with C1 to C4 alkyl, C3 to C6 cycloalkyl, acetyl, benzyl or C3 to C6 cycloalkyl, and preferably isopropyl or cyclopentyl.

[0067] R2 may be C1 to C4 alkyl or C3 to C6 cycloalkyl, preferably methyl, and more preferably methyl bonded such that the chiral center of the carbon bonded to R2 is in the R configuration. For example, it may be methyl bonded as in compounds 68 to 70 manufactured in Preparation Example 7.

[0068] R8 may be hydrogen or halogen, preferably hydrogen or fluorine.

[0069] R9 can be alkyl or alkenyl having C2 to C4.

[0070] R a and R b can each independently be hydrogen or methyl.

[0071] R c may be hydrogen or C1 to C4 alkyl.

[0072] Preferably, the compound represented by the above chemical formula 1 may be a compound represented by the following chemical formula 2.

[0073] [Chemical Formula 2]

[0074]

[0075] In the above equation, R1, R2, R8, R a , R b , R c and X are the same as described above in chemical formula 1.

[0076] R3 to R7 are each independently hydrogen, C1 to C3 alkyl, C1 to C5 alkoxy, -OH, -CF3, -CN, -CH2OH, -NH2, -CH=NOH, halogen, phenyl, -NO2, -0CH2CH=CHC(=O)OH, -OCH2CH=CH 2, -C(=O)OH or -NHC(=O)R9 may be used. R9 is the same as in chemical formula 1.

[0077] R6 and R7 together can form 1,3-dioxane.

[0078] If X is carbon, R 10 It can be hydrogen, halogen (F, Cl, Br, or I), or methyl substituted with a halogen (CF3, CCl3, CBR3, or CI3).

[0079] If X is nitrogen, R 10 does not exist.

[0080] The compound represented by chemical formula 1 may be any one selected from the group consisting of the following compounds 1 to 86.

[0081]

[0082]

[0083]

[0084]

[0085]

[0086]

[0087]

[0088]

[0089]

[0090]

[0091]

[0092]

[0093] The compound represented by chemical formula 1 has excellent CMKLR1 (Chemokine like receptor 1) inhibitory ability.

[0094] The compound represented by chemical formula 1 inhibits CMKLR1 (Chemokine like receptor 1) and can be used to prevent or treat psoriasis.

[0095] The present invention provides a pharmaceutical composition for preventing or treating psoriasis, comprising a compound represented by the chemical formula 1 described above or a pharmaceutically acceptable salt thereof.

[0096] Psoriasis is an inflammatory disease of the skin or joints caused by an immune system disorder. It causes disfiguring, scaly, erythematous plaques, and pain. Psoriasis can include one or more of the following conditions: psoriatic arthritis, guttate psoriasis, pustular psoriasis, erythematous psoriasis, scalp psoriasis, nail psoriasis, and enthesitis.

[0097] Pharmaceutically acceptable salts may be, for example, acid addition salts, base addition salts or metal salts.

[0098] Acid addition salts can be formed from inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, nitrous or phosphorous acids and non-toxic organic acids such as aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxyalkanoates and alkanedioates, aromatic acids, aliphatic and aromatic sulfonic acids. These pharmaceutically non-toxic salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, fluorides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caprates, heptanoates, propylates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyn-1,4-dioate, hexanoate-1,6-dioate, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, It may include terephthalate, benzenesulfonate, tert-butyl sulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate or mandelate. For example, an acid addition salt of a compound represented by formula 1 can be obtained by dissolving the compound in an excess aqueous acid solution and precipitating the salt using a hydratable organic solvent, such as methanol, ethanol, acetone or acetonitrile.

[0099] The metal salt may be a sodium, potassium, or calcium salt. The metal salt may be prepared using a base, for example, an alkali metal or alkaline earth metal salt may be obtained by dissolving the compound in an excess of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering off the undissolved compound salt, and evaporating and / or drying the filtrate.

[0100] The pharmaceutical composition of the present invention may be in the form of a capsule, tablet, granule, injection, ointment, powder, or beverage.

[0101] The pharmaceutical composition of the present invention can be formulated and used in the form of oral dosage forms such as powders, granules, capsules, tablets, and aqueous suspensions, as well as external preparations, suppositories, and injections.

[0102] The pharmaceutical composition of the present invention may contain the active ingredient alone, or may further contain one or more pharmaceutically acceptable carriers, excipients, or diluents.

[0103] The pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers may include binders, lubricants, disintegrants, excipients, solubilizers, dispersants, stabilizers, suspending agents, coloring agents, fragrances, etc. for oral administration; buffers, preservatives, analgesics, solubilizers, isotonic agents, stabilizers, etc. for injections; and bases, excipients, lubricants, preservatives, etc. for topical administration.

[0104] The pharmaceutical composition of the present invention may be prepared in various forms by mixing it with a pharmaceutically acceptable carrier. For example, for oral administration, it may be prepared in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc., and for injections, it may be prepared in the form of unit dose ampoules or multiple doses. In addition, the pharmaceutical composition of the present invention may be prepared in the form of solutions, suspensions, tablets, capsules, sustained-release preparations, etc.

[0105] Carriers, excipients and diluents for formulation may be lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, malditol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, mineral oil, fillers, anticoagulants, lubricants, wetting agents, fragrances, emulsifiers or preservatives.

[0106] The route of administration of the pharmaceutical composition of the present invention may be oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual or rectal, but is not limited thereto.

[0107] The pharmaceutical composition of the present invention can be administered orally or parenterally, and when administered parenterally, the method of injection can be selected, such as topical application to the skin or intraperitoneal injection, intrarectal injection, subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection.

[0108] The dosage of the pharmaceutical composition of the present invention may vary depending on the patient's condition and weight, the degree of disease, the drug form, the route and period of administration, but may be appropriately selected by a person skilled in the art.

[0109] For example, the pharmaceutical composition of the present invention may be administered at a daily dose of 0.0001 mg to 1000 mg / kg or 0.001 mg to 500 mg / kg. The pharmaceutical composition of the present invention may be administered once a day or divided into several doses.

[0110] Hereinafter, the present invention will be described in more detail through examples.

[0111]

[0112] Manufacturing example

[0113] Manufacturing Example 1. Synthesis of Compounds 1 to 9

[0114]

[0115] (1) Synthesis of methyl 3-bromo-1-isopropyl-1H-indazole-6-carboxylate (A2)

[0116] Methyl 3-bromo-1H-indazole-6-carboxylate (A1) (20 mg, 0.078 mmol) was dissolved in DMF (0.5 mL), and NaH (60% in mineral oil, 0.156 mmol) was added. 2-Iodopropane (11 μL, 0.118 mmol) was then added to the reaction mixture, which was stirred at room temperature for 2 h. Water was added to the reaction mixture, and it was extracted with ethyl acetate and saturated aqueous NH4Cl solution. The combined extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (hexane:ethyl acetate = 25:1) to give white solid compound A2 (8 mg, 35% yield).

[0117] 1 H NMR (CDCl3, 400 MHz): δ 8.21 (s, 1H), 7.85 (dd,J= 1.22, 8.55 Hz, 1H), 7.65 (d,J= 8.55 Hz, 1H), 4.91 (td,J= 6.71, 13.43 Hz, 1H), 3.99 (s, 3H), 1.62 (d,J= 6.71 Hz, 6H). MS (ESI): [M + H] + = 298.82

[0118]

[0119] (2) Synthesis of methyl 1-isopropyl-3-phenyl-1H-indazole-6-carboxylate (A3)

[0120] A2 (18 mg, 0.061 mmol), phenylboronic acid (8.2 mg, 0.066 mmol), Pd(PPh3)4 (7 mg, 0.0061 mmol), and Na2CO3 (19 mg, 0.183 mmol) were dissolved in 1,4-dioxane (2 mL) and water (1 mL), and stirred under reflux for 4 h. The reaction mixture was evaporated. The residue was dissolved in water and extracted with ethyl acetate. The combined extracts were dried over Na2SO4, filtered, and concentrated by an evaporator to produce a crude product, which was then purified by silica gel column chromatography (hexane:ethyl acetate = 35:1) to obtain compound A3 (15 mg, yield 87%) as a white solid.

[0121] 1 H NMR (CDCl3, 400 MHz): δ 8.23 ​​- 8.27 (m, 1H), 8.05 (dd,J= 0.76, 8.70 Hz, 1H), 7.95 - 8.01 (m, 2H), 7.86 (dd,J= 1.22, 8.55 Hz, 1H), 7.49 - 7.55 (m, 2H), 7.38 - 7.44 (m, 1H), 4.93 - 5.05 (m, 1H), 4.00 (s, 3H), 1.68 (d,J= 6.71 Hz, 6H). MS (ESI): [M + H] + =295.11

[0122]

[0123] (3) Synthesis of 1-isopropyl-3-phenyl-1H-indazol-6-yl)methanol (A4)

[0124] A3 (15 mg, 0.051 mmol) was dissolved in THF (1 mL) and cooled to 0°C. Next, 1.0 M lithium aluminum hydride (102 μL, 0.102 mmol) dissolved in THF was added dropwise and stirred at 0°C for 1 h. The reaction mixture was poured into saturated aqueous NH4Cl solution and extracted with ethyl acetate. The combined extracts were dried over Na2SO4, filtered, and concentrated by evaporation to produce a crude product, which was purified by silica gel column chromatography (CHCl3:MeOH = 50:1) to obtain compound A4 (12 mg, yield 88%) as a white solid.

[0125] 1 H NMR (CDCl3, 400 MHz): δ 7.94 - 8.02 (m, 3H), 7.47 - 7.55 (m, 3H), 7.35 - 7.43 (m, 1H), 7.18 (dd,J= 1.22, 8.24 Hz, 1H), 4.89 - 4.95 (m, 1H), 4.88 (s, 2H), 1.66 (d,J= 6.71 Hz, 6H)). MS (ESI): [M + H] + = 267.14

[0126]

[0127] (4) Synthesis of methyl 3-(4-((1-isopropyl-3-phenyl-1H-indazol-6-yl)methoxy)phenyl)propanoate (Compound 1)

[0128] A3 (0.038 mmol) and methyl 3-(4-hydroxyphenyl)propanoate (0.056 mmol) were dissolved in toluene. Then, 1,1'-(azodicarbonyl)dipiperidine (0.076 mmol) and tributylphosphine (0.076 mmol) were added to the reaction mixture, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered and washed with hexane. The filtrate was concentrated using an evaporator to obtain a crude product, which was purified by silica gel column chromatography (hexane:ethyl acetate = 50:1) to obtain compound 1 as a white solid.

[0129] 1H NMR (CDCl3, 400 MHz): δ 8.02 (dd,J= 0.76, 8.39 Hz, 1H), 7.96 - 8.00 (m, 2H), 7.57 (s, 1H), 7.47 - 7.54 (m, 2H), 7.39 (tt,J= 1.26, 7.44 Hz, 1H), 7.23 - 7.27 (m, 1H), 7.11 - 7.15 (m, 2H), 6.95 - 6.98 (m, 2H), 5.22 (s, 2H), 4.91 (quin,J= 6.64 Hz, 1H), 2.51 - 2.61 (m, 2H), 1.59 - 1.69 (m, 8H), 0.92 - 0.97 (m, 3H). MS (ESI): [M + H] + = 385.4

[0130]

[0131] (5) Synthesis of 3-cyclopropyl-3-(4-((1-isopropyl-3-phenyl-1H-indazol-6-yl) methoxy) phenyl) propanoic acid (compound 2)

[0132] A3 (20 mg, 0.075 mmol) and methyl 3-cyclopropyl-3-(4-hydroxyphenyl)propanoate (26 mg, 0.112 mmol) were dissolved in toluene (1 mL). Next, 1,1'-(azodicarbonyl)dipiperidine (38 mg, 0.150 mmol) and tributylphosphine (37 μL, 0.150 mmol) were added to the reaction mixture and stirred at room temperature for 3 h. The reaction mixture was then concentrated, and the residue was dissolved in MeOH (4 mL). Afterwards, 2 N NaOH aqueous solution (1 mL) was added dropwise and stirred at room temperature for 12 h. The reaction mixture was then neutralized to pH = 7 with 1 N NaOH aqueous solution and evaporated. The residue was purified by silica gel column chromatography (CHCl3:MeOH) to obtain compound 2 (8 mg, yield 24%) as a white solid.

[0133] 1H NMR (CDCl3, 400 MHz): δ 8.02 (d,J= 8.24 Hz, 1H), 7.98 (dd,J= 1.37, 8.39 Hz, 2H), 7.57 (s, 1H), 7.47 - 7.53 (m, 2H), 7.36 - 7.41 (m, 1H), 7.23 - 7.27 (m, 2H), 6.85 - 6.96 (m, 3H), 5.22 (s, 2H), 4.84 - 4.98 (m, 1H), 2.80 (dd,J= 5.04, 7.48 Hz, 2H), 2.32 - 2.43 (m, 1H), 1.65 (d,J= 6.71 Hz, 6H), 0.95 - 1.09 (m, 1H), 0.55 - 0.63 (m, 1H), 0.38 - 0.46 (m, 1H), 0.26 - 0.33 (m, 1H), 0.11 - 0.22 (m, 1H). MS (ESI): [M + H] + = 455.11

[0134]

[0135] (6) Synthesis of 3-(4-((1-isopropyl-3-phenyl-1H-indazol-6-yl)methoxy)phenyl)-2,2-dimethylpropanoic acid (Compound 3)

[0136] Compound 3 (yield: 21%) as a white solid was synthesized using A3 and methyl 3-(4-hydroxyphenyl)-2,2-dimethylpropanoate according to the method described in (5) above.

[0137] 1H NMR (CDCl3, 400 MHz): δ 8.00 (dd,J= 0.61, 8.24 Hz, 1H), 7.95 - 7.98 (m, 2H), 7.54 (s, 1H), 7.47 - 7.52 (m, 2H), 7.35 - 7.42 (m, 1H), 7.23 (dd,J= 1.37, 8.39 Hz, 1H), 7.09 - 7.14 (m, 2H), 6.93 - 6.97 (m, 2H), 5.20 (s, 2H), 4.88 (quin,J= 6.71 Hz, 1H), 2.85 (s, 2H), 1.64 (d,J=6.40 Hz, 6H), 1.21 (s, 6H). MS (ESI): [M + H] + = 443.09

[0138]

[0139] (7) Synthesis of 3-(4-((1-isopropyl-3-phenyl-1H-indazol-6-yl)methoxy)phenyl)propanoic acid (compound 4)

[0140] Using A3 and methyl 3-(4-hydroxyphenyl)propanoate, compound 4 (yield: 18%) as a white solid was synthesized by the method described in (5) above.

[0141] 1 H NMR (CDCl3, 400 MHz): δ 7.99 - 8.03 (m, 1H), 7.95 - 7.99 (m, 2H), 7.55 (s, 1H), 7.47 - 7.54 (m, 2H), 7.35 - 7.42 (m, 1H), 7.24 (dd,J= 1.22, 8.24 Hz, 1H), 7.14 - 7.19 (m, 2H), 6.95 - 7.00 (m, 2H), 5.21 (s, 2H), 4.85 - 4.93 (m, 1H), 2.91 - 2.96 (m, 2H), 2.64 - 2.69 (m, 2H), 1.65 (d,J= 6.41 Hz, 6H). MS (ESI): [M + H] + = 414.98

[0142]

[0143] (8) Synthesis of 3-(4-((1-isopropyl-3-phenyl-1H-indazol-6-yl)methoxy)-3-methylphenyl)butanoic acid (Compound 5)

[0144] Compound 5 (yield: 45%) as a white solid was synthesized using A3 and methyl 3-(4-hydroxy-3-methylphenyl)butanoate by the method described in (5) above.

