Quinoline derivative compound or pharmaceutically acceptable salt thereof, and its production method and application

Abstract

The present invention discloses a quinoline-derived compound or a pharmaceutically acceptable salt thereof, as well as its preparation method and application. The structural formula of the quinoline-derived compound provided by the present invention is as shown in Formula I. The compound or a pharmaceutically acceptable salt, solvate, or pharmaceutical composition thereof can be used to manufacture a medicament for the prevention and / or treatment of inflammatory diseases. The quinoline-derived compound provided by the present invention has an ideal inhibitory effect on proinflammatory cytokines (e.g., IL-6, TNF-α, etc.) through upregulation of miR-124, and is therefore useful for the treatment of inflammatory diseases such as ulcerative colitis. TIFF2026503131000059.tif30169

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present invention claims priority from an earlier application filed with the State Intellectual Property Office of China on January 20, 2023, bearing application number 202310062976.0 and entitled "Quinoline derivative compounds or pharmaceutically acceptable salts thereof, and their preparation methods and applications." The entire contents of the above-referenced prior application are incorporated herein by reference. [Technical Field]

[0002] The present invention belongs to the technical field of small molecule pharmaceuticals, and particularly relates to a quinoline derivative compound or a pharmaceutically acceptable salt thereof, and a preparation method and application thereof. [Background technology]

[0003] Inflammation is a defense response of the body to stimuli, and is closely related to the pathological course of many diseases, including autoimmune-related inflammatory diseases, inflammatory diseases of the central nervous system (CNS), inflammatory diseases of the joints, inflammatory diseases of the gastrointestinal tract, inflammatory diseases of the skin, other inflammatory diseases related to epithelial cells, cancer-related inflammation, irritant-related inflammation, and injury-related inflammation.

[0004] Inflammatory bowel disease (IBD) is a chronic non-specific inflammatory disease of the intestine that primarily includes ulcerative colitis (UC) and Crohn's disease (CD). In recent years, with changes in people's living standards and eating habits, the incidence of IBD has been on the rise, and the incidence rate is higher in developed countries than in developing countries. Ulcerative colitis is a chronic disease that causes inflammation and ulcers in the colon and rectum, and its main symptoms at the onset include abdominal pain, bloody diarrhea, weight loss, fever, and the like. Complications of ulcerative colitis can include megacolon, inflammation of the eyes, joints and liver, and colon cancer.

[0005] Various cytokines are involved in immune responses and inflammatory processes and are mainly divided into pro-inflammatory cytokines (e.g., IL-1, IL-6, TNF-α, etc.) and anti-inflammatory cytokines (e.g., IL-4, IL-10, etc.). Studies have shown that the levels of pro-inflammatory cytokines (e.g., IL-6, TNF-α) are elevated in the intestinal mucosa of UC patients, and the secretion of anti-inflammatory cytokines is relatively insufficient, resulting in an excessive inflammatory response in the intestinal mucosa and intestinal damage. Among them, TNF-α is a key cytokine in the pathological course of IBD, and serum levels of TNF-α correlate with the clinical activity of UC and Crohn's disease (CD). Anti-TNF-α antibodies are widely used in the treatment of IBD and have shown good efficacy.

[0006] Research has shown that the specific downregulation of miR-124 in the bodies of pediatric patients with UC leads to increased expression of signal transducer and activator of transcription 3 (STAT3) and the transcriptional activation of its downstream targets (e.g., pro-inflammatory cytokines IL-6, TNF-α, etc.) (Koukos et al.; Gastroenterology, 145(4):842-52:2013), ultimately leading to a series of inflammatory symptoms. Therefore, selective upregulation of miR-124 levels in vivo plays a role in inhibiting the expression of signal transducer and activator of transcription 3 (STAT3) and the transcriptional activation of its downstream targets (e.g., proinflammatory cytokines IL-6, TNF-α, etc.).

[0007] Currently, UC is treated by surgery and medication, and commonly used medications include corticosteroids, aminosalicylates, glucocorticoids, antibiotics, and immunomodulators. Salazosulfapyridine-based treatments are often effective for patients with mild UC, but their therapeutic value is limited for those with moderate to severe disease. For patients with moderate to severe UC, corticosteroid drugs are commonly used to rapidly induce remission of the disease; however, their long-term use can induce many side effects (e.g., osteoporosis and fractures, infections, cataracts, delayed wound healing, and inhibition of adrenaline secretion), so it is not recommended to continue treating the disease with steroid drugs for a long period of time. Systemic immunosuppressants such as azathioprine, cyclosporine, and methotrexate have shown some therapeutic efficacy in patients with moderate to severe UC, reducing the frequency of attacks. However, long-term systemic immunosuppression may have serious consequences (e.g., increased risk of infection and risk of developing lymphoma), and long-term use may be problematic. Anti-TNF-α antibodies (e.g., infliximab and adalimumab) are expensive, require subcutaneous or intravenous administration, and are effective in only approximately 60% to 70% of patients with moderate to severe UC. Approximately one-third of patients do not respond adequately, and another third of initial responders gradually develop drug resistance after several weeks of treatment. Current mainstream UC treatments use vedolizumab and anti-α4β7 integrin antibodies, which are effective in patients with moderate to severe UC. However, these drugs must be administered by injection, and many treated patients do not achieve remission and ultimately require surgery. Therefore, there is an urgent need to develop drugs that are safer, more effective, and have fewer toxic side effects.

[0008] The enzyme system most closely related to drug metabolism is the cytochrome P450 (CYP) enzyme system, which is mainly present in the human liver, with smaller amounts also expressed in the kidneys, small intestine, lungs, and brain. It is involved in the biotransformation of many endogenous substances and xenobiotics (including most clinical drugs). CYP is a gene superfamily responsible for encoding over 500 enzyme proteins. Based on the similarity of the proteins encoded by these genes, they are classified into different gene families and subfamilies. Among them, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 are the six most major subtypes of CYP450, accounting for approximately 80% of the total amount of CYP450 enzymes in the liver. In the majority of humans, CYP3A4 accounts for 50% of the total CYPs, and 90% of drugs are metabolized by these six subtypes. When using drugs in clinical practice, it is necessary to consider drug-drug interactions (DDIs). The main reason for this is that many chemical substances can increase (inducers) or decrease (inhibitors) the activity of CYPs, thereby changing the metabolic rate of the drug and affecting its effectiveness. Of the drug interactions that have already been identified, those mediated by the CYP450 enzyme system account for 70%. Therefore, understanding the types of drugs catalyzed by each CYP has important implications for the rational use of drugs in clinical practice, avoidance of drug side effects, implementation of individualized dosing regimens, and elucidation of drug interactions occurring at the metabolic stage.

[0009] Patent WO2015001518A1 discloses the compound ABX464, an orally administered small molecule that is used to treat ulcerative colitis by upregulating miR-124, and is currently in Phase III clinical trials. However, there are problems with drug discovery potential, such as the effect of regulating proinflammatory cytokines (e.g., IL-6, TNF-α, etc.) being less than ideal, and the strong inhibition of individual subtypes of CYP450 enzymes. JPEG2026503131000002.jpg33169

[0010] Therefore, the current challenge is to find compounds that have more ideal regulatory effects on proinflammatory cytokines and do not have inhibitory effects on CYP450 enzymes, and to use them in the manufacture of drugs to treat inflammatory diseases. Summary of the Invention

[0011] To solve the problems in the technical background, the present invention provides a quinoline derivative compound or a pharmaceutically acceptable salt thereof, and a preparation method and application thereof.

