Indole compound, preparation method therefor and use thereof in up-regulation of mir

Abstract

The present invention relates to the technical field of chemical medicines, and relates to a compound represented by general formula (Ia), or a racemate thereof, or an isomer thereof, or a pharmaceutically acceptable salt thereof, and a use thereof in the preparation of a drug for treating related diseases by regulating the miRNA level.

Description

An indole compound and its preparation method and application in miR upregulation Technical Field

[0001] The present invention belongs to the technical field of chemical drugs, and provides an indole compound and a preparation method thereof and an application thereof in miR upregulation, which improve diseases by regulating miRNA levels. Background Art

[0002] Prior art WO2010143169 discloses compounds that can be used to treat HIV infection, particularly including the preparation and use of certain quinoline derivatives and pharmaceutically acceptable salts thereof, particularly disclosing 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine.

[0003] WO2021152131 discloses novel cocrystals and novel pharmaceutically acceptable salts of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine, methods for their preparation, their use as medicaments, and in particular for the prevention and / or treatment of inflammatory diseases, such as inflammatory bowel disease, rheumatoid arthritis, pulmonary hypertension, NASH (non-alcoholic steatohepatitis) and multiple sclerosis, diseases caused by viruses and / or cancer or dysplasia.

[0004] WO2022247920 discloses a quinolineamine compound, a preparation method thereof, and its application in medicine. In particular, the present disclosure relates to a quinolineamine compound of formula (I): The quinolineamine compounds, their preparation methods, pharmaceutical compositions containing the compounds, and their use as therapeutic agents improve diseases by regulating miRNA levels. Summary of the Invention

[0005] The present invention provides a series of indole compounds, preparation methods thereof and medical applications thereof.

[0006] Specifically, in a first aspect, the present application provides a compound represented by general formula (Ia), or its isomer, racemate, or pharmaceutically acceptable salt:

[0007] In a second aspect, the present invention further provides a pharmaceutical composition comprising a therapeutically effective amount of any one of the above-mentioned compounds or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0008] In a third aspect, the present invention also provides a medical use of a therapeutically effective amount of the above-mentioned compound or a pharmaceutically acceptable salt thereof, specifically, to improve diseases by regulating miRNA levels.

[0009] Specifically, the present invention is achieved through the following technical solutions:

[0010] A compound represented by general formula (Ia), or an isomer, a racemate, or a pharmaceutically acceptable salt thereof, characterized in that:

[0011] wherein X is selected from -NH-, -O, -CH2-, -C(O)-NH-, -NH-C(O)- or is absent;

[0012] T1 and T2 are independently selected from CH or N. When CH, H may be further substituted by alkyl, alkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, halogen, amino, or substituted amino. The substituent of the substituted amino is selected from alkyl, cycloalkyl, cycloalkylalkyl, or heterocyclylalkyl.

[0013] X is connected to T3, T4, T5 or a six-membered ring, T3 and T4 are connected by a single bond or a double bond, T4 and T5 are connected by a single bond or a double bond, T3 is selected from CR3, O, S or NR6, T4 is selected from CR4, O, S or NR7, T5 is selected from CR5, O, S or NR8, R3, R4, R5, R6, R7, R8 are independently selected from hydrogen, halogen, alkyl, hydroxy substituted alkyl, haloalkyl, alkyl substituted or unsubstituted amino, alkyl substituted or unsubstituted heterocyclyl alkyl,

[0014] R 1a 、R 1b 、R 1c 、R 1d Independently selected from hydrogen, halogen, alkyl, cyano, alkoxy, heterocyclylalkyloxy, substituted or unsubstituted amino, alkyl, substituents selected from hydroxy, halogen, alkyl, heterocyclylalkyl;

[0015] R 2a 、R 2b 、R 2c 、R 2d are independently selected from hydrogen, substituted or unsubstituted alkyl, alkoxy, alkylthio, alkylsulfonyl, the substituents being selected from alkyl, aminoalkyl, alkyl-substituted aminoalkyl or halogen, or R 2a With R 2b 、R 2b With R 2c 、R 2c With R 2d forming a substituted or unsubstituted cycloalkyl or heterocycloalkyl group, wherein the substituent is selected from an alkyl group or a halogen group;

[0016] Z, T6, and T7 are independently selected from CH or N. When T6 is N, R 2d Does not exist, when T7 is N, R 2aNot present, when X is selected from -NH-, R 2a 、R 2b 、R 2c 、R 2d Not hydrogen at the same time.

[0017] As a preferred technical solution of the present invention, a compound selected from the group consisting of the compounds represented by general formula (I), or their isomers, racemates, or pharmaceutically acceptable salts thereof,

[0018] Wherein, T1 and T2 are independently selected from CH or N;

[0019] Connected to T3 and T4, when connected to T3, T3 is CH, T4 is selected from CR3, and R3 is selected from hydrogen, halogen or alkyl; when connected to T4, T4 is CH, T3 is selected from CR4 or N, and R4 is selected from hydrogen or alkyl;

[0020] R 1a 、R 1b 、R 1c 、R 1d are independently selected from hydrogen, halogen, alkyl, alkoxy, substituted or unsubstituted amino, and the substituents are selected from alkyl, heterocyclylalkyl;

[0021] R 2a 、R 2b 、R 2c 、R 2d are independently selected from hydrogen, substituted or unsubstituted alkoxy, alkylthio, alkylsulfonyl, the substituents are selected from alkyl or halogen, or R 2a With R 2b 、R 2b With R 2c 、R 2c With R 2d To form a substituted or unsubstituted cycloalkyl or heterocycloalkyl group, the substituent is selected from alkyl or halogen.

[0022] As a preferred technical solution of the present invention, the alkyl group is selected from C 1-6 The alkyl group, the C 1-6 The alkyl group is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, 1-ethylpropyl, 2-methylbutyl, tert-pentyl, 1,2-dimethylpropyl, isopentyl, neopentyl, n-hexyl, isohexyl, sec-hexyl, tert-hexyl, neohexyl, 2-methylpentyl, 1,2-dimethylbutyl, and 1-ethylbutyl.

[0023] As a preferred technical solution of the present invention, the alkoxy group is selected from C 1-6 Alkoxy, the C 1-6The alkoxy group is selected from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, sec-pentoxy, 1-ethylpropoxy, 2-methylbutoxy, tert-pentoxy, 1,2-dimethylpropoxy, isopentoxy, neopentoxy, n-hexyloxy, isohexyloxy, sec-hexyloxy, tert-hexyloxy, neohexyloxy, 2-methylpentoxy, 1,2-dimethylbutoxy, and 1-ethylbutoxy; and the O of the alkylthio group is replaced by S.

[0024] As a preferred technical solution of the present invention, the halogen is selected from fluorine, chlorine, bromine and iodine.

[0025] As a preferred technical solution of the present invention, Selected from

[0026] As a preferred technical solution of the present invention, the cycloalkyl group is selected from C 3-6 The cycloalkyl group is further selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The heterocycloalkyl group refers to a cycloalkyl group in which one or more carbon atoms are replaced by heteroatoms selected from O, S and N.

[0027] As a preferred technical solution of the present invention, R 2a 、R 2c 、R 2d are independently selected from hydrogen, R 2b Selected from -OCF3, -SCF3, -S(O)2CH2F; or R 2c 、R 2d Selected from hydrogen, R 2a With R 2b form

[0028] As a preferred technical solution of the present invention, Selected from

[0029] More preferably,

[0030] As a preferred technical solution of the present invention, Selected from As a preferred technical solution of the present invention, the compound is selected from:

[0031] As a preferred technical solution of the present invention, a pharmaceutically acceptable salt of the compound is provided. The pharmaceutically acceptable salt of the compound refers to a compound, or an isomer thereof, or a racemate thereof, prepared with a pharmaceutically acceptable acid or base.

[0032] As a preferred technical solution of the present invention, a pharmaceutical composition is provided, comprising a therapeutically effective amount of the aforementioned compound, or an isomer thereof, or a racemate thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0033] As a preferred technical solution of the present invention, provided is the medical use of the compound, or its isomer, or its racemate, or its pharmaceutically acceptable salt, specifically, its use in the preparation of a drug for regulating diseases related to miRNA levels (miR-124).

[0034] The related diseases include, but are not limited to, diseases for preventing and / or treating inflammatory diseases, such as inflammatory diseases, pulmonary hypertension, premature aging, MASH (metabolic steatohepatitis), diseases caused by viruses and / or cancer or dysplasia.

[0035] The inflammatory disease is selected from the following list: inflammatory bowel disease, rheumatoid arthritis, Crohn's disease, ulcerative colitis, multiple sclerosis, Alzheimer's disease, Parkinson's disease, osteoarthritis, atherosclerosis, ankylosing spondylitis, psoriasis, dermatitis, Sjogren's syndrome, bronchitis, asthma and inflammation associated with colon cancer.

[0036] The method for preventing, inhibiting or treating a pathological or non-pathological condition associated with premature aging is selected from the group consisting of Guillain-Barré progeria syndrome (HGPS), premature aging associated with HIV infection, Charcot-Marie-Tooth disorder, Werner syndrome, atherosclerosis, insulin-resistant type II diabetes, cataracts, osteoporosis, skin aging and restrictive skin diseases.

[0037] For the sake of clarity, general terms used in the description of the compounds are defined herein.

[0038] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered as undefined or unclear in the absence of a specific definition, but should be understood according to its ordinary meaning. When a trade name appears in this article, it is intended to refer to its corresponding commercial product or its active ingredient. The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms that are suitable for use in contact with human and animal tissues within the scope of sound medical judgment without excessive toxicity, irritation, allergic reaction or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0039] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention, which is prepared by reacting a compound having a specific substituent discovered in the present invention with a pharmaceutically acceptable acid or base.

[0040] In addition to the form of salts, the compounds provided by the present invention also exist in prodrug form. The prodrugs of the compounds described herein easily undergo chemical changes under physiological conditions to be converted into the compounds of the present invention. In addition, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an in vivo environment.

[0041] Certain compounds of the present invention may exist in unsolvated forms as well as solvated forms, including hydrates. In general, the solvated forms are equivalent to the unsolvated forms and are encompassed within the scope of the present invention.

[0042] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are encompassed within the scope of the present invention.

[0043] Optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are resolved by conventional methods known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is typically accomplished using chromatography, which employs a chiral stationary phase and is optionally combined with a chemical derivatization method (e.g., carbamate formation from an amine).

[0044] The atoms of the molecules of the compounds of the present invention are isotopes, and isotope derivatization can generally extend half-life, reduce clearance, stabilize metabolism, and increase in vivo activity. In addition, an embodiment is included in which at least one atom is replaced by an atom having the same atomic number (number of protons) and a different mass number (protons and neutrons). Examples of isotopes included in the compounds of the present invention include hydrogen atoms, carbon atoms, nitrogen atoms, oxygen atoms, phosphorus atoms, sulfur atoms, fluorine atoms, chlorine atoms, which respectively include 2 H. 3 H. 13 C. 14 C. 15 N. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 36 In particular, radioactive isotopes that emit radiation as they decay, such as 3 H or 14 C can be used for local anatomy testing of pharmaceutical preparations or compounds in vivo. Stable isotopes neither decay nor change with their amount nor are they radioactive, so they can be used safely. When the atoms constituting the molecules of the compounds of the present invention are isotopes, the isotopes can be converted according to general methods by replacing the reagents used in the synthesis with reagents containing the corresponding isotopes.

[0045] The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, the compounds may be labeled with radioactive isotopes, such as deuterium ( 2 H), iodine-125( 125 I) or C-14( 14 C) All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0046] Furthermore, the compounds of the present invention may have one or more hydrogen atoms replaced by deuterium isotopes ( 2 After deuteration, the compounds of the present invention have the effects of extending half-life, reducing clearance rate, stabilizing metabolism and improving in vivo activity.

[0047] The preparation method of the isotopic derivative generally includes a phase transfer catalytic method. For example, a preferred deuteration method uses a phase transfer catalyst (e.g., a tetraalkylammonium salt, NBu4HSO4). The use of a phase transfer catalyst to exchange the methylene protons of the diphenylmethane compound results in a higher deuterium incorporation than reduction with a deuterated silane (e.g., triethyldeuterated monosilane) in the presence of an acid (e.g., methanesulfonic acid) or with a Lewis acid such as aluminum trichloride using sodium deuterated borate.

[0048] The term "pharmaceutically acceptable carrier" refers to any formulation carrier or medium that can deliver an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects on the host or patient. Representative carriers include water, oils, vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, viscosity increasing agents, transdermal enhancers, etc. Their preparations are well known to those skilled in the art of cosmetics or topical medicine. For additional information about carriers, reference can be made to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.

[0049] The term "excipient" generally refers to a carrier, diluent and / or vehicle required to formulate an effective pharmaceutical composition.

[0050] With respect to a drug or pharmacologically active agent, the term "effective amount" or "therapeutically effective amount" refers to a non-toxic amount of the drug or agent sufficient to achieve the intended effect. For the oral dosage forms of the present invention, an "effective amount" of an active substance in the composition means the amount required to achieve the intended effect when used in combination with another active substance in the composition. The determination of an effective amount varies from person to person, depending on the age and general condition of the recipient, as well as the specific active substance. The appropriate effective amount in each individual case can be determined by those skilled in the art through routine experimentation.

[0051] The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that is effective in treating a target disorder, disease, or condition.

[0052] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0053] The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present invention. DETAILED DESCRIPTION

[0054] The present application is further described in detail below with reference to examples, but the implementation methods of the present application are not limited thereto.

[0055] Example 1 Synthesis of 8-chloro-2-(5-(trifluoromethoxy)-1H-indol-2-yl)quinoline

[0056] Step A: Synthesis of 5-trifluoromethoxyindole-2-boronic acid pinacol ester

[0057] Under N2 protection, 5-trifluoromethoxyindole (0.2 g, 0.1 mmol), pinacol borate (0.18 g, 0.7 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (8 mg, 0.03 mmol), and methoxy(cyclooctadiene)iridium dimer (20 mg, 0.03 mmol) were dissolved in 2-methyltetrahydrofuran (10 ml), heated to 80°C, and reacted for 3 hours. After the reaction, 20 ml of water was added, and the mixture was extracted three times with 20 ml of ethyl acetate. The organic phase was then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 5 / 1) to obtain 0.15 g of 5-trifluoromethoxyindole-2-pinacol borate as a yellow oil (yield: 47.7%).

[0058] Step B: Synthesis of 8-chloro-2-(5-(trifluoromethoxy)-1H-indol-2-yl)quinoline

[0059] Under N2 protection, 5-trifluoromethoxyindole-2-boronic acid pinacol ester (0.15 g, 0.46 mmol), 2-bromo-8-chloroquinoline (0.11 g, 0.46 mmol), tetrakis(triphenylphosphine)palladium (27 mg, 0.023 mmol), and sodium carbonate (100 mg, 0.7 mmol) were dissolved in dioxane (10 ml) and heated to 110°C for 2 hours. After the reaction, 20 ml of water was added, and the mixture was extracted three times with 20 ml of ethyl acetate. The organic phase was then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 5 / 1) to obtain 45 mg of 8-chloro-2-(5-(trifluoromethoxy)-1H-indol-2-yl)quinoline as a yellow solid (yield: 27.05%).

[0060] LCMS: RT = 2.34 min, [M+H] + =362.91. 1H NMR (400MHz, DMSO-d6) δ11.83(s,1H),8.54(d,J=8.6Hz,1H),8.29(d,J=8.6Hz,1H),8.03–7.97(m,2H),7.72(d,J=8.9 Hz,1H),7.66(d,J=2.1Hz,1H),7.59(t,J=7.8Hz,1H),7.53(dd,J=2.1,0.9Hz,1H),7.20(ddd,J=8.9,2.4,0.9Hz,1H).

[0061] Example 2 Synthesis of 8-chloro-2-(5-(trifluoromethoxy)-1H-benzimidazol-2-yl)quinoline

[0062] 8-Chloroquinoline 2-carbaldehyde (0.2 g, 1.04 mmol), 4-(trifluoromethoxy)benzene-1,2-diamine (0.2 g, 1.04 mmol), and sodium bisulfite (0.054 g, 0.52 mmol) were added to anhydrous ethanol solution (30 mL) at room temperature and allowed to react openly at 80°C for 6 hours. TLC indicated the reaction was complete. The reaction solution was cooled to room temperature, evaporated to dryness, and extracted three times with ethyl acetate. The organic layer was washed with saturated sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography to yield 101 mg of 8-chloro-2-(5-(trifluoromethoxy)-1H-benzimidazol-2-yl)quinoline as a yellow solid (yield: 26.5%).

[0063] LCMS: RT = 2.25 min, [MH] - =362.08. 1 H NMR (400MHz, DMSO-d6) δ8.68(d,J=8.6Hz,1H),8.57(d,J=8.7Hz,1H),8.09(t,J=8.1Hz,2H),7.89-7.62(m,3H),7.32(d,J=8.7Hz,1H).

[0064] Example 3 Synthesis of 8-chloro-2-(5-(trifluoromethoxy)-1H-indol-2-yl)quinazoline

[0065] Step A: Synthesis of 5-trifluoromethoxyindole-2-boronic acid pinacol ester

[0066] Under N2 protection, 5-trifluoromethoxyindole (0.2 g, 0.1 mmol), pinacol bisboronate (0.18 g, 0.7 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (8 mg, 0.03 mmol), and methoxy(cyclooctadiene)iridium dimer (20 mg, 0.03 mmol) were dissolved in 2-methyltetrahydrofuran (10 ml), heated to 80°C, and reacted for 3 hours. After the reaction, 20 ml of water was added, and the mixture was extracted three times with 20 ml of ethyl acetate. The organic phase was then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 5 / 1) to obtain 0.13 g of 5-trifluoromethoxyindole-2-boronate as a yellow oil (yield: 43.21%).

[0067] Step B: Synthesis of 8-chloro-2-(5-(trifluoromethoxy)-1H-indol-2-yl)quinazoline

[0068] Under N₂ protection, 5-trifluoromethoxyindole-2-boronic acid pinacol ester (0.10 g, 0.26 mmol), 2,8-dichloroquinazoline (0.058 g, 0.26 mmol), tetrakis(triphenylphosphine)palladium (11.55 mg, 0.026 mmol), and potassium carbonate (70.13 mg, 0.51 mmol) were dissolved in dioxane (5 mL) and heated to 100°C for 8 hours. After completion of the reaction, 20 mL of water was added, and the mixture was extracted three times with 20 mL of ethyl acetate. The organic phase was then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 5 / 1) to obtain 29.35 mg of 8-chloro-2-(5-(trifluoromethoxy)-1H-indol-2-yl)quinazoline as a yellow solid (yield: 27.05%). LCMS: RT = 2.25 min, [M+H] + =363.72. 1 H NMR (400MHz, DMSO-d6) δ12.11(s,1H),9.77(d,J=3.4Hz,1H),8.21(m,2H),7.80–7.64(m,3H),7.59(d,J=3.1Hz,1H),7.22(d,J=9.0Hz,1H).

[0069] Example 4 Synthesis of 8-chloro-2-(2-methyl-5-(trifluoromethoxy)-1H-indol-3-yl)quinoline

[0070] Step A: Synthesis of 2-methyl-5-(trifluoromethoxy)indole-3-boronic acid pinacol ester

[0071] Under N2 protection, 2-methyl-5-(trifluoromethoxy)-1H-indole (0.2 g, 0.1 mmol), pinacol bis(borono) (0.18 g, 0.7 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (8 mg, 0.03 mmol), and methoxy(cyclooctadiene)iridium dimer (20 mg, 0.03 mmol) were dissolved in 2-methyltetrahydrofuran (10 ml), heated to 80°C, and reacted for 3 hours. After the reaction, 20 ml of water was added, and the mixture was extracted three times with 20 ml of ethyl acetate. The organic phase was then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 5 / 1) to obtain 0.12 g of 2-methyl-5-(trifluoromethoxy)indole-3-borono-pinacol bis(borono) (yield: 38.71%).

[0072] Step B: Synthesis of 8-chloro-2-(2-methyl-5-(trifluoromethoxy)-1H-indol-3-yl)quinoline

[0073] Under N2 protection, 2-methyl-5-(trifluoromethoxy)indole-3-boronic acid pinacol ester (0.15 g, 0.46 mmol), 2,8-dichloroquinoline (0.92 g, 0.46 mmol), tetrakis(triphenylphosphine)palladium (27 mg, 0.023 mmol), and potassium carbonate (128 mg, 0.93 mmol) were dissolved in dioxane (10 ml), heated to 100°C, and reacted for 8 hours. After the reaction, 20 ml of water was added, and the mixture was extracted three times with 20 ml of ethyl acetate. The organic phase was then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 5 / 1) to obtain 29.87 mg of 8-chloro-2-(2-methyl-5-(trifluoromethoxy)-1H-indol-3-yl)quinoline as a yellow solid (yield: 13.05%). LCMS: RT = 2.34 min, [M+H] + =377.02.

