Quinoline compound as well as preparation method and miR up-regulation application thereof

Abstract

The invention belongs to the technical field of chemical medicines, and relates to a compound as shown in a general formula (I), or a racemate, an isomer or a medicinal salt thereof, and application of the compound in preparation of medicines for treating and regulating miRNA level related diseases.

Description

Technical Field

[0001] The present invention belongs to the technical field of chemical drugs, and provides a quinoline 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 quinoline compounds, preparation methods thereof and medical applications thereof.

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

[0007]

[0008] 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.

[0009] 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.

[0010] Specifically, the present invention is achieved through the following technical solutions:

[0011] A compound represented by general formula (I), or its isomer, racemate, or pharmaceutically acceptable salt,

[0012]

[0013] Wherein, ring A is selected from a benzene ring, a cycloalkyl ring, a five-membered or six-membered aromatic heterocycle, a five-membered and six-membered aromatic heterocycle or a six-membered and six-membered aromatic heterocycle;

[0014] R 1a 、R 1b 、R 1c 、R 1d 、R 2a 、R 2b independently selected from hydrogen, halogen, alkyl, alkoxy, substituted or unsubstituted amino, the substituents being selected from alkyl, cycloalkyl, cycloalkylalkyl, heterocyclylalkyl;

[0015] Ring A may be substituted and selected from halogen, hydroxy, alkyl, haloalkyl, oxo, substituted or unsubstituted alkoxy, alkylthio, alkoxyhaloalkyl, alkylsulfonyl, cycloalkyl, heterocycloalkyl, cycloalkyloxy, cycloalkylalkyloxy, aminoacyl, the substituents being selected from alkyl, haloalkyl or halogen, or adjacent substituents forming a substituted or unsubstituted saturated or unsaturated cycloalkyl or heterocycloalkyl, the substituents being selected from alkyl or halogen;

[0016] X is absent or selected from O, NR4, -CR5R6-(O) n -, -NH-C(O)-CR7R8-, -NH-C(O)-NH2, -NH-CR9R 10 -, -NH-C(O)-, -C(O)-NH-, or -NH-NH-C(O)-, n=0 or 1;

[0017] R4 is selected from hydrogen, substituted or unsubstituted cycloalkyl, heterocyclyl, heterocyclylalkyl, cycloalkylalkyl, the substituent is selected from hydroxyl, halogen, carboxyl, or forms a cycloalkyl or heterocycloalkyl with the substituent of ring A, and the cycloalkyl or heterocycloalkyl may be further substituted with oxo;

[0018] R5 and R6 are independently selected from hydrogen, hydroxy, cyano, carboxyl, substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, amino, and alkylamino, and the substituents are selected from alkyl, haloalkyl, hydroxyalkyl, hydroxy, cycloalkyl, halogen, carboxyl, aminoacyl, amino, alkylamino, saccharyl, and halogen-substituted or unsubstituted phenyl, or R5 and R6 form a cycloalkyl or heterocycloalkyl group;

[0019] R7 and R8 are independently selected from hydrogen and alkyl;

[0020] R9, R 10 independently selected from hydrogen, carboxyl;

[0021] When R4 is selected from hydrogen, at least one of the substituents of ring A is selected from substituted or unsubstituted alkoxyhaloalkyl, alkylsulfonyl, cycloalkyl, cycloalkyloxy, cycloalkylalkyloxy, aminoacyl, and the substituent is selected from alkyl, haloalkyl or halogen, or the substituent of ring A forms a cycloalkyl.

[0022] As a preferred technical solution of the present invention, a compound selected from formula (Ia), or an isomer, or a racemate, or a pharmaceutically acceptable salt thereof,

[0023]

[0024] Wherein, ring A is selected from benzene ring or cyclohexane;

[0025] R 1a 、R 1b 、R 1c 、R 1d 、R 2a 、R 2b independently selected from hydrogen, halogen, alkyl, alkoxy, substituted or unsubstituted amino, the substituents being selected from alkyl, cycloalkyl, cycloalkylalkyl, heterocyclylalkyl;

[0026] R 3a 、R 3b 、R 3c 、R 3d 、R 3e independently selected from hydrogen, halogen, hydroxy, substituted or unsubstituted alkoxy, alkylthio, alkoxyhaloalkyl, alkylsulfonyl, cycloalkyl, heterocycloalkyl, cycloalkyloxy, cycloalkylalkyloxy, aminoacyl, the substituents being selected from alkyl, haloalkyl or halogen, or R 3a With R 3b 、R 3a With R 3e 、R 3b With R 3c 、R 3c With R 3d forming a substituted or unsubstituted saturated or unsaturated cycloalkyl or heterocycloalkyl group, wherein the substituent is selected from alkyl or halogen;

[0027] X is selected from O, NR4, -CR5R6-(O) n -, -NH-C(O)-CR7R8-, -NH-C(O)-NH2, -NH-CR9R 10 -, -NH-C(O)-, -C(O)-NH-, or -NH-NH-C(O)-, n=0 or 1;

[0028] R4 is selected from hydrogen, substituted or unsubstituted cycloalkyl, heterocyclyl, heterocyclylalkyl, cycloalkylalkyl, and the substituent is selected from hydroxyl, halogen, carboxyl, or R 3d forming a cycloalkyl group or a heterocycloalkyl group;

[0029] R5 and R6 are independently selected from hydrogen, hydroxy, cyano, carboxyl, substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, amino, and alkylamino, and the substituents are selected from alkyl, haloalkyl, hydroxyalkyl, hydroxy, cycloalkyl, halogen, carboxyl, aminoacyl, amino, alkylamino, saccharyl, and halogen-substituted or unsubstituted phenyl, or R5 and R6 form a cycloalkyl or heterocycloalkyl group;

[0030] R7 and R8 are independently selected from hydrogen and alkyl;

[0031] R9, R 10 independently selected from hydrogen, carboxyl;

[0032] When R4 is selected from hydrogen, R 3a 、R 3b 、R 3c 、R 3d 、R 3e At least one selected from substituted or unsubstituted alkoxyhaloalkyl, alkylsulfonyl, cycloalkyl, cycloalkyloxy, cycloalkylalkyloxy, aminoacyl, the substituent being selected from alkyl, haloalkyl or halogen, or R 3b With R 3c Forming a cycloalkyl group.

[0033] As a preferred technical solution of the present invention, the five-membered or six-membered aromatic heterocycle, the five-membered and six-membered aromatic heterocycle or the six-membered and six-membered aromatic heterocycle is selected from:

[0034] 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 the group consisting of methyl, ethyl, 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.

[0035] 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, 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.

[0036] As a preferred technical solution of the present invention, the halogen is selected from fluorine, chlorine, bromine and iodine.

[0037] As a preferred technical solution of the present invention, R 1a 、R 1b 、R 1c 、R 2a 、R 2b Selected from hydrogen, R 1d Selected from chlorine.

[0038] As a preferred technical solution of the present invention, the cycloalkyl group is selected from C 3-6 The monocyclic alkyl group is further selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or C 7-10 The bicyclic or tricyclic ring is further selected from Heterocycloalkyl refers to a cycloalkyl group in which one or more carbon atoms are replaced by heteroatoms, wherein the heteroatoms are selected from O, S, and N. An unsaturated cycloalkyl or heterocycloalkyl group is a cycloalkyl or heterocycloalkyl group containing double bonds between carbon atoms.

[0039] As a preferred technical solution of the present invention, when X is selected from O, NR4, -CR5R6-(O) n , -NH-C(O)-CR7R8-, -NH-C(O)-NH2, -NH-CR9R 10 -, or -NH-NH-C(O)-, n=0 or 1, or R4 and R 3d When forming a cycloalkyl or heterocycloalkyl group, and R4 is not hydrogen;

[0040] R 3a 、R 3c 、R 3d 、R 3e Selected from hydrogen, R 3b Selected from -OCF3, -SCF3, -S(O)2CH2F; or R 3c 、R 3d 、R 3e Selected from hydrogen, R 3a With R 3b form

[0041] As a preferred technical solution of the present invention, when R4 is selected from hydrogen, A ring is selected from benzene ring, R 3a 、R 3b 、R 3c 、R 3d At least one selected from or R 3a 、R 3b form Or when R4 is selected from hydrogen, the A ring is selected from cyclohexane, further, the substituted cyclohexane is selected from

[0042] As a preferred technical solution of the present invention, R 3a With R 3b 、R 3a With R 3e 、R 3b With R 3c 、R 3c With R 3d To form a substituted or unsubstituted saturated or unsaturated cycloalkyl or heterocycloalkyl, for example, ring A is selected from

[0043] As a preferred technical solution of the present invention, the glycosyl-substituted phenyl group is selected from The halogen-substituted phenyl group is selected from

[0044] As a preferred technical solution of the present invention, NR4, -CR5R6-(O) n -, -NH-C(O)-CR7R8-, -NH-CR9R 10 - is selected from: -NH-, -CH2-,

[0045]

[0046]

[0047] As a preferred technical solution of the present invention, the substituted five-membered aromatic heterocycle or five-membered and six-membered aromatic heterocycle is selected from:

[0048]

[0049] As a preferred technical solution of the present invention, the compound is selected from the compounds shown in Table 1:

[0050] Table 1

[0051]

[0052]

[0053]

[0054] 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.

[0055] 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.

[0056] 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).

[0057] 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.

[0058] The inflammatory disease is selected from the group consisting of 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.

[0059] 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.

[0060] For the sake of clarity, general terms used in the description of the compounds are defined herein.

[0061] 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.

[0062] 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.

[0063] 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.

[0064] 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.

[0065] 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.

[0066] For example, isomer 13A of compound 13:

[0067] 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).

[0068] 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.

[0069] 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( 14C) All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0070] Furthermore, the compounds of the present invention may have one or more hydrogen atoms deuterated with isotopes of deuterium ( 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.

[0071] 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.

[0072] 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.

[0073] The term "excipient" generally refers to a carrier, diluent and / or vehicle required to formulate an effective pharmaceutical composition.

[0074] 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.

[0075] 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.

[0076] "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.

[0077] 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

[0078] 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.

[0079] Example 1 Synthesis of 8-chloro-N-(4-(3-fluorocyclobutyloxy)phenyl)quinolin-2-amine

[0080]

[0081] Step A: Synthesis of 1-(3-fluorocyclobutyloxy)-4-nitrobenzene

[0082] 3-Fluorocyclobutanol (0.15 g, 1.66 mmol) was dissolved in tetrahydrofuran (10 ml) at 0°C, and sodium hydride (0.08 g, 3.32 mmol) was added. The mixture was allowed to react for 10 minutes, followed by the addition of p-fluoronitrobenzene (0.23 g, 1.66 mmol). The reaction was continued at room temperature 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 0.15 g of 1-(3-fluorocyclobutoxy)-4-nitrobenzene (yield: 42.7%).

[0083] Step B: Synthesis of 4-(3-fluorocyclobutyloxy)aniline

[0084] At room temperature, 1-(3-fluorocyclobutyloxy)-4-nitrobenzene (0.15 g, 0.71 mmol) was dissolved in ethyl acetate (20 ml), palladium on carbon (0.02 g) was added, and the temperature was raised to 50°C under H2 protection. The reaction was allowed to proceed for 2 hours. After the reaction was completed, the mixture was filtered and concentrated under reduced pressure to obtain 102 mg of yellow solid 4-(3-fluorocyclobutyloxy)aniline (yield: 77.05%).

[0085] Step C: Synthesis of 8-chloro-N-(4-(3-fluorocyclobutyloxy)phenyl)quinolin-2-amine

[0086] At room temperature, 2,8-dichloroquinoline (0.10 g, 0.55 mmol) and 1-(3-fluorocyclobutyloxy)-4-nitrobenzene (0.11 g, 0.55 mmol) were dissolved in isopropanol (20 ml), heated to 100°C, and reacted for 5 hours. After the reaction, the mixture was filtered and the filter cake was dried to obtain 100 mg of a yellow solid 8-chloro-N-(4-(3-fluorocyclobutyloxy)phenyl)quinolin-2-amine (yield: 52.86%).

[0087] LCMS: RT = 2.24 min, [M+H] + =343.15. 1 H NMR(400MHz, DMSO-d6)δ9.59(s,1H),8.13–8.05(m,3H),7.74(ddd,J=18.3,7.8,1.4Hz,2H),7.26(t,J=7.8Hz,1H),7.09(d,J=8.9Hz,1H),6.91– 6.82(m,2H),5.42(tt,J=6.7,3.9Hz,0.5H),5.28(tt,J=6.7,3.9Hz,0.5 H),4.96(ddt,J=11.3,7.1,4.1Hz,1H),2.70(m,2H),2.53–2.42(m,2H).

[0088] Example 2 Synthesis of 8-chloro-N-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)quinolin-2-amine

[0089]

[0090] Under N2 protection, 8-chloroquinolin-2-amine (150 mg, 0.84 mmol), 1-bromo-4-(1-(trifluoromethyl)cyclopropyl)benzene (280 mg, 1.05 mmol), tris(dibenzylideneacetone)dipalladium (38 mg, 0.042 mmol), 1,1'-bis(diphenylphosphino)ferrocene (47 mg, 0.084 mmol) and sodium tert-butoxide (110 mg, 1.18 mmol) were added to 1,4-dioxane (6 ml). The temperature was raised to 100°C and stirred for 12 hours. The reaction was monitored by LC-MS until completion.

[0091] 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 resulting residue was purified by HPLC to obtain 214 mg of 8-chloro-N-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)quinolin-2-amine as a pale yellow solid (yield: 70.24%).

[0092] LCMS: RT = 2.32 min, [M+H] + =362.93. 1 H NMR (400MHz, DMSO-d6) δ9.83 (s, 1H), 8.27–8.18 (m, 2H), 8.16 (d, J = 8.9Hz, 1H), 7.84–7.72 (m, 2H), 7. 45(d,J=8.4Hz,2H),7.34–7.27(m,1H),7.17(d,J=8.9Hz,1H),1.37–1.29(m,2H),1.16–1.10(m,2H).

[0093] Example 3 Synthesis of 8-chloro-N-(5,6,7,8-methylhydroquinolin-2-yl)quinolin-2-amine

[0094]

[0095] Under N2 protection, 8-chloroquinolin-2-amine (100 mg, 0.56 mmol), 2-chloro-5,6,7,8-tetrahydroquinoline (120 mg, 0.70 mmol), tris(dibenzylideneacetone)dipalladium(0) (26 mg, 0.028 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (35 mg, 0.056 mmol) and sodium tert-butoxide (75 mg, 0.78 mmol) were added to 1,4-dioxane (6 ml), the temperature was raised to 100°C and stirred for 12 hours. The reaction was monitored by LC-MS until completion.

[0096] 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 resulting residue was purified by HPLC to obtain 111 mg of 8-chloro-N-(5,6,7,8-tetrahydroquinolin-2-yl)quinolin-2-amine as a pale yellow solid (yield: 65.29%).

[0097] LCMS: RT = 1.79 min, [M+H] + =309.99. 1 H NMR (400MHz, DMSO-d6) δ10.17(s,1H),8.78(d,J=8.4Hz,1H),8.16(d,J=8.9Hz,1H),7.83–7.72(m,2H), 7.52(d,J=8.5Hz,1H),7.44(d,J=8.9Hz,1H),7.34–7.28(m,1H),2.84–2.68(m,4H),1.90–1.73(m,4H).

[0098] Example 4 Synthesis of 8-chloro-N-(4-((trifluoromethyl)sulfonyl)phenyl)quinolin-2-amine

[0099]

[0100] 2,8-Dichloroquinoline (0.10 g, 0.55 mmol) and 4-trifluoromethylsulfonylanilide (0.12 g, 0.55 mmol) were dissolved in isopropanol (20 ml) at room temperature and heated to 100°C for 5 hours. After completion of the reaction, the mixture was filtered and the filter cake was dried to obtain 80 mg of a yellow solid 8-chloro-N-(4-((trifluoromethyl)sulfonyl)phenyl)quinolin-2-amine (yield: 23.80%).

[0101] LCMS: RT = 2.08 min, [M+H] + =387.15. 1 H NMR (400MHz, DMSO-d6) δ10.65(s,1H),8.64–8.57(m,2H),8.34(d,J=8.9Hz,1H),8.09(d,J=8 .8Hz,2H),7.88(ddd,J=13.0,7.8,1.3Hz,2H),7.43(t,J=7.8Hz,1H),7.31(d,J=8.9Hz,1H).

[0102] Example 5 Synthesis of N-(4-((8-chloroquinolin-2-yl)amino)phenyl)acetamide

[0103]

[0104] At room temperature, 2,8-dichloroquinoline (0.15 g, 0.76 mmol) and 4-amino-N-methylbenzamide (0.11 g, 0.76 mmol) were dissolved in isopropanol (20 ml), heated to 100°C, and reacted for 5 hours. After the reaction, the mixture was filtered and the filter cake was dried to obtain 110 mg of a yellow solid N-(4-((8-chloroquinolin-2-yl)amino)phenyl)acetamide (yield: 46.58%).

[0105] LCMS: RT = 2.09 min, [M+H] + =312.17. 1 H NMR (400MHz, DMSO-d6) δ10.09(s,1H),8.32–8.25(m,3H),8.20(d,J=8.9Hz,1H),7.80(d dd,J=15.9,7.8,1.3Hz,2H),7.33(t,J=7.8Hz,1H),7.24(d,J=8.9Hz,1H),2.80(s,3H).

[0106] Example 6 Synthesis of 2-(2-chlorophenyl)-N-(8-chloroquinolin-2-yl)propionamide

[0107]

[0108] 8-Chloroquinolin-2-amine (100 mg, 0.56 mmol), 2-(2-chlorophenyl)propionic acid (110 mg, 0.59 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.

[0109] Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by high-performance liquid chromatography to obtain 124 mg of 2-(2-chlorophenyl)-N-(8-chloroquinolin-2-yl)propanamide as a white solid (yield: 64.16%).

[0110] LCMS: RT = 2.20 min, [M+H] + =344.97. 1 H NMR(400MHz,DMSO-d6)δ11.19(s,1H),8.49–8.35(m,2H),7.96–7.88(m,2H),7.5 3–7.45(m,3H),7.41–7.29(m,2H),4.57(d,J=7.4Hz,1H),1.53(d,J=7.1Hz,3H).

[0111] Example 7 Synthesis of 8-chloro-N-(4-(3,3-difluorocyclobutyloxy)phenyl)quinolin-2-amine

[0112]

[0113] Step A: Synthesis of 1-(3,3-difluorocyclobutyloxy)-4-nitrobenzene

[0114] Under ice-bath, sodium bicarbonate (250 mg, 6.37 mmol) was added portionwise to a solution of 3,3-difluorocyclobutanol (420 mg, 3.89 mmol) in N,N-dimethylformamide (6 ml). After reacting at this temperature for 0.5 hour, p-fluoronitrobenzene (500 mg, 3.54 mmol) was added. After the addition was complete, the mixture was moved to room temperature and reacted for 3 hours. The reaction was monitored by TLC until completion.

[0115] 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 0.75 g of yellow oily 1-(3,3-difluorocyclobutyloxy)-4-nitrobenzene (yield: 92.35%).

[0116] Step B: Synthesis of 4-(3,3-difluorocyclobutyloxy)aniline

[0117] 1-(3,3-Difluorocyclobutyloxy)-4-nitrobenzene (750 mg, 3.27 mmol) was dissolved in methanol (10 mL), followed by the addition of 10% Pd / C (2.78 g, 2.62 mmol). The mixture was reacted at room temperature under a hydrogen atmosphere for 3 hours, monitored by TLC until the reaction was complete. The palladium on carbon was removed by filtration, and the filtrate was concentrated under reduced pressure to afford 500 mg of 4-(3,3-difluorocyclobutyloxy)aniline as a yellow oil (yield: 76.70%).

[0118] Step C: Synthesis of 8-chloro-N-(4-(3,3-difluorocyclobutyloxy)phenyl)quinolin-2-amine

[0119] 2,8-Dichloroquinoline (0.5 g, 2.51 mmol) and 4-(3,3-difluorocyclobutyloxy)aniline (0.50 g, 2.51 mmol) were added to isopropanol (20 mL) at room temperature. Trifluoroacetic acid (0.29 g, 2.51 mmol) was added dropwise. The mixture was heated to 80°C and allowed to react for 12 hours. LC-MS monitoring was performed until the reaction was complete. The solvent was removed under reduced pressure, and the resulting residue was purified by HPLC to yield 590 mg of a pale yellow solid, 8-chloro-N-(4-(3,3-difluorocyclobutyloxy)phenyl)quinolin-2-amine (yield: 65.15%). LCMS: RT = 2.20 min, [M+H] + =360.96. 1 H NMR(400MHz, DMSO-d6)δ9.61(s,1H),8.17–8.07(m,3H),7.81–7.69(m,2H),7.31–7.23(m,1H),7. 10(d,J=8.9Hz,1H),6.97–6.89(m,2H),4.82–4.71(m,1H),3.30–3.16(m,2H),2.78–2.63(m,2H).