[0145]

[0146] (9) Synthesis of 3-(4-((1-isopropyl-3-phenyl-1H-indazol-6-yl)methoxy)-2-methylphenyl)butanoic acid (compound 6)

[0147] Compound 6 (yield: 22%) as a white solid was synthesized using A3 and methyl 3-(4-hydroxy-2-methylphenyl)butanoate according to the method described in (5) above.

[0148]

[0149] (10) Synthesis of 4-((1-isopropyl-3-phenyl-1H-indazol-6-yl)methoxy)benzaldehyde (A5 precursor)

[0150] Using A3 and 4-hydroxybenzaldehyde, a white solid compound (yield: 82%) was synthesized by the method described in (4) above.

[0151] 1H NMR (CDCl3, 400 MHz): δ 8.02 (d,J= 8.24 Hz, 1H), 7.98 (dd,J= 1.37, 8.39 Hz, 2H), 7.57 (s, 1H), 7.47 - 7.53 (m, 2H), 7.36 - 7.41 (m, 1H), 7.23 - 7.27 (m, 2H), 6.85 - 6.96 (m, 3H), 5.22 (s, 2H), 4.84 - 4.98 (m, 1H), 2.80 (dd,J= 5.04, 7.48 Hz, 2H), 2.32 - 2.43 (m, 1H), 1.65 (d,J= 6.71 Hz, 6H), 0.95 - 1.09 (m, 1H), 0.55 - 0.63 (m, 1H), 0.38 - 0.46 (m, 1H), 0.26 - 0.33 (m, 1H), 0.11 - 0.22 (m, 1H). MS (ESI): [M + H] + = 455.11

[0152]

[0153] (11) Synthesis of 5-(4-((1-isopropyl-3-phenyl-1H-indazol-6-yl)methoxy)benzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (A5)

[0154] The compound synthesized in (10) above (10) (100 mg, 0.267 mmol) and Meldrum's acid (120 mg, 0.801 mmol) were dissolved in EtOH (4 mL), and piperidine (50 μL) and AcOH (50 μL) were added. The mixture was irradiated using a microwave reactor at 80°C for 30 min and concentrated in vacuo. The mixture was then purified by silica gel column chromatography (hexane:ethyl acetate = 4:1) to obtain compound A5 (92 mg, yield 69%) as a white solid.

[0155] 1H NMR (CDCl3, 400 MHz): δ 8.40 (s, 1H), 8.23 ​​- 8.28 (m, 2H), 8.02 - 8.07 (m, 1H), 7.94 - 8.00 (m, 2H), 7.55 (s, 1H), 7.48 - 7.54 (m, 2H), 7.36 - 7.43 (m, 1H), 7.24 (dd,J= 1.37, 8.39 Hz, 1H), 7.10 - 7.14 (m, 2H), 5.34 (s, 2H), 4.91 (quin,J= 6.71 Hz, 1H), 1.80 (s, 6H), 1.66 (d,J= 6.71 Hz, 6H).MS (ESI): [M + H] + = 497.3

[0156]

[0157] (12) Synthesis of 3-(4-((1-isopropyl-3-phenyl-1H-indazol-6-yl)methoxy)phenyl)butanoic acid (Compound 7)

[0158] A5 (20 mg, 0.040 mmol) was dissolved in THF (2 mL). The reaction mixture was cooled to 0°C, and 3.0 M methylmagnesium bromide THF solution (16 μL, 0.048 mmol) was added dropwise, followed by stirring for 30 min. After the reaction was completed, DMF (9 mL) and H2O (1 mL) were added, heated to 100°C, and stirred for 1 h. The reaction mixture was poured into water and extracted with ethyl acetate. The combined extracts were dried over Na2SO4, filtered, and concentrated by evaporation to produce a crude product, which was purified by silica gel column chromatography (CHCl3:MeOH = 25:1) to obtain compound 7 as a yellow solid (7.4 mg, 43% yield).

[0159] 1H NMR (CDCl3, 400 MHz): δ 7.95 - 8.05 (m, 3H), 7.55 (s, 1H), 7.47 - 7.53 (m, 2H), 7.37 - 7.42 (m, 1H), 7.24 (dd,J= 1.22, 8.24 Hz, 1H), 7.14 - 7.21 (m, 2H), 6.95 - 7.02 (m, 2H), 5.21 (s, 2H), 4.90 (quin,J= 6.64 Hz, 1H), 3.22 - 3.34 (m, 1H), 2.52 - 2.70 (m, 2H), 1.65 (d,J=6.71 Hz, 6H), 1.32 (d,J= 7.02 Hz, 3H). MS (ESI): [M + H] + = 429.01

[0160]

[0161] (13) Synthesis of 3-(4-((1-isopropyl-3-phenyl-1H-indazol-6-yl)methoxy)phenyl)-4-methylpentanoic acid (Compound 8)

[0162] Using A5 (20 mg, 0.040 mmol) and isopropylmagnesium bromide THF solution, compound 8 was obtained as a yellow solid (yield: 32%) by the method of (12) above.

[0163] 1H NMR (CDCl3, 400 MHz): δ 8.01 (dd,J= 0.61, 8.55 Hz, 1H), 7.95 - 7.99 (m, 2H), 7.55 (s, 1H), 7.47 - 7.53 (m, 2H), 7.36 - 7.41 (m, 1H), 7.24 (dd,J= 1.22, 8.24 Hz, 1H), 7.07 - 7.13 (m, 2H), 6.93 - 6.98 (m, 2H), 5.20 (s, 2H), 4.83 - 4.95 (m, 1H), 2.76 - 2.88 (m, 2H), 2.56 - 2.66 (m, 1H), 1.78 - 1.88 (m, 1H), 1.64 (d,J= 6.71 Hz, 6H), 0.94 (d,J= 6.71 Hz, 3H), 0.77 (d,J= 6.71 Hz, 3H)).MS (ESI): [M + H] + = 457.07

[0164]

[0165] (14) 3-(4-((1-Isopropyl-3-phenyl-1H-indazol-6-yl)methoxy)phenyl)pentanoic acid (Compound 9)

[0166] Compound 9, a yellow solid (yield: 31%), was obtained using A5 (20 mg, 0.040 mmol) and ethyl magnesium bromide THF solution by the method described above (12).

[0167]

[0168] Manufacturing Example 2. Synthesis of Compounds 10 to 34

[0169]

[0170] (1) Synthesis of methyl 3-bromo-1-cyclopentyl-1H-indazole-6-carboxylate (B1)

[0171] Methyl 3-bromo-1H-indazole-6-carboxylate (20 mg, 0.078 mmol) and K2CO3 (32 mg, 0.234 mmol) were dissolved in DMF (0.4 mL), and bromocyclopentane (13 μL, 0.117 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 8 h, poured into water, and extracted with ethyl acetate. The combined extracts were dried over Na2SO4, filtered, and concentrated by evaporation to give the crude product, which was purified by silica gel column chromatography (hexane:ethyl acetate = 6:1) to give compound B1 (24.6 mg, 98% yield) as a colorless oil.

[0172] 1 H NMR (CDCl3, 400 MHz): δ 8.22 (t,J= 1.07 Hz, 1H), 7.85 (dd,J= 1.22, 8.55 Hz, 1H), 7.64 (dd,J= 0.61, 8.55 Hz, 1H), 5.04 (quin,J= 7.32 Hz, 1H), 3.99 (s, 3H), 2.15 - 2.23 (m, 4H), 1.95 - 2.05 (m, 2H), 1.69 - 1.83 (m, 2H). MS (ESI): [M + H] + = 323.3

[0173]

[0174] (2) Synthesis of (3-bromo-1-cyclopentyl-1H-indazol-6-yl)methanol (B2)

[0175] B1 (20 mg, 0.062 mmol) was dissolved in THF (0.6 mL). A 1 M DIBAL-H solution in toluene (160 μL, 0.160 mmol) was added at 0°C. The reaction mixture was stirred at room temperature for 2 h, poured into aq. 1 N HCl, and extracted with ethyl acetate. The combined extracts were dried over Na2SO4, filtered, and concentrated by evaporation to give a crude product, which was purified by silica gel column chromatography (CHCl3:MeOH = 300:1) to give B2 as a colorless oil.

[0176] 1H NMR (CDCl3, 400 MHz): δ 7.54 - 7.59 (m, 1H), 7.48 (d, J = 0.92 Hz, 1H), 7.11 - 7.19 (m, 1H), 4.96 (quin, J = 7.48 Hz, 1H), 4.88 (d, J = 5.19 Hz, 2H), 2.12 - 2.22 (m, 4H), 1.90 - 2.06 (m, 2H), 1.66 - 1.79 (m, 2H). MS (ESI): [M + H]+ = 297.00.

[0177]

[0178] (3) Synthesis of methyl 3-(4-((3-bromo-1-cyclopentyl-1H-indazol-6-yl)methoxy)phenyl)butanoate (B3)

[0179] B2 (10 mg, 0.034 mmol) was dissolved in toluene (2 mL), and methyl 3-(4-hydroxyphenyl)butanoate (9.9 mg, 0.051 mmol) was added. Subsequently, tributylphosphine (25 μL, 0.102 mmol) and 1,1'-(azodicarbonyl)dipiperidine (26 mg, 0.102 mmol) were added, and the mixture was stirred at room temperature for 3 h. The reaction mixture was then filtered and washed with hexane. The filtrate was concentrated using an evaporator to produce a crude product, which was purified by silica gel column chromatography (hexane:ethyl acetate = 8:1) to obtain compound B3 (11 mg, yield 69%) as a colorless oil.

[0180] 1H NMR (CDCl3, 400 MHz): δ 7.60 (dd,J= 0.90, 8.60 Hz, 1H), 7.50 - 7.53 (m, 1H), 7.22 (dd,J= 1.22, 8.24 Hz, 1H), 7.12 - 7.20 (m, 2H), 6.92 - 6.97 (m, 2H), 5.19 (s, 2H), 4.90 - 5.02 (m, 1H), 3.63 (s, 3H), 3.19 - 3.30 (m, 1H), 2.48 - 2.66 (m, 2H), 2.13 - 2.22 (m, 4H), 1.94 - 2.04 (m, 2H), 1.71 - 1.83 (m, 2H), 1.29 (d,J= 6.71 Hz, 3H). MS (ESI): [M + H] + = 471.1

[0181]

[0182] (4) Synthesis of 3-(4-((3-bromo-1-cyclopentyl-1H-indazol-6-yl)methoxy)phenyl)butanoic acid (B4).

[0183] B3 (10 mg, 0.0212 mmol) was dissolved in THF (0.3 mL); aqueous 1 N NaOH solution (0.1 mL) was added dropwise and stirred at 60°C for 4 h. The reaction mixture was added aq. 1 N HCl solution and extracted with ethyl acetate. The combined extracts were dried over Na2SO4, filtered, and concentrated by evaporation to obtain a crude product, which was purified by silica gel column chromatography (CHCl3:MeOH = 20:1) to obtain compound B4 (8.2 mg, yield 85%) as a white solid.

[0184] 1H NMR (CDCl3, 400 MHz): δ 7.59 (d,J= 11.00 Hz, 1H), 7.52 (s, 1H), 7.22 (dd,J= 1.15, 8.41 Hz, 1H), 7.14 - 7.20 (m, 2H), 6.92 - 6.99 (m, 2H), 5.19 (s, 2H), 4.88 - 5.03 (m, 1H), 3.26 (d,J= 7.25 Hz, 1H), 2.52 - 2.71 (m, 2H), 2.10 - 2.25 (m, 4H), 1.98 (d,J= 3.30 Hz, 2H), 1.70 - 1.77 (m, 2H), 1.31 (d,J= 6.92 Hz, 3H). MS (ESI): [M + H] + = 458.93

[0185]

[0186] (5) Synthesis of 3-(4-((1-cyclopentyl-3-(o-tolyl)-1H-indazol-6-yl)methoxy)phenyl)butanoic acid (Compound 10)

[0187] B4 (20 mg, 0.043 mmol), Na2CO3 (14 mg, 0.131 mmol), o-tolylboronic acid (9 mg, 0.064 mmol), Pd(PPh3)4 (10 mg, 0.008 mmol) were added to 1,4-dioxane (2 mL) and water (1 mL) and stirred under reflux for 12 h. The reaction mixture was then evaporated. The residue was taken up in water and extracted with ethyl acetate. The combined extracts were dried over Na2SO4, filtered, and concentrated by evaporation to obtain a crude product, which was purified by silica gel column chromatography (CHCl3:MeOH = 50:1) to obtain compound 10 (8 mg, yield 40%) as a white solid.

[0188] 1H NMR (CDCl3, 400 MHz): δ 7.68 (d,J= 8.24 Hz, 1H), 7.58 (s, 1H), 7.53 - 7.57 (m, 1H), 7.33 - 7.37 (m, 1H), 7.29 - 7.33 (m, 2H), 7.16 - 7.21 (m, 3H), 6.96 - 7.00 (m, 2H), 5.21 (s, 2H), 5.05 (quin,J= 7.17 Hz, 1H), 3.22 - 3.30 (m, 1H), 2.53 - 2.70 (m, 2H), 2.43 (s, 3H), 2.17 - 2.29 (m, 4H), 1.97 - 2.05 (m, 2H), 1.72 - 1.79 (m, 2H), 1.32 (d,J= 7.02 Hz, 3H). MS (ESI): [M + H] + = 469.08

[0189]

[0190] (6) Synthesis of 3-(4-((1-cyclopentyl-3-(p-tolyl)-1H-indazol-6-yl)methoxy)phenyl)butanoic acid (Compound 11)

[0191] Compound 11 was synthesized from B4 and p-tolylboronic acid according to the procedure described for the synthesis of compound 10. White solid (67% yield).

[0192] 1H NMR (CDCl3, 400 MHz): δ 7.99 (d,J= 8.24 Hz, 1H), 7.84 - 7.89 (m, 2H), 7.55 (s, 1H), 7.28 - 7.34 (m,J= 7.93 Hz, 2H), 7.22 (dd,J= 1.22, 8.24 Hz, 1H), 7.16 - 7.19 (m, 2H), 6.96 - 7.01 (m, 2H), 5.21 (s, 2H), 5.00 - 5.07 (m, 1H), 3.21 - 3.29 (m, 1H), 2.54 - 2.65 (m, 2H), 2.42 (s, 3H), 2.14 - 2.28 (m, 4H), 1.96 - 2.04 (m, 2H), 1.73 - 1.79 (m, 2H), 1.31 (d,J= 7.02 Hz, 3H). MS (ESI): [M + H] + =469.08

[0193]

[0194] (7) Synthesis of 3-(4-((1-cyclopentyl-3-(4-hydroxyphenyl)-1H-indazol-6-yl)methoxy)phenyl)butanoic acid (Compound 12)

[0195] Compound 12 was synthesized from B4 and (4-hydroxyphenyl)boronic acid according to the procedure described for the synthesis of compound 10. Yellow solid (47% yield).