[0074] Example 5 & 6 Synthesis of 8-chloro-2-(5-(trifluoromethoxy)-1H-benzo[d]imidazol-1-yl)quinoline / 8-chloro-2-(6-(trifluoromethoxy)-1H-benzo[d]imidazol-1-yl)quinoline

[0075] Step A: Synthesis of N 1 -(8-chloroquinolin-2-yl)-4-(trifluoromethoxy)benzene-1,2-diamine / N 1 -(8-chloroquinolin-2-yl)-5-(trifluoromethoxy)benzene-1,2-dione

[0076] Dissolve 4-(trifluoromethoxy)benzene-1,2-diamine (0.25 g, 1.3 mmol) and 2,8-dichloroquinoline (0.2 g, 1.0 mmol) in isopropanol (10 ml). Add trifluoroacetic acid (0.25 g, 2.2 mmol) and heat to 80°C for 4 hours. After the reaction, concentrate to obtain 0.35 g of a crude blue solid, which is used directly in the next reaction. RT = 2.09 min, [M+H] + =353.85

[0077] Step B: Synthesis of 8-chloro-2-(5-(trifluoromethoxy)-1H-benzo[d]imidazol-1-yl)quinoline / 8-chloro-2-(6-(trifluoromethoxy)-1H-benzo[d]imidazol-1-yl)quinoline

[0078] The compound from the previous step (0.3 g, 0.85 mmol) was dissolved in triethyl orthoformate (10 mL), and formic acid (0.2 g, 4.34 mmol) was added. The mixture was heated to 100°C and allowed to react for 1 hour. After completion of the reaction, the reaction solution was concentrated, and the residue was purified by silica gel column chromatography (20-100% ethyl acetate / n-hexane). The purified crude product was subjected to preparative liquid phase separation and lyophilization to obtain 28 mg of the product P1: 8-chloro-2-(5-(trifluoromethoxy)-1H-benzo[d]imidazol-1-yl)quinoline as a white solid (yield: 8.34%). RT = 2.24 min, [M+H] + = 363.80. 3.1 mg of white solid product P2 (yield: 1.32%): 8-chloro-2-(6-(trifluoromethoxy)-1H-benzo[d]imidazol-1-yl)quinoline. RT = 2.24 min, [M+H] + =363.83. 1 H NMR (400MHz, DMSO-d6) δ9.46(s,1H),9.18(d,J=8.8Hz,1H),8.75(d,J=8.8Hz,1H),8.37(d,J=8 .8Hz,1H),8.06(d,J=7.6Hz,2H),7.91–7.78(m,1H),7.63(t,J=7.6Hz,1H),7.57–7.46(m,1H).

[0079] Example 7 Synthesis of 8-chloro-2-(5-(trifluoromethoxy)-1H-indazol-3-yl)quinoline

[0080] Step A: Synthesis of (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethoxy)-1H-indazole

[0081] Under N2 protection, 5-(trifluoromethoxy)-1H-indazole (0.20 g, 0.1 mmol), pinacol diboronate (0.18 g, 0.7 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (8 mg, 0.03 mmol) and methoxy(cyclooctadiene)iridium dimer (20 mg, 0.03 mmol) were dissolved in 2-methyltetrahydrofuran (10 ml) and heated to 80 degrees Celsius for 3 hours. After the reaction, 20 ml of water was added, and the mixture was extracted three times with ethyl acetate. The organic phase was then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 5 / 1) to obtain 0.13 g of a yellow oily substance, 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethoxy)-1H-indazole (yield: 43.21%).

[0082] Step B: Synthesis of 8-chloro-2-(5-(trifluoromethoxy)-1H-indazol-3-yl)quinoline

[0083] Under nitrogen protection, 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethoxy)-1H-indazole (0.10 g, 0.26 mmol), 2,8-dichloroquinoline (0.058 g, 0.26 mmol), tetrakis(triphenylphosphine)palladium (11.55 mg, 0.026 mmol), and potassium carbonate (70.13 mg, 0.51 mmol) were dissolved in dioxane (5 mL) and heated to 100°C for 8 hours. After completion of the reaction, 20 mL of water was added, and the mixture was extracted three times with ethyl acetate. The organic phase was then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by HPLC to yield 1.35 mg of a gray solid, 8-chloro-2-(5-(trifluoromethoxy)-1H-indazol-3-yl)quinoline (yield: 0.15%). LCMS: RT = 2.22 min, [M+H] + =363.98.

[0084] Example 8 Synthesis of 8-fluoro-2-(5-(trifluoromethoxy)-1H-indol-2-yl)quinoline

[0085] Under N₂ protection, 5-trifluoromethoxyindole-2-boronic acid pinacol ester (0.10 g, 0.26 mmol), 2-chloro-8-fluoroquinoline (0.058 g, 0.26 mmol), tetrakis(triphenylphosphine)palladium (11.55 mg, 0.026 mmol), and potassium carbonate (70.13 mg, 0.51 mmol) were dissolved in dioxane (5 mL) and heated to 100°C for 8 hours. After the reaction, 20 mL of water was added, and the mixture was extracted three times with 20 mL of ethyl acetate. The organic phase was then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 5 / 1) to yield 29.35 mg of 8-fluoro-2-(5-(trifluoromethoxy)-1H-indol-2-yl)quinoline as a white solid (yield: 11.12%). LCMS: RT = 2.30 min, [M+H] + =346.95. 1 H NMR (400MHz, DMSO-d6) δ12.11(s,1H),9.77(d,J=3.4Hz,1H),8.21(m,J=23.0,8 .0,3.8Hz,2H),7.80–7.64(m,3H),7.59(d,J=3.1Hz,1H),7.22(d,J=9.0Hz,1H).

[0086] Example 9 Synthesis of 8-chloro-2-(1-methyl-5-(trifluoromethoxy)-1H-indol-2-yl)quinoline

[0087] Under N₂ protection, 8-chloro-2-(5-(trifluoromethoxy)-1H-indol-2-yl)quinoline (0.10 g, 0.27 mmol) and sodium hydride (13.20 mg, 0.54 mmol) were dissolved in tetrahydrofuran (5 mL) and reacted at room temperature for 0.5 hour. Methyl iodide (91.02 mg, 0.54 mmol) was then added and the reaction continued at room temperature for 8 hours. After completion of the reaction, 20 mL of water was added, and the mixture was extracted three times with 20 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by HPLC to yield 7.22 mg of 8-chloro-2-(1-methyl-5-(trifluoromethoxy)-1H-indol-2-yl)quinoline as a white solid (yield: 27.05%). LCMS: RT = 2.55 min, [M+H] + =376.95.

[0088] Example 10 Synthesis of 8-chloro-5-methoxy-2-(5-(trifluoromethoxy)-1H-indol-2-yl)quinoline

[0089] Step A: Synthesis of N-(2-chloro-5-methoxyphenyl)-3,3-diethoxypropionamide

[0090] To a solution of 2-chloro-5-methoxyaniline (1 g, 6.35 mmol) and 3,3-diethoxypropionic acid (1.24 g, 7.62 mmol) in N,N-dimethylformamide (10 mL) at room temperature was added HATU (3.62 g, 9.52 mmol) and ethyldiisopropylamine (2.46 g, 19.05 mmol). The mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was diluted with water and extracted with dichloromethane (50 mL x 3). The combined organic phases were washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 3) to obtain 1.1 g of N-(2-chloro-5-methoxyphenyl)-3,3-diethoxypropionamide as a colorless oil (yield: 50.07%).

[0091] Step B: Synthesis of 8-chloro-5-methoxyquinolin-2(1H)-one

[0092] At room temperature, concentrated sulfuric acid (1.95 g, 19.9 mmol) was added to a solution of N-(2-chloro-5-methoxyphenyl)-3,3-diethoxypropionamide (0.6 g, 1.99 mmol) in dichloromethane (10 mL). The reaction was allowed to proceed at room temperature for 2 hours. After the reaction was completed, the mixture was diluted with water and extracted with dichloromethane (50 mL*3). The organic phases were combined, washed with saturated brine (50 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 3) to obtain 400 mg of 8-chloro-5-methoxyquinolin-2(1H)-one as a colorless oil (yield: 95.57%).

[0093] Step C: Synthesis of 2,8-dioxo-5-methoxyquinoline

[0094] Phosphorus oxychloride (4.39 g, 28.60 mmol) was added to 8-chloro-5-methoxyquinolin-2(1H)-one (0.6 g, 2.86 mmol) at room temperature, and the mixture was heated to 90°C for 2 hours. After completion of the reaction, the mixture was quenched in an ice-water bath and extracted with dichloromethane (50 mL x 3). The combined organic phases were washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 3) to obtain 500 mg of 2,8-dichloro-5-methoxyquinoline as a white solid (yield: 76.6%).

[0095] Step D: Synthesis of 8-chloro-5-methoxy-2-(5-(trifluoromethoxy)-1H-indol-2-yl)quinoline

[0096] To a mixture of 2,8-dichloro-5-methoxyquinoline (50 mg, 0.22 mmol), 5-trifluoromethoxyindole-2-boronic acid pinacol ester (80.84 mg, 0.33 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (16.10 mg, 0.022 mmol), and potassium carbonate (0.091 g, 0.66 mmol) was added dioxane (5 mL) and water (1 mL) at room temperature. After the addition, the atmosphere was purged with nitrogen three times, and the mixture was heated to 90°C and stirred overnight. After the reaction was completed, the mixture was diluted with water and extracted with dichloromethane (50 mL*3). The organic phases were combined, washed with saturated brine (50 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was prepared to give 19.2 mg of 8-chloro-5-methoxy-2-(5-(trifluoromethoxy)-1H-indol-2-yl)quinoline as a white solid (yield: 22.3%). LC-MS: RT = 2.45 min, [M+H] + =392.95. 1 H NMR (400MHz, DMSO-d6) δ11.94–11.70(m,1H),8.62(d,J=8.8Hz,1H),8.22(d,J=8.8Hz,1H),7.88(d,J=8.4Hz,1H),7.70(d, J=8.8Hz,1H),7.66–7.61(m,1H),7.52–7.45(m,1H),7.18(ddd,J=8.9,2.4,1.0Hz,1H),7.05(d,J=8.5Hz,1H),4.01(s,3H).

[0097] Example 11 Synthesis of 8-chloro-N-(6-(trifluoromethoxy)-1H-benzimidazol-2-yl)quinolin-2-amine

[0098] Under N2 protection, 2-amino-6-(trifluoromethoxy)benzimidazole (15 mg, 0.069 mmol), 2,8-dichloroquinoline (15 mg, 0.076 mmol), tris(dibenzylideneacetone)dipalladium(0) (1.3 mg, 0.0014 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.8 mg, 0.014 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.82 mg, 0.0017 mmol) and cesium carbonate (45 mg, 0.14 mmol) were added to 1,4-dioxane (6 ml). The mixture was heated to 140°C with stirring for 4 hours, then cooled to room temperature and the reaction was continued overnight. The reaction was monitored by LC-MS until completion.

[0099] Water (20 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 ml x 3 times). The organic phases were combined, washed with saturated brine (20 ml x 3 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by HPLC to obtain 2.2 mg of 8-chloro-N-(6-(trifluoromethoxy)-1H-benzimidazol-2-yl)quinolin-2-amine as a white solid (yield: 8.41%). LCMS: RT = 2.05 min, [M+H] + =378.98.

[0100] Example 12 Synthesis of 8-chloro-2-(6-(trifluoromethoxy)-1H-indol-2-yl)quinoline

[0101] Step A: Synthesis of 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethoxy)-1H-indole

[0102] Under N2 protection, 6-trifluoromethoxyindole (0.1 g, 0.50 mmol), pinacol diboronate (0.19 g, 0.75 mmol), methoxy(cyclooctadiene)iridium dimer (0.017 g, 0.025 mmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (0.0081 g, 0.03 mmol) were added to 2-methyltetrahydrofuran (8 ml), the temperature was raised to 80°C and stirred for 2 hours. The reaction was monitored by TLC until completion.

[0103] Water (20 ml) was added to the reaction solution, extracted with ethyl acetate (20 ml × 3 times), the organic phases were combined, washed with saturated brine (20 ml × 3 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 0-20%) to obtain 0.15 g of yellow oily 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethoxy)-1H-indole (yield: 92.24%).

[0104] Step B: Synthesis of 8-chloro-2-(6-(trifluoromethoxy)-1H-indol-2-yl)quinoline

[0105] Under N2 protection, 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethoxy)-1H-indole (0.15 g, 0.46 mmol), 2,8-dichloroquinoline (0.10 g, 0.51 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.034 g, 0.046 mmol) and potassium carbonate (0.19 g, 1.38 mmol) were added to 8 mL of a 1,4-dioxane / water (4 / 1) mixed solvent, the temperature was raised to 100°C and stirred for 12 hours. The reaction was monitored by LC-MS until completion.

[0106] Water (20 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 ml x 3 times). The organic phases were combined, washed with saturated brine (20 ml x 3 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by HPLC to obtain 70 mg of a slightly yellow solid, 8-chloro-2-(6-(trifluoromethoxy)-1H-indol-2-yl)quinoline (yield: 42.08%). LCMS: RT = 2.65 min, [M+H] + =362.93. 1 H NMR (400MHz, DMSO-d6) δ11.78(s,1H),8.53(d,J=8.7Hz,1H),8.29(d,J=8.7Hz,1H),8.00(d ,J=7.7Hz,2H),7.77(d,J=8.6Hz,1H),7.65–7.52(m,3H),7.06(dd,J=8.6,2.3,1.0Hz,1H).

[0107] Example 13 Synthesis of 5,8-dichloro-2-(5-(trifluoromethoxy)-1H-indol-2-yl)quinoline

[0108] Step A: Synthesis of N-(2,5-dichlorophenyl)-3,3-diethoxypropionamide

[0109] 2,5-Dichloroaniline (1 g, 6.17 mmol), 3,3-diethoxypropionic acid (1.2 g, 7.40 mmol), HATU (3.99 g, 10.49 mmol), and N,N-diisopropylethylamine (1.99 g, 15.43 mmol) were added to N,N-dimethylformamide (15 mL) at room temperature. The reaction was maintained at this temperature overnight. TLC was used to monitor the reaction until completion.

[0110] Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 0-15%) to obtain 1.1 g of N-(2,5-dichlorophenyl)-3,3-diethoxypropionamide as a brown oil (yield: 58.21%).

[0111] Step B: Synthesis of 5,8-dichloroquinoline-2-ol

[0112] Under ice-cooling, concentrated sulfuric acid (2.5 mL) was added dropwise to a solution of N-(2,5-dichlorophenyl)-3,3-diethoxypropionamide (1.1 g, 3.59 mmol) in dichloromethane (5 mL), and the mixture was allowed to react at room temperature overnight. The reaction was monitored by TLC until completion.

[0113] The reaction mixture was poured into ice water (20 mL) and extracted with dichloromethane (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 0-40%) to obtain 0.36 g of 5,8-dichloroquinolin-2-ol as a pale yellow solid (yield: 46.81%).

[0114] Step C: Synthesis of 2,5,8-trichloroquinoline

[0115] At room temperature, 5,8-dichloroquinolin-2-ol (0.36 g, 1.68 mmol) was added to phosphorus oxychloride (5 ml), and then the temperature was raised to 90 degrees Celsius for 1.5 hours. TLC was monitored until the reaction was complete. The reaction solution was poured into ice water (40 ml) and extracted with ethyl acetate (20 ml × 3 times). The organic phases were combined, washed with saturated brine (20 ml × 3 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 0-5%) to obtain 0.3 g of white solid 2,5,8-trichloroquinoline (yield: 76.72%). LCMS: RT = 2.27 min, [M+H] + =233.91.

[0116] Step D: Synthesis of 5,8-dichloro-2-(5-(trifluoromethoxy)-1H-indol-2-yl)quinoline

[0117] Under N2 protection, 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethoxy)-1H-indole (0.46 g, 1.42 mmol), 2,5,8-trichloroquinoline (0.3 g, 1.29 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.094 g, 0.13 mmol) and potassium carbonate (0.53 g, 3.87 mmol) were added to 15 mL of a 1,4-dioxane / water (4 / 1) mixed solvent, the temperature was raised to 100°C and stirred for 12 hours. The reaction was monitored by LC-MS until completion.

[0118] Water (20 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 ml x 3 times). The organic phases were combined, washed with saturated brine (20 ml x 3 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 0-5%). The resulting product was then slurried in 8 ml of a mixed solvent (dichloromethane / methanol = 1 / 10) for 12 hours to obtain 120 mg of 5,8-dichloro-2-(5-(trifluoromethoxy)-1H-indol-2-yl)quinoline as a white solid (yield: 23.41%). LCMS: RT = 2.52 min, [M+H] + =396.89. 1 H NMR (400MHz, DMSO-d6) δ11.92(s,1H),8.68(d,J=8.9Hz,1H),8.42(d,J=8.9Hz,1H),8.01(d,J =8.2Hz,1H),7.78(d,J=8.2Hz,1H),7.75–7.66(m,2H),7.61–7.57(m,1H),7.26–7.19(m,1H).

[0119] Example 14 Synthesis of 8-chloro-N-(7-methoxy-1H-indol-4-yl)quinolin-2-amine

[0120] Step A: Synthesis of 7-methoxy-1H-indole-4-amine

[0121] Under a hydrogen atmosphere, 10% palladium on carbon (0.083 g, 0.078 mmol) was added to a solution of 4-bromo-7-methoxyindole (0.15 g, 0.78 mmol) in methanol (15 ml). The mixture was allowed to react at room temperature for 3 h. TLC was used to monitor the reaction until completion. The palladium on carbon was filtered off, and the solvent was evaporated to afford 0.11 g of 7-methoxy-1H-indol-4-amine as a purple oil (yield: 86.89%).

[0122] Step B: Synthesis of 8-chloro-N-(7-methoxy-1H-indol-4-yl)quinolin-2-amine

[0123] At room temperature, 7-methoxy-1H-indol-4-amine (0.11 g, 0.68 mmol) and 2,8-dichloroquinoline (0.13 g, 0.68 mmol) were added to isopropanol (8 mL). Trifluoroacetic acid (0.078 g, 0.68 mmol) was added dropwise, and the mixture was heated to 80°C for 12 h. The solvent was removed under reduced pressure, and the resulting residue was purified by HPLC to yield 15 mg of 8-chloro-N-(7-methoxy-1H-indol-4-yl)quinolin-2-amine as an orange solid (yield: 6.83%). LCMS: RT = 1.89 min, [M+H] + =324.02.

[0124] Example 15 Synthesis of N-(8-chloroquinolin-2-yl)-6-(trifluoromethoxy)benzo[d]thiazol-2-amine

[0125] Step A: Synthesis of 6-(trifluoromethoxy)benzo[d]thiazol-2-amine

[0126] Bromine (0.45 g, 2.82 mmol) was added dropwise to glacial acetic acid (20 mL) stirred with p-trifluoromethoxyaniline (0.5 g, 2.82 mmol) and potassium thiocyanate (1.1 g, 11.28 mmol) under an ice bath. The mixture was allowed to react at room temperature overnight. TLC was used to monitor the reaction until completion. Most of the acetic acid was removed by swirl, and the residue was basified with saturated sodium bicarbonate solution and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 0-50%) to obtain 0.52 g of 6-(trifluoromethoxy)benzo[d]thiazol-2-amine as a white solid (yield: 78.65%).

[0127] Step B: Synthesis of N-(8-chloroquinolin-2-yl)-6-(trifluoromethoxy)benzo[d]thiazol-2-amine

[0128] Under N2 protection, 6-(trifluoromethoxy)benzo[d]thiazol-2-amine (0.42 g, 1.81 mmol), 2,8-dichloroquinoline (0.3 g, 1.51 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.14 g, 0.15 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (0.26 g, 0.45 mmol) and sodium carbonate (0.22 g, 2.11 mmol) were added to toluene (8 ml) and the temperature was raised to 110 °C under microwave conditions and stirred for 1.5 hours.

