PRMT5 inhibitor and preparation method thereof

Abstract

The invention relates to the field of medicine, in particular to a PRMT5 inhibitor as well as a preparation method and application thereof, and the PRMT5 inhibitor is a compound shown as a formula (I), an enantiomer, a diastereoisomer, a raceme, a solvate, a hydrate, a polymorph, a prodrug, an isotope variant or a pharmaceutically acceptable salt thereof. The compound provided by the invention has better activity, selectivity, pharmacokinetic characteristics and safety or a wider therapeutic window.

Description

PRMT5 inhibitors and preparation methods thereof Technical Field

[0001] The present invention relates to the field of medicine, and in particular to a PRMT5 inhibitor, a preparation method and an application thereof. Background Art

[0002] Protein arginine methyltransferase 5 (PRMT5) is an epigenetic target with clinical potential. It is a type II arginine methyltransferase that modifies histones and other proteins through symmetrical dimethylation and post-translational modification. PRMT5 plays an important role in regulating key cellular processes, including DNA damage repair, cell cycle progression, transcriptional regulation, and RNA splicing. Upregulation of PRMT5 can lead to tumor cell proliferation and invasion in a variety of cancers, including colorectal, lung, ovarian, and prostate cancers, as well as hematologic malignancies. First-generation PRMT5 inhibitors such as GSK-3326595, JNJ-64619178, PF-06939999, PRT-543, and PRT-811, resulting from their inhibition of PRMT5 activity in normal cells, have been associated with dose-limiting toxicities such as thrombocytopenia, anemia, and neutropenia.

[0003] Loss of the tumor suppressor gene CDKN2A is often accompanied by co-deletion of the proximal gene methylthioadenosine phosphorylase (MTAP). MTAP-deficient patients account for approximately 15% of all solid tumors, including approximately 15% of NSCLC, 28% of esophageal cancer, 26% of bladder cancer, and 10% of esophagogastric cancer. MTAP deficiency leads to accumulation of the metabolite methylthioadenosine (MTA) in MTAP-deficient cancer cells. MTA, an intermediate in the methionine compensation pathway, has a weak inhibitory effect on PRMT5, competing with its natural substrate SAM to form a PRMT5-MTA complex. Second-generation PRMT5 inhibitors enhance MTA's inhibition of PRMT5 by binding to and stabilizing the PRMT5-MTA complex, thereby inhibiting PRMT5 activity in MTAP-deficient cancer cells while preserving PRMT5 activity in normal cells, thereby improving the therapeutic index of second-generation PRMT5 inhibitors.

[0004] WO2021163344A1 relates to compounds that can be used to inhibit PRMT5 activity and treat proliferative, metabolic, and hematological disorders. The invention relates to PRMT5 inhibitors that are synergistic with an aromatic heterocyclic core group (MTA), some of which exhibit significant inhibition of cancer cell growth and high selectivity.

[0005] Currently, PRMT5 inhibitors in clinical practice lack selective killing effects on tumor cells and also inhibit normal cells, resulting in a narrow therapeutic window. In order to better improve the safety, efficacy and other properties of PRMT5 inhibitors, it is necessary to further conduct more in-depth research on PRMT5 inhibitor drugs to provide improved PRMT5 inhibitor drugs.

[0006] Summary of the Invention

[0007] In view of the above technical status, the present invention provides a new PRMT5 inhibitor, which is a compound of formula (I), an enantiomer, a diastereomer, a racemate, a solvate, a hydrate, a polymorph, a prodrug, an isotopic variant, or a pharmaceutically acceptable salt thereof:

[0008] in,

[0009] X is: C or N;

[0010] Z is: C=O or S(O)2;

[0011] R1 and R2 are each independently:

[0012] H;

[0013] C1-6 alkyl, C2-6 alkene, C2-6 alkynyl, wherein one or more H on the carbon atom is optionally substituted by the same or different halogen, hydroxyl, amino, carbonyl, keto, or cyano; when it is C3-6 alkyl, C3-6 alkene, or C3-6 alkynyl, it includes straight chain, branched chain, or cyclic;

[0014] RaRbRcC-O- or RaRbRcC-CO-, wherein Ra, Rb, and Rc are each independently H, C1-6 alkyl, C2-6 alkene, or C2-6 alkynyl, and optionally one or more H on the carbon atom is substituted by the same or different halogen, hydroxyl, amino, carbonyl, keto, or cyano; when it is C3-6 alkyl, C3-6 alkene, or C3-6 alkynyl, it includes straight chain, branched chain, or cyclic; or

[0015] RdReN- or RdReN-CO-, wherein Rd and Re are each independently H, C1-6 alkyl, C2-6 alkene, or C2-6 alkynyl, and optionally, one or more H on the carbon atom are each independently substituted by the same or different halogen, hydroxyl, amino, carbonyl, keto, or cyano groups; when they are C3-6 alkyl, C3-6 alkene, or C3-6 alkynyl, they include straight chain, branched chain, or cyclic;

[0016] R3 is H, halogen, hydroxyl, amino, carbonyl, keto, or cyano, wherein one or two H groups on the amino group are independently substituted by the same or different C1-6 alkyl, C2-6 alkene, or C2-6 alkynyl groups;

[0017] R4 is -NR5R6, wherein

[0018] R5 or R6 are each independently C1-6 alkyl, saturated or unsaturated C3-6 cycloalkyl or heterocyclic group, aryl, aromatic heteroyl, aryl and saturated or unsaturated C3-6 cycloalkyl or heterocyclic group, aromatic heteroyl and saturated or unsaturated C3-6 cycloalkyl or heterocyclic group, said saturated or unsaturated C3-6 cycloalkyl or aromatic heterocyclic ring containing one or more identical or different heteroatoms selected from N, O, and S; one or more H in said optional substituents are each independently substituted by halogen, C1-6 haloalkyl, C1-6 alkoxy, hydroxyl, amino, cyano, carbonyl, saturated or unsaturated C3-6 cycloalkyl or heterocyclic group; or

[0019] In the NR5R6, the N atom and the atoms in R6 and R5 form a ring;

[0020] When R1 is methyl, X is N.

[0021] In the present invention, as one embodiment, when R1 is -CH2OH, R2 is not CH3.

[0022] In the present invention, as one of the embodiments, the C1-6 alkyl group, as an exemplary illustration, may include but is not limited to methyl, ethyl, propyl, isopropyl, cyclopropyl, isobutyl, n-butyl, sec-butyl, tert-butyl, cyclobutyl, pentyl, isopentyl, cyclopentyl, hexyl, or cyclohexyl, etc.

[0023] In the present invention, as one embodiment, the C2-6 olefin group can be, for example, vinyl, propenyl, cyclopropenyl, butenyl, isobutenyl, cyclobutenyl, pentenyl, isopentenyl, cyclopentenyl, hexenyl, cyclohexenyl, etc.

[0024] In the present invention, as one embodiment, the C2-6 alkynyl group can be, for example, ethynyl, propynyl, butynyl, isobutynyl, cyclobutynyl, pentynyl, isopentenyl, hexynyl, etc.

[0025] In the present invention, as one of the embodiments, the saturated or unsaturated C3-6 cycloalkyl group can be, for example, cyclopropane, cyclopropene, cyclobutane, cyclobutene, cyclopentane, cyclopentene, cyclohexane, cyclohexene, etc., and one, two or more carbon atoms in the ring are independently substituted by N or S.

[0026] In the present invention, as one embodiment, the aryl group includes but is not limited to substituted or unsubstituted phenyl, naphthyl, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indanyl and purinyl;

[0027] In the present invention, as one embodiment, the aromatic hetero group refers to one, two or more carbon atoms in the above aromatic ring being independently substituted by N or S.

[0028] In the present invention, as one of the embodiments, the C1-6 haloalkyl group is exemplified by a halomethyl group, a haloethyl group, a halopropyl group, a haloisopropyl group, a halocyclopropyl group, a haloisobutyl group, a halo-n-butyl group, a halosec-butyl group, a halotert-butyl group, a halocyclobutyl group, a halopentyl group, a haloisopentyl group, a halocyclopentyl group, a halohexyl group, or a halocyclohexyl group, and the halo group is fluorine, chlorine, bromine, or iodine.

[0029] In the present invention, as one embodiment, the C1-6 alkoxy group is, for example, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, isobutoxy, n-butoxy, sec-butoxy, tert-butoxy, cyclobutyloxy, pentyloxy, isopentyloxy, cyclopentyloxy, hexyloxy or cyclohexyloxy.

[0030] In the present invention, as one embodiment, in the compound of structural formula (I), the halogen is F, Cl, Br or I.

[0031] In the present invention, as one embodiment, in the compound of structural formula (I), the halogenated group includes being substituted by one or more identical or different F, Cl, Br or I.

[0032] In the present invention, as one of the embodiments, in the compound of structural formula (I), R1 is H, CH3, CH3O, OHCH2, CH3(OH)CH, NH2CO, CH3NHCO, CH2NH2 or CH3CO.

[0033] In the present invention, as one of the embodiments, in the compound of structural formula (I), R2 is H, CH3, CH3O, OHCH2, CH3NH, (CH3)2N, CH3(OH)CH, NH2CO, CH3NHCO or CH3CO.

[0034] In the present invention, as one embodiment, in the compound of structural formula (I), R3 is hydrogen, halogen, hydroxyl or C1-6 alkoxy.

[0035] In the present invention, as one embodiment, X in the compound of structural formula (I) is C.

[0036] In the present invention, as one embodiment, Z in the compound of structural formula (I) is C=O.

[0037] In the present invention, as one embodiment, in the compound of structural formula (I), R5 is selected from the following structures:

[0038] In the present invention, as one embodiment, in the compound of structural formula (I), R6 is selected from the following structures:

[0039] -CH2CH3 or CH3.

[0040] In the present invention, as one embodiment, in the compound of structural formula (I), R4 is NR5R6, and when the N atom and the atoms in R6 and R5 form a ring, it is selected from the following structures:

[0041] In the present invention, as one embodiment, the compound of structural formula (I) is selected from the following:

[0042] In the present invention, as one of the embodiments, the isomers can be in the form of enantiomers and / or diastereoisomers, including one or more asymmetric centers, and thus can exist in a variety of stereoisomeric forms, for example, the compounds of the present invention can be individual enantiomers, diastereomers or geometric isomers (e.g., cis and trans isomers), or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be separated from the mixture by methods known to those skilled in the art, including chiral high pressure liquid chromatography and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric synthesis.

[0043] The compounds of the present invention may also exist in the form of tautomers. For compounds that exist in different tautomeric forms, a compound is not limited to any specific tautomer, but is intended to encompass all tautomeric forms.

[0044] In the present invention, as one of the embodiments, the solvate or hydrate may be in the form of a compound or salt thereof formed by combining the compound of the present invention with a solvent. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, ether, and the like. The compounds described herein may be prepared, for example, in crystalline form and may be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric solvates and non-stoichiometric solvates. In some cases, the solvate will be able to separate, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. "Solvate" includes solvates in solution and separable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0045] The term "hydrate" refers to a compound that is combined with water. Generally, the ratio of the number of water molecules contained in the hydrate of a compound to the number of molecules of the compound in the hydrate is determined. A given compound can form more than one type of hydrate, including, for example, monohydrates, lower hydrates (e.g., hemihydrates), and polyhydrates (e.g., dihydrates, trihydrates, tetrahydrates).

[0046] In the present invention, as one of embodiments, the polymorph can be an amorphous or crystalline form (polymorph). In addition, the compounds of the present invention can exist in one or more crystalline forms. Therefore, the present invention includes all amorphous or crystalline forms of the compounds of the present invention within its scope. The term "polymorph" refers to the crystalline form (or its salt, hydrate or solvate) of a compound with a specific crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms generally have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, photoelectric properties, stability and solubility. Recrystallization solvents, crystallization rate, storage temperature and other factors can cause a crystalline form to dominate. The various polymorphs of a compound can be prepared by crystallization under different conditions.

[0047] In the present invention, as one embodiment, the prodrug can be converted into its active form having medical effects through metabolic reactions in vivo, for example, hydrolysis in the blood.

[0048] In the present invention, as one embodiment, the isotopic variant is a structure described in formula (I), but one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number commonly found in nature. Examples of isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, for example 2 H. 3 H. 11 C. 13 C. 14C. 15 N. 17 O. 18 O. 18 F. 31 P. 32 P. 35 S and 36 The compounds of the present invention, their prodrugs, and pharmaceutically acceptable salts of the compounds or prodrugs that contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the present invention.

[0049] In the present invention, as one embodiment, the pharmaceutically acceptable salt comprises a salt formed by a compound of formula (I) and a pharmaceutically acceptable base. As an exemplary illustration, the base includes but is not limited to sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium bicarbonate, basic amino acids, ethanolamine, ethylenediamine, triethylamine, triethanolamine, triisopropanolamine, and ammonium hydroxide.

[0050] In the present invention, as one embodiment, the pharmaceutically acceptable salt comprises a salt of a compound of formula (I) and a pharmaceutically acceptable acid. As an exemplary illustration, the acid includes but is not limited to inorganic acids, organic acids, and amino acids. The inorganic acids include but are not limited to hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, and carbonic acid; the organic acids include but are not limited to acetic acid, propionic acid, butyric acid, ascorbic acid, boric acid, fatty acids, formic acid, fumaric acid, gluconic acid, lactic acid, maleic acid, oxalic acid, salicylic acid, stearic acid, succinic acid, tannic acid, thioglycolic acid, amino acids, citric acid, malic acid, tartaric acid, succinic acid, and the like.

[0051] The present invention also provides a pharmaceutical composition comprising a compound of formula (I), an enantiomer, a diastereomer, a racemate, a solvate, a hydrate, a polymorph, a prodrug, an isotopic variant, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0052] In the present invention, as one of the embodiments, the pharmaceutical composition includes but is not limited to oral preparations or injection preparations, the oral preparations include ordinary tablets, capsules, oral liquids, granules, capsules, dispersible tablets, chewable tablets, effervescent tablets or sustained-release preparations; the injection preparations include: injection solutions, lyophilized injections, or powder injections.

[0053] In the present invention, pharmaceutically acceptable carriers include, but are not limited to, fillers, flavoring agents, surfactants, osmotic pressure regulators, pH regulators, lubricants, preservatives, adhesives, disintegrants, coating materials, plasticizers, thickeners, suspending agents, plasticizers, opacifiers, solubilizers, emulsifiers, colorants, or a combination of two or more thereof.

[0054] In the present invention, as an exemplary illustration, the filler includes but is not limited to starch, dextrin, pregelatinized starch, lactose, mannitol, microcrystalline cellulose, calcium sulfate, calcium phosphate or calcium carbonate, or a combination of two or more thereof.

[0055] In the present invention, as an exemplary illustration, the flavoring agent includes but is not limited to saccharin sodium, sucralose, maltose, steviol glycosides, etc., or a combination of two or more thereof.

[0056] In the present invention, as an exemplary illustration, the surfactant includes but is not limited to stearic acid, sodium dodecylbenzenesulfonate, quaternary ammonium, lecithin, Tween, Span, fatty acid glyceride, etc., or a combination of two or more thereof.

[0057] In the present invention, as an exemplary illustration, the osmotic pressure regulator includes but is not limited to glucose, sodium chloride, phosphate or citrate, or a combination of two or more thereof.

[0058] In the present invention, as an exemplary illustration, the pH adjuster includes an acid or a base, and the acid includes but is not limited to hydrochloric acid, sulfuric acid, acetic acid, phosphoric acid, citric acid, tartaric acid, maleic acid, acidic amino acids, malic acid, etc.; the base includes but is not limited to sodium hydroxide, potassium hydroxide, sodium bicarbonate, ammonia solution, organic amines (exemplary illustrations such as ethanolamine, ethylenediamine), basic amino acids, or a combination of two or more thereof.

[0059] In the present invention, as an exemplary illustration, the lubricant includes but is not limited to magnesium stearate, micronized silica gel, talc, hydrogenated vegetable oil, polyethylene glycols or magnesium lauryl sulfate, or a combination of two or more thereof.

[0060] In the present invention, as an exemplary illustration, the binder includes starch slurry, sodium carboxymethyl cellulose, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose or hydroxypropyl methyl cellulose, or a combination of two or more thereof.

[0061] In the present invention, as an exemplary illustration, the disintegrant includes but is not limited to dry starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose or cross-linked polyvinylpyrrolidone, or a combination of two or more thereof.

[0062] In the present invention, according to the different characteristics and requirements of different preparations, those skilled in the art can select a suitable pharmaceutically acceptable carrier based on the properties of the compound of formula (I) of the present invention and in combination with common technical knowledge in the art.

[0063] In the present invention, the amount of the compound of formula (I), its enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs or isotopic variants, or pharmaceutically acceptable salts thereof, in the pharmaceutical composition can be determined according to the specific formulation form and the disease to be prevented or treated. As an example of the invention, the amount of the active drug in the composition can be 0.001 to 100% (excluding 100%) by mass, volume or mass / volume. %), as 0.001%, 0.003%, 0.005%, 0.007%, 0.009%, 0.01%, 0.02%, 0.04%, 0.06%, 0.08%, 0.1%, 0.3%, 0.5%, 0.07%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 99%, or an amount in the range defined by any two of the above numbers or any natural number between any two of the above numbers.

[0064] The present invention also provides the use of the compound of formula (I), its enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs, isotopic variants, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition containing the compound of formula (I), its enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs or isotopic variants, or pharmaceutically acceptable salts thereof, in the preparation of a drug for treating cancer.

[0065] The present invention also provides a compound of formula (I), enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs, isotopic variants, or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof for use in the preparation of a drug for treating adenocarcinoma, squamous cell carcinoma, lung cancer, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, bronchial cancer, esophageal / duct cancer, esophageal adenocarcinoma, gastric cancer, gastric adenocarcinoma, gastrointestinal stromal tumor, colorectal cancer, colon cancer, rectal cancer, colorectal adenocarcinoma, melanoma, brain tumor, meningioma, glioma, astrocytoma, oligodendroglioma, medulloblastoma, neuroblastoma, glioblastoma tumor, neurofibroma, neurofibromatosis type 1 or type 2, neurilemmoma, malignant schwannoma, neuroendocrine carcinoma, gastroenteropancreatic neuroendocrine tumor, breast cancer, prostate cancer, ovarian cancer, ovarian adenocarcinoma, cystadenocarcinoma, ovarian embryonal carcinoma, uterine cancer, endometrial cancer, uterine sarcoma, cervical cancer, cervical adenocarcinoma, bladder cancer, germ cell tumor, pancreatic cancer, liver cancer, hepatocellular carcinoma, cholangiocarcinoma, kidney cancer, renal cell carcinoma, papillary renal cell carcinoma, clear cell renal carcinoma, Wilms tumor, head and neck cancer, head and neck squamous cell carcinoma, sarcoma, angiosarcoma, lymphangiosarcoma, lymphangioendothelial sarcoma, hemangioma, osteosarcoma, Ewing's sarcoma, endothelial sarcoma, Kaposi's sarcoma, Multiple idiopathic hemorrhagic sarcomas, eye cancer, intraocular melanoma, retinoblastoma, oral cancer, oral squamous cell carcinoma, laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer, mesothelioma, adenoid cystic carcinoma, thymoma, adrenal cancer, anal cancer, appendix cancer and hematopoietic system cancers, such as lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, small lymphocytic lymphoma, marginal zone B-cell lymphoma, mucosa-associated lymphoid tissue lymphoma, lymph node marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma, primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma, immunoblastic large cell lymphoma The application of the drug in the treatment of hematological malignancies including lymphoma, precursor B-lymphoblastic lymphoma and primary central nervous system lymphoma, T-cell non-Hodgkin's lymphoma, precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma, angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy-type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma, multiple myeloma (MM), leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, chronic myeloid leukemia, myelodysplastic syndrome or myelofibrosis.

[0066] In the application of the present invention in the preparation of drugs for treating the above-mentioned diseases, a therapeutically effective amount of the above-mentioned compound (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, can be administered to the subject according to the actual condition of the subject.

[0067] The term "therapeutically effective amount" refers to an amount of the compound (I) or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof that can alleviate one or more symptoms of the condition being treated. The term "treating" is understood by those skilled in the art based on common sense to mean reversing, alleviating, or inhibiting one or more symptoms of the above-mentioned condition or illness.

[0068] The amount of the compound (I) or its pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant or its composition administered in the present invention can be determined by a person skilled in the art based on the compound of the present invention and the disease to be treated and the characteristics of the subject. For example, when administering the compound (I) of the present invention, or its pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant or its composition to an adult subject, the amount of the compound (I) of the present invention, or its pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant or its composition, includes administering (based on the amount of the active ingredient) 0.0001-100 mg / Kg / day, 0.001-100 mg / Kg / day, 0.005-100 mg / Kg / day, 0.05-100 mg / Kg / day, 0.01-100 mg / Kg / day, 0.1-100 mg / Kg / day;

[0069] As an exemplary illustration, it can be 0.0001 mg / Kg / day, 0.001 mg / Kg / day, 0.003 mg / Kg / day, 0.005 mg / Kg / day, 0.007 mg / Kg / day, 0.009 mg / Kg / day, 0.01 mg / Kg / day, 0.02 mg / Kg / day, 0.04 mg / Kg / day, 0.06 mg / Kg / day, 0.08 mg / Kg / day, 0.1 mg / Kg / day, 0.3 mg / Kg / day, 0.5 mg / Kg / day, 0.07 mg / Kg / day, 0.9 mg / Kg / day, 1 mg / Kg / day, 2 mg / Kg / day, 3 mg / Kg / day. / Kg / day, 4mg / Kg / day, 5mg / Kg / day, 6mg / Kg / day, 7mg / Kg / day, 8mg / Kg / day, 9mg / Kg / day, 10mg / Kg / day, 11mg / Kg / day, 12mg / Kg / day, 13mg / Kg / day, 14mg / Kg / day, 15mg / Kg / day, 16mg / Kg / day, 17mg / Kg / day, 18mg / Kg / day, 19mg / Kg / day, 2mg / Kg / day, 22mg / Kg / day, 24mg / Kg / day, 26mg / Kg / day, 28mg / Kg / day, 30mg / Kg / day, 32mg / Kg / day, 33mg / Kg / day, 35mg / Kg / day, 37mg / Kg / day, 39mg / Kg / day, 40mg / Kg / day, 42mg / Kg / day, 44mg / Kg / day, 46mg / Kg / day, 48mg / Kg / day, 50mg / Kg / day, 51mg / Kg / day, 53mg / Kg / per day, 55 mg / Kg / day, 57 mg / Kg / day, 59 mg / Kg / day, 60 mg / Kg / day, 62 mg / Kg / day, 64 mg / Kg / day, 66 mg / Kg / day, 68 mg / Kg / day, 70 mg / Kg / day, 71 mg / Kg / day, 73 mg / Kg / day, 75 mg / Kg / day, 77 mg / Kg / day, 79 mg / Kg / day, 80 mg / Kg / day, 90 mg / Kg / day or 100 mg / Kg / day.

[0070] In the present invention, the routes of administration of compound (I), or its pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs or isotopic variants or compositions thereof include, but are not limited to, gastrointestinal tract, inhalation administration, topical administration, and sublingual administration; the gastrointestinal route includes, but is not limited to, oral administration and rectal administration; and parenteral injection includes, but is not limited to, intravenous injection, subcutaneous injection, intramuscular injection, topical, and rectal administration.

[0071] The compound of the present invention (I), or its pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant, or pharmaceutical composition thereof, may be administered once, twice, three times, or more frequently per day. Administration may be performed every other day, once a week, once every two weeks, or once a month.

[0072] The compound of the present invention (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, or a pharmaceutical composition thereof, is administered for no less than 3 days, for example, about 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 1.5 months, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 2 years or 3 years.

[0073] The compound of the present invention (I), or its pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant or its pharmaceutical composition can be used alone or in combination with one or more other medicaments, which are also usually used in the form of a pharmaceutical composition. One or more compounds of the present invention and one or more other medicaments can be mixed into a preparation, or the two components can be formulated into a separate preparation for use alone or in combination.

[0074] Drugs used in combination with the compound of the present invention (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof include, but are not limited to, PD-1 inhibitors, tyrosine kinase inhibitors or MAT2A inhibitors, and as an example, may be abemaciclib, sotorasib, osimertinib, etc.

[0075] The PRMT5 inhibitors of the present invention have better activity, selectivity, pharmacokinetic properties, safety or a wider therapeutic window. DETAILED DESCRIPTION

[0076] The following examples are used to further illustrate the present invention, but are not intended to limit the effective scope of the present invention in any way.

[0077] Example 1: 2-amino-N 6-((3-fluoropyridin-2-yl)methyl)-N 6 -((5-(Trifluoromethyl)pyridin-2-yl)methyl)quinoline-3,6-dicarboxamide

[0078] (1) 2-Chloro-6-(methoxycarbonyl)quinoline-3-carboxylic acid

[0079] 2-Chloro-3-formylquinoline-6-carboxylic acid methyl ester (200 mg, 0.8 mmol) was dissolved in n-butanol (n-BuOH) (2 mL) and water (2 mL), sodium chlorite (144 mg, 1.6 mmol) and sodium dihydrogen phosphate (192 mg, 1.6 mmol) were added, and the mixture was stirred at room temperature for 16 hours. 1N HCl solution was added to the reaction solution to adjust the pH to 2, and a white solid was generated. The reaction solution was filtered and the filtered solid was vacuum dried to obtain 2-chloro-6-(methoxycarbonyl)quinoline-3-carboxylic acid (120 mg) as a white solid. Yield 56%. MS+H + =266.

[0080] (2) Methyl 2-chloro-3-((4-methoxybenzyl)carbamoyl)quinoline-6-carboxylate

[0081] 2-Chloro-6-(methoxycarbonyl)quinoline-3-carboxylic acid (120 mg, 0.45 mmol) was dissolved in dimethylformamide (DMF) (2 mL), and triethylamine (136 mg, 1.35 mmol), HATU (205 mg, 0.54 mmol), and 4-methoxybenzylamine (74 mg, 0.54 mmol) were added. The mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled and diluted with water and extracted three times with ethyl acetate (5 mL). The organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was separated and purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 2:1) to obtain methyl 2-chloro-3-((4-methoxybenzyl)carbamoyl)quinoline-6-carboxylate (120 mg) as a white solid. Yield: 70%. MS+H + =385.

[0082] (3) Methyl 2-((4-methoxybenzyl)amino)-3-((4-methoxybenzyl)carbamoyl)quinoline-6-carboxylate

[0083] Methyl 2-chloro-3-((4-methoxybenzyl)carbamoyl)quinoline-6-carboxylate (120 mg, 0.31 mmol) was dissolved in 1,4-dioxane (2 mL). N,N-diisopropylethylamine (120 mg, 0.93 mmol) and 4-methoxybenzylamine (85 mg, 0.62 mmol) were added. The reaction was stirred at 120°C for 16 hours. The reaction solution was cooled and concentrated under reduced pressure. The concentrate was separated and purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 1:1) to obtain methyl 2-((4-methoxybenzyl)amino)-3-((4-methoxybenzyl)carbamoyl)quinoline-6-carboxylate (100 mg) as a white solid. Yield: 66%. MS+H + =486.

[0084] (4) 2-((4-methoxybenzyl)amino)-3-((4-methoxybenzyl)carbamoyl)quinoline-6-carboxylic acid

[0085] 2-((4-methoxybenzyl)amino)-3-((4-methoxybenzyl)carbamoyl)quinoline-6-carboxylic acid methyl ester (100 mg, 0.2 mmol) was dissolved in methanol (1 mL) and water (1 mL), and lithium hydroxide (24 mg, 1.0 mmol) was added. The reaction was stirred at room temperature for 16 hours. 1N HCl solution was added to the reaction solution to adjust the pH of the reaction solution to 2. A white solid was generated. The mixed solution was filtered and the filtered solid was vacuum dried to obtain 2-((4-methoxybenzyl)amino)-3-((4-methoxybenzyl)carbamoyl)quinoline-6-carboxylic acid (80 mg) as a white solid. Yield 83%. MS+H + =472.

[0086] (5)N 6 -((3-fluoropyridin-2-yl)methyl)-N 3 -(4-methoxybenzyl)-2-((4-methoxybenzyl)amino)-N 6 -((5-(Trifluoromethyl)pyridin-2-yl)methyl)quinoline-3,6-dicarboxamide

[0087] 2-((4-methoxybenzyl)amino)-3-((4-methoxybenzyl)carbamoyl)quinoline-6-carboxylic acid (80 mg, 0.17 mmol) was dissolved in dimethylformamide (DMF) (1 mL), and triethylamine (52 mg, 0.51 mmol), HATU (76 mg, 0.2 mmol) and 1-(3-fluoropyridin-2-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)methanamine (57 mg, 0.2 mmol) were added. The mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with water and extracted three times with ethyl acetate (5 mL). The organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was separated and purified by silica gel column chromatography (eluent: dichloromethane:methanol=15:1) to obtain N 6 -((3-fluoropyridin-2-yl)methyl)-N 3 -(4-methoxybenzyl)-2-((4-methoxybenzyl)amino)-N 6 -((5-(Trifluoromethyl)pyridin-2-yl)methyl)quinoline-3,6-dicarboxamide (60 mg) as a white solid. Yield 48%. MS+H + =739.

[0088] (6)2-amino-N 6 -((3-fluoropyridin-2-yl)methyl)-N 6 -((5-(Trifluoromethyl)pyridin-2-yl)methyl)quinoline-3,6-dicarboxamide

[0089] N 6 -((3-fluoropyridin-2-yl)methyl)-N 3 -(4-methoxybenzyl)-2-((4-methoxybenzyl)amino)-N 6 -((5-(Trifluoromethyl)pyridin-2-yl)methyl)quinoline-3,6-dicarboxamide (60 mg, 0.08 mmol) was dissolved in trifluoroacetic acid (1 mL) and the reaction was stirred at 80°C for 16 hours. The reaction solution was concentrated under reduced pressure and the residue was purified by prep-HPLC (eluent: acetonitrile: water (10 mM NH4HCO3) = 35% to 60%) to obtain 2-amino-N 6 -((3-fluoropyridin-2-yl)methyl)-N 6 -((5-(Trifluoromethyl)pyridin-2-yl)methyl)quinoline-3,6-dicarboxamide (7 mg) was obtained as a white solid in an 18% yield. ESI-MS: [M+H] + =499.1 1H NMR (400MHz, DMSO-d6) δ8.91(s,1H),8.44(s,2H),8.17(d,J=8.3Hz,2H),7.96(s,1H),7.64–7.58(m,4H),7.45–7.37(m,4H),4.85(d,J=8.0Hz,4H).

[0090] Example 2: 2-amino-3-(hydroxymethyl)-N-methyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carboxamide

[0091] (1) Methyl 4-acetamidobenzoate

[0092] Methyl 4-aminobenzoate (8.0 g, 53.0 mmol) was dissolved in dichloromethane (100 mL), and triethylamine (16.0 g, 159.0 mmol) was added. Acetyl chloride (4.96 g, 63.6 mmol) was slowly added dropwise in an ice bath. The reaction was stirred at room temperature for 1 hour. The reaction solution was diluted with water and extracted three times with ethyl acetate (100 mL). The organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain methyl 4-acetamidobenzoate (7.0 g) as a white solid with a yield of 70%. MS+H + =194.

[0093] (2) Methyl 2-chloro-3-formylquinoline-6-carboxylate

[0094] Dimethylformamide (DMF) (2.65 g, 36.3 mmol) was added dropwise to phosphorus oxychloride (55.2 g, 363.0 mmol) under ice bath conditions, and the mixture was stirred for 1 hour while maintaining the ice bath condition. Methyl 4-acetamidobenzoate (7.0 g, 36.3 mmol) was added, and the temperature was raised to 80° C. and stirred for 16 hours. The reaction solution was cooled, quenched with saturated sodium bicarbonate solution, and extracted three times with ethyl acetate (100 mL). The organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was separated and purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate=2:1) ​​to obtain methyl 2-chloro-3-formylquinoline-6-carboxylate (1.6 g) as a white solid with a yield of 18%. MS+H + =250.