[0120] Example 8 Synthesis of 8-chloro-N-(4-(methoxybis(trifluoromethyl)methyl)phenyl)quinolin-2-amine

[0121]

[0122] At room temperature, 2,8-dichloroquinoline (0.15 g, 0.76 mmol) and 4-(methoxybis(trifluoromethyl)methyl)aniline (0.21 g, 0.76 mmol) were dissolved in isopropanol (20 ml). The temperature was raised to 100°C and the reaction was allowed to proceed for 5 hours. After completion of the reaction, the mixture was filtered and the filter cake dried to obtain 40 mg of a yellow solid, 8-chloro-N-(4-(methoxybis(trifluoromethyl)methyl)phenyl)quinolin-2-amine (yield: 12.15%). LCMS: RT = 2.32 min, [M+H] + =434.17.

[0123] Example 9 Synthesis of N-(2-((8-chloroquinolin-2-yl)amino)phenyl)acetamide

[0124]

[0125] 2,8-Dichloroquinoline (0.15 g, 0.76 mmol) and 2-amino-N-methylbenzamide (0.11 g, 0.76 mmol) were dissolved in isopropanol (20 ml) at room temperature and heated to 100°C for 5 hours. After completion of the reaction, the mixture was filtered and the filter cake dried to afford 89 mg of a yellow solid, N-(2-((8-chloroquinolin-2-yl)amino)phenyl)acetamide (yield: 37.71%). LCMS: RT = 2.25 min, [M+H] + =311.95.

[0126] Example 10 Synthesis of (1S,2S,3R,4S,5S)-5-((8-chloroquinolin-2-yl)amino)-1-(hydroxymethyl)cyclohexane-1,2,3,4-tetrol

[0127]

[0128] 2,8-Dichloroquinoline (0.25 g, 1.26 mmol), cinnamylamine (0.24 g, 1.26 mmol), and cesium carbonate (0.82 g, 2.52 mmol) were dissolved in N,N-dimethylformamide (20 mL) at room temperature and heated to 80°C for 12 hours. After completion of the reaction, the reaction solution was cooled to room temperature and extracted three times with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. The solution was concentrated under vacuum and purified by HPLC to give 15 mg of (1S,2S,3R,4S,5S)-5-((8-chloroquinolin-2-yl)amino)-1-(hydroxymethyl)cyclohexane-1,2,3,4-tetrol as a white solid (yield: 3.3%). LCMS: RT = 1.65 min, [M+H] + =355.27.

[0129] Example 11 Synthesis of 8-chloro-N-(4-((2,2-dichlorocyclopropyl)methoxy)phenyl)quinolin-2-amine

[0130]

[0131] Step A: Synthesis of (2,2-difluorocyclopropyl)methanol

[0132] Under ice, lithium aluminum hydride (0.3 g, 7.86 mmol) was added to 2,2-difluorocyclopropylcarboxylic acid (0.8 g, 6.55 mmol) dissolved in tetrahydrofuran (20 mL). The mixture was then slowly warmed to room temperature and allowed to react for 2 hours. The reaction mixture was quenched with 2N sodium hydroxide solution, filtered through celite to remove insoluble matter, and the filtrate was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 500 mg of (2,2-difluorocyclopropyl)methanol as a slightly yellow oil (yield: 70.58%).

[0133] Step B: Synthesis of 1-((2,2-difluorocyclopropyl)methoxy)-4-nitrobenzene

[0134] Under ice-cooling, sodium bicarbonate (250 mg, 6.37 mmol) was added portionwise to a solution of 2,2-difluorocyclopropylmethanol (460 mg, 4.25 mmol) in N,N-dimethylformamide (6 ml). The mixture was reacted at this temperature for 0.5 h, followed by the addition of p-fluoronitrobenzene (500 mg, 3.54 mmol). After the addition was complete, the mixture was moved to room temperature and reacted for 3 h. The reaction was monitored by TLC until completion.

[0135] 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. Finally, the mixture was concentrated under reduced pressure to obtain 750 mg of a yellow oily substance, 1-((2,2-difluorocyclopropyl)methoxy)-4-nitrobenzene (yield: 92.35%).

[0136] Step C: Synthesis of 4-((2,2-difluorocyclopropyl)methoxy)aniline

[0137] 1-((2,2-difluorocyclopropyl)methoxy)-4-nitrobenzene (750 mg, 3.27 mmol) was dissolved in methanol (15 mL) at room temperature, followed by the addition of 10% Pd / C (2.78 g, 2.62 mmol). The mixture was reacted under a hydrogen atmosphere at room temperature for 3 h, monitored by TLC until the reaction was complete. The palladium on carbon was removed by filtration, and the filtrate was concentrated under reduced pressure to afford 500 mg of 4-((2,2-difluorocyclopropyl)methoxy)aniline as a yellow oil (yield: 76.70%).

[0138] Step D: Synthesis of 8-chloro-N-(4-((2,2-difluorocyclopropyl)methoxy)phenyl)quinolin-2-amine

[0139] At room temperature, 2,8-dichloroquinoline (500 mg, 2.51 mmol) and 4-((2,2-difluorocyclopropyl)methoxy)aniline (500 mg, 2.51 mmol) were added to isopropanol (8 mL). Trifluoroacetic acid (290 mg, 2.51 mmol) was added dropwise. The temperature was raised to 80°C and the reaction was allowed to react for 12 h. LC-MS monitoring was performed until the reaction was complete. The solvent was removed under reduced pressure, and the resulting residue was purified by HPLC to obtain 420 mg of 8-chloro-N-(4-((2,2-difluorocyclopropyl)methoxy)phenyl)quinolin-2-amine (yield: 46.38%). LCMS: RT = 2.20 min, [M+H] + =360.96. 1 H NMR(400MHz, DMSO-d6)δ9.59(s,1H),8.17–8.04(m,3H),7.74(ddd,J=17.5,7.8,1.4Hz,2H),7.30–7.20(m,1H),7.10(d,J=8.9Hz,1H),7.02–6 .94(m,2H),4.23–4.13(m,1H),3.99(ddd,J=10.5,8.4,1.8Hz,1H),2.30–2.16(m,1H),1.74(tdd,J=12.3,7.9,4.7Hz,1H),1.54–1.41(m,1H).

[0140] Example 12 Synthesis of 8-chloro-N-(4-(((1R,2R)-2-fluorocyclopropyl)methoxy)phenyl)quinolin-2-amine

[0141]

[0142] Step A: Synthesis of ((1R,2R)-2-fluorocyclopropyl)methanol

[0143] Under ice, lithium aluminum hydride (310 mg, 8.08 mmol) was added portionwise to (1R,2R)-2-fluoro-cyclopropylcarboxylic acid (700 mg, 6.73 mmol) dissolved in tetrahydrofuran (20 mL). The mixture was then slowly warmed to room temperature and allowed to react for 2 hours. The reaction mixture was quenched with 2N sodium hydroxide solution, and the insoluble material was removed by filtration through Celite. The filtrate was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 400 mg of ((1R,2R)-2-fluorocyclopropyl)methanol as a slightly yellow oil (yield: 66.01%).

[0144] Step B: Synthesis of 1-(((1R,2R)-2-fluorocyclopropyl)methoxy)-4-nitrobenzene

[0145] Under ice-cooling, sodium bicarbonate (200 mg, 5.09 mmol) was added portionwise to a solution of ((1R,2R)-2-fluorocyclopropyl)methanol (310 mg, 3.40 mmol) in N,N-dimethylformamide (10 ml). After reacting at this temperature for 0.5 hour, p-fluoronitrobenzene (400 mg, 2.83 mmol) was added. The mixture was brought to room temperature and reacted for 2 hours. The reaction was monitored by TLC until completion.

[0146] Water (10 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. Finally, the mixture was concentrated under reduced pressure to obtain 500 mg of a yellow oily product, 1-(((1R,2R)-2-fluorocyclopropyl)methoxy)-4-nitrobenzene (yield: 83.51%).

[0147] Step C: Synthesis of 4-(((1R,2R)-2-fluorocyclopropyl)methoxy)aniline

[0148] 1-(((1R,2R)-2-fluorocyclopropyl)methoxy)-4-nitrobenzene (500 mg, 2.37 mmol) was dissolved in methanol (10 mL), followed by the addition of 10% Pd / C (202 mg, 1.90 mmol). The mixture was reacted at room temperature under a hydrogen atmosphere for 3 hours, monitored by TLC until completion. The palladium on carbon was removed by filtration, and the mixture was concentrated under reduced pressure to afford 400 mg of 4-(((1R,2R)-2-fluorocyclopropyl)methoxy)aniline as a yellow oil (yield: 93.24%).

[0149] Step D: Synthesis of 8-chloro-N-(4-(((1R,2R)-2-fluorocyclopropyl)methoxy)phenyl)quinolin-2-amine

[0150] 2,8-Dichloroquinoline (440 mg, 2.21 mmol) and 4-(((1R,2R)-2-fluorocyclopropyl)methoxyaniline (400 mg, 2.21 mmol) were added to isopropanol (10 mL) at room temperature. Trifluoroacetic acid (250 mg, 2.21 mmol) was added dropwise. The temperature was raised to 80°C and the reaction was allowed to react for 12 h. LC-MS monitoring was performed until the reaction was complete. The solvent was removed under reduced pressure, and the resulting residue was purified by high performance liquid chromatography to give 450 mg of 8-chloro-N-(4-(((1R,2R)-2-fluorocyclopropyl)methoxy)phenyl)quinolin-2-amine as a pale yellow solid (yield: 59.47%).

[0151] LCMS: RT = 2.16 min, [M+H] + =342.98. 1H NMR(400MHz, DMSO-d6)δ9.58(s,1H),8.16–8.04(m,3H),7.74(ddd,J=18.1,7.8,1.4Hz,2H),7.26(t,J=7.7Hz,1H),7.10(d,J=9.0Hz,1H),7.02–6 .94(m,2H),4.22(ddd,J=10.4,6.0,1.4Hz,2H),3.96(ddd,J=10.2,8.7,1.1Hz,1H),1.40(dddt,J=11.0,8.6,7.3,5.9Hz,1H),1.01–0.78(m,2H).

[0152] Example 13 Synthesis of (8-chloroquinolin-2-yl)(4-(trifluoromethoxy)phenyl)methanol

[0153]

[0154] Under ice, 8-chloroquinoline 2-carboxaldehyde (0.5 g, 2.61 mmol) was added to a tetrahydrofuran solution (10 mL). p-Trifluoromethoxyphenylmagnesium bromide (0.73 g, 2.74 mmol) was slowly added dropwise and allowed to react under ice for 1 h. TLC indicated the reaction was complete, and the reaction solution was quenched by adding aqueous ammonium chloride. Extraction was performed three times with ethyl acetate, and the organic layer was washed with brine and dried over magnesium sulfate. The residue was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3 / 1) to obtain 0.75 g of (8-chloroquinolin-2-yl)(4-(trifluoromethoxy)phenyl)methanol as a yellow solid (yield: 48.75%). LCMS: RT = 2.16 min, [M+H] + =353.94. 1 H NMR (400MHz, DMSO-d6) δ8.46(d,J=8.6Hz,1H),7.97(dq,J=7.9,1.4Hz,2H),7.80(d,J=8.6Hz,1H),7.68-7.61(m ,2H),7.58(t,J=7.9Hz,1H),7.37-7.31(m,2H),6.00(s,1H),2.69(p,J=1.9Hz,0.5H),2.35(p,J=1.8Hz,0.5H).

[0155] Example 14 Synthesis of 1-(8-chloroquinolin-2-yl)-6-(trifluoromethoxy)-1,2,3,4-tetrahydroquinoxaline

[0156]

[0157] The specific synthetic route is as follows:

[0158] Step A: Synthesis of 6-(trifluoromethoxy)-3,4-dihydroquinoxalin-2(1H)-one

[0159] Under ice, 4-(trifluoromethoxy)benzene-1,2-diamine (1.0 g, 5.2 mmol) and ethyl bromoacetate (0.91 g, 5.46 mmol) were added to a 10 mL N,N-dimethylformamide solution. Triethylamine (1.05 g, 10.4 mmol) was added and the mixture was allowed to react at room temperature for 2 hours. The temperature was then raised to 80°C for 6 hours. TLC indicated the reaction was complete. The reaction mixture was cooled to room temperature and extracted three times with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and saturated sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 4 / 1) to obtain 550 mg of 6-(trifluoromethoxy)-3,4-dihydroquinoxalin-2(1H)-one as a yellow solid (yield: 45.52%).

[0160] Step B: Synthesis of 6-(trifluoromethoxy)-1,2,3,4-tetrahydroquinoxaline

[0161] Under ice, 6-(trifluoromethoxy)-3,4-dihydroquinoxalin-2(1H)-one (0.15 g, 0.65 mmol) was added to a tetrahydrofuran solution (10 mL). Lithium aluminum tetrahydride (49 mg, 1.3 mmol) was slowly added, and the reaction mixture was heated to 60°C for 4 hours. TLC indicated the reaction was complete. The reaction solution was cooled to room temperature, quenched with water, and filtered. The filtrate was extracted three times with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to afford 100 mg of 6-(trifluoromethoxy)-1,2,3,4-tetrahydroquinoxaline as a gray solid (yield: 70.94%).

[0162] Step C: Synthesis of 1-(8-chloroquinolin-2-yl)-6-(trifluoromethoxy)-1,2,3,4-methylhydroquinoxaline

[0163] At room temperature, 2,8-dichloroquinoline (0.10 g, 0.50 mmol) and 6-(trifluoromethoxy)-1,2,3,4-tetrahydroquinoxaline (0.11 g, 0.50 mmol) were dissolved in isopropanol (10 ml), heated to 100°C, and reacted for 5 hours. After the reaction was completed, the mixture was filtered and the filter cake was purified by high performance liquid chromatography to obtain 19 mg of a yellow solid 1-(8-chloroquinolin-2-yl)-6-(trifluoromethoxy)-1,2,3,4-tetrahydroquinoxaline (yield: 10%).

[0164] LCMS: RT = 2.30 min, [M+H] + =379.98. 1H NMR(400MHz,Chloroform-d)δ7.90(d,J=9.1Hz,1H),7.74(dd,J=7.5,1.4Hz,1H),7.59(dd,J=8.0,1.4Hz,1H),7.47(d ,J=9.1Hz,1H),7.32-7.19(m,3H),6.57-6.51(m,2H),4.41(t,J=5.1Hz,2H),4.25(s,1H),3.55(td,J=5.2,2.7Hz,2H).

[0165] Example 15 Synthesis of 8-chloro-2-((3-(4-(trifluoromethoxy)phenyl)azetidin-3-yl)oxy)quinoline

[0166]

[0167] Step A: Synthesis of tert-butyl 3-carboxy-3-(4-(trifluoromethoxy)phenyl)azetidine-1-carboxylate

[0168] 4-(Trifluoromethoxy)phenylmagnesium bromide (1.01 g, 3.80 mmol) was added dropwise to 1-Boc-3-azetidinone (500 mg, 2.92 mmol) in tetrahydrofuran (20 mL) at -40°C, and the mixture was slowly warmed to room temperature for 6 hours. The reaction mixture was quenched by pouring into saturated ammonium chloride solution and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 682 mg of tert-butyl 3-hydroxy-3-(4-(trifluoromethoxy)phenyl)azetidine-1-carboxylate as a yellow oil (yield: 70.06%).

[0169] Step B: Synthesis of tert-butyl 3-((8-chloroquinolin-2-yl)oxy)-3-(4-(trifluoromethoxy)phenyl)azetidine-1-carboxylate

[0170] Under ice bath, sodium bicarbonate (43 mg, 1.08 mmol) was added portionwise to tert-butyl 3-hydroxy-3-(4-(trifluoromethoxy)phenyl)azetidine-1-carboxylate (200 mg, 0.60 mmol) in N,N-dimethylformamide (10 ml). After reacting at this temperature for 0.5 hour, 2,8-dichloroquinoline (40 mg, 0.72 mmol) was added. The mixture was moved to room temperature and reacted for 3 hours. The reaction was monitored by TLC until completion.

[0171] 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), 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 = 1 / 5) to give 200 mg of yellow oily tert-butyl 3-((8-chloroquinolin-2-yl)oxy)-3-(4-(trifluoromethoxy)phenyl)azetidine-1-carboxylate (yield: 67.35%).

[0172] Step C: Synthesis of 8-chloro-2-((3-(4-(trifluoromethoxy)phenyl)azetidin-3-yl)oxy)quinoline

[0173] At room temperature, a 4M solution of dioxane hydrochloride (0.12 ml, 0.48 mmol) was added dropwise to a solution of tert-butyl 3-((8-chloroquinolin-2-yl)oxy)-3-(4-(trifluoromethoxy)phenyl)azetidine-1-carboxylate (200 mg, 0.40 mmol) in methanol (5 ml). The reaction was then maintained at this temperature for 3 h. TLC monitoring indicated the reaction was complete. Excess solvent was removed by vortexing, and the residue was poured into water. The pH was adjusted to a weakly alkaline state with saturated sodium bicarbonate solution, followed by extraction 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 HPLC to yield 96 mg of 8-chloro-2-((3-(4-(trifluoromethoxy)phenyl)azetidin-3-yl)oxy)quinoline (yield: 60.17%).

[0174] LCMS: RT = 1.63 min, [M+H] + =394.86. 1 H NMR (400MHz, DMSO-d6) δ9.22 (s, 1H), 8.42 (d, J = 8.9Hz, 1H), 7.94–7.88 (m, 3H), 7.85 (dd,J=7.7,1.3Hz,1H),7.49–7.39(m,3H),7.27(d,J=8.9Hz,1H),4.82–4.71(m,4H).

[0175] Example 16 Synthesis of 1-(8-chloroquinolin-2-yl)-2-cyclopropyl-1-(4-(trifluoromethoxy)phenyl)ethyl-1-ol

[0176]

[0177] Step A: Synthesis of (8-chloroquinolin-2-yl)(4-(trifluoromethoxy)phenyl)methanone

[0178] Under ice, (8-chloroquinolin-2-yl)(4-(trifluoromethoxy)phenyl)methanol (0.1 g, 0.28 mmol) was added to a dichloromethane solution (5 mL). Dess-Martin periodinane (0.12 g, 0.28 mmol) was then added. The mixture was allowed to react at room temperature for 1 h. TLC indicated completion of the reaction, and the reaction solution was quenched by addition of saturated aqueous sodium bicarbonate. Extraction was performed three times with dichloromethane, and the organic layer was washed with brine and dried over magnesium sulfate. The residue was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 4 / 1) to afford 80 mg of (8-chloroquinolin-2-yl)(4-(trifluoromethoxy)phenyl)methanone as a yellow solid (yield: 80.46%).

[0179] Step B: 1-(8-chloroquinolin-2-yl)-2-cyclopropyl-1-(4-(trihydromethoxy)phenyl)ethyl-1-ol

[0180] Under ice-cooling, (8-chloroquinolin-2-yl)(4-(trifluoromethoxy)phenyl)methanone (0.1 g, 0.28 mmol) was added to a tetrahydrofuran solution (10 mL). Cyclopropylmethylmagnesium bromide (0.34 mL, 0.34 mmol) was slowly added dropwise and allowed to react under ice-cooling for 1 h. TLC indicated the reaction was complete, and the reaction solution was quenched by adding aqueous ammonium chloride. Extraction was performed three times with ethyl acetate, and the organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to obtain the residue. HPLC was used to obtain 20 mg of 1-(8-chloroquinolin-2-yl)-2-cyclopropyl-1-(4-(trifluoromethoxy)phenyl)ethyl-1-ol as a yellow oil (yield: 17.25%).

[0181] LCMS: RT = 2.37 min, [M+H] + =407.90.

[0182] Example 17 Synthesis of 1-(8-chloroquinolin-2-yl)-2-cyclopropyl-1-(4-(trifluoromethoxy)phenyl)ethyl-1-ol

[0183]

[0184] Under ice-cooling, (8-chloroquinolin-2-yl)(4-(trifluoromethoxy)phenyl)methanone (0.1 g, 0.28 mmol) was added to a tetrahydrofuran solution (10 mL). Cyclopropylmethylmagnesium bromide (0.36 mL, 0.36 mmol) was slowly added dropwise and allowed to react under ice-cooling for 1 h. TLC indicated the reaction was complete, and the reaction solution was quenched by adding aqueous ammonium chloride. Extraction was performed three times with ethyl acetate, and the organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to obtain the residue, which was then purified by HPLC to yield 17 mg of 1-(8-chloroquinolin-2-yl)-1-(4-(trifluoromethoxy)phenyl)ethyl-1-ol as a yellow oil (yield: 16.88%).

[0185] LCMS: RT = 2.25 min, [M+H] + =367.94. 1 H NMR(400MHz,DMSO-d6)δ8.41(d,J=8.7Hz,1H),8.00-7.93(m,2H),7.87(d,J=8.6Hz,1H) ,7.73-7.67(m,2H),7.59(t,J=7.8Hz,1H),7.33-7.27(m,2H),6.42(s,1H),2.06(s,3H).