[0196] 1H NMR (CDCl3, 400 MHz): δ 7.95 (d,J= 8.55 Hz, 1H), 7.83 - 7.87 (m, 2H), 7.53 (s, 1H), 7.21 (dd,J= 1.22, 8.55 Hz, 1H), 7.16 - 7.20 (m, 2H), 6.94 - 6.99 (m, 4H), 5.20 (s, 2H), 4.96 - 5.06 (m, 1H), 3.21 - 3.30 (m, 1H), 2.54 - 2.69 (m, 2H), 2.18 - 2.28 (m, 4H), 1.97 - 2.05 (m, 2H), 1.73 - 1.78 (m, 2H), 1.31 (d,J= 5.80 Hz, 3H). MS (ESI): [M + H] + =471.03

[0197]

[0198] (8) Synthesis of 3-(4-((1-cyclopentyl-3-(2-hydroxyphenyl)-1H-indazol-6-yl)methoxy)phenyl)butanoic acid (Compound 13)

[0199] Compound 13 was synthesized from B4 and (2-hydroxyphenyl)boronic acid according to the procedure described for the synthesis of compound 10. Yellow solid (40% yield).

[0200] 1H NMR (CDCl3, 400 MHz): δ 8.21 (d,J= 8.55 Hz, 1H), 8.07 (dd,J= 1.53, 7.94 Hz, 1H), 7.61 (s, 1H), 7.27 - 7.32 (m, 2H), 7.16 - 7.22 (m, 2H), 7.10 - 7.13 (m, 1H), 7.02 - 7.06 (m, 1H), 6.94 - 7.00 (m, 2H), 5.23 (s, 2H), 5.03 - 5.11 (m, 1H), 3.19 - 3.29 (m, 1H), 2.55 - 2.72 (m, 2H), 2.16 - 2.24 (m, 4H), 2.01 (dt,J= 1.07, 3.13 Hz, 2H), 1.78 - 1.83 (m, 2H), 1.32 (d,J= 7.02 Hz, 3H). MS (ESI): [M + H] + = 471.3

[0201]

[0202] (9) Synthesis of 3-(4-((1-cyclopentyl-3-(3-hydroxyphenyl)-1H-indazol-6-yl)methoxy)phenyl)butanoic acid (Compound 14)

[0203] Compound 14 was synthesized from B4 and (3-hydroxyphenyl)boronic acid according to the procedure described for the synthesis of compound 10. Yellow solid (yield 33%).

[0204] 1H NMR (CDCl3, 400 MHz): δ 8.20 (d,J= 8.55 Hz, 1H), 8.07 (dd,J= 1.53, 7.93 Hz, 1H), 7.61 (s, 1H), 7.27 - 7.33 (m, 2H), 7.16 - 7.22 (m, 2H), 7.10 - 7.14 (m, 1H), 7.02 - 7.06 (m, 1H), 6.96 - 7.00 (m, 2H), 5.22 (s, 2H), 5.05 - 5.11 (m, 1H), 3.22 - 3.30 (m, 1H), 2.57 - 2.67 (m, 2H), 2.16 - 2.23 (m, 4H), 1.98 - 2.03 (m, 2H), 1.77 - 1.83 (m, 2H), 1.32 (d,J= 7.02 Hz, 3H).MS (ESI): [M - H] - = 469.5

[0205]

[0206] (10) Synthesis of 3-(4-((1-cyclopentyl-3-(4-methoxyphenyl)-1H-indazol-6-yl)methoxy)phenyl)butanoic acid (Compound 15)

[0207] Compound 15 was synthesized from B4 and (4-methoxyphenyl)boronic acid according to the procedure described for the synthesis of compound 10. White solid (62% yield).

[0208] 1H NMR (CDCl3, 400 MHz): δ 7.97 (d,J= 8.55 Hz, 1H), 7.87 - 7.92 (m, 2H), 7.54 (s, 1H), 7.21 (dd,J= 1.22, 8.55 Hz, 1H), 7.15 - 7.20 (m, 2H), 7.02 - 7.06 (m, 2H), 6.95 - 7.00 (m, 2H), 5.20 (s, 2H), 4.97 - 5.05 (m, 1H), 3.88 (s, 3H), 3.14 - 3.35 (m, 1H), 2.52 - 2.72 (m, 2H), 2.13 - 2.30 (m, 4H), 1.98 - 2.06 (m, 2H), 1.74 - 1.79 (m, 2H), 1.31 (d,J= 6.71 Hz, 3H). MS (ESI): [M + H] + = 485.07

[0209]

[0210] (11)3-(4-((1-cyclopentyl-3-(4-nitrophenyl)-1H-indazol-6-yl)methoxy)phenyl)butanoic acid (compound 16) synthesis

[0211] Compound 16 was synthesized from B4 and (4-nitrophenyl)boronic acid according to the procedure described for the synthesis of compound 10. Yellow solid (41% yield).

[0212] 1H NMR (CDCl3, 400 MHz): δ 8.33 - 8.38 (m, 2H), 8.16 - 8.21 (m, 2H), 8.03 (d,J= 8.47 Hz, 1H), 7.62 (s, 1H), 7.32 (dd,J= 1.37, 8.24 Hz, 1H), 7.15 - 7.23 (m, 2H), 6.95 - 7.05 (m, 2H), 5.23 (s, 2H), 5.04 - 5.14 (m, 1H), 3.20 - 3.28 (m, 1H), 2.53 - 2.69 (m, 2H), 2.16 - 2.32 (m, 4H), 1.98 - 2.07 (m, 2H), 1.76 - 1.85 (m, 2H), 1.31 (d,J= 6.87 Hz, 3H). MS (ESI): [M + H] + =500.05

[0213]

[0214] (12) Synthesis of 3-(4-((1-cyclopentyl-3-(4-(trifluoromethyl)phenyl)-1H-indazol-6-yl)methoxy)phenyl)butanoic acid (Compound 17)

[0215] Compound 17 was synthesized from B4 and (4-(trifluoromethyl)phenyl)boronic acid according to the procedure described for the synthesis of compound 10. White solid (42% yield).

[0216] 1H NMR (CDCl3, 400 MHz): δ 8.08 - 8.16 (m, 2H), 8.00 (d,J= 8.24 Hz, 1H), 7.71 - 7.79 (m, 2H), 7.59 - 7.63 (m, 1H), 7.29 - 7.33 (m, 1H), 7.14 - 7.24 (m, 2H), 6.95 - 7.03 (m, 2H), 5.24 (s, 2H), 5.01 - 5.13 (m, 1H), 3.22 - 3.30 (m, 1H), 2.54 - 2.69 (m, 2H), 2.17 - 2.30 (m, 4H), 2.00 - 2.09 (m, 2H), 1.74 - 1.84 (m, 2H), 1.32 (d,J= 6.71 Hz, 3H). MS (ESI): [M + H] + =523.5.

[0217]

[0218] (13) Synthesis of 3-(4-((3-(4-chlorophenyl)-1-cyclopentyl-1H-indazol-6-yl)methoxy)phenyl)butanoic acid (Compound 18)

[0219] Compound 18 was synthesized from B4 and (4-chlorophenyl)boronic acid according to the procedure described for the synthesis of compound 10. White solid (yield 33%).

[0220] 1H NMR (CDCl3, 400 MHz): δ 7.95 (d,J= 7.32 Hz, 1H), 7.89 - 7.93 (m, 2H), 7.57 (s, 1H), 7.42 - 7.49 (m, 2H), 7.24 (dd,J= 1.22, 8.55 Hz, 1H), 7.14 - 7.20 (m, 2H), 6.94 - 7.00 (m, 2H), 5.18 - 5.22 (m, 2H), 4.99 - 5.08 (m, 1H), 3.21 - 3.30 (m, 1H), 2.52 - 2.66 (m, 2H), 2.16 - 2.30 (m, 4H), 1.96 - 2.07 (m, 2H), 1.72 - 1.87 (m, 2H), 1.31 (d,J= 7.02 Hz, 3H). MS (ESI): [M + H] + =489.2

[0221]

[0222] (14) Synthesis of 3-(4-((3-(4-cyanophenyl)-1-cyclopentyl-1H-indazol-6-yl)methoxy)phenyl)butanoic acid (Compound 19)

[0223] Compound 19 was synthesized from B4 and (4-cyanophenyl)boronic acid according to the procedure described for the synthesis of compound 10. White solid (42% yield).

[0224] 1H NMR (CDCl3, 400 MHz): δ 8.09 - 8.14 (m, 2H), 7.99 (d,J= 8.24 Hz, 1H), 7.74 - 7.79 (m, 2H), 7.60 (s, 1H), 7.29 (dd,J= 1.22, 8.55 Hz, 1H), 7.16 - 7.21 (m, 2H), 6.95 - 7.00 (m, 2H), 5.22 (s, 2H), 5.01 - 5.10 (m, 1H), 3.21 - 3.31 (m, 1H), 2.55 - 2.67 (m, 2H), 2.18 - 2.27 (m, 4H), 1.99 - 2.05 (m, 2H), 1.75 - 1.81 (m, 2H), 1.32 (d,J= 7.02 Hz, 3H). MS (ESI): [M + H] + = 480.03

[0225]

[0226] (15) Synthesis of 3-(4-((1-cyclopentyl-3-(3,5-dichloro-4-hydroxyphenyl)-1H-indazol-6-yl)methoxy)phenyl)butanoic acid (Compound 20)

[0227] Compound 20 was synthesized from B4 and (3,5-dichloro-4-hydroxyphenyl)boronic acid according to the procedure described for the synthesis of compound 10. White solid (yield 46%).

[0228] 1H NMR (CDCl3, 400 MHz): δ 7.93 (d,J= 8.70 Hz, 1H), 7.89 (s, 2H), 7.57 (s, 1H), 7.25 (d,J= 0.92 Hz, 1H), 7.13 - 7.20 (m, 2H), 6.93 - 7.01 (m, 2H), 5.21 (s, 2H), 5.02 (quin,J= 7.33 Hz, 1H), 3.21 - 3.29 (m, 1H), 2.55 - 2.68 (m, 2H), 2.16 - 2.26 (m, 4H), 2.02 (dt,J= 2.06, 7.67 Hz, 2H), 1.74 - 1.81 (m, 2H), 1.32 (d,J= 7.33 Hz, 3H).MS (ESI): [M + H] + = 539.5

[0229]

[0230] (16) Synthesis of 3-(4-((1-cyclopentyl-3-(3,5-dichloro-4-(hydroxymethyl)phenyl)-1H-indazol-6-yl)methoxy)phenyl)butanoic acid (Compound 21)

[0231] Compound 21 was synthesized from B4 and (3,5-dichloro-4-(hydroxymethyl)phenyl)boronic acid according to the procedure described for the synthesis of compound 10. White solid (yield 41%).

[0232] 1 H NMR (CDCl3, 400 MHz): δ 7.90 - 7.99 (m, 3H), 7.59 (s, 1H), 7.30 (d,J= 0.92 Hz, 1H), 7.15 - 7.21 (m, 2H), 6.94 - 7.00 (m, 2H), 5.21 (s, 2H), 5.00 - 5.08 (m, 3H), 3.19 - 3.30 (m, 1H), 2.54 - 2.68 (m, 2H), 2.15 - 2.28 (m, 4H), 1.98 - 2.06 (m, 2H), 1.73 - 1.80 (m, 2H), 1.32 (d,J= 7.33 Hz, 3H). MS (ESI): [M + H] + = 554.65

[0233]

[0234] (17) Synthesis of 3-(4-((3-(3,5-bis(trifluoromethyl)phenyl)-1-cyclopentyl-1H-indazol-6-yl)methoxy)phenyl)butanoic acid (Compound 22)

[0235] Compound 22 was synthesized from B4 and (3,5-bis(trifluoromethyl)phenyl)boronic acid according to the procedure described for the synthesis of compound 10. White solid (21% yield).

[0236]

[0237] (18) Synthesis of 3-(4-((1-cyclopentyl-3-(pyridin-4-yl)-1H-indazol-6-yl)methoxy)phenyl)butanoic acid (Compound 23)

[0238] Compound 23 was synthesized from B4 and pyridin-4-ylboronic acid according to the procedure described for the synthesis of compound 10. White solid (yield 27%).

[0239]

[0240] (19) Synthesis of 3-(4-((3-([1,1'-biphenyl]-4-yl)-1-cyclopentyl-1H-indazol-6-yl)methoxy)phenyl)butanoic acid (Compound 24)

[0241] Compound 24 was synthesized from B4 and [1,1'-biphenyl]-4-ylboronic acid according to the procedure described for the synthesis of compound 10. White solid (yield 17%).

[0242]

[0243] (20) Synthesis of 3-(4-((3-(benzo[b]thiophen-2-yl)-1-cyclopentyl-1H-indazol-6-yl)methoxy)phenyl)butanoic acid (Compound 25)

[0244] Compound 25 was synthesized from B4 and benzo[b]thiophene-2-ylboronic acid according to the procedure described for the synthesis of compound 10. White solid (yield 22%).

[0245]

[0246] (21) Synthesis of 3-(4-((1-cyclopentyl-3-(naphthalen-1-yl)-1H-indazol-6-yl)methoxy)phenyl)butanoic acid (Compound 26)

[0247] Compound 26 was synthesized from B4 and naphthalen-1-ylboronic acid according to the procedure described for the synthesis of compound 10. White solid (yield 31%).

[0248]

[0249] (22) Synthesis of 3-(4-((1-cyclopentyl-3-(4-(pentan-3-yloxy)phenyl)-1H-indazol-6-yl)methoxy)phenyl)butanoic acid (Compound 27)

[0250] Compound 27 was synthesized from B4 and (4-(pentan-3-yloxy)phenyl)boronic acid according to the procedure described for the synthesis of compound 10. White solid (yield 20%).

[0251]

[0252] (23) Synthesis of (E)-4-(4-(6-((4-(1-carboxypropan-2-yl)phenoxy)methyl)-1-cyclopentyl-1H-indazol-3-yl)phenoxy)but-2-enoic acid (Compound 28)

[0253] Compound 28 was synthesized from B4 (E)-4-(4-boronophenoxy)but-2-enoic acid according to the procedure described for the synthesis of compound 10. White solid (yield 19%).

[0254]

[0255] (24) Synthesis of 3-(4-((1-cyclopentyl-3-(4-ethoxyphenyl)-1H-indazol-6-yl)methoxy)phenyl)butanoic acid (Compound 29)

[0256] Compound 29 was synthesized from B4 and (4-ethoxyphenyl)boronic acid according to the procedure described for the synthesis of compound 10. White solid (yield 38%).

[0257]

[0258] (25) Synthesis of 3-(4-((1-cyclopentyl-3-(4-ethoxyphenyl)-1H-indazol-6-yl)methoxy)phenyl)butanoic acid (Compound 29)

[0259] Compound 29 was synthesized from B4 and (4-ethoxyphenyl)boronic acid according to the procedure described for the synthesis of compound 10. White solid (yield 38%).

[0260]

[0261] (26) Synthesis of 3-(4-((3-(4-(allyloxy)phenyl)-1-cyclopentyl-1H-indazol-6-yl)methoxy)phenyl)butanoic acid (Compound 30)

[0262] Compound 30 was synthesized from B4 and (4-(allyloxy)phenyl)boronic acid according to the procedure described for the synthesis of compound 10. White solid (yield 23%).

[0263]

[0264] (27) Synthesis of 3-(4-((3-(benzo[d][1,3]dioxol-5-yl)-1-cyclopentyl-1H-indazol-6-yl)methoxy)phenyl)butanoic acid (compound 31)

[0265] Compound 31 was synthesized from B4 and benzo[d][1,3]dioxol-5-ylboronic acid according to the procedure described for the synthesis of compound 10. White solid (yield 31%).