[0095] (3) 2-chloro-3-(hydroxymethyl)quinoline-6-carboxylic acid methyl ester (2-3)

[0096] Methyl 2-chloro-3-formylquinoline-6-carboxylate (1.6 g, 6.43 mmol) was dissolved in ethanol (20 mL), and sodium borohydride (488 mg, 12.9 mmol) was added. The reaction was stirred at room temperature for 1 hour. The reaction solution was quenched with saturated ammonium chloride solution and extracted three times with ethyl acetate (20 mL). The organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was separated and purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 1:1) to obtain methyl 2-chloro-3-(hydroxymethyl)quinoline-6-carboxylate (800 mg) as a colorless oil with a yield of 50%. MS+H + =252.

[0097] (4) Methyl 3-(hydroxymethyl)-2-((4-methoxybenzyl)amino)quinoline-6-carboxylate

[0098] Methyl 4-acetamidobenzoate (800 mg, 3.18 mmol) was dissolved in 1,4-dioxane (2 mL), and N,N-diisopropylethylamine (1.23 g, 9.54 mmol) and 4-methoxybenzylamine (872 mg, 6.36 mmol) were added. The reaction was stirred at 120°C for 16 hours. The reaction solution was cooled and concentrated under reduced pressure. The concentrate was separated and purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 1:1) to obtain methyl 3-(hydroxymethyl)-2-((4-methoxybenzyl)amino)quinoline-6-carboxylate (650 mg) as a colorless oil. Yield: 58%. MS+H + =353.

[0099] (5) 3-(Hydroxymethyl)-2-((4-methoxybenzyl)amino)quinoline-6-carboxylic acid

[0100] 3-(Hydroxymethyl)-2-((4-methoxybenzyl)amino)quinoline-6-carboxylic acid methyl ester (650 mg, 1.84 mmol) was dissolved in methanol (10 mL) and water (10 mL), and lithium hydroxide (221 mg, 9.20 mmol) was added. The reaction was stirred at room temperature for 16 hours. 1N HCl solution was added to the reaction solution to adjust the pH to 2. A white solid was generated. The mixed solution was filtered and the solid was vacuum dried to obtain 3-(hydroxymethyl)-2-((4-methoxybenzyl)amino)quinoline-6-carboxylic acid (500 mg) as a white solid. Yield 80%. MS+H + =339.

[0101] (6) 3-(Hydroxymethyl)-2-((4-methoxybenzyl)amino)-N-methyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carboxamide

[0102] 3-(Hydroxymethyl)-2-((4-methoxybenzyl)amino)quinoline-6-carboxylic acid (150 mg, 0.45 mmol) was dissolved in dimethylformamide (DMF) (2 mL), and triethylamine (136 mg, 1.35 mmol), HATU (205 mg, 0.54 mmol) and N-methyl-1-(5-(trifluoromethyl)pyridin-2-yl)methanamine (103 mg, 0.54 mmol) were added and stirred at room temperature. After stirring for 1 hour, the reaction mixture was diluted with water and extracted three times with ethyl acetate (3 mL). The organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was separated and purified by silica gel column chromatography (eluent: dichloromethane:methanol = 15:1) to obtain 3-(hydroxymethyl)-2-((4-methoxybenzyl)amino)-N-methyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carboxamide (120 mg) as a white solid. Yield: 53%. MS+H + =511.

[0103] (7) 2-amino-3-(hydroxymethyl)-N-methyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carboxamide

[0104] 3-(Hydroxymethyl)-2-((4-methoxybenzyl)amino)-N-methyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carboxamide (120 mg, 0.24 mmol) was dissolved in trifluoroacetic acid (2 mL) and stirred at 80°C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by prep-HPLC (eluent: acetonitrile: water (10 mM NH4HCO3) = 35% to 60%) to provide 2-amino-3-(hydroxymethyl)-N-methyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carboxamide (52 mg) as a white solid in a 56% yield. ESI-MS: [M+H] + =391.1. 1 H NMR(400MHz,DMSO-d6)δ8.97(d,J=2.1Hz,1H),8.25–8.18(m,1H),7.94(d,J=48.5Hz,2H) ,7.55(s,3H),6.56(s,2H),5.43(s,1H),4.86(s,2H),4.49(d,J=4.9Hz,2H),3.05(s,3H).

[0105] Example 3: 2-amino-N-((3-fluoropyridin-2-yl)methyl)-3-(hydroxymethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carboxamide

[0106] (1) N-((3-fluoropyridin-2-yl)methyl)-3-(hydroxymethyl)-2-((4-methoxybenzyl)amino)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carboxamide

[0107] 3-(Hydroxymethyl)-2-((4-methoxybenzyl)amino)quinoline-6-carboxylic acid (250 mg, 0.74 mmol) was dissolved in dimethylformamide (DMF) (3 mL), and triethylamine (224 mg, 2.22 mmol), HATU (338 mg, 0.89 mmol) and 1-(3-fluoropyridin-2-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)methanamine (254 mg, 0.89 mmol) were added and stirred at room temperature. After stirring for 1 hour, the reaction mixture was diluted with water and extracted three times with ethyl acetate (5 mL). The organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was separated and purified by silica gel column chromatography (eluent: dichloromethane:methanol = 15:1) to obtain N-((3-fluoropyridin-2-yl)methyl)-3-(hydroxymethyl)-2-((4-methoxybenzyl)amino)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carboxamide (220 mg) as a white solid. Yield: 50%. MS+H + =606.

[0108] (2) 2-amino-N-((3-fluoropyridin-2-yl)methyl)-3-(hydroxymethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carboxamide

[0109] N-((3-fluoropyridin-2-yl)methyl)-3-(hydroxymethyl)-2-((4-methoxybenzyl)amino)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carboxamide (220 mg, 0.36 mmol) was dissolved in trifluoroacetic acid (3 mL) and stirred at 80°C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by prep-HPLC (eluent: acetonitrile: water (10 mM NH4HCO3) = 35% to 60%) to provide 2-amino-N-((3-fluoropyridin-2-yl)methyl)-3-(hydroxymethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carboxamide (118 mg) as a white solid in a 63% yield. ESI-MS: [M+H]+ =486.1. 1 H NMR(400MHz,DMSO-d6)δ8.91(s,1H),8.44(s,1H),8.23–8.13(m,1H),7.88(s,1H),7.59(d,J=41.7Hz,3 H),7.48–7.38(m,2H),7.28–6.95(m,1H),6.49(s,2H),5.41(s,1H),4.86(d,J=5.2Hz,4H),4.47(s,2H).

[0110] Example 4: 2-amino-7-fluoro-N-((3-fluoropyridin-2-yl)methyl)-3-(hydroxymethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carboxamide

[0111] (1) Methyl 4-acetylamino-2-fluorobenzoate

[0112] Methyl 4-amino-2-fluorobenzoate (6.0 g, 35.5 mmol) was dissolved in dichloromethane (60 mL), and triethylamine (10.8 g, 106.5 mmol) was added. Acetyl chloride (3.32 g, 42.6 mmol) was slowly added dropwise in an ice bath. The reaction was stirred at room temperature for 1 hour. The reaction solution was diluted with water and extracted three times with ethyl acetate (60 mL). The organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain methyl 4-acetamido-2-fluorobenzoate (5.0 g) as a white solid with a yield of 68%. MS+H + =212.

[0113] (2) Methyl 2-chloro-7-fluoro-3-formylquinoline-6-carboxylate

[0114] Dimethylformamide (DMF) (1.73 g, 23.7 mmol) was added dropwise to phosphorus oxychloride (36.0 g, 237.0 mmol) in an ice bath. The mixture was stirred for 1 hour, followed by the addition of methyl 4-acetamido-2-fluorobenzoate (5.0 g, 23.7 mmol). The temperature was then raised to 80°C and stirred for 16 hours. The reaction mixture was cooled and quenched with saturated sodium bicarbonate solution. The mixture was extracted three times with ethyl acetate (50 mL). The organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was isolated and purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 2:1) to obtain methyl 2-chloro-7-fluoro-3-formylquinoline-6-carboxylate (1.0 g) as a white solid in a 16% yield. MS+H + =268.

[0115] (3) Methyl 2-chloro-7-fluoro-3-(hydroxymethyl)quinoline-6-carboxylate

[0116] 2-Chloro-7-fluoro-3-formylquinoline-6-carboxylic acid methyl ester (1.0 g, 3.73 mmol) was dissolved in ethanol (10 mL), sodium borohydride (284 mg, 7.46 mmol) was added, and the reaction was stirred at room temperature for 1 hour. The reaction solution was quenched with saturated ammonium chloride solution and extracted three times with ethyl acetate (10 mL). The organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was separated and purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 1:1) to obtain 2-chloro-7-fluoro-3-(hydroxymethyl)quinoline-6-carboxylic acid methyl ester (500 mg) as a colorless oil with a yield of 50%. MS+H + =270.

[0117] (4) Methyl 7-fluoro-3-(hydroxymethyl)-2-((4-methoxybenzyl)amino)quinoline-6-carboxylate

[0118] Methyl 2-chloro-7-fluoro-3-(hydroxymethyl)quinoline-6-carboxylate (500 mg, 1.85 mmol) was dissolved in 1,4-dioxane (5 mL). N,N-diisopropylethylamine (716 mg, 5.55 mmol) and 4-methoxybenzylamine (470 mg, 3.70 mmol) were added. The reaction was stirred at 120°C for 16 hours. The reaction solution was cooled and concentrated under reduced pressure. The concentrate was separated and purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 1:1) to obtain methyl 7-fluoro-3-(hydroxymethyl)-2-((4-methoxybenzyl)amino)quinoline-6-carboxylate (400 mg) as a colorless oil. Yield: 58%. MS+H + =371.

[0119] (5) 7-Fluoro-3-(hydroxymethyl)-2-((4-methoxybenzyl)amino)quinoline-6-carboxylic acid

[0120] 7-Fluoro-3-(hydroxymethyl)-2-((4-methoxybenzyl)amino)quinoline-6-carboxylic acid methyl ester (400 mg, 1.08 mmol) was dissolved in methanol (5 mL) and water (5 mL), and lithium hydroxide (130 mg, 5.4 mmol) was added. The reaction was stirred at room temperature for 16 hours. 1N HCl solution was added to the reaction solution to adjust the pH of the reaction solution to 2. A white solid was generated. The mixed solution was filtered and the solid was vacuum dried to obtain 7-fluoro-3-(hydroxymethyl)-2-((4-methoxybenzyl)amino)quinoline-6-carboxylic acid (300 mg) as a white solid. Yield 78%. MS+H+ =357.

[0121] (6) 2-amino-7-fluoro-N-((3-fluoropyridin-2-yl)methyl)-3-(hydroxymethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carboxamide

[0122] 7-Fluoro-3-(hydroxymethyl)-2-((4-methoxybenzyl)amino)quinoline-6-carboxylic acid (150 mg, 0.42 mmol) was dissolved in dimethylformamide (DMF) (2 mL), and triethylamine (127 mg, 1.26 mmol), HATU (192 mg, 0.51 mmol) and 1-(3-fluoropyridin-2-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)methanamine (172 mg, 0.51 mmol) were added and the mixture was stirred at room temperature. The mixture was stirred at room temperature for 1 hour, and the reaction solution was diluted with water and extracted three times with ethyl acetate (5 mL). The organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was separated and purified by silica gel column chromatography (eluent: dichloromethane:methanol = 15:1) to obtain 2-amino-7-fluoro-N-((3-fluoropyridin-2-yl)methyl)-3-(hydroxymethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carboxamide (100 mg) as a white solid. Yield: 40%. MS+H + =624.

[0123] (7) 2-amino-7-fluoro-N-((3-fluoropyridin-2-yl)methyl)-3-(hydroxymethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carboxamide

[0124] N-((3-fluoropyridin-2-yl)methyl)-3-(hydroxymethyl)-2-((4-methoxybenzyl)amino)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carboxamide (100 mg, 0.2 mmol) was dissolved in trifluoroacetic acid (2 mL) and stirred at 80°C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by prep-HPLC (eluent: acetonitrile: water (10 mM NH4HCO3) = 35% to 60%) to provide 2-amino-7-fluoro-N-((3-fluoropyridin-2-yl)methyl)-3-(hydroxymethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carboxamide (32 mg) as a white solid in a 40% yield. ESI-MS: [M+H] + =504.1. 1H NMR(400MHz, DMSO-d6)δ8.90(s,1H),8.40(dd,J=14.7,4.7Hz,1H),8.22(d,J=8.5Hz,1H),7.86(s,1H),7.79–7.59(m,2H),7.60– 7.32(m,2H),7.17(dd,J=22.2,11.7Hz,1H),6.51(s,2H),5.39(s,1H),4.93(s,2H),4.77(d,J=5.2Hz,2H),4.45(d,J=5.4Hz,2H).

[0125] Example 5: 2-amino-N-((3-fluoropyridin-2-yl)methyl)-3-methyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinazoline-6-carboxamide

[0126] (1) Methyl 3-((1-ethoxy-1-oxopropyl-2-yl)amino)-4-nitrobenzoate

[0127] Methyl 3-fluoro-4-nitrobenzoate (5.0 g, 25.0 mmol) was dissolved in N,N-diisopropylethylamine (9.7 g, 75.0 mmol), and ethyl alanine (2.94 g, 25.0 mmol) was added. The reaction was stirred at 100°C for 16 hours. The reaction solution was cooled and concentrated under reduced pressure. The concentrate was separated and purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 3:1) to obtain methyl 3-((1-ethoxy-1-oxopropan-2-yl)amino)-4-nitrobenzoate (5.0 g) as a yellow solid. Yield: 67%. MS+H + =297.

[0128] (2) 3-Methyl-2-oxo-1,2,3,4-tetrahydroquinoline-6-carboxylic acid methyl ester

[0129] Methyl 3-((1-ethoxy-1-oxopropyl-2-yl)amino)-4-nitrobenzoate (5.0 g, 16.9 mmol) was dissolved in ethanol (50 mL) and water (25 mL). Ammonium chloride (4.45 g, 84.5 mmol) and reduced iron powder (2.84 g, 50.7 mmol) were added. The reaction was stirred at 80°C for 16 hours. The reaction solution was filtered and the filtrate was decompressed to remove ethanol. A solid appeared in the solution. The mixed solution was filtered and the filtered solid was vacuum dried to obtain methyl 3-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-6-carboxylate (2.4 g) as a white solid. Yield: 65%. MS+H + =221.

[0130] (3) Methyl 3-methyl-2-oxo-1,2-dihydroquinoline-6-carboxylate

[0131] 3-Methyl-2-oxo-1,2,3,4-tetrahydroquinoline-6-carboxylic acid methyl ester (2.4 g, 10.9 mmol) was dissolved in tetrahydrofuran (30 mL), and manganese oxide (1.90 g, 21.8 mmol) was added. The reaction was stirred at room temperature for 16 hours, the reaction solution was filtered, and the filtrate was dried under reduced pressure to obtain 3-methyl-2-oxo-1,2-dihydroquinoline-6-carboxylic acid methyl ester (1.5 g) as a white solid with a yield of 63%. MS+H + =219.

[0132] (4) Methyl 2-chloro-3-methylquinoline-6-carboxylate

[0133] Methyl 3-methyl-2-oxo-1,2-dihydroquinoline-6-carboxylate (1.5 g, 6.90 mmol) was dissolved in dichloroethane (20 mL), and phosphorus oxychloride (3.15 g, 20.7 mmol) was added. The reaction was stirred at 70°C for 16 hours. After cooling, the reaction solution was quenched with saturated sodium bicarbonate solution and extracted three times with ethyl acetate (20 mL). The organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was separated and purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 2:1) to obtain methyl 2-chloro-3-methylquinoline-6-carboxylate (300 mg) as a white solid in an 18% yield. MS+H + =237.

[0134] (5) Methyl 2-((4-methoxybenzyl)amino)-3-methylquinoline-6-carboxylate

[0135] Methyl 2-chloro-3-methylquinoline-6-carboxylate (300 mg, 1.30 mmol) was dissolved in 1,4-dioxane (5 mL), and N,N-diisopropylethylamine (503 mg, 3.90 mmol) and 4-methoxybenzylamine (330 mg, 2.60 mmol) were added. The reaction was stirred at 100°C for 16 hours. After cooling, the reaction solution was concentrated under reduced pressure. The concentrate was separated and purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 1:1) to obtain methyl 2-((4-methoxybenzyl)amino)-3-methylquinoline-6-carboxylate (300 mg) as a white solid. Yield: 70%. MS+H + =338.

[0136] (6) 2-Amino-3-methylquinoline-6-carboxylic acid methyl ester

[0137] Methyl 2-((4-methoxybenzyl)amino)-3-methylquinoline-6-carboxylate (300 mg, 0.89 mmol) was dissolved in trifluoroacetic acid (3 mL) and the reaction was stirred at 80°C for 16 hours. The reaction solution was concentrated under reduced pressure, and the concentrate was separated and purified by silica gel column chromatography (eluent: dichloromethane:methanol = 15:1) to obtain methyl 2-amino-3-methylquinoline-6-carboxylate (120 mg) as a white solid in a yield of 62%. MS+H + =218.

[0138] (7) 2-Amino-3-methylquinoline-6-carboxylic acid

[0139] 2-amino-3-methylquinoline-6-carboxylic acid methyl ester (120 mg, 0.55 mmol) was dissolved in methanol (2 mL) and water (2 mL), and lithium hydroxide (132 mg, 5.5 mmol) was added. The reaction was stirred at room temperature for 16 hours. 1N HCl solution was added to the reaction solution to adjust the pH to 2. A white solid was generated. The mixed solution was filtered and the solid was vacuum dried to obtain 2-amino-3-methylquinoline-6-carboxylic acid (50 mg) as a white solid. Yield 45%. MS+H + =204.

[0140] (8) 2-amino-N-((3-fluoropyridin-2-yl)methyl)-3-methyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinazoline-6-carboxamide

[0141] 2-Amino-3-methylquinoline-6-carboxylic acid (50 mg, 0.25 mmol) was dissolved in N,N-dimethylformamide (1 mL), and triethylamine (76 mg, 0.75 mmol), HATU (114 mg, 0.30 mmol) and 1-(3-fluoropyridin-2-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)methanamine (101 mg, 0.30 mmol) were added. The mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with water and extracted three times with ethyl acetate (5 mL). The organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by prep-HPLC (eluent: acetonitrile: water (10 mM The reaction mixture was purified by separation with 1% NH4HCO3 (NH4HCO3) (35% to 50%) to give 2-amino-N-((3-fluoropyridin-2-yl)methyl)-3-methyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinazoline-6-carboxamide (26 mg) as a white solid in a 23% yield. ESI-MS: [M+H] + =471.1. 1H NMR(400MHz,Chloroform-d)δ8.78(s,1H),8.42(d,J=4.3Hz,1H),8.13(s,1H),7.90(d,J=8.1Hz,1H),7.80(s,1H), 7.69(d,J=8.5Hz,1H),7.60(s,1H),7.36(m,1H),7.29(m,1H),6.22(m,2H),4.95(s,2H),4.85(s,2H),2.65(s,3H).

[0142] Example 6: 2-amino-3-methyl-N-(pyrimidin-2-ylmethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinazoline-6-carboxamide

[0143] 2-Amino-3-methylquinoline-6-carboxylic acid (20 mg, 0.10 mmol) was dissolved in N,N-dimethylformamide (1 mL), and triethylamine (30 mg, 0.30 mmol), HATU (46 mg, 0.12 mmol) and 1-(2-pyrimidinyl)-N-(5-(trifluoromethyl)-2-pyrimidinyl)methyl)methanamine (101 mg, 0.12 mmol) were added. The mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with water and extracted three times with ethyl acetate (2 mL). The organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by prep-HPLC (eluent: acetonitrile: water (10 mM The reaction mixture was purified by separation with 1% NH4HCO3 (NH4HCO3) (35% to 50%) to give 2-amino-3-methyl-N-(pyrimidin-2-ylmethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinazoline-6-carboxamide (11 mg) as a white solid in a 25% yield. ESI-MS: [M+H] + =454.1. 1 H NMR(400MHz,Chloroform-d)δ8.78(s,1H),8.76–8.69(m,2H),8.13(s,1H),7.93(d,J=8.0Hz,1H),7.81(d,J=8.2 Hz,1H),7.74–7.60(m,2H),7.23(t,J=4.9Hz,1H),6.47(m,2H),5.01(s,2H),4.88(d,J=18.8Hz,2H),2.65(s,3H).

[0144] Example 7: 2-amino-N-((3-fluoropyridin-2-yl)methyl)-3-methoxy-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinazoline-6-carboxamide

[0145] (1) Methyl 2,3-dibromoquinoline-6-carboxylate

[0146] Methyl 2,3-dioxy-1,2,3,4-tetrahydroquinoline-6-carboxylate (220 mg, 1.0 mmol) was dissolved in 1,4-dioxane (2 mL), and phosphorus oxybromide (852 mg, 3.0 mmol) was added. The reaction was stirred at 80°C for 16 hours. After cooling, the reaction solution was quenched with saturated sodium bicarbonate solution and extracted three times with ethyl acetate (3 mL). The organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was separated and purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 2:1) to obtain methyl 2,3-dibromoquinoline-6-carboxylate (100 mg) as a white solid in a 30% yield. MS+H + =345,347,349.

[0147] (2) Methyl 3-bromo-2-((4-methoxybenzyl)amino)quinoxaline-6-carboxylate

[0148] Methyl 2,3-dibromoquinoline-6-carboxylate (100 mg, 0.3 mmol) was dissolved in N,N-dimethylformamide (1 mL), and N,N-diisopropylethylamine (116 mg, 0.90 mmol) and 4-methoxybenzylamine (42 mg, 0.33 mmol) were added. The reaction was stirred at 100°C for 16 hours. The reaction solution was cooled and concentrated under reduced pressure. The concentrate was separated and purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 1:1) to obtain methyl 3-bromo-2-((4-methoxybenzyl)amino)quinoxaline-6-carboxylate (100 mg) as a white solid. Yield: 85%. MS+H + =402,404.

[0149] (3) 3-Bromo-2-((4-methoxybenzyl)amino)quinoxaline-6-carboxylic acid

[0150] 3-Bromo-2-((4-methoxybenzyl)amino)quinoxaline-6-carboxylic acid methyl ester (100 mg, 0.25 mmol) was dissolved in methanol (1 mL) and water (1 mL), and lithium hydroxide (60 mg, 2.5 mmol) was added. The reaction was stirred at room temperature for 16 hours. 1N HCl solution was added to the reaction solution to adjust the pH to 2. A white solid was generated. The mixed solution was filtered and the filtered solid was dried under vacuum to obtain 3-Bromo-2-((4-methoxybenzyl)amino)quinoxaline-6-carboxylic acid (60 mg) as a white solid. Yield 63%. MS+H + =388,390.

[0151] (4) 3-Bromo-N-((3-fluoropyridin-2-yl)methyl)-2-((4-methoxybenzyl)amino)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinazoline-6-carboxamide

[0152] 3-Bromo-2-((4-methoxybenzyl)amino)quinoxaline-6-carboxylic acid (60 mg, 0.15 mmol) was dissolved in dimethylformamide (DMF) (1 mL), and triethylamine (46 mg, 0.45 mmol), HATU (68 mg, 0.18 mmol) and 1-(3-fluoropyridin-2-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)methanamine (61 mg, 0.18 mmol) were added, and the mixture was stirred at room temperature for 1 minute. After 1 h, the reaction mixture was diluted with water and extracted three times with ethyl acetate (2 mL). The organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was separated and purified by silica gel column chromatography (eluent: dichloromethane:methanol = 15:1) to obtain 3-bromo-N-((3-fluoropyridin-2-yl)methyl)-2-((4-methoxybenzyl)amino)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinazoline-6-carboxamide (60 mg) as a white solid. Yield: 60%. MS+H + =655,657.

[0153] (5) 2-amino-N-((3-fluoropyridin-2-yl)methyl)-3-methoxy-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinazoline-6-carboxamide

[0154] 3-Bromo-N-((3-fluoropyridin-2-yl)methyl)-2-((4-methoxybenzyl)amino)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinazoline-6-carboxamide (60 mg, 0.1 mmol) was dissolved in trifluoroacetic acid (1 mL) and stirred at 80°C for 16 hours. The reaction solution was concentrated under reduced pressure, and methanol (2 mL) was added to dissolve the residue. The residue was purified by prep-HPLC (eluent: acetonitrile: water (10 mM NH4HCO3) = 35% to 60%) to obtain 2-amino-7-fluoro-N-((3-fluoropyridin-2-yl)methyl)-3-(hydroxymethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carboxamide (13 mg) as a white solid in a 30% yield. ESI-MS: [M+H] + =487.1. 1H NMR (400MHz, DMSO-d6) δ12.15(s,1H),8.90(s,1H),8.43(s,1H),8.18(d,J=10.2Hz,1H),7 .63(m,2H),7.42(dt,J=8.6,4.4Hz,1H),7.25(s,3H),7.15(m,2H),4.82(d,J=4.5Hz,4H).

[0155] Example 8: General Intermediate 2-amino-3-(((tert-butyldimethylsilyl)oxy)methyl)-7-fluoroquinoline-6-carboxylic acid

[0156] (1) A mixture of 5-bromo-4-fluoro-2-nitrobenzaldehyde (100 g, 0.40 mol), diethyl malonate (64.58 g, 0.40 mol) and sodium bicarbonate (50.81 g, 0.60 mol) was stirred at 110°C for 16 hours. Ethyl acetate was then added to dilute the mixture and filtered. The filtrate was washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate and concentrated. The crude product was dissolved in acetic acid (1 L) and iron powder (112.6 g, 2.00 mol) was added. The reaction mixture was stirred at 85°C for 16 hours. The temperature was then lowered, the iron powder was removed, and the mixture was concentrated under reduced pressure to obtain ethyl 6-bromo-7-fluoro-2-oxo-1,2-dihydroquinoline-3-carboxylate (300 g, crude product) as a reddish-brown solid. ESI-MS: m / z = 313.9 [M+1] + .

[0157] (2) Add 6-bromo-7-fluoro-2-oxo-1,2-dihydroquinoline-3-carboxylic acid ethyl ester (300 g, crude product) to phosphorus oxychloride (3000 mL) and stir at 100°C for 16 hours. The reaction solution is spin-dried and poured into ice water. The pH is adjusted to 9 with saturated sodium bicarbonate solution. Then, the mixture is filtered and the filter cake is dried to obtain 6-bromo-2-chloro-7-fluoroquinoline-3-carboxylic acid ethyl ester (300 g, crude product) as a gray solid. ESI-MS: m / z = 331.9 [M+1] + .

[0158] (3) Under nitrogen protection, p-methoxybenzyl (123.6 g, 0.90 mol) was added to a solution of 6-bromo-2-chloro-7-fluoroquinoline-3-carboxylic acid ethyl ester (300 g, crude product) in N-methylpyrrolidone (3 L). The reaction mixture was stirred at 60 ° C for 16 hours. The reaction was quenched with water and extracted with ethyl acetate (1000 mL*3). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column (petroleum ether / ethyl acetate = 50:1) to obtain 6-bromo-7-fluoro-2-((4-methoxybenzyl)amino)quinoline-3-carboxylic acid ethyl ester (50 g, yield: 28.7%) as a yellow solid. ESI-MS: m / z = 432.9 [M+1] + . 1 H NMR(400MHz, DMSO_d6)δ8.79(s,1H),8.44-8.37(m,1H),8.34(d,J=8.0Hz,1H),7.44(d,J=10.8Hz,1H),7.36(d,J =8.8Hz,2H),6.89(d,J=8.8Hz,2H),4.66(d,J=5.6Hz,2H),4.40-4.29(m,2H),3.72(s,3H),3.51(t,J=7.2Hz,3H).

[0159] (4) Under nitrogen protection, NaBH4 (26.4 g, 0.69 mol) and ZnCl2 (63.0 g, 0.46 mol) were added to a solution of ethyl 6-bromo-7-fluoro-2-((4-methoxyphenyl)amino)quinoline-3-carboxylate (50.0 g, 0.11 mol) in THF (500 mL). The reaction mixture was stirred at 25°C for 16 hours. The reaction was quenched with water and extracted with ethyl acetate (200 mL*3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to give (6-bromo-7-fluoro-2-((4-methoxybenzyl)amino)quinolin-3-yl)methanol (50 g, crude product) as a yellow solid. ESI-MS: m / z = 392.9 [M+1] + .

[0160] (5) Under nitrogen protection, TBSCl (76.7 g, 0.51 mol) and imidazole (34.7 g, 0.51 mol) were added to a solution of (6-bromo-7-fluoro-2-((4-methoxyphenyl)amino)quinolin-3-yl)methanol (50.0 g, 0.13 mol) in DCM (500 mL). The reaction mixture was stirred at 25 ° C for 16 hours. The reaction was quenched with water and extracted with DCM (100 mL*3). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column (petroleum ether / ethyl acetate = 100:1) to give 6-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-7-fluoro-N-(4-methoxybenzyl)quinolin-2-amine (40 g, yield: 62.5%) as a yellow solid. ESI-MS: m / z = 505.0 [M+1] + .

[0161] (6) Under nitrogen protection, TEA (32.0 g, 0.32 mol) and Pd(dppf)Cl2 (5.76 g, 0.008 mol) were added to a solution of 6-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-7-fluoro-N-(4-methoxybenzyl)quinolin-2-amine (40.0 g, 0.08 mol) in methanol (400 mL). The reaction mixture was heated to 70°C and stirred for 16 hours under a carbon monoxide atmosphere. The reaction was quenched with water and extracted with EA (100 mL x 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to obtain a crude product. The crude product was purified on a silica gel column (petroleum ether / ethyl acetate = 5:1) to afford methyl 3-(((tert-butyldimethylsilyl)oxy)methyl)-7-fluoro-2-((4-methoxybenzyl)amino)quinoline-6-carboxylate (28.0 g, yield: 73.68%) as a brown solid. ESI-MS: m / z = 485.1 [M+1] + .

[0162] (7) Under nitrogen protection, a mixture of methyl 3-(((tert-butyldimethylsilyl)oxy)methyl)-7-fluoro-2-((4-methoxybenzyl)amino)quinoline-6-carboxylate (25.0 g, 0.05 mol) in TFA (150 mL) was stirred at 70°C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain methyl 2-amino-7-fluoro-3-(hydroxymethyl)quinoline-6-carboxylate (27.0 g, crude product) as a red solid. ESI-MS: m / z = 251.0 [M+1] + .

[0163] (8) Under nitrogen protection, TMSOK (41.4 g, 0.32 mol) was added to a solution of methyl 2-amino-7-fluoro-3-(hydroxymethyl)quinoline-6-carboxylate (27.0 g, 0.11 mol) in MeCN (400 mL). The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was then filtered, and the filter cake was dried to obtain 2-amino-7-fluoro-3-(hydroxymethyl)quinoline-6-carboxylic acid (30.0 g, crude) as a white solid. ESI-MS: m / z = 237.1 [M+1] + .

[0164] (9) Under nitrogen protection, TBSCl (76.2 g, 0.51 mol) and imidazole (34.5 g, 0.51 mol) were added to a solution of 2-amino-7-fluoro-3-(hydroxymethyl)quinoline-6-carboxylic acid (30.0 g, 0.13 mol) in DMF (300 mL). The reaction mixture was stirred at 25°C for 16 hours. The reaction solution was poured into water and filtered. The filter cake was purified by beating with ethyl acetate to obtain the universal intermediate 2-amino-3-(((tert-butyldimethylsilyl)oxy)methyl)-7-fluoroquinoline-6-carboxylic acid (6.4 g, yield: 14.5%) as a white solid. ESI-MS: m / z = 351.1 [M+1] + . 1 H NMR (400MHz, DMSO_d6) δ12.90(s,1H),8.27-8.17(m,1H),7.87(s,1H),7.03(s,1H),6.64(s,2H),4.53(s,2H),0.81(s,9H),0.14(s,6H).