[0129] Water (20 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 ml x 3 times). The organic phases were combined, washed with saturated brine (20 ml x 3 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 0-50%). The resulting product was then slurried in 8 ml of a mixed solvent (dichloromethane / methanol = 1 / 10) for 5 hours to obtain 0.21 g of an off-white solid, N-(8-chloroquinolin-2-yl)-6-(trifluoromethoxy)benzo[d]thiazol-2-amine (yield: 35.03%). LCMS: RT = 2.37 min, [M+H] + =395.86. 1 H NMR (400MHz, DMSO-d6) δ12.31(s,1H),8.41(d,J=8.9Hz,1H),8.19(dd,J=2.4,1. 1Hz,1H),7.93(dd,J=7.8,1.3Hz,2H),7.80(d,J=8.8Hz,1H),7.49–7.40(m,3H).

[0130] Example 16 Synthesis of 8-chloro-N-(2-morpholinoethyl)-2-(5-(trifluoromethoxy)-1H-indol-2-yl)quinolin-4-amine

[0131] To a solution of 4,8-dichloro-2-(5-(trifluoromethoxy)-1H-indol-2-yl)quinoline (50 mg, 0.13 mmol) in dimethyl sulfoxide (2 mL) was added 2-(morpholin-4-yl)ethan-1-amine (50.77 mg, 0.39 mmol) and N,N-diisopropylethylamine (168.01 mg, 1.3 mmol) at room temperature. The mixture was heated to 150°C in a microwave oven for 2 hours. After the reaction was completed, the mixture was diluted with water and extracted with dichloromethane (10 ml x 3 times). The organic phases were combined, washed with saturated brine (10 ml x 3 times), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was used to obtain 11.2 mg of 8-chloro-N-(2-morpholinoethyl)-2-(5-(trifluoromethoxy)-1H-indol-3-yl)quinolin-4-amine as a white solid (yield: 18.12%). RT = 1.73 min, [M+H] + =491.10.

[0132] Example 17 Synthesis of 8-chloro-N-(3-(piperazin-1-yl)propyl)-2-(5-(trifluoromethoxy)-1H-indol-2-yl)quinolin-5-amine

[0133] Step A: Synthesis of 4,8-dichloro-2-(5-(trifluoromethoxy)-1H-indol-2-yl)quinoline

[0134] To 2,4,8-trichloroquinoline (350 mg, 1.51 mmol), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethoxy)-1H-indole (554.83 mg, 2.27 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (110.49 mg, 0.15 mmol), and potassium carbonate (626.09 mg, 4.53 mmol) was added dioxane (5 ml) and water (1 ml) at room temperature. After the addition, the atmosphere was purged with nitrogen three times, and the temperature was raised to 90°C and the reaction was allowed to proceed overnight. After the reaction, the mixture was diluted with water and extracted with dichloromethane (10 ml × 3 times). The organic phases were combined, washed with saturated brine (10 ml × 3 times), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 5) to obtain 180 mg of 4,8-dichloro-2-(5-(trifluoromethoxy)-1H-indol-2-yl)quinoline as a white solid (yield: 30.10%).

[0135] Step B: Synthesis of 8-chloro-N-(3-(piperidin-1-yl)propyl)-2-(5-(trifluoromethoxy)-1H-indol-2-yl)quinolin-4-amine

[0136] To a solution of 4,8-dichloro-2-(5-(trifluoromethoxy)-1H-indol-2-yl)quinoline (50 mg, 0.13 mmol) in dimethyl sulfoxide (2 mL) was added 1-(3-aminopropyl)piperidine (55.47 mg, 0.39 mmol) and N,N-diisopropylethylamine (168.01 mg, 1.3 mmol) at room temperature. The mixture was heated to 150°C in a microwave oven for 2 hours. After the reaction was completed, the mixture was diluted with water and extracted with dichloromethane (10 ml x 3 times). The organic phases were combined, washed with saturated brine (10 ml x 3 times), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was prepared to give 9.6 mg of 8-chloro-N-(3-(piperidin-1-yl)propyl)-2-(5-(trifluoromethoxy)-1H-indol-2-yl)quinolin-4-amine as a white solid (yield: 15.16%). RT = 1.98 min, [M+H] + =503.02.

[0137] Example 18 Synthesis of 2-(8-chloroquinolin-2-yl)-6-(trifluoromethoxy)benzo[d]thioline

[0138] To a solution of 2,8-dichloroquinoline (101.06 mg, 0.50 mmol) in N,N-dimethylformamide (5 ml) were added 6-trifluoromethoxy-1,3-benzothiazole (110 mg, 0.50 mmol), potassium phosphate (640 mg, 3.0 mmol), 1,10-phenanthroline (2.7 mg, 0.015 mmol), triphenylphosphine (2.6 mg, 0.01 mmol) and tetrakistriphenylphosphine palladium (9.2 mg, 0.01 mmol) at room temperature. The reaction mixture was heated to 140°C and microwaved for 2 h.

[0139] After the reaction was completed, the mixture was diluted with water and extracted with ethyl acetate (5 mL x 3 times). The organic phases were combined, washed with saturated brine (5 mL x 3 times), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was subjected to preparative purification to afford 50.0 mg of 8-chloro-2-(6-(trifluoromethoxy)-1H-indazol-1-yl)quinoline as a white solid (yield: 26.01%). LC-MS: RT = 2.30 min, [M+H] + =380.98. 1 H NMR(400MHz, DMSO-d6)δ8.70(d,J=8.5Hz,1H),8.52(d,J=8.5Hz,1H),8.36(d,J=2.5Hz,1H), 8.26(d,J=8.9Hz,1H),8.13–8.04(m,2H),7.70(t,J=7.8Hz,1H),7.59(dd,J=9.0,2.5Hz,1H).

[0140] Example 19 Synthesis of 8-chloro-2-(5-(trifluoromethoxy)-1H-indol-1-yl)quinoline

[0141] To a solution of 2,8-dichloroquinoline (150 mg, 0.62 mmol) in toluene (5 mL) were added 5-trifluoromethoxyindole (150 mg, 0.74 mmol), potassium carbonate (170 mg, 1.24 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (30 mg, 0.062 mmol) and tris(dibenzylideneacetone)dipalladium (28 mg, 0.031 mmol) at room temperature. The reaction mixture was heated to 110°C and microwaved for 2 h.

[0142] After the reaction was completed, the mixture was diluted with water and extracted with ethyl acetate (5 ml x 3 times). The organic phases were combined, washed with saturated brine (5 ml x 3 times), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was subjected to preparative purification to obtain 3.4 mg of 8-chloro-2-(5-(trifluoromethoxy)-1H-indol-1-yl)quinoline (yield: 1.5%). LC-MS: RT = 2.52 min, [M+H]+ =362.97.

[0143] Example 20 Synthesis of 7,8-dichloro-2-(5-(trifluoromethoxy)-1H-indol-2-yl)quinoline

[0144] Step A: Synthesis of N-(2,3-dichlorophenyl)-3,3-dimethoxypropionamide

[0145] Dissolve 2,3-dichloroaniline (2 g, 12.34 mmol) and methyl 3,3-dimethoxypropionate (2.19 g, 14.81 mmol) in tetrahydrofuran (30 ml). Cool in an ice-water bath and slowly add sodium bis(trimethylsilyl)amide (24 ml, 24 mmol). After the addition is complete, warm to room temperature and allow to react overnight. After completion, the reaction mixture is quenched with saturated sodium bicarbonate aqueous solution, diluted with ethyl acetate, and separated. The aqueous phase is extracted once with ethyl acetate, and the organic phases are combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated to obtain 3.4 g of the product, N-(2,3-dichlorophenyl)-3,3-dimethoxypropionamide, which is used directly in the next reaction. RT = 2.05 min, [M+H] + =231.94.

[0146] Step B: Synthesis of 7,8-dichloroquinolin-2(1H)-one

[0147] Dissolve N-(2,3-dichlorophenyl)-3,3-dimethoxypropionamide (3.4 g, 12.2 mmol) in dichloromethane (30 mL). After cooling in an ice-water bath, add concentrated sulfuric acid (9 mL) dropwise and allow to react overnight at room temperature. After the reaction, concentrate the solution to remove the dichloromethane solvent. The residue is added dropwise to water, whereupon a yellow solid precipitates. Filter and filter cake dry to yield 2.3 g of the product, 7,8-dichloroquinolin-2(1H)-one, which is used directly in the next reaction. RT = 1.88 min, [M+H] + =213.98.

[0148] Step C: Synthesis of 2,7,8-trichloroquinoline

[0149] Dissolve 7,8-dichloroquinolin-2(1H)-one (1.8 g, 8.41 mmol) in phosphorus oxychloride (10 ml), heat to 90°C, and react for 2 hours. After the reaction, add the reaction solution dropwise to ice water, adjust the pH to 7-8 with solid sodium bicarbonate, and extract with ethyl acetate. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated. The residue is purified by silica gel column chromatography (ethyl acetate / n-hexane = 0-10%). LCMS: RT = 2.21 min, [M+H] + =231.91.

[0150] Step D: Synthesis of 7,8-dichloro-2-(5-(trifluoromethoxy)-1H-indol-2-yl)quinoline

[0151] To a mixture of 2,7,8-trichloroquinoline (100 mg, 0.43 mmol), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethoxy)-1H-indole (154.72 mg, 0.47 mmol), bis(tri-tert-butylphosphine)palladium (21.98 mg, 0.043 mmol), and potassium carbonate (178.29 mg, 1.29 mmol) was added dioxane (4 ml) and water (1 ml) at room temperature. After the addition, the reaction flask was purged with nitrogen three times and then heated to 90°C with stirring for 2 hours. After the reaction was completed, the mixture was diluted with water and extracted with dichloromethane (10 ml x 3 times). The organic phases were combined, washed with saturated brine (10 ml x 3 times), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was used to prepare 7,8-dichloro-2-(5-(trifluoromethoxy)-1H-indol-2-yl)quinoline (15.4 mg, 9.01%) as a white solid. RT = 2.41 min, [MH] - =394.89. 1 H NMR (400MHz, DMSO-d6) δ11.87(s,1H),8.57(d,J=8.7Hz,1H),8.31(d,J=8.6Hz,1H),8.04(d,J=8.8Hz,1H),7.81 (d,J=8.7Hz,1H),7.72(d,J=8.9Hz,1H),7.67(t,J=1.7Hz,1H),7.56(s,1H),7.21(ddd,J=8.8,2.4,1.1Hz,1H).

[0152] Example 21 Synthesis of 6,8-dichloro-2-(5-(trifluoromethoxy)-1H-indol-2-yl)quinoline

[0153] Step A: Synthesis of N-(2,4-dichlorophenyl)-3,3-dimethoxypropionamide

[0154] Dissolve 2,4-dichloroaniline (2 g, 12.34 mmol) and methyl 3,3-dimethoxypropionate (2.19 g, 14.81 mmol) in tetrahydrofuran (30 ml). Cool in an ice-water bath and slowly add sodium bis(trimethylsilyl)amide (24 ml, 24 mmol). After the addition is complete, warm to room temperature and allow to react overnight. After completion, the reaction mixture is quenched with saturated sodium bicarbonate aqueous solution, diluted with ethyl acetate, and separated. The aqueous phase is extracted once with ethyl acetate, and the organic phases are combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated to yield 3.3 g of the product, N-(2,4-dichlorophenyl)-3,3-dimethoxypropionamide, which is used directly in the next reaction. RT = 2.05 min, [M+H] + =231.95.

[0155] Step B: Synthesis of 6,8-dichloroquinolin-2(1H)-one

[0156] Dissolve N-(2,4-dichlorophenyl)-3,3-dimethoxypropionamide (3.4 g, 12.2 mmol) in dichloromethane (30 mL). After cooling in an ice-water bath, add concentrated sulfuric acid (9 mL) dropwise and allow to react overnight at room temperature. After completion of the reaction, concentrate the solution to remove the dichloromethane solvent. The residue is then added dropwise to water, whereupon a yellow solid precipitates. Filter and filter cake dry to yield 2.3 g of the product, 6,8-dichloroquinolin-2(1H)-one (yield: 88%), which is used directly in the next reaction. RT = 1.88 min, [M+H] + =213.98.

[0157] Step C: Synthesis of 2,6,8-trichloroquinoline

[0158] Dissolve 6,8-dichloroquinolin-2(1H)-one (2.3 g, 10.75 mmol) in phosphorus oxychloride (10 ml), heat to 90°C, and react for 2 hours. After the reaction, add the reaction solution dropwise to ice water, adjust the pH to 7-8 with solid sodium bicarbonate, extract with ethyl acetate, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate. The residue is purified by silica gel column chromatography (ethyl acetate / n-hexane = 0-10%) to obtain 0.4 g of the product 2,6,8-trichloroquinoline (yield: 16%). LCMS: RT = 2.05 min, [M+H] + =231.96.

[0159] Step D: Synthesis of 6,8-dichloro-2-(5-(trifluoromethoxy)-1H-indol-2-yl)quinoline

[0160] To a mixture of 2,6,8-trichloroquinoline (30 mg, 0.13 mmol), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethoxy)-1H-indole (46.78 mg, 0.14 mmol), bis(tri-tert-butylphosphine)palladium (6.64 mg, 0.013 mmol), and potassium carbonate (53.90 mg, 0.39 mmol) was added dioxane (4 ml) and water (1 ml) at room temperature. After the addition, the reaction flask was purged with nitrogen three times, then heated to 90°C and stirred for 2 hours. After the reaction was completed, the mixture was diluted with water and extracted with dichloromethane (50 ml x 3 times). The organic phases were combined, washed with saturated brine (50 ml x 3 times), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was used to obtain 5.5 mg of 6,8-dichloro-2-(5-(trifluoromethoxy)-1H-indol-2-yl)quinoline as a white solid (yield: 10.73%). RT = 2.45 min, [MH] - =394.85.

[0161] Example 22 Synthesis of 7-methyl-8-chloro-2-(5-(trifluoromethoxy)-1H-indol-2-yl)quinoline

[0162] Step A: Synthesis of N-(2-chloro-3-methylphenyl)-3,3-diethoxypropionamide

[0163] 2-Chloro-3-aminotoluene (1 g, 7.01 mmol), 3,3-diethoxypropionic acid (1.48 g, 9.11 mmol), HATU (4.8 g, 12.62 mmol), and triethylamine (2.13 g, 21.03 mmol) were added to N,N-dimethylformamide (15 mL) at room temperature. The reaction was maintained at this temperature overnight. TLC was used to monitor the reaction until completion.

[0164] Water (20 mL) was added to the reaction mixture, which was extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 0-15%) to obtain 1.8 g of N-(2-chloro-3-methylphenyl)-3,3-diethoxypropionamide as a white solid (yield: 89.83%).

[0165] Step B: Synthesis of 8-chloro-7-methylquinolin-2-ol

[0166] Under ice cooling, concentrated sulfuric acid (3.2 mL) was added dropwise to a solution of N-(2-chloro-3-methylphenyl)-3,3-diethoxypropionamide (1.8 g, 6.3 mmol) in dichloromethane (15 mL). The mixture was then allowed to react at room temperature overnight. TLC was used to monitor the reaction until completion.

[0167] The reaction mixture was poured into ice water (20 ml) and extracted with dichloromethane (20 ml x 3 times). The organic phases were combined, washed with saturated brine (20 ml x 3 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 0-40%) to obtain 0.58 g of 8-chloro-7-methylquinolin-2-ol as a light yellow solid (yield: 47.56%).

[0168] Step C: Synthesis of 2,8-dichloro-7-methylquinoline

[0169] 8-Chloro-7-methylquinolin-2-ol (0.58 g, 3.00 mmol) was added to phosphorus oxychloride (5 mL) at room temperature and then heated to 90°C for 1.5 h. TLC was used to monitor the reaction until completion. The reaction solution was poured into ice water (40 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 0-5%) to obtain 0.52 g of 2,8-dichloro-7-methylquinoline as a white solid (yield: 81.86%).

[0170] Step D: Synthesis of 8-chloro-7-methyl-2-(5-(trifluoromethoxy)-1H-indol-2-yl)quinoline

[0171] Under N2 protection, 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethoxy)-1H-indole (0.34 g, 1.03 mmol), 2,8-dichloro-7-methylquinoline (0.2 g, 0.94 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.069 g, 0.094 mmol) and potassium carbonate (0.3 g, 2.82 mmol) were added to 15 mL of a 1,4-dioxane / water (4 / 1) mixed solvent, the temperature was raised to 100°C and stirred for 12 hours. The reaction was monitored by LC-MS until completion.

[0172] Water (20 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 ml x 3 times). The organic phases were combined, washed with saturated brine (20 ml x 3 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 0-5%). The resulting product was then slurried in 8 ml of a mixed solvent (dichloromethane / methanol = 1 / 10) for 12 hours to obtain 150 mg of 8-chloro-7-methyl-2-(5-(trifluoromethoxy)-1H-indol-2-yl)quinoline as a white solid (yield: 42.22%). RT = 2.50 min, [M+H]+ =376.95. 1 H NMR (400MHz, DMSO-d6) δ11.78(s,1H),8.46(d,J=8.6Hz,1H),8.19(d,J=8.5Hz,1H),7.87(d,J=8.2Hz,1H),7.71(d,J=8.8H z,1H),7.63(d,J=2.3Hz,1H),7.57(d,J=8.3Hz,1H),7.48(d,J=2.1Hz,1H),7.17(ddd,J=8.9,2.4,1.0Hz,1H),2.62(s,3H).

[0173] Example 23 Synthesis of 8-chloro-2-(1-ethyl-5-(trifluoromethoxy)-1H-indol-2-yl)quinoline

[0174] Under ice-cooling, 8-chloro-2-(5-(trifluoromethoxy)-1H-indol-2-yl)quinoline (0.12 g, 0.33 mmol) was added to tetrahydrofuran (5 mL). Sodium hydride (28 mg, 0.70 mmol) was slowly added and the mixture was allowed to react under ice-cooling for 15 minutes. Subsequently, iodoethane (0.056 g, 0.36 mmol) was added dropwise to the solution. After the addition was complete, the reaction mixture was brought to room temperature and reacted for 2 hours. TLC was used to monitor the reaction until completion.

[0175] The reaction mixture was poured into water and extracted with ethyl acetate (10 mL x 3). The organic phases were combined and washed with saturated saline solution (15 mL x 1). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by high performance liquid chromatography to obtain 30 mg of a light yellow solid, 8-chloro-2-(1-ethyl-5-(trifluoromethoxy)-1H-indol-2-yl)quinoline (yield: 23.4%). LCMS: RT = 2.32 min, [M+H] + =390.79.

[0176] Example 24 Synthesis of 2-(8-chloroquinolin-2-yl)-5-(trifluoromethoxy)benzo[d]oxazole

[0177] Step A: Synthesis of 8-chloro-N-(2-hydroxy-5-(trifluoromethoxy)phenyl)quinoline-2-carboxamide

[0178] To a solution of 8-chloro-2-quinolinecarboxylic acid (200 mg, 0.96 mmol) and 2-amino-4-trifluoromethoxyphenol (194.66 mg, 1.01 mmol) in tetrahydrofuran (5 ml) was added 1-propylphosphonic anhydride (458.18 mg, 1.44 mmol) and N,N-diisopropylethylamine (248.14 mg, 1.92 mmol) in sequence at room temperature. After the addition, the mixture was stirred at room temperature for half an hour.

[0179] After the reaction, the mixture was diluted with water and extracted with dichloromethane (10 ml × 3 times). The organic phases were combined, washed with saturated brine (20 ml × 3 times), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 3) to give 150 mg of 8-chloro-N-(2-hydroxy-5-(trifluoromethoxy)phenyl)quinoline-2-carboxamide as a white solid (yield: 40.68%).

[0180] Step B: Synthesis of 2-(8-chloroquinolin-2-yl)-5-(trifluoromethoxy)benzo[d]oxazole

[0181] Toluene (5 ml) was added to 8-chloro-N-(2-hydroxy-5-(trifluoromethoxy)phenyl)quinoline-2-carboxamide (100 mg, 0.26 mmol) and p-toluenesulfonic acid (44.77 mg, 0.26 mmol) at room temperature. After the addition, the reaction mixture was refluxed for 2 hours.

[0182] After the reaction was completed, the mixture was diluted with water and extracted with dichloromethane (5 mL x 3 times). The organic phases were combined, washed with saturated brine (10 mL x 3 times), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was subjected to preparative purification to afford 32.05 mg of 2-(8-chloroquinolin-2-yl)-5-(trifluoromethoxy)benzo[d]oxazole as a white solid (yield: 33.63%). LC-MS: RT = 2.27 min, [M+H] + =364.92.

[0183] Examples 25 & 26 Synthesis of 8-chloro-2-(5-(trifluoromethoxy)-1H-indol-1-yl)quinoline and 8-chloro-2-(5-(trifluoromethoxy)-2H-indazol-2-yl)quinoline

[0184] To a solution of 5-(trifluoromethoxy)-1H-indazole (101.06 mg, 0.50 mmol) in tetrahydrofuran (5 ml) was added sodium hydride (30 mg, 0.75 mmol) under ice-cooling. After stirring for half an hour under ice-cooling, 2,8-dichloroquinoline (100 mg, 0.50 mmol) was added. After the addition, the reaction mixture was heated to 80°C and stirred for 2 hours.