[0266]

[0267] (28) Synthesis of 3-(4-((1-cyclopentyl-3-(1H-tetrazol-5-yl)-1H-indazol-6-yl)methoxy)phenyl)butanoic acid (Compound 32)

[0268] Compound 32 was synthesized from B4 and (1H-tetrazol-5-yl)boronic acid according to the procedure described for the synthesis of compound 10. White solid (yield 19%).

[0269]

[0270] (29) Synthesis of 3-(4-((1-cyclopentyl-3-(2,6-dichloropyridin-4-yl)-1H-indazol-6-yl)methoxy)phenyl)butanoic acid (Compound 33)

[0271] Compound 33 was synthesized from B4 and (2,6-dichloropyridin-4-yl)boronic acid according to the procedure described for the synthesis of compound 10. White solid (yield 31%).

[0272]

[0273] (30) Synthesis of (E)-3-(4-((1-cyclopentyl-3-(3,5-difluoro-4-((hydroxyimino)methyl)phenyl)-1H-indazol-6-yl)methoxy)phenyl)butanoic acid (Compound 34)

[0274] Compound 34 was synthesized from B4 and (E)-(3,5-difluoro-4-((hydroxyimino)methyl)phenyl)boronic acid according to the procedure described for the synthesis of compound 10. White solid (yield 10%).

[0275]

[0276] Manufacturing Example 3. Synthesis of Compounds 35 to 55

[0277]

[0278] (1) Synthesis of methyl (S)-3-(4-((3-bromo-1-cyclopentyl-1H-indazol-6-yl)methoxy)phenyl)butanoate (C2)

[0279] B2 (0.034 mmol) was dissolved in toluene (2 mL), and methyl (S)-3-(4-hydroxyphenyl)butanoate (0.051 mmol) was added. Subsequently, tributylphosphine (25 μL, 0.102 mmol) and 1,1'-(azodicarbonyl)dipiperidine (26 mg, 0.102 mmol) were added, and the mixture was stirred at room temperature for 3 h. The reaction mixture was then filtered and washed with hexane. The filtrate was concentrated using an evaporator to produce a crude product, which was purified by silica gel column chromatography (hexane:ethyl acetate = 8:1) to obtain compound C2 (yield 57%) as a colorless oil.

[0280] 1H NMR (CDCl3, 400 MHz): δ 7.60 (dd,J= 0.61, 8.24 Hz, 1H), 7.52 (s, 1H), 7.22 (dd,J= 1.22, 8.24 Hz, 1H), 7.14 - 7.18 (m, 2H), 6.93 - 6.97 (m, 2H), 5.19 (s, 2H), 4.91 - 5.01 (m, 1H), 3.63 (s, 3H), 3.21 - 3.30 (m, 1H), 2.50 - 2.64 (m, 2H), 2.12 - 2.20 (m, 4H), 1.93 - 2.04 (m, 2H), 1.70 - 1.79 (m, 2H), 1.29 (d,J= 7.02 Hz, 3H). MS (ESI): [M + H] + = 471.1

[0281]

[0282] (2) Synthesis of (S)-3-(4-((3-bromo-1-cyclopentyl-1H-indazol-6-yl)methoxy)phenyl)butanoic acid (C3)

[0283] C2 (0.034 mmol) was dissolved in toluene (2 mL), and methyl (S)-3-(4-hydroxyphenyl)butanoate (0.051 mmol) was added. Subsequently, tributylphosphine (25 μL, 0.102 mmol) and 1,1'-(azodicarbonyl)dipiperidine (26 mg, 0.102 mmol) were added, and the mixture was stirred at room temperature for 3 h. The reaction mixture was then filtered and washed with hexane. The filtrate was concentrated using an evaporator to produce a crude product, which was purified by silica gel column chromatography (hexane:ethyl acetate = 8:1) to obtain compound C3 as a white solid (yield 82%).

[0284] 1H NMR (CDCl3, 400 MHz): δ 7.60 (dd,J= 0.61, 8.55 Hz, 1H), 7.52 (s, 1H), 7.20 - 7.24 (m, 1H), 7.16 - 7.20 (m, 2H), 6.95 - 6.97 (m, 2H), 5.19 (s, 2H), 4.93 - 4.99 (m, 1H), 3.24 - 3.28 (m, 1H), 2.57 - 2.65 (m, 2H), 2.14 - 2.20 (m, 4H), 1.95 - 2.00 (m, 2H), 1.73 - 1.77 (m, 2H), 1.32 (d,J= 7.93 Hz, 3H). MS (ESI): [M + H] + = 458.93

[0285]

[0286] (3)(S)-3-(4-((1-cyclopentyl-3-(4-hydroxy-3-(trifluoromethyl)phenyl)-1H-indazol-6-yl)methoxy)phenyl)butanoic acid (Compound 35) synthesis

[0287] Compound 35 was synthesized from C3 and (4-hydroxy-3-(trifluoromethyl)phenyl)boronic acid according to the procedure described for the synthesis of compound 10. White solid (53% yield).

[0288] 1H NMR (CDCl3, 400 MHz): δ 8.11 (d,J= 1.83 Hz, 1H), 7.99 - 8.04 (m, 1H), 7.89 - 7.95 (m, 1H), 7.57 (s, 1H), 7.23 - 7.26 (m, 1H), 7.15 - 7.20 (m, 2H), 7.09 (d,J= 7.93 Hz, 1H), 6.95 - 7.00 (m, 2H), 5.21 (s, 2H), 4.99 - 5.08 (m, 1H), 3.23 - 3.29 (m, 1H), 2.56 - 2.66 (m, 2H), 2.18 - 2.27 (m, 4H), 2.00 - 2.05 (m, 2H), 1.74 - 1.80 (m, 2H), 1.32 (d,J= 7.02 Hz, 3H). MS (ESI): [M + H] + 538.62

[0289]

[0290] (4) Synthesis of (S)-3-(4-((3-(3-chloro-4-hydroxyphenyl)-1-cyclopentyl-1H-indazol-6-yl)methoxy)phenyl)butanoic acid (Compound 36)

[0291] Compound 36 was synthesized from C3 and (3-chloro-4-hydroxyphenyl)boronic acid according to the procedure described for the synthesis of compound 10. White solid (34% yield).

[0292] 1H NMR (CDCl3, 400 MHz): δ 7.92 - 7.96 (m, 2H), 7.79 (dd,J= 1.98, 8.39 Hz, 1H), 7.56 (s, 1H), 7.23 (dd,J= 1.07, 8.39 Hz, 1H), 7.16 - 7.20 (m, 2H), 7.14 (d,J= 8.55 Hz, 1H), 6.95 - 7.00 (m, 2H), 5.20 (s, 2H), 4.97 - 5.07 (m, 1H), 3.22 - 3.30 (m, 1H), 2.53 - 2.69 (m, 2H), 2.18 - 2.32 (m, 4H), 2.00 - 2.06 (m, 2H), 1.72 - 1.83 (m, 2H), 1.31 (d,J= 7.02 Hz, 3H). MS (ESI): [M + H] + = 504.64

[0293]

[0294] (5) Synthesis of (S)-3-(4-((1-cyclopentyl-3-(4-hydroxy-3-nitrophenyl)-1H-indazol-6-yl)methoxy)phenyl)butanoic acid (Compound 37)

[0295] Compound 37 was synthesized from C3 and (4-hydroxy-3-nitrophenyl)boronic acid according to the procedure described for the synthesis of compound 10. White solid (52% yield).

[0296] 1H NMR (CDCl3, 400 MHz): δ 8.69 (d,J= 2.14 Hz, 1H), 8.27 (dd,J= 2.14, 8.55 Hz, 1H), 7.97 (d,J= 8.55 Hz, 1H), 7.59 (s, 1H), 7.28 - 7.32 (m, 2H), 7.14 - 7.22 (m,J= 8.55 Hz, 2H), 6.92 - 7.03 (m, 2H), 5.22 (s, 2H), 4.98 - 5.07 (m, 1H), 3.21 - 3.33 (m, 1H), 2.51 - 2.74 (m, 2H), 2.14 - 2.30 (m, 4H), 1.70 - 1.85 (m, 2H), 1.56 - 1.69 (m, 2H), 1.32 (d,J= 7.02 Hz, 3H). MS (ESI): [M + H] + = 516.3

[0297]

[0298] (6) Synthesis of ((S)-3-(4-((1-cyclopentyl-3-(3,4-dihydroxyphenyl)-1H-indazol-6-yl)methoxy)phenyl)butanoic acid (Compound 38)

[0299] Compound 38 was synthesized from C3 and (3,4-dihydroxyphenyl)boronic acid according to the procedure described for the synthesis of compound 10. White solid (33% yield).

[0300] 1H NMR (CDCl3, 400 MHz): δ 7.88 (d,J= 8.41 Hz, 1H), 7.52 (s, 1H), 7.44 (d,J= 1.98 Hz, 1H), 7.36 (dd,J= 1.98, 8.24 Hz, 1H), 7.17 (d,J= 8.74 Hz, 3H), 6.95 (dd,J= 1.32, 8.41 Hz, 3H), 5.18 (s, 2H), 4.95 - 5.05 (m, 1H), 3.18 - 3.28 (m, 1H), 2.57 - 2.65 (m, 2H), 2.15 - 2.25 (m, 4H), 1.94 - 2.02 (m, 2H), 1.69 - 1.78 (m, 2H), 1.31 (d,J= 6.92 Hz, 3H). MS (ESI): [M + H] + = 487.3

[0301]

[0302] (7) Synthesis of (S)-3-(4-((1-cyclopentyl-3-(4-hydroxy-3-methoxyphenyl)-1H-indazol-6-yl)methoxy)phenyl)butanoic acid (Compound 39)

[0303] Compound 39 was synthesized from C3 and (4-hydroxy-3-methoxyphenyl)boronic acid according to the procedure described for the synthesis of compound 10. White solid (29% yield).

[0304] 1H NMR (CDCl3, 400 MHz): δ 7.92 - 7.99 (m, 1H), 7.51 - 7.56 (m, 1H), 7.43 - 7.49 (m, 2H), 7.20 - 7.23 (m, 1H), 7.18 (d,J= 8.85 Hz, 2H), 7.02 - 7.06 (m, 1H), 6.95 - 6.99 (m, 2H), 5.19 (s, 2H), 4.98 - 5.06 (m, 1H), 3.99 (s, 3H), 3.21 - 3.28 (m, 1H), 2.52 - 2.72 (m, 2H), 2.16 - 2.28 (m, 4H), 1.98 - 2.05 (m, 2H), 1.72 - 1.77 (m, 2H), 1.31 (d,J= 7.02 Hz, 3H).MS (ESI): [M + H] + = 501.4

[0305]

[0306] (8) Synthesis of (S)-3-(4-((3-(3-cyano-4-hydroxyphenyl)-1-cyclopentyl-1H-indazol-6-yl)methoxy)phenyl)butanoic acid (Compound 40)

[0307] Compound 40 was synthesized from C3 and (3-cyano-4-hydroxyphenyl)boronic acid according to the procedure described for the synthesis of compound 10. White solid (45% yield).

[0308] 1H NMR (CDCl3, 400 MHz): δ 8.01 - 8.13 (m, 2H), 7.89 (d,J= 8.24 Hz, 1H), 7.57 (s, 1H), 7.24 (d,J= 8.55 Hz, 1H), 7.14 - 7.21 (m,J= 8.55 Hz, 2H), 7.07 (d,J= 8.85 Hz, 1H), 6.91 - 7.01 (m, 2H), 5.20 (s, 2H), 4.97 - 5.08 (m, 1H), 3.19 - 3.30 (m, 1H), 2.53 - 2.71 (m, 2H), 2.13 - 2.29 (m, 4H), 1.96 - 2.05 (m, 2H), 1.72 - 1.81 (m, 2H), 1.33 (d,J= 7.02 Hz, 3H) MS (ESI): [M + H] + = 496.3

[0309]

[0310] (9) Synthesis of (S)-3-(4-((1-cyclopentyl-3-(2-fluoro-4-hydroxyphenyl)-1H-indazol-6yl)methoxy)phenyl)butanoic acid (Compound 41)

[0311] Compound 41 was synthesized from C3 and (2-fluoro-4-hydroxyphenyl)boronic acid according to the procedure described for the synthesis of compound 10. White solid (30% yield).

[0312] 1H NMR (CDCl3, 400 MHz): δ 7.78 (dd,J= 3.20, 8.39 Hz, 1H), 7.61 (t,J= 8.09 Hz, 1H), 7.52 - 7.56 (m, 1H), 7.15 - 7.22 (m, 3H), 6.94 - 7.01 (m, 2H), 6.66 - 6.73 (m, 2H), 5.20 (s, 2H), 5.04 (quin,J= 7.55 Hz, 1H), 3.19 - 3.30 (m, 1H), 2.54 - 2.70 (m, 2H), 2.14 - 2.30 (m, 4H), 1.94 - 2.05 (m, 2H), 1.67 - 1.82 (m, 2H), 1.32 (dd,J= 1.00, 6.71 Hz, 3H). MS (ESI): [M + H] + = 488.67

[0313]

[0314] (10) Synthesis of (S)-3-(4-((3-(2-chloro-4-hydroxyphenyl)-1-cyclopentyl-1H-indazol-6-yl)methoxy)phenyl)butanoic acid (Compound 42)

[0315] Compound 42 was synthesized from C3 and (2-chloro-4-hydroxyphenyl)boronic acid according to the procedure described for the synthesis of compound 10. White solid (52% yield).

[0316] 1H NMR (CDCl3, 400 MHz): δ 7.66 (d,J= 8.55 Hz, 1H), 7.57 (s, 1H), 7.46 (d,J= 8.24 Hz, 1H), 7.16 - 7.21 (m, 3H), 7.04 (d,J= 2.44 Hz, 1H), 6.95 - 7.00 (m, 2H), 6.84 (dd,J= 2.59, 8.39 Hz, 1H), 5.21 (s, 2H), 5.00 - 5.10 (m, 1H), 3.20 - 3.30 (m, 1H), 2.52 - 2.70 (m, 2H), 2.15 - 2.32 (m, 4H), 1.95 - 2.03 (m, 2H), 1.72 - 1.79 (m, 2H), 1.31 (d,J= 7.02 Hz, 3H)) MS (ESI): [M + H] + = 505.3

[0317]

[0318] (11) Synthesis of (S)-3-(4-((1-cyclopentyl-3-(3,5-difluoro-4-hydroxyphenyl)-1H-indazol-6-yl)methoxy)phenyl)butanoic acid (Compound 43)

[0319] Compound 43 was synthesized from C3 and (3,5-difluoro-4-hydroxyphenyl)boronic acid according to the procedure described for the synthesis of compound 10. White solid (49% yield).

[0320] 1H NMR (METHANOL-d4, 400 MHz): δ 7.89 (d,J= 8.47 Hz, 1H), 7.61 (s, 1H), 7.39 - 7.53 (m, 2H), 7.23 (dd,J= 1.15, 8.47 Hz, 1H), 7.08 - 7.18 (m, 2H), 6.86 - 6.97 (m, 2H), 5.15 (s, 2H), 5.07 (t,J= 7.21 Hz, 1H), 3.01 - 3.18 (m, 1H), 2.41 - 2.53 (m, 2H), 2.04 - 2.21 (m, 4H), 1.89 - 2.03 (m, 2H), 1.67 - 1.81 (m, 2H), 1.21 (d,J= 6.87 Hz, 3H). MS (ESI): [M + H] + = 507.3

[0321]

[0322] (12) Synthesis of (S)-3-(4-((1-cyclopentyl-3-(3,5-dichloro-4-hydroxyphenyl)-1H-indazol-6-yl)methoxy)phenyl)butanoic acid (Compound 44)

[0323] Compound 44 was synthesized from C3 and (3,5-dichloro-4-hydroxyphenyl)boronic acid according to the procedure described for the synthesis of compound 10. White solid (38% yield).