[0186] Example 18 Synthesis of 2-(8-chloroquinolin-2-yl)-3-hydroxy-2-(4-(trifluoromethoxy)phenyl)propionitrile

[0187]

[0188] Step A: Synthesis of 2-(8-chloroquinolin-2-yl)-2-(4-(trifluoromethoxy)phenyl)acetonitrile

[0189] Under ice, sodium bicarbonate (0.81 g, 33.55 mmol) was added portionwise to 2-(4-(trifluoromethoxy)phenyl)acetonitrile (4.5 g, 22.37 mmol) dissolved in N,N-dimethylformamide (50 mL). The mixture reacted at this temperature for 30 min. After addition, 2,8-dichloroquinoline (5.32 g, 26.84 mmol) was added. The mixture was allowed to react at room temperature overnight. TLC monitored the reaction until completion. The reaction solution was poured into water and extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated brine (150 mL x 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / n-hexane = 1 / 5) to afford 3.5 g of 2-(8-chloroquinolin-2-yl)-2-(4-(trifluoromethoxy)phenyl)acetonitrile as a pale yellow solid (yield: 43.13%).

[0190] Step B: 2-(8-chloroquinolin-2-yl)-3-hydroxy-2-(4-(trifluoromethoxy)phenyl)propionitrile

[0191] Under ice, sodium bicarbonate (0.02 g, 0.83 mmol) was added portionwise to 2-(8-chloroquinolin-2-yl)-2-(4-(trifluoromethoxy)phenyl)acetonitrile (0.2 g, 0.55 mmol) in N,N-dimethylformamide (6 mL). The reaction was allowed to proceed at this temperature for 30 min. After addition, paraformaldehyde (0.41 g, 2.75 mmol) was added. The mixture was allowed to react at room temperature overnight. LC-MS monitoring revealed that the reaction was complete. The reaction solution was poured into water and extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated brine (150 mL × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by HPLC to yield 110 mg of 2-(8-chloroquinolin-2-yl)-3-hydroxy-2-(4-(trifluoromethoxy)phenyl)propionitrile as a pale yellow solid (yield: 50.79%).

[0192] LCMS: RT = 2.14 min, [M+H] + =392.93. 1 H NMR(400MHz,DMSO-d6)δ8.56–8.45(m,1H),8.08–7.98(m,2H),7.80–7.62(m,4H),7.49–7.4 1(m,2H),5.90(t,J=5.5Hz,1H),4.69(dd,J=10.9,5.4Hz,1H),4.45(dd,J=10.9,5.8Hz,1H).

[0193] Example 19 Synthesis of 8-chloro-N-(4-((fluoromethyl)sulfonyl)phenyl)quinolin-2-amine

[0194]

[0195] Step A: Synthesis of (Fluoromethyl)(4-nitrophenyl)sulfane

[0196] 4-Nitrobenzenethiol (400 mg, 2.58 mmol), iodomethane (450 mg, 2.84 mmol), and cesium carbonate (1680 mg, 5.16 mmol) were added to N,N-dimethylformamide (6 mL) at room temperature and allowed to react for 2 hours. TLC was used to monitor the reaction until completion. The reaction solution was poured into water and extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated brine (150 mL x 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield 0.36 g of (fluoromethyl)(4-nitrophenyl)sulfane as a pale yellow solid (yield: 74.60%).

[0197] Step B: Synthesis of 1-((fluoromethyl)sulfonyl)-4-nitrobenzene

[0198] At room temperature, m-chloroperbenzoic acid (1.29 g, 7.48 mmol) was added portionwise to a solution of (fluoromethyl)(4-nitrophenyl)sulfane (0.56 g, 2.99 mmol) in dichloromethane (30 mL). The mixture was allowed to react for 2 hours at room temperature. TLC was used to monitor the reaction until completion. The reaction solution was quenched with saturated sodium thiosulfate solution and saturated sodium bicarbonate solution, then extracted with dichloromethane (100 mL x 3). The combined organic phases were washed with saturated brine (150 mL x 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield 0.43 g of 1-((fluoromethyl)sulfonyl)-4-nitrobenzene as a white solid (yield: 65.38%).

[0199] Step C: Synthesis of 4-((fluoromethyl)sulfonyl)aniline

[0200] 10% palladium on carbon (0.21 g, 1.96 mmol) was added to a solution of 1-((fluoromethyl)sulfonyl)-4-nitrobenzene (0.43 g, 1.96 mmol) in methanol (6 mL) at room temperature. The mixture was then reacted under a hydrogen atmosphere at room temperature for 4 hours. TLC confirmed the completion of the reaction. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to afford 0.32 g of 4-((fluoromethyl)sulfonyl)aniline as a colorless oil (yield: 86.21%).

[0201] Step D: Synthesis of 8-chloro-N-(4-((fluoromethyl)sulfonyl)phenyl)quinolin-2-amine

[0202] 2,8-Dichloroquinoline (0.33 g, 1.69 mmol) and 4-((fluoromethyl)sulfonyl)aniline (0.32 g, 1.69 mmol) were added to isopropanol (6 mL) at room temperature, followed by the dropwise addition of trifluoroacetic acid (0.19 g, 1.69 mmol). After addition, the temperature was raised to 80°C and the reaction was allowed to react overnight. TLC monitored the reaction completion, and the reaction solution was concentrated. The resulting crude product was separated by preparative HPLC to afford 0.4 g of 8-chloro-N-(4-((fluoromethyl)sulfonyl)phenyl)quinolin-2-amine as a brown solid (yield: 67.42%).

[0203] LCMS: RT = 2.11 min, [M+H] + =350.79. 1 H NMR (400MHz, DMSO-d6) δ10.40(s,1H),8.50(d,J=8.7Hz,2H),8.28(d,J=8.9Hz,1H),7.92(d,J=8.7Hz,2H ),7.85(dd,J=14.1,7.8Hz,2H),7.39(t,J=7.8Hz,1H),7.27(d,J=8.8Hz,1H),5.72(s,1H),5.61(s,1H).

[0204] Example 20 Synthesis of 8-chloro-2-(piperazin-1-yl(4-(trifluoromethoxy)phenyl)methyl)quinoline

[0205]

[0206] Step A: Synthesis of 8-chloro-2-(chloro(4-(trifluoromethoxy)phenyl)methyl)quinoline

[0207] The compound (8-chloroquinolin-2-yl)(4-(trifluoromethoxy)phenyl)methanol (120 mg, 0.34 mmol) was dissolved in dichloromethane (5 mL), and thionyl chloride (80 mg, 0.68 mmol) was added. The mixture was allowed to react at room temperature for 5 hours. After the reaction, the mixture was concentrated to obtain 0.15 g of the crude product (8-chloro-2-(chloro(4-(trifluoromethoxy)phenyl)methyl)quinoline) as a yellow solid, which was used directly in the next reaction. RT = 2.32 min, [M+H] + =371.91

[0208] Step B: Synthesis of 8-chloro-2-(piperazin-1-yl(4-(trifluoromethoxy)phenyl)methyl)quinoline

[0209] (8-Chloro-2-(chloro(4-(trifluoromethoxy)phenyl)methyl)quinoline (150 mg, 0.34 mmol) was dissolved in acetonitrile (10 ml), and piperazine (0.23 g, 2.7 mmol) was added. The temperature was raised to 70° C. and the reaction was allowed to proceed overnight under nitrogen. After completion of the reaction, the mixture was diluted with ethyl acetate and quenched with water. The pH was adjusted to 8-9 with solid sodium carbonate. The layers were separated, and the aqueous phase was extracted twice with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1). The resulting crude product was separated by preparative separation to obtain 46 mg of 8-chloro-2-(piperazin-1-yl(4-(trifluoromethoxy)phenyl)methyl)quinoline as a white solid (yield: 20%).

[0210] LCMS: RT = 1.88 min, [M+H] + =421.95. 1 H NMR (400MHz, DMSO-d6) δ8.52(s,1H),8.46(d,J=8.4Hz,1H),7.95(dd,J=8.0,4.4Hz,2H),7.84(d,J=8.4Hz ,1H),7.67(d,J=8.4Hz,2H),7.57(t,J=8.0Hz,1H),7.36(d,J=8.4Hz,1H),4.97(s,1H),2.75–2.53(m,8H).

[0211] Example 21 Synthesis of N'-(8-chloroquinolin-2-yl)-4-(trifluoromethoxy)benzohydrazide

[0212]

[0213] 2-8-Dichloroquinoline (100 mg, 0.5 mmol) and 4-trifluoromethoxybenzohydrazide (110 mg, 0.5 mmol) were added to isopropanol (5 ml) at room temperature. Trifluoroacetic acid (110 mg, 1.0 mmol) was then added and the mixture was heated to 80°C and allowed to react overnight. After completion of the reaction, the reaction solution was diluted with methanol, made alkaline with triethylamine, and concentrated. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3 / 1). After lyophilization, 29 mg of N'-(8-chloroquinolin-2-yl)-4-(trifluoromethoxy)benzohydrazide was obtained as a yellow solid (yield: 14%).

[0214] LCMS: RT = 2.05 min, [M+H] + =381.94. 1 H NMR(400MHz,DMSO-d6)δ10.66(s,1H),9.33(s,1H),8.18–8.08(m,3H),7.72(t,J =6.8Hz,2H),7.53(d,J=8.4Hz,2H),7.23(t,J=7.6Hz,1H),7.05(d,J=8.8Hz,1H).

[0215] Example 22 Synthesis of 8-chloro-2-((2,2-difluorobenzo[d][1,3]dihydroxy-5-yl)oxy)quinoline

[0216]

[0217] 2-8-Dichloroquinoline (70 mg, 0.35 mmol) and 2,2-difluorobenzo[d][1,3]dioxolane (70 mg, 0.4 mmol) were added to N,N-dimethylformamide (5 mL) at room temperature. Cuprous iodide (10 mg, 0.073 mmol) and cesium carbonate (280 mg, 0.86 mmol) were then added. The mixture was heated to 150°C under nitrogen for 1 hour. After completion of the reaction, the reaction solution was diluted with ethyl acetate and filtered. The filtrate was poured into water, separated, and the aqueous phase was extracted once with ethyl acetate. The combined organic phases were washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 10 / 1). After lyophilization, 70 mg of 8-chloro-2-((2,2-difluorobenzo[d][1,3]dihydroxy-5-yl)oxy)quinoline was obtained as a white solid (yield: 57%).

[0218] LCMS: RT = 2.28 min, [M+H] + =335.93. 1 H NMR (400MHz, DMSO-d6) δ8.51(d,J=8.8Hz,1H),7.96(dd,J=8.0,1.2Hz,1H),7.87(dd,J=7.6,1.2Hz ,1H),7.63(d,J=2.4Hz,1H),7.53–7.44(m,2H),7.38(d,J=8.8Hz,1H),7.20(dd,J=8.8,2.4Hz,1H).

[0219] Example 23 Synthesis of N-((3s, 5s, 7s)-adamantane-1-yl)-8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine

[0220]

[0221] Step A: Synthesis of (3s, 5s, 7s)-N-(4-(trifluoromethoxy)phenyl)adamantan-1-amine

[0222] Compound (3s,5s,7s)-adamantan-1-amine (1.0 g, 6.61 mmol), 4-trifluoromethoxybromobenzene (2.0 g, 8.33 mmol), tris(dibenzylideneacetone)dipalladium (0.2 g, 0.22 mmol), and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (0.25 g, 0.4 mmol) were added to toluene (10 ml). After stirring at room temperature for 10 minutes, sodium tert-butoxide (1.0 g, 10.4 mmol) was added. After replacing the nitrogen atmosphere, the mixture was heated to 110°C and allowed to react overnight. After completion of the reaction, the reaction solution was concentrated. The residue was purified by silica gel column chromatography (0-10% ethyl acetate / n-hexane). 1.2 g of (3s,5s,7s)-N-(4-(trifluoromethoxy)phenyl)adamantan-1-amine was obtained as a yellow solid (yield: 58%). RT=2.05min,[M+H] + =312.05

[0223] Step B: Synthesis of N-((3s,5s,7s)-adamantan-1-yl)-8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine

[0224] Compound (3s,5s,7s)-N-(4-(trifluoromethoxy)phenyl)adamantan-1-amine (0.5 g, 1.61 mmol), 2,8-dichloroquinoline (0.5 g, 2.52 mmol), tris(dibenzylideneacetone)dipalladium (0.15 g, 0.16 mmol), and tri-tert-butylphosphine (0.68 g, 0.34 mmol, 10% wt in pentane) were added to toluene (10 ml). After stirring at room temperature for 10 minutes, sodium tert-butoxide (0.335 g, 3.49 mmol) was added. After nitrogen displacement, the mixture was heated to 105°C and reacted for 48 hours. After completion of the reaction, the reaction solution was concentrated. The residue was purified by silica gel column chromatography (100% n-hexane). The crude product was dissolved in acetonitrile and precipitated, filtered, and lyophilized to yield 31 mg of a white solid product, N-((3s, 5s, 7s)-adamantan-1-yl)-8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine (yield: 3.92%). RT = 3.21 min, [M+H] + =472.89. 1 H NMR (400MHz, DMSO-d6) δ7.83(d,J=9.2Hz,1H),7.74(dd,J=7.6,1.2Hz,1H),7.61(dd,J=8.0,1.2Hz,1H),7.53–7.44(m,2H ),7.38(d,J=8.8Hz,2H),7.20(t,J=7.6Hz,1H),6.06(d,J=9.2Hz,1H),2.45–2.35(m,6H),2.09(s,3H),1.79–1.58(m,6H).

[0225] Example 24 Synthesis of (8-chloroquinolin-2-yl)(4-(difluoromethoxy)phenyl)methanamine

[0226]

[0227] Step A: Synthesis of (E)-(8-chloroquinolin-2-yl)(4-(trifluoromethoxy)phenyl)methanone oxime

[0228] To a solution of 8-chloro-2-(4-(trifluoromethoxy)benzoyl)quinoline (100 mg, 0.28 mmol) in ethanol (5 mL) at room temperature were added hydroxylamine hydrochloride (29.19 mg, 0.42 mmol) and sodium acetate (45.94 mg, 0.56 mmol) in sequence. The mixture was heated to 80°C and allowed to stand overnight. After the reaction, the reaction mixture was evaporated to dryness. The resulting crude brown oil, (E)-(8-chloroquinolin-2-yl)(4-(trifluoromethoxy)phenyl)methanone oxime (100 mg), was used directly in the next reaction.

[0229] Step B: Synthesis of (8-chloroquinolin-2-yl)(4-(trifluoromethoxy)phenyl)methanamine

[0230] To a solution of (E)-(8-chloroquinolin-2-yl)(4-(trifluoromethoxy)phenyl)methanone oxime (100 mg, 0.27 mmol) in acetic acid (5 mL) and ethanol (5 mL) was slowly added zinc powder (176.61 mg, 2.7 mmol) at room temperature. The mixture was stirred at room temperature for 4 hours. After the reaction, the reaction mixture was dried and purified by preparative HPLC to obtain 59.7 mg of (8-chloroquinolin-2-yl)(4-(trifluoromethoxy)phenyl)methanamine (yield: 62.07%) as a colorless oil. LC-MS: RT = 1.65 min, [M+H] + =353.22. 1 H NMR (400MHz, DMSO-d6) δ8.94(s,2H),8.52(d,J=8.5Hz,1H),8.04(ddd,J=12.2,7.9,1 .3Hz,2H),7.73–7.62(m,3H),7.58(d,J=8.5Hz,1H),7.50–7.45(m,2H),6.08(s,1H).

[0231] Example 25 Synthesis of N-((8-chloroquinolin-2-yl)(4-(trifluoromethoxy)phenyl)methyl)cyclopropylamine

[0232]

[0233] To a solution of 8-chloro-2-(chloro(4-(trifluoromethoxy)phenyl)methyl)quinoline (250 mg, 0.67 mmol) in acetonitrile (5 mL) was added cyclopropaneamine (382.50 mg, 6.7 mmol) at room temperature. The mixture was heated to 70°C and allowed to react overnight. After the reaction, the reaction mixture was spin-dried and purified by preparative chromatography to obtain 108.7 mg of N-((8-chloroquinolin-2-yl)(4-(trifluoromethoxy)phenyl)methyl)cyclopropaneamine (yield: 40.93%). LC-MS: RT = 1.91 min, [M+H] + =392.98. 1 HNMR (400MHz, DMSO-d6) δ8.40(d,J=8.5Hz,1H),7.93(d,J=7.8Hz,2H),7.78(d,J=8.5Hz,1H),7.65–7.47(m,3H),7. 38–7.22(m,2H),5.24(d,J=7.9Hz,1H),3.69(dd,J=8.2,2.8Hz,1H),2.05–1.88(m,1H),0.34(p,J=3.7,3.2Hz,4H).

[0234] Example 26 Synthesis of 2-(((8-chloroquinolin-2-yl)(4-(trifluoromethoxy)phenyl)methyl)amino)ethan-1-ol

[0235]

[0236] To a solution of 8-chloro-2-(chloro(4-(trifluoromethoxy)phenyl)methyl)quinoline (130 mg, 0.35 mmol) in acetonitrile (5 mL) was added ethanolamine (213.78 mg, 3.5 mmol) at room temperature. The mixture was heated to 70°C and stirred overnight. After the reaction, the reaction mixture was spin-dried to obtain 124.4 mg of 2-(((8-chloroquinolin-2-yl)(4-(trifluoromethoxy)phenyl)methyl)amino)ethan-1-ol as a colorless oil (yield: 89.47%). LC-MS: RT = 1.75 min, [M+H] + =396.98. 1 H NMR (400MHz, DMSO-d6) δ8.40(d,J=8.6Hz,1H),7.93(d,J=7.8Hz,2H),7.74(d,J=8.5Hz,1H),7.68–7.49(m,3H),7. 40–7.23(m,2H),5.20(s,1H),4.55(t,J=5.4Hz,1H),3.52(q,J=5.7Hz,2H),3.07(s,1H),2.58(hept,J=5.7Hz,2H).

[0237] Example 27 Synthesis of 3-(8-chloroquinolin-2-yl)-3-(4-(trifluoromethoxy)phenyl)propan-1-ol

[0238]

[0239] Step A: Synthesis of ethyl (E)-3-(8-chloroquinolin-2-yl)acrylate

[0240] At room temperature, a three-necked flask was charged with 2,8-dichloroquinoline (800 mg, 4.04 mmol), ethyl (2E)-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-enoate (1096.04 mg, 4.85 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (295.61 mg, 0.40 mmol), and sodium carbonate (5566.59 mg, 52.52 mmol). The atmosphere was replaced with nitrogen three times, and then dioxane (5 mL) and water (1 mL) were added. After addition, the mixture was stirred at 90°C for 2 hours. After the reaction, the mixture was diluted with water and extracted with dichloromethane (10 mL*3). The organic phases were combined, washed with saturated brine (20 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 ethyl (E)-3-(8-chloroquinolin-2-yl)acrylate (yield: 37.84%).

[0241] Step B: Synthesis of ethyl 3-(8-chloroquinolin-2-yl)-3-(4-(trifluoromethoxy)phenyl)propionate

[0242] To a mixture of ethyl (E)-3-(8-chloroquinolin-2-yl)acrylate (150 mg, 0.57 mmol) in dioxane (4 mL) and water (1 mL) at room temperature were added 4-trifluoromethoxyphenylboronic acid (152.59 mg, 0.74 mmol), (1,5-cyclooctadiene)chlororhodium(I) dimer (14.05 mg, 0.028 mmol), and triethylamine (173.03 mg, 1.71 mmol). After the addition, the temperature was raised to 90°C and heated overnight. After the reaction, the mixture was diluted with water and extracted with dichloromethane (10 mL*3). The organic phases were combined, washed with saturated brine (20 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 give 100 mg of ethyl 3-(8-chloroquinolin-2-yl)-3-(4-(trifluoromethoxy)phenyl)propanoate (yield: 41.17%).

[0243] Step C: Synthesis of 3-(8-chloroquinolin-2-yl)-3-(4-(trifluoromethoxy)phenyl)propan-1-ol

[0244] To a solution of ethyl 3-(8-chloroquinolin-2-yl)-3-(4-(trifluoromethoxy)phenyl)propanoate (100 mg, 0.24 mmol) in tetrahydrofuran (3 mL) was added lithium aluminum hydride (18.22 mg, 0.48 mmol) under ice-cooling. Stirring was continued under ice-cooling for 1 hour. After the reaction was complete, water (1 mL) was added to quench the reaction, yielding 79.4 mg of 3-(8-chloroquinolin-2-yl)-3-(4-(trifluoromethoxy)phenyl)propan-1-ol as a colorless oil (yield: 88.14%). LC-MS: RT = 2.20 min, [M+H] + =381.93. 1 H NMR(400MHz, DMSO-d6)δ8.34(d,J=8.5Hz,1H),7.92(ddd,J=8.2,5.3,1.3Hz,2H),7.65–7.48(m,4H),7.37–7.2 1(m,2H),4.65–4.49(m,2H),3.36(td,J=5.6,5.1,3.2Hz,2H),2.56(dd,J=13.7,6.7Hz,1H),2.33–2.12(m,1H).