[0012] First, the present application provides a quinoline-derived compound or a pharmaceutically acceptable salt thereof, the structural formula of which is shown in Formula I: JPEG2026503131000003.jpg30169 where: A1, A2, A3, A4 and A5 are each independently selected from N or C-R1, where A1, A2, A3, A4 and A5 simultaneously each contain at most two Ns; R1 is selected from hydrogen, deuterium, halogen, cyano group, amino group, hydroxy group, nitro group, C1-C3 alkyl group, C1-C3 alkanoyl group, C1-C3 alkylsulfonyl group, C1-C3 alkylamine group, C1-C3 alkylphosphate group, C1-C3 alkylaminosulfonyl group, aminosulfonyl group, C1-C3 alkoxy group and phosphate group, wherein the C1-C3 alkyl group, C1-C3 alkanoyl group, C1-C3 alkylsulfonyl group, C1-C3 alkylamine group, C1-C3 alkylphosphate group, C1-C3 alkylaminosulfonyl group and C1-C3 alkoxy group are each independently substituted with one or more identical or different substituents selected from C1-C3 alkyl group, C1-C6 alkoxy group, C3-C7 cycloalkyl group, C3-C6 heterocycloalkyl group, deuterium, halogen, cyano group, amino group, hydroxy group and nitro group; R2 is selected from hydrogen, an alkyl group, a cycloalkyl group, and a heterocycloalkyl group, wherein the alkyl group, the cycloalkyl group, and the heterocycloalkyl group are each independently substituted with one or more of the same or different substituents selected from halogen, hydroxy group, carboxy group, alkyl group, alkoxy group, deuterium, haloalkyl group, haloalkoxy group, nitro group, amino group, and cyano group; R3 and R4 are each independently selected from a cyano group, a hydroxy group, a C1-C3 alkyl group, a C1-C3 alkanoyl group, a C1-C3 alkylamine group, and a C1-C3 alkoxy group, wherein the C1-C3 alkyl group, the C1-C3 alkanoyl group, the C1-C3 alkylamine group, and the C1-C3 alkoxy group are each independently substituted with one or more identical or different substituents selected from a halogen, a hydroxy group, a carboxy group, an ester group, an alkyl group, an alkoxy group, deuterium, a haloalkyl group, a haloalkoxy group, a nitro group, an amino group, and a cyano group; or R3 and R4 combine with each other to form a C3-C6 cycloalkyl group or a C3-C6 heterocycloalkyl group; R5 is selected from halogen, an amino group, a hydroxy group, a nitro group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkanoyl group, a C1-C6 alkylsulfonyl group, a C1-C6 alkylamine group, a C1-C6 alkylphosphate group, a C1-C6 alkylaminosulfonyl group, an aminosulfonyl group, and a C1-C6 alkoxy group; R3, R4 and R5 cannot simultaneously be an alkyl group or a cycloalkyl group; Each R6 is the same or different and is independently selected from hydrogen, deuterium, halogen, cyano, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkanoyl, C1-C3 alkylamine, C1-C3 alkylsulfonyl, C1-C3 alkylphosphate, C1-C3 alkylaminosulfonyl, aminosulfonyl, C3-C7 cycloalkyl, C3-C6 heterocycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, and phosphate; the 1-C3 alkanoyl group, C1-C3 alkylamine group, C1-C3 alkylsulfonyl group, C1-C3 alkylphosphate group, C1-C3 alkylaminosulfonyl group, C3-C7 cycloalkyl group, C3-C6 heterocycloalkyl group, C2-C6 alkenyl group and C2-C6 alkynyl group are each independently optionally substituted with one or more of the same or different substituents selected from a C1-C6 alkyl group, a C1-C6 alkoxy group, a C3-C7 cycloalkyl group, a C3-C6 heterocycloalkyl group, deuterium, a halogen, a cyano group, an amino group, a hydroxy group and a nitro group; n=1, 2 or 3.

[0013] Preferably, the structural formula of the quinoline derivative compound is as shown in Formula I-1. JPEG2026503131000004.jpg30169 where: each R7 is the same or different and is independently selected from hydrogen, halogen, amino, hydroxy, nitro, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkanoyl, C1-C3 alkylsulfonyl, C1-C3 alkylamine, C1-C3 alkylphosphate, C1-C3 alkylaminosulfonyl, aminosulfonyl, and C1-C3 alkoxy; p=1, 2 or 3; A1, A2, A3, A4, A5, R2, R3, R4, and R6 are as defined in claim 1.

[0014] Preferably, the structural formula of the quinoline-derived compound is as shown in Formula I-2. JPEG2026503131000005.jpg30169

[0015] Preferably, R2 is hydrogen or a C3-C8 heterocycloalkyl group, wherein the C3-C8 heterocycloalkyl group is optionally substituted with one or more identical or different substituents selected from a hydroxy group and a carboxy group.

[0016] Preferably, the structural formula of the quinoline-derived compound is as shown in Formula I-3, Formula I-4 or Formula I-5. JPEG2026503131000006.jpg22169

[0017] JPEG2026503131000007.jpg36169

[0018] JPEG2026503131000008.jpg67169

[0019] Preferably, the structural formula of the quinoline-derived compound is as shown in Formula I-7 or Formula I-8. JPEG2026503131000009.jpg24169 where: R8 is selected from deuterium, halogen, cyano group, amino group, hydroxy group, nitro group, C1-C6 alkyl group, C1-C6 haloalkyl group, C1-C6 alkanoyl group, C1-C6 alkylsulfonyl group, C1-C6 alkylamine group, C1-C6 alkylphosphate group, C1-C6 alkylaminosulfonyl group, aminosulfonyl group, and C1-C6 alkoxy group; Each R9 is the same or different and is independently selected from hydrogen, deuterium, halogen, cyano, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkanoyl, C1-C3 alkylamine, C1-C3 alkylsulfonyl, C1-C3 alkylphosphate, C1-C3 alkylaminosulfonyl, aminosulfonyl, C3-C7 cycloalkyl, C3-C6 heterocycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, and phosphate; the C1-C3 alkanoyl group, C1-C3 alkylamine group, C1-C3 alkylsulfonyl group, C1-C3 alkylphosphate group, C1-C3 alkylaminosulfonyl group, C3-C7 cycloalkyl group, C3-C6 heterocycloalkyl group, C2-C6 alkenyl group and C2-C6 alkynyl group are each independently optionally substituted with one or more identical or different substituents selected from a C1-C6 alkyl group, a C1-C6 alkoxy group, a C3-C7 cycloalkyl group, a C3-C6 heterocycloalkyl group, deuterium, a halogen, a cyano group, an amino group, a hydroxy group and a nitro group; r=0, 1 or 2; A1, A2, A3, A4, A5, R2, R5, and R6 are as defined in claim 1.