[0324] 1 H NMR (CDCl3, 400 MHz): δ 7.93 (d,J= 8.55 Hz, 1H), 7.87 - 7.90 (m, 2H), 7.57 (s, 1H), 7.24 - 7.27 (m, 1H), 7.18 (d,J= 8.55 Hz, 2H), 6.93 - 7.02 (m, 2H), 5.21 (s, 2H), 4.97 - 5.09 (m, 1H), 3.20 - 3.32 (m, 1H), 2.54 - 2.70 (m, 2H), 2.16 - 2.27 (m, 4H), 1.99 - 2.05 (m, 2H), 1.74 - 1.81 (m, 2H), 1.32 (d,J= 7.02 Hz, 3H). MS (ESI): [M + H] += 539.2

[0325]

[0326] (13) Synthesis of (S)-3-(4-((1-cyclopentyl-3-(2,5-difluoro-4-hydroxyphenyl)-1H-indazol-6-yl)methoxy)phenyl)butanoic acid (Compound 45)

[0327] Compound 45 was synthesized from C3 and (2,5-difluoro-4-hydroxyphenyl)boronic acid according to the procedure described for the synthesis of compound 10. White solid (35% yield).

[0328] 1 H NMR (CDCl3, 400 MHz): δ 7.80 (dd,J= 3.43, 8.47 Hz, 1H), 7.50 - 7.58 (m, 2H), 7.14 - 7.24 (m, 3H), 6.97 (d,J= 8.70 Hz, 2H), 6.89 (dd,J= 7.33, 10.53 Hz, 1H), 5.20 (s, 2H), 5.00 - 5.09 (m, 1H), 3.22 - 3.32 (m, 1H), 2.55 - 2.69 (m, 2H), 2.15 - 2.28 (m, 4H), 1.95 - 2.02 (m, 2H), 1.71 - 1.80 (m, 2H), 1.31 (d,J= 7.33 Hz, 3H). MS (ESI): [M + H] + = 507.3

[0329]

[0330] (14) Synthesis of (S)-3-(4-((1-cyclopentyl-3-(2,5-dichloro-4-hydroxyphenyl)-1H-indazol-6-yl)methoxy)phenyl)butanoic acid (Compound 46)

[0331] Compound 46 was synthesized from C3 and (2,5-dichloro-4-hydroxyphenyl)boronic acid according to the procedure described for the synthesis of compound 10. White solid (42% yield).

[0332] 1H NMR (CDCl3, 400 MHz): δ 7.64 (d,J= 8.70 Hz, 1H), 7.52 - 7.57 (m, 2H), 7.12 - 7.22 (m, 4H), 6.90 - 7.00 (m, 2H), 5.18 (s, 2H), 5.02 (quin,J= 7.21 Hz, 1H), 3.19 - 3.28 (m, 1H), 2.59 (dq,J= 7.56, 15.80 Hz, 2H), 2.09 - 2.30 (m, 4H), 1.92 - 2.06 (m, 2H), 1.63 - 1.77 (m, 2H), 1.29 (d,J= 6.87 Hz, 3H). MS (ESI): [M + H] + = 539.2

[0333]

[0334] (15) Synthesis of (S)-3-(4-((1-cyclopentyl-3-(3,5-difluoro-4-(hydroxymethyl)phenyl)-1H-indazol-6-yl)methoxy)phenyl)butanoic acid (Compound 47)

[0335] Compound 47 was synthesized from C3 and (3,5-difluoro-4-(hydroxymethyl)phenyl)boronic acid according to the procedure described for the synthesis of compound 10. White solid (57% yield).

[0336] 1 H NMR (METHANOL-d 4,400 MHz) δ 8.03 (d,J= 8.47 Hz, 1H), 7.72 (s, 1H), 7.59 (d,J= 8.70 Hz, 2H), 7.35 (dd,J= 1.14, 8.47 Hz, 1H), 7.15 - 7.21 (m, 2H), 6.92 - 7.00 (m, 2H), 5.24 (s, 2H), 5.18 (t,J= 7.10 Hz, 1H), 4.73 (s, 2H), 3.13 - 3.23 (m, 1H), 2.52 (dd,J= 4.58, 7.56 Hz, 2H), 2.15 - 2.27 (m, 4H), 1.97 - 2.05 (m, 2H), 1.76 - 1.87 (m, 2H), 1.27 (d,J= 6.87 Hz, 3H). MS (ESI): [M + H] + = 521.3

[0337]

[0338] (16) Synthesis of (S)-3-(4-((1-cyclopentyl-3-(3,5-dichloro-4-(hydroxymethyl)phenyl)-1H-indazol-6-yl)methoxy)phenyl)butanoic acid (Compound 48)

[0339] Compound 48 was synthesized from C3 and (3,5-dichloro-4-(hydroxymethyl)phenyl)boronic acid according to the procedure described for the synthesis of compound 10. White solid (45% yield).

[0340] 1 H NMR (METHANOL-d4, 400 MHz) δ 7.97 - 8.02 (m, 3H), 7.74 (s, 1H), 7.34 - 7.38 (m, 1H), 7.14 - 7.22 (m, 2H), 6.92 - 7.01 (m, 2H), 5.24 (s, 2H), 5.13 - 5.22 (m, 1H), 4.91 - 4.98 (m, 2H), 3.13 - 3.24 (m, 1H), 2.47 - 2.55 (m, 2H), 2.16 - 2.28 (m, 4H), 2.00 - 2.06 (m, 2H), 1.77 - 1.86 (m, 2H), 1.23 - 1.29 (m, 3H). MS (ESI): [M + H]+ = 553.00

[0341]

[0342] (17) Synthesis of (S)-3-(4-((1-cyclopentyl-3-(4-methoxyphenyl)-1H-indazol-6-yl)methoxy)phenyl)butanoic acid (Compound 49)

[0343] Compound 49 was synthesized from C3 and (4-methoxyphenyl)boronic acid according to the procedure described for the synthesis of compound 10. White solid (31% yield).

[0344]

[0345] (18) Synthesis of (S)-3-(4-((1-cyclopentyl-3-(4-nitrophenyl)-1H-indazol-6-yl)methoxy)phenyl)butanoic acid (Compound 50)

[0346] Compound 50 was synthesized from C3 and (4-nitrophenyl)boronic acid according to the procedure described for the synthesis of compound 10. White solid (41% yield).

[0347]

[0348] (19) Synthesis of (S)-4-(6-((4-(1-carboxypropan-2-yl)phenoxy)methyl)-1-cyclopentyl-1H-indazol-3-yl)benzoic acid (Compound 51)

[0349] Compound 51 was synthesized from C3 and 4-boronobenzoic acid according to the procedure described for the synthesis of compound 10. White solid (15% yield).

[0350]

[0351] (20) Synthesis of (S)-4-(6-((4-(1-carboxypropan-2-yl)phenoxy)methyl)-1-cyclopentyl-1H-indazol-3-yl)-3-fluorobenzoic acid (Compound 52)

[0352] Compound 52 was synthesized from C3 and 4-borono-3-fluorobenzoic acid according to the procedure described for the synthesis of compound 10. White solid (11% yield).

[0353]

[0354] (21) Synthesis of (S)-3-(4-((1-cyclopentyl-3-(4-hydroxy-3,5-dimethylphenyl)-1H-indazol-6-yl)methoxy)phenyl)butanoic acid (Compound 53)

[0355] Compound 53 was synthesized from C3 and (4-hydroxy-3,5-dimethylphenyl)boronic acid according to the procedure described for the synthesis of compound 10. White solid (35% yield).

[0356]

[0357] (22) Synthesis of (S)-3-(4-((1-cyclopentyl-3-(3-(hydroxymethyl)phenyl)-1H-indazol-6-yl)methoxy)phenyl)butanoic acid (Compound 54)

[0358] Compound 54 was synthesized from C3 and (3-(hydroxymethyl)phenyl)boronic acid according to the procedure described for the synthesis of compound 10. White solid (47% yield).

[0359]

[0360] (23) Synthesis of (S)-3-(4-((1-cyclopentyl-3-(2,3-difluoro-4-hydroxyphenyl)-1H-indazol-6-yl)methoxy)phenyl)butanoic acid (Compound 55)

[0361] Compound 55 was synthesized from C3 and (2,3-difluoro-4-hydroxyphenyl)boronic acid according to the procedure described for the synthesis of compound 10. White solid (35% yield).

[0362]

[0363] Manufacturing Example 4. Synthesis of compounds 56 to 58

[0364]

[0365] (1) Synthesis of methyl (R)-3-(4-((3-bromo-1-cyclopentyl-1H-indazol-6-yl)methoxy)phenyl)butanoate (D2)

[0366] D1 (0.034 mmol) was dissolved in toluene (2 mL), and (R)-3-(4-hydroxyphenyl)butanoate (0.051 mmol) was added. Subsequently, tributylphosphine (25 μL, 0.102 mmol) and 1,1'-(azodicarbonyl)dipiperidine (26 mg, 0.102 mmol) were added, and the mixture was stirred at room temperature for 3 h. The reaction mixture was then filtered and washed with hexane. The filtrate was concentrated using an evaporator to produce a crude product, which was purified by silica gel column chromatography (hexane:ethyl acetate = 8:1) to obtain compound D2 (yield 53%) as a colorless oil.

[0367]

[0368] (2) Synthesis of (R)-3-(4-((3-bromo-1-cyclopentyl-1H-indazol-6-yl)methoxy)phenyl)butanoic acid (D3)

[0369] D2 was dissolved in THF (0.3 mL). Aqueous 1 N NaOH solution (0.1 mL) was added dropwise and stirred at 60°C for 4 h. The reaction mixture was added aq. 1 N HCl solution and extracted with ethyl acetate. The combined extracts were dried over Na2SO4, filtered, and concentrated using an evaporator to yield a crude product, which was purified by silica gel column chromatography (CHCl3:MeOH = 20:1) to obtain D3 (yield 71%) as a white solid.

[0370]

[0371] (3) Synthesis of (R)-3-(4-((1-cyclopentyl-3-(4-hydroxyphenyl)-1H-indazol-6-yl)methoxy)phenyl)butanoic acid (Compound 56)

[0372] Compound 56 was synthesized from D3 and (4-hydroxyphenyl)boronic acid according to the procedure described for the synthesis of compound 10. White solid (yield 32%).

[0373]

[0374] (4) Synthesis of (R)-3-(4-((1-cyclopentyl-3-(4-methoxyphenyl)-1H-indazol-6-yl)methoxy)phenyl)butanoic acid (Compound 57)

[0375] Compound 57 was synthesized from D3 and (4-methoxyphenyl)boronic acid according to the procedure described for the synthesis of compound 10. White solid (yield 45%).

[0376]

[0377] (5) Synthesis of (R)-3-(4-((1-cyclopentyl-3-(4-nitrophenyl)-1H-indazol-6-yl)methoxy)phenyl)butanoic acid (Compound 58)

[0378] Compound 58 was synthesized from D3 and (4-nitrophenyl)boronic acid according to the procedure described for the synthesis of compound 10. White solid (yield 30%).

[0379]

[0380] Manufacturing Example 5. Synthesis of Compounds 59 to 62

[0381]

[0382] (1) Synthesis of 3-(4-((3-(4-aminophenyl)-1-cyclopentyl-1H-indazol-6-yl)methoxy)phenyl)butanoic acid (Compound 59)

[0383] Compound 16 (50 mg, 0.1 mmol) and SnCl2 (56 mg 0.3 mmol) were dissolved in EtOH (2 ml). The reaction mixture was stirred at 80°C for 12 h. The reaction mixture was poured into water and extracted with ethyl acetate. The combined extracts were dried over Na2SO4, filtered, and concentrated by evaporation to give a crude product, which was purified by silica gel column chromatography (hexane:ethyl acetate = 4:1) to give compound 59 (23 mg, 50% yield) as a white solid.

[0384]

[0385] (2) Synthesis of 3-(4-((3-(4-acetamidophenyl)-1-cyclopentyl-1H-indazol-6-yl)methoxy)phenyl)butanoic acid (Compound 60)

[0386] Compound 59 (23 mg, 0.05 mmol), acetyl chloride (7.8 mg 0.1 mmol), and trimethylamine (10 mg) were dissolved in DMF (2 ml). The reaction mixture was stirred at 80°C for 12 h. The reaction mixture was poured into water and extracted with ethyl acetate. The combined extracts were dried over Na2SO4, filtered, and concentrated by evaporation to obtain a crude product, which was purified by silica gel column chromatography (hexane:ethyl acetate = 1:1) to obtain compound 60 (3.8 mg, 15% yield) as a white solid.

[0387]

[0388] (3) Synthesis of 3-(4-((3-(4-acetamidophenyl)-1-cyclopentyl-1H-indazol-6-yl)methoxy)phenyl)butanoic acid (Compound 61)

[0389] Compound 61 was synthesized from compound 59 and propionyl chloride according to the procedure described for the synthesis of compound 60. White solid (12% yield).

[0390]

[0391] (4) Synthesis of 3-(4-((3-(4-(but-3-enamido)phenyl)-1-cyclopentyl-1H-indazol-6-yl)methoxy)phenyl)butanoic acid (Compound 62)

[0392] Compound 62 was synthesized from compound 59 and but-3-enoyl chloride according to the procedure described for the synthesis of compound 60. White solid (yield 10%).

[0393]

[0394] Manufacturing Example 6. Synthesis of compounds 63 to 67

[0395]

[0396] (1) Synthesis of methyl 3-(4-((3-bromo-1-cyclopentyl-1H-indazol-6-yl)methoxy)-3,5-difluorophenyl)butanoate (F2)

[0397] F2 was synthesized from B2 and methyl 3-(3,5-difluoro-4-hydroxyphenyl)butanoate according to the procedure described in the synthesis of B3 in Preparation Example 2 (yield 35%).

[0398]

[0399] (2) Synthesis of 3-(4-((3-bromo-1-cyclopentyl-1H-indazol-6-yl)methoxy)-3,5-difluorophenyl)butanoic acid (F3)

[0400] F3 was synthesized from F2 according to the procedure described in the synthesis of B4 in Manufacturing Example 2 (yield 73%).

[0401]

[0402] (3) Synthesis of 3-(4-((1-cyclopentyl-3-(4-hydroxyphenyl)-1H-indazol-6-yl)methoxy)-3,5-difluorophenyl)butanoic acid (Compound 63)

[0403] Compound 63 was synthesized from F3 and (4-hydroxyphenyl)boronic acid according to the procedure described for the synthesis of compound 10. White solid (47% yield).

[0404]

[0405] (4) Synthesis of 3-(4-((3-(3-chloro-4-hydroxyphenyl)-1-cyclopentyl-1H-indazol-6-yl)methoxy)-3,5-difluorophenyl)butanoic acid (Compound 64)

[0406] Compound 64 was synthesized from F3 and (3-chloro-4-hydroxyphenyl)boronic acid according to the procedure described for the synthesis of compound 10. White solid (yield 24%).