[0165] Example 9: General Intermediate 2-amino-4-(((tert-butyldimethylsilyl)oxy)methyl)-7-fluoroquinoline-6-carboxylic acid

[0166] (1) At 40°C, anhydrous sodium sulfate (1.5 kg, 10.5 mol) was added in batches to an aqueous solution (4 L) of chloral hydrate (226.4 g, 1.37 mol). Then, a hydrochloric acid aqueous solution (2000 mL) of 4-bromo-3-fluoroaniline (200 g, 1.05 mol) and an aqueous solution (2 L) of hydroxylamine hydrochloride (292.7 g, 4.20 mol) were added dropwise. The reaction solution was stirred at 85°C for 3 hours. The temperature was then lowered and the mixture was filtered under reduced pressure. The filter cake was washed with water and dried to obtain an off-white solid (E)-N-(4-bromo-3-fluorophenyl)-2-(hydroxyimino)acetamide (200 g, yield: 65.53%). ESI-MS: m / z = 260.9 [M+1] + .

[0167] (2) At 60°C, (E)-N-(4-bromo-3-fluorophenyl)-2-(hydroxyimino)acetamide (150 g, 0.5746 mol) was added in batches to concentrated sulfuric acid (750 mL). The reaction mixture was heated to 80°C and stirred for 3 hours. After cooling, the reaction mixture was poured into crushed ice and stirred for 1 hour. The mixture was then filtered, and the filter cake was washed with water and dried to obtain 5-bromo-6-fluoroindoline-2,3-dione (120 g, yield: 77.03%) as an orange solid. ESI-MS: m / z = 242.0 [M-1] + . 1 H NMR (400MHz, DMSO) δ 11.49-11.06 (m, 1H), 7.88 (d, J = 7.2 Hz, 1H), 6.93 (d, J = 8.8 Hz, 1H).

[0168] (3) Under nitrogen protection, malonic acid (127.93 g, 1.23 mol) and sodium acetate (16.80 g, 0.20 mol) were added to a solution of 5-bromo-6-fluoroindoline-2,3-dione (100 g, 0.40 mol) in acetic acid (1000 mL). The reaction mixture was stirred at 130°C for 16 hours. The mixture was then spin-dried, diluted with water, adjusted to pH = 10 with a 2N aqueous sodium hydroxide solution, and filtered. The filtrate was further adjusted to pH = 2 with a 1N aqueous hydrochloric acid solution to precipitate a large amount of solid. The solid was filtered under reduced pressure, and the filter cake was washed with water and dried to obtain 6-bromo-7-fluoro-2-hydroxyquinoline-4-carboxylic acid (90 g, yield: 69.11%) as a yellow solid. 1 H NMR (400MHz, DMSO) δ12.26 (s, 1H), 8.59 (d, J = 7.6 Hz, 1H), 7.25 (d, J = 9.6 Hz, 1H), 6.96 (s, 1H).

[0169] (4) 6-Bromo-7-fluoro-2-hydroxyquinoline-4-carboxylic acid (60 g, 0.21 mol) was added to phosphorus oxychloride (600 mL) and stirred at 95°C for 16 hours. The reaction solution was spin-dried, dissolved in dichloromethane, and then added dropwise to methanol (1 L) at 0°C and stirred for 1 hour. The reaction solution was then spin-dried, diluted with dichloromethane, and washed with saturated sodium bicarbonate solution. The combined organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 6-bromo-2-chloro-7-fluoroquinoline-4-carboxylic acid methyl ester (70 g, yield: 83.79%) as a brown solid. ESI-MS: m / z = 317.8 [M+1] + .

[0170] (5) Under nitrogen protection, p-methoxybenzyl (48 g, 0.35 mol) was added to a solution of methyl 6-bromo-2-chloro-7-fluoroquinoline-4-carboxylate (70 g, 0.22 mol) in N-methylpyrrolidone (700 mL). The reaction mixture was stirred at 60°C for 16 hours. The reaction was quenched with water and extracted with ethyl acetate (100 mL*3). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column (petroleum ether / ethyl acetate = 10:1) to obtain methyl 6-bromo-7-fluoro-2-((4-methoxybenzyl)amino)quinoline-4-carboxylate (40 g, yield: 39%) as a yellow solid. 1 H NMR(400MHz, CDCl3) δ8.79(d,J=8.0Hz,1H),7.44(d,J=10.0Hz,1H),7.35-7.28(m,2H),7.17 (s,1H),6.91-6.84(m,2H),5.14-5.03(m,1H),4.67-4.61(m,1H),3.98(s,3H),3.80(s,3H).

[0171] (6) Under nitrogen protection, LiBH4 (15.4 g, 0.70 mol) was added to a solution of methyl 6-bromo-7-fluoro-2-((4-methoxybenzyl)amino)quinoline-4-carboxylate (37 g, 0.09 mol) in MeOH / THF = 1 / 5 (480 mL). The reaction mixture was stirred at 25 ° C for 16 hours. The reaction was quenched with water and extracted with ethyl acetate (200 mL * 3). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to obtain (6-bromo-7-fluoro-2-((4-methoxybenzyl)amino)quinolin-4-yl)methanol (30 g, yield: 69.42%) as a yellow solid. ESI-MS: m / z = 391.0 [M+1] + .

[0172] (7) Under nitrogen protection, TBSCl (14.1 g, 0.09 mol) and imidazole (5.4 g, 0.08 mol) were added to a solution of (6-bromo-7-fluoro-2-((4-methoxybenzyl)amino)quinolin-4-yl)methanol (30 g, 0.08 mol) in DCM (300 mL). The reaction mixture was stirred at 25°C for 16 hours. The reaction was quenched with water and extracted with DCM (100 mL*3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column (petroleum ether / ethyl acetate = 20:1) to give 6-bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)-7-fluoro-N-(4-methoxybenzyl)quinolin-2-amine (30 g, yield: 69.23%) as a white solid.1 H NMR (400MHz, CDCl3) δ7.63 (d, J = 7.2Hz, 1H), 7.31-7.24 (m, 1H), 7.21-7.14 (m, 2H), 6.77-6.70 (m, 2H), 6.6 1(s,1H),4.96-4.87(m,1H),4.85-4.78(m,2H),4.54-4.42(m,2H),3.66(s,3H),0.81(s,9H),0.01(s,6H).

[0173] (8) Under nitrogen protection, triethylamine (20.0 g, 0.2 mol) and Pd(dppf)Cl2 (7.20 g, 0.01 mol) were added to a solution of 6-bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)-7-fluoro-N-(4-methoxybenzyl)quinolin-2-amine (25.0 g, 0.05 mol) in methanol (300 mL). The reaction mixture was heated to 70°C and stirred for 16 hours under a carbon monoxide atmosphere. The reaction mixture was quenched with water and extracted with EA (100 mL x 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified on a silica gel column (petroleum ether / ethyl acetate = 15:1) to afford methyl 4-(((tert-butyldimethylsilyl)oxy)methyl)-7-fluoro-2-((4-methoxybenzyl)amino)quinoline-6-carboxylate (14.0 g, 58.33% yield) as a brown solid. ESI-MS: m / z = 485.1 [M+1] + .

[0174] (9) Under nitrogen protection, a mixture of methyl 4-(((tert-butyldimethylsilyl)oxy)methyl)-7-fluoro-2-((4-methoxybenzyl)amino)quinoline-6-carboxylate (14.0 g, 0.03 mol) in TFA (100 mL) was stirred at 70°C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain methyl 2-amino-7-fluoro-4-(hydroxymethyl)quinoline-6-carboxylate (15.0 g, crude product) as a red solid. ESI-MS: m / z = 251.0 [M+1] + .

[0175] (10) Under nitrogen protection, TMSOK (23.0 g, 0.18 mol) was added to a solution of methyl 2-amino-7-fluoro-4-(hydroxymethyl)quinoline-6-carboxylate (15.0 g, 0.06 mol) in MeCN (200 mL). The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was then filtered, and the filter cake was dried to obtain 2-amino-7-fluoro-4-(hydroxymethyl)quinoline-6-carboxylic acid (12.0 g, crude product) as a white solid. ESI-MS: m / z = 237.0 [M+1] + .

[0176] (11) Under nitrogen protection, TBSCl (30.5 g, 0.20 mol) and imidazole (13.8 g, 0.20 mol) were added to a solution of 2-amino-7-fluoro-4-(hydroxymethyl)quinoline-6-carboxylic acid (12.0 g, 0.50 mol) in DCM (200 mL). The reaction mixture was stirred at 25°C for 16 hours. The reaction solution was poured into water and filtered. The filter cake was purified by beating with ethyl acetate to obtain the universal intermediate 2-amino-4-(((tert-butyldimethylsilyl)oxy)methyl)-7-fluoroquinoline-6-carboxylic acid (3.1 g, yield: 18.2%) as a white solid. ESI-MS: m / z = 351.1 [M+1] + . 1 H NMR (400MHz, DMSO) δ8.25 (d, J = 8.3Hz, 1H), 7.24-7.10 (m, 3H), 6.84 (s, 1H), 5.04 (s, 2H), 0.95 (d, J = 16.4Hz, 9H), 0.17 (d, J = 18.3Hz, 6H).

[0177] Example 10: General intermediate 2-amino-4-(hydroxymethyl)quinoline-6-carboxylic acid

[0178] (1) Under nitrogen protection, malonic acid (55.3 g, 0.53 mol) was added to a solution of 5-bromoindole-2,3-dione (40 g, 0.12 mol) in acetic acid (400 mL). The reaction mixture was stirred at 130°C for 16 hours. The mixture was then spin-dried, diluted with water, and the pH was adjusted to 10 with a saturated sodium bicarbonate aqueous solution, and the solid was filtered out. The filtrate was then adjusted to pH 2 with a 1N hydrochloric acid aqueous solution, and a large amount of solid precipitated. The solid was filtered under reduced pressure, and the filter cake was washed with water and dried to obtain 6-bromo-2-hydroxyquinoline-4-carboxylic acid (30 g, yield: 50.56%) as a brown solid. ESI-MS: m / z = 269.0 [M+1] + . 1H NMR (400MHz, DMSO_d6) δ14.29-13.73(m,1H),12.21(s,1H),8.45-8.38(m,1H),7.76-7.67(m,1H),7.32(d,J=8.8Hz,1H),6.98(s,1H).

[0179] (2) Add 6-bromo-2-hydroxyquinoline-4-carboxylic acid (20 g, 0.07 mol) to phosphorus oxychloride (200 mL) and stir at 95°C for 16 hours. The reaction solution was spin-dried, dissolved with dichloromethane, and then added dropwise to methanol (600 mL) at 0°C and stirred for 1 hour. The reaction solution was then spin-dried, diluted with dichloromethane, and washed with saturated sodium bicarbonate solution. The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column (petroleum ether / ethyl acetate = 10:1) to obtain 6-bromo-2-chloroquinoline-4-carboxylic acid methyl ester (20 g, yield: 80.0%) as a yellow solid. ESI-MS: m / z = 299.8 [M+1] + . 1 H NMR (400MHz, DMSO_d6) δ8.85-8.78(m,1H),8.11-7.96(m,3H),3.97(s,3H).

[0180] (3) Under nitrogen protection, p-methoxybenzyl (14.6 g, 0.10 mol) was added to a solution of methyl 6-bromo-2-chloroquinoline-4-carboxylate (20 g, 0.07 mol) in N-methylpyrrolidone (200 mL). The reaction mixture was stirred at 60 ° C for 16 hours. The reaction was quenched with water and extracted with ethyl acetate (200 mL * 3). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column (petroleum ether / ethyl acetate = 10:1) to obtain methyl 6-bromo-2-((4-methoxybenzyl)amino)quinoline-4-carboxylate (15 g, yield: 55.97%) as a yellow solid. ESI-MS: m / z = 402.2 [M+1] + . 1 H NMR(400MHz,DMSO_d6)δ8.89(s,1H),7.69-7.59(m,2H),7.37-7.30(m,2H),7.23(s,1H) ),6.93-6.84(m,2H),5.21-5.04(m,1H),4.71-4.62(m,2H),4.00(s,3H),3.82(s,3H).

[0181] (4) Under nitrogen protection, LiBH4 (6.51 g, 0.30 mol) was added to a solution of methyl 6-bromo-2-((4-methoxybenzyl)amino)quinoline-4-carboxylate (Intermediate 4, 15.0 g, 0.04 mol) in MeOH / THF = 1 / 5 (300 mL). The reaction mixture was stirred at 25 ° C for 16 hours. The reaction was quenched with water and extracted with ethyl acetate (100 mL * 3). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to give (6-bromo-2-((4-methoxybenzyl)amino)quinolin-4-yl)methanol (Intermediate 5, 13.9 g, crude product) as a yellow solid. ESI-MS: m / z = 373.2 [M+1] + .

[0182] (5) Under nitrogen protection, TBSCl (6.7 g, 0.04 mol) and imidazole (5.1 g, 0.0744 mol) were added to a solution of (6-bromo-2-((4-methoxybenzyl)amino)quinolin-4-yl)methanol (Intermediate 5, 13.9 g, 0.04 mol) in DCM (300 mL). The reaction mixture was stirred at 25 ° C for 16 hours. The reaction was quenched with water and extracted with DCM (100 mL * 3). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column (petroleum ether / ethyl acetate = 10:1) to give 6-bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)-N-(4-methoxybenzyl)quinolin-2-amine (13.0 g, yield: 71.30%) as a yellow solid. ESI-MS: m / z = 487.1 [M+1] + . 1 H NMR(400MHz,DMSO_d6)δ7.84(s,1H),7.68(s,1H),7.54(s,1H),7.43(s,1H),7.30(s,2H),6.96-6.82(m,3H),4.99(s,2H),4.53 (s,2H),3.71(s,3H),0.93(s,9H),0.13(s,6H).

[0183] (6) Under nitrogen protection, TEA (4.17 g, 4 mol) and Pd(dppf)Cl2 (1.51 g, 0.2 mmol) were added to a solution of 6-bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)-N-(4-methoxybenzyl)quinolin-2-amine (5.0 g, 1 mmol) in methanol (100 mL). The reaction mixture was heated to 70°C and stirred for 16 hours under a carbon monoxide atmosphere. The reaction was quenched with water and extracted with EA (100 mL x 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain methyl 4-(((tert-butyldimethylsilyl)oxy)methyl)-2-((4-methoxybenzyl)amino)quinoline-6-carboxylate (3.3 g, yield: 68.65%) as a yellow solid. ESI-MS: m / z = 467.1 [M+1] + . 1 H NMR(400MHz,DMSO_d6)δ8.31(s,1H),7.96(s,2H),7.53(s,1H),7.31(s,2H),6.98-6.84 (m,3H),5.05(s,2H),4.57(s,2H),3.85(s,3H),3.71(s,3H),0.93(s,9H),0.15(s,6H).

[0184] (7) Under nitrogen protection, LiOH.H2O (0.36 g, 8.6 mmol) was added to a solution of methyl 4-(((tert-butyldimethylsilyl)oxy)methyl)-2-((4-methoxybenzyl)amino)quinoline-6-carboxylate (2.0 g, 4.3 mmol) in THF / MeOH / H2O=1:1:1 (100 mL). The reaction mixture was stirred at 25°C for 16 hours. The reaction solution was adjusted to pH=5 with 1N aqueous hydrochloric acid solution and then extracted with EA (50 mL x 3). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to give 4-(hydroxymethyl)-2-((4-methoxybenzyl)amino)quinoline-6-carboxylic acid (1.4 g, yield: 96.21%) as a yellow solid.

[0185] ESI-MS: m / z = 339.3 [M+1] + . 1H NMR(400MHz,DMSO_d6)δ13.67-12.95(m,1H),8.33(s,1H),8.14(s,1H),7.45-7.33( m,2H),7.25(s,1H),7.01-6.87(m,2H),5.80(s,1H),5.05-4.67(m,4H),3.74(s,3H).

[0186] (8) Under nitrogen protection, TBSCl (0.74 g, 4.9 mol) and imidazole (0.56 g, 8.2 mol) were added to a solution of 4-(hydroxymethyl)-2-((4-methoxybenzyl)amino)quinoline-6-carboxylic acid (1.4 g, 4 mmol) in DCM (40 mL). The reaction mixture was stirred at 25°C for 16 hours. The reaction was quenched with water and extracted with DCM (30 mL*3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The crude product was dissolved in THF / H2O = 1 / 1 (50 mL) and Na2CO3 (2.17 g, 20.5 mmol) was added. The reaction solution was stirred at 25°C for 4 hours. The reaction solution was then poured into water and extracted with EA (30 mL*3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 4-(((tert-butyldimethylsilyl)oxy)methyl)-2-((4-methoxybenzyl)amino)quinoline-6-carboxylic acid (1.8 g, yield: 97.00%) as a yellow solid. ESI-MS: m / z = 453.3 [M+1] +

[0187] (9) Under nitrogen protection, a mixture of 4-(((tert-butyldimethylsilyl)oxy)methyl)-2-((4-methoxybenzyl)amino)quinoline-6-carboxylic acid (1.8 g, 3.9 mmol) in TFA (30 mL) was stirred at 70°C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain the universal intermediate 2-amino-4-(hydroxymethyl)quinoline-6-carboxylic acid (1.2 g, crude product) as a red solid. ESI-MS: m / z = 219.1 [M+1] + .

[0188] Example 11: 2-amino-3-(hydroxymethyl)-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)quinoline-6-carboxamide

[0189] (1) Under nitrogen protection, TCFH (258 mg, 0.91 mmol) and NMI (374 mg, 4.57 mmol) were added to a solution of 2-amino-3-(((tert-butyldimethylsilyl)oxy)methyl)quinoline-6-carboxylic acid (200 mg, 0.57 mmol) and N-methyl-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine (124 mg, 0.57 mmol) in ACN (5 mL). The reaction mixture was stirred at 25°C for 16 hours. The reaction solution was poured into water and extracted with EA (20 mL*3). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel (PE / EA = 1:1) to give 2-amino-3-(((tert-butyldimethylsilyl)oxy)methyl)-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)quinoline-6-carboxamide (160 mg, yield: 52.8%) as a yellow solid. ESI-MS: m / z = 532.65 [M+1] + .

[0190] (2) Under nitrogen protection, 2-amino-3-(((tert-butyldimethylsilyl)oxy)methyl)-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)quinoline-6-carboxamide (160 mg, 0.30 mmol) was added to a 4M hydrochloric acid solution in dioxane (5 mL) and stirred at 25°C for 2 hours. The resulting mixture was concentrated under reduced pressure, saturated sodium bicarbonate aqueous solution was added to adjust the pH to >7, extracted three times with ethyl acetate, and dried over anhydrous sodium sulfate. The crude product was separated by flash reverse column chromatography to obtain the target compound 2-amino-3-(hydroxymethyl)-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)quinoline-6-carboxamide (Compound 11) as a white solid (100 mg, yield: 80%). ESI-MS: m / z = 418.39 [M+1] + Compound 11 (100 mg) was separated by SFC chiral column chromatography. Separation conditions: Column: Chiral ChIRALPAK-IH, 30*250 mm, 10 μm, Mobile phase A: 40% HEX + 0.2% DEA. Mobile phase B: 60% IPA + 0.2% DEA, Flow rate: 25 mL / min; Peak 1 retention time: 4.300 min, Peak 2 retention time: 5.612 min.

[0191] 11-1 (Peak 1): 1H NMR (400MHz, DMSO-d6) δ7.99(s,1H),7.88(s,1H),7.66-7.55(m,2H),7.52(d,J=8.6Hz,1H),7.32(d,J=7.7Hz ,1H),7.24(s,1H),6.48(s,1H),5.43(t,J=5.4Hz,1H),4.83-4.64(m,2H),4.50(d,J=5.3Hz,2H),2.65(s,3H).

[0192] 11-2 (Peak 2): 1 H NMR (400MHz, DMSO-d6) δ7.97(s,1H),7.86(s,1H),7.64-7.51(m,2H),7.51(d,J=8.6Hz,1H),7.31(d,J=7.7Hz ,1H),7.22(s,1H),6.46(s,1H),5.42(t,J=5.4Hz,1H),4.83-4.64(m,2H),4.50(d,J=5.3Hz,2H),2.65(s,3H).

[0193] Example 12: 2-amino-7-fluoro-3-(hydroxymethyl)-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)quinoline-6-carboxamide

[0194] (1) Under nitrogen protection, TCFH (258 mg, 0.92 mmol) and NMI (374 mg, 4.60 mmol) were added to a solution of 2-amino-3-(((tert-butyldimethylsilyl)oxy)methyl)-7-fluoroquinoline-6-carboxylic acid (160 mg, 0.46 mmol) and N-methyl-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine (120 mg, 0.55 mmol) in acetonitrile (5 mL). The reaction mixture was stirred at 25°C for 16 hours. The reaction solution was poured into water and extracted with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel (PE / EA = 1:1) to give 2-amino-3-(((tert-butyldimethylsilyl)oxy)methyl)-7-fluoro-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)quinoline-6-carboxamide (120 mg, yield: 47.43%) as a yellow solid. ESI-MS: m / z = 550.64 [M+1] + .

[0195] (2) Under nitrogen protection, 2-amino-3-(((tert-butyldimethylsilyl)oxy)methyl)-7-fluoro-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)quinoline-6-carboxamide (120 mg, 0.22 mmol) was added to a 4M hydrochloric acid solution in dioxane (4 mL) and stirred at 25°C for 2 hours. The resulting mixture was concentrated under reduced pressure. Aqueous sodium bicarbonate solution was added to adjust the pH to about 7. Extraction was performed with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The crude product was separated by flash reverse column chromatography to obtain the target compound 2-amino-7-fluoro-3-(hydroxymethyl)-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)quinoline-6-carboxamide (Compound 12) (80 mg) as a white solid with a yield of 83.6%. ESI-MS: m / z = 436.3 [M+1] + Compound 12 (80 mg) was separated by SFC chiral column chromatography. Separation conditions: Column: Chiral ChIRALPAK-IH, 30*250 mm, 10 μm, Mobile phase A: 50% HEX + 0.2% DEA. Mobile phase B: 50% IPA + 0.2% DEA, Flow rate: 25 mL / min; Peak 1 retention time: 6.16 min, Peak 2 retention time: 8.03 min.

[0196] 12-1 (Peak 1): 1 H NMR(400MHz,DMSO-d6)δ8.05-7.78(m,2H),7.63-7.43(m,1H),7.35-7.30(m,1H),7.28-7.18(m,2H),6.55(s,2H),5.66 -5.53(m,0.5H),5.48-5.35(m,1H),4.91-4.80(m,0.5H),4.73-4.60(m,1H),4.51-4.44(m,2H),2.62(d,J=44.5Hz,3H).

[0197] 12-2 (Peak 2): 1H NMR(400MHz,DMSO-d6)δ8.05-7.78(m,2H),7.63-7.43(m,1H),7.35-7.30(m,1H),7.28-7.18(m,2H),6.55(s,2H),5.66 -5.53(m,0.5H),5.48-5.35(m,1H),4.91-4.80(m,0.5H),4.73-4.60(m,1H),4.51-4.44(m,2H),2.62(d,J=44.5Hz,3H).

[0198] Example 13: 2-amino-N-(cyclopropylmethyl)-7-fluoro-3-(hydroxymethyl)-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)quinoline-6-carboxamide

[0199] (1) Under nitrogen protection, TCFH (258 mg, 0.91 mmol) and NMI (374 mg, 4.57 mmol) were added to a solution of 2-amino-3-(((tert-butyldimethylsilyl)oxy)methyl)-7-fluoroquinoline-6-carboxylic acid (200 mg, 0.57 mmol) and N-(cyclopropylmethyl)-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine (147 mg, 0.57 mmol) in ACN (5 mL). The reaction mixture was stirred at 25°C for 16 hours. The reaction solution was poured into water and extracted with EA (20 mL*3). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel (PE / EA = 1:1) to give the intermediate 2-amino-3-(((tert-butyldimethylsilyl)oxy)methyl)-N-(cyclopropylmethyl)-7-fluoro-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)quinoline-6-carboxamide (150 mg, yield: 25.23%) as a yellow solid. ESI-MS: m / z = 476.44 [M+1] +

[0200] (2) Under nitrogen protection, the intermediate 2-amino-3-(((tert-butyldimethylsilyl)oxy)methyl)-N-(cyclopropylmethyl)-7-fluoro-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)quinoline-6-carboxamide (150 mg, 0.25 mmol) was added to a 4M hydrochloric acid solution in dioxane (4 mL) and stirred at 25°C for 2 hours. The resulting mixture was concentrated under reduced pressure, saturated sodium bicarbonate aqueous solution was added to adjust the pH to >7, extracted three times with ethyl acetate, and dried over anhydrous sodium sulfate. The resulting crude product was separated by flash reverse column chromatography to obtain the target compound 2-amino-N-(cyclopropylmethyl)-7-fluoro-3-(hydroxymethyl)-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)quinoline-6-carboxamide (Compound 13) (80 mg, yield: 66.3%) as a white solid. ESI-MS: m / z = 450.0 [M+1] + Compound 13 (80 mg) was separated by SFC chiral column chromatography. Separation conditions: Column: Chiral ChIRALPAK-IH, 30*250 mm, 10 μm, Mobile phase A: 60% HEX + 0.2% DEA, Mobile phase B: 40% IPA + 0.2% DEA, Flow rate: 25 mL / min; Peak 1 retention time: 6.05 min, Peak 2 retention time: 7.64 min.

[0201] 13-1 (Peak 1): 1 H NMR(400MHz, DMSO_d6)δ8.20-7.70(m,1H),7.63-7.52(m,1H),7.35-7.16(m,3H),6.54(s,1H),6.20-5.48(m,1H),5.46-5.38( m,1H),5.05-4.55(m,2H),4.47(d,J=3.99Hz,2H),3.20-3.87(m,2H),0.97-0.65(m,1H),0.50-0.21(m,2H),0.19-0.21(m,2H), -0.08--0.40(m,2H).

[0202] 13-2 (Peak 2): 1H NMR(400MHz,DMSO_d6)δ8.20-7.70(m,1H),7.63-7.52(m,1H),7.35-7.16(m,3H),6.54(s,1H),6.20-5.48(m,1H),5.46-5.38(m,1H),5.0 5-4.55(m,2H),4.47(d,J=3.99Hz,2H),3.20-3.87(m,2H),0.97-0.65(m,1H),0.50-0.21(m,2H),0.19-0.21(m,2H),-0.08--0.40(m,2H).

[0203] Example 14: 2-amino-4-(hydroxymethyl)-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)quinoline-6-carboxamide

[0204] (1) Under nitrogen protection, TCFH (253 mg, 0.9 mmol) and NMI (371 mg, 4.50 mmol) were added to a solution of 2-amino-4-(((tert-butyldimethylsilyl)oxy)methyl)quinoline-6-carboxylic acid (150 mg, 0.45 mmol) and N-methyl-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine (118 mg, 0.54 mmol) in acetonitrile (4 mL) under nitrogen protection. The reaction mixture was stirred at 25 ° C for 16 hours. The reaction was quenched with water and extracted with EA (10 mL * 3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The crude product was purified on a silica gel plate (DCM / MeOH = 10:1) to afford 2-amino-4-(((tert-butyldimethylsilyl)oxy)methyl)-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)quinoline-6-carboxamide (95 mg, yield: 35.64%) as a brown solid. LCMS ESI-MS: m / z = 532.0 [M+1] + .

[0205] (2) Under nitrogen protection, 2-amino-4-(((tert-butyldimethylsilyl)oxy)methyl)-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)quinoline-6-carboxamide (90 mg, 0.17 mmol) was added to a 4M hydrochloric acid solution in dioxane (4 mL). The reaction mixture was stirred at 25°C for 3 hours. The solvent was evaporated under reduced pressure, and the resulting crude product was separated by flash reverse column chromatography to obtain the target compound 2-amino-4-(hydroxymethyl)-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)quinoline-6-carboxamide (14) (50 mg, yield: 63.67%) as a white solid. LCMS ESI-MS: m / z = 418.4 [M+1] + Compound 14 (50 mg) was separated by SFC chiral column chromatography. Separation conditions: Column: Chiral ChIRALPAK-AD, 20*250 mm, 5 μm, Mobile phase A: CO2, Mobile phase B: 40% ethanol (0.1% DEA), Flow rate: 40 mL / min; Peak 1 retention time: 0.564 min, Peak 2 retention time: 0.698 min.

[0206] 14-1 (Peak 1): 1 H NMR(400MHz,DMSO_d6)δ7.84-7.80(m,1H),7.66-7.61(m,1H),7.59-7.56(m,1H),7.51-7.46(m,1H),7.34-7.30(m,1H ),7.25(s,1H),6.92(s,1H),6.68-6.62(m,2H),5.52-5.43(m,1H),4.90-4.83(m,2H),4.82-4.68(m,2H),2.64(s,3H).

[0207] 14-2 (Peak 2): 1 H NMR(400MHz,DMSO_d6)δ7.84-7.81(m,1H),7.66-7.61(m,1H),7.60-7.55(m,1H),7.52-7.46(m,1H),7.35-7 .29(m,1H),7.25(s,1H),6.92(s,1H),6.68-6.63(m,2H),5.53-5.43(m,1H),4.91-4.67(m,4H),2.64(s,3H).

[0208] Example 15: 2-amino-N-(cyclopropylmethyl)-4-(hydroxymethyl)-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)quinoline-6-carboxamide

[0209] (1) Under nitrogen, 2-hydroxy-4-(trifluoromethyl)benzaldehyde (1.0 g, 5.3 mmol) was dissolved in DCM (10 mL), and cyclopropylmethylamine (0.75 g, 10.6 mmol) and anhydrous sodium sulfate (3.01 g, 21.2 mmol) were added. The mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered and the filtrate was concentrated to obtain (E)-2-(((cyclopropylmethyl)imino)methyl)-5-(trifluoromethyl)phenol (1.0 g, yield: 69.81%) as a yellow solid. ESI-MS: m / z = 244.2 [M+1] + . 1 H NMR(400MHz, CDCl3)δ13.97(s,1H),8.40(s,1H),7.38-7.34(m,1H),7.21(s,1H),7.12-7 .08(m,1H),3.54-3.50(m,2H),1.18-1.07(m,1H),0.63-0.57(m,2H),0.31-0.26(m,2H).

[0210] (2) Under nitrogen protection, potassium tert-butoxide (1.15 g, 10.25 mmol) was added in portions to a suspension of trimethylsulfoxide iodide (1.0 g, 4.1 mmol) in THF (13 mL). The mixture was stirred at room temperature for 1 hour, and then a solution of (E)-2-(((cyclopropylmethyl)imino)methyl)-5-(trifluoromethyl)phenol (2.26 g, 10.25 mmol) in THF (5 mL) was added. The resulting mixture was stirred at room temperature for 1 hour, and then stirred at 50°C for 3 hours. The reaction solution was cooled to room temperature, and additional potassium tert-butoxide (0.46 g, 4.1 mmol) was added, and the resulting mixture was stirred at room temperature for 11 hours. The reaction mixture was filtered, and the filtrate was added with water and extracted with EA (10 mL*3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified on a silica gel plate (P / E = 1:1) to obtain N-(cyclopropylmethyl)-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine (0.5 g, yield: 41.46%) as a brown solid. ESI-MS: m / z = 258.2 [M+1] +. 1H NMR (400MHz, CDCl3) δ7.43-7.34(m,1H),7.19-7.14(m,1H),7.05(s,1H),4.62-4.59(m,1H),4.56-4.51 (m,1H),4.46-4.41(m,1H),2.61-2.44(m,2H),0.99-0.88(m,1H),0.54-0.45(m,2H),0.17-0.06(m,2H).