[0020] JPEG2026503131000010.jpg34169

[0021] Specifically, the quinoline-derived compound provided by the present invention is preferably any one of the compounds selected from the following: JPEG2026503131000011.jpg180169JPEG2026503131000012.jpg250169

[0022] Next, the present invention provides a method for preparing a quinoline derivative compound or a pharmaceutically acceptable salt thereof, which is used for preparing the compound, and comprises the following steps: JPEG2026503131000013.jpg17169 where: A1, A2, A3, A4 and A5 are each independently selected from N or C-R1, where A1, A2, A3, A4 and A5 simultaneously each contain at most two Ns; R1 is selected from hydrogen, deuterium, halogen, cyano group, amino group, hydroxy group, nitro group, C1-C3 alkyl group, C1-C3 alkanoyl group, C1-C3 alkylsulfonyl group, C1-C3 alkylamine group, C1-C3 alkylphosphate group, C1-C3 alkylaminosulfonyl group, aminosulfonyl group, C1-C3 alkoxy group and phosphate group, wherein the C1-C3 alkyl group, C1-C3 alkanoyl group, C1-C3 alkylsulfonyl group, C1-C3 alkylamine group, C1-C3 alkylphosphate group, C1-C3 alkylaminosulfonyl group and C1-C3 alkoxy group are each independently substituted with one or more identical or different substituents selected from C1-C3 alkyl group, C1-C6 alkoxy group, C3-C7 cycloalkyl group, C3-C6 heterocycloalkyl group, deuterium, halogen, cyano group, amino group, hydroxy group and nitro group; R2 is selected from hydrogen, an alkyl group, a cycloalkyl group, and a heterocycloalkyl group, wherein the alkyl group, the cycloalkyl group, and the heterocycloalkyl group are each independently substituted with one or more of the same or different substituents selected from halogen, hydroxy group, carboxy group, alkyl group, alkoxy group, deuterium, haloalkyl group, haloalkoxy group, nitro group, amino group, and cyano group; R3 and R4 are each independently selected from a cyano group, a hydroxy group, a C1-C3 alkyl group, a C1-C3 alkanoyl group, a C1-C3 alkylamine group, and a C1-C3 alkoxy group; or R3 and R4 combine with each other to form a C3-C6 cycloalkyl group or a C3-C6 heterocycloalkyl group; R5 is selected from deuterium, halogen, an amino group, a hydroxy group, a nitro group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkanoyl group, a C1-C6 alkylsulfonyl group, a C1-C6 alkylamine group, a C1-C6 alkylphosphate group, a C1-C6 alkylaminosulfonyl group, an aminosulfonyl group, and a C1-C6 alkoxy group; R3, R4 and R5 cannot simultaneously be an alkyl group or a cycloalkyl group; Each R6 is the same or different and is independently selected from hydrogen, deuterium, halogen, cyano, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkanoyl, C1-C3 alkylamine, C1-C3 alkylsulfonyl, C1-C3 alkylphosphate, C1-C3 alkylaminosulfonyl, aminosulfonyl, C3-C7 cycloalkyl, C3-C6 heterocycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, and phosphate; the 1-C3 alkanoyl group, C1-C3 alkylamine group, C1-C3 alkylsulfonyl group, C1-C3 alkylphosphate group, C1-C3 alkylaminosulfonyl group, C3-C7 cycloalkyl group, C3-C6 heterocycloalkyl group, C2-C6 alkenyl group and C2-C6 alkynyl group are each independently optionally substituted with one or more of the same or different substituents selected from a C1-C6 alkyl group, a C1-C6 alkoxy group, a C3-C7 cycloalkyl group, a C3-C6 heterocycloalkyl group, deuterium, a halogen, a cyano group, an amino group, a hydroxy group and a nitro group; n=1, 2 or 3.

[0023] Additionally, the present invention further provides pharmaceutical compositions comprising the above-described compounds or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0024] Finally, the present invention further provides the use of the above compound or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the prevention and / or treatment of an inflammatory disease.

[0025] Furthermore, the inflammatory disease is selected from autoimmune-related inflammatory diseases, inflammatory diseases of the central nervous system (CNS), inflammatory diseases of the joints, inflammatory diseases of the gastrointestinal tract, inflammatory diseases of the skin, other inflammatory diseases associated with epithelial cells, cancer-related inflammation, irritant-related inflammation, and injury-related inflammation.

[0026] Further, the inflammatory disease herein is selected from inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, Alzheimer's disease, Parkinson's disease, osteoarthritis, atherosclerosis, ankylosing spondylitis, psoriasis, dermatitis, systemic lupus erythematosus, Sjogren's syndrome, bronchitis, asthma, and inflammation associated with colon cancer.

[0027] Unless otherwise stated, the following terms used in the specification and claims have the meanings set forth below. Certain terms, unless specifically defined, should not be deemed unclear or ambiguous, but should be understood according to their ordinary meaning in the art.

[0028] The term "pharmaceutically acceptable salt" refers to a salt of a pharmaceutically acceptable acid or base, and includes salts that a compound forms with an inorganic or organic acid, and salts that a compound forms with an inorganic or organic base.

[0029] The term "substituted" refers to the replacement of one or more hydrogen atoms in a given structure with a specified substituent. The one or more substituents may be different from one another or may be the same.

[0030] The term "optionally" or "optionally" means that the subsequently described event or circumstance may occur, but need not occur, and the description includes both instances where the event or circumstance occurs and instances where the event or circumstance does not occur. For example, "any C1-C6 alkyl group substituted with a halogen" means that a halogen may be present but is not required to be present, and the description includes situations where the alkyl group is substituted with a halogen and situations where the alkyl group is not substituted with a halogen.

[0031] The term "deuterium" refers to deuteration, i.e. 2 Refers to H or D.

[0032] The term "halogen" refers to fluorine, chlorine, bromine and iodine.

[0033] The term "hydroxy" refers to an -OH group.

[0034] The term "amino group" refers to an -NH2 group.

[0035] The term "cyano" refers to the group -CN.

[0036] The term "nitro group" refers to the -NO2 group.

[0037] The term "alkyl group" refers to saturated aliphatic hydrocarbon groups, including straight and branched chain groups, of 1 to 20 carbon atoms, with alkyl groups containing 1 to 6 carbon atoms being preferred, and alkyl groups containing 1 to 3 carbon atoms being more preferred. The alkyl group may be straight-chain or branched. For example, the term "C1-C6 alkyl group" refers to an alkyl group containing 1, 2, 3, 4, 5, or 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.). Similarly, the alkyl portion (ie, alkyl group) of an alkoxy group, an alkanoyl group, an alkylphosphate group, an alkylsulfonyl group, and an alkylaminosulfonyl group has the same meaning as defined above. For example, the term "C1-C3 alkyl group" refers to alkyl groups containing 1, 2, or 3 carbon atoms (eg, methyl, ethyl, propyl, and isopropyl groups). The alkyl group may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment and include deuterium, halogen, hydroxyl group, nitro group, amino group, cyano group, C1-C6 alkyl group, C1-C6 alkoxy group, C3-C7 cycloalkyl group, 3-membered to 6-membered heterocycloalkyl group, C6-C 10 One or more groups independently selected from an aryl group, a 5- to 10-membered heteroaryl group, and a C2 to C6 alkenyl group are preferred.

[0038] The term "alkoxy" refers to an --O-alkyl group. The term "C1-C6 alkoxy group" can be understood as "C1-C6 alkyloxy group" or "C1-C6 alkyl-O-", and more preferably "C1-C3 alkoxy group". Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.

[0039] The term "alkylsulfonyl" refers to an -S(=O)2-alkyl group.

[0040] JPEG2026503131000014.jpg12169

[0041] The term "ester group" refers to a -C(=O)O-alkyl group.