[0407]

[0408] (5) Synthesis of 3-(4-((1-cyclopentyl-3-(4-hydroxy-3-(trifluoromethyl)phenyl)-1H-indazol-6-yl)methoxy)-3,5-difluorophenyl)butanoic acid (Compound 65)

[0409] Compound 65 was synthesized from F3 and (4-hydroxy-3-(trifluoromethyl)phenyl)boronic acid according to the procedure described for the synthesis of compound 10. White solid (yield 35%).

[0410]

[0411] (6) Synthesis of 3-(4-((1-cyclopentyl-3-(3,5-difluoro-4-hydroxyphenyl)-1H-indazol-6-yl)methoxy)-3,5-difluorophenyl)butanoic acid (Compound 66)

[0412] Compound 66 was synthesized from F3 and (3,5-difluoro-4-hydroxyphenyl)boronic acid according to the procedure described for the synthesis of compound 10. White solid (27% yield).

[0413]

[0414] (7) Synthesis of 3-(4-((1-cyclopentyl-3-(3,5-dichloro-4-hydroxyphenyl)-1H-indazol-6-yl)methoxy)-3,5-difluorophenyl)butanoic acid (Compound 67)

[0415] Compound 67 was synthesized from F3 and (3,5-dichloro-4-hydroxyphenyl)boronic acid according to the procedure described for the synthesis of compound 10. White solid (yield 30%).

[0416]

[0417] Manufacturing Example 7. Synthesis of Compounds 68 to 71

[0418]

[0419] (1) Synthesis of methyl 3-bromo-1-cyclopentyl-4-fluoro-1H-indazole-6-carboxylate (G2)

[0420] G2 was synthesized from methyl 3-bromo-4-fluoro-1H-indazole-6-carboxylate (G1) according to the procedure described in the synthesis of B1 in Preparation Example 2. Colorless oil, (yield 43%).

[0421] 1H NMR (DMSO-d6, 400 MHz) δ 8.29 (d,J= 0.92 Hz, 1H), 7.40 (dd,J= 0.92, 10.99 Hz, 1H), 5.32 - 5.41 (m, 1H), 3.92 (s, 3H), 2.06 - 2.24 (m, 2H), 1.90 - 2.02 (m, 2H), 1.79 - 1.90 (m, 2H), 1.60 - 1.76 (m, 2H). MS (ESI): [M + H] + = 341.0

[0422]

[0423] (2) Synthesis of (3-bromo-1-cyclopentyl-4-fluoro-1H-indazol-6-yl)methanol (G3)

[0424] G3 was synthesized from G2 according to the procedure described in the synthesis of B2 in Manufacturing Example 2. Colorless oil, (yield 35%).

[0425] 1 H NMR (DMSO-d6, 400 MHz) δ 8.53 (s, 1H), 7.30 - 7.36 (m, 1H), 6.71 (d,J= 11.60 Hz, 1H), 4.96 - 5.05 (m, 1H), 4.53 (s, 2H), 2.13 - 2.23 (m, 2H), 2.02 - 2.13 (m, 2H), 1.82 - 1.94 (m, 2H), 1.65 - 1.76 (m, 2H). MS (ESI): [M + H] + = 313.0

[0426]

[0427] (3) Synthesis of methyl (S)-3-(4-((3-bromo-1-cyclopentyl-4-fluoro-1H-indazol-6-yl)methoxy)phenyl)butanoate (G4)

[0428] G4 was synthesized from G3 according to the procedure described in the synthesis of B3 in Manufacturing Example 2. Yellow oil, (yield 65%).

[0429] 1H NMR (CDCl3, 400 MHz): δ 7.30 (s, 1H), 7.12 - 7.19 (m, 2H), 6.90 - 6.98 (m, 2H), 6.85 (d,J= 10.53 Hz, 1H), 5.14 (s, 2H), 4.91 (quin,J= 7.38 Hz, 1H), 3.63 (s, 3H), 3.20 - 3.32 (m, 1H), 2.47 - 2.64 (m, 2H), 2.06 - 2.22 (m, 4H), 1.83 - 2.01 (m, 2H), 1.65 - 1.81 (m, 2H), 1.28 (d,J= 6.87 Hz, 3H). MS (ESI): [M + H] + = 489.2

[0430]

[0431] (5) Synthesis of (S)-3-(4-((3-bromo-1-cyclopentyl-4-fluoro-1H-indazol-6-yl)methoxy)phenyl)butanoic acid (G5)

[0432] G5 was synthesized from G4 according to the procedure described in the synthesis of B4 in Manufacturing Example 2. Colorless oil, (yield 40%).

[0433] 1 H NMR (CDCl3, 400 MHz): δ 7.30 (s, 1H), 7.13 - 7.20 (m, 2H), 6.90 - 6.97 (m, 2H), 6.85 (d,J= 10.76 Hz, 1H), 5.14 (s, 2H), 4.91 (quin,J= 7.33 Hz, 1H), 3.12 - 3.31 (m, 1H), 2.51 - 2.67 (m, 2H), 2.08 - 2.23 (m, 4H), 1.90 - 2.06 (m, 2H), 1.68 - 1.81 (m, 2H), 1.31 (d,J= 6.87 Hz, 3H). MS (ESI): [M + H] + = 476.2

[0434]

[0435] (6) Synthesis of (S)-3-(4-((1-cyclopentyl-3-(3,5-difluoro-4-hydroxyphenyl)-4-fluoro-1H-indazol-6-yl)methoxy)phenyl)butanoic acid (Compound 68)

[0436] Compound 68 was synthesized from G5 and (3,5-difluoro-4-hydroxyphenyl)boronic acid according to the procedure described for the synthesis of compound 10. White solid (41% yield).

[0437] 1 H NMR (METHANOL-d 4, 400 MHz) δ ppm 7.45 - 7.52 (m, 3 H), 7.15 - 7.20 (m, 2 H), 6.92 - 7.00 (m, 3 H), 5.15 - 5.24 (m, 2 H), 5.06 - 5.14 (m, 1 H), 3.11 - 3.24 (m, 1 H), 2.46 - 2.56 (m, 2 H), 2.13 - 2.27 (m, 4 H), 1.96 - 2.04 (m, 2 H), 1.76 - 1.86 (m, 2 H), 1.25 - 1.28 (m, 3 H). MS (ESI): [M + H] + = 525.3

[0438]

[0439] (7) Synthesis of (S)-3-(4-((1-cyclopentyl-3-(3,5-dichloro-4-hydroxyphenyl)-4-fluoro-1H-indazol-6-yl)methoxy)phenyl)butanoic acid (Compound 69)

[0440] Compound 69 was synthesized from G5 and (3,5-dichloro-4-hydroxyphenyl)boronic acid according to the procedure described for the synthesis of compound 10. White solid (45% yield).

[0441] 1 H NMR (METHANOL-d 4,400 MHz) δ ppm 7.78 - 7.82 (m, 2 H), 7.48 (s, 1 H), 7.13 - 7.21 (m, 2 H), 6.91 - 6.99 (m, 3 H), 5.17 (s, 2 H), 5.11 (quin,J=7.10 Hz, 1 H), 3.10 - 3.21 (m, 1 H), 2.49 - 2.56 (m, 2 H), 2.09 - 2.23 (m, 4 H), 1.88 - 2.06 (m, 2 H), 1.75 - 1.84 (m, 2 H), 1.23 - 1.29 (m, 3 H). MS (ESI): [M + H] + = 557.1

[0442]

[0443] (8) Synthesis of (S)-3-(4-((1-cyclopentyl-3-(3,5-difluoro-4-(hydroxymethyl)phenyl)-4-fluoro-1H-indazol-6-yl)methoxy)phenyl)butanoic acid (Compound 70)

[0444] Compound 70 was synthesized from G5 and (3,5-difluoro-4-(hydroxymethyl)phenyl)boronic acid according to the procedure described for the synthesis of compound 10. White solid (yield 58%).

[0445] 1 H NMR (METHANOL-d 4, 400 MHz) δ ppm 7.49 - 7.59 (m, 3 H), 7.14 - 7.21 (m, 2 H), 6.93 - 7.02 (m, 3 H), 5.19 (s, 2 H), 5.10 - 5.18 (m, 1 H), 4.72 (s, 2 H), 3.11 - 3.23 (m, 1 H), 2.47 - 2.59 (m, 2 H), 2.10 - 2.27 (m, 4 H), 1.96 - 2.05 (m, 2 H), 1.75 - 1.88 (m, 2 H), 1.26 (d,J=6.87 Hz, 3 H). MS (ESI): [M + H] + = 539.3

[0446]

[0447] (9) Synthesis of (S)-3-(4-((1-cyclopentyl-3-(3,5-dichloro-4-(hydroxymethyl)phenyl)-4-fluoro-1H-indazol-6-yl)methoxy)phenyl)butanoic acid (Compound 71)

[0448] Compound 71 was synthesized from G5 and (3,5-dichloro-4-(hydroxymethyl)phenyl)boronic acid according to the procedure described for the synthesis of compound 10. White solid (yield 36%).

[0449] 1 H NMR (METHANOL-d 4, 400 MHz) δ ppm 7.92 (s, 2 H), 7.52 (s, 1 H), 7.13 - 7.21 (m, 2 H), 6.92 - 7.01 (m, 3 H), 5.17 (s, 2 H), 5.10 - 5.16 (m, 1 H), 4.91 (s, 2) H), 3.11 - 3.22 (m, 1 H), 2.43 - 2.57 (m, 2 H), 2.10 - 2.25 (m, 4 H), 1.90 - 2.06 (m, 2 H), 1.71 - 1.86 (m, 2 H), 1.26 (d,J=6.87 Hz, 3 H). MS (ESI): [M + H] + = 571.2

[0450]

[0451] Manufacturing Example 8. Synthesis of Compounds 72 to 75

[0452]

[0453] (1) Synthesis of methyl 3-bromo-1H-pyrazolo[4,3-b]pyridine-6-carboxylate (H2)

[0454] Methyl 1H-pyrazolo[4,3-b]pyridine-6-carboxylate (H1) (20 mg, 0.113 mmol) and n-bromosuccinimide (22 mg, 0.124 mmol) were dissolved in ACN (2 ml). The reaction mixture was stirred at room temperature for 12 h. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give a crude product, which was purified by silica gel column chromatography (hexane:ethyl acetate = 1:1) to give compound H2. Colorless oil (8 mg, 30% yield).

[0455]

[0456] (2) Synthesis of methyl 3-bromo-1-cyclopentyl-1H-pyrazolo[4,3-b]pyridine-6-carboxylate (H3)

[0457] Compound H3 was synthesized from H2 according to the procedure described in the synthesis of B1 in Preparation Example 2. White solid (yield 41%).

[0458]

[0459] (3) Synthesis of (3-bromo-1-cyclopentyl-1H-pyrazolo[4,3-b]pyridin-6-yl)methanol (H4)

[0460] Compound H4 was synthesized from H3 according to the procedure described in the synthesis of B2 in Preparation Example 2. White solid (yield 36%).

[0461]

[0462] (4) Synthesis of (3-bromo-1-cyclopentyl-1H-pyrazolo[4,3-b]pyridin-6-yl)methyl methanesulfonate (H5)

[0463] Compound H4 (20 mg, 0.08 mmol), methanesulfonyl chloride (9 mg, 0.169 mmol), and trimethylamine (17 mg, 0.169 mmol) were dissolved in DCM (2 ml). The reaction mixture was stirred at room temperature for 12 h. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give a crude product, which was purified by silica gel column chromatography (hexane:ethyl acetate = 3:1) to give compound H5. Colorless oil (21 mg, yield 66%).

[0464]

[0465] (5) Synthesis of methyl 3-(4-((3-bromo-1-cyclopentyl-1H-pyrazolo[4,3-b]pyridin-6-yl)methoxy)phenyl)butanoate (H6)

[0466] Compound H5 (273 mg, 0.731 mmol), potassium carbonate (202 mg, 1.462 mmol), and methyl 3-(4-hydroxyphenyl)butanoate (160 mg, 0.804 mmol) were dissolved in DMF (2 ml). The reaction mixture was stirred at room temperature for 12 h. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined extracts were dried over Na2SO4, filtered, and concentrated in vacuo to obtain a crude product, which was purified by silica gel column chromatography (hexane:ethyl acetate = 5:1) to obtain compound H6. Colorless oil (237 mg, yield 68%).

[0467]

[0468] (6) Synthesis of 3-(4-((3-bromo-1-cyclopentyl-1H-pyrazolo[4,3-b]pyridin-6-yl)methoxy)phenyl)butanoic acid (H7)

[0469] Compound H7 was synthesized from H6 according to the procedure described in the synthesis of B3 in Preparation Example 2. White solid (yield 56%).

[0470]

[0471] (7) Synthesis of 3-(4-((1-cyclopentyl-3-(4-hydroxyphenyl)-1H-pyrazolo[4,3-b]pyridin-6-yl)methoxy)phenyl)butanoic acid (Compound 72)

[0472] Compound 72 was synthesized from H7 and (4-hydroxyphenyl)boronic acid according to the procedure described for the synthesis of compound 10. White solid, (35% yield).

[0473]

[0474] (8) Synthesis of 3-(4-((1-cyclopentyl-3-(3,5-dichloro-4-hydroxyphenyl)-1H-pyrazolo[4,3-b]pyridin-6-yl)methoxy)phenyl)butanoic acid (Compound 73)

[0475] Compound 73 was synthesized from H7 and (3,5-dichloro-4-hydroxyphenyl)boronic acid according to the procedure described for the synthesis of compound 10. White solid, (41% yield).

[0476]

[0477] (9) Synthesis of 3-(4-((1-cyclopentyl-3-(3,5-difluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-b]pyridin-6-yl)methoxy)phenyl)butanoic acid (Compound 74)

[0478] Compound 74 was synthesized from H7 and (3,5-difluoro-4-hydroxyphenyl)boronic acid according to the procedure described for the synthesis of compound 10. White solid, (31% yield).

[0479]

[0480] (10) Synthesis of 3-(4-((3-(3-chloro-4-hydroxyphenyl)-1-cyclopentyl-1H-pyrazolo[4,3-b]pyridin-6-yl)methoxy)phenyl)butanoic acid (Compound 75)

[0481] Compound 75 was synthesized from H7 and (3-chloro-4-hydroxyphenyl)boronic acid according to the procedure described for the synthesis of compound 10. White solid, (43% yield).

[0482]

[0483] Manufacturing Example 9. Synthesis of Compounds 76 to 86

[0484]

[0485] (1) Synthesis of methyl 3-bromo-1-trityl-1H-indazole-6-carboxylate (J2)

[0486] Methyl 3-bromo-1H-indazole-6-carboxylate (J1) (20 mg, 0.078 mmol), trityl chloride (23 mg, 0.082 mmol), and K2CO3 (32 mg, 0.235 mmol) were dissolved in THF (0.3 mL) and DMF (0.1 mL). The mixture was stirred at room temperature for 12 h. The reaction mixture was evaporated. The residue was dissolved in water and extracted with ethyl acetate. The combined extracts were dried over Na2SO4, filtered, and concentrated by evaporation to obtain the crude product, which was purified by silica gel column chromatography (CHCl3:hexane:DCM = 30:1:1) to obtain compound J2 as a white solid. (22 mg, 57% yield).