[0211] (3) Under nitrogen protection, PyBrOP (412 mg, 0.88 mmol) and TEA (446.3 mg, 4.42 mmol) were added to a solution of 2-amino-4-(((tert-butyldimethylsilyl)oxy)methyl)quinoline-6-carboxylic acid (200 mg, 0.44 mmol) and N-(cyclopropylmethyl)-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine (136 mg, 0.53 mmol) in DMAC (5 mL). The reaction mixture was stirred at 25°C for 16 hours. The reaction was quenched with water and extracted with EA (20 mL*3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The crude product was purified on a silica gel plate (P / E = 1:2) to afford 2-amino-4-(((tert-butyldimethylsilyl)oxy)methyl)-N-(cyclopropylmethyl)-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)quinoline-6-carboxamide (200 mg, 58.89% yield) as a brown solid. ESI-MS: m / z = 572.7 [M+1] + .

[0212] (4) Under nitrogen protection, to a solution of 2-amino-4-(((tert-butyldimethylsilyl)oxy)methyl)-N-(cyclopropylmethyl)-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)quinoline-6-carboxamide (190 mg, 0.27 mmol) in ACN:H2O=1:1 (5 mL) was added cerium ammonium nitrate (452 ​​mg, 0.82 mmol). The reaction mixture was stirred at 50°C for 16 hours. After cooling to room temperature, water was added to the reaction solution, and extraction was performed with EA (3*20 mL). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reverse phase column chromatography (acetonitrile / water, 5 / 5) to afford the target compound 2-amino-N-(cyclopropylmethyl)-4-(hydroxymethyl)-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)quinoline-6-carboxamide (Compound 15) as a white solid (30 mg, yield: 21.49%). ESI-MS: m / z = 458.4 [M+1] +Compound 15 (30 mg) was separated by SFC chiral column chromatography. Separation conditions: Column: Chiral ChIRALPAK-IH, 20*250 mm, 5 μm, Mobile phase A: CO2, Mobile phase B: 20% ethanol (0.1% DEA), Flow rate: 40 mL / min; Peak 1 retention time: 1.104 min, Peak 2 retention time: 1.714 min.

[0213] 15-1 (Peak 1): 1 H NMR(400MHz,DMSO_d6)δ7.79-7.75(m,1H),7.68-7.63(m,1H),7.55-7.46(m,2H),7.03-7.26(m,1H),7.20(s,1H),6.92(s,1H),6 .64(s,2H),5.89-5.83(m,1H),4.94-4.73(m,4H),3.15-3.05(m,2H),0.87-0.78(m,1H),0.39-0.23(m,2H),-0.08--0.28(m,2H).

[0214] 15-2 (Peak 2): 1 H NMR(400MHz,DMSO_d6)δ7.82-7.76(m,1H),7.69-7.64(m,1H),7.60-7.49(m,2H),7.32-7.26(m,1H),7.20(s,1H),6.98(s,1H),5.89 -5.82(m,1H),5.57-5.50(m,1H),4.94-4.72(m,4H),3.20-3.04(m,2H),0.85-0.77(m,1H),0.39-0.24(m,2H),-0.07--0.28(m,2H).

[0215] Example 16: 2-amino-4-(hydroxymethyl)-N-(1-methyl-1H-pyrazol-4-yl)-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)quinoline-6-carboxamide

[0216] (1) Under nitrogen protection, acetic acid (0.29 g, 4.9 mmol) was added to a mixture of 6-(trifluoromethyl)benzofuran-3(2H)-one (1 g, 4.9 mmol) and 1-methyl-1H-pyrazol-4-amine (0.57 g, 5.9 mmol) in DCM (15 mL). The mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (2.08 g, 9.8 mmol) was then added. The reaction mixture was stirred at room temperature for another 1 hour. The reaction mixture was concentrated under reduced pressure to obtain 1-methyl-N-(6-(trifluoromethyl)benzofuran-3-yl)-1H-pyrazol-4-amine (1.2 g, crude product) as a brown solid. ESI-MS: m / z = 282.0 [M+1] + .

[0217] (2) Under hydrogen protection, Pd / C (1.08 g, 10.2 mmol) was added to a solution of 1-methyl-N-(6-(trifluoromethyl)benzofuran-3-yl)-1H-pyrazol-4-amine (1.2 g, 3.4 mmol) in MeOH (20 mL). The reaction mixture was stirred at room temperature for 16 hours. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The crude product was slurried with petroleum ether and filtered to obtain 1-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)-1H-pyrazol-4-amine (0.40 g, yield: 41.56%) as a brown solid. ESI-MS: m / z = 284.1 [M+1] + . 1 H NMR (400MHz, CDCl3) δ7.43-7.39(m,1H),7.19-7.15(m,1H),7.13(s,1H),7.08(s,1H) ,6.91(s,1H),4.96-4.90(m,1H),4.72-4.66(m,1H),4.54-4.46(m,1H),3.82(s,3H).

[0218] (3) Under nitrogen protection, TCFH (338 mg, 1.2 mmol) and NMI (494 mg, 6 mmol) were added to a solution of 2-amino-4-(((tert-butyldimethylsilyl)oxy)methyl)quinoline-6-carboxylic acid (200 mg, 0.60 mmol) and 1-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)-1H-pyrazol-4-amine (205 mg, 0.72 mmol) in ACN (5 mL). The reaction mixture was stirred at room temperature for 16 hours. Water was added to the reaction solution and extracted with EA (20 mL*3). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The crude product was purified on a silica gel plate (P / E = 1:2) to afford 2-amino-4-(((tert-butyldimethylsilyl)oxy)methyl)-N-(1-methyl-1H-pyrazol-4-yl)-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)quinoline-6-carboxamide as a yellow solid (100 mg, yield: 25.03%). ESI-MS: m / z = 598.4 [M+1] +

[0219] (4): Under nitrogen protection, 1M TBAF in THF (0.50 mL, 0.5 mol) was added to a solution of 2-amino-4-(((tert-butyldimethylsilyl)oxy)methyl)-N-(1-methyl-1H-pyrazol-4-yl)-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)quinoline-6-carboxamide (100 mg, 0.17 mmol) in THF (3 mL). The reaction mixture was stirred at 25°C for 3 hours. Water was added to the reaction solution, extracted with EA (20 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The crude product was separated by flash reverse phase column chromatography to obtain the target compound 2-amino-4-(hydroxymethyl)-N-(1-methyl-1H-pyrazol-4-yl)-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)quinoline-6-carboxamide (Compound 16) as an off-white solid (20 mg, yield: 24.72%). ESI-MS: m / z = 484.2 [M+1] + Compound 16 (20 mg) was separated by SFC chiral column chromatography. Separation conditions: Column: Chiral ChIRALPAK-IH, 20*250 mm, 5 μm, Mobile phase A: CO2, Mobile phase B: 10% ethanol (0.1% DEA, Flow rate: 40 mL / min; Peak 1 retention time: 2.428 min, Peak 2 retention time: 2.930 min.

[0220] 16-1 (Peak 1): 1H NMR(400MHz,DMSO_d6)δ8.27(s,1H),7.78-7.72(m,1H),7.70-7.64(m,1H),7.51-7.45(m,1H),7.42(s,1H),7.33-7.22(m,2H),7 .06(s,1H),6.93-6.82(m,2H),6.62(s,1H),6.54-6.47(m,1H),5.44(s,2H),4.91-4.83(m,1H),4.76-4.61(m,3H),3.52(s,3H).

[0221] 16-2 (Peak 2): 1 H NMR(400MHz,DMSO_d6)δ8.25(s,1H),7.79-7.72(m,1H),7.70-7.62(m,1H),7.53-7.45(m,1H),7.42(s,1H),7.35-7.21(m,2H),7 .06(s,1H),6.94-6.79(m,2H),6.62(s,1H),6.54-6.46(m,1H),5.43(s,2H),4.91-4.83(m,1H),4.78-4.60(m,3H),3.52(s,3H).

[0222] Example 17: 2-amino-7-fluoro-4-(hydroxymethyl)-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)quinoline-6-carboxamide

[0223] (1) Under nitrogen protection, TFA (1.5 mL) was added to a solution of tert-butyl (6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)-methyl-carbamate (500 mg, 1.57 mmol) in DCM (5 mL). The reaction mixture was stirred at 25°C for 2 hours. The resulting mixture was concentrated under reduced pressure to obtain the intermediate N-methyl-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine as a crude brown solid (330 mg, yield: 77.38%). ESI-MS: m / z = 218.2 [M+1] + . 1 H NMR (400MHz, CDCl3) δ7.66-7.59(m,1H),7.34-7.29(m,1H),7.20(s,1H),5.14-5.04(m,1H),4.93-4.82(m,1H),4.75-4.64(m,1H),2.56(s,3H).

[0224] (2) Under nitrogen protection, TCFH (240 mg, 0.86 mmol) and NMI (351 mg, 4.28 mmol) were added to a solution of 2-amino-4-(((tert-butyldimethylsilyl)oxy)methyl)-7-fluoroquinoline-6-carboxylic acid (150 mg, 0.43 mmol) and N-methyl-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine (112 mg, 0.51 mmol) in ACN (4 mL). The reaction mixture was stirred at 25°C for 16 hours. The reaction solution was poured into water and extracted with EA (20 mL*3). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel (PE / EA = 1:1) to give 2-amino-4-(((tert-butyldimethylsilyl)oxy)methyl)-7-fluoro-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)quinoline-6-carboxamide (150 mg, yield: 57.38%) as a brown solid. ESI-MS: m / z = 550.2 [M+1] +

[0225] (3) Under nitrogen protection, 2-amino-4-(((tert-butyldimethylsilyl)oxy)methyl)-7-fluoro-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)quinoline-6-carboxamide (140 mg, 0.24 mmol) was added to a 4M hydrochloric acid solution in dioxane (4 mL) and stirred at 25°C for 3 hours. The resulting mixture was concentrated under reduced pressure, and the crude product was separated by flash reverse column chromatography to obtain the target compound 2-amino-7-fluoro-4-(hydroxymethyl)-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)quinoline-6-carboxamide (Compound 17) as a white solid (100 mg, yield: 80%). ESI-MS: m / z = 436.3 [M+1] + Compound 17 (100 mg) was separated by SFC chiral column chromatography. Separation conditions: Column: Chiral ChIRALPAK-AD, 20*250 mm, 5 μm, Mobile phase A: CO2, Mobile phase B: 30% ethanol (0.1% DEA), Flow rate: 40 mL / min; Peak 1 retention time: 0.660 min, Peak 2 retention time: 0.787 min.

[0226] 17-1 (Peak 1): 1H NMR(400MHz,DMSO_d6)δ7.86-7.69(m,1H),7.62-7.47(m,1H),7.37-7.13(m,3H),6.91-6.85(m,1H),6.78( s,2H),6.50-6.44(m,0.5H),5.63-5.56(m,0.5H),5.53-5.46(m,1H),4.92-4.63(m,4H),2.71-2.53(m,3H).

[0227] 17-2 (Peak 2): 1 H NMR(400MHz,DMSO_d6)δ7.81-7.71(m,1H),7.61-7.52(m,1H),7.36-7.16(m,3H),6.91-6.85(m,1H),6.78( s,2H),6.49-6.44(m,0.5H),5.62-5.56(m,0.5H),5.53-5.46(m,1H),4.89-4.65(m,4H),2.68-2.53(m,3H).

[0228] Example 18: 2-amino-N-(cyclopropylmethyl)-7-fluoro-4-(hydroxymethyl)-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)quinoline-6-carboxamide

[0229] (1) Under nitrogen protection, 2-amino-4-(((tert-butyldimethylsilyl)oxy)methyl)-7-fluoroquinoline-6-carboxylic acid (200 mg, 0.57 mmol) was dissolved in ACN (5 mL), and then N-(cyclopropylmethyl)-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine (176 mg, 0.68 mmol), TCFH (320 mg, 1.14 mmol) and NMI (469 mg, 5.70 mmol) were added. The reaction mixture was stirred at 25°C for 16 hours. The reaction solution was then poured into water and extracted with EA (20 mL*3). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The crude product was purified on a silica gel plate (P / E = 1:1) to give 2-amino-4-(((tert-butyldimethylsilyl)oxy)methyl)-N-(cyclopropylmethyl)-7-fluoro-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)quinoline-6-carboxamide (200 mg, 53.48% yield) as a brown solid. ESI-MS: m / z = 590.3 [M+1] +

[0230] (2) Under nitrogen protection, lithium hydroxide (16 mg, 0.66 mmol) was added to a solution of 2-amino-4-(((tert-butyldimethylsilyl)oxy)methyl)-N-(cyclopropylmethyl)-7-fluoro-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)quinoline-6-carboxamide (195 mg, 0.33 mmol) in THF / MeOH / H2O=1:1:1 (5 mL). The reaction mixture was stirred at 25°C for 16 hours. The reaction solution was poured into water and extracted with EA (20 mL*3). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The crude product was separated by flash reverse phase column chromatography to obtain the target compound 2-amino-N-(cyclopropylmethyl)-7-fluoro-4-(hydroxymethyl)-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)quinoline-6-carboxamide (Compound 18) as a white solid (100 mg, yield: 60.42%). ESI-MS: m / z = 476.4 [M+1] + Compound 18 (100 mg) was separated by SFC chiral column chromatography. Separation conditions: Column: Chiral ChIRALPAK-IC, 20*250 mm, 5 μm, Mobile phase A: CO2, Mobile phase B: 30% ethanol (0.1% DEA), Flow rate: 40 mL / min; Peak 1 retention time: 0.839 min, Peak 2 retention time: 1.147 min.

[0231] 18-1 (Peak 1): 1 H NMR(400MHz,DMSO_d6)δ7.80-7.66(m,1H),7.62-7.53(m,1H),7.33-7.27(m,1H),7.24-7.14(m,2H),6.88(s,1H),6.77(s,2H),5.96(s,0. 5H),5.56(s,0.5H),5.54-5.44(m,1H),4.95-4.67(m,4H),3.20-2.98(m,2H),0.89-0.68(m,1H),0.44-0.21(m,2H),-0.10--0.41(m,2H).

[0232] 18-2 (Peak 2): 1H NMR(400MHz,DMSO_d6)δ7.85-7.68(m,1H),7.62-7.52(m,1H),7.33-7.26(m,1H),7.23-7.14(m,2H),6.88(s,1H),6.78(s,2H),5.96(s,0. 5H),5.56(s,0.5H),5.53-5.44(m,1H),4.95-4.65(m,4H),3.19-2.97(m,2H),0.95-0.71(m,1H),0.43-0.21(m,2H),-0.10--0.41(m,2H).

[0233] Example 19: 2-amino-4-(hydroxymethyl)-N-methyl-N-(7-(trifluoromethyl)-3,4-dihydro-1H-2-chromen-4-yl)quinoline-6-carboxamide

[0234] (1) Under nitrogen protection, a mixture of (2-bromo-5-(trifluoromethyl)phenyl)methanol (9 g, 35.3 mmol), 3-bromoprop-1-ene (4.27 g, 35.3 mol), potassium hydroxide (3.96 g, 70.6 mmol) and tetrabutylammonium hydrogen sulfate (1.80 g, 52.9 mmol) was stirred at 25°C for 16 hours. The reaction was quenched with water and extracted with EA (100 mL*3). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column (PE / EA=200 / 1~100 / 1) to obtain 2-((allyloxy)methyl)-1-bromo-4-(trifluoromethyl)benzene (7.2 g, yield: 62.32%) as a yellow oil. 1 H NMR (400MHz, CDCl3): δ7.80-7.77(m,1H),7.68-7.63(m,1H),7.42-7.37(m, 1H),6.06-5.93(m,1H),5.41-5.24(m,2H),4.59(s,2H),4.17-4.14(m,2H).

[0235] (2) Under nitrogen protection, cesium carbonate (9.31 g, 28 mmol), triphenylphosphine (2.8 g, 10.7 mmol) and palladium acetate (0.77 g, 3.5 mmol) were added to a solution of 2-((allyloxy)methyl)-1-bromo-4-(trifluoromethyl)benzene (7.0 g, 23.8 mmol) in DMF (100 mL). The reaction mixture was heated to 90 °C and stirred for 16 hours. The reaction was quenched with water and extracted with EA (100 mL*3). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column (PE / EA=100 / 1~50 / 1) to obtain 4-methylene-7-(trifluoromethyl)-3,4-dihydro-1H-2-benzopyran (2.40 g, yield: 47.24%) as a yellow oil. 1 H NMR (400MHz, CDCl3): δ7.80-7.76(m,1H),7.50-7.46(m,1H),7.30(s,1H),7.72(s,1H),5.17-5.13(m,1H),4.84(s,2H),4.48-4.45(m,2H).

[0236] (3) Under nitrogen protection, potassium osmate (VI) dihydrate (0.41 g, 10 mmol) and 4-methylmorpholine N-oxide (4.63 g, 39.5 mmol) were added to a solution of 4-methylene-7-(trifluoromethyl)-3,4-dihydro-1H-2-benzopyran (2.4 g, 11.3 mmol) in acetone / water = 5:1 (30 mL). The reaction mixture was stirred at 25°C for 16 hours. The reaction was then quenched by adding sodium sulfite and extracted with EA (50 mL*3). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 4-(hydroxymethyl)-7-(trifluoromethyl)-3,4-dihydro-1H-2-benzopyran-4-ol (2.0 g, yield: 71.91%) as a yellow solid. 1 H NMR (400MHz, CDCl3): δ7.75-7.69(m,1H),7.59-7.51(m,2H),7.27(s,1H),4.82(s ,2H),4.20-4.06(m,1H),3.99-3.86(m,1H),3.72-3.66(m,1H),3.65-3.57(m,1H).

[0237] (4) Under nitrogen protection, sodium periodate (5.87 g, 27.4 mmol) was added to a solution of 4-(hydroxymethyl)-7-(trifluoromethyl)-3,4-dihydro-1H-2-benzopyran-4-ol (2.0 g, 8.1 mmol) in tetrahydrofuran / water = 30:1 (25 mL). The reaction mixture was stirred at 25°C for 16 hours. The reaction was quenched with sodium sulfite and extracted with EA (50 mL*3). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 7-(trifluoromethyl)-3,4-dihydro-1H-2-benzopyran-4-one (750 mg, yield: 43.06%) as a yellow solid.

[0238] (5) Under nitrogen protection, NaBH4 (279.80 mg, 7.40 mmol) was added to a solution of 7-(trifluoromethyl)-3,4-dihydro-1H-2-benzopyran-4-one (800 mg, 3.70 mmol) in methanol (10 mL). The reaction mixture was stirred at 25°C for 2 hours. The reaction was quenched with water and extracted with EA (50 mL*3). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to obtain 7-trifluoromethyl-3,4-dihydro-1H-2-benzopyran-4-one (600 mg, yield: 57.06%) as a white solid. 1 H NMR (400MHz, CDCl3): δ7.62-7.51(m,2H),7.29(s,1H),4.86-4.68(m,2H),4.63-4.56(m,1H),4.12-4.05(m,1H),3.94-3.86(m,1H),2.72(s,1H).

[0239] (6) Under nitrogen protection, TEA (806 mg, 7.80 mmol) and MsCl (606 mg, 5.32 mmol) were added to a solution of 7-trifluoromethyl-3,4-dihydro-1H-2-benzopyran-4-one (580 mg, 2.66 mmol) in DCM (5 mL) at 0°C. The reaction mixture was stirred at 25°C for 2 hours. The reaction was quenched with water and extracted with DCM (20 mL*3). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to give 7-(trifluoromethyl)-3,4-dihydro-1H-2-benzopyran-4-ylmethanesulfonate (435 mg, yield: 55.23%) as a yellow oil.

[0240] (7) Under nitrogen protection, a solution of 7-(trifluoromethyl)-3,4-dihydro-1H-2-chromene-4-ylmethanesulfonate (435 mg, 1.47 mmol) in MeNH2 / MeOH (10 mL) was stirred at 60°C for 16 hours. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel plate (DCM / MeOH = 10:1) to give N-methyl-7-(trifluoromethyl)-3,4-dihydro-1H-2-chromene-4-amine (300 mg, yield: 79.53%) as a brown oil. ESI-MS: m / z = 232.2 [M+1] + . 1 H NMR (400MHz, CDCl3) δ7.60-7.48(m,2H),7.30(s,1H),4.94-4.69(m,2H),4.37-4.28(m,1H),3.88-3.78(m,1H),3.78-3.73(m,1H),2.55(s,3H).

[0241] (8) Under nitrogen protection, TCFH (248.0 mg, 0.88 mmol) and NMI (363.0 mg, 4.40 mmol) were added to a solution of 2-amino-4-(((tert-butyldimethylsilyl)oxy)methyl)quinoline-6-carboxylic acid (200.0 mg, 0.44 mmol) and N-methyl-7-(trifluoromethyl)-3,4-dihydro-1H-2-benzopyran-4-amine (122.6 mg, 0.53 mmol) in ACN (5 mL). The reaction mixture was stirred at 25 ° C for 16 hours. The reaction was quenched with water and extracted with EA (20 mL * 3). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel (DCM / MeOH = 10:1) to give 2-amino-4-(((tert-butyldimethylsilyl)oxy)methyl)-N-methyl-N-(7-(trifluoromethyl)-3,4-dihydro-1H-2-chromen-4-yl)quinoline-6-carboxamide (200 mg, yield: 67.98%) as a yellow solid. ESI-MS: m / z = 546.6 [M+1] + .

[0242] (9) Under nitrogen protection, a mixture of 2-amino-4-(((tert-butyldimethylsilyl)oxy)methyl)-N-methyl-N-(7-(trifluoromethyl)-3,4-dihydro-1H-2-benzopyran-4-yl)quinoline-6-carboxamide (200 mg, 0.30 mmol) in TFA (4 mL) was stirred at 70°C for 16 hours. The resulting mixture was concentrated under reduced pressure. The crude product was separated by flash reverse column chromatography to obtain the target compound 2-amino-4-(hydroxymethyl)-N-methyl-N-(7-(trifluoromethyl)-3,4-dihydro-1H-2-benzopyran-4-yl)quinoline-6-carboxamide (Compound 19) (100 mg, yield: 65.58%) as a white solid. ESI-MS: m / z = 432.4 [M+1] + Compound 19 (100 mg) was separated by SFC chiral column chromatography. Separation conditions: Column: Chiral ChIRALPAK-IH, 20*250 mm, 5 μm, Mobile phase A: CO2, Mobile phase B: 30% ethanol (0.1% DEA), Flow rate: 40 mL / min; Peak 1 retention time: 0.656 min, Peak 2 retention time: 0.850 min.

[0243] 19-1 (Peak 1): 1 H NMR(400MHz,DMSO_d6)δ7.87-7.80(m,1H),7.72-7.52(m,4H),7.51-7.46(m,1H),6.92(s ,1H),5.75(s,1H),4.98-4.79(m,3H),4.77-4.60(m,1H),4.21-4.02(m,2H),2.71(s,3H).

[0244] 19-2 (Peak 2): 1 H NMR(400MHz,DMSO_d6)δ7.85-7.80(m,1H),7.68-7.47(m,5H),6.90(s,1H),5.7 2(s,1H),4.90-4.76(m,3H),4.74-4.57(m,1H),4.18-4.01(m,2H),2.71(s,3H).

[0245] Example 20: 2-amino-7-fluoro-4-(hydroxymethyl)-N-methyl-N-(7-(trifluoromethyl)-3,4-dihydro-1H-2-chromen-4-yl)quinoline-6-carboxamide

[0246] (1) Under nitrogen protection, TCFH (258 mg, 0.91 mmol) and NMI (374 mg, 4.60 mmol) were added to a solution of 2-amino-4-(((tert-butyldimethylsilyl)oxy)methyl)-7-fluoroquinoline-6-carboxylic acid (160 mg, 0.46 mmol) and 2-amino-4-(((tert-butyldimethylsilyl)oxy)methyl)-7-fluoroquinoline-6-carboxylic acid (127 mg, 0.55 mmol) in ACN (5 mL). The reaction mixture was stirred at 25°C for 16 hours. The reaction solution was poured into water and extracted with EA (20 mL*3). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel (PE / EA = 1:1) to give 2-amino-4-(((tert-butyldimethylsilyl)oxy)methyl)-7-fluoro-N-methyl-N-(7-(trifluoromethyl)-3,4-dihydro-1H-2-chromen-4-yl)quinoline-6-carboxamide (100 mg, yield: 38.91%) as a yellow solid. ESI-MS: m / z = 564.0 [M+1] +

[0247] (2) Under nitrogen protection, 2-amino-4-(((tert-butyldimethylsilyl)oxy)methyl)-7-fluoro-N-methyl-N-(7-(trifluoromethyl)-3,4-dihydro-1H-2-benzopyran-4-yl)quinoline-6-carboxamide (100 mg, 0.18 mmol) was added to a 4M hydrochloric acid solution in dioxane (4 mL) and stirred at 25°C for 2 hours. The resulting mixture was concentrated under reduced pressure. The crude product was separated by flash reverse column chromatography to obtain the target compound 2-amino-7-fluoro-4-(hydroxymethyl)-N-methyl-N-(7-(trifluoromethyl)-3,4-dihydro-1H-2-benzopyran-4-yl)quinoline-6-carboxamide (Compound 20) (70 mg, yield: 88.61%) as a white solid. ESI-MS: m / z = 450.0 [M+1] + Compound 20 (70 mg) was separated by SFC chiral column chromatography. Separation conditions: Column: Chiral ChIRALPAK-IG, 20*250 mm, 5 μm, Mobile phase A: CO2, Mobile phase B: 30% ethanol (0.1% DEA), Flow rate: 40 mL / min; Peak 1 retention time: 0.983 min, Peak 2 retention time: 1.157 min. ESI-MS: m / z = 450.0 [M+1] + .

[0248] 20-1 (Peak 1): 1H NMR(400MHz,DMSO_d6)δ8.13-7.90(m,1H),7.72-7.34(m,5H),7.01(s,1H),5.81(s,1H), 5.66(s,1H),4.93-4.88(m,2H),4.83-4.62(m,2H),4.19-3.97(m,2H),2.76-2.62(m,3H).

[0249] 20-2 (Peak 2): 1 H NMR(400MHz,DMSO_d6)δ8.14-7.91(m,1H),7.71-7.39(m,5H),7.02(s,1H),5.81(s,1H), 5.68(s,1H),4.94-4.86(m,2H),4.82-4.62(m,2H),4.14-3.97(m,2H),2.76-2.62(m,3H).

[0250] Example 21: (2-amino-4-(hydroxymethyl)quinolin-6-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone

[0251] Step 1: Under nitrogen, to a solution of 4-(hydroxymethyl)-2-((4-methoxybenzyl)amino)quinoline-6-carboxylic acid (200.0 mg, 0.59 mmol) and 3-[4-(trifluoromethyl)phenyl]morpholine (136.7 mg, 0.59 mmol) in N,N-dimethylacetamide (8 mL) was added PyBrOP (551.1 mg, 1.18 mmol) and triethylamine (299.1 mg, 2.96 mmol). The reaction mixture was stirred at 25°C for 16 hours. The reaction was quenched with water and extracted with ethyl acetate (30 mL*3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified on a silica gel prep plate (dichloromethane / methanol = 20:1) to afford (4-(hydroxymethyl)-2-((4-methoxybenzyl)amino)quinolin-6-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone as a yellow solid (120 mg, 36.80% yield). ESI-MS: m / z = 551.2 / 552.3 [M+1]+.

[0252] Step 2: Under nitrogen protection, a solution of (4-(hydroxymethyl)-2-((4-methoxybenzyl)amino)quinolin-6-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone (120 mg, 0.22 mmol) in trifluoroacetic acid (4 mL) was stirred at 70°C for 16 hours. The reaction solution was concentrated under reduced pressure, adjusted to pH 8 with saturated aqueous sodium carbonate solution, and extracted with dichloromethane (30 mL*3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified on a silica gel preparation plate (dichloromethane / methanol = 10:1) to give (2-amino-4-(hydroxymethyl)quinolin-6-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone (i.e., Compound 21) (65 mg, yield: 69.24%) as a yellow solid. ESI-MS: m / z=431.1 / 432.1[M+1]+.

[0253] Step 3: The racemate (65 mg) was separated by SFC chiral column chromatography. Separation conditions: Column: Chiral ChIRALPAK-IH, 30 x 250 mm, 10 μm, Mobile Phase A: CO2, Mobile Phase B: 20% ethanol + 0.1% DEA, Flow rate: 25 mL / min; Peak 1 retention time: 1.505 min, Peak 2 retention time: 1.737 min.

[0254] 21-1 (Peak 1): 1 H NMR(400MHz,DMSO-d6)δ7.81-7.63(m,5H),7.54-7.43(m,2H),6.90(s,1H),6.64(s,2H),5.66-5.29(m,2H),4.8 8-4.66(m,2H),4.52-4.41(m,1H),3.95-3.88(m,1H),3.83-3.73(m,1H),3.65-3.56(m,1H),3.23-3.11(m,1H).

[0255] 21-2 (Peak 2): 1 H NMR(400MHz,DMSO-d6)δ7.80-7.64(m,5H),7.54-7.44(m,2H),6.90(s,1H),6.63(s,2H),5.65-5.27(m,2H),4.8 6-4.66(m,2H),4.52-4.41(m,1H),3.95-3.88(m,1H),3.83-3.74(m,1H),3.64-3.56(m,1H),3.23-3.11(m,1H).

[0256] Example 22: (2-amino-4-(hydroxymethyl)quinolin-6-yl)(2-(4-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

[0257] Step 1: Under nitrogen protection, to a solution of 4-(((tert-butyldimethylsilyl)oxy)methyl)-2-((4-methoxybenzyl)amino)quinoline-6-carboxylic acid (400.0 mg, 0.88 mmol) and 2-[4-(trifluoromethyl)phenyl]piperidine (202.6 mg, 0.88 mmol) in N,N-dimethylacetamide (10 mL) was added PyBrOP (823.9 mg, 1.77 mmol) and triethylamine (446.3 mg, 4.42 mmol). The reaction mixture was stirred at 25°C for 16 hours. The reaction was quenched with water and extracted with ethyl acetate (30 mL*3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified on a silica gel preparative plate (petroleum ether / ethyl acetate = 1:1) to afford (4-(((tert-butyldimethylsilyl)oxy)methyl)-2-((4-methoxybenzyl)amino)quinolin-6-yl)(2-(4-(trifluoromethyl)phenyl)piperidin-1-yl)methanone (350 mg, 59.66% yield) as a yellow solid. ESI-MS: m / z = 663.3 / 664.3 [M+1]+.

[0258] Step 2: Under nitrogen protection, a solution of (4-(((tert-butyldimethylsilyl)oxy)methyl)-2-((4-methoxybenzyl)amino)quinolin-6-yl)(2-(4-(trifluoromethyl)phenyl)piperidin-1-yl)methanone (120 mg, 0.1808 mmol) in trifluoroacetic acid (6 mL) was stirred at 70°C for 16 hours. The reaction solution was concentrated under reduced pressure, adjusted to pH 8 with saturated aqueous sodium carbonate solution, and extracted with dichloromethane (30 mL*3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified on a silica gel preparative plate (dichloromethane / methanol = 10:1) to obtain (2-amino-4-(hydroxymethyl)quinolin-6-yl)(2-(4-(trifluoromethyl)phenyl)piperidin-1-yl)methanone (i.e., Compound 22) (60 mg, yield: 77.28%) as a white solid. ESI-MS: m / z=429.2 / 430.2[M+1]+.

[0259] Step 3: The racemate (60 mg) was separated by SFC chiral column chromatography. Separation conditions: Column: Chiral ChIRALPAK-IH, 30 x 250 mm, 10 μm, Mobile Phase A: CO2, Mobile Phase B: 40% ethanol + 0.1% DEA, Flow rate: 25 mL / min; Peak 1 retention time: 0.526 min, Peak 2 retention time: 0.785 min.

[0260] 22-1 (Peak 1): 1 H NMR(400MHz,DMSO-d6)δ7.83-7.70(m,3H),7.63-7.42(m,4H),6.90(s,1H),6.61(s,2H),5.74-5.2 6(m,2H),4.89-4.61(m,2H),2.83(s,1H),2.02-1.90(m,1H),1.70-1.50(m,3H),1.39-1.20(m,2H).