[0042] The term "C1-C6 alkanoyl group" refers to the monovalent group of atoms remaining after removal of the hydroxy group from a C1-C6 alkyl acid, and is usually used to refer to "C 0-5For example, "C1-C(=O)-" refers to an acetyl group, "C2-C(=O)-" refers to a propionyl group, and "C3-C(=O)-" refers to a butyryl group or an isobutyryl group.

[0043] The term "aminosulfonyl" refers to a radical of formula -S(=O)2NH2.

[0044] The term "alkylamine group" refers to a group in which an alkyl group is linked to a nitrogen atom, the nitrogen atom having at least one hydrogen atom, and the nitrogen atom may have one or two alkyl groups linked to it.

[0045] The term "C1-C6 alkylaminosulfonyl group" refers to a group of formula -S(=O)2NH(alkyl group), where the alkyl group has 1 to 6 carbon atoms. In some implementations, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0046] The term "phosphate group" refers to -PO3H.

[0047] The term "C1-C6 alkyl phosphate group" refers to the group -PO3 (alkyl group).

[0048] The term "haloalkyl group" refers to an alkyl group substituted with one or more halogens, where alkyl group is as defined above.

[0049] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, where alkoxy is as defined above.

[0050] The term "C2-C6 alkenyl group" refers to a straight-chain or branched-chain monovalent hydrocarbon group containing 2 to 6 carbon atoms (e.g., 2, 3, 4, 5, or 6 carbon atoms), and specific examples include, but are not limited to, a vinyl group (-CH=CH2), an allyl group (-CH2CH=CH2), and the like.

[0051] The term "C2-C6 alkynyl group" refers to a group containing 2 to 6 carbon atoms (e.g., 2, 3, 4, 5, 6 carbon atoms) and one or two triple bonds, which can be, but are not limited to, ethynyl, propargyl, butynyl, isobutynyl, pentynyl, isopentynyl, and hexynyl groups.

[0052] The term "cycloalkyl group" refers to carbocyclic rings that are fully saturated and that exist as monocyclic, fused, bridged, or spirocyclic rings. Unless otherwise specified, the carbocyclic ring is generally a 3- to 10-membered ring. Preferably, it contains 3 to 8 ring atoms. Specific examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, spiro[4.5]decane, and the like. A spirocycloalkyl group refers to a cycloalkyl group present in a spiro ring. The term "C3-C7 cycloalkyl group" should be understood as a saturated monovalent monocyclic, fused, spiro or bridged ring, having 3 to 7 carbon atoms, and specific examples include, but are not limited to, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, etc. The cycloalkyl group can be substituted or unsubstituted. When substituted, the number of substituents is preferably one or more, more preferably one, two or three, and even more preferably one or two, and the substituents are selected from the group consisting of halogen, hydroxy group, nitro group, amino group, cyano group, C1-C6 alkyl group, C1-C6 alkoxy group, C3-C6 cycloalkyl group, 3- to 6-membered heterocycloalkyl group, C6-C 10 It is selected from an aryl group, a 5- to 10-membered heteroaryl group, and a C2 to C6 alkenyl group.

[0053] The term "heterocycloalkyl group" refers to a cyclic group that is saturated or partially unsaturated and exists in the form of a monocyclic, fused, bridged, spirocyclic, or the like, containing 3 to 20 ring atoms, wherein the heterocyclo ring atoms include 1 to 5 heteroatoms, including, but not limited to, nitrogen (N), oxygen (O), sulfur (S), phosphorus (P), -S(=O)-, -S(=O)-, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms, more preferably 3 to 8 ring atoms, more preferably 3 to 6 ring atoms. The term "C3-C6 heterocycloalkyl group" refers to a group containing 3 to 6 ring atoms.

[0054] Examples of 3-membered heterocycloalkyl groups include, but are not limited to, oxiranyl, thiiranyl, and aziridinyl groups. Examples of 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, and thietanyl groups; examples of 5-membered heterocycloalkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, and pyrazolidinyl groups; and examples of 6-membered heterocycloalkyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, and 1,4-dithianyl groups. A heterocycloalkyl group can be substituted or unsubstituted. When substituted, the number of substituents is preferably one or more, more preferably one, two or three, and even more preferably one or two, and the substituents are selected from the group consisting of halogen, hydroxy group, carboxy group, nitro group, amino group, cyano group, C1-C6 alkyl group, C1-C6 alkoxy group, C3-C6 cycloalkyl group, 3- to 6-membered heterocycloalkyl group, C6-C 10 It is selected from an aryl group, a 5- to 10-membered heteroaryl group, and a C2 to C6 alkenyl group.

[0055] A "heteroaryl group" is a monocyclic, bicyclic, or tricyclic ring system containing one, two, or three aromatic rings and containing at least one nitrogen, oxygen, or sulfur atom in the aromatic ring, which may be unsubstituted or substituted. The heteroaryl group can be any divalent group. Examples of heteroaryl groups include, but are not limited to, 2H-pyrrolyl, 3H-indolyl, 4H-quinolidinyl, 4H-carbazolyl, acridinyl, benzo[b]thiophenyl, benzothiazolyl, β-carbolinyl, carbazolyl, chromenyl, cinnaolinyl, dibenzo[b,d]furanyl, furazanyl, furanyl, imidazolyl, imidizolyl, indazolyl, indolisinyl, indolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, naphtho[2,3-b], and oxazolyl groups.

[0056] "Pharmaceutically acceptable carrier" refers to an inactive ingredient in a pharmaceutical composition that does not cause significant irritation to an organism and does not interfere with the biological activity and properties of a given compound, including, but not limited to, a fluidization aid, a sweetener, a diluent, a preservative, a dye / colorant, a flavor enhancer, a surfactant, a wetting agent, a dispersant, a disintegrant, a suspending agent, a stabilizer, an isotonic agent, a solvent, or an emulsifier.

[0057] The term "treatment" means administering a compound or formulation described herein to improve or eliminate a disease or one or more symptoms associated with said disease, and includes (i) inhibiting the disease or disease state, i.e., inhibiting its progression, and (ii) ameliorating the disease or disease state, i.e., alleviating the disease or disease state.

[0058] The term "prevention" refers to the administration of a compound or formulation described herein to prevent a disease or one or more symptoms associated with said disease, and includes the prevention of the occurrence of a disease or disease state in a mammal, particularly when the mammal is susceptible to the disease state but has not yet been diagnosed with the disease state.

[0059] The term "therapeutically effective amount" refers to the amount of a compound that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount" may vary depending on the compound, the disease and its severity, and the condition, age, weight, sex, etc. of the subject being treated.

[0060] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or salts thereof and a pharmaceutically acceptable carrier. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present application to an organism. [Brief explanation of the drawings]

[0061] [Figure 1] 1 is a graph showing changes in body weight of mice in each group during the drug efficacy period. [Figure 2] 1 is a graph showing changes in mouse DAI scores for each group during the drug efficacy period. DETAILED DESCRIPTION OF THE INVENTION

[0062] Hereinafter, with reference to the drawings of the embodiments of the present invention, the technical solutions of the embodiments of the present invention will be clearly and completely described. Obviously, the described embodiments are only a part of the embodiments of the present invention, but not all of the embodiments. Any other embodiments that a person skilled in the art can obtain based on the embodiments of the present invention without creative effort shall fall within the scope of protection of the present invention.