[0185] After the reaction, the mixture was diluted with water and extracted with dichloromethane (5 ml × 3 times). The organic phases were combined, washed with saturated brine (5 ml × 3 times), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by preparative purification to obtain 15.7 mg of white solid P1 (yield: 8.6%). LC-MS: RT = 2.43 min, [M+H] + =363.92, 1 H NMR (400 MHz, DMSO-d6) δ 9.54 (d, J = 1.0 Hz, 1H), 8.79 (d, J = 8.8 Hz, 1H), 8.52 (d, J = 8.8 Hz, 1H), 8.10 (ddd, J = 17.0, 7.9, 1.3 Hz, 2H), 8.00–7.86 (m, 2H), 7.67 (t, J = 7.9 Hz, 1H), 7.43–7.28 (m, 1H) and 12.5 mg of white solid P2 (yield: 6.9%) LC-MS: RT = 2.53 min, [M+H] + =363.94, 1 H NMR (400MHz, DMSO-d6) δ9.40 (dt, J=9.1, 0.7Hz, 1H), 8.73–8.56 (m, 2H), 8.36 (d, J=8. 9Hz,1H),8.04(ddd,J=9.9,3.8,1.8Hz,3H),7.81–7.69(m,1H),7.59(t,J=7.8Hz,1H).

[0186] Example 27 Synthesis of 8-chloro-2-(6-(trifluoromethoxy)-1H-indazol-1-yl)quinoline

[0187] To a solution of 6-(trifluoromethoxy)-1H-indazole (101.06 mg, 0.50 mmol) in tetrahydrofuran (5 ml) was added sodium hydride (30 mg, 0.75 mmol) under ice-cooling. After stirring for half an hour under ice-cooling, 2,8-dichloroquinoline (100 mg, 0.50 mmol) was added. After the addition, the reaction mixture was heated to 80°C and stirred for 2 hours.

[0188] After the reaction was completed, the mixture was diluted with water and extracted with dichloromethane (5 mL x 3 times). The organic phases were combined, washed with saturated brine (5 mL x 3 times), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was subjected to preparative purification to yield 42.5 mg of 8-chloro-2-(6-(trifluoromethoxy)-1H-indazol-1-yl)quinoline as a white solid (yield: 23.14%). LC-MS: RT = 2.29 min, [M+H] + =363.94. 1H NMR (400MHz, DMSO-d6) δ9.88(s,1H),9.02(dd,J=2.4,1.1Hz,1H),8.30(d,J=8.9Hz,1H),7.97(d,J=8.6Hz, 1H),7.83(d,J=7.8Hz,2H),7.49(d,J=8.9Hz,1H),7.38(t,J=7.8Hz,1H),7.20(ddd,J=8.7,2.5,1.1Hz,1H).

[0189] Example 28 Synthesis of N-(8-chloroquinolin-2-yl)-6-(trifluoromethoxy)benzo[d]oxazol-2-amine

[0190] Step A: Synthesis of 2-nitro-5-(trifluoromethoxy)phenol

[0191] 2-Fluoro-1-nitro-4-(trifluoromethoxy)benzene (1 g, 4.44 mmol) and potassium carbonate (3.07 g, 22.20 mmol) were added to a 1 / 1 DMSO / H₂O solution (20 mL) at room temperature and then heated to 100°C for overnight reaction. TLC monitored the reaction until complete. The reaction solution was poured into water, acidified with dilute hydrochloric acid, and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. 0.8 g of 2-nitro-5-(trifluoromethoxy)phenol was obtained as a white solid (yield: 80.71%).

[0192] Step B: Synthesis of 2-nitro-5-(trifluoromethoxy)phenol

[0193] 10% palladium on carbon (0.19 g, 1.79 mmol) was added to a solution of 2-nitro-5-(trifluoromethoxy)phenol (0.8 g, 3.59 mmol) in methanol (20 mL) at room temperature. The mixture was then reacted under a hydrogen atmosphere at room temperature for 4 h. TLC confirmed the reaction was complete. The reaction solution was filtered through celite and the filtrate was concentrated under reduced pressure to afford 0.6 g of 2-nitro-5-(trifluoromethoxy)phenol as a brown oil (yield: 86.65%).

[0194] Step C: Synthesis of 6-(trifluoromethoxy)benzo[d]oxazol-2-amine

[0195] 2-Nitro-5-(trifluoromethoxy)phenol (0.42 g, 2.17 mmol) and bis(1H-imidazol-1-yl)formimine (0.35 g, 2.17 mmol) were added to tetrahydrofuran (20 mL) at room temperature and then heated to 70°C for 6 h. TLC monitored the reaction until completion. The reaction solution was poured into water and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / n-hexane = 0-35%) to afford 0.32 g of 6-(trifluoromethoxy)benzo[d]oxazol-2-amine as a white solid (yield: 67.45%).

[0196] Step D: Synthesis of N-(8-chloroquinolin-2-yl)-6-(trifluoromethoxy)benzo[d]oxazol-2-amine

[0197] Under N2 protection, 6-(trifluoromethoxy)benzo[d]oxazol-2-amine (0.12 g, 0.55 mmol), 2,8-dichloroquinoline (0.12 g, 0.61 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.05 g, 0.055 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.095 g, 0.17 mmol) and cesium carbonate (0.36 g, 1.1 mmol) were added to 1,4-dioxane (8 ml) and stirred at 140 °C under microwave conditions for 1.5 hours.

[0198] Water (20 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 ml x 3 times). The combined organic phases were washed with saturated brine (20 ml x 3 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 0-50%). The resulting product was then purified by high-performance liquid chromatography to obtain 105 mg of N-(8-chloroquinolin-2-yl)-6-(trifluoromethoxy)benzo[d]oxazol-2-amine as a yellow solid (yield: 50.26%). LCMS: RT = 2.29 min, [M+H] + =379.95. 1 H NMR (400MHz, DMSO-d6) δ12.01(s,1H),8.47(s,1H),7.97–7.89(m,3H),7.78(d,J= 2.2Hz,1H),7.67(d,J=8.6Hz,1H),7.52–7.43(m,1H),7.32(dd,J=8.6,2.2Hz,1H).

[0199] Example 29 Synthesis of (2-(8-chloroquinolin-2-yl)-5-(trifluoromethoxy)-1H-indol-1-yl)methanol

[0200] At room temperature, 8-chloro-2-(5-(trifluoromethoxy)-1H-indol-2-yl)quinoline (0.12 g, 0.33 mmol), paraformaldehyde (0.20 g, 1.65 mmol), and potassium carbonate (0.14 g, 0.99 mmol) were added to dioxane (18 mL) and the temperature was raised to 60°C for overnight reaction. The reaction solvent was removed by evaporation, and the resulting product was purified by HPLC to give 52 mg of (2-(8-chloroquinolin-2-yl)-5-(trifluoromethoxy)-1H-indol-1-yl)methanol as a white solid (yield: 40.02%). LCMS: RT = 2.11 min, [M+H] + =392.93. 1 H NMR (400MHz, DMSO-d6) δ8.61(d,J=8.7Hz,1H),8.30(d,J=8.7Hz,1H),8.06(dd,J=7.4,1.3Hz,2H),7.86(d,J=9.0Hz,1H),7.71(d, J=1.5Hz,1H),7.67(d,J=7.8Hz,1H),7.54(s,1H),7.31(dd,J=9.0,1.1Hz,1H),6.40(dd,J=8.5,6.9Hz,1H),6.30(d,J=7.8Hz,2H).

[0201] Example 30 Synthesis of 8-chloro-7-methoxy-2-(5-(trifluoromethoxy)-1H-indol-2-yl)quinoline

[0202] Step A: Synthesis of N-(2-chloro-3-methoxyphenyl)-3,3-diethoxypropionamide

[0203] 2-Chloro-3-methoxyaniline (1 g, 6.35 mmol), 3,3-diethoxypropionic acid (1.34 g, 8.25 mmol), HATU (3.62 g, 9.52 mmol), and triethylamine (1.29 g, 12.7 mmol) were added to N,N-dimethylformamide (15 mL) at room temperature. The reaction was maintained at this temperature overnight. TLC was used to monitor the reaction until completion.

[0204] Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 0-20%) to obtain 1.6 g of N-(2-chloro-3-methoxyphenyl)-3,3-diethoxypropionamide as a brown oil (yield: 92.13%).

[0205] Step B: Synthesis of 8-chloro-7-methoxyquinoline-2-ol

[0206] Under ice cooling, concentrated sulfuric acid (3.2 ml) was added dropwise to a solution of N-(2-chloro-3-methoxyphenyl)-3,3-diethoxypropionamide (1.6 g, 5.31 mmol) in dichloromethane (15 ml), and the mixture was allowed to react at room temperature overnight. The reaction was monitored by TLC until completion.

[0207] The reaction mixture was poured into ice water (20 ml) and extracted with dichloromethane (20 ml x 3 times). The organic phases were combined, washed with saturated brine (20 ml x 3 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 0-50%) to obtain 0.6 g of 8-chloro-7-methoxyquinolin-2-ol as a white solid (yield: 54.05%).

[0208] Step C: Synthesis of 2,8-dichloro-7-methoxyquinoline

[0209] 8-Chloro-7-methoxyquinolin-2-ol (0.58 g, 3.00 mmol) was added to phosphorus oxychloride (5 mL) at room temperature and then heated to 90°C for 1.5 h. TLC was used to monitor the reaction until completion. The reaction mixture was poured into ice water (40 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 0-5%) to obtain 0.52 g of 2,8-dichloro-7-methoxyquinoline as a white solid (yield: 79.66%).

[0210] Step D: Synthesis of 8-chloro-7-methoxy-2-(5-(trifluoromethoxy)-1H-indol-2-yl)quinoline

[0211] Under N2 protection, 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethoxy)-1H-indole (0.34 g, 1.03 mmol), 2,8-dichloro-7-methoxyquinoline (0.2 g, 0.94 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.069 g, 0.094 mmol) and potassium carbonate (0.3 g, 2.82 mmol) were added to 15 mL of a 1,4-dioxane / water (4 / 1) mixed solvent, the temperature was raised to 100°C and stirred for 12 hours. The reaction was monitored by LC-MS until completion.

[0212] Water (20 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 ml x 3 times). The organic phases were combined, washed with saturated brine (20 ml x 3 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 0-15%). The resulting product was then slurried in 8 ml of a mixed solvent (dichloromethane / methanol = 1 / 10) for 12 hours to obtain 0.18 g of a light yellow solid 8-chloro-7-methoxy-2-(5-(trifluoromethoxy)-1H-indol-2-yl)quinoline (yield: 52.26%). LCMS: RT = 2.14 min, [M+H] + =392.97. 1 H NMR (400MHz, DMSO-d6) δ11.79(s,1H),8.46(d,J=8.6Hz,1H),8.11(d,J=8.6Hz,1H),8.01(d,J=9.0H z,1H),7.72(d,J=8.8Hz,1H),7.67–7.62(m,2H),7.50–7.47(m,1H),7.23–7.16(m,1H),4.08(s,3H).

[0213] Example 31 Synthesis of 8-chloro-2-(1-(2,2,2-trifluoroethyl)-5-(trifluoromethoxy)-1H-indol-2-yl)quinoline

[0214] Trifluoroethyl trifluoromethanesulfonate (0.092 g, 0.40 mmol) was added dropwise to a mixture of 8-chloro-2-(5-(trifluoromethoxy)-1H-indol-2-yl)quinoline (0.12 g, 0.33 mmol) and cesium carbonate (0.22 g, 0.66 mmol) in acetonitrile (18 mL) at room temperature. The reaction was continued at this temperature for 4 h. TLC was used to monitor the reaction until completion. The solvent was then removed by evaporation, and the resulting product was purified by HPLC to yield 98 mg of 8-chloro-2-(1-(2,2,2-trifluoroethyl)-5-(trifluoromethoxy)-1H-indol-2-yl)quinoline as a white solid (yield: 66.60%). LCMS: RT = 2.27 min, [M+H] + =444.97. 1 H NMR (400MHz, DMSO-d6) δ8.58(d,J=8.7Hz,1H),8.35(d,J=8.7Hz,1H),8.04(d,J=7.8Hz,2H),7.92(d ,J=9.0Hz,1H),7.74(d,J=2.1Hz,2H),7.64(d,J=7.8Hz,1H),7.40–7.34(m,1H),6.59–6.46(m,2H).

[0215] Example 32 Synthesis of 8-chloro-2-(3-methyl-5-(trifluoromethoxy)-1H-indol-2-yl)quinoline

[0216] Step A: Synthesis of 1-(8-chloroquinolin-2-yl)propan-1-ol

[0217] To a solution of 8-chloroquinoline-2-carbaldehyde (1.0 g, 5.22 mmol) in tetrahydrofuran (5 mL) was slowly added dropwise ethylmagnesium bromide (7.8 mL, 7.83 mmol, 1 M in THF) in an ice bath. The mixture was stirred for 2 hours in an ice bath. After completion of the reaction, the mixture was diluted with water and extracted with dichloromethane (50 mL x 3). The combined organic phases were washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 5) to obtain 600 mg of colorless liquid 1-(8-chloroquinolin-2-yl)propan-1-ol (yield: 51.86%).

[0218] Step B: Synthesis of 1-(8-chloroquinolin-2-yl)propan-1-one

[0219] To a solution of 1-(8-chloroquinolin-2-yl)propan-1-ol (300 mg, 1.35 mmol) in dichloromethane (5 mL) at room temperature was added manganese dioxide (234.74 mg, 2.7 mmol). The mixture was stirred at room temperature overnight. After the reaction was complete, the mixture was filtered and the mother liquor was concentrated to obtain 150 mg of 1-(8-chloroquinolin-2-yl)propan-1-one as a white solid (yield: 50.46%).

[0220] Step C: Synthesis of 8-chloro-2-(3-methyl-5-(trifluoromethoxy)-1H-indol-2-yl)quinoline

[0221] Acetic acid (5 mL) was added to 1-(8-chloroquinolin-2-yl)propan-1-one (150 mg, 0.68 mmol) and 4-trifluoromethoxyphenylhydrazine (130.66 mg, 0.68 mmol) at room temperature. The mixture was heated to 120°C and stirred overnight. After the reaction, the mixture was diluted with water and extracted with dichloromethane (50 mL x 3). The combined organic phases were washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was used to obtain 44.15 mg of 8-chloro-2-(3-methyl-5-(trifluoromethoxy)-1H-indol-2-yl)quinoline as a white solid (yield: 17.10%). LC-MS: RT = 2.27 min, [M+H] + =376.94. 1H NMR (400MHz, DMSO-d6) δ11.78(s,1H),8.57(d,J=8.7Hz,1H),8.17(d,J=8.7Hz,1H),7.98(d, J=7.8Hz,2H),7.63(s,1H),7.57(t,J=8.0Hz,2H),7.18(dd,J=9.1,2.2Hz,1H),2.82(s,3H).

[0222] Example 33 Synthesis of 8-chloro-2-(5-(trifluoromethoxy)-1H-indol-3-yl)quinoline

[0223] Step A: Synthesis of (E)-8-chloro-2-(2-ethoxyvinyl)quinoline

[0224] To a mixture of 2,8-dichloroquinoline (500 mg, 2.52 mmol), 2(E)-1-ethoxyvinyl-2-boronic acid pinacol ester (648.88 mg, 3.28 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (205.79 mg, 0.25 mmol), and potassium carbonate (1044.87 mg, 7.56 mmol) was added dioxane (5 ml) at room temperature. After the addition, the reaction flask was purged with nitrogen three times, then heated to 90°C and stirred for 2 hours. After the reaction, the mixture was diluted with water and extracted with dichloromethane (50 ml × 3 times). The organic phases were combined, washed with saturated brine (50 ml × 3 times), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 3) to obtain 300 mg of (E)-8-chloro-2-(2-ethoxyvinyl)quinoline as a colorless oil (yield: 50.85%).

[0225] Step B: Synthesis of 8-chloro-2-(5-(trifluoromethoxy)-1H-indol-3-yl)quinoline

[0226] To a solution of (E)-8-chloro-2-(2-ethoxyvinyl)quinoline (200 mg, 0.86 mmol) in acetic acid (5 mL) was added 4-trifluoromethoxyphenylhydrazine (165.24 mg, 0.86 mmol) at room temperature. The mixture was heated to 120°C and stirred overnight. After the reaction, the mixture was diluted with water and extracted with dichloromethane (20 mL x 3). The combined organic phases were washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to yield 4.2 mg of the crude product as a yellow solid (yield: 1.35%). LC-MS: RT = 2.14 min, [M+H] + =362.96. 1H NMR (400MHz, DMSO-d6) δ12.00(s,1H),9.18(s,1H),8.60(d,J=3.0Hz,1H),8.37(d,J=8.7Hz,1H),8.19(d,J=8.7 Hz,1H),7.91(td,J=7.5,1.3Hz,2H),7.58(d,J=8.8Hz,1H),7.48(t,J=7.8Hz,1H),7.20(dd,J=8.8,2.6Hz,1H).

[0227] Example 34 Synthesis of 4-(2-(2-(8-chloroquinolin-2-yl)-5-(trifluoromethoxy)-1H-indol-1-yl)ethyl)morpholine

[0228] 8-Chloro-2-(5-(trifluoromethoxy)-1H-indol-2-yl)quinoline (0.12 g, 0.33 mmol), 4-(2-chloroethyl)morpholine (0.059 g, 0.4 mmol) and cesium carbonate (0.16 g, 0.5 mmol) were added to acetonitrile (10 ml) and the temperature was raised to 70°C for 4 hours.

[0229] Water (20 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 ml x 3 times). The organic phases were combined, washed with saturated brine (20 ml x 3 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by HPLC to obtain 70 mg of 4-(2-(2-(8-chloroquinolin-2-yl)-5-(trifluoromethoxy)-1H-indol-1-yl)ethyl)morpholine as a white solid (yield: 44.46%). LCMS: RT = 1.88 min, [M+H] + =476.14. 1 H NMR(400MHz,Chloroform-d)δ8.29(d,J=8.7Hz,1H),7.99(d,J=8.6Hz,1H),7.92(dd,J=7.6,1.3Hz,1H),7.83(dd,J=8.2,1.3Hz,1H),7.76(d,J=9.0Hz,1 H),7.58–7.50(m,2H),7.27(dd,J=9.1,2.2Hz,1H),7.18(s,1H),5.38(t,J= 7.7Hz,2H),4.01(t,J=4.8Hz,4H),3.72(t,J=7.6Hz,2H),3.48–2.99(m,4H).

[0230] Example 35 Synthesis of 4-(2-((8-chloro-2-(5-(trifluoromethoxy)-1H-indol-2-yl)quinolin-7-yl)oxy)ethyl)morpholine

[0231] Step A: Synthesis of 4-(2-(2-chloro-3-nitrophenoxy)ethyl)morpholine

[0232] 2-Chloro-3-nitrophenol (3 g, 17.29 mmol), 4-(2-chloroethyl)morpholine (3.1 g, 20.75 mmol) and cesium carbonate (11.27 g, 34.58 mmol) were added to DMF (15 ml) and the temperature was raised to 70°C for 4 hours.

[0233] Water (20 ml) was added to the reaction solution, extracted with ethyl acetate (20 ml × 3 times), and the organic phases were combined, washed with saturated brine (20 ml × 3 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure to obtain 4.5 g of yellow oily 4-(2-(2-chloro-3-nitrophenoxy)ethyl)morpholine (yield: 90.80%).

[0234] Step B: Synthesis of 4-(2-(2-chloro-3-aminophenoxy)ethyl)morpholine

[0235] A solution of 4-(2-(2-chloro-3-nitrophenoxy)ethyl)morpholine (4.5 g, 15.70 mmol) in ethanol (80 ml) was added dropwise to water (20 ml) containing iron powder (4.38 g, 78.5 mmol) and ammonium chloride (8.40 g, 157 mmol), and the mixture was reacted at 80°C for 6 hours.

[0236] After filtering off the iron powder and removing the excess ethanol by vortexing, water (80 ml) was added to the residual liquid, and the mixture was extracted with ethyl acetate (20 ml × 3 times). The organic phases were combined, washed with saturated brine (20 ml × 3 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure to obtain 3.7 g of yellow solid 4-(2-(2-chloro-3-aminophenoxy)ethyl)morpholine (yield: 91.80%).