[0245] Example 28 Synthesis of 1-(8-chloroquinolin-2-yl)-N,N-dimethyl-1-(4-(trifluoromethoxy)phenyl)methanamine

[0246]

[0247] To a solution of (8-chloroquinolin-2-yl)(4-(trifluoromethoxy)phenyl)methanamine (130 mg, 0.37 mmol) in tetrahydrofuran (5 mL) was added sodium hydride (29.60 mg, 0.74 mmol) under ice-cooling. After stirring on ice for 1 hour, iodomethane (105.04 mg, 0.74 mmol) was added, and the mixture was returned to room temperature and stirred overnight. After completion of the reaction, the mixture was quenched with water (1 mL) to obtain 32.61 mg of 1-(8-chloroquinolin-2-yl)-N,N-dimethyl-1-(4-(trifluoromethoxy)phenyl)methanamine (yield: 23.16%) as a colorless oil. LC-MS: RT = 1.77 min, [M+H] + =381.02.

[0248] Example 29 Synthesis of 8-chloro-2-(4-(trifluoromethoxy)benzyl)quinoline

[0249]

[0250] To a mixture of 2,8-dichloroquinoline (1 g, 5.05 mmol), 4,4,5,5-tetramethyl-2-[(4-(trifluoromethoxy)phenyl)methyl]-1,3,2-dioxaborolane (1.83 g, 6.06 mmol), bis(tri-tert-butylphosphine)palladium (0.26 g, 0.51 mmol), and potassium carbonate (2.09 g, 15.15 mmol) was added dioxane (10 ml) and water (2 ml) at room temperature. After the addition, the atmosphere was purged with nitrogen three times, then the temperature was raised to 90°C and the mixture was heated overnight. After the reaction was completed, the mixture was diluted with water and extracted with dichloromethane (10 mL x 3). The organic phases were combined, washed with saturated brine (10 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 / 3) to obtain 1.1 g of 8-chloro-2-(4-(trifluoromethoxy)benzyl)quinoline as a colorless oil (yield: 64.51%). LC-MS: RT = 2.30 min, [M+H] + =337.96. 1 H NMR (400MHz, DMSO-d6) δ8.35(d,J=8.4Hz,1H),7.91(d,J=7.8Hz,2H),7.57–7.44(m,4H),7.32–7.25(m,2H),4.36(s,2H).

[0251] Example 30 2-((8-chloroquinolin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)acetic acid

[0252]

[0253] Step A: Synthesis of ethyl 2-diazo-2-(4-(trifluoromethoxy)phenyl)acetate

[0254] Ethyl 2-(4-(trifluoromethoxy)phenyl)acetate (0.50 g, 2.01 mmol), p-toluenesulfonyl azide (0.59 g, 3.00 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.45 g, 1.50 mmol) were dissolved in acetonitrile (5 mL) and allowed to react at room temperature for 24 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 to afford 350 mg of ethyl 2-diazo-2-(4-(trifluoromethoxy)phenyl)acetate as a red solid (yield: 75.05%).

[0255] Step B Synthesis of ethyl 2-((8-chloroquinolin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)acetate

[0256] Ethyl 2-diazo-2-(4-(trifluoromethoxy)phenyl)acetate (0.20 g, 0.47 mmol), 8-chloroquinolin-2-amine (0.59 g, 0.31 mmol), and palladium dichloride (9.37 mg, 0.05 mmol) were dissolved in 1,2-dichloroethane (10 mL) and reacted at 80°C for 12 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 to obtain a residue. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 5 / 1) to obtain 150 mg of ethyl 2-((8-chloroquinolin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)acetate as a red solid (yield: 75.37%).

[0257] Step C Synthesis of 2-((8-chloroquinolin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)acetic acid

[0258] Ethyl 2-((8-chloroquinolin-2-yl)amino)-2-(4-(trifluoromethoxy)phenyl)acetate (0.153 g, 0.35 mmol) and sodium hydroxide (0.14 g, 3.5 mmol) were dissolved in a 3:1 tetrahydrofuran:water (8 mL) solution and heated to 50°C for 8 hours at room temperature. 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 to afford a residue. HPLC analysis yielded 40.15 mg of 1-chloro-N-(4-(trifluoromethoxy)phenyl)naphthalen-2-amine as a white solid (yield: 28.95%). LCMS: RT = 2.02 min, [M+H] + =396.89. 1 H NMR(400MHz, DMSO-d6)δ8.15(s,1H),8.01(d,J=8.9Hz,1H),7.74–7.63(m,4H),7.43( d,J=8.2Hz,2H),7.19(t,J=7.7Hz,1H),7.11(d,J=8.9Hz,1H),5.83(d,J=4.7Hz,1H).

[0259] Example 31 Synthesis of (2S,3R,4S,5R,6R)-2-(4-(((8-chloroquinolin-2-yl)(4-(trifluoromethoxy)phenyl)methyl)amino)phenoxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

[0260]

[0261] Step A: Synthesis of (8-chloroquinolin-2-yl)(4-(trifluoromethoxy)phenyl)methanol

[0262] 8-Chloroquinoline-2-carbaldehyde (0.50 g, 2.61 mmol) was dissolved in ultra-dry tetrahydrofuran (5 ml) at -20°C, and (4-(trifluoromethoxy)phenyl)magnesium bromide (7.84 ml, 3.92 mmol) was added dropwise. After the addition was complete, the mixture was reacted at room temperature for 8 hours. After the reaction was complete, 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 to obtain a residue, which was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 5 / 1) to obtain 250 mg of (8-chloroquinolin-2-yl)(4-(trifluoromethoxy)phenyl)methanol as a yellow solid (yield: 41.28%).

[0263] Step B: Synthesis of 2-(bromo(4-(trifluoromethoxy)phenyl)methyl)-8-chloroquinoline

[0264] (8-Chloroquinolin-2-yl)(4-(trifluoromethoxy)phenyl)methanol (0.20 g, 0.56 mmol), carbon tetrabromide (0.35 g, 1.12 mmol), and triphenylphosphine (0.29 g, 1.12 mmol) were dissolved in ultra-dry dichloromethane (5 ml) and allowed to react at room temperature for 8 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 = 2 / 1) to provide 201 mg of 2-(bromo(4-(trifluoromethoxy)phenyl)methyl)-8-chloroquinoline as a yellow solid (yield: 76.23%).

[0265] Step C: Synthesis of (2S,3R,4S,5R,6R)-2-(4-(((8-chloroquinolin-2-yl)(4-(trifluoromethoxy)phenyl)methyl)amino)phenoxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

[0266] 2-(Bromo(4-(trifluoromethoxy)phenyl)methyl)-8-chloroquinoline (0.20 g, 0.56 mmol), (2S,3R,4S,5R,6R)-2-(4-aminophenoxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (0.37 g, 1.12 mmol), and potassium carbonate (0.29 g, 1.12 mmol) were dissolved in acetonitrile (5 mL) and reacted at 80°C for 8 hours at room temperature. 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 to obtain a residue. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 5 / 1) and then purified by high-performance liquid chromatography to obtain 90.50 mg of 2-(bromo(4-(trifluoromethoxy)phenyl)methyl)-8-chloroquinoline as a yellow solid (yield: 26.52%). LCMS: RT = 2.02 min, [M+H] +=606.91. 1 H NMR (400MHz, DMSO-d6) δ8.45(d,J=8.5Hz,1H),7.97(t,J=7.4Hz,2H),7.79(d,J=8.5Hz,1 H),7.67(d,J=8.5Hz,2H),7.59(t,J=7.8Hz,1H),7.36(d,J=8.2Hz,2H),6.85–6.78(m,2H ),6.67(dd,J=9.1,2.7Hz,2H),5.95(d,J=3.1Hz,1H),4.56(d,J=7.6Hz,1H),3.66(d,J=3 .4Hz,2H),3.53(dd,J=12.9,8.3Hz,1H),3.49–3.43(m,3H),3.34(dd,J=9.6,3.3Hz,1H).

[0267] Example 32 Synthesis of 8-chloro-N-(4,4-difluorocyclohexyl)-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine

[0268]

[0269] Step A: Synthesis of N-(4,4-difluorocyclohexyl)-4-(trifluoromethoxy)aniline

[0270] Under N2 protection, 1-bromo-4-(trifluoromethoxy)benzene (0.26 g, 1.08 mmol), 4,4-difluorocyclohexylamine (0.16 g, 1.19 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.099 g, 0.11 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (0.13 g, 0.22 mmol) and sodium tert-butoxide (0.31 g, 3.24 mmol) were added to toluene (6 ml), the temperature was raised to 100°C and stirred for 12 hours. The reaction was monitored by LC-MS until completion.

[0271] 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 = 0-10%) to obtain 0.3 g of N-(4,4-difluorocyclohexyl)-4-(trifluoromethoxy)aniline as a colorless oil (yield: 94.19%). LCMS: RT = 2.14 min, [M+H] + =295.95.

[0272] Step B: Synthesis of 8-chloro-N-(4,4-difluorocyclohexyl)-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine

[0273] Under N2 protection, N-(4,4-difluorocyclohexyl)-4-(trifluoromethoxy)aniline (0.3 g, 1.02 mmol), 2,8-dichloroquinoline (0.3 g, 1.53 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.093 g, 0.10 mmol), tri-tert-butylphosphine (0.041 g, 0.20 mmol) and sodium tert-butoxide (0.29 g, 3.06 mmol) were added to toluene (8 ml), the temperature was raised to 100 °C and stirred for 12 h. 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 crude product was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 0-10%). The resulting product was then slurried in 8 mL of a mixed solvent (dichloromethane / methanol = 1 / 10) for 5 h to obtain 0.21 g of 8-chloro-N-(4,4-difluorocyclohexyl)-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as a white solid (yield: 45.24%). LCMS: RT = 2.52 min, [M+H] + =456.80. 1 H NMR (400MHz, DMSO-d6) δ7.97(d,J=9.2Hz,1H),7.78(dd,J=7.6,1.3Hz,1H),7.70(dd,J=8.0,1.3Hz,1H),7.60–7.53(m,2H),7.50–7.43(m ,2H),7.28–7.20(m,1H),6.32(d,J=9.1Hz,1H),5.03(dd,J=13.6,10.1Hz,1H),2.21–2.08(m,5H),2.07–1.93(m,1H),1.61–1.47(m,2H).

[0275] Example 33 Synthesis of 3-((8-chloroquinolin-2-yl)(4-(trifluoromethoxy)phenyl)amino)cyclohexane-1-carboxylic acid

[0276]

[0277] Step A: Synthesis of 3-((4-(trifluoromethoxy)phenyl)amino)cyclohexane-1-carboxylic acid

[0278] Under N2 protection, 3-aminocyclohexanecarboxylic acid (0.5 g, 3.49 mmol), 1-bromo-4-(trifluoromethoxy)benzene (0.93 g, 3.84 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.32 g, 0.35 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (0.43 g, 0.70 mmol) and sodium tert-butoxide (0.34 g, 3.49 mmol) were added to toluene (6 ml), the temperature was raised to 100°C and stirred for 12 hours. The reaction was monitored by LC-MS until completion.

[0279] 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 = 0-25%) to obtain 0.49 g of 3-((4-(trifluoromethoxy)phenyl)amino)cyclohexane-1-carboxylic acid as a brown oil (yield: 46.27%). LCMS: RT = 2.06 min, [MH] - =302.03.

[0280] Step B: Synthesis of 3-((8-chloroquinolin-2-yl)(4-(trifluoromethoxy)phenyl)amino)cyclohexane-1-carboxylic acid

[0281] Under N2 protection, 3-((4-(trifluoromethoxy)phenyl)amino)cyclohexane-1-carboxylic acid (0.49 g, 1.62 mmol), 2,8-dichloroquinoline (0.48 g, 2.43 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.15 g, 0.16 mmol), tri-tert-butylphosphine (0.066 g, 0.32 mmol) and sodium tert-butoxide (0.47 g, 4.86 mmol) were added to toluene (8 ml), the temperature was raised to 100 °C and stirred for 12 h. The reaction was monitored by LC-MS until completion.

[0282] 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 = 0-20%). The resulting product was then slurried in 8 ml of a mixed solvent (dichloromethane / methanol = 1 / 10) for 5 h to obtain 0.32 g of 3-((8-chloroquinolin-2-yl)(4-(trifluoromethoxy)phenyl)amino)cyclohexane-1-carboxylic acid as a white solid (yield: 42.61%). LCMS: RT = 2.34 min, [M+H] + =464.97. 1H NMR (400MHz, DMSO-d6) δ12.15(s,1H),7.95(d,J=9.2Hz,1H),7.76(dd,J=7.6, 1.4Hz,1H),7.68(dd,J=8.0,1.3Hz,1H),7.60–7.52(m,2H),7.49–7.41(m,2H) ,7.27–7.18(m,1H),6.29(d,J=9.1Hz,1H),5.10–4.97(m,1H),2.50–2.40(m,1 H), 2.29 (d, J = 12.1Hz, 1H), 2.03 (s, 1H), 1.92–1.81 (m, 2H), 1.57–1.08 (m, 4H).

[0283] Example 34 Synthesis of (1R,3S,5R,7S)-3-((8-chloroquinolin-2-yl)(4-(trifluoromethoxy)phenyl)amino)adamantane-1-carboxylic acid

[0284]

[0285] Step A: Synthesis of (1R, 3S, 5R, 7S)-3-aminoadamantane-1-carboxylic acid ethyl ester

[0286] At room temperature, 3-amino-1-adamantanecarboxylic acid hydrochloride (1.0 g, 4.32 mmol) was added to ethanol (20 mL), followed by thionyl chloride (2.57 g, 21.6 mmol). The mixture was heated to 80°C and allowed to react for 3 hours. After completion of the reaction, the reaction solution was concentrated and diluted with ethyl acetate. The mixture was adjusted to neutrality with saturated sodium bicarbonate aqueous solution. The layers were separated, and the aqueous phase was extracted five times with ethyl acetate / methanol (10 / 1). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to yield 0.9 g of crude (1R,3S,5R,7S)-3-aminoadamantane-1-carboxylic acid ethyl ester (yield: 94%) as a yellow oil. This was used directly in the next reaction. 1 H NMR (400MHz, Chloroform-d) δ4.10 (q, J = 7.2Hz, 2H), 2.21–2.15 (m, 2H), 1.85–1.69 (m, 6H), 1.64–1.55 (m, 8H), 1.23 (d, J = 7.2Hz, 3H).

[0287] Step B: Synthesis of (1R,3S,5R,7S)-3-((4-(trifluoromethoxy)phenyl)amino)adamantane-1-carboxylic acid ethyl ester

[0288] Ethyl (1R,3S,5R,7S)-3-aminoadamantane-1-carboxylate (0.8 g, 3.58 mmol), 4-trifluoromethoxybromobenzene (1.1 g, 4.56 mmol), tris(dibenzylideneacetone)dipalladium (0.16 g, 0.17 mmol), and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (240 mg, 0.39 mmol) were added to toluene (20 ml) and stirred at room temperature for 10 minutes. Sodium tert-butoxide (700 mg, 7.28 mmol) was then added. After nitrogen replacement, the mixture was heated to 100°C and allowed to react overnight. After completion of the reaction, the reaction solution was concentrated. The residue was purified by silica gel column chromatography (5-15% ethyl acetate / n-hexane). 240 mg of a light yellow solid product (1R,3S,5R,7S)-3-((4-(trifluoromethoxy)phenyl)amino)adamantane-1-carboxylic acid ethyl ester was obtained (yield: 17%). RT = 2.18 min, [M+H] + =383.94.

[0289] Step C: Synthesis of (1R,3S,5R,7S)-3-((8-chloroquinolin-2-yl)(4-(trifluoromethoxy)phenyl)amino)adamantane-1-carboxylic acid ethyl ester

[0290] At room temperature, ethyl (1R,3S,5R,7S)-3-((4-(trifluoromethoxy)phenyl)amino)adamantane-1-carboxylate (0.24 g, 0.63 mmol), 2,8-dichloroquinoline (0.3 g, 1.51 mmol), tris(dibenzylideneacetone)dipalladium (0.06 g, 0.066 mmol), and tri-tert-butylphosphine (0.24 g, 0.12 mmol, 10% wt in pentane) were added to toluene (20 ml). After stirring at room temperature for 10 minutes, sodium tert-butoxide (0.15 g, 1.56 mmol) was added. After nitrogen displacement, the mixture was heated to 105°C and allowed to react overnight. After completion of the reaction, the reaction solution was concentrated. The residue was purified by silica gel column chromatography (5-30% ethyl acetate / n-hexane). 100 mg of yellow solid product (1R,3S,5R,7S)-3-((8-chloroquinolin-2-yl)(4-(trifluoromethoxy)phenyl)amino)adamantane-1-carboxylic acid ethyl ester was obtained (yield: 29%). RT = 2.31 min, [M+H] + =544.79.

[0291] Step D: Synthesis of (1R,3S,5R,7S)-3-((8-fluoroquinolin-2-yl)(4-(trifluoromethoxy)phenyl)amino)adamantane-1-carboxylic acid

[0292] The compound (1R,3S,5R,7S)-3-((8-chloroquinolin-2-yl)(4-(trifluoromethoxy)phenyl)amino)adamantane-1-carboxylic acid ethyl ester was dissolved in a mixed solvent of tetrahydrofuran (10 mL), methanol (3 mL) and water (3 mL), and sodium hydroxide (0.1 g, 2.5 mmol) was added, and the reaction was carried out at 35°C overnight.

[0293] After the reaction, the reaction mixture was diluted with water, the pH adjusted to 5-6 with dilute hydrochloric acid, and extracted with ethyl acetate. The mixture was separated, and the aqueous phase was extracted once with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (0-10% ethyl acetate / n-hexane). The crude product was slurried with n-hexane / ethyl acetate = 5 / 1 to obtain a white solid. After lyophilization, 71 mg of the white solid product (1R,3S,5R,7S)-3-((8-chloroquinolin-2-yl)(4-(trifluoromethoxy)phenyl)amino)adamantane-1-carboxylic acid was obtained (yield: 72%). RT = 2.41 min, [M+H] + =516.96. 1 H NMR (400MHz, DMSO-d6) δ12.03(s,1H),7.85(d,J=9.3Hz,1H),7.74(dd,J=7.6,1.3Hz,1H),7.62(dd,J=8.0,1.4Hz,1H),7.50(d,J=8.3Hz,2H),7.44–7.37 (m,2H),7.21(t,J=7.8Hz,1H),6.06(d,J=9.2Hz,1H),2.65(s,2H),2.47(d,J =12.8Hz,2H),2.23–2.04(m,4H),1.87(d,J=12.2Hz,2H),1.78–1.51(m,4H).

[0294] Example 35 Synthesis of (1R,3S,5R,7S)-3-((8-chloroquinolin-2-yl)(4-(trifluoromethoxy)phenyl)amino)adamantan-1-ol

[0295]

[0296]

[0297] Step A: Synthesis of benzyl ((1R, 3S, 5R, 7S)-3-hydroxyadamantan-1-yl) carbamate

[0298] Compound (1R,3S,5R,7S)-3-aminoadamantan-1-ol (2.0 g, 11.96 mmol) and potassium carbonate (2.5 g, 18.09 mmol) were added to tetrahydrofuran (100 ml). After cooling in an ice-water bath, benzyl chloroformate (2.0 g, 11.72 mmol) was added dropwise and the mixture was reacted at room temperature for 3 hours.

[0299] After the reaction was completed, the reaction solution was diluted with water, and ethyl acetate was added for separation. The aqueous phase was extracted once with ethyl acetate, and the organic phases were combined and washed with 10% NaOH aqueous solution and brine in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a white solid product, benzyl ((1R, 3S, 5R, 7S)-3-hydroxyadamantan-1-yl)carbamate (yield: 88%). 1 H NMR(400MHz,Chloroform-d)δ7.40–7.27(m,5H),5.04(s,2H),4.69(s,1H),2.32–2 .23(m,2H),1.93(s,2H),1.89–1.81(m,4H),1.72–1.63(m,4H),1.55–1.40(m,3H).

[0300] Step B: Synthesis of benzyl ((1R, 3S, 5R, 7S)-3-((2-(trimethylsilyl)ethoxy)methoxy)adamantan-1-yl)carbamate

[0301] Dissolve ((1r,3s,5R,7S)-3-hydroxyadamantan-1-yl)carbamate (0.5 g, 1.66 mmol) and diisopropylethylamine (0.86 g, 6.64 mmol) in dichloromethane (5 mL). After cooling in an ice-water bath, add 2-(trimethylsilyl)ethoxymethyl chloride (0.6 g, 3.60 mmol) and allow to react overnight at room temperature. The reaction solution changes color from colorless to brown.