[0261] 22-2 (Peak 2): 1 H NMR(400MHz,DMSO-d6)δ7.81-7.72(m,3H),7.61-7.43(m,4H),6.90(s,1H),6.61(s,2H),5.67-5.3 0(m,2H),4.91-4.69(m,2H),2.84(s,1H),2.01-1.91(m,1H),1.69-1.51(m,3H),1.40-1.22(m,2H).

[0262] Example 23: (2-amino-7-fluoro-4-(hydroxymethyl)quinolin-6-yl)(2-(4-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

[0263] Step 1: Under nitrogen protection, PyBrOP (593 mg, 1.27 mmol) and triethylamine (643 mg, 6.36 mmol) were added to a solution of 4-(((tert-butyldimethylsilyl)oxy)methyl)-7-fluoro-2-((4-methoxybenzyl)amino)quinoline-6-carboxylic acid (300 mg, 0.64 mmol) and 2-(4-(trifluoromethyl)phenyl)piperidine (189 mg, 0.83 mmol) in N,N-dimethylacetamide (4 mL). The reaction mixture was stirred at 25 ° C for 16 hours. The reaction was quenched with water and extracted with ethyl acetate (20 mL * 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The crude product was purified on a silica gel preparative plate (petroleum ether / ethyl acetate = 5:1) to afford (4-(((tert-butyldimethylsilyl)oxy)methyl)-7-fluoro-2-((4-methoxybenzyl)amino)quinolin-6-yl)(2-(4-(trifluoromethyl)phenyl)piperidin-1-yl)methanone as a yellow solid (210 mg, 48.83% yield). ESI-MS: m / z = 681.3 / 682.2 [M+1]+.

[0264] Step 2: Under nitrogen protection, a solution of (4-(((tert-butyldimethylsilyl)oxy)methyl)-7-fluoro-2-((4-methoxybenzyl)amino)quinolin-6-yl)(2-(4-(trifluoromethyl)phenyl)piperidin-1-yl)methanone (210 mg, 0.31 mmol) in trifluoroacetic acid (5 mL) was stirred at 70°C for 16 hours. The reaction solution was concentrated under reduced pressure. The crude product was purified by high pressure preparative purification to give (2-amino-7-fluoro-4-(hydroxymethyl)quinolin-6-yl)(2-(4-(trifluoromethyl)phenyl)piperidin-1-yl)methanone (i.e., Compound 23) (45.2 mg, yield: 32.99%) as a white solid. ESI-MS: m / z = 447.1 / 448.1 [M+1]+.

[0265] Step 3: The racemate (45.2 mg) was separated by SFC chiral column chromatography. Separation conditions: Column: Chiral ChIRALPAK-IH, 30 x 250 mm, 10 μm; Mobile phase A: CO2; Mobile phase B: 20% ethanol + 0.1% DEA; Flow rate: 25 mL / min; Peak 1 retention time: 1.474 min; Peak 2 retention time: 1.913 min.

[0266] 23-1 (Peak 1): 1H NMR (400MHz, DMSO-d6) δ7.79(s,3H),7.59(d,J=6.6Hz,2H),7.23(d,J=11.4Hz,1H),6.89-6.76(m,3H),5. 98(s,1H),5.49(s,1H),4.85(s,2H),3.40(s,1H),2.94(s,1H),1.97(d,J=28.0Hz,1H),1.64-1.13(m,5H).

[0267] 23-2 (Peak 2): 1 H NMR (400MHz, DMSO-d6) δ7.79(s,3H),7.60(d,J=6.4Hz,2H),7.23(d,J=11.3Hz,1H),6.89-6.76(m,3H),5.98( s,1H),5.49(s,1H),4.85(s,2H),3.40(s,1H),2.95-2.83(m,1H),1.93(d,J=13.4Hz,1H),1.49-1.06(m,5H).

[0268] Example 24: Synthesis of (2-amino-7-fluoro-4-(hydroxymethyl)quinolin-6-yl)(3-(4-(trifluoromethyl)phenyl)morpholinyl)methanone

[0269] Step 1: Under nitrogen protection, PyBrOP (593 mg, 1.27 mmol) and triethylamine (643 mg, 6.36 mmol) were added to a solution of 4-(((tert-butyldimethylsilyl)oxy)methyl)-7-fluoro-2-((4-methoxybenzyl)amino)quinoline-6-carboxylic acid (300 mg, 0.64 mmol) and 3-(4-(trifluoromethyl)phenyl)morpholine (191 mg, 0.83 mmol) in N,N-dimethylacetamide (4 mL). The reaction mixture was stirred at 25 ° C for 16 hours. The reaction was quenched with water and extracted with ethyl acetate (20 mL * 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The crude product was purified on a silica gel preparative plate (petroleum ether / ethyl acetate = 5:1) to afford (4-(((tert-butyldimethylsilyl)oxy)methyl)-7-fluoro-2-((4-methoxybenzyl)amino)quinolin-6-yl)(3-(4-(trifluoromethyl)phenyl)morpholinyl)methanone (230 mg, 52.87% yield) as a yellow solid. ESI-MS: m / z = 683.3 / 684.2 [M+1]+.

[0270] Step 2: Under nitrogen protection, a solution of (4-(((tert-butyldimethylsilyl)oxy)methyl)-7-fluoro-2-((4-methoxybenzyl)amino)quinolin-6-yl)(3-(4-(trifluoromethyl)phenyl)morpholinyl)methanone (230 mg, 0.34 mmol) in trifluoroacetic acid (5 mL) was stirred at 70°C for 16 hours. The reaction solution was concentrated under reduced pressure. The crude product was purified by high pressure preparative purification to give (2-amino-7-fluoro-4-(hydroxymethyl)quinolin-6-yl)(3-(4-(trifluoromethyl)phenyl)morpholinyl)methanone (i.e., Compound 24) (58.8 mg, yield: 38.94%) as a white solid. ESI-MS: m / z = 449.1 / 450.1 [M+1]+.

[0271] Step 3: The racemate (58.8 mg) was separated by SFC chiral column chromatography. Separation conditions: Column: Chiral ChIRALPAK-IH, 30 x 250 mm, 10 μm, Mobile Phase A: CO2, Mobile Phase B: 30% ethanol + 0.1% DEA, Flow rate: 25 mL / min; Peak 1 retention time: 1.778 min, Peak 2 retention time: 2.130 min.

[0272] Peak 1 (i.e. 24-1): 1 H NMR (400MHz, DMSO-d6) δ7.77(d,J=21.3Hz,4H),7.53(s,1H),7.23(s,1H),6.94(d,J=17.3Hz,2H),5.76(s,1H),5 .52(s,1H),4.85(s,2H),4.62-4.30(m,2H),3.89(d,J=10.3Hz,1H),3.72(s,1H),3.53(s,1H),3.25-3.12(m,1H).

[0273] Peak 2 (i.e. 24-2): 1 H NMR (400MHz, DMSO-d6) δ7.77(d,J=21.7Hz,4H),7.53(s,1H),7.23(d,J=11.1Hz,1H),6.91(s,2H),5.76(s,1H),5 .52(s,1H),4.85(s,2H),4.64-4.29(m,2H),3.88(d,J=9.9Hz,1H),3.72(s,1H),3.53(s,1H),3.28-3.15(m,1H).

[0274] Example 25: (2-amino-4-(aminomethyl)quinolin-6-yl)(2-(4-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

[0275] Step 1: Under nitrogen protection, TBAF (3 mL) was added to a solution of (4-(((tert-butyldimethylsilyl)oxy)methyl)-2-((4-methoxybenzyl)amino)quinolin-6-yl)(2-(4-(trifluoromethyl)phenyl)piperidin-1-yl)methanone (250.0 mg, 0.38 mmol) in tetrahydrofuran (8 mL). The reaction mixture was stirred at 25 ° C for 2 hours. The reaction was quenched with water and extracted with ethyl acetate (30 mL * 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The crude product was purified on a silica gel preparative plate (dichloromethane / methanol = 10:1) to afford (4-(hydroxymethyl)-2-((4-methoxybenzyl)amino)quinolin-6-yl)(2-(4-(trifluoromethyl)phenyl)piperidin-1-yl)methanone (170 mg, 82.13% yield) as a yellow solid. ESI-MS: m / z = 549.2 / 550.3 [M+1]+.

[0276] Step 2: Under nitrogen protection, DIEA (294.0 mg, 2.27 mmol) and MsCl (62.2 mg, 0.55 mmol) were added to a solution of (4-(hydroxymethyl)-2-((4-methoxybenzyl)amino)quinolin-6-yl)(2-(4-(trifluoromethyl)phenyl)piperidin-1-yl)methanone (250.0 mg, 0.45 mmol) in dichloromethane (8 mL) at 0°C. The reaction solution was stirred at 0°C for 2 hours. The reaction was quenched with water and extracted with dichloromethane (30 mL*3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. (2-((4-methoxybenzyl)amino)-6-(2-(4-(trifluoromethyl)phenyl)piperidin-1-carbonyl)quinolin-4-yl)methyl methanesulfonate (300 mg, crude product) was obtained as a yellow solid. ESI-MS: m / z=627.2 / 628.2[M+1]+.

[0277] Step 3: To a solution of ((2-((4-methoxybenzyl)amino)-6-(2-(4-(trifluoromethyl)phenyl)piperidin-1-carbonyl)quinolin-4-yl)methyl methanesulfonate (300.0 mg, 0.48 mmol) in N,N-dimethylformamide (10 mL) at 0°C were added potassium carbonate (330.3 mg, 2.39 mmol) and potassium phthalimide (351.1 mg, 1.91 mmol) under nitrogen protection. The reaction mixture was stirred at room temperature for 3 minutes. The reaction mixture was quenched with water and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. 2-((2-((4-methoxybenzyl)amino)-6-(2-(4-(trifluoromethyl)phenyl)piperidin-1-carbonyl)quinolin-4-yl)methyl)isoindole-1,3-dione (270 mg, yield: 88.09%) was obtained as a yellow solid. ESI-MS: m / z = 678.2 / 679.2 [M+1]+.

[0278] Step 4: Under nitrogen, a mixture of 2-((2-((4-methoxybenzyl)amino)-6-(2-(4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)quinolin-4-yl)methyl)isoindole-1,3-dione (270.0 mg, 0.40 mmol) in trifluoroacetic acid (6 mL) was stirred at 70°C for 16 hours. The reaction mixture was concentrated under reduced pressure, the pH was adjusted to 8 with saturated aqueous sodium carbonate, and then extracted with dichloromethane (30 mL x 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. 2-((2-amino-6-(2-(4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)quinolin-4-yl)methyl)isoindole-1,3-dione (220 mg, crude) was obtained as a yellow oil. ESI-MS:m / z=558.2 / 559.2[M+1]+

[0279] Step 5: Under nitrogen, a solution of 2-((2-amino-6-(2-(4-(trifluoromethyl)phenyl)piperidin-1-carbonyl)quinolin-4-yl)methyl)isoindole-1,3-dione (220.0 mg, 0.39 mmol) and hydrazine hydrate (5 mL) in ethanol (50 mL) was stirred at 50°C for 1 hour. The reaction mixture was poured into water and extracted with dichloromethane (30 mL x 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified on a silica gel prep plate (dichloromethane / methanol = 10:1) to afford (2-amino-4-(aminomethyl)quinolin-6-yl)(2-(4-(trifluoromethyl)phenyl)piperidin-1-yl)methanone (i.e., Compound 25) (120 mg, 70.44% yield) as a yellow solid. ESI-MS: m / z=428.2 / 429.1[M+1]+.

[0280] Step 6: The racemate (120 mg) was separated by chiral HPLC. Separation conditions: Column: Chiral ChIRALPAK-OJ, 30 x 250 mm, 10 μm; Mobile phase A: n-hexane; Mobile phase B: 20% ethanol + 0.1% DEA; Flow rate: 25 mL / min; Peak 1 retention time: 19.253 min; Peak 2 retention time: 24.201 min.

[0281] Peak 1 (25-1): 1 H NMR(400MHz,DMSO-d6)δ7.87(s,1H),7.81-7.72(m,2H),7.64-7.41(m,4H),6.86(s,1H),6.74-6.60(m,2H), 5.88-5.16(m,3H),4.17(s,2H),3.00-2.73(m,1H),2.01-1.92(m,1H),1.73-1.50(m,3H),1.41-1.21(m,2H).

[0282] Peak 2 (i.e. 25-2): 1 H NMR(400MHz,DMSO-d6)δ7.88(s,1H),7.81-7.73(m,2H),7.64-7.43(m,4H),6.85(s,1H),6.76-6.61(m,2H), 6.37-5.48(m,3H),4.20(s,2H),3.02-2.68(m,1H),2.02-1.91(m,1H),1.70-1.49(m,3H),1.41-1.20(m,2H).

[0283] Example 26: (2-amino-3-(hydroxymethyl)quinolin-6-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone

[0284] Step 1: 3-(Hydroxymethyl)-2-(4-methoxybenzyl)amino)quinoline-6-carboxylic acid (200 mg, 0.59 mmol) was dissolved in dimethylformamide (DMF) (2 mL), and PyBrOP (550 mg, 1.18 mmol) and TEA (300 mg, 2.95 mmol) and 3-(4-(trifluoromethyl)phenyl)morpholine (136 mg, 0.59 mmol) were added. The mixture was stirred at room temperature for 1 hour. After completion of the reaction, the mixture was diluted with water and extracted three times with ethyl acetate. The organic phase was washed three times with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was separated and purified by silica gel column chromatography (eluent: dichloromethane:methanol=15:1) to obtain (3-(hydroxymethyl)-2-(4-methoxybenzyl)amino)quinolin-6-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone (260 mg, yield 74%) as a white solid. ESI-MS: m / z = 552.5 [M+1] + .

[0285] Step 2: Dissolve 3-(hydroxymethyl)-2-(4-methoxybenzyl)amino)quinolin-6-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone (260 mg, 0.47 mmol) in trifluoroacetic acid (10 mL) and stir at 80°C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by Prep-HPLC (eluent: acetonitrile: water (NH4HCO3) = 35% to 60%) to obtain the target compound (2-amino-3-(hydroxymethyl)quinolin-6-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone (i.e., Compound 26) (140 mg, 69% yield) as a white solid. ESI-MS: [M+H] + =432.4.

[0286] Step 3: The racemate (140 mg) was separated by SFC chiral column chromatography. Separation conditions: Column: Chiral ChIRALPAK-IC, 30 x 250 mm, 10 μm, Mobile Phase A: 85% ACN + 0.2% DEA, Mobile Phase B: 15% IPA + 0.2% DEA, Flow rate: 25 mL / min; Peak 1 retention time: 4.442 min, Peak 2 retention time: 5.452 min.

[0287] Peak 1 (i.e. 26-1): 1H NMR(400MHz,DMSO-d6)δ7.98(s,1H),7.86(d,J=1.8Hz,1H),7.80(d,J=8.1Hz,2 H),7.70(d,J=8.1Hz,2H),7.59-7.49(m,2H),6.45(s,2H),5.57(brs,1H),5.44 (t,J=5.4Hz,1H),4.55-4.47(m,3H),4.01-3.90(m,1H),3.88-3.75(m,1H),3.70-3.55(m,1H),3.23(brs,1H).

[0288] Peak 2 (i.e. 26-2): 1 H NMR (400MHz, DMSO-d6) δ7.99(s,1H),7.87(d,J=1.8Hz,1H),7.81(d,J=8.1Hz,2H),7.70(d,J=8.1Hz,2H),7.60-7.48(m,2H),6.46(s,2 H),5.59(brs,1H),5.44(t,J=5.4Hz,1H),4.57-4.45(m,3H),4.01-3.90(m,1H),3.88-3.75(m,1H),3.70-3.55(m,1H),3.23(brs,1H).

[0289] Example 27: ((2-amino-3-(hydroxymethyl)quinolin-6-yl)(2-(4-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

[0290] Step 1: Under nitrogen protection, potassium carbonate (2.48 g, 18.0 mmol) and Pd(dppf)Cl2 (439.2 mg, 0.6 mmol) were added to a solution of tert-butyl 6-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydropyridine-1(2H)-carboxylate (2.0 g, 6.0 mmol) and 4,4,5,5-tetramethyl-2-(4-(trifluoromethyl)phenyl)-1,3,2-dioxaborolane (1.63 g, 6.0 mmol) in dioxane / water = 4:1 (30 mL). The reaction mixture was stirred at 70°C under nitrogen protection for 16 hours. The reaction solution was poured into water and extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30:1) to afford tert-butyl 2-(4-(trifluoromethyl)phenyl)-3,4-dihydropyridine-1(2H)-carboxylate as a white solid (700 mg, yield: 35.8%). ESI-MS: m / z = 328.3 [M+H]+ .

[0291] Step 2: Under nitrogen, add hydrogen chloride in ethyl acetate (20 mL, 1 mol / L) to tert-butyl 2-(4-(trifluoromethyl)phenyl)-3,4-dihydropyridine-1(2H)-carboxylate (700 mg, 2.14 mmol). The reaction mixture is stirred at 25°C for 5 hours. The reaction mixture is concentrated and quenched with saturated sodium bicarbonate aqueous solution, adjusting the pH of the reaction mixture to 8. Extract with dichloromethane (20 mL*3). The combined organic layers are washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. 2-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyridine (450 mg, yield: 92.6%) is obtained as a brown solid. ESI-MS: m / z = 228.1 [M+1] + .

[0292] Step 3: Under nitrogen protection, sodium borohydride (114 mg, 3.0 mmol) was added to a solution of 2-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyridine (450 mg, 2.0 mmol) in methanol (10 mL) at 0°C. The reaction solution was stirred at 25°C for 2 hours. The reaction was quenched by adding a saturated aqueous solution of ammonium chloride and extracted with dichloromethane (20 mL*3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. 2-(4-(trifluoromethyl)phenyl)piperidine (400 mg, yield: 87.3%) was obtained as a brown solid. ESI-MS: m / z = 230.2 [M+1] + .

[0293] Step 4: Under nitrogen protection, PyBrOP (810.8 mg, 1.74 mmol) and triethylamine (440 mg, 4.35 mmol) were added to a solution of 3-(hydroxymethyl)-2-((4-methoxybenzyl)amino)quinoline-6-carboxylic acid (294 mg, 0.87 mmol) and 2-(4-(trifluoromethyl)phenyl)piperidine (200 mg, 0.87 mmol) in DMF (5 mL). The reaction mixture was stirred at 25 ° C for 16 hours. The reaction was quenched with water and extracted with ethyl acetate (20 mL * 3). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified on a silica gel preparative plate (dichloromethane / methanol = 10:1) to afford (3-(hydroxymethyl)-2-((4-methoxybenzyl)amino)quinolin-6-yl)(2-(4-(trifluoromethyl)phenyl)piperidin-1-yl)methanone (260 mg, 54.4% yield) as a white solid. ESI-MS: m / z = 230.2 [M+1] + .

[0294] Step 5: (3-(hydroxymethyl)-2-((4-methoxybenzyl)amino)quinolin-6-yl)(2-(4-(trifluoromethyl)phenyl)piperidin-1-yl)methanone (260 mg, 0.45 mmol) was dissolved in trifluoroacetic acid (10 mL), and the reaction was stirred at 80°C for 16 hours. The reaction solution was concentrated under reduced pressure, and the crude product was separated by flash reverse column chromatography to give a white solid (2-amino-3-(hydroxymethyl)quinolin-6-yl)(2-(4-(trifluoromethyl)phenyl)piperidin-1-yl)methanone (i.e., Compound 27) (85 mg, 54.4% yield) ESI-MS: m / z = 430.4 [M+1] + .

[0295] Step 6: The racemate (85 mg) was separated by SFC chiral column chromatography. Separation conditions: Column: Chiral ChIRALPAK-IC, 30 x 250 mm, 10 μm, Mobile Phase A: 70% ACN + 0.2% DEA, Mobile Phase B: 30% IPA + 0.2% DEA, Flow rate: 25 mL / min; Peak 1 retention time: 4.049 min, Peak 2 retention time: 4.912 min.

[0296] Peak 1 (i.e. 27-1): 1 H NMR (400MHz, DMSO-d6) δ7.96 (s, 1H), 7.83 (s, 1H), 7.78 (d, J = 8.0Hz, 2H), 7.5 8(d,J=8.0Hz,2H),7.55-7.45(m,2H),6.40(s,2H),5.72(brs,1H),5.42(t,J= 5.4Hz,1H),4.48(d,J=5.5Hz,2H),3.90(brs,1H),2.86(brs,1H),2.45(s,1H) ,2.08-1.85(m,1H),1.70-1.60(m,1H),1.59-1.51(m,2H),1.45-1.25(m,1H).

[0297] Peak 2 (i.e. 27-2): 1H NMR (400MHz, DMSO-d6) δ7.96 (s, 1H), 7.83 (s, 1H), 7.78 (d, J = 8.0Hz, 2H), 7.5 8(d,J=8.0Hz,2H),7.55-7.45(m,2H),6.40(s,2H),5.68(brs,1H),5.42(t,J= 5.4Hz,1H),4.49(d,J=5.5Hz,2H),3.90(brs,1H),2.86(brs,1H),2.45(s,1H) ,2.08-1.85(m,1H),1.70-1.60(m,1H),1.59-1.51(m,2H),1.45-1.25(m,1H).

[0298] Example 28: (2-amino-3-(aminomethyl)quinolin-6-yl)(2-(4-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

[0299] Step 1: Under nitrogen, MsCl (64 mg, 0.56 mmol) was slowly added dropwise to a solution of (2-amino-3-(hydroxymethyl)quinolin-6-yl)(2-(4-(trifluoromethyl)phenyl)piperidin-1-yl)methanone (120 mg, 0.28 mmol) and triethylamine (85 mg, 0.84 mmol) in dichloromethane (5 mL) at 0°C. The reaction was allowed to react for 2 hours at room temperature. The reaction was quenched with water and extracted with DCM (20 mL x 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified on a silica gel column (dichloromethane / methanol = 20:1) to afford (2-amino-3-(chloromethyl)quinolin-6-yl)(2-(4-(trifluoromethyl)phenyl)piperidin-1-yl)methanone (100 mg, 80% yield) as a white solid. ESI-MS: m / z = 448.9 [M+1] + .

[0300] Step 2: A methanolic ammonia solution (1.9 mL, 0.28 mmol, 7 mol / L) was added to a methanolic solution of (2-amino-3-(chloromethyl)quinolin-6-yl)(2-(4-(trifluoromethyl)phenyl)piperidin-1-yl)methanone (100 mg, 0.23 mmol) at 0°C and stirred at room temperature for 1 hour. The reaction solution was directly concentrated to obtain a crude product, which was separated by flash reverse phase column chromatography to obtain (2-amino-3-(aminomethyl)quinolin-6-yl)(2-(4-(trifluoromethyl)phenyl)piperidin-1-yl)methanone (i.e., Compound 28) (30 mg, yield: 30%) as a white solid. ESI-MS: m / z = 428.4 [M+1] + .

[0301] Step 3: The racemate (30 mg) was separated by SFC chiral column chromatography. Separation conditions: Column: Chiral ChIRALPAK-IC, 30 x 250 mm, 10 μm, Mobile Phase A: 60% ACN + 0.2% DEA, Mobile Phase B: 40% IPA + 0.2% DEA, Flow rate: 25 mL / min; Peak 1 retention time: 4.788 min, Peak 2 retention time: 7.136 min.

[0302] Peak 1 (i.e. 28-1): 1 H NMR (400MHz, DMSO-d6) δ7.90 (s, 1H), 7.84-7.75 (m, 4H), 7.58 (d, J = 8.0Hz, 3H), 7.55-7.45 (m, 2H), 6.65 (s, 2H) ,3.73(s,2H),2.89-2.75(m,1H),2.03-1.94(m,2H),1.72-1.62(m,2H),1.60-1.50(m,2H),1.45-1.28(m,2H).

[0303] Peak 2 (i.e. 28-2): 1 H NMR (400MHz, DMSO-d6) δ7.90 (s, 1H), 7.84-7.75 (m, 4H), 7.58 (d, J = 8.0Hz, 3H), 7.55-7.45 (m, 2H), 6.65 (s, 2H) ,3.73(s,2H),2.89-2.75(m,1H),2.03-1.94(m,2H),1.72-1.62(m,2H),1.60-1.50(m,2H),1.45-1.28(m,2H).

[0304] Example 29: (2-(1H-indol-4-yl)piperidin-1-yl)(2-amino-4-(hydroxymethyl)quinolin-6-yl)methanone

[0305] Step 1: Under nitrogen, add KHMDS (124.8 mL, 0.12 mol) to a solution of tert-butyl (2-oxopiperidin-1-yl)carboxylate (20 g, 0.10 mol) in tetrahydrofuran (200 mL) at -78°C. The reaction mixture is stirred at room temperature for 1.5 hours. Then, PhNTf2 (44.56 g, 0.12 mol) is added at -78°C. The reaction mixture is stirred at -78°C for 3.5 hours. The reaction is quenched with 10% NaOH at 0°C and extracted with ethyl acetate (300 mL x 3). The combined organic layers are washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to give tert-butyl 6-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydropyridine-1(2H)-carboxylate (25 g, yield: 75.38%) as a yellow oil. 1 H NMR (400MHz, DMSO_d6) δ5.56-5.46(m,1H),3.51-3.44(m,2H),2.25-2.19(m,2H),1.69-1.61(m,2H),1.42(s,9H).

[0306] Step 2: Under nitrogen protection, potassium carbonate (2.26 g, 16.4 mmol) and Pd(dppf)Cl2 (0.24 g, 0.3 mmol) were added to a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (2.0 g, 8.2 mmol) and tert-butyl 6-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydropyridine-1(2H)-carboxylate (3.27 g, 9.8 mmol) in dioxane / water = 4:1 (50 mL). The reaction mixture was stirred at 60°C under nitrogen protection for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to afford tert-butyl 6-(1H-indol-4-yl)-3,4-dihydropyridine-1(2H)-carboxylate as a brown solid (1.0 g, 40.92% yield). ESI-MS: m / z = 298.2 / 299.1 [M+1]+, 243.1 [M-56]+.

[0307] Step 3: Under nitrogen, trifluoroacetic acid (3 mL) was added to a solution of tert-butyl 6-(1H-indol-4-yl)-3,4-dihydropyridine-1(2H)-carboxylate (1.1 g, 3.7 mmol) in dichloromethane (9 mL). The reaction mixture was stirred at 0°C for 2 hours. The reaction was then quenched with saturated aqueous sodium bicarbonate and the pH adjusted to 8. The mixture was extracted with dichloromethane (50 mL x 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. 4-(3,4,5,6-tetrahydropyridin-2-yl)-1H-indole (600 mg, yield: 65.49%) was obtained as a brown solid. ESI-MS: m / z = 198.1 / 199.2 [M+1]+.

[0308] Step 4: Under nitrogen, sodium borohydride (230 mg, 0.0061 mol) was added to a solution of 4-(3,4,5,6-tetrahydropyridin-2-yl)-1H-indole (600 mg, 0.0030 mol) in methanol (4 mL). The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain 4-(piperidin-2-yl)-1H-indole as a brown solid (500 mg, yield: 83.33%). ESI-MS: m / z = 200.1 / 201.3 [M+1]+. 1 H NMR(400MHz,DMSO_d6)δ10.93(s,1H),7.42-7.23(m,2H),7.19-6.99(m,2H),6.25(s,1 H),4.13(s,1H),3.22-3.11(m,1H),2.90-2.79(m,1H),1.83(s,2H),1.69-1.51(m,4H).

[0309] Step 5: Under nitrogen protection, a solution of 4-(((tert-butyldimethylsilyl)oxy)methyl)-2-((4-methoxybenzyl)amino)quinoline-6-carboxylic acid (200.00 mg, 0.44 mmol) in trifluoroacetic acid (6 mL) was stirred at 70 ° C for 16 hours. The reaction solution was concentrated, then adjusted to pH = 8 with saturated aqueous sodium carbonate solution, and extracted with dichloromethane (20 mL * 3). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. 2-amino-4-(hydroxymethyl)quinoline-6-carboxylic acid (150 mg, crude product) was obtained as a brown solid. ESI-MS: m / z = 218.1 / 219.1 [M+1] +.

[0310] Step 6: Under nitrogen, to a solution of 2-amino-4-(hydroxymethyl)quinoline-6-carboxylic acid (90.00 mg, 0.41 mmol) and 4-(piperidin-2-yl)-1H-indole (82.62 mg, 0.41 mmol) in N,N-dimethylacetamide (4 mL) was added PyBrOP (429.00 mg, 0.82 mmol) and triethylamine (416.32 mg, 4.12 mmol). The reaction mixture was stirred at 25°C for 16 hours. The reaction was quenched with water and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified on a silica gel preparative plate (dichloromethane / methanol = 10:1) to afford (2-(1H-indol-4-yl)piperidin-1-yl)(2-amino-4-(hydroxymethyl)quinolin-6-yl)methanone (Compound 29) (50 mg, 30.29% yield) as a white solid. ESI-MS: m / z = 400.2 / 401.1 [M+1]+.

[0311] Step 7: The racemate (50 mg) was separated by SFC chiral column chromatography. Separation conditions: Column: Chiral ChIRALPAK-IH, 30 x 250 mm, 10 μm, Mobile Phase A: CO2, Mobile Phase B: 25% ethanol + 0.1% DEA, Flow rate: 25 mL / min; Peak 1 retention time: 2.707 min, Peak 2 retention time: 3.374 min.

[0312] Peak 1 (i.e. 29-1): 1 H NMR(400MHz,DMSO-d6)δ11.19(s,1H),7.67-7.57(m,1H),7.47-7.37(m,2H),7.37-7.30(m,2H),7.17-7.10(m,1H),7.08-7.04(m,1H), 6.86(s,1H),6.61-6.53(m,2H),6.45-6.37(m,1H),5.37(s,2H),4.64(s,2H),3.13-3.03(m,1H),2.05-1.92(m,1H),1.68-1.45(m,5H).

[0313] Peak 2 (i.e. 29-2): 1H NMR (400MHz, DMSO-d6) δ11.19(s,1H),8.13(s,1H),7.74-7.60(m,1H),7.57-7.47(m,2H),7.38-7.30(m,2H),7.17-7.10(m,1H),7.09- 7.04(m,1H),6.96(s,1H),6.49-6.32(m,1H),5.64-5.33(m,2H),4.69(s,2H),3.15-3.04(m,1H),2.06-1.94(m,1H),1.74-1.36(m,5H).

[0314] Example 30: (2-amino-4-(hydroxymethyl)quinolin-6-yl)(2-(1-methyl-1H-indol-4-yl)piperidin-1-yl)methanone

[0315] Step 1: Under nitrogen protection, sodium hydride (80.2 mg, 3.34 mmol) was added to a solution of tert-butyl 6-(1H-indol-4-yl)-3,4-dihydropyridine-1(2H)-carboxylate (500 mg, 1.67 mmol) in tetrahydrofuran (5 mL) at 0°C. The reaction solution was stirred at 0°C for 1 hour, followed by the addition of iodomethane (320.2 mg, 2.25 mmol). The reaction mixture was stirred at 0°C for 2 hours. The reaction was quenched with water and extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified on a silica gel preparative plate (dichloromethane / methanol = 10:1) to afford tert-butyl 6-(1-methyl-1H-indol-4-yl)-3,4-dihydropyridine-1(2H)-carboxylate as a brown solid (200 mg, 34.38% yield). ESI-MS: m / z = 312.4 / 257.1 [M-55]+.