[0237] Step C: Synthesis of N-(2-chloro-3-(2-morpholinoethoxy)phenyl)-3,3-diethoxypropionamide

[0238] 4-(2-(2-chloro-3-aminophenoxy)ethyl)morpholine (3.7 g, 14.41 mmol), 3,3-diethoxypropionic acid (2.8 g, 17.29 mmol), HATU (8.22 g, 21.62 mmol), and N,N-diisopropylethylamine (3.72 g, 28.82 mmol) were added to N,N-dimethylformamide (15 ml) at room temperature and allowed to react overnight. The reaction was monitored by TLC until completion.

[0239] Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 0-80%) to obtain 3.2 g of N-(2-chloro-3-(2-morpholinoethoxy)phenyl)-3,3-diethoxypropionamide as a brown oil (yield: 55.38%).

[0240] Step D: Synthesis of 8-chloro-7-(2-morpholinoethoxy)quinolin-2-ol

[0241] Under ice cooling, concentrated sulfuric acid (8 mL) was added dropwise to a solution of N-(2-chloro-3-(2-morpholinoethoxy)phenyl)-3,3-diethoxypropionamide (3.2 g, 8.58 mmol) in dichloromethane (25 mL). The mixture was then allowed to react at room temperature overnight. TLC was used to monitor the reaction until completion.

[0242] The reaction mixture was poured into ice water (20 ml) and extracted with dichloromethane (20 ml x 3 times). The organic phases were combined, washed with saturated brine (20 ml x 3 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 0-90%) to obtain 1.52 g of 8-chloro-7-(2-morpholinoethoxy)quinolin-2-ol as a pale yellow solid (yield: 57.36%).

[0243] Step E: Synthesis of 4-(2-((2,8-dichloroquinolin-7-yl)oxy)ethyl)morpholine

[0244] 5,8-Dichloroquinolin-2-ol (1.52 g, 4.92 mmol) was added to phosphorus oxychloride (12 mL) at room temperature and then heated to 90°C for 1.5 hours. TLC was used to monitor the reaction until completion. The reaction mixture was poured into ice water (40 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 0-70%) to obtain 0.8 g of 4-(2-((2,8-dichloroquinolin-7-yl)oxy)ethyl)morpholine as a white solid (yield: 49.66%).

[0245] Step F: Synthesis of 4-(2-((8-chloro-2-(5-(trifluoromethoxy)-1H-indol-2-yl)quinolin-7-yl)oxy)ethyl)morpholine

[0246] Under N2 protection, 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethoxy)-1H-indole (0.13 g, 0.41 mmol), 4-(2-((2,8-dichloroquinolin-7-yl)oxy)ethyl)morpholine (0.12 g, 0.37 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.027 g, 0.037 mmol) and potassium carbonate (0.15 g, 1.11 mmol) were added to 15 mL of a 1,4-dioxane / water (4 / 1) mixed solvent. The mixture was heated to 100°C and stirred for 12 hours. The reaction was monitored by LC-MS until completion.

[0247] Water (20 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 ml x 3 times). The organic phases were combined, washed with saturated brine (20 ml x 3 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 0-80%). The resulting product was then slurried in 8 ml of a mixed solvent (dichloromethane / methanol = 1 / 10) for 12 hours to obtain 120 mg of 4-(2-((8-chloro-2-(5-(trifluoromethoxy)-1H-indol-2-yl)quinolin-7-yl)oxy)ethyl)morpholine as a white solid (yield: 66.52%). LCMS: RT = 1.77 min, [M+H] + =492.12. 1 H NMR(400MHz,Chloroform-d)δ9.82(s,1H),8.05(d,J=8.6Hz,1H),7.75(d,J=8.5Hz,1H),7.63(d,J=8.9Hz,1H),7.46(d,J=2.1Hz,1H),7.4 1(d,J=8.8Hz,1H),7.19(s,1H),7.12–7.03(m,2H),4.32(t,J=5.6Hz,2H),3.74–3.64(m,4H),2.89(t,J=5.6Hz,2H),2.63(t,J=4.7Hz,4H).

[0248] Example 36 Synthesis of 2-((2-(8-chloroquinolin-2-yl)-5-(trifluoromethoxy)-1H-indol-6-yl)oxy)-N,N-dimethylethan-1-amine

[0249] Step A: Synthesis of 5-bromo-2-iodo-4-(trifluoromethoxy)aniline

[0250] To a solution of 3-bromo-4-(trifluoromethoxy)aniline (2.0 g, 7.81 mmol) in acetic acid (20 mL) was added N-iodosuccinimide (1.53 g, 8.59 mmol) at room temperature. The mixture was stirred overnight at room temperature. After completion of the reaction, the mixture was diluted with 30 mL of water and extracted with dichloromethane (50 mL x 3). The combined organic phases were washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1 / 5) to afford 1.5 g of 5-bromo-2-iodo-4-(trifluoromethoxy)aniline as a white solid (yield: 50.28%).

[0251] Step B: Synthesis of 5-bromo-4-(trifluoromethoxy)-2-((trimethylsilyl)ethynyl)aniline

[0252] To a mixture of 5-bromo-2-iodo-4-(trifluoromethoxy)aniline (1.0 g, 2.62 mmol), ethynyltrimethylsilane (0.31 g, 3.14 mmol), and bis(triphenylphosphine)palladium(II) chloride (183.94 mg, 0.262 mmol) was added triethylamine (10 ml) at room temperature. The reaction flask was purged with nitrogen three times, then heated to 90°C and stirred for 2 hours. After the reaction, the mixture was diluted with 30 ml of water and extracted with dichloromethane (50 ml x 3). The organic phases were combined, washed with saturated brine (50 ml x 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1 / 5) to afford 0.9 g of 5-bromo-4-(trifluoromethoxy)-2-((trimethylsilyl)ethynyl)aniline as a colorless oil (yield: 97.59%).

[0253] Step C: Synthesis of 5-bromo-2-ethynyl-4-(trifluoromethoxy)aniline

[0254] To a solution of 5-bromo-4-(trifluoromethoxy)-2-(2-(trimethylsilyl)ethynyl)aniline (1.0 g, 2.84 mmol) in methanol (10 ml) was added potassium carbonate (785.03 mg, 5.68 mmol) at room temperature. The mixture was stirred at room temperature for half an hour. After the reaction, the solvent was removed by vacuum concentration. 50 ml of water was added to the resulting solid, which was then extracted with dichloromethane (50 ml x 3). The organic phases were combined, washed with saturated brine (50 ml x 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product, 5-bromo-2-ethynyl-4-(trifluoromethoxy)aniline (650 mg), was used directly in the next reaction.

[0255] Step D: Synthesis of 5-bromo-2-((8-chloroquinolin-2-yl)ethynyl)-4-(trifluoromethoxy)aniline

[0256] To a mixture of 5-bromo-2-ethynyl-4-(trifluoromethoxy)aniline (650 mg, 2.32 mmol), 2,8-dichloroquinoline (505.42 mg, 2.55 mmol), bistriphenylphosphine palladium dichloride (162.84 mg, 0.23 mmol), and cuprous iodide (44.18 mg, 0.23 mmol) was added triethylamine (10 ml) at room temperature. After the addition, the reaction flask was purged with nitrogen three times, then heated to 90°C and stirred for 2 hours.

[0257] After the reaction, the mixture was diluted with 10 ml of water and extracted with dichloromethane (20 ml × 3). The organic phases were combined, washed with saturated brine (20 ml × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1 / 2) to give 420 mg of 5-bromo-2-((8-chloroquinolin-2-yl)ethynyl)-4-(trifluoromethoxy)aniline as a white solid (yield: 45.05%).

[0258] Step E: Synthesis of 2-(6-bromo-5-(trifluoromethoxy)-1H-indol-2-yl)-8-chloroquinoline

[0259] To a solution of 5-bromo-2-((8-chloroquinolin-2-yl)ethynyl)-4-(trifluoromethoxy)aniline (400 mg, 1.0 mmol) in tetrahydrofuran (5 ml) was added tetrabutylammonium fluoride (2614.6 mg, 10 mmol) at room temperature. After the addition, the mixture was heated to 90°C and stirred for 24 hours.

[0260] After the reaction, the mixture was diluted with 50 ml of water and extracted with dichloromethane (50 ml × 3). The organic phases were combined, washed with saturated brine (50 ml × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1 / 2) to give 250 mg of 2-(6-bromo-5-(trifluoromethoxy)-1H-indol-2-yl)-8-chloroquinoline as a white solid (yield: 56.84%).

[0261] Step F: Synthesis of 2-(6-bromo-5-(trifluoromethoxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-2-yl)-8-chloroquinoline

[0262] To a solution of 2-(6-bromo-5-(trifluoromethoxy)-1H-indol-2-yl)-8-chloroquinoline (300 mg, 0.68 mmol) in tetrahydrofuran (5 ml) was added sodium hydride (24.48 mg, 1.02 mmol) under ice-cooling. After stirring for half an hour, 2-(trimethylsilyl)ethoxymethyl chloride (136.04 mg, 0.82 mmol) was added to the reaction solution. After the reaction, the mixture was diluted with 10 ml of water and extracted with dichloromethane (10 ml × 3). The organic phases were combined, washed with saturated brine (10 ml × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1 / 5) to give 385 mg of 2-(6-bromo-5-(trifluoromethoxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-2-yl)-8-chloroquinoline as a white solid (yield: 99.10%).

[0263] Step G: Synthesis of 2-(8-chloroquinolin-2-yl)-5-(trifluoromethoxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-6-ol

[0264] To a mixture of 2-(6-bromo-5-(trifluoromethoxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-2-yl)-8-chloroquinoline (200 mg, 0.35 mmol) and 2-(di-tert-butylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl(2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (29.91 mg, 0.035 mmol) was added dioxane (4 mL) and water (1 mL) at room temperature. After the addition, the reaction flask was purged with nitrogen three times, then heated to 90°C and stirred for 2 hours.

[0265] After the reaction, the mixture was diluted with 10 ml of water and extracted with dichloromethane (15 ml × 3). The organic phases were combined, washed with saturated brine (15 ml × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1 / 5) to give 110 mg of a colorless oily substance, 2-(8-chloroquinolin-2-yl)-5-(trifluoromethoxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-6-ol (yield: 61.82%).

[0266] Step H: Synthesis of 2-(8-chloroquinolin-2-yl)-5-(trifluoromethoxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-6-ol

[0267] To a solution of 2-(8-chloroquinolin-2-yl)-5-(trifluoromethoxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-6-ol (110 mg, 0.22 mmol) in acetonitrile (5 ml) was added cesium carbonate (215.04 mg, 0.66 mmol) and (2-bromoethyl)dimethylamine (33.45 mg, 0.22 mmol) at room temperature. After the addition, the mixture was heated to 50°C and stirred for 1 hour.

[0268] After the reaction, the mixture was diluted with 10 ml of water and extracted with dichloromethane (15 ml × 3). The organic phases were combined, washed with saturated brine (15 ml × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1 / 5) to give 100 mg of a white solid (2-((2-(8-chloroquinolin-2-yl)-5-(trifluoromethoxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-6-yl)oxy)ethyl)dimethylamine (yield: 79.76%).

[0269] Step I: Synthesis of 2-((2-(8-chloroquinolin-2-yl)-5-(trifluoromethoxy)-1H-indol-6-yl)oxy)-N,N-dimethylethan-1-amine

[0270] To a solution of (2-((2-(8-chloroquinolin-2-yl)-5-(trifluoromethoxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-6-yl)oxy)ethyl)dimethylamine (100 mg, 0.17 mmol) in tetrahydrofuran (5 ml) was added tetrabutylammonium fluoride (88.90 mg, 0.34 mmol) at room temperature. After the addition, the mixture was heated to 80°C and stirred for 24 hours.

[0271] After the reaction, the mixture was diluted with 10 ml of water and extracted with dichloromethane (15 ml x 3). The organic phases were combined, washed with saturated brine (15 ml x 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was subjected to preparative purification to afford 17.0 mg of 2-((2-(8-chloroquinolin-2-yl)-5-(trifluoromethoxy)-1H-indol-6-yl)oxy)-N,N-dimethylethan-1-amine as a white solid (yield: 21.92%). LCMS: RT = 1.88 min, [M+H] + =449.90.

[0272] Example 37 Synthesis of 5-chloro-3-(5-(trifluoromethoxy)-1H-indol-2-yl)isoquinoline

[0273] Under N2 protection, 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethoxy)-1H-indole (0.15 g, 0.46 mmol), 3,5-dichloroisoquinoline (0.10 g, 0.51 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.034 g, 0.046 mmol) and potassium carbonate (0.19 g, 1.38 mmol) were added to 8 mL of a 1,4-dioxane / water (4 / 1) mixed solvent, the temperature was raised to 100°C and stirred for 12 hours. The reaction was monitored by LC-MS until completion.

[0274] Water (20 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 ml x 3 times). The combined organic phases were washed with saturated brine (20 ml x 3 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by HPLC to obtain 70 mg of 5-chloro-3-(5-(trifluoromethoxy)-1H-indol-2-yl)isoquinoline as a slightly yellow solid (yield: 42.08%). LCMS: RT = 2.18 min, [M+H] + =362.93.

[0275] Example 38 Synthesis of 2-(8-chloronaphthalen-2-yl)-5-(trifluoromethoxy)-1H-indole

[0276] Under N2 protection, 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethoxy)-1H-indole (0.15 g, 0.46 mmol), 7-bromo-1-chloronaphthalene (0.12 g, 0.5 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.034 g, 0.046 mmol) and potassium carbonate (0.19 g, 1.38 mmol) were added to 8 mL of a 1,4-dioxane / water (4 / 1) mixed solvent, the temperature was raised to 100°C and stirred for 12 hours. The reaction was monitored by LC-MS until completion.

[0277] Water (20 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 ml x 3 times). The organic phases were combined, washed with saturated brine (20 ml x 3 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by HPLC to obtain 70 mg of a slightly yellow solid, 2-(8-chloronaphthalen-2-yl)-5-(trifluoromethoxy)-1H-indole (yield: 42.40%). LCMS: RT = 2.65 min, [M+H] + =361.93. 1H NMR (400MHz, DMSO-d6) δ12.19(s,1H),8.67–8.62(m,1H),8.19–8.10(m,2H),7.98(d,J=8.2Hz, 1H),7.77(dd,J=7.5,1.0Hz,1H),7.61–7.51(m,3H),7.22(d,J=2.3Hz,1H),7.17–7.11(m,1H).

[0278] Example 39 Synthesis of 8-chloro-2-(5-(trifluoromethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl)quinoline

[0279] Step A: Synthesis of 5-(trichloromethoxy)-3-(2-(trimethylsilyl)ethynyl)pyridin-2-amine

[0280] To a mixture of 3-bromo-5-(trifluoromethoxy)pyridin-2-amine (500 mg, 1.95 mmol), ethynyltrimethylsilane (229.83 mg, 2.34 mmol), cuprous iodide (37.14 mg, 0.20 mmol), and bistriphenylphosphine palladium dichloride (136.87 mg, 0.20 mmol) was added triethylamine (10 ml) at room temperature. After the addition, the reaction flask was purged with nitrogen three times, then heated to 90°C and stirred for 2 hours.

[0281] After the reaction, the mixture was diluted with 10 ml of water and extracted with dichloromethane (15 ml × 3). The organic phases were combined, washed with saturated brine (15 ml × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1 / 5) to give 450 mg of 5-(trifluoromethoxy)-3-(2-(trimethylsilyl)ethynyl)pyridin-2-amine as a white solid (yield: 84.32%).

[0282] Step B: Synthesis of 3-ethynyl-5-(trifluoromethoxy)pyridin-2-amine

[0283] To a solution of 5-(trifluoromethoxy)-3-(2-(trimethylsilyl)ethynyl)pyridin-2-amine (500 mg, 1.82 mmol) in methanol (10 mL) was added potassium carbonate (503.08 mg, 3.64 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. After completion of the reaction, it was diluted with 10 mL of water and extracted with dichloromethane (15 mL x 3). The combined organic phases were washed with saturated brine (15 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1 / 5) to afford 220 mg of 3-ethynyl-5-(trifluoromethoxy)pyridin-2-amine as a white solid (yield: 59.71%).

[0284] Step C: Synthesis of 3-(2-(8-chloroquinolin-2-yl)ethynyl)-5-(trifluoromethoxy)pyridin-2-amine

[0285] To a mixture of 3-ethynyl-5-(trifluoromethoxy)pyridin-2-amine (220 mg, 1.09 mmol), 2,8-dichloroquinoline (237.46 mg, 1.20 mmol), bis(triphenylphosphine)palladium(II) chloride (76.51 mg, 0.11 mmol), and cuprous iodide (20.76 mg, 0.11 mmol) was added triethylamine (10 ml) at room temperature. After the addition, the reaction flask was purged with nitrogen three times and then heated to 90°C with stirring for 2 hours. After the reaction, 10 ml of water was added to dilute the mixture, and the mixture was extracted with dichloromethane (15 ml × 3). The organic phases were combined, washed with saturated brine (15 ml × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1 / 5) to give 170 mg of 3-(2-(8-chloroquinolin-2-yl)ethynyl)-5-(trifluoromethoxy)pyridin-2-amine as a white solid (yield: 42.94%).

[0286] Step D: Synthesis of 8-chloro-2-(5-(trifluoromethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl)quinoline

[0287] To a solution of 3-(2-(8-chloroquinolin-2-yl)ethynyl)-5-(trifluoromethoxy)pyridin-2-amine (170 mg, 0.47 mmol) in tetrahydrofuran (10 mL) was added sodium tert-butoxide (90.33 mg, 0.94 mmol) at room temperature. The reaction flask was purged with nitrogen three times, then heated to 90°C and stirred for 2 hours. After the reaction, the mixture was diluted with 10 mL of water and extracted with dichloromethane (15 mL x 3). The combined organic phases were washed with saturated brine (15 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by preparative purification to yield 17.56 mg of 8-chloro-2-(5-(trifluoromethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl)quinoline as a white solid (yield: 10.33%). LCMS: RT = 2.21 min, [M+H] + =363.90. 1 H NMR (400MHz, DMSO-d6) δ12.65(s,1H),8.58(d,J=8.6Hz,1H),8.39(d,J=2.5Hz,1H),8.34(d,J=8.6H z,1H),8.21(dd,J=2.6,1.2Hz,1H),7.99(dd,J=7.9,1.8Hz,2H),7.59(t,J=7.8Hz,1H),7.52(s,1H).

[0288] Example 40 Synthesis of 4-(3-(2-(8-chloroquinolin-2-yl)-5-(trifluoromethoxy)-1H-indol-1-yl)propyl)morpholine

[0289] To a solution of 8-chloro-2-(5-(trifluoromethoxy)-1H-indol-2-yl)quinoline (50 mg, 0.14 mmol) in acetonitrile (5 mL) at room temperature were added 4-(3-chloropropyl)morpholine (27.49 mg) and cesium carbonate (136.84 mg, 0.42 mmol). The mixture was heated to 50°C and stirred for 2 hours. After the reaction, the mixture was diluted with 10 mL of water and extracted with dichloromethane (15 mL x 3). The combined organic phases were washed with saturated brine (15 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was subjected to preparative purification to yield 20.4 mg of 4-(3-(2-(8-chloroquinolin-2-yl)-5-(trifluoromethoxy)-1H-indol-1-yl)propyl)morpholine as a colorless oil (yield: 29.63%). LCMS: RT = 1.95 min, [M+H] + =489.91. 1 H NMR (400MHz, DMSO-d6) δ8.53(d,J=8.7Hz,1H),8.25(d,J=8.7Hz,1H),8.09–7.93(m,2H),7.77(d,J=9.0Hz,1H),7.67(t,J=1.6Hz,1 H),7.61(t,J=7.8Hz,1H),7.49(s,1H),7.31–7.22(m,1H),5.16(t,J=7.0Hz,2H),3.39(d,J=4.6Hz,3H),2.16(m,7H),1.91(m,2H).

[0290] Example 41 Synthesis of 8-chloro-2-(1-(2-(pyrrolidin-1-yl)ethyl)-5-(trifluoromethoxy)-1H-indol-2-yl)quinoline

[0291] To a solution of 8-chloro-2-(5-(trifluoromethoxy)-1H-indol-2-yl)quinoline (40 mg, 0.11 mmol) in acetonitrile (5 ml) was added 1-(2-chloroethyl)pyrrolidine (17.64 mg, 0.13 mmol) and cesium carbonate (107.52 mg, 0.33 mmol) at room temperature. After the addition, the mixture was heated to 50°C and stirred for 2 hours.