[0302] After completion of the reaction, the reaction solution was concentrated. The residue was purified by silica gel column chromatography (0-10% ethyl acetate / n-hexane). 0.61 g of the product, benzyl ((1R,3S,5R,7S)-3-((2-(trimethylsilyl)ethoxy)methoxy)adamantan-1-yl)carbamate, was obtained as a colorless oil (yield: 85%). 1H NMR(400MHz,Chloroform-d)δ7.37–7.29(m,5H),5.04(s,2H),4.79(s,2H),4.68(s,1H),3.66–3.59(m,2H),2.30–2 .23(m,2H),2.00(s,2H),1.94–1.82(m,4H),1.80–1.74(m,4H),1.57–1.52(m,2H),0.95–0.88(m,2H),0.02(s,9H).

[0303] Step C: Synthesis of (1R,3S,5R,7S)-3-((2-(trimethylsilyl)ethoxy)methoxy)adamantan-1-amine

[0304] Benzyl ((1R,3S,5R,7S)-3-((2-(trimethylsilyl)ethoxy)methoxy)adamantan-1-yl)carbamate (0.6 g, 1.39 mmol) was dissolved in methanol (10 mL). After replacing the nitrogen atmosphere, palladium on carbon (0.1 g, Purity 10%) was added. The atmosphere was replaced again with hydrogen and the reaction was allowed to react at room temperature for 2 hours. After completion of the reaction, the reaction solution was filtered through celite, and the filtrate was concentrated to obtain 0.4 g of (1R,3S,5R,7S)-3-((2-(trimethylsilyl)ethoxy)methoxy)adamantan-1-amine as a light yellow oil (yield: 96%). This product was used directly in the next reaction. RT = 1.77 min, [M+H] + =298.18

[0305] Step D: Synthesis of (1R,3S,5R,7S)-N-(4-(trifluoromethoxy)phenyl)-3-((2(trimethylsilyl)ethoxy)methoxy)adamantan-1-amine

[0306] Compound (1R,3S,5R,7S)-3-((2-(trimethylsilyl)ethoxy)methoxy)adamantan-1-amine (0.4 g, 1.34 mmol), 4-trifluoromethoxybromobenzene (0.5 g, 2.07 mmol), tris[dibenzylideneacetone]dipalladium (0.1 g, 0.11 mmol), and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (150 mg, 0.24 mmol) were added to toluene (10 ml), and the mixture was stirred at room temperature for 10 minutes. Then, sodium tert-butoxide (200 mg, 2.08 mmol) was added. After replacing the nitrogen atmosphere, the mixture was heated to 100 degrees Celsius and reacted overnight.

[0307] After the reaction was complete, the reaction mixture was concentrated. The residue was purified by silica gel column chromatography (5-15% ethyl acetate / n-hexane). 0.5 g of the yellow oily product (1R,3S,5R,7S)-N-(4-(trifluoromethoxy)phenyl)-3-((2-(trimethylsilyl)ethoxy)methoxy)adamantan-1-amine) was obtained (yield: 81%). RT = 2.49 min, [M+H] + =458.08

[0308] Step E: Synthesis of 8-chloro-N-(4-(trifluoromethoxy)phenyl)-N-((1R,3S,5R,7S)-3-((2(trimethylsilyl)ethoxy)methoxy)adamantan-1-yl)quinolin-2-amine

[0309] At room temperature, the compound (1R,3S,5R,7S)-N-(4-(trifluoromethoxy)phenyl)-3-((2-(trimethylsilyl)ethoxy)methoxy)adamantan-1-amine (0.5 g, 1.09 mmol), 2,8-dichloroquinoline (0.54 g, 2.73 mmol), tris[dibenzylideneacetone]dipalladium (0.06 g, 0.066 mmol), and tri-tert-butylphosphine (0.26 g, 0.13 mmol, 10% wt in pentane) were added to toluene (15 ml). After stirring at room temperature for 10 minutes, sodium tert-butoxide (0.21 g, 2.18 mmol) was added. After replacing the nitrogen atmosphere, the mixture was heated to 105°C and reacted overnight.

[0310] After the reaction was complete, the reaction mixture was concentrated, and the residue was separated by silica gel column chromatography (0-10% ethyl acetate / n-hexane). 0.35 g of the yellow solid product, 8-chloro-N-(4-(trifluoromethoxy)phenyl)-N-((1r,3s,5r,7s)-3-((2(trimethylsilyl)ethoxy)methoxy)adamantan-1-yl)quinolin-2-amine, was obtained (yield: 51%). RT = 2.96 min, [M+H] + =619.25

[0311] Step F: Synthesis of (1R,3S,5R,7S)-3-((8-chloroquinolin-2-yl)(4-(trifluoromethoxy)phenyl)amino)adamantan-1-ol

[0312] The compound 8-chloro-N-(4-(trifluoromethoxy)phenyl)-N-((1R,3S,5R,7S)-3-((2-(trimethylsilyl)ethoxy)methoxy)adamantan-1-yl)quinolin-2-amine (350 mg, 0.57 mmol) was dissolved in dichloromethane (10 ml), cooled in an ice-water bath, and trifluoroacetic acid (1 ml) was added, and the reaction was allowed to react at low temperature for 2 hours.

[0313] After the reaction is complete, the reaction solution is diluted with water and the pH is adjusted to 7-8 with solid sodium bicarbonate. The layers are separated, and the aqueous phase is extracted once with dichloromethane. The organic phases are combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated. The residue is purified by silica gel column chromatography (0-10% ethyl acetate / n-hexane). The concentrated solid is lyophilized to yield 210 mg of (1R,3S,5R,7S)-3-((8-chloroquinolin-2-yl)(4-(trifluoromethoxy)phenyl)amino)adamantan-1-ol as a white solid (yield: 73%). RT = 2.43 min, [M+H] + =489.03. 1 H NMR (400MHz, DMSO-d6) δ7.84(d,J=9.2Hz,1H),7.75(dd,J=7.6,1.2Hz,1H),7.62(dd,J=8.0,1.2Hz,1H),7.55–7.47(m,2H),7.43–7.33(m,2H),7. 20(t,J=7.6Hz,1H),6.06(d,J=9.2Hz,1H),4.47(s,1H),2.74–2.62(m,2 H),2.21(s,2H),2.12(d,J=11.6Hz,2H),2.02(s,2H),1.70–1.40(m,6H).

[0314] Example 36 Synthesis of N-((8-chloroquinolin-2-yl)(4-(trifluoromethoxy)phenyl)methyl)cyclobutane

[0315]

[0316] To a solution of 8-chloro-2-(chloro(4-(trifluoromethoxy)phenyl)methyl)quinoline (150 mg, 0.40 mmol) in acetonitrile (5 mL) was added cyclobutylamine (85.34 mg, 1.20 mmol) at room temperature. The mixture was heated to 80°C and stirred overnight. After the reaction, the reaction mixture was dried to give 25.85 mg of N-((8-chloroquinolin-2-yl)(4-(trifluoromethoxy)phenyl)methyl)cyclobutane (yield: 15.77%). LC-MS: RT = 1.91 min, [M+H] + =407.03. 1H NMR (400MHz, DMSO-d6) δ8.39(d,J=8.5Hz,1H),7.98–7.89(m,2H),7.73(d,J=8.6Hz,1H),7.61(d,J=8.5Hz,2H),7.55(t,J=7 .8Hz,1H),7.31(d,J=8.2Hz,2H),5.17(s,1H),3.19–2.95(m,2H),2.08–1.89(m,2H),1.87–1.66(m,2H),1.62–1.39(m,2H).

[0317] Example 37 Synthesis of 1-(8-chloroquinolin-2-yl)-N-(oxetane-2-ylmethyl)-1-(4-(trifluoromethoxy)phenyl)methanamine

[0318]

[0319] To a solution of 8-chloro-2-(chloro(4-(trifluoromethoxy)phenyl)methyl)quinoline (150 mg, 0.40 mmol) in acetonitrile (5 mL) was added 2-aminomethyloxetane (104.54 mg, 1.20 mmol) at room temperature. The mixture was heated to 80°C and stirred overnight. After the reaction, the reaction mixture was dried to give 25.85 mg of 1-(8-chloroquinolin-2-yl)-N-(oxetane-2-ylmethyl)-1-(4-(trifluoromethoxy)phenyl)methanamine as a colorless oil (yield: 15.77%). LC-MS: RT = 1.85 min, [M+H] + =422.98. 1 H NMR(400MHz, DMSO-d6)δ8.40(d,J=8.5Hz,1H),8.01–7.87(m,2H),7.72(dd,J=8.5,6.4Hz,1H),7.65–7.48(m,3H),7.40–7.23(m,2H),5.23 (d,J=4.3Hz,1H),4.90–4.74(m,1H),4.56–4.31(m,2H),3.22(s,1H),2.74(s,2H),2.57(dtd,J=10.9,8.2,6.2Hz,1H),2.47–2.37(m,1H).

[0320] Example 38 Synthesis of N 1 -((8-chloroquinolin-2-yl)(4-(trifluoromethoxy)phenyl)methyl)-N 2 -Methylethane-1,2-diamine

[0321]

[0322] At room temperature, N-Boc-N-methylethylenediamine (209.09 mg, 1.20 mmol) was added to a solution of 8-chloro-2-(chloro(4-(trifluoromethoxy)phenyl)methyl)quinoline (150 mg, 0.40 mmol) in acetonitrile (5 ml). After the addition, the mixture was heated to 80°C and stirred overnight. After returning to room temperature, 5 ml of 2N aqueous HCl was added to the reaction mixture. After stirring for 2 hours, the reaction mixture was concentrated to obtain 25.85 mg of N-Boc-N-methylethylenediamine. 1 -((8-chloroquinolin-2-yl)(4-(trifluoromethoxy)phenyl)methyl)-N 2 -Methylethane-1,2-diamine (yield: 15.77%). LC-MS: RT=1.79 min, [M+H] + =410.00.

[0323] Example 39 Synthesis of N-((8-chloroquinolin-2-yl)(4-(trifluoromethoxy)phenyl)methyl)aniline

[0324]

[0325] To a solution of 8-chloro-2-(chloro(4-(trifluoromethoxy)phenyl)methyl)quinoline (250 mg, 0.67 mmol) in acetonitrile (5 mL) was added aniline (186 mg, 2.01 mmol) at room temperature. The mixture was heated to 80°C and stirred overnight. After the reaction, the reaction mixture was dried to give 85 mg of N-((8-chloroquinolin-2-yl)(4-(trifluoromethoxy)phenyl)methyl)aniline (yield: 29.71%). LC-MS: RT = 2.42 min, [M+H] + =428.96. 1 H NMR (400MHz, DMSO-d6) δ8.44(d,J=8.6Hz,1H),7.95(ddd,J=8.2,6.6,1.3Hz,2H),7.77(d,J=8.5Hz,1H),7.69–7.63(m,2H),7.58(dd,J=8.2,7 .5Hz,1H),7.37–7.31(m,2H),7.05(dd,J=8.5,7.2Hz,2H),6.78(d,J=6.8Hz,1H),6.73–6.67(m,2H),6.59–6.51(m,1H),5.98(d,J=6.8Hz,1H).

[0326] Example 40 Synthesis of N-((8-chloroquinolin-2-yl)(4-(trifluoromethoxy)phenyl)methyl)-N-methylcyclobutane

[0327]

[0328] To a solution of N-((8-chloroquinolin-2-yl)(4-(trifluoromethoxy)phenyl)methyl)cyclobutane (120 mg, 0.29 mmol) in tetrahydrofuran (5 mL) was added sodium hydride (23.20 mg, 0.58 mmol) under ice-cooling. After stirring on ice for 1 hour, iodomethane (49.40 mg, 0.35 mmol) was added. After addition, the mixture was returned to room temperature and stirred overnight. After completion of the reaction, the mixture was quenched with water (1 mL) to obtain 68.08 mg of a colorless oil, synthesizing N-((8-chloroquinolin-2-yl)(4-(trifluoromethoxy)phenyl)methyl)-N-methylcyclobutane (yield: 5.84%). LC-MS: RT = 2.04 min, [M+H] + =421.00.

[0329] Example 41 Synthesis of 1-((8-chloroquinolin-2-yl)(4-(trifluoromethoxy)phenyl)methyl)urea

[0330]

[0331] Step A: Synthesis of 2,2,2-trichloro-N-((8-chloroquinolin-2-yl)(4-(trifluoromethoxy)phenyl)methyl)carbamoyl)acetamide

[0332] To a solution of (8-chloroquinolin-2-yl)(4-(trifluoromethoxy)phenyl)methanamine (100 mg, 0.28 mmol) in dichloromethane (3 mL) was added trichloroacetyl isocyanate (79.13 mg, 0.42 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was diluted with water and extracted with dichloromethane (10 mL x 3). The combined organic phases were washed with saturated brine (20 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 / 3) to obtain 150 mg of 2,2,2-trichloro-N-((8-chloroquinolin-2-yl)(4-(trifluoromethoxy)phenyl)methyl)carbamoyl)acetamide as a colorless oil (yield: 82.49%).

[0333] Step B: Synthesis of 1-((8-chloroquinolin-2-yl)(4-(trifluoromethoxy)phenyl)methyl)urea

[0334] To a solution of 2,2,2-trichloro-N-((8-chloroquinolin-2-yl)(4-(trifluoromethoxy)phenyl)methyl)carbamoyl)acetamide (150 mg, 0.28 mmol) in methanol (3 mL) was added 3 mL of saturated NaHCO₃ solution at room temperature. The mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was diluted with water and extracted with dichloromethane (10 mL x 3). The combined organic phases were washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was used to obtain 9.4 mg of 1-((8-chloroquinolin-2-yl)(4-(trifluoromethoxy)phenyl)methyl)urea as a white solid (yield: 8.57%). LC-MS: RT = 2.04 min, [M+H] + =395.95.

[0335] Example 42 Synthesis of N-((8-chloroquinolin-2-yl)(4-(trifluoromethoxy)phenyl)methyl)-2,2-difluoroethane-1-amine

[0336]

[0337] To a solution of 8-chloro-2-(chloro(4-(trifluoromethoxy)phenyl)methyl)quinoline (80 mg, 0.21 mmol) in acetonitrile (5 mL) at room temperature was added 2,2-difluoroethane-1-amine (85.11 mg, 1.05 mmol). After the addition, the reaction mixture was heated to 80°C and stirred overnight. After the reaction, the reaction mixture was spin-dried to obtain 44.4 mg of N-((8-chloroquinolin-2-yl)(4-(trifluoromethoxy)phenyl)methyl)-2,2-difluoroethane-1-amine as a colorless oil (yield: 49.56%). LC-MS: RT = 2.20 min, [M+H] + =416.95. 1 H NMR(400MHz, DMSO-d6)δ8.42(d,J=8.5Hz,1H),8.05–7.86(m,2H),7.71(d,J=8.6Hz,1H),7.66–7.50(m,3H),7.38–7.27 (m,2H),6.16(dt,J=56.2,4.2Hz,1H),5.29(d,J=7.1Hz,1H),3.54(q,J=7.2Hz,1H),2.91(tdt,J=15.3,7.5,4.0Hz,2H).

[0338] Example 43 Synthesis of 8-chloro-N-(8-(trifluoromethoxy)quinolin-5-yl)quinolin-2-amine

[0339]

[0340] Under N2 protection, 8-chloroquinolin-2-amine (150 mg, 0.84 mmol), 5-bromo-8-trifluoromethoxyquinoline (270 mg, 0.92 mmol), tris(dibenzylideneacetone)dipalladium (38 mg, 0.042 mmol), 1,1'-bis(diphenylphosphino)ferrocene (47 mg, 0.084 mmol) and sodium tert-butoxide (110 mg, 1.18 mmol) were added to 1,4-dioxane (6 ml). The temperature was raised to 110°C and stirred for 12 hours. The reaction was monitored by LC-MS until completion.

[0341] 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 205 mg of 8-chloro-N-(8-(trifluoromethoxy)quinolin-5-yl)quinolin-2-amine as an orange solid (yield: 62.63%). LCMS: RT = 2.16 min, [M+H] + =389.96. 1 H NMR (400MHz, DMSO-d6) δ9.80 (s, 1H), 9.08 (d, J = 5.6Hz, 2H), 8.96 (dd, J = 8.7, 1.5Hz, 1H), 8.26 (d, J = 8.9Hz, 1H), 7. 88(d,J=8.7Hz,1H),7.81(d,J=7.8Hz,2H),7.75(dd,J=8.7,4.1Hz,1H),7.52(d,J=8.9Hz,1H),7.39–7.31(m,1H).

[0342] Example 44 Synthesis of 3-(((8-chloroquinolin-2-yl)(4-(trifluoromethoxy)phenyl)methyl)amino)propane-1,2-diol

[0343]

[0344] To a solution of 8-chloro-2-(chloro(4-(trifluoromethoxy)phenyl)methyl)quinoline (280 mg, 0.75 mmol) in acetonitrile (5 mL) was added 3-amino-1,2-propanediol (205.00 mg, 2.25 mmol) at room temperature. The mixture was heated to 80°C and stirred overnight. After the reaction, the reaction mixture was dried to obtain 234.2 mg of 3-(((8-chloroquinolin-2-yl)(4-(trifluoromethoxy)phenyl)methyl)amino)propane-1,2-diol (yield: 72.93%). LC-MS: RT = 1.65 min, [M+H] + =426.96.

[0345] Example 45 Synthesis of N-((8-chloroquinolin-2-yl)(4-(trifluoromethoxy)phenyl)methyl)-2,4-difluoroaniline

[0346]

[0347] To a solution of 8-chloro-2-(chloro(4-(trifluoromethoxy)phenyl)methyl)quinoline (250 mg, 0.67 mmol) in acetonitrile (5 mL) was added 2,6-difluoroaniline (259.51 mg, 2.01 mmol) at room temperature. The mixture was heated to 80°C and stirred overnight. After the reaction, the reaction mixture was dried to obtain 55.96 mg of N-((8-chloroquinolin-2-yl)(4-(trifluoromethoxy)phenyl)methyl)-2,4-difluoroaniline (yield: 17.92%). LC-MS: RT = 2.29 min, [M+H] + =464.96. 1 HNMR (400MHz, DMSO-d6) δ8.45(d,J=8.5Hz,1H),7.98(ddd,J=13.6,7.9,1.3Hz,2H),7.70(d,J=8.5Hz,3H),7.60(t,J=7.8Hz,1H),7.40– 7.29(m,2H),7.17(ddd,J=11.8,8.9,2.8Hz,1H),6.83(ddt,J=11.5,6.5,1.9Hz,2H),6.69(td,J=9.4,5.6Hz,1H),6.12(d,J=6.5Hz,1H).

[0348] Example 46 Synthesis of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-carboxamide

[0349]

[0350] To a solution of 8-chloroquinoline-2-carboxylic acid (100 mg, 0.48 mmol) and 4-(trifluoromethoxy)aniline (93.52 mg, 0.5 mmol) in dichloromethane (5 ml) was added 1-propylphosphoric anhydride (229.09 mg, 0.72 mmol) and N,N-diisopropylethylamine (124.07 mg, 0.96 mmol) at room temperature. The mixture was stirred at room temperature for half an hour.

[0351] After the reaction was completed, the mixture was diluted with 2 ml of water and extracted with dichloromethane (5 ml x 3). The organic phases were combined, washed with saturated brine (5 ml x 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was subjected to preparative purification to afford 65.33 mg of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-carboxamide as a white solid (yield: 36.99%). LCMS: RT = 2.23 min, [M+H] + =366.88. 1 H NMR (400MHz, DMSO-d6) δ10.65(s,1H),8.74(dd,J=8.5,1.8Hz,1H),8.30(dd,J=8.5,1.9Hz,1H) ,8.12(td,J=8.5,1.3Hz,2H),8.05–7.96(m,2H),7.74(t,J=7.9Hz,1H),7.43(d,J=8.6Hz,2H).

[0352] Example 47 Synthesis of 8-chloro-2-(5-(trifluoromethyl)-1H-pyrazol-3-yl)quinoline

[0353]

[0354] Under N2 protection, 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-pyrazole (0.15 g, 0.8 mmol), 2,8-dichloroquinoline (0.29 g, 0.88 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.06 g, 0.08 mmol) and potassium carbonate (0.25 g, 2.4 mmol) were added to 15 mL of a 1,4-dioxane / water (5 / 1) mixed solvent, the temperature was raised to 100°C and stirred for 12 hours. The reaction was monitored by LC-MS until completion.

[0355] 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 separated and purified by HPLC to obtain 70 mg of 8-chloro-2-(5-(trifluoromethyl)-1H-pyrazol-3-yl)quinoline. LCMS: RT = 2.07 min, [M+H] + =298.01. 1 H NMR (400MHz, DMSO-d6) δ8.61(d,J=8.6Hz,1H),8.19(d,J=8.7Hz,1H),8.02(d,J=7.9Hz,2H),7.71–7.48(m,2H).