[0316] Step 2: Under nitrogen, trifluoroacetic acid (1 mL) was added to a solution of tert-butyl 6-(1-methyl-1H-indol-4-yl)-3,4-dihydropyridine-1(2H)-carboxylate (180 mg, 0.57 mol) in dichloromethane (3 mL). The reaction was stirred at 25°C for 1 hour. The reaction was then quenched with saturated aqueous sodium bicarbonate and the pH adjusted to 8. The mixture was extracted with dichloromethane (20 mL x 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. This afforded 1-methyl-4-(3,4,5,6-tetrahydropyridin-2-yl)-1H-indole as a brown solid (144 mg, yield: 82.67%). ESI-MS: m / z = 212.3 / 213.1 [M+1]+.

[0317] Step 3: Under nitrogen, sodium borohydride (51.3 mg, 1.36 mmol) was added to a solution of 1-methyl-4-(3,4,5,6-tetrahydropyridin-2-yl)-1H-indole (144 mg, 0.68 mmol) in methanol (3 mL). The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain 1-methyl-4-(piperidin-2-yl)-1H-indole as a brown solid (80 mg, yield: 44.02%). ESI-MS: m / z = 214.1 / 215.3 [M+1]+.

[0318] Step 4: Under nitrogen, to a solution of 2-amino-4-(hydroxymethyl)quinoline-6-carboxylic acid (100 mg, 0.46 mmol) and 1-methyl-4-(piperidin-2-yl)-1H-indole (117.9 mg, 0.55 mmol) in N,N-dimethylacetamide (5 mL) was added PyBrOP (427.3 mg, 0.92 mmol) and triethylamine (462.9 mg, 4.58 mmol). The reaction mixture was stirred at 25°C for 16 hours. The reaction was quenched with water and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified on a silica gel preparative plate (dichloromethane / methanol = 10:1) to afford (2-amino-4-(hydroxymethyl)quinolin-6-yl)(2-(1-methyl-1H-indol-4-yl)piperidin-1-yl)methanone (Compound 30) (30 mg, 15.64% yield) as a white solid. ESI-MS: m / z = 414.2 / 415.2 [M+1]+.

[0319] Step 5: The racemate (30 mg) was separated by SFC chiral column chromatography. Separation conditions: Column: Chiral ChIRALPAK-IH, 30 x 250 mm, 10 μm, Mobile Phase A: CO2, Mobile Phase B: 30% ethanol + 0.1% DEA, Flow rate: 25 mL / min; Peak 1 retention time: 1.566 min, Peak 2 retention time: 2.220 min.

[0320] Peak 1 (30-1): 1H NMR(400MHz,DMSO-d6)δ13.70(s,1H),7.77-7.55(m,3H),7.42-7.37(m,1H),7.33-7.29(m,1H),7.24-7.18(m,1H),7.14-6.99(m,2H),6.4 7-6.33(m,1H),5.85(s,1H),4.92-4.58(m,2H),3.80(s,3H),3.18-3.05(m,1H),2.44-2.36(m,2H),2.07-1.92(m,2H),1.71-1.49(m,4H).

[0321] Peak 2 (30-2): 1 H NMR(400MHz,DMSO-d6)δ7.62(s,1H),7.53-7.43(m,2H),7.42-7.36(m,1H),7.34-7.28(m,1H),7.25-7.17(m,1H),7.15-7.09(m,1H),6.90(s,1 H),6.39(s,1H)5.64-5.35(m,1H),4.81-4.44(m,2H),3.80(s,3H),3.16 -3.01(m,1H),2.45-2.38(m,2H),2.07-1.93(m,2H),1.71-1.47(m,4H).

[0322] Example 31: 1-(4-(1-(2-amino-7-fluoro-4-(hydroxymethyl)quinoline-6-carbonyl)piperidin-2-yl)-1H-indol-1-yl)ethanone

[0323] Step 1: Under nitrogen, sodium hydride (240.5 mg, 10.02 mmol) was added to a solution of tert-butyl 6-(1H-indol-4-yl)-3,4-dihydropyridine-1(2H)-carboxylate (2.0 g, 6.68 mmol) in tetrahydrofuran (20 mL) at 0°C. The reaction mixture was stirred at 0°C for 1 hour, followed by the addition of acetyl chloride (786.6 mg, 10.02 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction was quenched with ice water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by high pressure preparative purification to afford tert-butyl 6-(1-acetyl-1H-indol-4-yl)-3,4-dihydropyridine-1(2H)-carboxylate (800 mg, 31.57% yield) as a white solid. ESI-MS: m / z=340.4 / ,285.1[M-55]+.

[0324] Step 2: Under nitrogen, trifluoroacetic acid (2 mL) was added to a solution of tert-butyl 6-(1-acetyl-1H-indol-4-yl)-3,4-dihydropyridine-1(2H)-carboxylate (800 mg, 2.34 mol) in dichloromethane (6 mL). The reaction was stirred at 25°C for 1 hour. The reaction was then quenched with saturated aqueous sodium bicarbonate and the pH adjusted to 8. The mixture was extracted with dichloromethane (50 mL x 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. 1-(4-(3,4,5,6-tetrahydropyridin-2-yl)-1H-indol-1-yl)ethanone (640 mg, yield: 68.20%) was obtained as a brown solid. ESI-MS: m / z = 240.3 / 241.1 [M+1]+.

[0325] Step 3: Under nitrogen, sodium triacetoxyborohydride (1128 mg, 5.32 mmol) was added to a solution of 1-(4-(3,4,5,6-tetrahydropyridin-2-yl)-1H-indol-1-yl)ethanone (640 mg, 2.66 mmol) in dichloromethane (6 mL). The reaction mixture was stirred at 0°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain 1-(4-(piperidin-2-yl)-1H-indol-1-yl)ethanone (400 mg, yield: 61.98%) as a brown solid. ESI-MS: m / z = 242.3 / 243.1 [M+1]+.

[0326] Step 4: Under nitrogen protection, TCFH (320 mg, 1.14 mmol) and NMI (469 mg, 5.71 mmol) were added to a solution of 2-amino-4-(((tert-butyldimethylsilyl)oxy)methyl)-7-fluoroquinoline-6-carboxylic acid (200 mg, 0.57 mmol) and 1-(4-(piperidin-2-yl)-1H-indol-1-yl)ethanone (166 mg, 0.68 mmol) in acetonitrile (5 mL). The reaction mixture was stirred at 25 ° C for 16 hours. The reaction was quenched with water and extracted with ethyl acetate (20 mL * 3). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The crude product was purified on a silica gel preparative plate (petroleum ether / ethyl acetate = 1:2) to afford 1-(4-(1-(2-amino-4-(((tert-butyldimethylsilyl)oxy)methyl)-7-fluoroquinoline-6-carbonyl)piperidin-2-yl)-1H-indol-1-yl)ethanone as a white solid (150 mg, 41.16% yield). ESI-MS: m / z = 574.3 / 575.3 [M+1]+.

[0327] Step 5: Under nitrogen, 1-(4-(1-(2-amino-4-(((tert-butyldimethylsilyl)oxy)methyl)-7-fluoroquinoline-6-carbonyl)piperidin-2-yl)-1H-indol-1-yl)ethanone (125 mg, 0.22 mmol) was added to a 4M solution of hydrochloric acid in dioxane (4 mL). The reaction mixture was stirred at 25°C for 3 hours. The reaction mixture was concentrated, and the resulting crude product was purified by high pressure preparative purification to give 1-(4-(1-(2-amino-7-fluoro-4-(hydroxymethyl)quinoline-6-carbonyl)piperidin-2-yl)-1H-indol-1-yl)ethanone (Compound 31) as a white solid (100 mg, 80.03% yield). ESI-MS: m / z = 460.2 / 461.1 [M+1]+.

[0328] Step 6: The racemate (100 mg) was separated by SFC chiral column chromatography. Separation conditions: Column: Chiral ChIRALPAK-AD, 30 x 250 mm, 10 μm, Mobile Phase A: CO2, Mobile Phase B: 40% ethanol + 0.1% DEA, Flow rate: 25 mL / min; Peak 1 retention time: 1.047 min, Peak 2 retention time: 1.383 min.

[0329] Peak 1 (i.e. 31-1): 1 H NMR(400MHz,DMSO-d6)δ13.92(s,1H),9.24(s,1H),8.35-8.28(m,1H),8.09(s,1H),7.95-7.86(m,1H),7.70-7.56(m,1H),7.40-7.30(m,2H),7.2 1(s,1H),6.98-6.84(m,1H),6.24-6.01(m,1H),5.91(s,1H),4.97(s,2H ),3.28-3.03(m,2H),2.67(s,3H),2.21-1.93(m,2H),1.76-1.46(m,4H).

[0330] Peak 2 (i.e. 31-2): 1H NMR(400MHz,DMSO-d6)δ13.99(s,1H),9.23(s,1H),8.34-8.27(m,1H),8.09( s,1H),7.95-7.87(m,1H),7.71-7.57(m,1H),7.39-7.32(m,2H),7.21(s,1H), 6.95-6.84(m,1H),6.22-6.12(m,1H),5.91(s,1H),4.97(s,2H),3.28-3.03( m,2H),2.67(s,3H),2.19-1.95(m,2H),1.76-1.64(m,2H),1.61-1.48(m,2H).

[0331] Example 32: (2-amino-7-fluoro-4-(hydroxymethyl)quinolin-6-yl)(2-(1-(1-methylpiperidin-4-yl)-1H-indol-4-yl)piperidin-1-yl)methanone

[0332] Step 1: Under nitrogen, to a solution of 4-bromoindoline (4.40 g, 22.2 mmol) in acetic acid (50 mL) were added 1-methylpiperidin-4-one (2.76 g, 24.4 mmol) and sodium triacetoxyborohydride (7.06 g, 33.3 mmol). The reaction was stirred at room temperature for 6 hours. The reaction was quenched with 10% aqueous NaOH at 0°C and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. 4-Bromo-1-(1-methylpiperidin-4-yl)indoline (3.3 g, yield: 67.35%) was obtained as a yellow oil. ESI-MS: m / z = 294.1 / 295.0 [M-55]+.

[0333] Step 2: Under nitrogen, DDQ (2.89 g, 12.7 mmol) was added to a solution of 4-bromo-1-(1-methylpiperidin-4-yl)indoline (3 g, 10.2 mmol) in tetrahydrofuran (30 mL). The reaction was stirred at 25°C for 16 hours. The reaction was quenched with water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 50:1) to afford 4-bromo-1-(1-methylpiperidin-4-yl)indole (1.8 g, yield: 62.06%) as a red oil. ESI-MS: m / z = 292.1 / 293.0 [M+1]+.

[0334] Step 3: Under nitrogen, to a solution of 4-bromo-1-(1-methylpiperidin-4-yl)indole (1.60 g, 5.4 mmol) and tert-butyl 6-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydropyridine-1(2H)-carboxylate (2.55 g, 8.2 mmol) in dioxane (20 mL) were added Pd(AcO)2 (0.491 g, 2.2 mmol), bipyraclostrobin (2.09 g, 8.2 mmol), cesium carbonate (5.35 g, 16.4 mmol), and Cataxium A (0.784 g, 2.2 mmol). The reaction mixture was stirred at 100°C for 16 hours. The reaction was quenched with water and extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 50:1) to afford tert-butyl 6-(1-(1-methylpiperidin-4-yl)-1H-indol-4-yl)-3,4-dihydropyridine-1(2H)-carboxylate as a yellow solid (1.0 g, 47.62% yield). ESI-MS: m / z = 395.3 / 396.1 [M+1]+.

[0335] Step 4: Under nitrogen, trifluoroacetic acid (2 mL) was added to a solution of tert-butyl 6-(1-(1-methylpiperidin-4-yl)-1H-indol-4-yl)-3,4-dihydropyridine-1(2H)-carboxylate (700 mg, 1.77 mmol) in dichloromethane (7 mL). The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated to afford 1-(1-methylpiperidin-4-yl)-4-(3,4,5,6-tetrahydropyridin-2-yl)-1H-indole as a yellow solid (400 mg, yield: 86.9%). ESI-MS: m / z = 295.2 / 296.2 [M+1]+.

[0336] Step 5: Under nitrogen, sodium borohydride (359 mg, 9.45 mmol) was added to a solution of 1-(1-methylpiperidin-4-yl)-4-(3,4,5,6-tetrahydropyridin-2-yl)-1H-indole (400 mg, 1.35 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at 0°C for 1 hour. The reaction was quenched with water and extracted with dichloromethane (50 mL x 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. 1-(1-methylpiperidin-4-yl)-4-(piperidin-2-yl)-1H-indole (200 mg, 49.87% yield) was obtained as a yellow solid. ESI-MS: m / z = 297.2 / 298.1 [M+1]+.

[0337] Step 6: Under nitrogen protection, TCFH (545 mg, 1.71 mmol) and NMI (546 mg, 5.87 mmol) were added to a solution of 2-amino-4-(((tert-butyldimethylsilyl)oxy)methyl)-7-fluoroquinoline-6-carboxylic acid (300 mg, 0.587 mmol) and 1-(1-methylpiperidin-4-yl)-4-(piperidin-2-yl)-1H-indole (209 mg, 0.704 mmol) in acetonitrile (5 mL). The reaction mixture was stirred at 25 ° C for 16 hours. The reaction was quenched with water and extracted with ethyl acetate (20 mL * 3). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The crude product was purified on a silica gel preparative plate (dichloromethane / methanol = 10:1) to afford (2-amino-4-(((tert-butyldimethylsilyl)oxy)methyl)-7-fluoroquinolin-6-yl)(2-(1-(1-methylpiperidin-4-yl)-1H-indol-4-yl)piperidin-1-yl)methanone as a yellow solid (185 mg, 34.38% yield). ESI-MS: m / z = 629.4 / 630.1 [M+1]+.

[0338] Step 7: Under nitrogen protection, lithium hydroxide (14.1 mg, 0.587 mmol) was added to a solution of (2-amino-4-(((tert-butyldimethylsilyl)oxy)methyl)-7-fluoroquinolin-6-yl)(2-(1-(1-methylpiperidin-4-yl)-1H-indol-4-yl)piperidin-1-yl)methanone (185 mg, 0.293 mmol) in tetrahydrofuran / methanol / water = 1 / 1 / 1 (5 mL). The reaction mixture was stirred at 25 ° C for 16 hours. The reaction was quenched with water and extracted with ethyl acetate (20 mL * 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by high pressure preparative analysis to give (2-amino-7-fluoro-4-(hydroxymethyl)quinolin-6-yl)(2-(1-(1-methylpiperidin-4-yl)-1H-indol-4-yl)piperidin-1-yl)methanone (Compound 32) (50 mg, 49.02% yield) as a white solid. ESI-MS: m / z = 515.3 / 516.4 [M+1]+.

[0339] Step 8: The racemate (50 mg) was separated by SFC chiral column chromatography. Separation conditions: Column: Chiral ChIRALPAK-IC, 30 x 250 mm, 10 μm, Mobile Phase A: CO2, Mobile Phase B: 30% ethanol + 0.1% DEA, Flow rate: 25 mL / min; Peak 1 retention time: 0.766 min, Peak 2 retention time: 1.055 min.

[0340] Peak 1 (i.e. 32-1):1 H NMR(400MHz,DMSO-d6)δ7.56–7.43(m,2H),7.34-7.08(m,4H),6.87(s,1H),6.87 -6.62(m,3H),6.18(s,1H),5.49(s,1H),4.82(s,2H),4.34(s,2H),3.40(s,1H), 3.19(s,1H),2.89(s,2H),2.24(s,3H),2.14(d,J=9.6Hz,2H),2.09-1.85(m,6H),1.76-1.53(m,4H).

[0341] Peak 2 (i.e. 32-2): 1 H NMR (400MHz, DMSO-d6) δ7.55–7.41(m,2H),7.24–7.04(m,4H),6.87(s,1H),6.74-6.62(m,3H),6.18(s,1H),5.48(s,1H),4.82-4.68 (m,2H),4.34(s,2H),3.40(s,1H),3.18(s,1H),2.89(s,2H),2.24(s,3H),2.19–2.10(m,2H),1.91-1.75(m,6H),1.64-1.53(m,4H).

[0342] Example 33: 2-amino-4-(hydroxymethyl)-N-(1-(pyrimidin-2-yl)ethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carboxamide

[0343] Step 1: Under nitrogen protection, a solution of methyl 2-(bis(4-methoxybenzyl)amino)-6-((1-(pyrimidin-2-yl)ethyl)((5-(trifluoromethyl)pyridin-2-yl)methyl)carbamoyl)quinoline-4-carboxylate (400 mg, 0.53 mmol) in trifluoroacetic acid (20 mL) was stirred at 70 ° C for 16 hours. The reaction solution was concentrated under reduced pressure, adjusted to pH = 8 with saturated sodium carbonate aqueous solution, and extracted with dichloromethane (50 mL * 3). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel preparation plate (dichloromethane / methanol = 10:1) to give methyl 2-amino-6-((1-(pyrimidin-2-yl)ethyl)((5-(trifluoromethyl)pyridin-2-yl)methyl)carbamoyl)quinoline-4-carboxylate (175 mg, yield: 64.34%) as a yellow solid. 1H NMR(400MHz,DMSO_d6)δ8.85-8.75(m,3H),8.51-8.08(m,2H),7.82-7.64(m,1H),7.62-7.50(m,2H),7.42-7.38(m,1H),7.3 6-7.26(m,1H),6.95(s,2H),5.50-5.29(m,1H),4.99-4.87(m,1H),4.62-4.43(m,1H),3.96-3.79(m,3H),1.65-1.58(m,3H).

[0344] Step 2: Under nitrogen protection, to a solution of methyl 2-amino-6-((1-(pyrimidin-2-yl)ethyl)((5-(trifluoromethyl)pyridin-2-yl)methyl)carbamoyl)quinoline-4-carboxylate (200 mg, 0.39 mmol) in tetrahydrofuran / methanol = 5 / 1 (12 mL) at 0°C was added lithium borohydride (68.3 mg, 3.13 mmol). The reaction solution was stirred at 0°C for 3 hours, quenched with sodium sulfate decahydrate, and filtered. The filter cake was rinsed with methanol, and the filtrate was concentrated. The crude product was purified on a silica gel preparative plate (dichloromethane / methanol = 10:1) to obtain 2-amino-4-(hydroxymethyl)-N-(1-(pyrimidin-2-yl)ethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carboxamide (i.e., Compound 33) (130 mg, 68.77% yield) as a yellow solid. ESI-MS: m / z = 482.2 / 483.0 [M+1]+.

[0345] Step 3: The racemate (130 mg) was separated by SFC chiral column chromatography. Separation conditions: Column: Chiral ChIRALPAK-IC, 30 x 250 mm, 10 μm, Mobile Phase A: CO2, Mobile Phase B: 40% methanol + 0.1% NH4OH, Flow rate: 25 mL / min; Peak 1 retention time: 2.202 min, Peak 2 retention time: 2.976 min.

[0346] Peak 1 (i.e. 33-1): 1 H NMR(400MHz,DMSO-d6)δ8.87-8.76(m,3H),8.14-7.84(m,2H),7.65-7.37(m,4H ),6.91(s,1H),6.62(s,2H),5.43(s,2H),4.94-4.53(m,4H),1.62-1.55(m,3H).

[0347] Peak 2 (i.e. 33-2): 1H NMR(400MHz,DMSO-d6)δ8.86-8.76(m,3H),8.14-7.85(m,2H), 7.66-7.38(m,4H),6.91(s,1H),6.61(s,2H),5.43(s,2H),4.95-4.53(m,4H),1.63-1.55(m,3H).

[0348] Example 34: 2-amino-N 6 -(1-(pyrimidin-2-yl)ethyl)-N 6 -((5-(Trifluoromethyl)pyridin-2-yl)methyl)quinoline-4,6-dicarboxamide

[0349] Step 1: Under nitrogen protection, a solution of methyl 2-(bis(4-methoxybenzyl)amino)-6-((1-(pyrimidin-2-yl)ethyl)((5-(trifluoromethyl)pyridin-2-yl)methyl)carbamoyl)quinoline-4-carboxylate (400 mg, 0.53 mmol) in 7M ammonia methanol (10 mL) was stirred at 70°C for 16 hours. The reaction solution was concentrated under reduced pressure, and the resulting crude product was purified on a silica gel preparative plate (dichloromethane / methanol = 10:1) to obtain 2-(bis(4-methoxybenzyl)amino)-N-((1-(pyrimidin-2-yl)ethyl)((5-(trifluoromethyl)pyridin-2-yl)methyl)carbamoyl)quinoline-4-carboxylate as a yellow solid. 6 -(1-(pyrimidin-2-yl)ethyl)-N 6 -((5-(Trifluoromethyl)pyridin-2-yl)methyl)quinoline-4,6-dicarboxamide (200 mg, yield: 51.02%). ESI-MS: m / z=735.3 / 736.2 [M+1]+.

[0350] Step 2: Under nitrogen protection at 0 °C, 2-(bis(4-methoxybenzyl)amino)-N 6 -(1-(pyrimidin-2-yl)ethyl)-N 6 A solution of -((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-4,6-dicarboxamide (180 mg, 0.24 mmol) in trifluoroacetic acid (3 mL) was stirred at 70 ° C for 16 hours. The reaction solution was concentrated under reduced pressure, the pH of the reaction solution was adjusted to 8 with saturated aqueous sodium carbonate solution, and extracted with dichloromethane (10 mL * 3). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The crude product was purified on a silica gel preparation plate (dichloromethane / methanol = 10:1) to obtain 2-amino-N-[4-(5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-4,6-dicarboxamide. 6 -(1-(pyrimidin-2-yl)ethyl)-N 6-((5-(Trifluoromethyl)pyridin-2-yl)methyl)quinoline-4,6-dicarboxamide (ie, Compound 34) (80 mg, yield: 66.11%). ESI-MS: m / z=495.2 / 496.2 [M+1]+.

[0351] Step 3: The racemate (80 mg) was separated by SFC chiral column chromatography. Separation conditions: Column: Chiral ChIRALPAK-IC, 30 x 250 mm, 10 μm, Mobile Phase A: CO2, Mobile Phase B: 40% methanol + 0.1% DEA, Flow rate: 25 mL / min; Peak 1 retention time: 0.977 min, Peak 2 retention time: 1.408 min.

[0352] Peak 1 (i.e. 34-1): 1 H NMR(400MHz,DMSO-d6)δ8.83(s,1H),8.78-8.77(m,2H),8.12-8.08(m,3H),7.70-7.52(m,4H),7 .40-7.37(m,1H),6.82-6.78(m,3H),5.45(s,1H),4.93-4.89(m,1H),4.53(s,1H),1.60(s,3H).

[0353] Peak 2 (i.e. 34-2): 1 H NMR(400MHz,DMSO-d6)δ8.83(s,1H),8.78-8.77(m,2H),8.12-8.08(m,3H),7.70-7.52(m,4H),7 .40-7.37(m,1H),6.82-6.79(m,3H),5.45(s,1H),4.93-4.89(m,1H),4.52(s,1H),1.60(s,3H).

[0354] Example 35: 4-Acetyl-2-amino-N-(1-(pyrimidin-2-yl)ethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carboxamide

[0355] Step 1: Under nitrogen protection, tributyl(1-ethoxyvinyl)tin (1.26 g, 3.5 mmol) and Pd(dppf)Cl2 (0.2 g, 0.28 mmol) were added to a solution of 2-(bis(4-methoxybenzyl)amino)-4-chloro-N-(1-(pyrimidin-2-yl)ethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carboxamide (1.0 g, 1.4 mmol) in dioxane (40 mL). The reaction solution was stirred at 100°C for 16 hours. The reaction was quenched with water and extracted with ethyl acetate (100 mL*3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was dissolved in methanol (30 mL) and 3N aqueous hydrochloric acid was added. The reaction solution was reacted at room temperature for 16 hours. The reaction solution was poured into water and extracted with dichloromethane (100 mL*3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. Purification by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) afforded 4-acetyl-2-(bis(4-methoxybenzyl)amino)-N-(1-(pyrimidin-2-yl)ethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carboxamide (350 mg, 34.02% yield) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ8.74-8.63(m,3H),8.43(s,1H),7.92-7.73(m,3H),7.59-7.50(m,1H),7.24-7.17(m,4H),7.16-7.13(m,1H),7.00( s,1H),6.90-6.76(m,4H),5.53(s,1H),5.16-5.05(m,1H),4.86(s,4H),4.71-4.61(m,1H),3.78(s,6H),2.46(s,3H),1.70-1.61(m,3H).

[0356] Step 2: Under nitrogen protection, a solution of 4-acetyl-2-(bis(4-methoxybenzyl)amino)-N-(1-(pyrimidin-2-yl)ethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carboxamide (350 mg, 0.48 mmol) in trifluoroacetic acid (10 mL) was stirred at 70°C for 16 hours. The reaction solution was concentrated under reduced pressure, adjusted to pH 8 with saturated aqueous sodium carbonate solution, and extracted with dichloromethane (20 mL*3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified on a silica gel preparative plate (dichloromethane / methanol = 10:1) to afford 4-acetyl-2-amino-N-(1-(pyrimidin-2-yl)ethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carboxamide (Compound 35) (200 mg, 84.92% yield) as a yellow solid. ESI-MS: m / z = 494.2 / 495.1 [M+1]+.

[0357] Step 3: The racemate (50 mg) was separated by SFC chiral column chromatography. Separation conditions: Column: Chiral ChIRALPAK-IC, 30 x 250 mm, 10 μm, Mobile Phase A: CO2, Mobile Phase B: 40% ethanol + 0.1% DEA, Flow rate: 25 mL / min; Peak 1 retention time: 1.061 min, Peak 2 retention time: 1.374 min.

[0358] Peak 1 (i.e. 35-1): 1 H NMR(400MHz,DMSO-d6)δ8.85-8.74(m,3H),8.32-8.09(m,2H),7.73-7.49(m,3H),7.42-7.38(m,1H),7.22(s,1H ),6.88(s,2H),5.47-5.31(m,1H),4.97-4.87(m,1H),4.62-4.44(m,1H),2.68-2.52(m,3H),1.65-1.55(m,3H).

[0359] Peak 2 (i.e. 35-2): 1H NMR(400MHz,DMSO-d6)δ8.86-8.72(m,3H),8.32-8.06(m,2H),7.77-7.48(m,3H),7.43-7.36(m,1H),7.22(s,1H ),6.88(s,2H),5.47-5.29(m,1H),4.98-4.87(m,1H),4.62-4.39(m,1H),2.70-2.51(m,3H),1.65-1.55(m,3H).

[0360] Example 36: 2-amino-4-(1-hydroxyethyl)-N-(1-(pyrimidin-2-yl)ethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carboxamide

[0361] Step 1: Under nitrogen, sodium borohydride (22.96 mg, 0.61 mmol) was added to a solution of 4-acetyl-2-amino-N-(1-(pyrimidin-2-yl)ethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carboxamide (150 mg, 0.30 mmol) in methanol (5 mL) at 0°C. The reaction was stirred at 0°C for 2 hours. The reaction was quenched with sodium sulfate decahydrate, filtered, and the filter cake rinsed with methanol. The filtrate was then concentrated, and the crude product was purified on a silica gel prep plate (dichloromethane / methanol = 10:1) to afford 2-amino-4-(1-hydroxyethyl)-N-(1-(pyrimidin-2-yl)ethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carboxamide (i.e., Compound 36) as a yellow solid (100 mg, 66.38% yield). ESI-MS: m / z=496.2 / 497.3[M+1]+.

[0362] Step 2: The racemate (100 mg) was separated by SFC chiral column chromatography. Separation conditions: Column: Chiral ChIRALPAK-IC, 30 x 250 mm, 10 μm, Mobile Phase A: CO2, Mobile Phase B: 30% methanol + 0.1% NH4OH, Flow rate: 25 mL / min; Peak 1 retention time: 3.880 min, Peak 2 retention time: 4.750 min, Peak 3 retention time: 5.675 min, Peak 4 retention time: 8.518 min.

[0363] Peak 1 (i.e. 36-1): 1H NMR(400MHz,DMSO-d6)δ8.94-8.66(m,3H),8.21-7.92(m,2H),7.72-7.33(m,4H),7.00-6.89(m,1H),6.6 2(s,2H),5.59-5.12(m,3H),4.95-4.85(m,1H),4.68-4.41(m,1H),1.69-1.52(m,3H),1.39-1.14(m,3H).

[0364] Peak 2 (i.e. 36-2): 1 H NMR(400MHz,DMSO-d6)δ8.90-8.72(m,3H),8.20-7.95(m,2H),7.66-7.35(m,4H),7.02-6.86(m,1H),6.6 4(s,2H),5.53-5.14(m,3H),4.95-4.87(m,1H),4.68-4.46(m,1H),1.64-1.51(m,3H),1.31-1.19(m,3H).

[0365] Peak 3 (36-3): 1 H NMR(400MHz,DMSO-d6)δ8.92-8.73(m,3H),8.20-7.93(m,2H),7.66-7.36(m,4H),6.99-6.88(m,1H),6.6 0(s,2H),5.53-5.13(m,3H),4.96-4.86(m,1H),4.68-4.43(m,1H),1.65-1.51(m,3H),1.28-1.20(m,3H).

[0366] Peak 4 (i.e. 36-4): 1 H NMR(400MHz,DMSO-d6)δ8.89-8.72(m,3H),8.19-7.96(m,2H),7.69-7.37(m,4H),6.95(s,1H),6.60(s,2H),5.5 9-5.34(m,2H),5.29-5.07(m,1H),4.96-4.85(m,1H),4.67-4.44(m,1H),1.65-1.56(m,3H),1.51-1.24(m,3H).

[0367] Example 37: 2-amino-3-(hydroxymethyl)-N-(1-(pyrimidin-2-yl)ethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carboxamide

[0368] Step 1: Dissolve (5-(trifluoromethyl)pyridin-2-yl)methanamine hydrochloride (1.0 g, 4.7 mmol) in 1,2-dichloroethane (20 mL), add 1-(pyrimidin-2-yl)ethan-1-one (573 mg, 4.7 mmol) and acetic acid (282 mg, 4.7 mmol) at room temperature, stir at room temperature for 1 hour, add sodium cyanoborohydride (592.3 mg, 9.4 mmol) to the system, and continue the reaction at room temperature for 3 hours. After the reaction, water (5 mL) was added, and the aqueous phase was extracted three times with dichloromethane. The organic phase was washed once with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was separated and purified by silica gel column chromatography (eluent: dichloromethane:methanol = 15:1) to obtain a yellow liquid 1-(pyrimidin-2-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)ethan-1-amine (650 mg, 49.2% yield). ESI-MS: m / z = 283.2 [M+1] +

[0369] Step 2: 3-(Hydroxymethyl)-2-(4-methoxybenzyl)amino)quinoline-6-carboxylic acid (200 mg, 0.59 mmol) was dissolved in DMF (2 mL) and PyBrOP (550 mg, 1.18 mmol), TEA (300 mg, 2.95 mmol) and 1-(pyrimidin-2-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)ethan-1-amine (167 mg, 0.59 mmol) were added. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, it was diluted with water. Extraction was performed three times with ethyl acetate, and the organic phase was washed three times with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was separated and purified by silica gel column chromatography (eluent: dichloromethane:methanol = 20:1) to obtain (3-(hydroxymethyl)-2-((4-methoxybenzyl)amino)-N-(1-(pyrimidin-2-yl)ethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carboxamide (220 mg, 74% yield) as a white solid. ESI-MS: m / z = 603.6 [M+1]. + .

[0370] Step 3: (3-(Hydroxymethyl)-2-((4-methoxybenzyl)amino)-N-(1-(pyrimidin-2-yl)ethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carboxamide (220 mg, 0.36 mmol) was dissolved in 10 mL of trifluoroacetic acid and stirred at 80°C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by Prep-HPLC (eluent: acetonitrile: water (NH4HCO3) = 35% to 60%) to obtain the target compound 2-amino-3-(hydroxymethyl)-N-(1-(pyrimidin-2-yl)ethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carboxamide (i.e., Compound 37) (120 mg, 69% yield) as a white solid. ESI-MS: [M+H] + =483.4.