[0487] 1 H NMR (DMSO-d6, 400 MHz) δ 7.72 (d,J= 0.92 Hz, 2H), 7.30 - 7.39 (m, 9H), 7.13 - 7.17 (m, 6H), 7.03 (t,J= 1.07 Hz, 1H), 3.72 (s, 3H)

[0488]

[0489] (2) Synthesis of methyl 3-phenyl-1-trityl-1H-indazole-6-carboxylate (J3)

[0490] Compound J2 (1.5 g, 3.016 mmol), phenylboronic acid (411 mg, 3.62 mmol), Pd(PPh3)4 (174 mg, 0.15 mmol), and Na2CO3 (959 mg, 9.047 mmol) were added to 1,4-dioxane (25 mL) and water (5 mL), and the mixture was stirred under reflux for 4 h. The reaction mixture was evaporated. The residue was dissolved in water and extracted with ethyl acetate. The combined extracts were dried over Na2SO4, filtered, and concentrated by evaporation to obtain the crude product, which was purified by silica gel column chromatography (CHCl3-:hexane = 2:1) to obtain compound J3 as a white solid. (1.25 g, 84% yield).

[0491] 1 H NMR (DMSO-d6, 400 MHz) δ ppm 8.20 (dd,J=8.55, 0.61 Hz, 1 H), 7.85 - 7.92 (m, 2 H), 7.67 - 7.77 (m, 1 H), 7.49 - 7.55 (m, 2 H), 7.40 - 7.46 (m, 1 H), 7.30 - 7.39 (m, 9 H), 7.19 - 7.25 (m, 6 H), 7.10 - 7.13 (m, 1 H), 3.73 (s, 3 H)

[0492]

[0493] (3) Synthesis of (3-phenyl-1-trityl-1H-indazol-6-yl)methanol (J4)

[0494] Compound J3 (50 mg, 0.101 mmol) was dissolved in THF (1 mL) and cooled to 0°C. 1.0 M lithium aluminum hydride in THF (202 μL, 0.202 mmol) was added dropwise. The reaction mixture was stirred at 0°C for 30 min. The reaction mixture was extracted with saturated aq. NH4Cl and then with ethyl acetate. The combined extracts were dried over Na2SO4, filtered, and concentrated by evaporation to obtain the crude product, which was purified by silica gel column chromatography (CHCl3:hexane = 40:1) to obtain compound J4 as a white solid. (38 mg, yield 81%).

[0495] 1 H NMR (DMSO-d6, 400 MHz) δ ppm 8.01 (d,J=8.55 Hz, 1 H), 7.85 - 7.89 (m, 2 H), 7.46 - 7.51 (m, 2 H), 7.28 - 7.42 (m, 10 H), 7.19 - 7.27 (m, 6) H), 7.11 (d,J=8.55 Hz, 1 H), 6.45 - 6.48 (m, 1 H), 5.07 - 5.13 (m, 1 H), 4.32 (d,J=4.27 Hz, 2 H)

[0496]

[0497] (4) Synthesis of methyl 3-(4-((3-phenyl-1-trityl-1H-indazol-6-yl)methoxy)phenyl)butanoate (J5)

[0498] Compound J4 (8 mg, 0.017 mmol) and methyl 3-(4-hydroxyphenyl)butanoate (5 mg, 0.026 mmol) were dissolved in toluene (1 mL). 1,1'-(azodicarbonyl)dipiperidine (13 mg, 0.051 mmol) and tributylphosphine (13 μL, 0.051 mmol) were added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered and washed with hexane. The filtrate was concentrated using an evaporator to obtain a crude product, which was purified by silica gel column chromatography (hexane:ethyl acetate = 4:1) to obtain compound J5 as a white solid. (10 mg, yield 91%).

[0499] 1 H NMR (CDCl3, 400 MHz) δ ppm 8.00 - 8.05 (m, 1 H), 7.90 - 7.94 (m, 2 H), 7.42 - 7.47 (m, 2 H), 7.32 - 7.38 (m, 1 H), 7.26 (s, 15 H), 7.19 (dd,J=8.39, 1.37 Hz, 1 H), 7.05 - 7.11 (m, 2 H), 6.68 - 6.75 (m, 2 H), 6.46 (s, 1 H), 4.86 (s, 2 H), 3.63 (s, 3 H), 3.19 - 3.27 (m, 1) H), 2.51 - 2.61 (m, 2 H), 1.27 (d,J=7.02 Hz, 3 H)

[0500]

[0501] (5) Synthesis of methyl 3-(4-((3-phenyl-1H-indazol-6-yl)methoxy)phenyl)butanoate (J6)

[0502] Compound J5 (10 mg, 0.016 mmol) was dissolved in DCM (2 mL). TFA (20 μL) was added dropwise at 0°C, and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was evaporated to obtain a crude product, which was purified by silica gel column chromatography (CHCl3:MeOH = 50:1) to obtain compound J6 as a white solid. (3.7 mg, 58% yield)

[0503] 1 H NMR (CDCl3, 400 MHz) δ ppm 8.02 - 8.07 (m, 1 H), 7.93 - 8.01 (m, 2 H), 7.58 - 7.62 (m, 1 H), 7.50 - 7.55 (m, 2 H), 7.40 - 7.46 (m, 1 H), 7.28 - 7.31 (m, 1 H), 7.13 - 7.19 (m, 2 H), 6.91 - 6.97 (m, 2 H), 5.20 - 5.24 (m, 2 H), 3.60 - 3.65 (m, 3 H), 3.21 - 3.30 (m, 1 H), 2.50 - 2.62 (m, 2 H), 1.26 - 1.32 (m, 3 H). MS (ESI): [M + H] + = 400.95

[0504]

[0505] (6) Synthesis of methyl 3-(4-((1-methyl-3-phenyl-1H-indazol-6-yl)methoxy)phenyl)butanoate (J76)

[0506] Compound J6 (20 mg, 0.050 mmol) and K2CO3 (21 mg, 0.150 mmol) were dissolved in DMF (0.25 mL); iodomethane (8 μL, 0.125 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 5 h, poured into water, and extracted with ethyl acetate. The combined extracts were dried over Na2SO4, filtered, and concentrated by evaporation to give a crude product, which was purified by silica gel column chromatography (hexane:ethyl acetate = 3:1) to give compound J76 as a colorless oil. (16.5 mg, 80% yield).

[0507] 1H NMR (CDCl3, 400 MHz): δ 8.02 (d,J= 8.47 Hz, 1H), 7.94 - 7.99 (m, 2H), 7.48 - 7.54 (m, 3H), 7.38 - 7.44 (m, 1H), 7.24 - 7.27 (m, 1H), 7.14 - 7.20 (m,J= 8.70 Hz, 2H), 6.93 - 6.99 (m,J= 8.70 Hz, 2H), 5.22 (s, 2H), 4.14 (s, 3H), 3.63 (s, 3H), 3.15 - 3.32 (m, 1H), 2.57 (s, 2H), 1.29 (d,J= 7.10 Hz, 3H). MS (ESI): [M + H] + = 415.10

[0508]

[0509] (7) Synthesis of 3-(4-((3-phenyl-1H-indazol-6-yl)methoxy)phenyl)butanoic acid (Compound 76)

[0510] Compound J6 (30 mg, 0.075 mmol) was dissolved in THF (0.3 mL); aqueous 1 N NaOH solution (0.100 mL) was added dropwise and stirred at 40°C for 12 h. The reaction mixture was added aq. 1 N HCl solution and extracted with ethyl acetate. The combined extracts were dried over Na2SO4, filtered, and concentrated by evaporation to give a crude product, which was purified by silica gel column chromatography (CHCl3:MeOH = 80:1) to give compound 76 as a white solid. (16.7 mg, 57% yield).

[0511] 1H NMR (METHANOL-d4, 400 MHz): δ 8.02 (dd,J= 0.61, 8.55 Hz, 1H), 7.92 - 7.96 (m, 2H), 7.62 - 7.65 (m, 1H), 7.49 - 7.55 (m, 2H), 7.38 - 7.45 (m, 1H), 7.30 (dd,J= 1.53, 8.55 Hz, 1H), 7.15 - 7.20 (m, 2H), 6.93 - 6.99 (m, 2H), 5.23 (s, 2H), 3.12 - 3.22 (m, 1H), 2.47 - 2.58 (m, 2H), 1.27 (d,J= 7.00 Hz, 3H). MS (ESI): [M + H] + = 386.98

[0512]

[0513] (8) Synthesis of methyl 3-(4-((1-ethyl-3-phenyl-1H-indazol-6-yl)methoxy)phenyl)butanoate (J77)

[0514] Compound J77 was synthesized from J76 and iodoethane according to the procedure described for the synthesis of compound J76 above. White solid, (yield 73%).

[0515] 1 H NMR (CDCl3, 400 MHz): δ 8.02 (dd,J= 0.76, 8.39 Hz, 1H), 7.94 - 7.98 (m, 2H), 7.48 - 7.55 (m, 3H), 7.38 - 7.43 (m, 1H), 7.25 (dd,J= 1.22, 8.24 Hz, 1H), 7.14 - 7.19 (m, 2H), 6.94 - 7.02 (m, 2H), 5.22 (s, 2H), 4.50 (q,J= 7.32 Hz, 2H), 3.60 - 3.65 (m, 3H), 3.18 - 3.32 (m, 1H), 2.49 - 2.64 (m, 2H), 1.53 - 1.57 (m, 3H), 1.29 (d,J= 7.02 Hz, 3H). MS (ESI): [M + H] + = 429.01

[0516]

[0517] (9) Synthesis of 3-(4-((1-methyl-3-phenyl-1H-indazol-6-yl)methoxy)phenyl)butanoic acid (Compound 77)

[0518] Compound 77 was synthesized from compound J76 according to the procedure described for the synthesis of compound 76. White solid, (62% yield).

[0519] 1 H NMR (CDCl3, 400 MHz): δ 8.02 (d,J= 8.47 Hz, 1H), 7.96 (dd,J= 0.92, 8.24 Hz, 2H), 7.47 - 7.57 (m, 3H), 7.37 - 7.45 (m, 1H), 7.25 (d,J= 1.14 Hz, 1H), 7.15 - 7.21 (m, 2H), 6.95 - 7.02 (m, 2H), 5.22 (s, 2H), 4.08 - 4.16 (m, 3H), 3.19 - 3.31 (m, 1H), 2.46 - 2.73 (m, 2H), 1.32 (d,J= 6.87 Hz, 3H). MS (ESI): [M + H] + = 401.01

[0520]

[0521] (10) Synthesis of methyl 3-(4-((3-phenyl-1-propyl-1H-indazol-6-yl)methoxy)phenyl)butanoate (J78)

[0522] Compound J78 was synthesized from J6 and 1-iodopropane according to the procedure described for compound J76 above. Colorless oil, (yield 90%).

[0523] 1H NMR (CDCl3, 400 MHz): δ 8.02 (d,J= 8.47 Hz, 1H), 7.94 - 7.98 (m, 2H), 7.48 - 7.55 (m, 3H), 7.37 - 7.42 (m, 1H), 7.25 (dd,J= 1.03, 8.36 Hz, 1H), 7.14 - 7.19 (m, 2H), 6.95 - 7.01 (m, 2H), 5.22 (s, 2H), 4.40 (t,J= 7.10 Hz, 2H), 3.60 - 3.65 (m, 3H), 3.20 - 3.31 (m, 1H), 2.50 - 2.66 (m, 2H), 1.93 - 2.07 (m, 2H), 1.29 (d,J= 6.87 Hz, 3H), 0.97 (t,J= 7.44 Hz, 3H). MS (ESI): [M + H] + = 443.10

[0524]

[0525] (11) Synthesis of 3-(4-((1-ethyl-3-phenyl-1H-indazol-6-yl)methoxy)phenyl)butanoic acid (Compound 78)

[0526] Compound 78 was synthesized from compound J77 according to the procedure described for the synthesis of compound 76. White solid, (62% yield).

[0527] 1 H NMR (CDCl3, 400 MHz): δ 8.00 - 8.04 (m, 1H), 7.93 - 7.99 (m, 2H), 7.48 - 7.54 (m, 3H), 7.37 - 7.43 (m, 1H), 7.25 (dd,J= 1.22, 8.55 Hz, 1H), 7.16 - 7.20 (m, 2H), 6.95 - 7.01 (m, 2H), 5.22 (s, 2H), 4.50 (q,J= 7.22 Hz, 2H), 3.23 - 3.32 (m, 1H), 2.61 (dq,J= 7.48, 15.51 Hz, 2H), 1.56 (t,J= 7.17 Hz, 3H), 1.32 (d,J= 7.02 Hz, 3H). MS (ESI): [M + H] += 415.04

[0528]

[0529] (12) Synthesis of methyl 3-(4-((1-isobutyl-3-phenyl-1H-indazol-6-yl)methoxy)phenyl)butanoate (J79)

[0530] Compound J79 was synthesized from J6 and 1-iodo-2-methylproplane according to the procedure described for compound J76 above. Colorless oil, (yield 71%).

[0531] 1 H NMR (CDCl3, 400 MHz): δ 8.01 (d,J= 8.24 Hz, 1H), 7.93 - 7.98 (m, 2H), 7.47 - 7.53 (m, 3H), 7.38 - 7.44 (m, 1H), 7.23 - 7.26 (m, 1H), 7.14 - 7.19 (m, 2H), 6.92 - 6.99 (m, 2H), 5.21 (s, 2H), 4.23 (d,J= 7.32 Hz, 2H), 3.63 (s, 3H), 3.22 - 3.32 (m, 1H), 2.51 - 2.65 (m, 2H), 2.37 - 2.43 (m, 1H), 1.28 (d,J= 6.71 Hz, 3H), 0.98 (d,J= 6.71 Hz, 6H). MS (ESI): [M + H] + = 457.19

[0532]

[0533] (13) Synthesis of 3-(4-((3-phenyl-1-propyl-1H-indazol-6-yl)methoxy)phenyl)butanoic acid (Compound 79)

[0534] Compound 79 was synthesized from compound J78 according to the procedure described for the synthesis of compound 76. White solid, (34% yield).

[0535] 1H NMR (CDCl3, 400 MHz): δ 8.01 (dd,J= 0.46, 8.24 Hz, 1H), 7.93 - 7.97 (m, 2H), 7.47 - 7.54 (m, 3H), 7.36 - 7.43 (m, 1H), 7.25 (dd,J= 1.26, 8.36 Hz, 1H), 7.15 - 7.20 (m, 2H), 6.95 - 7.00 (m, 2H), 5.22 (s, 2H), 4.36 - 4.47 (m, 2H), 3.17 - 3.31 (m, 1H), 2.51- 2.69 (m, 2H), 1.95 - 2.05 (m, 2H), 1.31 (d,J= 7.10 Hz, 3H), 0.92 - 1.00 (m, 3H). MS (ESI): [M + H] + = 429.07

[0536]

[0537] (14) Synthesis of methyl 3-(4-((1-(cyclopropylmethyl)-3-phenyl-1H-indazol-6-yl)methoxy)phenyl)butanoate (J80)

[0538] Compound J79 was synthesized from J6 and (bromomethyl)cyclopropane according to the procedure described for compound J76 above. Colorless oil, (yield 65%).

[0539] 1H NMR (CDCl3, 400 MHz): δ 8.02 (dd,J= 0.69, 8.24 Hz, 1H), 7.94 - 7.99 (m, 2H), 7.47 - 7.55 (m, 3H), 7.36 - 7.43 (m, 1H), 7.25 (dd,J= 1.37, 8.24 Hz, 1H), 7.13 - 7.19 (m, 2H), 6.92 - 7.00 (m, 2H), 5.24 (s, 2H), 4.34 (d,J= 6.64 Hz, 2H), 3.63 (s, 3H), 3.18 - 3.30 (m, 1H), 2.46 - 2.64 (m, 2H), 1.35 - 1.45 (m, 1H), 1.28 (d,J= 7.10 Hz, 3H), 0.56 - 0.65 (m, 2H), 0.36 - 0.49 (m, 2H). MS (ESI): [M + H] + = 455.12

[0540]

[0541] (15) Synthesis of 3-(4-((1-isobutyl-3-phenyl-1H-indazol-6-yl)methoxy)phenyl)butanoic acid (Compound 80)

[0542] Compound 80 was synthesized from compound J79 according to the procedure described for the synthesis of compound 76. White solid, (93% yield).