[0356] Example 48 Synthesis of N-(8-chloroquinolin-2-yl)-4-(trifluoromethoxy)benzamide

[0357]

[0358] 8-Chloroquinolin-2-amine (0.15 g, 0.84 mmol), 4-trifluoromethoxybenzoic acid (0.19 g, 0.92 mmol), HATU (0.38 g, 1 mmol) and N,N-diisopropylethylamine (0.25 g, 2.52 mmol) were added to N,N-dimethylformamide (15 ml) at room temperature and reacted overnight at room temperature.

[0359] 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. After concentration, HPLC separation and purification were performed to obtain 0.13 g of N-(8-chloroquinolin-2-yl)-4-(trifluoromethoxy)benzamide. LCMS: RT = 2.18 min, [M+H] + =366.88. 1 H NMR (400MHz, DMSO-d6) δ11.34(s,1H),8.52(d,J=9.0Hz,1H),8.38(d,J=8.9Hz,1H),8.25–8.19(m,2H),8.00–7.92(m,2H),7.58–7.50(m,3H).

[0360] Example 49 Synthesis of 8-chloro-N-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)quinolin-2-amine

[0361]

[0362] 2-Amino-5-trifluoromethyl-1,3,4-thiadiazole (77 mg, 0.46 mmol), 2-bromo-8-chloroquinoline (111 mg, 0.46 mmol), tris(dibenzylideneacetone)dipalladium (21 mg, 0.023 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (22 mg, 0.046 mmol), and cesium carbonate (225 mg, 0.69 mmol) were added to dioxane (3 ml). The atmosphere was replaced with nitrogen and the reaction was carried out in a microwave oven at 110°C for 1.5 hours.

[0363] After the reaction was complete, the mixture was filtered and the filtrate was concentrated to dryness to obtain a crude product, which was purified by preparative chromatography to yield 22.3 mg of 8-chloro-N-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)quinolin-2-amine. LCMS: RT = 2.20 min, [M+H] + =330.75. 1H NMR (400MHz, DMSO-d6) δ13.06 (s, 1H), 8.49 (d, J = 8.7Hz, 1H), 8.16–7.78 (m, 2H), 7.72–7.19 (m, 2H).

[0364] Example 50 Synthesis of 8-chloro-N-(3-(trifluoromethyl)-1H-pyrazol-5-yl)quinolin-2-amine

[0365]

[0366] 3-Amino-5-trifluoromethylpyrazole (93 mg, 0.62 mmol), 2-bromo-8-chloroquinoline (150 mg, 0.62 mmol), tris(dibenzylideneacetone)dipalladium (28 mg, 0.031 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (29 mg, 0.062 mmol), and cesium carbonate (303 mg, 0.93 mmol) were added to dioxane (3 ml). The atmosphere was replaced with nitrogen and the reaction was carried out in a microwave oven at 110°C for 1.5 hours.

[0367] After the reaction was complete, the mixture was filtered and the filtrate was concentrated to dryness to obtain a crude product, which was purified by preparative chromatography to afford 8.5 mg of 8-chloro-N-(3-(trifluoromethyl)-1H-pyrazol-5-yl)quinolin-2-amine. LCMS: RT = 2.14 min, [M+H] + =312.61.

[0368] Example 51 Synthesis of Compound 8-Chloro-N-(4-(oxetan-3-yl)phenyl)quinolin-2-amine

[0369]

[0370] 2,8-Dichloroquinoline (100 mg, 0.43 mmol) and 4-(oxetan-3-yl)aniline (75.6 mg, 0.43 mmol) were added to isopropanol (10 ml) at room temperature and refluxed for 4 hours.

[0371] After the reaction was complete, the mixture was filtered and the filtrate was concentrated to dryness to obtain a crude product, which was purified by preparative chromatography to yield 69 mg of 8-chloro-N-(4-(oxetan-3-yl)phenyl)quinolin-2-amine. LCMS: RT = 2.13 min, [M+H] + =311.03.

[0372] Example 52 Synthesis of 8-chloro-N-(5-(trifluoromethyl)-1,3-oxazol-2-yl)quinolin-2-amine

[0373]

[0374] 5-(Trifluoromethyl)-1,3-oxazol-2-amine (65 mg, 0.43 mmol), 2-bromo-8-chloroquinoline (104 mg, 0.43 mmol), tris(dibenzylideneacetone)dipalladium (20 mg, 0.022 mmol), 2-dicyclohexylphosphino-2",4",6"-triisopropylbiphenyl (20.5 mg, 0.043 mmol), and cesium carbonate (210 mg, 0.65 mmol) were added to dioxane (3 ml). The atmosphere was replaced with nitrogen and the reaction was carried out in a microwave oven at 110°C for 1 hour.

[0375] After the reaction is complete, the mixture is filtered and the filtrate is concentrated to dryness to obtain a crude product, which is then purified by preparative chromatography to yield 61 mg of 8-chloro-N-(5-(trifluoromethyl)-1,3-oxazol-2-yl)quinolin-2-amine. LCMS: RT = 2.20 min, [M+H] + =313.79. 1 H NMR (400MHz, DMSO-d6) δ11.72(s,1H),8.64–8.55(m,1H),8.48(d,J=9.0Hz,1H),8.21(t,J=9.3Hz,1H),7.98–7.82(m,2H),7.44(t,J=7.8Hz,1H).

[0376] Example 53 Synthesis of N-(8-chloroquinolin-2-yl)-6-fluorobenzo[d]isoxazol-3-amine

[0377]

[0378] 2-Bromo-8-chloroquinoline (50 mg, 0.21 mmol), 6-fluorobenzo[d]isoxazol-3-amine (35 mg, 0.23 mmol), cesium carbonate (171 mg, 0.53 mmol), tris(dibenzylideneacetone)dipalladium (19 mg, 0.021 mmol), and 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (24 mg, 0.042 mmol) were added to dioxane (5 ml), the atmosphere was replaced with nitrogen three times, and the temperature was raised to 100° C. for 3 hours.

[0379] Water (10 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 ml x 3 times). The combined organic phases were washed with saturated brine (10 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 = 1 / 5) to obtain the crude product, which was then purified by HPLC to obtain 29 mg of N-(8-chloroquinolin-2-yl)-6-fluorobenzo[d]isoxazol-3-amine. LCMS: RT = 2.07 min, [M+H] + =313.88.

[0380] Example 54 Synthesis of 8-chloro-N-(7-cyclopropyl-2,2-difluorobenzo[d][1,3]dioxolane-5-yl)quinolin-2-amine

[0381]

[0382] Under N2 protection, 4-bromo-2,2-difluoro-6-nitrobenzo[d][1,3]dioxane (1.30 g, 4.61 mmol), cyclopropylboronic acid (0.51 g, 5.99 mmol), cesium carbonate (4.51 g, 13.83 mmol), and bistriphenylphosphine palladium dichloride (0.32 g, 0.46 mmol) were added to dioxane (15 ml) and water (1.5 ml), and the atmosphere was replaced with nitrogen three times. The temperature was raised to 100 degrees Celsius and stirred for 18 hours.

[0383] 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 = 1 / 5) to obtain 0.92 g of 4-cyclopropyl-2,2-difluoro-6-nitrobenz[d][1,3]dioxane as a white solid (yield: 82.07%). 1 H NMR (400MHz, Chloroform-d) δ7.68(d,J=2.2Hz,1H),7.62(d,J=2.2Hz,1H),1.98(tt,J=8.4,5.1Hz,1H),1.15–1.02(m,2H),0.89(dt,J=7.0,4.9Hz,2H).

[0384] Step B: Synthesis of 4-cyclopropyl-2,2-difluoro-6-amino-benzo[d][1,3]dioxane

[0385] 4-Cyclopropyl-2,2-difluoro-6-nitrobenz[d][1,3]dioxane (200 mg, 0.82 mmol) was added to ethyl acetate (15 ml) and anhydrous ethanol (15 ml), and the atmosphere was replaced with nitrogen three times. Wetted palladium carbon (100 mg) was then added and replaced with hydrogen. The mixture was kept under a hydrogen balloon atmosphere at room temperature for 2 hours.

[0386] After the reaction was complete, palladium carbon was removed by filtration and the mixture was concentrated to dryness to obtain 130 mg of 4-cyclopropyl-2,2-difluoro-6-amino-benzo[d][1,3]dioxane (yield: 74.14%). LCMS: RT = 1.82 min, [M+H] + =213.90. 1H NMR (400MHz, DMSO-d6) δ6.34(d,J=2.1Hz,1H),5.98(d,J=2.1Hz,1H),5.17(s,2H),1.86(tt,J=8.5,5.1Hz,1H),1.04–0.96(m,2H),0.77–0.70(m,2H).

[0387] Step C: Synthesis of 8-chloro-N-(7-cyclopropyl-2,2-difluorobenzo[d][1,3]dioxolan-5-yl)quinolin-2-amine

[0388] 2,8-Dichloroquinoline (30 mg, 0.15 mmol), 4-cyclopropyl-2,2-difluoro-6-amino-benzo[d][1,3]dioxane (32 mg, 0.15 mmol), cesium carbonate (122 mg, 0.38 mmol), tris(dibenzylideneacetone)dipalladium (14 mg, 0.015 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (17 mg, 0.030 mmol) were added to dioxane (3 ml), the atmosphere was replaced with nitrogen three times, and the temperature was raised to 100°C for reaction for 3 hours.

[0389] Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL x 3 times). The combined organic phases were washed with saturated brine (10 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 = 1 / 5) to obtain a crude product. High-performance liquid chromatography (HPLC) was then used to obtain 22 mg of 8-chloro-N-(7-cyclopropyl-2,2-difluorobenzo[d][1,3]dioxolan-5-yl)quinolin-2-amine. LCMS: RT = 2.27 min, [M+H] + =374.80. 1 H NMR (400MHz, DMSO-d6) δ9.88(s,1H),8.22(d,J=2.0Hz,1H),8.16(d,J=8.9Hz,1H),7.79(ddd,J=17.8,7.8,1.4Hz,2H),7.55(d, J=2.1Hz,1H),7.32(t,J=7.8Hz,1H),7.11(d,J=8.9Hz,1H),2.03(tt,J=8.3,5.1Hz,1H),1.15–1.02(m,2H),1.02–0.88(m,2H).

[0390] Example 55 Synthesis of 1-(8-chloroquinolin-2-yl)-5-(trifluoromethoxy)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0391]

[0392] Step A: Synthesis of 8-chloro-N-(2-nitro-4-(trifluoromethoxy)phenyl)quinolin-2-amine

[0393] Under N2 protection, 2,8-dichloroquinoline (2 g, 10.1 mmol), 2-nitro-4-(trifluoromethoxy)aniline (2.47 g, 11.1 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.9 g, 1.01 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (1.89 g, 3.03 mmol) and sodium tert-butoxide (1.94 g, 20.2 mmol) were added to 1,4-dioxane (30 ml), the temperature was raised to 100°C and stirred for 12 hours. The reaction was monitored by TLC until completion.

[0394] 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 concentrated to obtain 2.0 g of yellow solid 8-chloro-N-(2-nitro-4-(trifluoromethoxy)phenyl)quinolin-2-amine (yield: 51.61%).

[0395] Step B: Synthesis of N 1 -(8-Fluoroquinolin-2-yl)-4-(trifluoromethoxy)benzene-1,2-diamine

[0396] At room temperature, 8-chloro-N-(2-nitro-4-(trifluoromethoxy)phenyl)quinolin-2-amine (2 g, 5.21 mmol) and palladium carbon (0.5 g) were added to ethanol (30 ml), and the atmosphere was replaced with hydrogen three times. The mixture was then reacted at room temperature for 2 hours. The palladium carbon was filtered off to obtain 1.5 g of a brown oily substance. 1 -(8-Chloroquinolin-2-yl)-4-(trifluoromethoxy)benzene-1,2-diamine (yield: 81.36%) was used directly in the next step.

[0397] Step C: Synthesis of 1-(8-chloroquinolin-2-yl)-5-(trifluoromethoxy)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0398] Under ice, diphosgene (0.84 g, 4.24 mmol) was added dropwise to a solution of 4-(trifluoromethoxy)benzene-1,2-diamine (1.5 g, 4.24 mmol) and triethylamine (0.86 g, 8.48 mmol) in dichloromethane (15 mL). The mixture was allowed to react at room temperature for 3 hours. After quenching with water, the mixture was extracted with ethyl acetate (20 mL x 3), dried, and concentrated. The resulting residue was purified by HPLC to yield 800 mg of 1-(8-chloroquinolin-2-yl)-5-(trifluoromethoxy)-1,3-dihydro-2H-benzo[d]imidazol-2-one. LCMS: RT = 2.12 min, [M+H]+ =379.75. 1 H NMR (400MHz, DMSO-d6) δ8.90(d,J=8.8Hz,1H),8.74(d,J=9.1Hz,1H),8.62(d,J=9.1Hz,1H) ,8.06–8.01(m,2H),7.64–7.57(m,1H),7.15(dd,J=8.8,2.3Hz,1H),7.08(d,J=2.4Hz,1H).

[0399] Example 56 Synthesis of N-(8-chloroquinolin-2-yl)-6-(trifluoromethoxy)benzo[d]isoxazol-3-amine

[0400]

[0401] Step A: N-hydroxyacetamide (238 mg, 3.17 mmol) was added to N,N-dimethylformamide (15 ml), followed by potassium tert-butoxide (356 mg, 3.17 mmol), and the mixture was reacted at room temperature for 0.5 hour. 2-Fluoro-4-(trifluoromethoxy)benzonitrile (500 mg, 2.44 mmol) was then added to the mixture, and the temperature was raised to 50°C for 3 hours.

[0402] After the reaction was complete, the mixture was cooled to room temperature and quenched with saturated aqueous ammonium chloride (30 mL). The mixture was extracted with ethyl acetate (20 mL x 3 times). The combined organic phases were washed with saturated brine (10 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 = 1 / 3) to obtain 258 mg of 6-(trifluoromethoxy)benzo[d]isoxazol-3-amine (yield: 48.52%). LCMS: RT = 1.82 min, [M+H] + =218.80. 1 HNMR (400MHz, DMSO-d6) δ7.96(d,J=8.6Hz,1H),7.61(d,J=2.0Hz,1H),7.30(ddd,J=8.5,2.1,1.1Hz,1H),6.60(s,2H).

[0403] Step B: 2-Bromo-8-chloroquinoline (30 mg, 0.12 mmol), 6-(trifluoromethoxy)-1,2-benzoxazol-3-amine (29 mg, 0.13 mmol), cesium carbonate (98 mg, 0.30 mmol), tris(dibenzylideneacetone)dipalladium (11 mg, 0.012 mmol), and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (14 mg, 0.024 mmol) were added to dioxane (3 ml), replaced with nitrogen three times, and heated to 100° C. for 3 hours.

[0404] Water (10 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 ml x 3 times). The combined organic phases were washed with saturated brine (10 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 = 1 / 3) to obtain a crude product, which was then purified by high-performance liquid chromatography to obtain 14.6 mg of N-(8-chloroquinolin-2-yl)-6-(trifluoromethoxy)benzo[d]isoxazol-3-amine. LCMS: RT = 2.47 min, [M+H] + =379.87.

[0405] Example 57 Synthesis of 8-chloro-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)quinolin-2-amine

[0406]

[0407] Under N2 protection, 2-bromo-8-chloroquinoline (0.15 g, 0.62 mmol), 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-amine (0.1 g, 0.68 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.057 g, 0.062 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.11 g, 0.19 mmol) and cesium carbonate (0.61 g, 1.86 mmol) were added to 15 ml of dioxane and reacted at 100 °C overnight.

[0408] 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-N-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)quinolin-2-amine as a white solid (yield: 15.78%). LCMS: RT = 2.14 min, [M+H] + =312.86.

[0409] Example 58 / 59 Synthesis of Compounds 8-Chloro-N-((1R,3R,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)quinolin-2-amine and 8-Chloro-N-((1R,3S,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)quinolin-2-amine

[0410]

[0411] 6,6-Difluorobicyclo[3.1.0]hexan-3-amine hydrochloride (70 mg, 0.41 mmol), 2-bromo-8-chloroquinoline (99 mg, 0.41 mmol), tris(dibenzylideneacetone)dipalladium (9.2 mg, 0.041 mmol), 2-dicyclohexylphosphino-2",4",6"-triisopropylbiphenyl (29 mg, 0.082 mmol), and cesium carbonate (200 mg, 0.61 mmol) were added to dioxane (4 ml) at room temperature. The atmosphere was replaced with nitrogen and the reaction was carried out in a microwave oven at 110°C for 1 hour.

[0412] After the reaction was completed, the mixture was filtered and the filtrate was concentrated to dryness to obtain a crude product, which was purified by HPLC preparative chromatography to obtain 4 mg of a yellow solid P1 (yield: 3.3%). LCMS: RT = 2.77 min, [M+H] + =295.14. Yellow solid P2: 15 mg (yield: 12.3%). LCMS: RT=2.93 min, [M+H] + =294.94.

[0413] Example 60 Synthesis of Compound 8-chloro-N-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)quinolin-2-amine

[0414]

[0415] 1-Methyl-5-(trifluoromethyl)-1H-pyrazol-3-ylamine (68 mg, 0.41 mmol), 2-bromo-8-chloroquinoline (99 mg, 0.41 mmol), tris(dibenzylideneacetone)dipalladium (19 mg, 0.021 mmol), 2-dicyclohexylphosphino-2",4",6"-triisopropylbiphenyl (19.5 mg, 0.041 mmol), and cesium carbonate (200 mg, 0.61 mmol) were added to dioxane (3 ml) at room temperature. The atmosphere was replaced with nitrogen and the reaction was carried out under microwave heating at 110°C for 1.5 hours.

[0416] After the reaction was complete, the mixture was filtered and the filtrate was concentrated to dryness to obtain the crude product, which was purified by preparative chromatography to afford 73 mg of an off-white solid, 8-chloro-N-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)quinolin-2-amine (yield: 54.2%). LCMS: RT = 2.1 min, [M+H] + =326.86. 1H NMR (400MHz, DMSO-d6) δ10.69–10.35(m,1H),8.17(d,J=8.9Hz,1H),7.95(s,1H),7.79( ddd,J=14.7,7.8,1.3Hz,2H),7.31(t,J=7.8Hz,1H),7.21(d,J=8.9Hz,1H),3.93(s,3H).

[0417] Example 61 Synthesis of 8-chloro-N-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)quinolin-2-amine

[0418]

[0419] To a mixture of 2-bromo-8-chloroquinoline (100 mg, 0.41 mmol), 5-(trifluoromethyl)-4H-1,2,4-triazol-3-amine (74.82 mg, 0.49 mmol), tris(dibenzylideneacetone)dipalladium (18.77 mg, 0.021 mmol), dimethylbis(diphenylphosphino)anthracene (23.72 mg, 0.041 mmol), and cesium carbonate (400.76 mg, 1.23 mmol) was added 1,4-dioxane (5 ml) at room temperature. After the addition, the reaction flask was purged with nitrogen three times, then heated to 100°C and stirred for 2 hours. After the reaction, the mixture was diluted with 10 ml of water and extracted with dichloromethane (10 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 obtain 4.16 mg of 8-chloro-N-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)quinolin-2-amine as a white solid (yield: 3.22%). LCMS: RT = 2.07 min, [M+H] + =313.86

[0420] Example 62 Synthesis of 2-(8-chloroquinolin-2-yl)-5-(trifluoromethoxy)isoindolin-1-one

[0421]

[0422] At room temperature, 2-bromo-8-chloroquinoline (56 mg, 0.23 mmol), 5-(trifluoromethoxy)isoindolin-1-one (50 mg, 0.23 mmol), cesium carbonate (225 mg, 0.69 mmol), tris(dibenzylideneacetone)dipalladium (21 mg, 0.023 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (27 mg, 0.046 mmol) were added to dioxane (5 ml), the atmosphere was replaced with nitrogen three times, and the temperature was raised to 100°C for 3 hours.

[0423] Water (10 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 ml x 3 times). The organic phases were combined, washed with saturated brine (10 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 = 1 / 5) to obtain the crude product, which was then purified by high-performance liquid chromatography to obtain 22 mg of 2-(8-chloroquinolin-2-yl)-5-(trifluoromethoxy)isoindolin-1-one (yield: 25.6%). LCMS: RT = 2.32 min, [M+H] + =378.77. 1 H NMR (400MHz, DMSO-d6) δ8.82(d,J=9.0Hz,1H),8.55(d,J=9.1Hz,1H),8.03–7.92(m,3H),7.91(s,1H),7.60–7.48(m,2H),5.33(s,2H).