[0371] Step 4: The racemate (80 mg) was separated by SFC chiral column chromatography. Separation conditions: Column: Chiral ChIRALPAK-IG, 30 x 250 mm, 10 μm, Mobile Phase A: 90% ACN + 0.2% DEA, Mobile Phase B: 10% IPA + 0.2% DEA, Flow rate: 25 mL / min; Peak 1 retention time: 8.202 min, Peak 2 retention time: 13.135 min.

[0372] Peak 1 (i.e. 37-1): 1 H NMR (400MHz, DMSO-d6) δ8.83(s,1H),8.78(d,J=4.9Hz,2H),8.11(d,J=8.3Hz,1H),7.94(d,J=13.7Hz,2H),7.71-7.48 (m,3H),7.39(t,J=4.9Hz,1H),6.41(s,2H),5.42(s,2H),4.92(d,J=17.0Hz,1H),4.49(s,2H),1.62(d,J=7.0Hz,3H).

[0373] Peak 2 (i.e. 37-2): 1 H NMR (400MHz, DMSO-d6) δ8.83(s,1H),8.78(d,J=4.9Hz,2H),8.11(d,J=8.3Hz,1H),7.94(d,J=13.9Hz,2H),7.70-7.45 (m,3H),7.39(t,J=4.9Hz,1H),6.41(s,2H),5.42(s,2H),4.92(d,J=16.9Hz,1H),4.48(s,2H),1.62(d,J=6.9Hz,3H).

[0374] Example 38: 2-amino-N-(cyclopropylmethyl)-4-(hydroxymethyl)-N-((6-(trifluoromethyl)pyridazin-3-yl)methyl)quinoline-6-carboxamide

[0375] Step 1: To a solution of ethyl 6-(trifluoromethyl)pyridazine-3-carboxylate (500 mg, 2.27 mmol) in dichloromethane (5 mL) was added DIBALH (5.2 mL, 5.22 mmol) at -78°C under nitrogen. The reaction mixture was stirred at -78°C for 1 hour and then at room temperature for 12 hours. The reaction mixture was concentrated to afford 6-(trifluoromethyl)pyridazine-3-carboxaldehyde (150 mg, 37.50% yield) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ10.43(s,1H),7.98(s,1H),7.66(s,1H).

[0376] Step 2: Under nitrogen, acetic acid (51.15 mg, 0.85 mmol) and NaBH(AcO)3 (270.81 mg, 1.28 mmol) were added to a solution of 6-(trifluoromethyl)pyridazine-3-carboxaldehyde (150 mg, 0.85 mmol) and cyclopropylmethylamine (72.71 mg, 1.02 mmol) in dichloromethane (4 mL). The reaction mixture was stirred at 25°C for 2 hours. The reaction was quenched with water and extracted with dichloromethane (20 mL*3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to afford 1-cyclopropyl-N-((6-(trifluoromethyl)pyridazin-3-yl)methyl)methanamine (150 mg, yield: 76.16%) as a brown oil. ESI-MS: m / z = 231.1 / 232.2 [M+1] + .

[0377] Step 3: Under nitrogen protection, PyBrOP (412.01 mg, 0.88 mmol) and triethylamine (446.32 mg, 4.42 mmol) were added to a solution of 4-(((tert-butyldimethylsilyl)oxy)methyl)-2-((4-methoxybenzyl)amino)quinoline-6-carboxylic acid (122.61 mg, 0.53 mmol) in N,N-dimethylacetamide (4 mL). The reaction mixture was stirred at 25 ° C for 16 hours. The reaction was quenched with water and extracted with ethyl acetate (50 mL * 3). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified on a silica gel preparation plate (dichloromethane / methanol = 10:1) to afford 4-(((tert-butyldimethylsilyl)oxy)methyl)-N-(cyclopropylmethyl)-2-((4-methoxybenzyl)amino)-N-((6-(trifluoromethyl)pyridazin-3-yl)methyl)quinoline-6-carboxamide (150 mg, 45.90% yield) as a brown solid. ESI-MS: m / z = 665.3 / 666.3 [M+1] + .

[0378] Step 4: Under nitrogen protection, a solution of 4-(((tert-butyldimethylsilyl)oxy)methyl)-N-(cyclopropylmethyl)-2-((4-methoxybenzyl)amino)-N-((6-(trifluoromethyl)pyridazin-3-yl)methyl)quinoline-6-carboxamide (145 mg, 0.22 mmol) in trifluoroacetic acid (5 mL) was stirred at 70°C for 16 hours. The reaction solution was concentrated under reduced pressure. The crude product was purified by high pressure preparative purification to give 2-amino-N-(cyclopropylmethyl)-4-(hydroxymethyl)-N-((6-(trifluoromethyl)pyridazin-3-yl)methyl)quinoline-6-carboxamide (i.e., Compound 38) (54 mg, yield: 57.48%) as a white solid. ESI-MS: m / z = 431.2 / 432.0 [M+1] + . 1 H NMR(400MHz,DMSO_d6)δ8.28-8.22(m,1H),8.09-7.98(m,1H),7.82(s,1H),7.65-7.47(m,2H),7.23-6 .82(m,3H),5.54(s,1H),5.16(s,2H),4.86(s,2H),0.99(s,1H),0.43-0.27(m,2H),0.19-0.01(m,2H).

[0379] Example 39: 2-amino-4-(hydroxymethyl)-N-(1-methyl-1H-pyrazol-4-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carboxamide

[0380] Step 1: Under nitrogen, add acetic acid (171.47 mg, 2.8554 mmol) to a solution of 5-(trifluoromethyl)picolinaldehyde (500 mg, 2.86 mmol) and 1-methylpyrazol-4-amine (332.8 mg, 3.43 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at 25°C for 1 hour, followed by the addition of sodium triacetoxyborohydride (907.76 mg, 4.2831 mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction was quenched with water and extracted with dichloromethane (20 mL x 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified on a silica gel preparation plate (dichloromethane / methanol = 10:1) to give 1-methyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)-1H-pyrazol-4-amine (400 mg, yield: 49.21%) as a yellow oil. 1 HNMR (400MHz, CDCl3) δ8.83(s,1H),7.92-7.85(m,1H),7.52-7.46(m,1H),7.13(s,1H),6.85(s,1H),4.35(s,2H),3.77(s,3H).

[0381] Step 2: Under nitrogen protection, PyBrOP (412.2 mg, 0.88 mmol) and triethylamine (447.2 mg, 4.42 mmol) were added to a solution of 4-(((tert-butyldimethylsilyl)oxy)methyl)-2-((4-methoxybenzyl)amino)quinoline-6-carboxylic acid (200 mg, 0.44 mmol) and 1-methyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)-1H-pyrazol-4-amine (136.0 mg, 0.53 mmol) in N,N-dimethylacetamide (5 mL). The reaction mixture was stirred at 25°C for 16 hours. The reaction was quenched with water and extracted with ethyl acetate (20 mL*3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified on a silica gel preparative plate (dichloromethane / methanol = 10:1) to afford 4-(((tert-butyldimethylsilyl)oxy)methyl)-2-((4-methoxybenzyl)amino)-N-(1-methyl-1H-pyrazol-4-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carboxamide (90 mg, 29.48% yield) as a brown solid. ESI-MS: m / z = 690.3 / 691.2 [M+1].

[0382] Step 3: Under nitrogen, a solution of 4-(((tert-butyldimethylsilyl)oxy)methyl)-2-((4-methoxybenzyl)amino)-N-(1-methyl-1H-pyrazol-4-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carboxamide (90 mg, 0.13 mmol) in trifluoroacetic acid (4 mL) was stirred at 70°C for 16 hours. The reaction solution was concentrated under reduced pressure. The crude product was purified by high pressure preparative purification to give 2-amino-4-(hydroxymethyl)-N-(1-methyl-1H-pyrazol-4-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carboxamide (i.e., Compound 39) (36.4 mg, 61.22% yield) as a white solid. ESI-MS: m / z = 456.4 / 457.2 [M+1]+. 1 H NMR(400MHz,DMSO_d6)δ8.94(s,1H),8.22-8.17(m,1H),7.76-7.62(m,3H),7.51-7.46(m,1H),7.35-7.29(m, 1H),7.23(s,1H),6.87(s,1H),6.63(s,2H),5.45-5.39(m,1H),5.13(s,2H),4.70-4.62(m,2H),3.65(s,3H).

[0383] Example 40: 2-amino-7-fluoro-3-(hydroxymethyl)-N-((1-methylcyclopropyl)methyl)-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)quinoline-6-carboxamide

[0384] Step 1: Under nitrogen, 4-trifluoromethyl salicylaldehyde (1.5 g, 7.8 mmol) was dissolved in dichloromethane (20 mL), and (1-methylcyclopropyl)methylamine (0.805 g, 9.4 mmol) and anhydrous sodium sulfate (4.43 g, 31.2 mmol) were added. The mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered and the filtrate was concentrated to give (E)-2-((((1-methylcyclopropyl)methyl)imino)methyl)-5-(trifluoromethyl)phenol (2.0 g, crude) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ13.99 (s, 1H), 8.35 (s, 1H), 7.36 (d, J = 8.0Hz, 1H), 7.21 (s, 2H) ,7.11-7.09(m,1H),3.46(s,2H),1.14(s,3H),0.51–0.44(m,2H),0.40-0.39(m,2H).

[0385] Step 2: Under nitrogen, potassium tert-butoxide (3.47 g, 0.031 mol) was added portionwise to a suspension of trimethylsulfoxide iodide (6.84 g, 0.031 mol) in tetrahydrofuran (40 mL). The mixture was stirred at room temperature for 1 hour, followed by the addition of a solution of (E)-2-((((1-methylcyclopropyl)methyl)imino)methyl)-5-(trifluoromethyl)phenol (2.0 g, 7.7 mmol) in tetrahydrofuran (10 mL). The resulting mixture was stirred at room temperature for 1 hour, then at 50°C for 3 hours. The reaction mixture was cooled to room temperature, and additional potassium tert-butoxide (0.862 g, 7.7 mmol) was added, and the resulting mixture was stirred at room temperature for 11 hours. The reaction mixture was filtered, and the filtrate was poured into water and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The crude product obtained was purified by silica gel column (petroleum ether / ethyl acetate = 5:1) to give yellow oily N-((1-methylcyclopropyl)methyl)-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine (0.7 g, yield: 35.0%). 1 H NMR(400MHz, CDCl3) δ7.39(d,J=7.7Hz,1H),7.16(d,J=7.7Hz,1H),7.05(s,1H),4.63-4.52(m,2H),4 .42-4.39(m,1H),2.54(d,J=11.6Hz,1H),2.42(d,J=11.6Hz,1H),1.11(s,3H),0.30(d,J=5.5Hz,4H).

[0386] Step 3: Under nitrogen protection, DIEA (736 mg, 5.71 mmol) was added to a dichloromethane (5 mL) solution of the compound 2-amino-3-(((tert-butyldimethylsilyl)oxy)methyl)-7-fluoroquinoline-6-carboxylic acid (200 mg, 0.57 mmol) and N-((1-methylcyclopropyl)methyl)-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine (154 mg, 0.57 mmol). Phosphorus oxychloride (131 mg, 0.86 mmol) was added at 0°C. The reaction mixture was stirred at 25°C for 2 hours. The reaction was quenched with water and extracted with dichloromethane (20 mL*3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column purification (petroleum ether / ethyl acetate = 3:1) to give 2-amino-3-(((tert-butyldimethylsilyl)oxy)methyl)-7-fluoro-N-((1-methylcyclopropyl)methyl)-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)quinoline-6-carboxamide as a yellow solid (80 mg, yield: 23.25%). ESI-MS: m / z = 603.3 / 604.1 [M+1]+.

[0387] Step 4: Under nitrogen protection, lithium hydroxide (12.7 mg, 0.53 mmol) was added to a solution of 2-amino-3-(((tert-butyldimethylsilyl)oxy)methyl)-7-fluoro-N-((1-methylcyclopropyl)methyl)-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)quinoline-6-carboxamide (80 mg, 0.13 mmol) in tetrahydrofuran / methanol / water = 1:1:1 (3 mL). The reaction mixture was stirred at 25°C for 3 hours, poured into water, and extracted with ethyl acetate (20 mL*3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. 2-Amino-7-fluoro-3-(hydroxymethyl)-N-((1-methylcyclopropyl)methyl)-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)quinoline-6-carboxamide (i.e., Compound 40) was obtained as a crude yellow solid (58 mg, 89.23% yield). ESI-MS: m / z = 489.4 / 490.0 [M+1]+.

[0388] Step 5: The racemate (58 mg) was separated by SFC chiral column chromatography. Separation conditions: Column: Chiral ChIRALPAK-AD, 20 x 250 mm, 5 μm, Mobile Phase A: CO2, Mobile Phase B: 30% ethanol (0.1% DEA), Flow rate: 40 mL / min; Peak 1 retention time: 0.822 min, Peak 2 retention time: 1.039 min.

[0389] Peak 1 (i.e. 40-1): 1 H NMR(400MHz,DMSO_d6)δ7.96(s,1H),7.79(s,1H),7.51(s,1H),7.27–7.14(m,3H),6.56(s,2H),5.67(s,1H),5.42 (s,1H),4.88-4.76(m,2H),4.46(d,J=5.0Hz,2H),3.34(s,1H),3.27(s,1H),1.00-0.85(m,3H),0.42-1.15(m,4H).

[0390] Peak 2 (i.e. 40-2): 1 H NMR(400MHz,DMSO_d6)δ7.96(s,1H),7.79(s,1H),7.51(s,1H),7.28–7.14(m,3H),6.56(s,2H),5.67(s,1H),5.42 (s,1H),4.89-4.76(m,2H),4.46(d,J=5.1Hz,2H),3.35(s,1H),3.27(s,1H),1.07–0.85(m,3H),0.42-0.15(m,4H).

[0391] Example 41: 2-amino-7-fluoro-3-(hydroxymethyl)-N-(oxetan-3-ylmethyl)-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)quinoline-6-carboxamide

[0392] The first step: Under nitrogen protection, 4-trifluoromethyl salicylaldehyde (1.8 g, 9.4 mmol) was dissolved in dichloromethane (20 mL), and oxetane-3-ylmethylamine (0.974 g, 11.2 mmol) and anhydrous sodium sulfate (5.33 g, 37.6 mmol) were added. The mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered and the filtrate was concentrated to give ((E)-2-(((oxetane-3-ylmethyl)imino)methyl)-5-(trifluoromethyl)phenol (2.6 g, crude) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ13.30 (s, 1H), 8.48 (s, 1H), 7.39 (d, J = 8.0Hz, 1H), 7.21 (s, 1H), 7.14 -7.12(m,1H),4.89-4.85(m,2H),4.50-4.28(m,2H),4.01-3.96(m,2H),3.38–3.29(m,1H).

[0393] Step 2: Under nitrogen protection, potassium tert-butoxide (3.4 g, 0.03 mol) was added portionwise to a suspension of trimethylsulfoxide iodide (6.6 g, 0.03 mol) in tetrahydrofuran (30 mL). The mixture was stirred at room temperature for 1 hour, and then a solution of ((E)-2-(((oxotan-3-ylmethyl)imino)methyl)-5-(trifluoromethyl)phenol (2.6 g, 0.01 mol) in tetrahydrofuran (10 mL) was added. The resulting mixture was stirred at room temperature for 1 hour and then at 50°C for 3 hours. The reaction solution was cooled to room temperature, and additional potassium tert-butoxide (1.12 g, 0.01 mol) was added. The resulting mixture was stirred at room temperature for 11 hours. The reaction mixture was filtered, and the filtrate was poured into water and extracted with ethyl acetate (30 mL*3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified on a silica gel column (petroleum ether / ethyl acetate = 5:1) to obtain N-(oxetan-3-ylmethyl)-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine (1.1 g, yield: 57.89%) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ7.41(d,J=7.7Hz,1H),7.18(d,J=7.7Hz,1H),7.07(s,1H),4.82–4.78(m,2H ),4.65-4.60(m,1H),4.55–4.49(m,1H),4.45–4.33(m,3H),3.09–2.96(m,2H),2.92–2.87(m,1H).

[0394] Step 3: Under nitrogen protection, DIEA (736 mg, 5.71 mmol) was added to a dichloromethane (5 mL) solution of the compound 2-amino-3-(((tert-butyldimethylsilyl)oxy)methyl)-7-fluoroquinoline-6-carboxylic acid (200 mg, 0.57 mmol) and N-(oxetane-3-ylmethyl)-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine (155.9 mg, 0.57 mmol). Phosphorus oxychloride (131 mg, 0.856 mmol) was added at 0°C. The reaction mixture was stirred at 25°C for 2 hours. The reaction was quenched with water and extracted with ethyl acetate (20 mL*3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column purification (petroleum ether / ethyl acetate = 6:1) to give 2-amino-3-(((tert-butyldimethylsilyl)oxy)methyl)-7-fluoro-N-(oxetan-3-ylmethyl)-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)quinoline-6-carboxamide as a yellow solid (70 mg, yield: 20.28%) ESI-MS: m / z = 605.2 / 606.0 [M+1]+.

[0395] Step 4: Under nitrogen protection, lithium hydroxide (11.1 mg, 0.463 mmol) was added to a solution of 2-amino-3-(((tert-butyldimethylsilyl)oxy)methyl)-7-fluoro-N-(oxetan-3-ylmethyl)-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)quinoline-6-carboxamide (70 mg, 0.115 mmol) in tetrahydrofuran / methanol / water = 1:1:1 (6 mL). The reaction mixture was stirred at 25 ° C for 3 hours, poured into water, and extracted with ethyl acetate (20 mL * 3). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. 2-Amino-7-fluoro-3-(hydroxymethyl)-N-(oxetan-3-ylmethyl)-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)quinoline-6-carboxamide (i.e., Compound 41) was obtained as a yellow solid (50 mg, 89.28% yield). ESI-MS: m / z = 491.44 / 492.1 [M+1]+.

[0396] Step 5: The racemate (50 mg) was separated by SFC chiral column chromatography. Separation conditions: Column: Chiral ChIRALPAK-IC, 20 x 250 mm, 5 μm, Mobile Phase A: CO2, Mobile Phase B: 40% ethanol (0.1% DEA), Flow rate: 40 mL / min; Peak 1 retention time: 0.962 min, Peak 2 retention time: 1.282 min.

[0397] Peak 1 (i.e. 41-1): 1 H NMR(400MHz,DMSO_d6)δ7.97-7.85(m,2H),7.51(s,1H),7.31-7.23(m,3H),6.58(s,2H),5.87(s,0.5H),5.55(s,0.5H),5.42-5.31( m,1H),4.85–4.51(m,3H),4.47(d,J=5.2Hz,2H),4.30(s,2H),3.85-3.81(m,1H),3.63-3.55(m,1.5H),3.34(s,0.5H),3.03(s,1H).

[0398] Peak 2 (i.e. 41-2): 1 H NMR(400MHz, DMSO_d6)δ7.97-7.84(m,2H),7.51(s,1H),7.32-7.23(m,3H),6.58(s,2H),5.88(s,0.5H),5.55(s,0.5H),5.44-5. 31(m,1H),4.84–4.65(m,3H),4.47(d,J=5.2Hz,2H),4.30(s,2H),3.85-3.82(m,1H),3.54(s,1.5H),3.34(s,0.5H),3.02(s,1H).

[0399] Example 42: 2-amino-N-(2-cyclopropyloxyethyl)-7-fluoro-3-(hydroxymethyl)-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)quinoline-6-carboxamide

[0400] Step 1: Under nitrogen, dissolve 4-trifluoromethyl salicylaldehyde (1.0 g, 5.3 mmol) in dichloromethane (10 mL). Add 2-cyclopropyloxyethylamine hydrochloride (1.3 g, 6.3 mmol), anhydrous sodium sulfate (3.01 g, 21.2 mmol), and triethylamine (1.60 g, 15.9 mmol). Stir the mixture at room temperature for 16 hours. Filter the reaction mixture, and concentrate the filtrate to obtain (E)-2-(((2-cyclopropyloxyethyl)imino)methyl)-5-(trifluoromethyl)phenol (1.5 g, crude) as a yellow solid. 1HNMR(400MHz, CDCl3)δ8.40(s,1H),7.37(d,J=8.0Hz,1H),7.20(s,1H),7.11(d,J=8.0Hz,1H),3.85–3.7 9(m,4H),3.63-3.5(m,1H),3.31-3.28(m,,1H),3.20-3.17(m,1H),0.57–0.51(m,2H),0.49–0.44(m,2H).

[0401] Step 2: Under nitrogen, potassium tert-butoxide (2.24 g, 20 mmol) was added portionwise to a suspension of trimethylsulfoxide iodide (4.4 g, 20 mmol) in tetrahydrofuran (13 mL). The mixture was stirred at room temperature for 1 hour, followed by the addition of a solution of (E)-2-(((2-cyclopropyloxyethyl)imino)methyl)-5-(trifluoromethyl)phenol (1.50 g, 5 mmol) in tetrahydrofuran (10 mL). The resulting mixture was stirred at room temperature for 1 hour, then at 50°C for 3 hours. The reaction mixture was cooled to room temperature, and additional potassium tert-butoxide (0.56 g, 5 mmol) was added, and the resulting mixture was stirred at room temperature for 11 hours. The reaction mixture was filtered, and the filtrate was poured into water and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The crude product obtained was purified by silica gel column (petroleum ether / ethyl acetate = 5:1) to give yellow oily N-(2-cyclopropyloxyethyl)-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine (0.4 g, yield: 26.66%). 1 H NMR (400MHz, CDCl3) δ7.41 (d, J = 7.7Hz, 1H), 7.19-7.15 (m, 1H), 7.05 (s, 1H), 4.70-4.58 (m, 1H), 4.51-4 .45(m,1H),4.43-4.40(m,1H),3.63–3.55(m,2H),3.27-3.24(m,1H),2.88-2.83(m,1H),2.73-2.61(m, 1H),0.57–0.51(m,2H),0.45–0.41(m,2H).

[0402] Step 3: Under nitrogen protection, DIEA (665 mg, 1.42 mmol) was added to a solution of 2-amino-3-(((tert-butyldimethylsilyl)oxy)methyl)-7-fluoroquinoline-6-carboxylic acid (250.00 mg, 0.71 mmol) and N-(2-cyclopropyloxyethyl)-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine (204.9 mg, 0.71 mmol) in dichloromethane (5 mL). Phosphorus oxychloride (164 mg, 1.07 mmol) was added at 0°C. The reaction mixture was stirred at 25°C for 2 hours. The reaction was quenched with water and extracted with ethyl acetate (20 mL*3). Then, 2-amino-3-(((tert-butyldimethylsilyl)oxy)methyl)-N-(2-cyclopropyloxyethyl)-7-fluoro-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)quinoline-6-carboxamide (330 mg, yield: 74.66%) was obtained as a crude yellow solid. ESI-MS: m / z = 619.2 / 620.0 [M+1]+.

[0403] Step 4: Under nitrogen protection, lithium hydroxide (51.2 mg, 2.13 mmol) was added to a solution of 2-amino-3-(((tert-butyldimethylsilyl)oxy)methyl)-N-(2-cyclopropyloxyethyl)-7-fluoro-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)quinoline-6-carboxamide (330 mg, 0.53 mmol) in tetrahydrofuran / methanol / water = 1:1:1 (3 mL). The reaction mixture was stirred at 25°C for 3 hours, poured into water, and extracted with ethyl acetate (20 mL*3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The resulting crude product was separated by flash reverse phase column chromatography (acetonitrile / water, 6 / 5) to afford 2-amino-N-(2-cyclopropyloxyethyl)-7-fluoro-3-(hydroxymethyl)-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)quinoline-6-carboxamide (Compound 42) (52 mg, 19.33% yield) as a white solid. ESI-MS: m / z = 505.1 / 506.3 [M+1]+.

[0404] Step 5: The racemate (52 mg) was separated by SFC chiral column chromatography. Separation conditions: Column: Chiral ChIRALPAK-AD, 20 x 250 mm, 5 μm, Mobile Phase A: CO2, Mobile Phase B: 30% ethanol (0.1% DEA), Flow rate: 40 mL / min; Peak 1 retention time: 0.828 min, Peak 2 retention time: 1.018 min.

[0405] Peak 1 (i.e. 42-1):1 H NMR(400MHz,DMSO_d6)δ7.99–7.78(m,2H),7.55(s,1H),7.30–7.20(m,3H),6.55(s,2H),5.91(s,0.5H),5.53(s,0.5H) ,5.43(s,1H),4.85–4.67(m,2H),4.47(d,J=4.5Hz,2H),3.56-3.40(m,1H),3.22-3.02(m,4H),0.32(d,J=27.2Hz,4H).

[0406] Peak 2 (i.e. 42-2): 1 H NMR(400MHz,DMSO_d6)δ7.99–7.78(m,2H),7.55(s,1H),7.31–7.21(m,3H),6.55(s,2H),5.91(s,0.53H),5.53(s,0.51H ),5.43(s,1H),4.86–4.66(m,2H),4.47(d,J=4.7Hz,2H),3.66-3.40(m,1H),3.23-3.02(m,4H),0.32(d,J=26.9Hz,4H).

[0407] Example 43: 2-amino-N-(cyclobutylmethyl)-7-fluoro-3-(hydroxymethyl)-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)quinoline-6-carboxamide

[0408] Step 1: Under nitrogen, 4-trifluoromethyl salicylaldehyde (1.8 g, 9.4 mmol) was dissolved in dichloromethane (20 mL). Cyclobutylmethylamine (0.958 g, 11.2 mmol) and anhydrous sodium sulfate (5.33 g, 37.6 mmol) were added. The mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered and the filtrate was concentrated to give crude (E)-2-(((cyclobutylmethyl)imino)methyl)-5-(trifluoromethyl)phenol (2.4 g, 98.76% yield) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ13.93 (s, 1H), 8.37 (s, 1H), 7.35 (d, J = 8.0Hz, 1H), 7.20 (s, 1H), 7.11 -7.08(m,1H),3.66-3.64(m,2H),2.70–2.62(m,1H),2.11–2.06(m,2H),1.98–1.73(m,4H).

[0409] Step 2: Under nitrogen, potassium tert-butoxide (4.1 g, 0.037 mol) was added portionwise to a suspension of trimethylsulfoxide iodide (8.2 g, 0.037 mol) in tetrahydrofuran (30 mL). The mixture was stirred at room temperature for 1 hour, followed by the addition of a solution of (E)-2-(((cyclobutylmethyl)imino)methyl)-5-(trifluoromethyl)phenol (2.4 g, 9.3 mmol) in tetrahydrofuran (10 mL). The resulting mixture was stirred at room temperature for 1 hour, then at 50°C for 3 hours. The reaction mixture was cooled to room temperature, and additional potassium tert-butoxide (1.04 g, 9.3 mmol) was added, and the resulting mixture was stirred at room temperature for 11 hours. The reaction mixture was filtered, and the filtrate was poured into water and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by silica gel column purification (petroleum ether / ethyl acetate = 5:1) to give yellow oily N-(cyclobutylmethyl)-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine (1.0 g, yield: 40.0%). 1 H NMR (400MHz, CDCl3) δ7.41(d,J=7.7Hz,1H),7.17(d,J=7.7Hz,1H),7.06(d,J=6.7Hz,1H),4.63-4.58(m,1H),4.51-4.48(m,1H),4. 44-4.40(m,1H),2.74–2.69(m,1H),2.61–2.57(m,1H),2.44-2.35(m,1H),2.07–2.02(m,2H),1.92–1.79(m,2H),1.70–1.54(m,2H).

[0410] Step 3: Under nitrogen protection, DIEA (736 mg, 5.71 mmol) was added to a dichloromethane (5 mL) solution of the compound 2-amino-3-(((tert-butyldimethylsilyl)oxy)methyl)-7-fluoro-quinoline-6-carboxylic acid (200 mg, 0.57 mmol) and N-(cyclobutylmethyl)-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine (154.8 mg, 0.57 mmol). Phosphorus oxychloride (131 mg, 0.86 mmol) was added at 0°C. The reaction mixture was stirred at 25°C for 2 hours. The reaction was quenched with water and extracted with ethyl acetate (20 mL*3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. Then the crude product of 2-amino-3-(((tert-butyldimethylsilyl)oxy)methyl)-N-(cyclobutylmethyl)-7-fluoro-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)quinoline-6-carboxamide was obtained as a yellow solid (300 mg, yield: 87.08%) ESI-MS: m / z = 603.2 / 604.1 [M+1] +.

[0411] Step 4: Under nitrogen protection, lithium hydroxide (47.7 mg, 1.99 mmol) was added to a solution of 2-amino-3-(((tert-butyldimethylsilyl)oxy)methyl)-N-(cyclobutylmethyl)-7-fluoro-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)quinoline-6-carboxamide (300 mg, 0.50 mmol) in tetrahydrofuran / methanol / water = 1:1:1 (6 mL). The reaction mixture was stirred at 25°C for 3 hours, poured into water, and extracted with ethyl acetate (20 mL*3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reverse phase column chromatography (acetonitrile / water, 6 / 5) to afford 2-amino-N-(cyclobutylmethyl)-7-fluoro-3-(hydroxymethyl)-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)quinoline-6-carboxamide (Compound 43) (45 mg, 18.52% yield) as a white solid. ESI-MS: m / z = 489.1 / 490.0 [M+1]+.

[0412] Step 5: The racemate (45 mg) was separated by SFC chiral column chromatography. Separation conditions: Column: Chiral ChIRALPAK-AD, 20 x 250 mm, 5 μm, Mobile Phase A: CO2, Mobile Phase B: 20% ethanol (0.1% DEA), Flow rate: 40 mL / min; Peak 1 retention time: 1.772 min, Peak 2 retention time: 1.968 min.

[0413] Peak 1 (i.e. 43-1): 1 H NMR(400MHz, DMSO_d6)δ7.96(s,1H),7.80(s,1H),7.52(d,J=7.6Hz,1H),7.31–7.20(m,3H),6.56(s,2H),5.80(s,0.5H),5.50-5. 32(m,1.5H),4.87(s,0.6H),4.58(s,1.5H),4.47(d,J=3.2Hz,2H),3.24(s,2H),2.28(s,0.6H),1.92(s,0.5H),1.82-1.25(m,6H).

[0414] Peak 2 (i.e. 43-2): 1 H NMR(400MHz, DMSO_d6)δ7.97(s,1H),7.80(s,1H),7.52(d,J=7.4Hz,1H),7.33–7.16(m,3H),6.57(s,2H),5.80(s,0.5H),5.51-5.33( m,1.5H),4.87(s,0.6H),4.58(s,1.4H),4.47(d,J=5.2Hz,2H),3.24(s,2H),2.28(s,0.6H),2.01–1.92(m,0.5H),1.83–1.27(m,6H).

[0415] Example 44: 2-amino-N-(cyclopropylmethyl)-3-(hydroxymethyl)-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)quinoline-6-carboxamide

[0416] Step 1: Dissolve 3-(hydroxymethyl)-2-((4-methoxybenzyl)amino)quinoline-6-carboxylic acid (1.0 g, 2.95 mmol) in trifluoroacetic acid (10 mL) and heat to 80°C for 4 hours. After completion of the reaction, the trifluoroacetic acid was removed by concentration under reduced pressure. The solid was vigorously stirred with petroleum ether / ethyl acetate (5:1) for 1 hour and then filtered to obtain 2-amino-3-(hydroxymethyl)quinoline-6-carboxylic acid (600 mg, 93%) as an off-white solid. ESI-MS: m / z = 219.2 [M+1] + .

[0417] Step 2: Under nitrogen, to a solution of 2-amino-3-(hydroxymethyl)quinoline-6-carboxylic acid (110 mg, 0.50 mmol) and N-(cyclopropylmethyl)-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine (130 mg, 0.50 mmol) in DMF (5 mL) was added PyBrOP (350 mg, 0.75 mmol) and DIEA (258 mg, 2.0 mmol). The reaction mixture was stirred at 25°C for 2 hours. The reaction was quenched with water and extracted with EA (20 mL*3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reverse phase column chromatography (acetonitrile / water, 5 / 5) to afford 2-amino-N-(cyclopropylmethyl)-3-(hydroxymethyl)-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)quinoline-6-carboxamide (Compound 44) ​​(90 mg, 39% yield) as a pale yellow solid. ESI-MS: m / z = 458.4 [M+1] + .