[0063] Example 1: 8-chloro-N-(4-(1-(difluoromethyl)cyclopropyl)phenyl)quinolin-2-amine (Compound 1) JPEG2026503131000015.jpg45169 Step 1: 1-(4-Bromophenyl)cyclopropane-1-carbaldehyde At a reaction temperature of −78° C. under nitrogen gas protection, 1-(4-bromophenyl)cyclopropane-1-carbonitrile (1a) (0.50 g, 2.25 mmol) was dissolved in ultra-dry dichloromethane (12 mL), and DIBAL-H (1 M, 2.7 mL, 2.70 mmol) was added dropwise. After the dropwise addition was completed, the mixture was stirred at -78°C for 2 hours to allow the reaction to proceed, and then the temperature was raised to room temperature and the reaction was completed by stirring for 2 hours. The reaction was quenched by adding 1M aqueous hydrochloric acid solution (6 mL) in an ice bath. Dichloromethane was added to the mixture, which was then extracted, washed, dried, filtered and concentrated. The crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate=6:1) to obtain the target compound, 1-(4-bromophenyl)cyclopropane-1-carbaldehyde (1b). 1 H NMR (400 MHz, CDCl3) δ 9.15 (s, 1H), 7.52-7.45 (m, 2H), 7.22-7.15 (m, 2H), 1.60-1.55 (m, 2H), 1.41-1.36 (m, 2H).

[0064] Step 2: 1-Bromo-4-(1-(difluoromethyl)cyclopropyl)benzene At room temperature, 1-(4-bromophenyl)cyclopropane-1-carbaldehyde (1b) (0.40 g, 1.60 mmol) was dissolved in dichloromethane (12 mL). The temperature was lowered to -20°C, DAST (0.65 g, 4.00 mmol) was added dropwise, and the mixture was stirred for 10 minutes, then the temperature was raised to room temperature and the reaction was completed after 3 hours. The reaction mixture was quenched with water, adjusted to pH 8-9 with saturated sodium bicarbonate solution, extracted with ethyl acetate, washed, dried, filtered and concentrated. The crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate=1:0) to obtain the target compound, 1-bromo-4-(1-(difluoromethyl)cyclopropyl)benzene (1c). 1 H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 8.4 Hz, 2H), 7.28 (d, J = 8.4 Hz, 2H), 5.58 (t, J = 57.0 Hz, 1H), 1.15 (q, J = 5.0 Hz, 2H), 0.97 - 0.91 (m, 2H).

[0065] Step 3: N-(4-(1-(difluoromethyl)cyclopropyl)phenyl)-1,1-diphenylmethanimine At room temperature under nitrogen gas protection, 1-bromo-4-(1-(difluoromethyl)cyclopropyl)benzene (1c) (0.20 g, 0.81 mmol), benzophenone imine (0.18 g, 0.97 mmol), Pd2(dba)3 (14.83 mg, 0.03 mmol), BINAP (30.24 mg, 0.05 mmol), and sodium tert-butoxide (0.12 g, 1.21 mmol) were added to a toluene solution (10 mL), and the mixture was stirred at 90 °C under a nitrogen gas atmosphere for 10 hours. After cooling to room temperature, the reaction mixture was filtered through diatomaceous earth and the filtrate was concentrated in vacuo. The crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate=5:1) to obtain the target compound, N-(4-(1-(difluoromethyl)cyclopropyl)phenyl)-1,1-diphenylmethanimine (1d). LCMS (ESI) calculation for C 23 H 19 F2N [M + H] + m / z 348, found 348.1.

[0066] Step 4: 4-(1-(difluoromethyl)cyclopropyl)aniline At room temperature, N-(4-(1-(difluoromethyl)cyclopropyl)phenyl)-1,1-diphenylmethanimine (1d) (0.20 g, 0.58 mmol) was dissolved in ethyl acetate (3 mL), and ethyl acetate hydrochloric acid solution (4 M, 6 mL) was added. The reaction was carried out at room temperature for 2 hours and then terminated. The pH was adjusted to 11 by adding saturated sodium carbonate solution, extracted with ethyl acetate, dried, filtered and concentrated. The crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate=5:1) to obtain the target compound, 4-(1-(difluoromethyl)cyclopropyl)aniline (1e). LCMS (ESI) calculation for C 10 H 11 F2N [M + H] + m / z 184, found 184.1.

[0067] Step 5: 8-chloro-N-(4-(1-(difluoromethyl)cyclopropyl)phenyl)quinolin-2-amine At room temperature under nitrogen gas protection, 4-(1-(difluoromethyl)cyclopropyl)aniline (1e) (0.10 g, 0.55 mmol), 2,8-dichloroquinoline (0.13 g, 0.66 mmol), palladium acetate (6.13 mg, 0.03 mmol), Xantphos (15.79 mg, 0.03 mmol), and cesium carbonate (0.53 g, 1.64 mmol) were added to a solution of tert-butanol (50 mL), and the mixture was stirred at 90°C under nitrogen gas atmosphere for 3 hours to complete the reaction. After cooling to room temperature, the reaction mixture was filtered through diatomaceous earth and the filtrate was concentrated in vacuo. The crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate=4:1) to obtain the target compound, 8-chloro-N-(4-(1-(difluoromethyl)cyclopropyl)phenyl)quinolin-2-amine (Compound 1). LCMS (ESI) calculation for C 19 H 15 ClF2N2[M + H] + m / z 345, found 345.1. 1H NMR (400 MHz, DMSO) δ 9.70 (s, 1H), 8.13 (dd, J = 12.4, 8.8 Hz, 3H), 7.77 (dd, J = 7.6, 1.2 Hz, 1H), 7.72 (dd, J = 8.0, 1.2 Hz, 1H), 7.35 (d, J = 8.6 Hz, 2H), 7.27 (t, J = 7.8 Hz, 1H), 7.14 (d, J = 9.2 Hz, 1H), 5.85 (t, J = 56.8 Hz, 1H), 1.09 (dd, J = 6.4 Hz, 4.8 Hz, 2H), 0.99 - 0.91 (m, 2H).

[0068] Example 2: 8-chloro-N-(5-(1-(trifluoromethyl)cyclopropyl)pyridin-2-yl)quinolin-2-amine (Compound 2) JPEG2026503131000016.jpg51169 Step 1: 2-chloro-5-(3,3,3-trifluoropropyl-1-en-2-yl)pyridine (6-Chloropyridin-3-yl)boronic acid (2a) (5.00 g, 31.77 mmol), 2-bromo-3,3,3-trifluoro-1-propene (8.39 g, 47.96 mmol), Pd(dppf)Cl (2.33 g, 3.18 mmol), and potassium carbonate (10.09 g, 79.52 mmol) were added to 1,4-dioxane:water (5:1; 30 mL) at room temperature under nitrogen gas protection, and the mixture was stirred at 70 °C under nitrogen gas atmosphere for 6 h to complete the reaction. After cooling to room temperature, the reaction mixture was filtered through diatomaceous earth, extracted with ethyl acetate, dried, filtered, and concentrated. The crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate=12:1) to obtain the target compound, 2-chloro-5-(3,3,3-trifluoropropyl-1-en-2-yl)pyridine (2b). 1H NMR (400 MHz, DMSO-d6) δ 8.56 (d, J = 2.4Hz, 1H), 7.98 (dd, J = 8.4, 2.2Hz, 1H), 7.64 (d, J = 8.4Hz, 1H), 6.34-6.30 (m, 1H), 6.28-6.23 (m, 1H).