[0424] Example 63 Synthesis of 3-((8-chloroquinolin-2-yl)amino)-6-(trifluoromethyl)pyridin-2(1H)-one

[0425]

[0426] Under N2 protection, 2,8-dichloroquinoline (0.15 g, 0.76 mmol), 3-amino-6-(trifluoromethyl)-2-hydroxypyridine (0.14 g, 0.76 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.07 g, 0.076 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.13 g, 0.23 mmol) and cesium carbonate (0.74 g, 2.28 mmol) were added to 15 ml of dioxane and reacted at 100 °C overnight. 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 110 mg of a gray solid, 3-((8-chloroquinolin-2-yl)amino)-6-(trifluoromethyl)pyridin-2(1H)-one (yield: 42.75%). LCMS: RT = 2.07 min, [M+H] + =339.92. 1 H NMR (400MHz, DMSO-d6) δ13.02(s,1H),12.67(s,1H),9.45(s,2H),8.23(d,J=8.9Hz,1H),7. 85(dd,J=7.6,1.2Hz,1H),7.81(d,J=7.9Hz,1H),7.73(d,J=9.0Hz,1H),7.41–7.35(m,1H).

[0427] Example 64 Synthesis of 2-(8-chloroquinolin-2-yl)-5-(trifluoromethyl)pyridazin-3(2H)-one

[0428]

[0429] 5-(Trifluoromethyl)pyridazin-3(2H)-one (50 mg, 0.30 mmol) and 2-bromo-8-chloroquinoline (81 mg, 0.33 mmol) were dissolved in N,N-dimethylformamide (2 ml) at 0°C. Cuprous iodide (30 mg, 0.16 mmol), N,N'-dimethylethylenediamine (20 mg, 0.23 mmol), and potassium phosphate (162 mg, 0.76 mmol) were added sequentially. The mixture was heated to 110°C under nitrogen and stirred for 12 hours. The reaction was monitored by LCMS until completion.

[0430] 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 = 0-60%). The resulting product was then purified by high-performance liquid chromatography to obtain 44 mg of 2-(8-chloroquinolin-2-yl)-5-(trifluoromethyl)pyridazin-3(2H)-one as a yellow solid (yield: 45.04%). LCMS: RT = 1.91 min, [M+H] + =325.92. 1 H NMR (400MHz, DMSO-d6) δ8.75(d,J=8.6Hz,1H),8.57(d,J=2.1Hz,1H),8.15(dd,J=8.3,1.3Hz,1H),8. 09(dd,J=7.6,1.2Hz,1H),7.91(d,J=8.6Hz,1H),7.79(dd,J=2.4,1.2Hz,1H),7.75(t,J=7.9Hz,1H).

[0431] Example 65 / 66 Synthesis of 3-(8-chloroquinolin-2-yl)-6-(trifluoromethyl)isoindolin-1-one and 3-(8-chloroquinolin-2-yl)-5-(trifluoromethyl)isoindolin-1-one

[0432]

[0433] Step A: Synthesis of 3-(8-chloroquinolin-2-yl)-3-hydroxy-6-(trifluoromethyl)isoindolin-1-one and 3-(8-chloroquinolin-2-yl)-3-hydroxy-5-(trifluoromethyl)isoindolin-1-one

[0434] Under ice bath, magnesium stick (192 mg, 7.90 mmol), lithium chloride (167 mg, 3.95 mmol), and diisobutylaluminum hydride (0.36 ml, 1.0 mol / L) were added to tetrahydrofuran (50 ml). The atmosphere was replaced with nitrogen and cooled with ice water. 2-Bromo-8-chloroquinoline (765 mg, 3.15 mmol) was then added and the mixture was reacted under ice water for 2 hours. The mixture was then used directly in the next step.

[0435] Dissolve 5-(Trifluoromethyl)isoindole-1,3-dione in dichloromethane (50 ml), replace the atmosphere with nitrogen, and add the solution from the previous step to the reaction mixture. React at 30°C for 2 hours. Concentrate to dryness to obtain crude 3-(8-chloroquinolin-2-yl)-3-hydroxy-6-(trifluoromethyl)isoindolin-1-one and 3-(8-chloroquinolin-2-yl)-3-hydroxy-5-(trifluoromethyl)isoindolin-1-one, which are used directly in the next step. LCMS: RT = 1.98 min, [M+H] + =378.88.

[0436] Step B: Synthesis of 3-(8-chloroquinolin-2-yl)-6-(trifluoromethyl)isoindolin-1-one and 3-(8-chloroquinolin-2-yl)-5-(trifluoromethyl)isoindolin-1-one

[0437] At room temperature, the crude products of 3-(8-chloroquinolin-2-yl)-3-hydroxy-6-(trifluoromethyl)isoindolin-1-one and 3-(8-chloroquinolin-2-yl)-3-hydroxy-5-(trifluoromethyl)isoindolin-1-one were dissolved in anhydrous dichloromethane (30 ml), and trifluoroacetic acid (5 ml) and triethylsilane (5 ml) were added. The mixture was heated to 40°C and reacted for 18 hours.

[0438] The reaction was stopped, the temperature was lowered to room temperature, the pH was adjusted to 8 with aqueous sodium carbonate solution, and the mixture was extracted with ethyl acetate. The crude product was purified by column chromatography and then purified by preparative HPLC to afford 2 mg of a white solid P1 and 4 mg of a white solid P2 (combined yield: 2.0%). LCMS: RT = 2.03 min, [M+H] + =362.85.

[0439] Example 67 Synthesis of 8-chloro-2-(3,3-dimethyl-5-(trifluoromethoxy)indol-2-yl)quinoline

[0440]

[0441] Step A: Synthesis of ethyl 3-(8-chloroquinolin-2-yl)-3-oxopropionate

[0442] At -78°C, ethyl acetate (848 mg, 9.64 mmol) was dissolved in tetrahydrofuran (10 mL). Lithium diisopropylamide (4.82 mL, 9.64 mmol) was added and stirred for 1 hour. Methyl 8-chloroquinoline-2-carboxylate (1.1 g, 4.82 mmol) was then slowly added and allowed to react for 4 hours. LCMS monitoring was performed until the reaction was complete.

[0443] Saturated ammonium chloride solution (20 ml) was added to the reaction solution, which 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), 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 = 0-30%) to obtain 0.82 g of ethyl 3-(8-chloroquinolin-2-yl)-3-oxopropanoate as a yellow solid (yield: 61.40%). LCMS: RT = 2.19 min, [M+H] + =278.01.

[0444] Step B: Ethyl 3-(8-chloroquinolin-2-yl)-2-(2-nitro-5-(trifluoromethoxy)phenyl)-3-oxopropanoate

[0445] Ethyl 3-(8-chloroquinolin-2-yl)-3-oxopropanoate (820 mg, 2.96 mmol) was dissolved in N,N-dimethylformamide (10 ml) at room temperature. 2-Fluoro-1-nitro-4-(trifluoromethoxy)benzene (799 mg, 3.55 mmol) and potassium carbonate (817 mg, 5.92 mmol) were added. The mixture was heated to 50°C and stirred for 6 hours. The reaction was monitored by LCMS until completion.

[0446] Water (30 ml) was added to the reaction solution, cooled to room temperature, and extracted with ethyl acetate (30 ml x 2 times). The organic phases were combined, 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 0.76 g of ethyl 3-(8-chloroquinolin-2-yl)-2-(2-nitro-5-(trifluoromethoxy)phenyl)-3-oxopropanoate as a yellow solid (yield: 53.27%). LCMS: RT = 2.29 min, [M+H] + =482.73.

[0447] Step C: Synthesis of 1-(8-chloroquinolin-2-yl)-2-(2-nitro-5-(trifluoromethoxy)phenyl)ethan-1-one

[0448] Ethyl 3-(8-chloroquinolin-2-yl)-2-(2-nitro-5-(trifluoromethoxy)phenyl)-3-oxopropanoate (760 mg, 1.58 mmol) was dissolved in a mixture of dimethyl sulfoxide and water (1 / 1, 15 ml) at room temperature. Lithium chloride (572 mg, 13.5 mmol) was added, and the mixture was heated to 140°C and stirred for 1 hour under nitrogen. The reaction was monitored by LCMS until completion.

[0449] Aqueous solution (20 ml) was added to the reaction solution, cooled to room temperature, and extracted with ethyl acetate (30 ml x 3 times). The organic phases were combined, 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 = 0-25%) to obtain 0.48 g of 1-(8-chloroquinolin-2-yl)-2-(2-nitro-5-(trifluoromethoxy)phenyl)ethan-1-one as a brown oil (yield: 74.09%). LCMS: RT = 2.20 min, [M+H] + =410.89.

[0450] Step D: Synthesis of 1-(8-chloroquinolin-2-yl)-2-methyl-2-(2-nitro-5-(trifluoromethoxy)phenyl)propan-1-one

[0451] At 0°C, 1-(8-chloroquinolin-2-yl)-2-(2-nitro-5-(trifluoromethoxy)phenyl)ethan-1-one (480 mg, 1.17 mmol) was dissolved in N,N-dimethylformamide (5 mL). Sodium hydride (60%, 94 mg, 3.51 mmol) was added and stirred at room temperature for 30 minutes. Methyl iodide (498 mg, 3.51 mmol) was slowly added dropwise and stirred under nitrogen for 5 hours. The reaction was monitored by LCMS until completion.

[0452] Saturated ammonium chloride solution (20 ml) was added to the reaction solution, cooled 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 finally concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 0-35%) to obtain 0.28 g of 1-(8-chloroquinolin-2-yl)-2-methyl-2-(2-nitro-5-(trifluoromethoxy)phenyl)propan-1-one as a brown oil (yield: 54.64%). LCMS: RT = 2.21 min, [M+H] + =438.88.

[0453] Step E: Synthesis of 8-chloro-2-(3,3-dimethyl-5-(trifluoromethoxy)indolin-2-yl)quinoline

[0454] 1-(8-Chloroquinolin-2-yl)-2-methyl-2-(2-nitro-5-(trifluoromethoxy)phenyl)propan-1-one (280 mg, 0.64 mmol) was dissolved in a mixture of ethanol and water (3 / 1, 10 ml) at room temperature. Reduced iron powder (179 mg, 3.2 mmol) and ammonium chloride (171 mg, 3.2 mmol) were added, and the mixture was stirred at reflux under nitrogen for 15 hours. The reaction was monitored by LCMS until completion.

[0455] Filter while hot, cool to room temperature, and extract with ethyl acetate (50 ml x 3 times). The combined organic phases are washed with saturated brine (30 ml x 3 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. High-resolution liquid chromatography yields 5 mg of a pale yellow solid, 8-chloro-2-(3,3-dimethyl-5-(trifluoromethoxy)indolin-2-yl)quinoline (yield: 2.00%). LCMS: RT = 2.09 min, [M+H] + =392.94.

[0456] Example 68 Synthesis of 2-(8-chloro-2-((4-(trifluoromethoxy)phenyl)amino)quinolin-7-yl)propan-2-ol

[0457]

[0458] At room temperature, 2-(2,8-dichloroquinolin-7-yl)propan-2-ol (50 mg, 0.20 mmol), 4-trifluoromethoxyaniline (35 mg, 0.20 mmol), cesium carbonate (195 mg, 0.60 mmol), tris(dibenzylideneacetone)dipalladium (18 mg, 0.020 mmol), and 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (23 mg, 0.040 mmol) were added to dioxane (5 ml). The atmosphere was replaced with nitrogen three times, and the temperature was raised to 100° C. for 3 hours.

[0459] The reaction was stopped and the temperature was lowered to room temperature. Water (10 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 ml x 3 times). The organic phases were combined, washed with saturated brine (10 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 = 1 / 3) to obtain a crude product, which was then purified by high performance liquid chromatography to obtain 33 mg of 2-(8-chloro-2-((4-(trifluoromethoxy)phenyl)amino)quinolin-7-yl)propan-2-ol. (Yield: 42.6%). LCMS: RT = 2.07 min, [M+H] + =397.13. 1H NMR(400MHz,DMSO-d6)δ9.88(s,1H),8.38–8.31(m,2H),8.13(d,J=8.8Hz,1H),7.88(d,J=8.5Hz,1 H),7.73(d,J=8.5Hz,1H),7.37(d,J=8.7Hz,2H),7.13(d,J=8.8Hz,1H),5.43(s,1H),1.75(s,6H).

[0460] Example 69 Synthesis of 8'-chloro-6-(trifluoromethoxy)-2H-[1,2'-biquinolinyl]-2-one

[0461]

[0462] Step A: Synthesis of (E)-methyl 3-(2-amino-5-(trifluoromethoxy)phenyl)acrylate

[0463] To a mixture of 2-bromo-4-(trifluoromethoxy)aniline (1 g, 3.91 mmol), methyl acrylate (0.50 g, 5.87 mmol), palladium(II) acetate (0.088 g, 0.39 mmol), tri(o-methylphenyl)phosphine (0.12 g, 0.39 mmol), and triethylamine (1.19 g, 11.73 mmol) was added N,N-dimethylformamide (5 ml) at room temperature. After the addition, the reaction flask was flushed with nitrogen three times and then heated to 90°C with stirring for 2 hours. After the reaction, the mixture was diluted with 100 ml of water and extracted with dichloromethane (150 ml × 3). The organic phases were combined, washed with saturated brine (150 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 300 mg of methyl (E)-3-(2-amino-5-(trifluoromethoxy)phenyl)acrylate as a white solid (yield: 29.41%).

[0464] Step B: Synthesis of 6-(trifluoromethoxy)quinolin-2(1H)-one

[0465] To a solution of methyl (E)-3-(2-amino-5-(trifluoromethoxy)phenyl)acrylate (300 mg, 1.15 mmol) in tetrahydrofuran (5 mL) and water (5 mL) was added 10 mL of concentrated hydrochloric acid at room temperature. After the addition, the mixture was heated to 80°C and stirred for 8 hours. 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 purified by column chromatography (eluent: ethyl acetate / n-hexane = 1 / 5) to afford 180 mg of 6-(trifluoromethoxy)quinolin-2(1H)-one as a white solid (yield: 68.39%).

[0466] Step C: Synthesis of 8'-chloro-6-(trifluoromethoxy)-2H-[1,2'-biquinolinyl]-2-one

[0467] To a mixture of 6-(trifluoromethoxy)quinolin-2(1H)-one (120 mg, 0.52 mmol), 2,8-dichloroquinoline (102.99 mg, 0.52 mmol), cuprous iodide (9.90 mg, 0.052 mmol), and potassium carbonate (215.61 mg, 1.56 mmol) was added N,N-dimethylformamide (5 ml) at room temperature. After the addition was complete, the reaction flask was purged with nitrogen three times, then heated to 160°C and stirred for 8 hours. 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 purified by preparative purification to yield 52.42 mg of 8'-chloro-6-(trifluoromethoxy)-2H-[1,2'-biquinolin]-2-one as a white solid (yield: 25.62%). LCMS: RT = 2.21 min, [M+H] + =390.93. 1 HNMR(400MHz,DMSO-d6)δ8.62(m,2H),8.16–8.09(m,1H),8.04(dd,J=8.2,1.2Hz,1H),7.93( dd,J=7.7,1.2Hz,1H),7.87(d,J=9.1Hz,1H),7.71(dd,J=9.1,2.7Hz,1H),7.64–7.53(m,3H).

[0468] Example 70 Synthesis of Compound 8-Chloro-N-(3-(trifluoromethyl)-1H-pyrazol-5-yl)quinolin-2-amine

[0469]

[0470] 5-Amino-3-trifluoromethylpyrazole (200 mg, 1.32 mmol), 2-bromo-8-chloroquinoline (320 mg, 1.32 mmol), tris(dibenzylideneacetone)dipalladium (60 mg, 0.066 mmol), 2-dicyclohexylphosphino-2",4",6"-triisopropylbiphenyl (63 mg, 0.13 mmol), and cesium carbonate (645 mg, 1.98 mmol) were added to dioxane (8 ml) at room temperature. The atmosphere was replaced with nitrogen and the reaction was carried out in a microwave oven at 110°C for 1 hour.

[0471] After the reaction was complete, the mixture was filtered and the filtrate was concentrated to dryness to obtain a crude product, which was purified by preparative chromatography to afford 156 mg of an off-white solid 8-chloro-N-(3-(trifluoromethyl)-1H-pyrazol-5-yl)quinolin-2-amine (yield: 37.7%). LCMS: RT = 2.07 min, [M+H] + =312.97. 1 H NMR (400MHz, DMSO-d6) δ10.86(s,1H),8.28(d,J=8.9Hz,1H),7.88(d,J=7.7Hz,1H) ,7.85(d,J=8.1Hz,1H),7.39(t,J=7.8Hz,1H),7.23(d,J=8.9Hz,1H),6.90(s,1H).

[0472] Example 71 Synthesis of 3-(8-chloroquinolin-2-yl)-7-(trifluoromethoxy)quinazolin-4(3H)-one

[0473]

[0474] At room temperature, 7-(trifluoromethoxy)quinazolin-4(3H)-one (100 mg, 0.43 mmol), 2-bromo-8-chloroquinoline (130 mg, 0.54 mmol), cesium carbonate (527 mg, 1.62 mmol), tris(dibenzylideneacetone)dipalladium (49 mg, 0.054 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (62 mg, 0.11 mmol) were added to dioxane (10 ml), the atmosphere was replaced with nitrogen three times, and the temperature was raised to 100 °C for 5 hours.

[0475] The reaction was stopped and the temperature was lowered to room temperature. The mixture was concentrated to dryness under reduced pressure to obtain a crude product, which was slurried with water (20 mL), slurried with isopropanol (20 mL) at 60°C, filtered hot, and dried to obtain 112 mg of 3-(8-chloroquinolin-2-yl)-7-(trifluoromethoxy)quinazolin-4(3H)-one (yield: 53.3%). LCMS: RT = 2.13 min, [M+H] + =391.73.

[0476] Example 72 / 73 Synthesis of 2-(8-chloroquinolin-2-yl)-5-(trifluoromethoxy)-1,2-dihydro-3H-indazol-3-one and 1-(8-chloroquinolin-2-yl)-5-(trifluoromethoxy)-1,2-dihydro-3H-indazol-3-one

[0477]

[0478] Step A: Synthesis of 2-hydrazino-5-(trifluoromethoxy)benzoic acid

[0479] To 2-fluoro-5-(trifluoromethoxy)benzoic acid (1 g, 4.46 mmol) was added 10 ml of hydrazine hydrate at room temperature. After addition, the mixture was heated to 160°C and stirred for 8 hours. After completion of the reaction, the reaction mixture was concentrated to yield 500 mg of crude 2-hydrazino-5-(trifluoromethoxy)benzoic acid as a colorless oil, which was used directly in the next step.

[0480] Step B: Synthesis of 5-(trifluoromethoxy)-1,2-dihydro-3H-indazol-3-one

[0481] To 2-hydrazino-5-(trifluoromethoxy)benzoic acid (0.5 g, 2.12 mmol) was added 10 mL of concentrated hydrochloric acid at room temperature. After the addition, the mixture was heated to 100°C and stirred for 8 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 column chromatography (eluent: ethyl acetate / n-hexane = 1 / 1) to afford 250 mg of 5-(trifluoromethoxy)-1,2-dihydro-3H-indazol-3-one as a white solid (yield: 54.13%).

[0482] Step C: Synthesis of 2-(8-chloroquinolin-2-yl)-5-(trifluoromethoxy)-1,2-dihydro-3H-indazol-3-one and 1-(8-chloroquinolin-2-yl)-5-(difluoromethoxy)-1,2-dihydro-3H-indazol-3-one

[0483] To a mixture of 5-(trifluoromethoxy)-1,2-dihydro-3H-indazol-3-one (50 mg, 0.23 mmol), 2-bromo-8-chloroquinoline (55.78 mg, 0.23 mmol), potassium carbonate (95.36 mg, 0.69 mmol), and cuprous iodide (4.38 mg, 0.023 mmol) was added N,N-dimethylformamide (5 mL) at room temperature. After the addition, the reaction flask was purged with nitrogen three times, then heated to 160°C and stirred 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 33.861 mg of P1, a white solid (yield: 38.90%). 1 H NMR (400MHz, DMSO-d6) δ13.00(s,1H),8.57(d,J=8.8Hz,1H),7.99(d,J=8.0Hz,1H),7.84(d,J=7.5Hz ,1H),7.66(d,J=9.0Hz,1H),7.57–7.44(m,3H),7.40(dd,J=9.0,2.1Hz,1H).LCMS:RT=2.16min,[M+H]+ =379.82 and 2.017 mg of white solid P2 (yield: 2.32%). LCMS: RT = 2.34 min, [M+H] + =379.84

[0484] Example 74 Synthesis of 8-chloro-N-(2-(trifluoromethyl)pyrimidin-5-yl)quinolin-2-amine

[0485]

[0486] Under N2 protection, 2-bromo-8-chloroquinoline (0.12 g, 0.49 mmol), 2-trifluoromethyl-5-aminopyrimidine (0.08 g, 0.9 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.045 g, 0.049 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.085 g, 0.15 mmol) and cesium carbonate (0.32 g, 0.98 mmol) were added to 5 ml of dioxane and reacted at 100 °C overnight.