[0292] After the reaction was completed, the mixture was diluted with 10 ml of water and extracted with dichloromethane (15 ml x 3). The organic phases were combined, washed with saturated brine (15 ml x 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was subjected to preparative purification to afford 37.0 mg of a colorless oily substance, 8-chloro-2-(1-(2-(pyrrolidin-1-yl)ethyl)-5-(trifluoromethoxy)-1H-indol-2-yl)quinoline (yield: 72.96%). LCMS: RT = 1.93 min, [M+H] + =459.95. 1 H NMR (400MHz, DMSO-d6) δ8.54(d,J=8.7Hz,1H),8.21(d,J=8.7Hz,1H),8.01(ddd,J=7.6,6.5,1.3Hz,2H),7.72(d,J=9.0Hz,1H),7.67(t,J=1.7Hz,1 H),7.61(t,J=7.8Hz,1H),7.43(s,1H),7.30–7.22(m,1H),5.20(t,J=6.9 Hz,2H),2.74(t,J=6.8Hz,2H),2.41–2.22(m,4H),1.49(p,J=3.0Hz,4H).

[0293] Example 42 Synthesis of 8-chloro-2-(1-(2-(piperazin-1-yl)ethyl)-5-(trifluoromethoxy)-1H-indol-2-yl)quinoline

[0294] Step A: Synthesis of tert-butyl 4-(2-(2-(8-chloroquinolin-2-yl)-5-(trifluoromethoxy)-1H-indol-1-yl)ethyl)piperazine-1-carboxylate

[0295] To a solution of 8-chloro-2-(5-(trifluoromethoxy)-1H-indol-2-yl)quinoline (50 mg, 0.14 mmol) in acetonitrile (5 ml) was added tert-butyl 4-(2-bromoethyl)piperazine-1-carboxylate (49.26 mg, 0.17 mmol) and cesium carbonate (136.84 mg, 0.42 mmol) at room temperature. After the addition, the mixture was heated to 50°C and stirred for 2 hours.

[0296] After the reaction, the mixture was diluted with 10 ml of water and extracted with dichloromethane (15 ml × 3). The organic phases were combined, washed with saturated brine (15 ml × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1 / 5) to give 70 mg of tert-butyl 4-(2-(2-(8-chloroquinolin-2-yl)-5-(trifluoromethoxy)-1H-indol-1-yl)ethyl)piperazine-1-carboxylate as a white solid (yield: 88.31%).

[0297] Step B: Synthesis of 8-chloro-2-(1-(2-(piperazin-1-yl)ethyl)-5-(difluoromethoxy)-1H-indol-2-yl)quinoline

[0298] To a solution of tert-butyl 4-(2-(2-(8-chloroquinolin-2-yl)-5-(trifluoromethoxy)-1H-indol-1-yl)ethyl)piperazine-1-carboxylate (70 mg, 0.12 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (27.36 mg, 0.24 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was diluted with 10 mL of water and extracted with dichloromethane (15 mL x 3). The combined organic phases were washed with saturated brine (15 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was subjected to preparative purification to afford 56 mg of 8-chloro-2-(1-(2-(piperazin-1-yl)ethyl)-5-(trifluoromethoxy)-1H-indol-2-yl)quinoline as a colorless oil (yield: 96.86%). LCMS: RT = 1.93 min, [M+H] + =474.90. 1 H NMR (400MHz, DMSO-d6) δ8.55(d,J=8.7Hz,1H),8.26(d,J=8.7Hz,1H),8.09–7.96(m,2H),7.74(d,J=9.0Hz,1H),7.67(d,J=2.2Hz,1H) ,7.62(t,J=7.8Hz,1H),7.48(s,1H),7.27(dd,J=8.9,2.3Hz,1H),5.25(t,J=6.4Hz,2H),2.68(t,J=5.6Hz,6H),2.45(t,J=5.0Hz,4H).

[0299] Example 43 Synthesis of 8-chloro-2-(1-(2-(4-methylpiperazin-1-yl)ethyl)-5-(difluoromethoxy)-1H-indol-2-yl)quinoline

[0300] To a solution of 8-chloro-2-(5-(trifluoromethoxy)-1H-indol-2-yl)quinoline (40 mg, 0.11 mmol) in acetonitrile (5 ml) was added 1-(2-chloroethyl)-4-methylpiperazine (21.47 mg, 0.13 mmol) and cesium carbonate (107.52 mg, 0.33 mmol) at room temperature. After the addition, the mixture was heated to 50°C and stirred for 2 hours.

[0301] After the reaction was completed, the mixture was diluted with 10 ml of water and extracted with dichloromethane (15 ml x 3). The organic phases were combined, washed with saturated brine (15 ml x 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was subjected to preparative purification to afford 37 mg of a colorless oily substance, 8-chloro-2-(1-(2-(4-methylpiperazin-1-yl)ethyl)-5-(trifluoromethoxy)-1H-indol-2-yl)quinoline (yield: 68.62%). LCMS: RT = 2.05 min, [M+H] + =488.91. 1 H NMR (400MHz, DMSO-d6) δ8.56(d,J=8.7Hz,1H),8.25(d,J=8.7Hz,1H),8.02(td,J=7.7,1.3Hz,2H),7.74(d,J=9.0Hz,1H),7.68(d,J=2.1Hz,1 H),7.62(t,J=7.8Hz,1H),7.46(s,1H),7.27(dt,J=9.0,1.5Hz,1H),5.25(t,J=6.5Hz,2H),2.62(t,J=6.4Hz,2H),2.30(s,4H),2.05(m,7H).

[0302] Example 44 Synthesis of N-(8-chloroquinolin-2-yl)-5-(trifluoromethoxy)-1H-indole-2-carboxamide

[0303] 8-Chloroquinolin-2-amine (100 mg, 0.56 mmol), 5-(trifluoromethoxy)indole-2-carboxylic acid (150 mg, 0.62 mmol), HATU (320 mg, 0.84 mmol) and triethylamine (140 mg, 1.12 mmol) were added to N,N-dimethylformamide (6 ml) at room temperature, and stirring was continued at room temperature for 2 hours. The reaction was monitored by LC-MS until completion.

[0304] After the reaction, water (20 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 ml x 3 times). The organic phases were combined, washed with saturated brine (20 ml x 3 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by HPLC to obtain 150 mg of N-(8-chloroquinolin-2-yl)-5-(trifluoromethoxy)-1H-indole-2-carboxamide as a white solid (yield: 66.03%). LCMS: RT = 2.20 min, [M+H] + =405.97. 1H NMR (400MHz, DMSO-d6) δ12.19(s,1H),11.24(s,1H),8.51(d,J=9.0Hz,1H),8.45(d,J=9.0Hz,1H),7.98–7.91(m,2H) ,7.81(d,J=2.1Hz,1H),7.73(d,J=2.3Hz,1H),7.61(d,J=8.9Hz,1H),7.55–7.47(m,1H),7.26(dd,J=8.9,2.2Hz,1H).

[0305] Example 45 Synthesis of 1-(2-(8-chloroquinolin-2-yl)-5-(trifluoromethoxy)-1H-indol-3-yl)-N,N-dimethylmethanamine

[0306] To a solution of 8-chloro-2-(5-(trifluoromethoxy)-1H-indol-2-yl)quinoline (50 mg, 0.14 mmol) in N,N-dimethylformamide (1 mL) and water (1 mL) at room temperature were added dimethylamine (9.47 mg, 0.21 mmol) and paraformaldehyde (6.31 mg, 0.21 mmol). The mixture was stirred at room temperature for 2 hours. After the reaction, it was diluted with 10 mL of water and extracted with dichloromethane (15 mL x 3). The combined organic phases were washed with saturated brine (15 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by preparative purification to yield 19.1 mg of 1-(2-(8-chloroquinolin-2-yl)-5-(trifluoromethoxy)-1H-indol-3-yl)-N,N-dimethylmethanamine. LCMS: RT = 1.82 min, [M+H] + =419.92. 1 H NMR (400MHz, DMSO-d6) δ12.80(s,1H),9.31(s,1H),8.77(d,J=8.7Hz,1H),8.35(d,J=8.7Hz, 1H),8.13–8.05(m,3H),7.77–7.60(m,2H),7.32(d,J=8.9Hz,1H),5.21(s,2H),2.91(s,6H).

[0307] Example 46 Synthesis of 8-chloro-N-(1-(2-morpholinoethyl)-5-(trifluoromethoxy)-1H-benzo[d]imidazol-2-yl)quinolin-2-amine

[0308] Step A: Synthesis of 5-(trifluoromethoxy)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0309] Under ice bath, diphosgene (1.07 g, 5.41 mmol) was added to a solution of 4-(trifluoromethoxy)benzene-1,2-diamine (2 g, 10.41 mmol) and triethylamine (2.63 g, 26 mmol) in dichloromethane (15 ml). The mixture was reacted at room temperature for 3 hours, filtered, and dried to give 5-(trifluoromethoxy)-1,3-dihydro-2H-benzo[d]imidazol-2-one as a gray solid (yield 88.1%).

[0310] Step B: Synthesis of 2-chloro-6-(trifluoromethoxy)-1H-benzo[d]imidazole

[0311] 5-(Trifluoromethoxy)-1,3-dihydro-2H-benzo[d]imidazole-2-one (1.6 g, 7.34 mmol) was added to 15 mL of phosphorus oxychloride at room temperature and allowed to react at 50°C for 2 hours. The reaction mixture was poured into ice water, extracted with ethyl acetate, dried, and concentrated to yield 1.74 g of 2-chloro-6-(trifluoromethoxy)-1H-benzo[d]imidazole as a white solid (yield: 86.44%).

[0312] Step C: Synthesis of 2-(2-chloro-6-(trifluoromethoxy)-1H-benzo[d]imidazol-1-yl)ethyl)morpholine

[0313] 2-Chloro-6-(trifluoromethoxy)-1H-benzo[d]imidazole (1.74 g, 7.34 mmol), 2-chloroethylmorpholine (1.1 g, 7.34 mmol), and cesium carbonate (4.8 g, 14.7 mmol) were dissolved in 15 mL of acetonitrile at room temperature and reacted at 50°C for 2 h. The reaction mixture was poured into ice water, extracted with ethyl acetate, dried, and concentrated to afford 1.9 g of 4-(2-(2-chloro-6-(trifluoromethoxy)-1H-benzo[d]imidazol-1-yl)ethyl)morpholine as a pale yellow oil (yield: 73.86%).

[0314] Step C: Synthesis of 8-chloro-N-(1-(2-morpholinoethyl)-5-(trifluoromethoxy)-1H-benzo[d]imidazol-2-yl)quinolin-2-amine

[0315] At room temperature, 4-(2-(2-chloro-6-(trifluoromethoxy)-1H-benzo[d]imidazol-1-yl)ethyl)morpholine (0.22 g, 0.59 mmol), 8-chloroquinolin-2-amine (0.1 g, 0.56 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.01 g, 0.011 mmol), Xphos (0.021 g, 0.034 mmol) and cesium carbonate (0.55 g, 1.68 mmol) were added to 15 ml of dioxane and reacted at 100° C. overnight.

[0316] Water (20 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 ml x 3 times). The organic phases were combined, washed with saturated brine (20 ml x 3 times), and then dried over anhydrous sodium sulfate. The resulting product was then purified by high-performance liquid chromatography to obtain 60 mg of 8-chloro-N-(1-(2-morpholinoethyl)-5-(trifluoromethoxy)-1H-benzo[d]imidazol-2-yl)quinolin-2-amine. LCMS: RT = 1.91 min, [M+H] + =491.98.

[0317] Example 47 Synthesis of 2-(5-(trifluoromethoxy)-1H-indol-2-yl)quinoline-8-carbonitrile

[0318] Step A: Synthesis of N-(2-iodophenyl)-3,3-dimethoxypropionamide

[0319] At room temperature, o-iodoaniline (5 g, 22.83 mmol), 3,3-dimethoxypropionic acid (3.4 g, 25.11 mmol), HATU (13 g, 34.24 mmol) and N,N-diisopropylethylamine (6 g, 45.6 mmol) were added to N,N-dimethylformamide (15 ml) and reacted at room temperature overnight.

[0320] Water (20 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 ml × 3 times). The organic phases were combined, washed with saturated brine (20 ml × 3 times), and then dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure to obtain 5.2 g of brown oily N-(2-iodophenyl)-3,3-dimethoxypropionamide (yield: 67.97%).

[0321] Step B: Synthesis of 8-iodoquinolin-2-ol

[0322] Under ice-cooling, concentrated sulfuric acid (8 ml) was added dropwise to a solution of N-(2-iodophenyl)-3,3-dimethoxypropionamide (5.2 g, 15.5 mmol) in dichloromethane (25 ml), and the mixture was allowed to react at room temperature overnight.

[0323] The reaction mixture was poured into ice water (20 ml) and extracted with dichloromethane (20 ml x 3 times). The organic phases were combined, washed with saturated brine (20 ml x 3 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 0-70%) to obtain 2.2 g of 8-iodoquinolin-2-ol as a yellow solid (yield: 52.38%).

[0324] Step C: Synthesis of 2-chloro-8-iodoquinoline

[0325] 8-Iodoquinolin-2-ol (2.2 g, 8.12 mmol) was added to phosphorus oxychloride (12 ml) at room temperature and then heated to 90 degrees Celsius for 1.5 hours. TLC was used to monitor the reaction until completion. The reaction solution was poured into ice water (40 ml) and extracted with ethyl acetate (20 ml x 3 times). The organic phases were combined, washed with saturated brine (20 ml x 3 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 0-50%) to obtain 2.2 g of 2-chloro-8-iodoquinoline as a white solid (yield: 93.63%).

[0326] Step D: Synthesis of 2-chloroquinoline-8-carbonitrile

[0327] 2-Chloro-8-iodoquinoline (2.2 g, 7.6 mmol) and cuprous cyanide (1.7 g, 19 mmol) were added to DMF (12 ml) at room temperature and reacted at 120 degrees for 5 hours. TLC was monitored until the reaction was complete. The reaction solution was poured into ice water (40 ml) and extracted with ethyl acetate (20 ml × 3 times). The organic phases were combined, washed with saturated brine (20 ml × 3 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 0-80%) to obtain 1 g of 2-chloroquinoline-8-carbonitrile as a white solid (yield: 69.99%).

[0328] Step E: Synthesis of 2-(5-(trifluoromethoxy)-1H-indol-2-yl)quinoline-8-carbonitrile

[0329] Under N2 protection, 2-chloroquinoline-8-carbonitrile (0.15 g, 0.8 mmol), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethoxy)-1H-indole (0.29 g, 0.88 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.06 g, 0.08 mmol) and sodium carbonate (0.25 g, 2.4 mmol) were added to 15 mL of a mixed solvent of 1,4-dioxane / water (5 / 1), the mixture was heated to 100°C and stirred for 12 hours. The reaction was monitored by LC-MS until completion.

[0330] Water (20 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 ml x 3 times). The organic phases were combined, washed with saturated brine (20 ml x 3 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 0-40%). The resulting product was then slurried in 8 ml of a mixed solvent (dichloromethane / methanol = 1 / 10) for 12 hours to obtain 100 mg of 2-(5-(trifluoromethoxy)-1H-indol-2-yl)quinoline-8-carbonitrile. LCMS: RT = 2.20 min, [M+H] + =354.02.

[0331] Example 48 Synthesis of 8-chloro-6-fluoro-2-(5-(trifluoromethoxy)-1H-indol-2-yl)quinoline

[0332] Step A: Synthesis of N-(2-chloro-4-fluorophenyl)cinnamamide

[0333] Cinnamoyl chloride (1.14 g, 6.87 mmol) was added dropwise to a mixture of 2-chloro-4-fluoroaniline (1 g, 6.87 mmol) and potassium carbonate (2.82 g, 20.61 mmol) in acetonitrile and water (3 / 1, 20 ml) under an ice bath. The mixture was allowed to react at room temperature for 3 hours. TLC was used to monitor the reaction until completion. The reaction solution was poured into ice water (40 ml) and extracted with ethyl acetate (20 ml x 3). The organic phases were combined, washed with saturated brine (20 ml x 3), and concentrated to yield 1.6 g of N-(2-chloro-4-fluorophenyl)cinnamamide as a white solid (yield: 84.5%).

[0334] Step B: Synthesis of 8-chloro-6-fluoroquinoline-2-ol

[0335] Aluminum trichloride (7 g, 29 mmol) and N-(2-chloro-4-fluorophenyl)cinnamamide (1.6 g, 5.8 mmol) were added to chlorobenzene (20 mL) at room temperature and reacted at 110°C for 5 hours. TLC was used to monitor the reaction until completion. The reaction solution was poured into ice water (40 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL x 3) and concentrated to yield 0.6 g of 8-chloro-6-fluoroquinolin-2-ol as a gray solid (yield: 52.33%).

[0336] Step C: Synthesis of 2,8-dichloro-6-fluoroquinoline

[0337] 8-Chloro-6-fluoroquinolin-2-ol (0.6 g, 3.04 mmol) was added to phosphorus oxychloride (12 mL) at room temperature and then heated to 70°C for 1.5 hours. TLC was used to monitor the reaction until completion. The reaction mixture was poured into ice water (40 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL x 3) and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 0-30%) to obtain 0.5 g of 2,8-dichloro-6-fluoroquinoline as a red solid (yield: 76.22%).

[0338] Step D: Synthesis of 8-chloro-6-fluoro-2-(5-(trifluoromethoxy)-1H-indol-2-yl)quinoline

[0339] Under N2 protection, 2,8-dichloro-6-fluoroquinoline (0.15 g, 0.69 mmol), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethoxy)-1H-indole (0.25 g, 0.76 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.05 g, 0.07 mmol) and sodium carbonate (0.22 g, 2.08 mmol) were added to 15 mL of a mixed solvent of 1,4-dioxane / water (5 / 1). The mixture was heated to 100°C and stirred for 12 hours. The reaction was monitored by LC-MS until completion.

[0340] Water (20 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 ml x 3 times). The organic phases were combined, washed with saturated brine (20 ml x 3 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 0-40%). The resulting product was then slurried in 8 ml of a mixed solvent (dichloromethane / methanol = 1 / 10) for 12 hours to obtain 120 mg of 8-chloro-6-fluoro-2-(5-(trifluoromethoxy)-1H-indol-2-yl)quinoline. LCMS: RT = 2.32 min, [M+H] + =380.93.

[0341] Example 49 Synthesis of 8-chloro-2-(5-(trifluoromethoxy)benzofuran-2-yl)quinoline

[0342] Step A: Synthesis of 2-((8-chloroquinolin-2-yl)methoxy)-5-(trifluoromethyl)benzaldehyde

[0343] To a mixture of 8-chloro-2-(chloromethyl)quinoline (100 mg, 0.47 mmol), 2-hydroxy-5-(trifluoromethoxy)benzaldehyde (106.56 mg, 0.52 mmol) and potassium carbonate (194.88 mg, 1.41 mmol) was added N,N-dimethylformamide (5 ml) at room temperature. After the addition, the mixture was stirred at 80°C for 2 hours.

[0344] After the reaction, the mixture was diluted with 10 ml of water and extracted with dichloromethane (15 ml × 3 times). The organic phases were combined, washed with saturated brine (15 ml × 3 times), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1 / 5) to give 150 mg of 2-((8-chloroquinolin-2-yl)methoxy)-5-(trifluoromethyl)benzaldehyde as a white solid (yield: 83.34%).

[0345] Step B: Synthesis of 8-chloro-2-(5-(trifluoromethoxy)benzofuran-2-yl)quinoline

[0346] To a solution of 2-((8-chloroquinolin-2-yl)methoxy)-5-(trifluoromethyl)benzaldehyde (150 mg, 0.39 mmol) in dioxane (5 ml) was added trifluoromethanesulfonic acid (58.53 mg, 0.39 mmol) at room temperature. After the addition, the mixture was stirred at 120°C for 2 hours.

[0347] After the reaction, the mixture was diluted with 10 mL of water and extracted with dichloromethane (15 mL x 3 times). The organic phases were combined, washed with saturated brine (15 mL x 3 times), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was subjected to preparative purification to yield 15.7 mg of 8-chloro-2-(5-(trifluoromethoxy)benzofuran-2-yl)quinoline. LCMS: RT = 2.37 min, [M+H] + =363.93. 1 H NMR (400MHz, DMSO-d6) δ8.63(d,J=8.6Hz,1H),8.26(d,J=8.6Hz,1H),8.03(t,J=6.8Hz,2H) ,7.94(s,1H),7.90(d,J=9.0Hz,1H),7.86(s,1H),7.63(t,J=7.8Hz,1H),7.50–7.38(m,1H).