[0543] 1H NMR (CDCl3, 400 MHz): δ 8.01 (d,J=8.55 Hz, 1H), 7.92 - 7.99 (m, 2H), 7.47 - 7.54 (m, 3H), 7.36 - 7.43 (m, 1H), 7.22 - 7.26 (m, 1H), 7.14 - 7.20 (m, 2H), 6.92 - 7.01 (m, 2H), 5.21 (s, 2H), 4.22 (d,J= 7.32 Hz, 2H), 3.12 - 3.30 (m, 1H), 2.50 - 2.71 (m, 2H), 2.32 - 2.46 (m, 1H), 1.31 (d,J= 6.60 Hz, 3H), 0.96 (d,J= 6.70 Hz, 6H)). MS (ESI): [M + H] + = 443.10

[0544]

[0545] (16) Synthesis of methyl 3-(4-((1-cyclopentyl-3-phenyl-1H-indazol-6-yl)methoxy)phenyl)butanoate (J81)

[0546] Compound J79 was synthesized from J6 and bromocyclopentane according to the procedure described for compound J76 above. Colorless oil, (yield 69%).

[0547] 1H NMR (CDCl3, 400 MHz): δ 8.00 - 8.03 (m, 1H), 7.95 - 7.99 (m, 2H), 7.56 (s,1H), 7.47 - 7.52 (m, 2H), 7.35 - 7.41 (m, 1H), 7.24 (dd,J= 1.37, 8.47 Hz, 1H), 7.14 - 7.20 (m, 2H), 6.92 - 7.01 (m, 2H), 5.21 (s, 2H), 4.98 - 5.10 (m, 1H), 3.64 (s, 3H), 3.20 - 3.31 (m, 1H), 2.50 - 2.64 (m, 2H), 2.15 - 2.32 (m, 4H), 1.99 - 2.07 (m, 2H), 1.74 - 1.81 (m, 2H), 1.28 (d,J= 7.10 Hz, 3H).MS (ESI): [M + H] + = 469.14

[0548]

[0549] (17) Synthesis of 3-(4-((1-(cyclopropylmethyl)-3-phenyl-1H-indazol-6-yl)methoxy)phenyl)butanoic acid (Compound 81)

[0550] Compound 81 was synthesized from compound J80 according to the procedure described for the synthesis of compound 76. White solid, (97% yield).

[0551] 1H NMR (CDCl3, 400 MHz): δ 8.02 (dd,J= 0.69, 8.47 Hz, 1H), 7.92 - 7.99 (m, 2H), 7.48 - 7.56 (m, 3H), 7.37 - 7.44 (m, 1H), 7.24 (dd,J= 1.14, 8.47 Hz, 1H), 7.15 - 7.22 (m, 2H), 6.93 - 7.02 (m, 2H), 5.23 (s, 2H), 4.23 - 4.36 (m, 2H), 3.20 - 3.31 (m, 1H), 2.61 (dq,J= 7.56, 15.42 Hz, 2H), 1.40 (s, 1H), 1.31 (d,J= 6.87 Hz, 3H), 0.53 - 0.62 (m, 2H), 0.38 - 0.49 (m, 2H). MS (ESI): [M + H] + = 441.14

[0552]

[0553] (18) Synthesis of methyl 3-(4-((1-(cyclohexylmethyl)-3-phenyl-1H-indazol-6-yl)methoxy)phenyl)butanoate (J82)

[0554] Compound J82 was synthesized from J6 and (bromomethyl)cyclohexane according to the procedure described for compound J76 above. Colorless oil, (yield 78%).

[0555] 1H NMR (CDCl3, 400 MHz): δ 7.99 - 8.03 (m, 1H), 7.95 - 7.98 (m, 2H), 7.48 - 7.54 (m, 3H), 7.38 - 7.43 (m, 1H), 7.23 - 7.26 (m, 1H), 7.14 - 7.20 (m, 2H), 6.94 - 7.01 (m, 2H), 5.24 (s, 2H), 4.22 - 4.31 (m, 2H), 3.65 (s, 3H), 3.20 - 3.31 (m, 1H), 2.44 - 2.66 (m, 2H), 2.01 - 2.13 (m, 1H), 1.62 - 1.74 (m, 5H), 1.28 (d,J= 7.02 Hz, 3H), 0.99 - 1.24 (m, 5H). MS (ESI): [M + H] + = 497.22

[0556]

[0557] (19) Synthesis of 3-(4-((1-cyclopentyl-3-phenyl-1H-indazol-6-yl)methoxy)phenyl)butanoic acid (Compound 82)

[0558] Compound 82 was synthesized from compound J81 according to the procedure described for the synthesis of compound 76. White solid, (86% yield).

[0559] 1H NMR (CDCl3, 400 MHz): δ 8.01 (d,J=8.47 Hz, 1H), 7.95 - 7.99 (m, 2H), 7.56 (s, 1H), 7.47 - 7.52 (m, 2H), 7.35 - 7.41 (m, 1H), 7.24 (dd,J= 1.14, 8.47 Hz, 1H), 7.15 - 7.21 (m, 2H), 6.95 - 7.01 (m, 2H), 5.21 (s, 2H), 4.99 - 5.11 (m, 1H), 3.17 - 3.33 (m, 1H), 2.49 - 2.72 (m, 2H), 2.14 - 2.29 (m, 4H), 1.97 - 2.07 (m, 2H), 1.74 - 1.82 (m, 2H), 1.32 (d,J= 6.87 Hz, 3H). MS (ESI): [M + H] + = 455.12

[0560]

[0561] (20) Synthesis of methyl 3-(4-((1-(chlorocarbonyl)-3-phenyl-1H-pyrazolo[4,3-b]pyridin-6-yl)methoxy)phenyl)butanoate (J83)

[0562] Compound J83 was synthesized from J6 and acetyl chloride according to the procedure described for compound J76 above. Colorless oil, (yield 52%).

[0563]

[0564] (21) Synthesis of 3-(4-((1-(cyclohexylmethyl)-3-phenyl-1H-indazol-6-yl)methoxy)phenyl)butanoic acid (Compound 83)

[0565] Compound 83 was synthesized from compound J82 according to the procedure described for the synthesis of compound 76. White solid, (85% yield).

[0566] 1H NMR (CDCl3, 400 MHz): δ 8.01 (dd,J= 0.70, 8.50 Hz, 1H), 7.93 - 7.98 (m, 2H), 7.45 - 7.54 (m, 3H), 7.37 - 7.43 (m, 1H), 7.24 (dd,J= 1.37, 8.47 Hz, 1H), 7.15 - 7.20 (m, 2H), 6.94 - 7.00 (m, 2H), 5.22 (s, 2H), 4.25 (d,J= 7.33 Hz, 2H), 3.21 - 3.32 (m, 1H), 2.62 (dq,J= 7.56, 15.49 Hz, 2H), 2.02 - 2.14 (m, 1H), 1.47 - 1.71 (m, 10H), 1.29 - 1.33 (m, 3H), 0.80 - 0.93 (m, 1H). MS (ESI): [M + H] + = 483.12

[0567]

[0568] (22) Synthesis of methyl 3-(4-((1-benzyl-3-phenyl-1H-pyrazolo[4,3-b]pyridin-6-yl)methoxy)phenyl)butanoate (J84)

[0569] Compound J84 was synthesized from J6 and (bromomethyl)benzene according to the procedure described for compound J76 above. Colorless oil, (yield 41%).

[0570]

[0571] (23) Synthesis of 3-(4-((1-acetyl-3-phenyl-1H-pyrazolo[4,3-b]pyridin-6-yl)methoxy)phenyl)butanoic acid (Compound 84)

[0572] Compound 84 was synthesized from compound J83 according to the procedure described for the synthesis of compound 76. White solid, (65% yield).

[0573]

[0574] (24) Synthesis of methyl 3-(4-((1-benzoyl-3-phenyl-1H-pyrazolo[4,3-b]pyridin-6-yl)methoxy)phenyl)butanoate (J85)

[0575] Compound J85 was synthesized from J6 and benzoyl chloride according to the procedure described for compound J76 above. Colorless oil, (yield 31%).

[0576]

[0577] (25) (Compound 85) Synthesis

[0578] Compound 85 was synthesized from compound J84 according to the procedure described for the synthesis of compound 76. White solid, (71% yield).

[0579]

[0580] (26) (Compound 86) Synthesis

[0581] Compound 86 was synthesized from compound J85 according to the procedure described for the synthesis of compound 76. White solid, (59% yield).

[0582]

[0583] Experimental example

[0584] Experimental Example 1. Cell line construction and culture

[0585] To establish a CMKLR1 calcium mobilization cell evaluation system, CHO-K1 cells expressing Gα-16 were transfected with pcDNA3.1-derived human CMKLR1-expressing plasmids using Lipofectamine 2000 (Invitrogen, Waltham, Massachusetts, USA). Cells were selected using 0.8 mg / mL geneticin (Invitrogen), and CMKLR1 expression in the cells was confirmed through calcium mobilization using chemerin-9 (Genscript, New Jersey, USA). The constructed cell line (CHO-G a16-CMKLR1) was cultured in F-12 medium (Invitrogen) supplemented with 10% (v / v) fetal bovine serum (FBS; Invitrogen), 0.5 mg / mL geneticin, 0.2 mg / mL hygromycin B (Clontech), and 1% (v / v) antibiotic-antimycotic solution (Invitrogen) under 5% CO2 and at 37°C.

[0586]

[0587] Experimental Example 2. Calcium mobilization assay

[0588] Cells at a final concentration of 3 Х 10 5 The cells / mL were diluted with culture medium. 100 μL / well was added to a 96-well plate (Corning) and cultured for 24 hours. The buffer solution was prepared by adding 1 M HEPES solution to HBSS (Hanks' Balanced Salt Solution) (Invitrogen) and adjusting the pH to 7.4 by dropwise addition of 1 M NaOH.

[0589] Fluorescent dye solutions were prepared using the buffer solution provided by the Calcium 5 Assay Kit (Molecular Devices). 40 μL / well of dye solution was added to each well and incubated at 5% CO2, 37°C for 30 minutes. 5X stock solutions were prepared by diluting various concentrations of test compounds and diluting them with buffer solution (0.00064 μM to 10 μM). The final concentration of DMSO was adjusted to 2%. 40 μL of each compound was added to each well and incubated for 30 minutes. Intracellular calcium concentration was measured using FlexStation II384 (Molecular Devices) after adding 50 μL of 2.5 nM chemerin-9 (200 X dilution with buffer). The CMKLR1 inhibitory activity of the compounds was confirmed as a relative value compared to the calcium fluorescent signal induced by 2.5 nM of chemerin-9. The IC of various compounds was then determined. 50 Prism 5 software (GraphPad) was used to obtain the values. Based on the concentration-response curve, IC 50 The values ​​were obtained and all experiments were repeated at least three times.

[0590] Compound CMKLR1 activity in CHO cells (% inhibition at 10 mM) Compound CMKLR1 activity in CHO cells (% inhibition at 10 mM) 310805278181358258294981832877248427786685237960

[0591]

[0592] Compound CMKLR1 activity in CHO cell Compound CMKLR1 activity in CHO cell 10*20**11*21**12**22*13*23*14*24*15*25*16*26*17*27*18*28*19*29*IC 50<100 nM, ***; 100 nM≤IC 50 <1000 nM, **; 1000 nM <IC 50 , *

[0593]

[0594] Compound CMKLR1 activity in CHO cell Compound CMKLR1 activity in CHO cell 30**40*31*41**32*42**33*43**34**44**35**45**36**46**37*47***38*48***39*51**IC 50 <100 nM, ***; 100 nM≤IC 50 <1000 nM, **; 1000 nM <IC 50 , *

[0595]

[0596] Compound CMKLR1 activity in CHO cell Compound CMKLR1 activity in CHO cell 52**68**53**69***54*70**55*71***56*72**57*73**58*74**59*75**60*61*IC 50 <100 nM, ***; 100 nM≤IC 50 <1000 nM, **; 1000 nM <IC 50 , *

[0597]

[0598] Experimental Example 3. Confirmation of the efficacy of psoriasis treatment (in vivo)

[0599] To establish a psoriasis-induced mouse model, 8-10 week-old female BALB / c mice were used. The mice were assigned to each group of 6, and each group was as follows: the normal group (no administration of anything, Normal), the control group (psoriasis induced with imiquimod), the MTX group (psoriasis induced with imiquimod followed by methotrexate 0.4 mg / kg administration), and the test drug group (psoriasis induced with imiquimod followed by compound 71 (=30 days) administration). After shaving the backs of the mice, 65 mg of imiquimod was evenly applied to the backs for 7 consecutive days. Methotrexate and compound 71 were administered orally. The severity of the psoriasis lesions was evaluated using the PASI scoring, which evaluated the erythema, keratin, and thickness of the psoriasis lesions of each mouse from 0 (normal) to 4 (severe). After the experiment was completed on the 7th day, each tissue of the mouse was collected for staining evaluation.

Claims

1. A compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] (In the formula, A is a substituted or unsubstituted 5- to 10-membered aryl or heteroaryl, R1 is methyl substituted with C1 to C4 alkyl, C3 to C6 cycloalkyl, acetyl, benzyl or C3 to C6 cycloalkyl; R2 is C1 to C4 alkyl or C3 to C6 cycloalkyl; R8 is hydrogen or halogen; Ra and Rb are each independently hydrogen or methyl; Rc is hydrogen or C1 to C4 alkyl, X is carbon or nitrogen, and R 10 is absent, hydrogen; halogen; or methyl substituted or unsubstituted with halogen).

2. In claim 1, A is a compound or a pharmaceutically acceptable salt thereof, wherein A is substituted or unsubstituted phenyl, pyridine, benzo[b]thiophene or 1H-tetrazole.

3. In claim 1, the substituent of A is C1 to C3 alkyl, C1 to C5 alkoxy, -OH, -CF3, -CN, -CH2OH, -NH2, -CH=NOH, halogen, phenyl, -NO2, -0CH2CH=CHC(=O)OH, -OCH2CH=CH 2, -C(=O)OH, -NHC(=O)R9 or dioxane, A compound or a pharmaceutically acceptable salt thereof, wherein R9 is alkyl or alkenyl having C2 to C4.

4. In claim 1, A is substituted or unsubstituted phenyl, and the substitution is C1 to C3 alkyl, C1 to C5 alkoxy, -OH, -CF3, -CN, -CH2OH, -NH2, -CH=NOH, halogen, phenyl, -NO2, -0CH2CH=CHC(=O)OH, -OCH2CH=CH 2, -C(=O)OH, A compound or a pharmaceutically acceptable salt thereof, comprising -NHC(=O)R9 (R9 is alkyl or alkenyl of C2 to C4) or dioxane.

5. In claim 1, the compound represented by the chemical formula 1 is any one selected from the group consisting of the following compounds, or a pharmaceutically acceptable salt thereof:

6. A pharmaceutical composition for preventing or treating psoriasis, comprising a compound of any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof.

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