[0418] Step 3: The racemate (90 mg) was separated by SFC chiral column chromatography. Separation conditions: Column: Chiral ChIRALPAK-IH, 30 x 250 mm, 10 μm, Mobile Phase A: 60% HEX + 0.2% DEA, Mobile Phase B: 40% EtOH + 0.2% DEA, Flow rate: 25 mL / min; Peak 1 retention time: 4.974 min, Peak 2 retention time: 6.482 min.

[0419] Peak 1 (i.e. 44-1): 1 H NMR (400MHz, DMSO-d6) δ7.99 (s, 1H), 7.83 (s, 1H), 7.66 (d, J = 7.8Hz, 1H), 7.5 3(s,2H),7.32-7.25(m,1H),7.21(d,J=1.5Hz,1H),6.46(s,2H),5.86(s,1H) ,5.44(t,J=5.4Hz,1H),4.84-4.70(m,2H),4.50(d,J=4.8Hz,2H),3.20-3.05 (m,2H),0.81(brs,1H),0.39-0.24(m,2H),-0.08(brs,1H),-0.3-0.2(m,1H).

[0420] Peak 2 (i.e. 44-2): 1H NMR(400MHz,DMSO-d6)δ7.97(s,1H),7.82(s,1H),7.65(d,J=7.8Hz,1H),7.5 1(s,2H),7.32-7.25(m,1H),7.21(d,J=1.5Hz,1H),6.40(s,2H),5.86(s,1H) ,5.41(t,J=5.4Hz,1H),4.84-4.70(m,2H),4.49(d,J=4.8Hz,2H),3.20-3.05 (m,2H),0.81(brs,1H),0.39-0.24(m,2H),-0.08(brs,1H),-0.3-0.2(m,1H).

[0421] Example 45: 2-amino-N-(cyclopropylmethyl)-7-fluoro-3-(hydroxymethyl)-N-(7-(trifluoromethyl)isochroman-4-yl)quinoline-6-carboxamide

[0422] Step 1: Under nitrogen, DIEA (553 mg, 4.29 mmol) was added to a solution of 2-amino-3-(((tert-butyldimethylsilyl)oxy)methyl)-7-fluoroquinoline-6-carboxylic acid (150 mg, 0.43 mmol) and N-(cyclopropylmethyl)-7-(trifluoromethyl)isochroman-4-amine (116 mg, 0.43 mmol) in dichloromethane (5 mL). Phosphorus oxychloride (98.4 mg, 0.64 mmol) was added at 0°C. The reaction mixture was stirred at 25°C for 2 hours. The reaction was quenched with water and extracted with ethyl acetate (20 mL*3). Then, 2-amino-3-(((tert-butyldimethylsilyl)oxy)methyl)-N-(cyclopropylmethyl)-7-fluoro-N-(7-(trifluoromethyl)isochroman-4-yl)quinoline-6-carboxamide (200 mg, yield: 77.52%) was obtained as a crude yellow solid. ESI-MS: m / z = 603.2 / 604.0 [M+1]+.

[0423] Step 2: Under nitrogen protection, lithium hydroxide (31.8 mg, 1.32 mmol) was added to a solution of 2-amino-3-(((tert-butyldimethylsilyl)oxy)methyl)-N-(cyclopropylmethyl)-7-fluoro-N-(7-(trifluoromethyl)isochroman-4-yl)quinoline-6-carboxamide (200 mg, 0.33 mmol) in tetrahydrofuran / methanol / water = 1:1:1 (6 mL). The reaction mixture was stirred at 25°C for 3 hours, poured into water, and extracted with dichloromethane (20 mL*3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The resulting crude product was separated by flash reverse phase column chromatography (acetonitrile / water, 6 / 5) to afford 2-amino-N-(cyclopropylmethyl)-7-fluoro-3-(hydroxymethyl)-N-(7-(trifluoromethyl)isochroman-4-yl)quinoline-6-carboxamide (Compound 45) (41 mg, 25.30% yield) as a white solid. ESI-MS: m / z = 489.1 / 490.2 [M+1]+.

[0424] Step 3: The racemate (41 mg) was separated by SFC chiral column chromatography. Separation conditions: Column: Chiral ChIRALPAK-OJ, 20 x 250 mm, 5 μm, Mobile Phase A: CO2, Mobile Phase B: 15% ethanol (0.1% DEA), Flow rate: 40 mL / min; Peak 1 retention time: 1.255 min, Peak 2 retention time: 1.675 min.

[0425] Peak 1 (i.e. 45-1): 1 H NMR(400MHz, DMSO_d6)δ7.98(d,J=6.7Hz,1.4H),7.83(d,J=7.7Hz,0.6H),7.64(s,1.5H),7.56– 7.49(m,1.6H),7.28-7.21(m,1H),6.54(s,2H),5.48-5.41(m,1.5H),4.91–4.78(m,2H),4.60(d, J=15.4Hz,0.5H),4.47(d,J=4.9Hz,2H),4.22–4.13(m,2H),3.37(s,0.5H),3.17–3.08(m,1H),2. 91(s,0.5H),1.05(s,0.5H),0.76(s,0.6H),0.37–0.15(m,2.5H),-0.15(s,1H),-0.30(s,0.6H).

[0426] Peak 2 (i.e. 45-2): 1H NMR(400MHz, DMSO_d6))δ7.98(d,J=6.9Hz,1.5H),7.83(d,J=7.7Hz,0.6H),7.64(s,1.5H),7.56– 7.48(m,1.5H),7.27-7.21(m,1H),6.54(s,2H),5.48-5.41(m,1.5H),4.91–4.78(m,2H),4.60(d, J=15.4Hz,0.5H),4.47(d,J=5.1Hz,2H),4.26-4.03(m,2H),3.37(s,0.5H),3.17–3.09(m,1H),2. 91(s,0.5H),1.05(s,0.6H),0.76(s,0.5H),0.37–0.14(m,2.6H),-0.15(s,1H),-0.29(s,0.5H).

[0427] Example 54: 2-amino-N-(1-cyclopropylethyl)-7-fluoro-3-(hydroxymethyl)-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)quinoline-6-carboxamide

[0428] The first step: Under nitrogen protection, 4-trifluoromethyl salicylaldehyde (2.0 g, 10.5 mmol) was dissolved in dichloromethane (20 mL), and 1-cyclopropylethyl-1-amine (1.07 g, 0.0126 mol) and anhydrous sodium sulfate (5.96 g, 0.0042 mol) were added. The mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered and the filtrate was concentrated to give (E)-2-(((1-cyclopropylethyl)imino)methyl)-5-(trifluoromethyl)phenol (2.3 g, crude) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ14.00(s,1H),8.36(s,1H),7.36(d,J=8.0Hz,1H),7.20(s,1H),7.10(d, J=8.0Hz,1H),2.78–2.73(m,1H),1.07(d,J=8.1Hz,1H),0.60–0.51(m,2H),0.27–0.20(m,2H).

[0429] Step 2: Under nitrogen, potassium tert-butoxide (4.03 g, 0.036 mol) was added portionwise to a suspension of trimethylsulfoxide iodide (7.87 g, 0.036 mol) in tetrahydrofuran (40 mL). The mixture was stirred at room temperature for 1 hour, followed by the addition of a solution of (E)-2-(((1-cyclopropylethyl)imino)methyl)-5-(trifluoromethyl)phenol (2.3 g, 8.9 mmol) in tetrahydrofuran (10 mL). The resulting mixture was stirred at room temperature for 1 hour, then at 50°C for 3 hours. The reaction mixture was cooled to room temperature, and additional potassium tert-butoxide (1.0 g, 8.9 mmol) was added, and the resulting mixture was stirred at room temperature for 11 hours. The reaction mixture was filtered, and the filtrate was poured into water and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The resulting crude product was purified on a silica gel column (petroleum ether / ethyl acetate = 6:1) to give yellow oily N-(1-cyclopropylethyl)-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine (P1, 0.37 g) and (P2, 0.45 g). P1: 1 H NMR (400MHz, CDCl3) δ7.39-7.34(m,1H),7.19-7.12(m,1H),7.05(s,1H),4.70-4.60(m,2H),4.43-4.35 (m,1H),2.14-2.06(m,1H),1.23-1.19(m,3H),0.80-0.71(m,1H),0.58-0.43(m,2H),0.16-0.04(m,2H). P2: 1 H NMR (400MHz, CDCl3) δ7.44-7.38(m,1H),7.19-7.12(m,1H),7.04(s,1H),4.70-4.60(m,2H),4.43-4.35 (m,1H),2.10-2.01(m,1H),1.23-1.19(m,3H),0.80-0.71(m,1H),0.60-0.46(m,2H),0.25-0.10(m,2H).

[0430] Step 3: Under nitrogen protection, DIEA (1.1 g, 8.6 mmol) was added to a solution of 2-amino-3-(((tert-butyldimethylsilyl)oxy)methyl)-7-fluoroquinoline-6-carboxylic acid (300 mg, 0.86 mmol) and N-(1-cyclopropylethyl)-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine (232 mg, 0.86 mmol) in dichloromethane (5 mL). The temperature was lowered and phosphorus oxychloride (197 mg, 1.28 mmol) was added at 0°C. The reaction mixture was stirred at 25°C for 2 hours. The reaction was quenched with water and extracted with dichloromethane (20 mL*3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The crude product was purified on a silica gel column (petroleum ether / ethyl acetate = 3:1) to afford 2-amino-3-(((tert-butyldimethylsilyl)oxy)methyl)-N-(1-cyclopropylethyl)-7-fluoro-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)quinoline-6-carboxamide (P1, 77 mg) and (P2, 78 mg) as yellow solids. ESI-MS: m / z = 603.7 / 604.0 [M+1].

[0431] Step 4: Under nitrogen protection, lithium hydroxide (12.4 mg, 0.52 mmol) was added to a solution of 2-amino-3-(((tert-butyldimethylsilyl)oxy)methyl)-N-(1-cyclopropylethyl)-7-fluoro-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)quinoline-6-carboxamide (78 mg, 0.25 mmol) in tetrahydrofuran / methanol / water = 1:1:1 (6 mL). The reaction mixture was stirred at 25 ° C for 3 hours. The reaction solution was poured into water and extracted with ethyl acetate (20 mL * 3). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. 2-Amino-N-(1-cyclopropylethyl)-7-fluoro-3-(hydroxymethyl)-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)quinoline-6-carboxamide (P1, 50 mg) and (P2, 50 mg) were obtained as crude yellow solids. ESI-MS: m / z = 489.4 / 490.2 [M+1]+.

[0432] Step 5: Separate the racemate by SFC chiral column chromatography. Separation conditions: Column: Chiral ChIRALPAK-AD, 20 x 250 mm, 5 μm, Mobile Phase A: CO2, Mobile Phase B: 30% ethanol (0.1% DEA), Flow rate: 40 mL / min; P1-Peak 1 retention time: 1.431 min, P1-Peak 2 retention time: 2.254 min, P2-Peak 1 retention time: 1.510 min, P2-Peak 2 retention time: 2.519 min.

[0433] P1-Peak1 (i.e. 54-1): 1 H NMR(400MHz,DMSO_d6)δ7.92(s,1H),7.78-7.58(m,1H),7.56-7.42(m,1H),7.35-7.02(m,3H),6.52(s,2H),5.70-5.57(m,1H),5.46-5.35(m ,1H),4.93-4.80(m,1H),4.74-4.57(m,1H),4.51-4.36(m,2H),2.92- 2.79(m,1H),1.38-1.10(m,4H),0.72-0.48(m,2H),0.30-0.06(m,2H).

[0434] P1-Peak 2 (i.e. 54-2): 1 H NMR(400MHz,DMSO_d6)δ7.92(s,1H),7.78-7.58(m,1H),7.56-7.42(m,1H),7.32-7.05(m,3H),6.52(s,2H),5.70-5.57(m,1H),5.48-5.36(m ,1H),4.93-4.80(m,1H),4.74-4.57(m,1H),4.51-4.36(m,2H),2.92- 2.79(m,1H),1.34-1.16(m,4H),0.72-0.48(m,2H),0.30-0.05(m,2H).

[0435] P2-Peak 1 (i.e. 54-3): 1H NMR(400MHz,DMSO_d6)δ7.99(s,1H),7.82-7.70(m,1H),7.56-7.37(m,1H), 7.28-7.09(m,3H),6.90-6.53(m,2H),5.68-5.56(m,1H),5.50-5.39(m,1H), 4.92-4.82(m,1H),4.81-4.69(m,1H),4.50-4.35(m,2H),2.83-2.70(m,1H), 1.53-1.37(m,3H),1.14-1.01(m,1H),0.56-0.39(m,2H),0.18-0.01(m,2H).

[0436] P2-Peak 2 (i.e. 54-4): 1 H NMR(400MHz,DMSO_d6)δ7.95(s,1H),7.75-7.65(m,1H),7.56-7.37(m,1H), 7.28-7.09(m,3H),6.65-6.43(m,2H),5.68-5.56(m,1H),5.50-5.39(m,1H), 4.92-4.82(m,1H),4.79-4.69(m,1H),4.50-4.39(m,2H),2.83-2.70(m,1H), 1.53-1.37(m,3H),1.12-1.05(m,1H),0.56-0.39(m,2H),0.14-0.01(m,2H).

[0437] Example 55: 2-amino-3-(hydroxymethyl)-N-(2-(oxetan-3-yl)ethyl)-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)quinoline-6-carboxamide

[0438] The first step: Under nitrogen protection, 4-trifluoromethyl salicylaldehyde (1.5 g, 7.8 mmol) was dissolved in dichloromethane (20 mL), and 2-(oxetane-3-yl)ethylamine (0.95 g, 9.4 mmol) and anhydrous sodium sulfate (4.43 g, 31.2 mmol) were added. The mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered and the filtrate was concentrated to give (E)-2-(((2-(oxetane-3-yl)ethyl)imino)methyl)-5-(trifluoromethyl)phenol (2.0 g, crude) as a yellow solid. 1H NMR (400MHz, CDCl3) δ13.79-13.28(m,1H),8.39(d,J=15.6Hz,1H),7.38-7.33(m,1H),7.21(s,1H),7.14-7.09(m,1H),4.86-4.77(m,1H),4.7 4-4.66(m,1H),4.47-4.40(m,2H),3.70(t,J=7.2Hz,1H),3.61(t,J=6.8Hz,1H),3.23-3.03(m,1H),2.34(t,J=6.8Hz,1H),2.16-2.09(m,1H).

[0439] Step 2: Under nitrogen, potassium tert-butoxide (3.47 g, 0.031 mol) was added portionwise to a suspension of trimethylsulfoxide iodide (6.84 g, 0.031 mol) in tetrahydrofuran (40 mL). The mixture was stirred at room temperature for 1 hour, followed by the addition of a solution of (E)-2-(((2-(oxetan-3-yl)ethyl)imino)methyl)-5-(trifluoromethyl)phenol (2.0 g, 7.3 mmol) in tetrahydrofuran (10 mL). The resulting mixture was stirred at room temperature for 1 hour, then at 50°C for 3 hours. The reaction mixture was cooled to room temperature, and additional potassium tert-butoxide (0.82 g, 7.3 mmol) was added, and the resulting mixture was stirred at room temperature for 11 hours. The reaction mixture was filtered, and the filtrate was poured into water and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The crude product obtained was purified by silica gel column (petroleum ether / ethyl acetate = 5:1) to give yellow oily N-(2-(oxetane-3-yl)ethyl)-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine (0.6 g, yield: 30%). 1 H NMR (400MHz, CDCl3) δ7.45-7.35(m,1H),7.21-7.11(m,1H),7.06(s,1H),4.69-4.58(m,1H),4.54-4.40 (m,2H),3.69-3.57(m,1H),3.56-3.45(m,1H),2.87-2.29(m,5H),2.00-1.91(m,1H),1.66-1.53(m,1H).

[0440] Step 3: Under nitrogen protection, TCFH (213 mg, 0.76 mmol) and NMI (119 mg, 1.45 mmol) were added to a solution of 2-amino-3-((tert-butyldimethylsilyl)oxy)methyl)quinoline-6-carboxylic acid (230 mg, 0.69 mmol) and N-(2-(oxetane-3-yl)ethyl)-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine (199 mg, 0.69 mmol) in acetonitrile (5 mL). The reaction mixture was stirred at 25 ° C for 16 hours. The reaction was quenched with water and extracted with ethyl acetate (20 mL * 3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column purification (petroleum ether / ethyl acetate = 10:1) to give 2-amino-3-(((tert-butyldimethylsilyl)oxy)methyl)-N-(2-(oxetan-3-yl)ethyl)-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)quinoline-6-carboxamide as a white solid (150 mg, yield: 35.9%) ESI-MS: m / z = 601.3 / 602.1 [M+1]+.

[0441] Step 4: Under nitrogen protection, TBAF (196 mg, 0.75 mmol) was added to a solution of 2-amino-3-(((tert-butyldimethylsilyl)oxy)methyl)-N-(2-(oxetane-3-yl)ethyl)-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)quinoline-6-carboxamide (150 mg, 0.25 mmol) in tetrahydrofuran (5 mL). The reaction mixture was stirred at 25 ° C for 2 hours. The reaction solution was poured into water and extracted with dichloromethane (20 mL * 3). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by high pressure preparative purification to afford 2-amino-3-(hydroxymethyl)-N-(2-(oxetan-3-yl)ethyl)-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)quinoline-6-carboxamide (70 mg, 57.71% yield) as a white solid. ESI-MS: m / z = 487.2 / 488.0 [M+1]+.

[0442] Step 5: The racemate (70 mg) was separated by SFC chiral column chromatography. Separation conditions: Column: Chiral ChIRALPAK-AD, 20 x 250 mm, 5 μm, Mobile Phase A: CO2, Mobile Phase B: 30% ethanol (0.1% DEA), Flow rate: 40 mL / min; Peak 1 retention time: 0.821 min, 0.872 min, Peak 2 retention time: 1.141 min.

[0443] Peak 1 (i.e. 55-1): 1 H NMR(400MHz,DMSO_d6)δ8.32(s,1H),8.03(s,1H),7.96-7.87(m,1H),7.64-7. 53(m,1H),7.53-7.45(m,1H),7.26-7.19(m,1H),7.16(s,1H),6.64(s,2H),5. 49-5.39(m,1H),4.69-4.61(m,1H),4.58-4.40(m,4H),4.24-4.10(m,2H),2.8 5-2.57(m,2.5H),2.48-2.28(m,2.5H),2.00-1.84(m,1H),1.57-1.44(m,1H).

[0444] Peak 2 (i.e. 55-2): 1 H NMR(400MHz,DMSO_d6)δ8.37-8.29(m,1H),8.03(s,1H),7.96-7.87(m,1H),7.6 4-7.53(m,1H),7.53-7.45(m,1H),7.26-7.19(m,1H),7.17(s,1H),6.64(s,2H) ,5.49-5.39(m,1H),4.69-4.61(m,1H),4.58-4.40(m,4H),4.24-4.10(m,2H),2 .74-2.55(m,2.5H),2.49-2.36(m,2.5H),2.00-1.84(m,1H),1.57-1.44(m,1H).

[0445] Reference is made to the aforementioned method for synthesizing the embodiment:

[0446] Experimental Example 1: HCT116 (MTAP+ / -) cell arginine symmetric dimethylation (SDMA) inhibitory activity test method

[0447] MTAP wild-type (MTAP WT) or knockout (MTAP del) HCT116 cells were seeded in 384-well plates, 30 μL / well, and incubated overnight at 37°C, 5% CO2; 60 nL of serially diluted compounds were added to each well and incubated at 37°C, 5% CO2 for 96 hours. 50 μL of 4% paraformaldehyde solution was added to each well, and the cells were fixed by incubation at room temperature for 20 minutes. The solution was discarded, and the cells were washed with PBS solution containing 0.1% Tween 20 (PBST), and the process was repeated 4 times. 30 μL of pre-chilled methanol was added to each well, and the cells were incubated at -20°C for 10 minutes. The methanol was discarded, and the cells were washed with PBST, and the process was repeated 4 times. 30 μL of Odyssey blocking solution containing 0.05% Tween 20 was added to each well, and the cells were incubated at room temperature for 2 hours with shaking. The blocking solution was discarded, and 30 μL of primary antibody (Symmetric Di-Methyl Arginine Motif [sdme-RG] MultiMab) diluted (1:500) in Odyssey blocking solution containing 0.05% Tween 20 was added. TM Rabbit mAb mix), incubated overnight at 4°C, washed four times with PBST, 5 minutes each time; 30 μL of secondary antibody (goat anti-rabbit IRDye 800CW, 1:800) and nuclear stain (DRAQ5, 1:10000) diluted in Odyssey blocking solution containing 0.05% Tween 20 were added to each well, incubated at room temperature for 2 hours in the dark, then discarded and washed four times with PBST. The Li-Cor Odyssey instrument was used to scan sdme-RG and DRAQ5 signals at 800 nm and 700 nm, respectively, to collect data. The ratio of sdme-RG / DRAQ5 was used to calculate the percentage of inhibition of symmetric dimethylation of arginine (SDMA), and the IC was calculated using GraphPad Prism software. 50 value.

[0448] Inhibition rate calculation formula: SDMA Inhibition (%) = 100 * (1-SDMA dose / SDMA DMSO control)

[0449] Table: Arginine symmetric dimethylation (SDMA) inhibitory activity (IC) of compounds in MTAP wild-type or knockout colorectal cancer HCT-116 cells 50 , nM)

[0450] Test Example 2: PRMT5-MTA inhibitory activity test method

[0451] All compounds were dissolved in DMSO to a 20 mM or 10 mM stock solution. Test compounds were serially diluted 3-fold in DMSO from 200 μM to 10 concentration gradients. 1 μL of the serially diluted compound was added to 65.67 μL of assay buffer to obtain 3X compound and positive compound working solutions. 3X positive control (3uM positive compound solution) and 3X negative control (1.5% DMSO) were prepared. Seal the dilution plate and shake the dilution plate on a plate shaker for 15 minutes. Add 4 μL of the 3X serially diluted compound to the 384-well assay plate. Prepare a 3X PRMT5 mixed working solution containing MTA. Add 4 μL of the 3X PRMT5 enzyme to the 384-well assay plate. Seal the assay plate, centrifuge the 384-well assay plate at 1000 rpm for 1 minute, and place in a 25°C incubator for 30 minutes. Prepare a 3X PRMT5 substrate working solution. Start the reaction by adding 4 μL of 3X PRMT5 substrate working solution to a 384-well assay plate. Seal the plate, centrifuge at 1000 rpm for 1 minute, and incubate in a 25°C incubator for 90 minutes. Prepare a 4X detection solution using Protin-A-Eu, Anti-Histone H4 (symmetric dimethyl R3) Antibody, and streptavidin-d2. Add 4 μL of 4X detection solution to a 384-well assay plate. Seal the plate and centrifuge at 1000 rpm for 1 minute. Read at 665 nm and 615 nm on a BMG plate reader.

[0452] Inhibition rate calculation formula:

[0453] Table: Inhibitory activity of compounds against PRMT5-MTA (IC 50 , nM)

[0454] Compared with the control compound, the compound of the present invention has better inhibitory activity against PRMT5-MTA.

[0455] Test Example 3: Mouse Pharmacokinetic Test Method

[0456] The pharmacokinetic properties of the compounds of the present invention were tested in ICR mice.

[0457] Experimental materials: ICR mice (male, 6-8 weeks, 17-21 g).

[0458] Experimental operation:

[0459] Compound formulation and administration

[0460] The compound was accurately weighed, dissolved in 5% DMSO / 10% Solutol / 85% water to prepare a clear solution and administered intravenously to mice at a single dose of 1 mg / kg. It was also dissolved in 0.5% CMC-Na to prepare a homogeneous suspension and administered orally to mice at a single dose of 10 mg / kg.

[0461] Sample collection

[0462] Whole blood samples were collected within 24 hours and centrifuged at 2000g for 10 minutes at 4°C. The supernatant was separated to obtain plasma samples. To each sample, 10 μL of plasma was added to 5 μL of working solution and 50 μL of acetonitrile containing an internal standard. The sample was vortexed for 1 minute and centrifuged at 13000g for 10 minutes at 4°C. The supernatant was injected and the plasma drug concentration was quantified by LC-MS / MS analysis, and pharmacokinetic parameters were calculated.

[0463] The compound of the present invention has good in vivo pharmacokinetic properties.

Claims

1. The PRMT5 inhibitor is a compound of formula (I), an enantiomer, a diastereomer, a racemate, a solvate, a hydrate, a polymorph, a prodrug, an isotopic variant, or a pharmaceutically acceptable salt thereof: in, X is: C or N; Z is: C=O or S(O)2; R1 and R2 are each independently: H； C 1～6 Alkyl, C 2～6 Olefin group, C 2～6 Alkyne, optionally one or more H on the carbon atom thereof is substituted by the same or different halogen, hydroxyl, amino, carbonyl, keto, cyano; when C 3～6 Alkyl, C 3～6 Olefin group, C 3～6 When it is an alkynyl group, it includes straight chain, branched chain or cyclic; R a R b R c CO- or R a R b R c C-CO-, where R a , R b , R c Each independently is H, C 1～6 Alkyl, C 2～6 Olefin group, C 2～6 Alkyne, optionally wherein one or more H on the carbon atom is replaced by the same or different halogen, hydroxyl, amino, carbonyl, keto, cyano; when C 3～6 Alkyl, C 3～6 Olefin group, C 3～6 When alkynyl is a straight chain, branched chain or cyclic; or R d R e N- or R d R e N-CO-, where R d , R e Each is independent of H and C 1～6 Alkyl, C 2～6 Olefin group, C 2～6 Alkyne, optionally wherein one or more H on the carbon atom is independently substituted by the same or different halogen, hydroxyl, amino, carbonyl, keto, cyano; when C 3～6 Alkyl, C 3～6 Olefin group, C 3～6 When it is an alkynyl group, it includes straight chain, branched chain or cyclic; R3 is H, halogen, hydroxyl, amino, carbonyl, keto, cyano, wherein one or two H on the amino group are independently replaced by the same or different C 1～6 Alkyl, C 2～6 Olefin group, C 2～6 Alkyne substituted; R4 is -NR5R6, wherein R5 or R6 are each independently C 1～6 Alkyl, saturated or unsaturated C 3～6 Cycloalkyl or heterocyclic group, aryl, aromatic hetero group, aryl and saturated or unsaturated C 3～6 Cycloalkyl or heterocyclic, aromatic and saturated or unsaturated C 3～6 Cycloalkyl or heterocyclic group, the saturated or unsaturated C 3～6 The cycloalkyl or aromatic heterocyclic ring contains one or more identical or different heteroatoms selected from N, O, and S; one or more H in the optional substituents are independently replaced by halogen, C 1～6 Haloalkyl, C 1～6 Alkoxy, hydroxy, amino, cyano, carbonyl, saturated or unsaturated C 3～6 Cycloalkyl or heterocyclyl substituted; or In the -NR5R6, the N atom and the atoms in R6 and R5 form a ring; When R1 is methyl, X is N.

2. The PRMT5 inhibitor according to claim 1, characterized in that When R1 is -CH2OH, R2 is not CH3.

3. The PRMT5 inhibitor according to claim 1, characterized in that In the compound of structural formula (I), the halogen is F, Cl, Br or I; the halogenated includes substitution by one or more identical or different F, Cl, Br or I.

4. The PRMT5 inhibitor according to claim 1, characterized in that In the compound of structural formula (I), R1 is H, CH3, CH3O, OHCH2, CH3(OH)CH, NH2CO, CH3NHCO, CH2NH2 or CH3CO.

5. The PRMT5 inhibitor according to claim 1, characterized in that In the compound of structural formula (I), R2 is H, CH3, CH3O, OHCH2, CH3NH, (CH3)2N, CH3(OH)CH, NH2CO, CH3NHCO or CH3CO.

6. The PRMT5 inhibitor according to claim 1, characterized in that In the compound of formula (I), R3 is hydrogen, halogen, hydroxyl or C 1～6 Alkoxy.

7. The PRMT5 inhibitor according to claim 1, characterized in that In the compound of structural formula (I), X is C.

8. The PRMT5 inhibitor according to claim 1, characterized in that In the compound of the structural formula (I), Z is C=O.

9. The PRMT5 inhibitor according to claim 1, characterized in that In the compound of structural formula (I), R5 is selected from the following structures:

10. The PRMT5 inhibitor according to claim 1, characterized in that In the compound of structural formula (I), R6 is selected from the following structures: -CH2CH3 or CH3.

11. The PRMT5 inhibitor according to claim 1, characterized in that In the compound of structural formula (I), R4 is -NR5R6, and when the N atom and the atoms in R6 and R5 form a ring, it is selected from the following structures:

12. The PRMT5 inhibitor according to claim 1, characterized in that The compound of structural formula (I) is selected from the following:

13. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises the compound of formula (I), enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, isotopic variant, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12 and a pharmaceutically acceptable carrier.

14. The pharmaceutical composition according to claim 13, characterized in that The pharmaceutical composition includes oral preparations or injection preparations. The oral preparations include ordinary tablets, capsules, oral liquids, granules, capsules, dispersible tablets, chewable tablets, effervescent tablets or sustained-release preparations; the injection preparations include: solutions for injection, freeze-dried injections, or powder injections.

15. Use of the compound of formula (I) according to any one of claims 1 to 12, its enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, isotopic variant, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of claims 13 to 14 in the preparation of a drug for treating cancer.

16. The compound of formula (I) according to any one of claims 1 to 12, its enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, isotopic variant, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of claims 13 to 14, in the preparation of a therapeutic agent for adenocarcinoma, squamous cell carcinoma, lung cancer, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, bronchial cancer, esophageal / duct cancer, esophageal adenocarcinoma, gastric cancer, gastric adenocarcinoma, gastrointestinal stromal tumor, colorectal cancer, colon cancer, rectal cancer, colorectal adenocarcinoma, melanoma, brain tumor, meningioma, glioma, astrocytoma, oligodendroglioma, medulloblastoma, Neuroblastoma, glioblastoma, neurofibroma, neurofibromatosis type 1 or type 2, schwannomatosis, malignant schwannoma, neuroendocrine carcinoma, gastroenteropancreatic neuroendocrine tumor, breast cancer, prostate cancer, ovarian cancer, ovarian adenocarcinoma, cystadenocarcinoma, ovarian embryonal carcinoma, uterine cancer, endometrial cancer, uterine sarcoma, cervical cancer, cervical adenocarcinoma, bladder cancer, germ cell tumor, pancreatic cancer, liver cancer, hepatocellular carcinoma, cholangiocarcinoma, kidney cancer, renal cell carcinoma, papillary renal cell carcinoma, renal clear cell carcinoma, Wilms tumor, head and neck cancer, head and neck squamous cell carcinoma, sarcoma, angiosarcoma, lymphangiosarcoma, lymphangioendothelial sarcoma, hemangioma, osteosarcoma, Ewing's sarcoma, endothelial carcinoma tumors, Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcomas, eye cancer, intraocular melanoma, retinoblastoma, oral cancer, oral squamous cell carcinoma, laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer, mesothelioma, adenoid cystic carcinoma, thymoma, adrenal cancer, anal cancer, appendix cancer and hematopoietic system cancers, such as lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, small lymphocytic lymphoma, marginal zone B-cell lymphoma, mucosa-associated lymphoid tissue lymphoma, lymph node marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma, primary mediastinal B-cell lymphoma, Burkitt's lymphoma, lymphoplasmacytic lymphoma, immunoblastic Application of drugs in large cell lymphoma, precursor B lymphoblastic lymphoma and primary central nervous system lymphoma, T-cell non-Hodgkin's lymphoma, precursor T lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma, angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy-type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma, multiple myeloma (MM), leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, chronic myeloid leukemia, myelodysplastic syndrome or myelofibrosis.

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