[0348] Example 50 Synthesis of 2-(8-chloroquinolin-2-yl)-1H-pyrrolo[3,2-b]pyridine-5-carbonitrile

[0349] Step A: Synthesis of 5-amino-6-iodopyridinecarbonitrile

[0350] 3-Amino-6-cyanopyridine (6 g, 50.39 mmol), iodine (16.62 g, 65.48 mmol), and silver trifluoroacetate (14.46 g, 65.48 mmol) were added to ethanol (20 ml) at room temperature and allowed to react overnight at room temperature. The reaction was monitored by TLC until completion. The insoluble material was filtered off, the mixture was concentrated, and purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 0-30%) to provide 10 g of 5-amino-6-iodopicolinonitrile as a brown solid (yield: 81.03%).

[0351] Step B: Synthesis of 5-amino-6-((8-chloroquinolin-2-yl)ethynyl)picolinonitrile

[0352] 5-Amino-6-iodopicolinonitrile (0.72 g, 2.93 mmol), 8-chloro-2-ethynylquinoline (0.5 g, 2.66 mmol), bistriphenylphosphine palladium dichloride (0.19 g, 0.27 mmol), and cuprous iodide (0.05 g, 0.27 mmol) were added to 15 ml of triethylamine at room temperature and reacted at 90°C for 2 hours. The reaction was monitored by TLC until completion. The insoluble material was filtered off, the mixture was concentrated, and purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 0-30%) to obtain 0.6 g of 5-amino-6-((8-chloroquinolin-2-yl)ethynyl)picolinonitrile as a brown solid (yield: 73.89%).

[0353] Step C: Synthesis of 2-(8-chloroquinolin-2-yl)-1H-pyrrolo[3,2-b]pyridine-5-carbonitrile

[0354] TBAF (0.51 g, 1.96 mmol) was added to a solution of 5-amino-6-((8-chloroquinolin-2-yl)ethynyl)picolinonitrile (0.3 g, 0.98 mmol) in tetrahydrofuran (15 ml) at room temperature and allowed to react overnight at 90°C. The reaction was monitored by TLC until complete. After concentration and HPLC, 90 mg of 2-(8-chloroquinolin-2-yl)-1H-pyrrolo[3,2-b]pyridine-5-carbonitrile was obtained. LCMS: RT = 2.15 min, [M+H] + =304.97. 1 H NMR (400MHz, DMSO-d6) δ12.29(s,1H),8.64(d,J=8.6Hz,1H),8.45(d,J=8.6Hz,1H),8. 16(d,J=8.4Hz,1H),8.05(dd,J=8.0,3.5Hz,2H),7.83–7.74(m,2H),7.69–7.58(m,1H).

[0355] Example 51 Synthesis of 8-chloro-2-(3-fluoro-5-(trifluoromethoxy)-1H-indol-2-yl)quinoline

[0356] To a solution of 8-chloro-2-(5-(trifluoromethoxy)-1H-indol-2-yl)quinoline (100 mg, 0.28 mmol) in acetonitrile (3 ml) under nitrogen was added 1-chloromethyl-4-fluoro-1,4-diazidebicyclo[2.2.2]octane bistetrafluoroborate (107 mg, 0.30 mmol) at room temperature, and the mixture was stirred at room temperature for 2 hours.

[0357] After the reaction, the solvent was removed by vortexing, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 10) to obtain 24 mg of 8-chloro-2-(3-fluoro-5-(trifluoromethoxy)-1H-indol-2-yl)quinoline. RT = 2.46 min [M+H] + =380.96; 1 H NMR (400MHz, DMSO-d6) δ8.61(d,J=8.7Hz,1H),8.17(d,J=8.6Hz,1H),8.03(d,J=7.8Hz,2H),7.74 (dd,J=9.0,2.2Hz,1H),7.68(d,J=2.3Hz,1H),7.62(t,J=7.8Hz,1H),7.29(dd,J=8.9,2.1Hz,1H).

[0358] Example 52 Synthesis of 8-chloro-3-methoxy-2-(5-(trifluoromethoxy)-1H-indol-2-yl)quinoline

[0359] Step A: Synthesis of (2,8-dichloroquinolin-3-yl)boronic acid

[0360] 2,8-Dichloroquinoline (1.98 g, 10 mmol) was dissolved in tetrahydrofuran (20 mL) at -78°C, followed by the slow dropwise addition of lithium diisopropylamide (10 mL, 2 mol / L). The mixture was incubated for 1 hour. Trimethyl borate (2.08 g, 10 mmol) was then slowly added dropwise, and the mixture was stirred for 3 hours. The reaction was monitored by TLC until complete.

[0361] Saturated ammonium chloride solution (40 ml) was added to the reaction solution, and the temperature was raised to room temperature. The mixture was extracted with ethyl acetate (50 ml × 3 times). The organic phases were combined, washed with saturated brine (20 ml × 3 times), and then dried over anhydrous sodium sulfate. Finally, the mixture was concentrated under reduced pressure and used directly in the next step.

[0362] Step B: Synthesis of 2,8-dichloroquinolin-3-ol

[0363] (2,8-Dichloroquinolin-3-yl)boronic acid (2.41 g, 10 mmol) was dissolved in ethyl acetate (10 mL) and water (10 mL) at room temperature. Hydrogen peroxide (28%, 10 mL) was slowly added dropwise, followed by ammonium chloride (1.07 g, 20 mmol). The mixture was incubated for 10 hours. LCMS monitoring was used to monitor the reaction until completion.

[0364] Saturated sodium thiosulfate solution (20 ml) was added to the reaction mixture and stirred for 30 minutes. The mixture was extracted with ethyl acetate (50 ml x 3 times). The organic phases were combined, washed with saturated brine (20 ml x 3 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 0-40%) to obtain 1.2 g of 2,8-dichloroquinolin-3-ol as a yellow oil (two-step yield: 56.34%). LCMS: RT = 1.94 min, [M+H] + =213.89.

[0365] Step C: Synthesis of 2,8-dichloro-3-methoxyquinoline

[0366] 2,8-Dichloroquinolin-3-ol (500 mg, 2.35 mmol) was dissolved in acetonitrile (8 mL) at room temperature, followed by the addition of iodomethane (501 mg, 3.53 mmol) and potassium carbonate (649 mg, 4.70 mmol). The mixture was refluxed for 2 hours and monitored by LCMS until the reaction was complete.

[0367] Saturated sodium chloride solution (20 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 ml x 3 times). The organic phases were combined, washed with saturated brine (20 ml x 3 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 0-20%) to obtain 510 mg of 2,8-dichloro-3-methoxyquinoline as a yellow solid (yield: 95.2%). LCMS: RT = 2.11 min, [M+H] + =227.89.

[0368] Step D: Synthesis of 8-chloro-3-methoxy-2-(5-(trifluoromethoxy)-1H-indol-2-yl)quinoline

[0369] At room temperature, 2,8-dichloro-3-methoxyquinoline (50 mg, 0.22 mmol) and (5-(trifluoromethoxy)-1H-indol-2-yl)boronic acid (81 mg, 0.33 mmol) were dissolved in 1,4-dioxane (4 mL) and water (1 mL). Tris(dibenzylideneindeneacetone)dipalladium(0) (9.15 mg, 0.01 mmol), tricyclohexylphosphine (5.6 mg, 0.02 mmol), and potassium phosphate (93 mg, 0.44 mmol) were then added. The temperature was raised to 100°C under nitrogen protection and the reaction was allowed to react for 8 hours. LCMS monitoring was performed until the reaction was complete.

[0370] Saturated sodium chloride solution (20 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 ml x 3 times). The combined organic phases were washed with saturated brine (20 ml x 3 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 0-30%). The resulting product was then purified by high-performance liquid chromatography to yield 56 mg of 8-chloro-3-methoxy-2-(5-(trifluoromethoxy)-1H-indol-2-yl)quinoline. LCMS: RT = 2.41 min, [M+H] + =392.80. 1 H NMR (400MHz, DMSO-d6) δ11.54(s,1H),8.07(s,1H),7.93(d,J=9.5Hz,1H),7.82(d,J=7.5Hz,1H),7.78( d,J=8.9Hz,1H),7.69(s,1H),7.64(s,1H),7.55(t,J=7.8Hz,1H),7.20(d,J=10.5Hz,1H),4.17(s,3H).

[0371] Example 53 Synthesis of 8-chloro-2-(2-(trifluoromethyl)-5H-pyrrolo[2,3-b]pyrazin-6-yl)quinoline

[0372] Step A: Synthesis of 2-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine

[0373] At 0°C, 2-bromo-5H-pyrrolo[2,3-b]pyrazine (500 mg, 2.54 mmol) was dissolved in N,N-dimethylformamide (8 mL). Sodium hydride (60%, 152 mg, 3.81 mmol) was added, and the mixture was warmed to room temperature and stirred for 1 hour. The temperature was then lowered to 0°C, and 2-(trimethylsilyl)ethoxymethyl chloride (507 mg, 3.04 mmol) was slowly added dropwise. The mixture was allowed to react at room temperature for 4 hours. LCMS monitoring was performed until the reaction was complete.

[0374] Saturated ammonium chloride solution (20 ml) was added to the reaction solution, and the mixture was warmed to room temperature and extracted with ethyl acetate (50 ml x 3 times). The organic phases were combined, washed with saturated brine (30 ml x 3 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The product was used directly in the next step. LCMS: RT = 2.25 min, [M+H] + =327.88 / 329.84.

[0375] Step B: Combining 2-(trifluoromethyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine

[0376] 2-Bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (830 mg, 2.54 mmol) was dissolved in N,N-dimethylformamide (10 ml) at room temperature. Methyl difluoro(fluorosulfonyl)acetate (1.46 g, 7.62 mmol), cuprous iodide (726 mg, 3.81 mmol), and tetrabutylammonium iodide (469 mg, 1.27 mmol) were added, and the mixture was heated to 100°C and stirred for 5 hours. LCMS monitoring was performed until the reaction was complete.

[0377] Water (20 ml) was added to the reaction solution, cooled to room temperature, and extracted with ethyl acetate (30 ml × 3 times). The organic phases were combined, washed with saturated brine (30 ml × 3 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 0-60%) to obtain 0.4 g of 2-(trifluoromethyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine as a brown oil (yield for two steps: 49.68%). LCMS: RT = 2.21 min, [M+H] + =317.98.

[0378] Step C: Synthesis of (2-(trifluoromethyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-6-yl)boronic acid

[0379] At -78°C, 2-(trifluoromethyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (0.4 g, 1.26 mmol) was dissolved in tetrahydrofuran (8 mL). Lithium diisopropylamide (1.26 mL, 2 mol / L) was slowly added dropwise. The mixture was incubated for 0.5 hours. Trimethyl borate (262 mg, 2.52 mmol) was then slowly added dropwise. The mixture was stirred at this temperature for 2 hours and monitored by TLC until the reaction was complete.

[0380] Saturated aqueous ammonium chloride (10 mL) was added to the reaction solution, cooled to room temperature, and extracted with ethyl acetate (30 mL x 3 times). The combined organic phases were washed with saturated brine (30 mL x 3 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 0-40%) to obtain 240 mg of (2-(trifluoromethyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-6-yl)boronic acid as a brown oil (yield: 52.76%). LCMS: RT = 2.09 min, [M+H] + =361.94.

[0381] Step D: Combine 8-chloro-2-(2-(trifluoromethyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-6-yl)quinoline

[0382] At room temperature, 2,8-dichloroquinoline (74 mg, 0.37 mmol) and (2-(trifluoromethyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-6-yl)boronic acid (90 mg, 0.25 mmol) were dissolved in 1,4-dioxane (4 mL) and water (1 mL). Tris(dibenzylideneinacetone)dipalladium(0) (9.15 mg, 0.01 mmol), tricyclohexylphosphine (5.6 mg, 0.02 mmol), and potassium phosphate (93 mg, 0.44 mmol) were then added. The temperature was raised to 100°C under nitrogen protection and the reaction was allowed to react for 8 hours. LCMS monitoring was performed until the reaction was complete.

[0383] Saturated aqueous ammonium chloride (10 mL) was added to the reaction solution, cooled to room temperature, and extracted with ethyl acetate (30 mL x 3 times). The combined organic phases were washed with saturated brine (30 mL x 3 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 0-30%) to obtain 85 mg of 8-chloro-2-(2-(trifluoromethyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-6-yl)quinoline as a brown oil (yield: 71.12%). LCMS: RT = 2.57 min, [M+H] + =478.82.

[0384] Step E: Synthesis of 8-chloro-2-(2-(trifluoromethyl)-5H-pyrrolo[2,3-b]pyrazin-6-yl)quinoline

[0385] 8-Chloro-2-(2-(trifluoromethyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-6-yl)quinoline (85 mg, 0.18 mmol) was dissolved in methanol (4 mL) at room temperature. Aqueous hydrochloric acid (6N, 4 mL) was then added and the reaction was heated to 90°C for 2 hours. LCMS monitoring indicated that the reaction was complete. The mixture was cooled to room temperature, concentrated, and quenched with saturated aqueous sodium bicarbonate (10 mL). The mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. High-performance liquid chromatography (HPLC) yielded 8.5 mg of 8-chloro-2-(2-(trifluoromethyl)-5H-pyrrolo[2,3-b]pyrazin-6-yl)quinoline as a pale yellow solid (yield: 13.53%). LCMS: RT = 2.07 min, [M+H] + =349.01.

[0386] Example 54 Synthesis of 2-(8-chloro-2-(5-(trifluoromethoxy)-1H-indol-2-yl)quinolin-7-yl)propan-2-ol

[0387] Step A: Synthesis of N-(3-bromo-2-chlorophenyl)-3,3-diethoxypropionamide

[0388] At 0°C, 3-bromo-2-chloroaniline (2.06 g, 10 mmol) and 3,3-diethoxypropionic acid (2.423 g, 15 mmol) were dissolved in dichloromethane (25 mL). N,N-diisopropylethylamine (3.2 g, 25 mmol) was added, followed by the slow dropwise addition of 1-propylphosphonic anhydride (50%, 13 g, 20 mmol). The mixture was allowed to warm to room temperature and stirred for 3 hours. LCMS monitoring was performed until the reaction was complete.

[0389] Saturated sodium chloride solution (20 ml) was added to the reaction solution, and the mixture was extracted with dichloromethane (30 ml × 3 times). The organic phases were combined, washed with saturated brine (30 ml × 3 times), and then dried over anhydrous sodium sulfate. Finally, the mixture was concentrated under reduced pressure and used directly in the next step. LCMS: RT = 2.09 min, [M+H] + =276.07 / 278.12.

[0390] Step B: Synthesis of 7-bromo-8-chloroquinolin-2(1H)-one

[0391] At 0°C, N-(3-bromo-2-chlorophenyl)-3,3-diethoxypropionamide (2.76 g, 10 mmol) was dissolved in dichloromethane (30 mL), and concentrated sulfuric acid (3 mL) was slowly added. The mixture was then warmed to room temperature and stirred for 5 hours. LCMS monitoring indicated that the reaction was complete.

[0392] The reaction mixture was poured into ice water (30 ml) to quench the reaction mixture, warmed to room temperature, extracted with dichloromethane (30 ml x 3 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 0-60%) to obtain 1.8 g of 7-bromo-8-chloroquinolin-2(1H)-one as a brown solid (two-step yield: 69.77%). LCMS: RT = 1.79 min, [M+H] + =257.78 / 259.78.

[0393] Step C: Synthesis of methyl 8-chloro-2-oxo-1,2-dihydroquinoline-7-carboxylate

[0394] Dissolve 7-bromo-8-chloroquinolin-2(1H)-one (1.8 g, 6.98 mmol) in methanol (20 ml). Add phenyl 2,4,6-trichloroformate (4.72 g, 20.94 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene)palladium dichloride (0.53 g, 0.7 mmol), and triethylamine (2.3 g, 23 mmol). Seal the tube and heat to 60°C for 5 hours. Monitor the reaction until complete.

[0395] The mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 0-40%) to obtain 820 mg of methyl 8-chloro-2-oxo-1,2-dihydroquinoline-7-carboxylate as a yellow solid (yield: 49.57%). LCMS: RT = 1.68 min, [M+H] + =237.91.

[0396] Step D: Synthesis of methyl 2,8-dichloroquinoline-7-carboxylate

[0397] Methyl 8-chloro-2-oxo-1,2-dihydroquinoline-7-carboxylate (820 mg, 3.45 mmol) was dissolved in phosphorus oxychloride (10 mL) and the temperature was raised to 95°C for 1.5 hours. The reaction was monitored by TLC until completion.

[0398] The mixture was cooled to room temperature and concentrated under reduced pressure. The reaction mixture was poured into ice water (50 mL), adjusted to neutrality with saturated sodium bicarbonate solution, and extracted with ethyl acetate (30 mL x 3 times). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was used directly in the next step. LCMS: RT = 1.98 min, [M+H] + =256.04.

[0399] Step E: Synthesis of 2-(2,8-dichloroquinolin-7-yl)propan-2-ol

[0400] At 0°C, methyl 2,8-dichloroquinoline-7-carboxylate (883 mg, 3.45 mmol) was dissolved in tetrahydrofuran (10 mL). A solution of methylmagnesium bromide in tetrahydrofuran (3.45 mL, 10.35 mmol) was slowly added dropwise. The mixture was allowed to warm to room temperature and reacted for 4 hours. The reaction was monitored by TLC until completion.

[0401] At 0°C, saturated ammonium chloride solution (10 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3 times). The combined organic phases were washed with saturated brine (30 mL x 3 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 0-20%) to obtain 550 mg of 2-(2,8-dichloroquinolin-7-yl)propan-2-ol as a yellow oil (two-step yield: 62.32%). LCMS: RT = 1.94 min, [M+H] + =255.88. 1 H NMR (400MHz, Chloroform-d) δ8.02(d,J=8.5Hz,1H),7.94(d,J=9.0Hz,1H),7.66(d,J=8.7Hz,1H),7.36(d,J=8.5Hz,1H),2.74(s,1H),1.79(s,6H).

[0402] Step F: Synthesis of 2-(8-chloro-2-(5-(trifluoromethoxy)-1H-indol-2-yl)quinolin-7-yl)propan-2-ol

[0403] At room temperature, 2-(2,8-dichloroquinolin-7-yl)propan-2-ol (56 mg, 0.22 mmol) and (5-(trifluoromethoxy)-1H-indol-2-yl)boronic acid (81 mg, 0.33 mmol) were dissolved in 1,4-dioxane (4 mL) and water (1 mL). Tris(dibenzylideneindeneacetone)dipalladium(0) (9.15 mg, 0.01 mmol), tricyclohexylphosphine (5.6 mg, 0.02 mmol), and potassium phosphate (93 mg, 0.44 mmol) were then added. The temperature was raised to 100°C under nitrogen protection and the reaction was allowed to react for 8 hours. LCMS monitoring was performed until the reaction was complete.

[0404] Saturated sodium chloride solution (20 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 ml x 3 times). The combined organic phases were washed with saturated brine (20 ml x 3 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 0-30%). The resulting product was then purified by high-performance liquid chromatography to obtain 16 mg of 2-(8-chloro-2-(5-(trifluoromethoxy)-1H-indol-2-yl)quinolin-7-yl)propan-2-ol as a yellow solid (yield: 17.23%). LCMS: RT = 2.21 min, [M+H] + =420.81.

[0405] Example 55 Synthesis of 2-(1-((1H-imidazol-2-yl)methyl)-5-(trifluoromethoxy)-1H-indol-2-yl)-8-chloroquinoline

[0406] At room temperature, 8-chloro-2-(5-(trifluoromethoxy)-1H-indol-2-yl)quinoline (0.12 g, 0.33 mmol), 4-(bromomethyl)-1H-pyrazole hydrobromide (0.1 g, 0.4 mmol) and cesium carbonate (0.32 g, 0.99 mmol) were added to 15 ml of acetonitrile and reacted at 90 °C overnight.

[0407] Water (20 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 ml x 3 times). The organic phases were combined, washed with saturated brine (20 ml x 3 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting product was purified by high performance liquid chromatography to give 60 mg of 2-(1-((1H-imidazol-2-yl)methyl)-5-(trifluoromethoxy)-1H-indol-2-yl)-8-chloroquinoline as a white solid (yield: 40.96%). LCMS: RT = 1.77 min, [M+H] + =442.95. 1 H NMR (400MHz, DMSO-d6) δ11.69(s,1H),8.57(d,J=8.8Hz,1H),8.32(d,J=8.7Hz,1H),8.02(dd,J=8.2,1.3Hz,1H),8.00–7. 96(m,1H),7.75–7.67(m,2H),7.61(t,J=7.9Hz,1H),7.57(s,1H),7.24(dd,J=8.9,2.3Hz,1H),6.81(s,2H),6.56(s,2H).