[0069] Step 2: 2-chloro-5-(1-(trifluoromethyl)cyclopropyl)pyridine At room temperature under nitrogen gas protection, 2-chloro-5-(3,3,3-trifluoropropyl-1-en-2-yl)pyridine (2b) (1.20 g, 5.75 mmol) and diphenyl(methyl)sulfonium tetrafluoroborate (2.15 g, 7.48 mmol) were dissolved in ultra-dry tetrahydrofuran (15 ml), the temperature was lowered to 0°C, and NaHMDS (1 M in THF, 9.2 mL, 9.20 mmol) was slowly added dropwise. The solution was reacted at 0°C for 15 minutes, then warmed to room temperature and reacted for 3 hours, after which the reaction was completed. It was quenched by the addition of saturated ammonium chloride solution, extracted with ethyl acetate, dried, filtered and concentrated. The crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate=15:1) to obtain the target compound, 2-chloro-5-(1-(trifluoromethyl)cyclopropyl)pyridine (2c). 1 H NMR (400 MHz, DMSO-d6) δ 8.51 (d, J = 2.4 Hz, 1H), 7.96 (dd, J = 8.0, 2.4 Hz, 1H), 7.57 (dd, J = 8.4 Hz, 0.4 Hz, 1H), 1.40 (dd, J = 7.2, 5.2 Hz, 2H), 1.26 - 1.20 (m, 2H).

[0070] Step 3: tert-butyl (5-(1-(trifluoromethyl)cyclopropyl)pyridin-2-yl)carbamate At room temperature under nitrogen gas protection, 2-chloro-5-[1-(trifluoromethyl)cyclopropyl]pyridine (2c) (0.50 g, 2.26 mmol), tert-butyl carbamate (1.06 g, 9.02 mmol), palladium acetate (25.33 mg, 0.11 mmol), Xphos (0.11 g, 0.23 mmol), and cesium carbonate (2.21 g, 6.77 mmol) were added to a 1,4-dioxane solution (12 mL), and the mixture was stirred at 90°C under nitrogen gas atmosphere for 4 hours to complete the reaction. After cooling to room temperature, the reaction mixture was filtered through diatomaceous earth, extracted with ethyl acetate, washed, dried, filtered, and concentrated. The crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate=4:1) to obtain the target compound tert-butyl (5-(1-(trifluoromethyl)cyclopropyl)pyridin-2-yl)carbamate (2d). LCMS (ESI) calculation for C 14 H 17 F3N2O2[M+H] + m / z 303, found 302.9.

[0071] Step 4: 5-(1-(trifluoromethyl)cyclopropyl)pyridin-2-amine At room temperature, tert-butyl (5-(1-(trifluoromethyl)cyclopropyl)pyridin-2-yl)carbamate (2d) (0.11 g, 0.36 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (2 mL) was added, and the reaction was completed after 2 hours at room temperature. The pH was adjusted to 9 with saturated sodium carbonate solution, extracted with dichloromethane, washed, dried, filtered and concentrated to give the target compound 5-(1-(trifluoromethyl)cyclopropyl)pyridin-2-amine (2e). LCMS (ESI) calcd for C9H9F3N2[M+H] + m / z 203, found 203.1.

[0072] Step 5: 8-chloro-N-(5-(1-(trifluoromethyl)cyclopropyl)pyridin-2-yl)quinolin-2-amine The target compound, 8-chloro-N-(5-(1-(trifluoromethyl)cyclopropyl)pyridin-2-yl)quinolin-2-amine (Compound 2), was obtained by following the preparation method in Step 5 of Example 1. LCMS (ESI) calculation for C 18 H 13 ClF3N3[M+H] + m / z 364, found 363.7. 1 H NMR (400 MHz, DMSO-d6) δ 10.47 (s, 1H), 9.02 (d, J = 8.8Hz, 1H), 8.39 (d, J = 2.2Hz, 1H), 8.23 ​​(d, J = 9.0Hz, 1H), 7.91 (dd, J = 8.4, 2.0Hz, 1H), 7.84-7.78 (m, 2H), 7.49 (d, J = 8.8Hz, 1H), 7.35 (t, J = 7.8Hz,1H), 1.36 (dd, J = 6.6, 5.2Hz, 2H), 1.31-1.22 (m, 2H).

[0073] Example 3: 8-chloro-N-(4-(1,1,1-trifluoro-2-methylpropan-2-yl)phenyl)quinolin-2-amine (Compound 3) JPEG2026503131000017.jpg46169 Step 1: 1,1,1-trifluoro-2-(4-nitrophenyl)propan-2-ol At 0 °C under nitrogen gas protection, 1-(4-nitrophenyl)ethanone (3a) (5.00 g, 30.00 mmol), TMS-CF3 (6.46 g, 45.00 mmol), and TBAF (15 mL, 15.00 mmol) were added together to a solution of THF (50 mL), and the mixture was stirred at room temperature for 1 h. The mixture was quenched with water and extracted with ethyl acetate. The combined organic phases were washed with water, dried and concentrated. The crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate:5:1) to obtain the target compound, 1,1,1-trifluoro-2-(4-nitrophenyl)propan-2-ol (3b). 1 H NMR (400 MHz, CDCl3) δ 8.25 (d, J = 8.8Hz, 2H), 7.79 (d, J = 8.8Hz, 2H), 2.80 (s, 1H), 1.83 (s, 3H).

[0074] Step 2: 1,1,1-trifluoro-2-(4-nitrophenyl)propan-2-yl methanesulfonate At 0°C under nitrogen gas protection, MsCl (0.58 g, 5.00 mmol) was slowly added dropwise to a solution of 1,1,1-trifluoro-2-(4-nitrophenyl)propan-2-ol (3b) (1.00 g, 4.00 mmol) and triethylamine (1.27 g, 12.60 mmol) in DCM (10 mL). After the addition was complete, the reaction mixture was stirred at room temperature for 2 hours. The mixture was quenched by addition of water, extracted with DCM, washed with water, dried and concentrated. The crude product was separated and purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate:5:1) to obtain the target compound, 1,1,1-trifluoro-2-(4-nitrophenyl)propan-2-yl methanesulfonate (3c). 1H NMR (400 MHz, CDCl3) δ 8.33-8.27 (m, 2H), 7.77 (d, J = 8.8Hz, 2H), 3.21 (s, 3H), 2.34(d, J = 0.8 Hz, 3H).

[0075] Step 3: 1-nitro-4-(1,1,1-trifluoro-2-methyl-2-propyl)benzene At 0°C under nitrogen gas protection, 1,1,1-trifluoro-2-(4-nitrophenyl)propan-2-yl methanesulfonate (3c) (0.50 g, 1.59 mmol) and trimethylaluminum (2 M in hexanes, 1.6 mL, 3.18 mmol) were added together to a solution of DCM (10 mL), and the mixture was stirred at room temperature for 2 hours. The mixture was quenched with water, extracted with DCM, washed with water, dried and concentrated. The crude product was separated and purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate:5:1) to obtain the target compound, 1-nitro-4-(1,1,1-trifluoro-2-methyl-2-propyl)benzene (3d). 1H NMR (400 MHz, CDCl3) δ 8.22 (d, J = 8.6Hz, 2H), 7.68 (d, J = 8.8Hz, 2H), 1.63(s, 6H).