[0487] 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 80 mg of 8-chloro-N-(2-(trifluoromethyl)pyrimidin-5-yl)quinolin-2-amine as a white solid (yield: 49.79%). LCMS: RT = 2.02 min, [M+H] + =324.87. 1 H NMR (400MHz, DMSO-d6) δ10.61(s,1H),9.80(s,2H),8.34(d,J=8.8Hz,1H),7.92–7.84(m,2H),7.46–7.38(m,1H),7.29(d,J=8.8Hz,1H).

[0488] Example 75 Synthesis of 2-(8-chloroquinolin-2-yl)-6-(trifluoromethoxy)isoindolin-1-one

[0489]

[0490] Step A: Synthesis of methyl 2-cyano-5-(trifluoromethoxy)benzoate

[0491] At room temperature, 2-bromo-4-trifluoromethoxybenzonitrile (2 g, 7.52 mmol), 2,4,6-trichlorophenyl formate (10.17 g, 45.12 mmol), dichloro[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene]palladium(II) (0.57 g, 0.75 mmol) and triethylamine (6.09 g, 60.12 mmol) were added to 15 ml of methanol and reacted at 60 °C overnight.

[0492] 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), 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 1.5 g of methyl 2-cyano-5-(trifluoromethoxy)benzoate as a white solid (yield: 81.38%).

[0493] Step B: Synthesis of 6-(trifluoromethoxy)isoindolin-1-one

[0494] Under a hydrogen atmosphere, methyl 2-cyano-5-(trifluoromethoxy)benzoate (1.5 g, 6.12 mmol) and Raney nickel (0.07 g, 1.22 mmol) were added to 15 mL of methanol and allowed to react overnight at room temperature. The insoluble material was filtered off, and the methanol was evaporated to dryness to afford 1 g of 6-(trifluoromethoxy)isoindolin-1-one as a white solid (yield: 75.27%).

[0495] Step C: Synthesis of 2-(8-chloroquinolin-2-yl)-6-(trifluoromethoxy)isoindolin-1-one

[0496] Under N2 protection, 2,8-dichloroquinoline (0.12 g, 0.61 mmol), 6-(trifluoromethoxy)isoindolin-1-one (0.13 g, 0.61 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.056 g, 0.061 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.11 g, 0.18 mmol) and cesium carbonate (0.4 g, 1.22 mmol) were added to 5 ml of dioxane and reacted at 100 °C overnight.

[0497] 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 80 mg of 2-(8-chloroquinolin-2-yl)-6-(trifluoromethoxy)isoindolin-1-one as a white solid (yield: 34.86%). LCMS: RT = 2.39 min, [M+H] + =378.87. 1H NMR (400MHz, DMSO-d6) δ8.83(d,J=9.0Hz,1H),8.56(d,J=9.0Hz,1H),8.04–7.93(m,3H),7.85–7.74(m,2H),7.60–7.49(m,1H),5.34(s,2H).

[0498] Example 76 Synthesis of 8'-chloro-6-(trifluoromethoxy)-4H-[1,2'-biquinolinyl]-4-one

[0499]

[0500] Step A: Synthesis of 2,2-dimethyl-5-((4-(trifluoromethoxy)phenyl)amino)methylene)-1,3-dioxane-4,6-dione

[0501] At room temperature, 2,2-dimethyl-1,3-dioxane-4,6-dione (2.43 g, 16.8 mmol) was mixed with trimethyl orthoformate (16 ml), heated to 100 degrees Celsius and reacted for 2 hours. Then, p-trifluoromethoxyaniline (2 g, 11.3 mmol) was added and stirred for 3 hours. LCMS was used to monitor the reaction until it was complete. After cooling to room temperature, n-hexane (50 ml) was added, filtered, and dried to obtain 3.8 g of light yellow solid 2,2-dimethyl-5-((4-(trifluoromethoxy)phenyl)amino)methylene)-1,3-dioxane-4,6-dione, which was used directly in the next step. LCMS: RT = 1.97 min, [M+H] + =329.92.

[0502] Step B: Synthesis of 6-(trifluoromethoxy)quinolin-4(1H)-one

[0503] 2,2-Dimethyl-5-((4-(trifluoromethoxy)phenyl)amino)methylene)-1,3-dioxane-4,6-dione (3.8 g, 11.3 mmol) was mixed in diphenyl ether (50 mL) at room temperature and heated to 180°C for 10 minutes. The reaction was monitored by LCMS until completion.

[0504] Cool to room temperature, add n-hexane (100 ml), filter, and dry to obtain 2.35 g of a brown solid 6-(trifluoromethoxy)quinolin-4(1H)-one (two-step yield: 90.42%), which is used directly in the next step. LCMS: RT = 1.66 min, [M+H] + =230.03.

[0505] Step C: Synthesis of 8'-chloro-6-(trifluoromethoxy)-4H-[1,2'-biquinolinyl]-4-one

[0506] At room temperature, 6-(trifluoromethoxy)quinolin-4(1H)-one (50 mg, 0.22 mmol) was dissolved in dimethyl sulfoxide (3 ml). 2-Bromo-8-chloroquinoline (53 mg, 0.22 mmol), cuprous iodide (21 mg, 0.11 mmol), and potassium carbonate (61 mg, 0.44 mmol) were added. The mixture was heated to 150°C under nitrogen and stirred for 3 hours. LCMS monitoring was performed until the reaction was complete.

[0507] The mixture was cooled to room temperature, water (10 ml) was added, and the mixture was extracted with ethyl acetate (10 ml x 3 times). The organic phases were combined, washed with saturated brine (10 ml x 3 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. High-resolution liquid chromatography was used to obtain 45 mg of a light yellow solid, 8'-chloro-6-(trifluoromethoxy)-4H-[1,2'-biquinolin]-4-one (yield: 52.59%). LCMS: RT = 2.09 min, [M+H] + =390.78.

[0508] Example 77 Synthesis of Compound 8-Chloro-N-(2-methoxypyrimidin-5-yl)quinolin-2-amine

[0509]

[0510] 2-Methoxy-5-aminopyrimidine (61 mg, 0.49 mmol), 2-bromo-8-chloroquinoline (120 mg, 0.49 mmol), tris(dibenzylideneacetone)dipalladium (22 mg, 0.025 mmol), 2-dicyclohexylphosphino-2",4",6"-triisopropylbiphenyl (23 mg, 0.049 mmol), and cesium carbonate (239 mg, 0.73 mmol) were added to dioxane (3 ml) at room temperature. The atmosphere was replaced with nitrogen and the reaction was carried out in a microwave oven at 110°C for 2 hours.

[0511] After the reaction, the mixture was filtered and the filtrate was concentrated to dryness to obtain a crude product, which was purified by preparative chromatography to obtain 51 mg of a white solid 8-chloro-N-(2-methoxypyrimidin-5-yl)quinolin-2-amine (yield: 36.1%). LCMS: RT = 1.92 min, [M+H] + =287.14. 1 HNMR(400MHz,DMSO-d6)δ9.93(s,1H),9.40(s,2H),8.20(d,J=8.8Hz,1H),7.81(d,J=8.2 Hz,1H),7.79(d,J=8.2Hz,1H),7.32(t,J=7.8Hz,1H),7.16(d,J=8.9Hz,1H),3.93(s,3H).

[0512] Example 78: Determination of the upregulation effect of the compounds of the present invention on miR-124

[0513] 1 Experimental materials and instruments

[0514] 1.1 Small RNA extraction kit

[0515] 1.2 Small RNA Reverse Transcription Kit

[0516] 2 Experimental steps

[0517] Compound-treated cells

[0518] 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.

[0519] 2.2 Harvest cells by centrifugation at 1000 rpm for 5 minutes;

[0520] 2.3 Use trypsin to digest the adherent cells, centrifuge and discard the supernatant, and add 1 mL of RNAIsolater reagent to the cell pellet;

[0521] 2.4 Vortex and let stand at room temperature for 2 to 3 minutes to allow complete lysis.

[0522] RNA extraction

[0523] 2.5 Add 200 μL of chloroform, shake vigorously for 15 seconds, and then let it stand at room temperature for 3 minutes;

[0524] 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.

[0525] 2.7 Add 160uL of anhydrous ethanol and mix thoroughly by inverting 3 to 5 times;

[0526] 2.8 Transfer the solution to a MiPure RNA collection column and centrifuge at 12,000 rpm for 30 seconds at room temperature.

[0527] 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;

[0528] 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;

[0529] 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;

[0530] 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;

[0531] 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;

[0532] 2.14 Centrifuge the empty collection column and centrifuge tube again at 12000 rpm for 2 minutes;

[0533] 2.15 Place the collection column in a 1.5 mL RNase-free centrifuge tube and dry at room temperature for 2–5 minutes.

[0534] 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;

[0535] 2.17 Place the collected RNA on ice and measure the RNA concentration using a microplate reader.

[0536] Genomic DNA

[0537] 2.18 Take 1 μg of RNA and add 1 μL of 5X gDNA wiper mix. Add RNase-free water to make up to 5 μL.

[0538] 2.19 Set the PCR machine to 42°C for 2 minutes.

[0539] RNA reverse transcription

[0540] 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.

[0541] 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.

[0542] QPCR detection

[0543] 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 components: 5 μL 2X miRNA Universal SYBR qPCR Master Mix, 0.2 μL each QPCR primer (10 μM), 1 μL template cDNA, and 3.6 μL ddH2O.

[0544] 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.

[0545] 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. ΔCt = Ct (target gene) – Ct (reference gene), ΔΔCt = ΔCt (treated group) – ΔCt (control group), and the relative ratio was calculated as: Relative mRNA expression = 2(-ΔΔCt). The results are shown in Table 2:

[0546] Table 2:

[0547] Compound miR-124 upregulation (fold) Compound miR-124 upregulation (fold) DMSO 1.00 DMSO 1.00 1 >2 46* >2 2 >2 47* >2 3 >2 48* >2 18 >2 49* >2 22 >2 50* >2 24 >2 55* >2 25 >2 57* >2 26 >2 58* >2 27 >2 59* >2 29 >2 60* >2 31 >2 61* >2 33 >2 62* >2 37 >2 65* >2 38 >2 68* >2 39 >2 69* >2 40 >2 70* >2 41 >2 72* >2 42 >2 74* >2 43* >2 75* >2 44* >2 76* >2 45* >2 77* >2

[0548] 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.

[0549] Pharmacokinetic study of the compound of Example 79 in rats

[0550] 1 Experimental Materials

[0551] SD rats: male, 180-250 g, purchased from Beijing Weitonglihua Experimental Animal Technology Co., Ltd.

[0552] Reagents: DMSO (dimethyl sulfoxide), PEG-400 (polyethylene glycol 400), normal saline, heparin, acetonitrile, formic acid, and propranolol (internal standard) are all commercially available.

[0553] Instrument: AB SCIEX QTRAP 5500+.

[0554] 2 Experimental methods

[0555] Compounds were weighed and dissolved in DMSO-PEG-400-saline (5:60:35, v / v / v). After intravenous or oral administration, 200 μL of venous blood was collected from rats at 15, 30, 1, 2, 5, 7, and 24 hours (5 minutes additionally for the IV group) in EDTA-K2 anticoagulant tubes. The blood was centrifuged at 12,000 rpm for 2 minutes, and plasma was frozen at -80°C for analysis. A precisely weighed amount of test compound was dissolved in DMSO to 2 mg / mL to prepare a stock solution. An appropriate amount of the stock solution was accurately aspirated and diluted with acetonitrile to prepare a series of standard solutions. 10 μL of each standard solution was accurately aspirated and added to 90 μL of blank plasma. Vortex-mixed, the samples were prepared to prepare plasma concentrations equivalent to 1, 3, 5, 10, 30, 100, 300, 1000, and 3000 ng / mL. Duplicate samples were analyzed at each concentration to construct a standard curve. 30 μL of plasma (5, 15, and 30 minutes after intravenous administration, diluted 5-fold) was collected and 150 μL of an acetonitrile solution of internal standard propranolol (50 ng / mL) was added. After vortex mixing, 100 μL of purified water was added and vortex mixing was repeated. The supernatant was centrifuged at 4000 rpm for 5 minutes and analyzed by LC-MS. LC-MS detection conditions were as follows:

[0556] Chromatographic column: YMC Triart C18, 50*3.0mm, 2.1μm.

[0557] Mobile phase: water (0.1% formic acid)-acetonitrile with gradient elution as shown in Table 3.

[0558] Table 3:

[0559] Time (min) Water (containing 0.1% formic acid) Acetonitrile 0 80％ 20％ 0.6 80％ 20％ 1.2 15％ 85％ 2.6 15％ 85％ 2.61 80％ 20％ 3.2 80％ 20％

[0560] 3 Data processing

[0561] After LC-MS detection of blood drug concentration, WinNonlin 6.1 software was used to calculate the pharmacokinetic parameters using the non-compartmental model method. The test results are shown in Table 4 below:

[0562] Table 4:

[0563]

[0564] As can be seen from the above table, the compounds of the present invention exhibit good oral exposure.

[0565] 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 (I), or an isomer, a racemate, or a pharmaceutically acceptable salt thereof, characterized in that: Wherein, ring A is selected from a benzene ring, a cycloalkyl ring, a five-membered or six-membered aromatic heterocycle, a five-membered and six-membered aromatic heterocycle or a six-membered and six-membered aromatic heterocycle; R 1a 、R 1b 、R 1c 、R 1d 、R 2a 、R 2b independently selected from hydrogen, halogen, alkyl, alkoxy, substituted or unsubstituted amino, the substituents being selected from alkyl, cycloalkyl, cycloalkylalkyl, heterocyclylalkyl; Ring A may be substituted and selected from halogen, hydroxy, alkyl, haloalkyl, oxo, substituted or unsubstituted alkoxy, alkylthio, alkoxyhaloalkyl, alkylsulfonyl, cycloalkyl, heterocycloalkyl, cycloalkyloxy, cycloalkylalkyloxy, aminoacyl, the substituents being selected from alkyl, haloalkyl or halogen, or adjacent substituents forming a substituted or unsubstituted saturated or unsaturated cycloalkyl or heterocycloalkyl, the substituents being selected from alkyl or halogen; X is absent or selected from O, NR4, -CR5R6-(O) n -, -NH-C(O)-CR7R8-, -NH-C(O)-NH2, -NH-CR9R 10 -, -NH-C(O)-, -C(O)-NH-, or -NH-NH-C(O)-, n=0 or 1; R4 is selected from hydrogen, substituted or unsubstituted cycloalkyl, heterocyclyl, heterocyclylalkyl, cycloalkylalkyl, the substituent is selected from hydroxyl, halogen, carboxyl, or forms a cycloalkyl or heterocycloalkyl with the substituent of ring A, and the cycloalkyl or heterocycloalkyl may be further substituted with oxo; R5 and R6 are independently selected from hydrogen, hydroxy, cyano, carboxyl, substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, amino, and alkylamino, and the substituents are selected from alkyl, haloalkyl, hydroxyalkyl, hydroxy, cycloalkyl, halogen, carboxyl, aminoacyl, amino, alkylamino, saccharyl, and halogen-substituted or unsubstituted phenyl, or R5 and R6 form a cycloalkyl or heterocycloalkyl group; R7 and R8 are independently selected from hydrogen and alkyl; R9, R 10 independently selected from hydrogen, carboxyl; When R4 is selected from hydrogen, at least one of the substituents of ring A is selected from substituted or unsubstituted alkoxyhaloalkyl, alkylsulfonyl, cycloalkyl, cycloalkyloxy, cycloalkylalkyloxy, aminoacyl, and the substituent is selected from alkyl, haloalkyl or halogen, or the substituent of ring A forms a cycloalkyl.

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: a compound represented by formula (Ia), an isomer thereof, a racemate thereof, or a pharmaceutically acceptable salt thereof, Wherein, ring A is selected from benzene ring or cyclohexane; R 1a 、R 1b 、R 1c 、R 1d 、R 2a 、R 2b independently selected from hydrogen, halogen, alkyl, alkoxy, substituted or unsubstituted amino, the substituents being selected from alkyl, cycloalkyl, cycloalkylalkyl, heterocyclylalkyl; R 3a 、R 3b 、R 3c 、R 3d 、R 3e independently selected from hydrogen, halogen, hydroxy, substituted or unsubstituted alkoxy, alkylthio, alkoxyhaloalkyl, alkylsulfonyl, cycloalkyl, heterocycloalkyl, cycloalkyloxy, cycloalkylalkyloxy, aminoacyl, the substituents being selected from alkyl, haloalkyl or halogen, or R 3a With R 3b 、R 3a With R 3e 、R 3b With R 3c 、R 3c With R 3d forming a substituted or unsubstituted saturated or unsaturated cycloalkyl or heterocycloalkyl group, wherein the substituent is selected from alkyl or halogen; X is selected from O, NR4, -CR5R6-(O) n -, -NH-C(O)-CR7R8-, -NH-C(O)-NH2, -NH-CR9R 10 -, -NH-C(O)-, -C(O)-NH-, or -NH-NH-C(O)-, n=0 or 1; R4 is selected from hydrogen, substituted or unsubstituted cycloalkyl, heterocyclyl, heterocyclylalkyl, cycloalkylalkyl, and the substituent is selected from hydroxyl, halogen, carboxyl, or R 3d forming a cycloalkyl group or a heterocycloalkyl group; R5 and R6 are independently selected from hydrogen, hydroxy, cyano, carboxyl, substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, amino, and alkylamino, and the substituents are selected from alkyl, haloalkyl, hydroxyalkyl, hydroxy, cycloalkyl, halogen, carboxyl, aminoacyl, amino, alkylamino, saccharyl, and halogen-substituted or unsubstituted phenyl, or R5 and R6 form a cycloalkyl or heterocycloalkyl group; R7 and R8 are independently selected from hydrogen and alkyl; R9, R 10 independently selected from hydrogen, carboxyl; When R4 is selected from hydrogen, R 3a 、R 3b 、R 3c 、R 3d 、R 3e At least one selected from substituted or unsubstituted alkoxyhaloalkyl, alkylsulfonyl, cycloalkyl, cycloalkyloxy, cycloalkylalkyloxy, aminoacyl, the substituent being selected from alkyl, haloalkyl or halogen, or R 3b With R 3c Forming a cycloalkyl group.

3. The compound according to claim 1, or its isomer, racemate, or pharmaceutically acceptable salt, characterized in that: The five-membered or six-membered aromatic heterocycle, the five-membered and six-membered aromatic heterocycle or the six-membered and six-membered aromatic heterocycle is selected from:

4. The compound according to any one of claims 1 to 3, or its isomer, racemate, or pharmaceutically acceptable salt, characterized in that: The alkyl group is selected from C 1-6 The alkyl group, the C 1-6 The alkyl group is selected from the group consisting of methyl, ethyl, 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, 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-hexoxy, isohexoxy, sec-hexoxy, tert-hexoxy, neohexoxy, 2-methylpentoxy, 1,2-dimethylbutoxy, and 1-ethylbutoxy; the O of the alkylthio group is replaced by S; The halogen is selected from fluorine, chlorine, bromine and iodine; Cycloalkyl is selected from C 3-6 The monocyclic alkyl group is further selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or C 7-10 The heterocycloalkyl group refers to a bicyclic or tricyclic group in which one or more carbon atoms on the cycloalkyl group are replaced by heteroatoms selected from O, S, and N.

5. The compound according to any one of claims 1 to 3, or its isomer, racemate, or pharmaceutically acceptable salt, characterized in that: R 1a 、R 1b 、R 1c 、R 2a 、R 2b Selected from hydrogen, R 1d Selected from chlorine.

6. The compound according to claim 2, or its isomer, racemate, or pharmaceutically acceptable salt, characterized in that: When X is selected from O, NR4, -CR5R6-(O) n , -NH-C(O)-CR7R8-, -NH-C(O)-NH2, -NH-CR9R 10 -, or -NH-NH-C(O)-, n=0 or 1, or R4 and R 3d When forming a cycloalkyl or heterocycloalkyl group, and R4 is not hydrogen; R 3a 、R 3c 、R 3d 、R 3e Selected from hydrogen, R 3b Selected from -OCF3, -SCF3, -S(O)2CH2F; or R 3c 、R 3d 、R 3e Selected from hydrogen, R 3a With R 3b form 7. The compound according to claim 2, or its isomer, racemate, or pharmaceutically acceptable salt thereof, characterized in that: When R4 is selected from hydrogen, the A ring is selected from a benzene ring, R 3a 、R 3b 、R 3c 、R 3d At least one selected from or R 3a 、R 3b form Or when R4 is selected from hydrogen, the A ring is selected from cyclohexane, further, the substituted cyclohexane is selected from 8. The compound according to claim 1, or its isomer, racemate, or pharmaceutically acceptable salt, characterized in that: The compound is selected from the compounds shown in Table 1.

9. A pharmaceutical composition, characterized in that The invention comprises a therapeutically effective amount of the compound according to any one of claims 1 to 8, or an isomer thereof, a racemate thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

10. Use of the compound according to any one of claims 1 to 8, or its isomer, racemate, or pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 9, in particular, in the preparation of a medicament for diseases related to regulating miRNA levels.

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