[0408] Example 56 Synthesis of the compound (2-(8-chloroquinolin-2-yl)-5-(trifluoromethoxy)-1H-indol-1-yl) L-valine methyl ester

[0409] Step A: Synthesis of chloromethyl ((9H-fluoren-9-yl) methoxy) carbonyl)-L-valine

[0410] Fmoc-L-valine (1.5 g, 4.42 mmol) was added to dichloromethane (15 ml), and water (15 ml), sodium bicarbonate (1.48 g, 17.68 mmol), and tetrabutylammonium hydrogen sulfate (150 mg, 0.44 mmol) were added with stirring. The mixture was cooled in an ice bath, and chloromethyl chlorosulfonate (0.88 g, 5.3 mmol) was added. After the addition was complete, the mixture was reacted at room temperature.

[0411] After the reaction, the organic phase was separated, dried over sodium sulfate, filtered and concentrated to obtain 1.7 g of white solid chloromethyl((9H-fluoren-9-yl)methoxy)carbonyl)-L-valine (yield: 99.1%).

[0412] Step B: Synthesis of (2-(8-chloroquinolin-2-yl)-5-(trifluoromethoxy)-1H-indol-1-yl)methyl(((9H-fluoren-9-yl)methoxycarbonyl)-L-valine

[0413] Sodium hydride (72 mg, 1.81 mmol) was added to DMF (7 ml) at room temperature, and 8-chloro-2-(5-(trifluoromethoxy)-1H-indol-2-yl)quinoline (600 mg, 1.65 mmol) was added with stirring, and the mixture was stirred at room temperature for 15 min. 8-chloro-2-(5-(trifluoromethoxy)-1H-indol-2-yl)quinoline (640 mg, 1.65 mmol) was then added, and the mixture was allowed to stand at room temperature for 16 hours.

[0414] After the reaction was completed, saturated ammonium chloride solution (15 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL). The organic phase was concentrated to dryness to obtain a crude product, which was used directly in the next reaction.

[0415] Step C: Synthesis of (2-(8-chloroquinolin-2-yl)-5-(trifluoromethoxy)-1H-indol-1-yl) L-valine methyl ester

[0416] The crude product of the previous reaction (1.2 g, 1.65 mmol) was added to THF (4 ml) at room temperature, and diethylamine (2.8 g, 38.83 mmol) was added with stirring, and the mixture was stirred at room temperature for 1 hour.

[0417] After the reaction, the crude product was concentrated to dryness and purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1 / 20) to obtain 106 mg of (2-(8-chloroquinolin-2-yl)-5-(trifluoromethoxy)-1H-indol-1-yl) L-valine methyl ester as a yellow solid (yield: 13.0%). LCMS: RT = 1.82 min, [M+H] +=491.97. 1 H NMR(400MHz,DMSO-d6)δ8.58(d,J=8.7Hz,1H),8.28(d,J=8.7Hz,1H),8.08–7 .99(m,2H),7.85(d,J=9.0Hz,1H),7.73(d,J=2.3Hz,1H),7.67–7.58(m,2H), 7.43(d,J=10.6Hz,1H),7.36(dd,J=8.8,2.3Hz,1H),7.18(d,J=10.6Hz,1H), 2.97(d,J=5.0Hz,1H), 2.83(d,J=63.6Hz,1H), 0.50(dd,J=44.1,6.8Hz,6H).

[0418] Example 57 Synthesis of 8-chloro-2-(5-(trifluoromethoxy)-1H-indol-2-yl)quinolin-3-ol

[0419] At room temperature, 2,8-dichloroquinolin-3-ol (50 mg, 0.24 mmol) and (5-(trifluoromethoxy)-1H-indol-2-yl)boronic acid (81 mg, 0.33 mmol) were dissolved in 1,4-dioxane (4 mL) and water (1 mL). Tris(dibenzylideneindeneacetone)dipalladium(0) (9.15 mg, 0.01 mmol), tricyclohexylphosphine (5.6 mg, 0.02 mmol), and potassium phosphate (93 mg, 0.44 mmol) were then added. The temperature was raised to 100°C under nitrogen protection and the reaction was allowed to react for 8 hours. LCMS monitoring was performed until the reaction was complete.

[0420] Saturated sodium chloride solution (20 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 ml x 3 times). The organic phases were combined, washed with saturated brine (20 ml x 3 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 0-50%). The resulting product was then purified by high-performance liquid chromatography to obtain 26 mg of 8-chloro-2-(5-(trifluoromethoxy)-1H-indol-2-yl)quinolin-3-ol as a yellow solid (yield: 24.00%). LCMS: RT = 2.25 min, [M+H] + =378.83. 1 H NMR (400MHz, DMSO-d6) δ11.48(d,J=2.2Hz,1H),11.37(s,1H),7.83(d,J=8.2Hz,1H),7.8 0–7.72(m,3H),7.70(d,J=2.3Hz,2H),7.48(d,J=7.4Hz,1H),7.18(dd,J=8.8,2.3Hz,1H).

[0421] Example 58 Synthesis of 8-chloro-3-((tetrahydro-2H-pyran-4-yl)oxy)-2-(5-(trifluoromethoxy)-1H-indol-2-yl)quinoline

[0422] Step A: Synthesis of 2,8-dichloro-3-((tetrahydro-2H-pyran-4-yl)oxy)quinoline

[0423] 2,8-Dichloroquinolin-3-ol (0.15 g, 0.7 mmol), 4-bromopyran (0.14 g, 0.84 mmol), and cesium carbonate (0.1 g, 1.42 mmol) were added to 15 mL of acetonitrile at room temperature and reacted at 90°C overnight. The crude product was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 0-50%) to obtain 0.11 g of 2,8-dichloro-3-((tetrahydro-2H-pyran-4-yl)oxy)quinoline as a brown oil (yield: 52.65%).

[0424] Step B: Synthesis of 8-chloro-3-((tetrahydro-2H-pyran-4-yl)oxy)-2-(5-(trifluoromethoxy)-1H-indol-2-yl)quinoline

[0425] Under N2 protection, 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethoxy)-1H-indole (0.13 g, 0.41 mmol), 2,8-dichloro-3-((tetrahydro-2H-pyran-4-yl)oxy)quinoline (0.11 g, 0.37 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.027 g, 0.037 mmol) and sodium carbonate (0.12 g, 1.11 mmol) were added to 15 mL of a 1,4-dioxane / water (4 / 1) mixed solvent, the mixture was heated to 100°C and stirred for 12 hours. The reaction was monitored by LC-MS until completion.

[0426] Water (20 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 ml x 3 times). The organic phases were combined, washed with saturated brine (20 ml x 3 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting product was purified by high performance liquid chromatography to obtain 30 mg of 8-chloro-3-((tetrahydro-2H-pyran-4-yl)oxy)-2-(5-(trifluoromethoxy)-1H-indol-2-yl)quinoline as a white solid (yield: 17.57%). LCMS: RT = 2.21 min, [M+H] + =462.85.

[0427] Example 59: Determination of the upregulation effect of the compounds of the present invention on miR-124

[0428] 1 Experimental materials and instruments

[0429] 1.1 Small RNA extraction kit

[0430] 1.2 Small RNA Reverse Transcription Kit

[0431] 2 Experimental steps

[0432] Compound-treated cells

[0433] 2.1 Isolate human PBMCs and seed 3 million cells per well of a 6-well plate. Add PMA / IO and incubate for 48 hours. Finally, add the test compound (0.1 μM, 0.5 μM) and incubate for 120 hours.

[0434] 2.2 Harvest cells by centrifugation at 1000 rpm for 5 minutes;

[0435] 2.3 Use trypsin to digest the adherent cells, centrifuge and discard the supernatant, and add 1 mL of RNA isolater reagent to the cell pellet;

[0436] 2.4 Vortex and let stand at room temperature for 2 to 3 minutes to allow complete lysis.

[0437] RNA extraction

[0438] 2.5 Add 200 μL of chloroform, shake vigorously for 15 seconds, and then let it stand at room temperature for 3 minutes;

[0439] 2.6 Centrifuge at 12,000 rpm for 15 minutes at 4°C. Transfer 500 μL of the supernatant to a 1.5 mL centrifuge tube.

[0440] 2.7 Add 160 μL of anhydrous ethanol and mix thoroughly by inverting 3 to 5 times;

[0441] 2.8 Transfer the solution to a MiPure RNA collection column and centrifuge at 12,000 rpm for 30 seconds at room temperature.

[0442] 2.9 Add 0.9 times the volume of anhydrous ethanol to the solution in the collection tube and mix well by pipetting 3 to 5 times;

[0443] 2.10 Transfer half of the solution to the miRNA collection column, centrifuge at 12,000 rpm for 30 seconds at room temperature, add the remaining solution to the miRNA collection column, and repeat once;

[0444] 2.11 Add 500 μL of miRW1 to the miRNA collection column, let it stand at room temperature for 1 minute, and then centrifuge at 12,000 rpm for 30 seconds;

[0445] 2.12 Add 500 μL of miRW2 to the miRNA collection column, let it stand at room temperature for 1 minute, and then centrifuge at 12,000 rpm for 30 seconds;

[0446] 2.13 Add 500 μL of 80% anhydrous ethanol to the miRNA collection column, let it stand at room temperature for 1 minute, and then centrifuge at 12,000 rpm for 30 seconds;

[0447] 2.14 Centrifuge the empty collection column and centrifuge tube again at 12000 rpm for 2 minutes;

[0448] 2.15 Place the collection column in an RNase-free 1.5 mL centrifuge tube and dry at room temperature for 2–5 minutes.

[0449] 2.16 Add 30 μL of RNase-free water to the filter membrane in the center of the collection column, let it stand at room temperature for 2 minutes, and centrifuge at 12,000 rpm for 1 minute;

[0450] 2.17 Place the collected RNA on ice and measure the RNA concentration using a microplate reader.

[0451] Genomic DNA

[0452] 2.18 Add 1 μg of RNA to 1 μL of 5X gDNA wiper mix and make up to 5 μL with RNase-free water.

[0453] 2.19 Set the PCR machine to 42°C for 2 minutes.

[0454] RNA reverse transcription

[0455] 2.20 Thaw the reverse transcriptase reagent on ice. Add 0.5 μL of stem-loop primer, 1 μL of 10X RT Mix, 1 μL of HiScript II Enzyme Mix, and 2.5 μL of RNase-free water to the 5 μL solution from the previous step, for a total volume of 20 μL.

[0456] 2.21 Perform reverse transcription using a PCR instrument at 25°C for 5 minutes, 50°C for 15 minutes, and 85°C for 5 minutes. The resulting sample is cDNA.

[0457] QPCR assay

[0458] 2.22 Prepare qPCR reagents by thawing on ice and adding the reaction mixture to a 384-well plate. Each reaction (10 μL) contains the following: 5 μL 2X miRNA Universal SYBR qPCR Master Mix, 0.2 μL each 10 μM qPCR primer, 1 μL template cDNA, and 3.6 μL ddH2O.

[0459] 2.23 Seal the plate with sealing film and centrifuge. Place the sample in the QPCR instrument and set the program as follows: 1.95℃, 5 minutes; 2.95℃, 10 seconds, 3.60℃, 30 seconds, set 40 cycles from step 2 to step 3.

[0460] 2.24 Based on the Ct values ​​obtained by the software, the ratio of miR-124 expression levels to the internal reference miR-194 in each sample was calculated according to ΔCt = Ct (target gene) – Ct (reference gene), ΔΔCt = ΔCt (treated group) – ΔCt (control group). Relative ratio calculation: Relative mRNA expression = 2(-ΔΔCt)

[0461] The results are shown in Table 1:

[0462] Table 1:

[0463] Conclusion: The compounds of the present invention showed an up-regulation effect on miR-124, * was at a concentration of 0.5 μM, and the others were at a concentration of 0.1 μM.

[0464] Example 60 Liver microsome test

[0465] The metabolic stability of the SAL0151 series of compounds was evaluated using cynomolgus monkey and human liver microsomes as in vitro drug metabolism models. The incubation concentration of the SAL0151 series of compounds was 1 μM, and the incubation time was 0, 20, and 60 min. Each sample was replicated in duplicate.

[0466] The stability results in liver microsomes are shown in Table 2 below:

[0467] Table 2:

[0468] Example 61 Tissue Distribution Study

[0469] C57 mice were administered a single oral dose of 40 mg / kg of the compound, with three mice at each time point. Tissues collected from the brain were collected at 1, 3, and 7 hours, and whole blood was collected at each time point for plasma preparation. The compounds were formulated in a solvent consisting of 50% CMC-Na, 20% PEG-400, and 30% TPGS.

[0470] LC-MS / MS was used to analyze the distribution of the drug in brain tissue. The results of tissue distribution are shown in Table 3 below:

[0471] Table 3:

[0472] The prior art compound exhibited an adverse reaction of headache, whereas the compound of the present invention exhibited lower brain entry levels (lower Brain / MLN ratio) compared to the control compound.

[0473] Example 62: Preventive and therapeutic effects of the compound on LPS-induced acute inflammation model in mice

[0474] This study evaluated the preventive and therapeutic effects of the compounds of the present invention on LPS-induced acute inflammation. This study used C57BL / 6 male mice from Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd. and induced an acute inflammation model with LPS.

[0475] Experimental process

[0476] In this study, an acute inflammatory model was established in male C57BL / 6 mice (Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd.) by intraperitoneal injection of LPS (30 mg / kg). After adaptive feeding, the mice were randomly divided into groups according to body weight. Grouping and dosing information are shown in Table 4 below. Mice in the normal and model groups were given blank vehicle. One hour after dosing, the normal control group received intraperitoneal injection of saline, while the other groups received intraperitoneal injection of LPS. Three hours after LPS administration, serum was collected from the mice, and the mice were euthanized. Colon tissue and mesenteric lymph nodes were obtained and analyzed for the inflammatory factors IL-17 and IL-6 using Elisa. The results are shown in Tables 5 and 6.

[0477] Table 4 Pharmacodynamic grouping and administration information

[0478] Table 5

[0479] Table 6

[0480] Example 63: Preventive and therapeutic effects of the compound on inflammatory bowel disease (IBD) in mice

[0481] This study evaluated the preventive and therapeutic effects of the compounds of the present invention on inflammatory bowel disease (IBD) in mice induced by dextran sulfate sodium (DSS). In this study, C57BL / 6 male mice from Beijing Weitonglihua Laboratory Animal Technology Co., Ltd. were used to establish an IBD model in mice induced by DSS.

[0482] Experimental process: In this experiment, male C57BL / 6 mice (Beijing Weitonglihua Experimental Animal Technology Co., Ltd.) were allowed to freely drink water containing 3% DSS to establish a colitis model. The mice were divided into groups and administered 25 mg / kg and 50 mg / kg. Compared with the DSS colitis model control group, the preferred compound of the present invention reduced colon weight and improved pathological scores, which was superior to CN107207463 compound 24.

[0483] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be considered as equivalent replacement methods and are included in the scope of protection of the present invention.

Claims

1. A compound represented by general formula (Ia), or an isomer, racemate, or pharmaceutically acceptable salt thereof, characterized in that: wherein X is selected from -NH-, -O, -CH2-, -C(O)-NH-, -NH-C(O)- or is absent; T1 and T2 are independently selected from CH or N. When CH, H may be further substituted by alkyl, alkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, halogen, amino, or substituted amino. The substituent of the substituted amino is selected from alkyl, cycloalkyl, cycloalkylalkyl, or heterocyclylalkyl. X is connected to T3, T4, T5 or a six-membered ring, T3 and T4 are connected by a single bond or a double bond, T4 and T5 are connected by a single bond or a double bond, T3 is selected from CR3, O, S or NR6, T4 is selected from CR4, O, S or NR7, T5 is selected from CR5, O, S or NR8, R3, R4, R5, R6, R7, R8 are independently selected from hydrogen, halogen, alkyl, hydroxy substituted alkyl, haloalkyl, alkyl substituted or unsubstituted amino, alkyl substituted or unsubstituted heterocyclyl alkyl, R 1a 、R 1b 、R 1c 、R 1d Independently selected from hydrogen, halogen, alkyl, cyano, alkoxy, heterocyclylalkyloxy, substituted or unsubstituted amino, alkyl, substituents selected from hydroxy, halogen, alkyl, heterocyclylalkyl; R 2a 、R 2b 、R 2c 、R 2d are independently selected from hydrogen, substituted or unsubstituted alkyl, alkoxy, alkylthio, alkylsulfonyl, the substituents being selected from alkyl, aminoalkyl, alkyl-substituted aminoalkyl or halogen, or R 2a With R 2b 、R 2b With R 2c 、R 2c With R 2d forming a substituted or unsubstituted cycloalkyl or heterocycloalkyl group, wherein the substituent is selected from an alkyl group or a halogen group; Z, T6, and T7 are independently selected from CH or N. When T6 is N, R 2d Does not exist, when T7 is N, R 2a Not present, when X is selected from -NH-, R 2a 、R 2b 、R 2c 、R 2d Not hydrogen at the same time.

2. The compound according to claim 1, or its isomer, racemate, or pharmaceutically acceptable salt, characterized in that: A compound selected from the group consisting of: When connected to T3, T3 is CH, T4 is selected from CR3, and R3 is selected from hydrogen, halogen or alkyl; when connected to T4, T4 is CH, T3 is selected from CR4 or N, and R4 is selected from hydrogen or alkyl; R 1a 、R 1b 、R 1c 、R 1d Independently selected from hydrogen, halogen, alkyl, alkoxy, substituted or unsubstituted amino, the substituents are selected from alkyl, heterocyclylalkyl; R 2a 、R 2b 、R 2c 、R 2d are independently selected from hydrogen, substituted or unsubstituted alkoxy, alkylthio, alkylsulfonyl, the substituents are selected from alkyl or halogen, or R 2a With R 2b 、R 2b With R 2c 、R 2c With R 2d To form a substituted or unsubstituted cycloalkyl or heterocycloalkyl group, the substituent is selected from alkyl or halogen.

3. The compound according to claim 1, or its isomer, racemate, or pharmaceutically acceptable salt, characterized in that: The alkyl group is selected from C 1- 6 alkyl, the C 1-6 The alkyl group is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, 1-ethylpropyl, 2-methylbutyl, tert-pentyl, 1,2-dimethylpropyl, isopentyl, neopentyl, n-hexyl, isohexyl, sec-hexyl, tert-hexyl, neohexyl, 2-methylpentyl, 1,2-dimethylbutyl, and 1-ethylbutyl; The alkoxy group is selected from C 1-6 Alkoxy, the C 1-6 The alkoxy group is selected from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, sec-pentoxy, 1-ethylpropoxy, 2-methylbutoxy, tert-pentoxy, 1,2-dimethylpropoxy, isopentoxy, neopentoxy, n-hexyloxy, isohexyloxy, sec-hexyloxy, tert-hexyloxy, neohexyloxy, 2-methylpentoxy, 1,2-dimethylbutoxy, and 1-ethylbutoxy; and the O of the alkylthio group is replaced by S.

4. The compound according to claim 1, or its isomer, racemate, or pharmaceutically acceptable salt, characterized in that: Halogen is selected from fluorine, chlorine, bromine and iodine.

5. The compound according to claim 1, or its isomer, racemate, or pharmaceutically acceptable salt, characterized in that: Selected from 6. The compound according to claim 1, or its isomer, racemate, or pharmaceutically acceptable salt, characterized in that: Cycloalkyl is selected from C 3-6 The cycloalkyl group is further selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The heterocycloalkyl group refers to a cycloalkyl group in which one or more carbon atoms are replaced by heteroatoms selected from O, S and N.

7. The compound according to claim 1, or its isomer, racemate, or pharmaceutically acceptable salt, characterized in that: R 2a 、R 2c 、R 2d are independently selected from hydrogen, R 2b Selected from -OCF3, -SCF3, -S(O)2CH2F; or R 2c 、R 2d Selected from hydrogen, R 2a With R 2b form 8. The compound according to claim 1, or its isomer, racemate, or pharmaceutically acceptable salt thereof, characterized in that: Selected from More preferably, 9. The compound according to claim 1, or its isomer, racemate, or pharmaceutically acceptable salt thereof, characterized in that: Selected from 10. The compound according to claim 1, or its isomer, racemate, or pharmaceutically acceptable salt, characterized in that: The compound is selected from:

11. A pharmaceutical composition, characterized in that The invention comprises a therapeutically effective amount of the compound according to any one of claims 1 to 10, or an isomer thereof, or a racemate thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

12. Use of the compound according to any one of claims 1 to 10, or its isomer, racemate, or pharmaceutically acceptable salt thereof, in medicine, particularly in the preparation of a medicament for regulating diseases related to miRNA levels.

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