[0076] Step 4: 4-(1,1,1-trifluoro-2-methyl-2-methylpropyl)aniline At room temperature under a hydrogen gas atmosphere, 1-nitro-4-(1,1,1-trifluoro-2-methyl-2-propyl)benzene (3d) (0.13 g, 0.56 mmol) and palladium on carbon (0.06 g, 1.15 mmol) were added together to a solution of methanol (3 mL) and THF (1 mL), and the mixture was stirred at room temperature for 2 hours to complete the reaction. The reaction was filtered through diatomaceous earth and concentrated. The crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate=5:1) to obtain the target compound, 4-(1,1,1-trifluoro-2-methyl-2-methylpropyl)aniline (3e). 1H NMR (400 MHz, DMSO-d6) δ 7.14 (d, J = 8.4Hz, 2H), 6.54 (d, J = 8.6Hz, 2H), 5.10 (s, 2H), 1.45 (s, 6H).

[0077] Step 5: 8-chloro-N-(4-(1,1,1-trifluoro-2-methylpropan-2-yl)phenyl)quinolin-2-amine The target compound, 8-chloro-N-(4-(1,1,1-trifluoro-2-methylpropan-2-yl)phenyl)quinolin-2-amine (Compound 3), was obtained by following the preparation method in Step 5 of Example 1. LCMS (ESI) calcd for C19H16ClF3N [M+H]+ 365.10 m / z, found 365.00. 1H NMR (400 MHz, DMSO-d6) δ 9.79 (s, 1H), 8.20 (d, J = 8.8Hz,2H), 8.13 (d, J = 8.8Hz, 1H), 7.76 (dd, J = 16.4, 7.8Hz, 2H), 7.50 (d, J = 8.6Hz, 2H), 7.28 (t, J = 7.8Hz, 1H), 7.15 (d, J = 8.8Hz, 1H), 1.56 (s, 6H).

[0078] Example 4: 8-chloro-N-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)quinolin-2-amine (Compound 4) JPEG2026503131000018.jpg21169 Step 1: tert-Butyl (4-(1-(trifluoromethyl)cyclopropyl)phenyl)carbamate At room temperature under nitrogen gas protection, 1-bromo-4-(1-(trifluoromethyl)cyclopropyl)benzene (4a) (0.84 g, 3.17 mmol), tert-butyl carbamate (1.48 g, 12.68 mmol), Pd(dba) (0.29 g, 0.32 mmol), Xantphos (0.55 g, 0.96 mmol), and cesium carbonate (5.16 g, 15.85 mmol) were added to a 1,4-dioxane solution (30 mL), and the mixture was stirred at 115 °C under nitrogen gas atmosphere for 7 h to complete the reaction. After cooling to room temperature, the reaction mixture was filtered through diatomaceous earth and the filtrate was concentrated in vacuo. The crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate=15:1) to give tert-butyl (4-(1-(trifluoromethyl)cyclopropyl)phenyl)carbamate (4b). 1 H NMR (400 MHz, CDCl3) δ7.37 (d, J =8.6Hz, 2H), 7.32 (d, J =8.6Hz, 2H), 6.48 (s, 1H), 1.51 (s, 9H), 1.51-1.30 (m, 2H), 1.04-0.88 (m, 2H).

[0079] Step 2: 4-(1-(trifluoromethyl)cyclopropyl)aniline At room temperature, tert-butyl (4-(1-(trifluoromethyl)cyclopropyl)phenyl)carbamate (4b) (0.50 g, 1.66 mmol) was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (4 mL) was added. The mixture was stirred at 25° C. for 1 hour. After the reaction was completed, the pH was adjusted to 11 with saturated sodium bicarbonate solution, and the mixture was extracted with dichloromethane solution (3×10 mL). The combined organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was collected. The filtrate was concentrated in vacuo to give crude product 4-(1-(trifluoromethyl)cyclopropyl)aniline (4c). LCMS(ESI) calculation for C 10 H 10 F3N [M+H] + m / z 202, found 202.1.

[0080] Step 3: 8-chloro-N-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)quinolin-2-amine The target compound, 8-chloro-N-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)quinolin-2-amine (Compound 4), was obtained by following the preparation method in Step 5 of Example 1. LCMS(ESI) calculation for C 19 H 14 ClF3N2[M+H] + m / z 363, found 363.1. 1 H NMR (400 MHz, DMSO-d6) δ 9.82 (s, 1H), 8.20 (d, J =8.4Hz, 2H), 8.13 (d, J =8.8Hz, 1H), 7.85-7.66 (m, 2H), 7.43 (d, J =8.6Hz, 2H), 7.29 (t, J =7.8Hz, 1H), 7.15 (d, J =8.8Hz, 1H), 1.32-1.30 (m, 2H), 1.12-1.08 (m, 2H).

[0081] Example 5: 8-chloro-N-(4-(1-(trifluoromethyl)cyclopropyl)pyridin-2-yl)quinolin-2-amine (Compound 6) JPEG2026503131000019.jpg54169 The target compound, 8-chloro-N-(4-(1-(trifluoromethyl)cyclopropyl)pyridin-2-yl)quinolin-2-amine (Compound 6), was obtained by referring to the production methods in Steps 1 to 5 of Example 2. LCMS(ESI) calculation for C 18 H 13 ClF3N3[M+H] + m / z 364.77, found 363.9. 1 H NMR (400 MHz, DMSO-d6) δ 10.44 (s,1H), 9.28 (s, 1H), 8.32 (d, J =5.1 Hz, 1H), 8.22 (d, J =8.9 Hz, 1H), 7.78-7.84 (m, 2H), 7.43 (d, J =8.8 Hz, 1H), 7.31 (d, J =7.6 Hz, 1H), 7.12 (d, J =5.1 Hz, 1H), 1.43-1.46 (m, 2H), 1.26-1.29 (m, 2H).

[0082] Example 6: 8-chloro-N-(6-(1-(trifluoromethyl)cyclopropyl)pyridin-3-yl)quinolin-2-amine (Compound 7) JPEG2026503131000020.jpg43169 Step 1: 5-Bromo-2-(3,3,3-trifluoro-1-propen-2-yl)pyridine At room temperature under nitrogen gas protection, 2,5-dibromopyridine (7a) (5.00 g, 21.10 mmol), 4,4,5,5-tetramethyl-2-(3,3,3-trifluoro-1-propen-2-yl)-1,3,2-dioxaborolane (4.41 g, 21.10 mmol), Pd(dppf)Cl (1.54 g, 2.11 mmol), and potassium carbonate (8.75 g, 63.30 mmol) were added together to a mixture of dioxane and water. The reaction was completed after 12 hours at 80°C. After cooling to room temperature, the mixture was filtered through diatomaceous earth and concentrated. The residue was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (eluent: PE: 100%) to give the desired 5-bromo-2-(3,3,3-trifluoro-1-propen-2-yl)pyridine (7b). LCMS(ESI) calcd for C8H5BrF3N [M+H] + m / z 252, found 252.9.

[0083] The remaining preparation methods were carried out with reference to the preparation methods in Steps 2 to 5 of Example 2, to obtain the target compound, 8-chloro-N-(6-(1-(trifluoromethyl)cyclopropyl)pyridin-3-yl)quinolin-2-amine (Compound 7). LCMS(ESI) calculation for C 18 H 13 ClF3N3[M+H] + m / z 364, found 364.0. 1H NMR (400 MHz, DMSO-d6) δ 10.02 (s, 1H), 9.21 (d, J =2.4 Hz, 1H), 8.75 (dd, J =8.8, 2.4 Hz, 1H), 8.20 (d, J =8.8 Hz, 1H), 7.85-7.71 (m, 2H), 7.54 (d, J =8.8 Hz, 1H), 7.33 (t, J =7.6 Hz, 1H), 7.18 (d, J =8.8 Hz, 1H), 1.39-1.32 (m, 4H).

[0084] Example 7: 8-chloro-N-(2-methoxy-4-(1-(trifluoromethyl)cyclopropyl)phenyl)quinolin-2-amine (Compound 8) JPEG2026503131000021.jpg46169 Step 1: 3-Methoxy-4-nitrophenylboronic acid pinacol ester 4-Bromo-2-methoxy-1-nitrobenzene (8a) (3.00 g, 12.90 mmol), bis(pinacolato)diboron (4.91 g, 19.35 mmol), potassium acetate (2.53 g, 25.80 mmol), and Pd(dppf)Cl (0.94 g, 1.29 mmol) were added to a dioxane solution (30 mL) at room temperature, and the mixture was stirred at 90 °C under a nitrogen atmosphere for 3 hours. After cooling to room temperature, the mixture was filtered through diatomaceous earth, the filtrate was diluted with water, extracted with ethyl acetate, and the organic phase was dried and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate:petroleum ether=1:10) to obtain the target compound, 3-methoxy-4-nitrophenylboronic acid pinacol ester (8b). LCMS(ESI) calculation for C 13 H 18 BNO5[M+H] + m / z 280.1, found 280.0.

[0085] Step 2: 2-Methoxy-1-nitro-4-(3,3,3-trifluoropropenyl)benzene 3-Methoxy-4-nitrophenylboronic acid pinacol ester (8b) (2.80 g, 10.03 mmol), 2-bromo-3,3,3-trifluoropropene (7.04 g, 40.12 mmol), potassium carbonate (2.76 g, 20.06 mmol), and Pd(dppf)Cl (0.73 g, 1.00 mmol) were added to dioxane (40 mL) and water (4 mL) at room temperature under a nitrogen atmosphere, and the mixture was stirred at 70 °C for 3 h to complete the reaction. After cooling to room temperature, the mixture was filtered through diatomaceous earth, the filtrate was diluted with water, extracted with ethyl acetate, and the organic phase was dried and concentrated in vacuo. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate:petroleum ether=1:20) to obtain the target compound, 2-methoxy-1-nitro-4-(3,3,3-trifluoropropenyl)benzene (8c). 1 H NMR (400 MHz, DMSO-d6) δ 7.97 (d, J =8.4Hz, 1H), 7.40 (d, J =1.2 Hz, 1H), 7.20 (d, J =8.4 Hz, 1H), 6.40-6.34 (m, 1H), 6.27-6.32 (m, 1H), 3.99 (s, 3H).

[0086] Step 3: 2-Methoxy-1-nitro-4-(1-(trifluoromethyl)cyclopropyl)benzene At room temperature, 2-methoxy-1-nitro-4-(3,3,3-trifluoropropenyl)benzene (8c) (0.50 g, 2.01 mmol) and diphenyl(methyl)sulfonium tetrafluoroborate (0.75 g, 2.62 mmol) were dissolved in 5 mL of tetrahydrofuran solution, and sodium bis(trimethylsilyl)amide (2 M in THF, 1.61 mL, 3.22 mmol) was added dropwise at 0°C. The mixture was stirred at room temperature for 3 hours. After the reaction was completed, the mixture was diluted with water and extracted with ethyl acetate, and the organic phase was dried and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate:petroleum ether=1:20) to obtain the target compound, 2-methoxy-1-nitro-4-(1-(trifluoromethyl)cyclopropyl)benzene (8d). 1 H NMR (400 MHz, DMSO-d6) δ 7.89 (d, J =8.4 Hz, 1H), 7.37 (d, J =1.2Hz, 1H), 7.22 (d, J =9.2 Hz, 1H), 3.96 (s, 3H), 1.37-1.43 (m, 2H), 1.25 -1.30 (m, 2H).

[0087] Step 4: 2-Methoxy-4-(1-(trifluoromethyl)cyclopropyl)aniline At room temperature, 2-methoxy-1-nitro-4-(1-(trifluoromethyl)cyclopropyl)benzene (8d) (0.42 g, 1.61 mmol) was dissolved in a methanol solution (5 mL), and 10% Pd / C (34.22 mg, 0.32 mmol) was added to the mixture, which was then purged with hydrogen gas three times. The mixture was stirred at room temperature under a hydrogen gas atmosphere for 16 hours to complete the reaction. The mixture was then filtered through diatomaceous earth and concentrated in vacuo to give the crude target compound 2-methoxy-4-(1-(trifluoromethyl)cyclopropyl)aniline (8e). LCMS(ESI) calculation for C 11 H 12 F3NO [M+H] + m / z 232.09, found 231.95.

[0088] Step 5: 8-chloro-N-(2-methoxy-4-(1-(trifluoromethyl)cyclopropyl)phenyl)quinolin-2-amine 2-Methoxy-4-(1-(trifluoromethyl)cyclopropyl)aniline (8e) (0.15 g, 0.65 mmol), 2,8-dichloroquinoline (0.13 g, 0.65 mmol), cesium carbonate (0.42 g, 1.30 mmol), Xantphos (0.04 g, 0.06 mmol), and palladium acetate (0.01 g, 0.06 mmol) were added to tert-butanol (5 mL) at room temperature, and the mixture was stirred at 80° C. under a nitrogen atmosphere for 1 hour to complete the reaction. After cooling to room temperature, the reaction mixture was filtered through diatomaceous earth, and the filtrate was diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate:petroleum ether=1:20) to obtain the target compound, 8-chloro-N-(2-methoxy-4-(1-(trifluoromethyl)cyclopropyl)phenyl)quinolin-2-amine (Compound 8). LCMS(ESI) calculation for C 20 H 16 ClF3N2O [M+H] + m / z 393.09, found 392.95. 1 H NMR (400 MHz, DMSO-d6) δ 9.23 (d, J =8.8 Hz, 1H), 8.87 (s, 1H), 8.12 (d, J =8.8Hz, 1H), 7.77 (d, J =7.2 Hz, 1H), 7.73 (d, J =8.0 Hz, 1H), 7.51 (d, J =8.8 Hz, 1H), 7.29 (t, J =8.0 Hz, 1H), 7.12-7.05 (m, 2H), 3.94 (s, 3H), 1.28-1.35 (m, 2H), 1.14-1.19 (m, 2H).

[0089] Example 8: 8-chloro-N-(3-(1-(trifluoromethyl)cyclopropyl)phenyl)quinolin-2-amine (Compound 9) JPEG2026503131000022.jpg55169 Step 1: 1-Nitro-3-trifluoropropenylbenzene At 0°C under a nitrogen atmosphere, Ph3PCHBr (0.97 g, 2.72 mmol) was dissolved in THF (10 mL) and added dropwise to a solution of potassium tert-butoxide in tetrahydrofuran (1 M in THF, 2.72 mL, 2.72 mmol), and the mixture was stirred at 0°C for 1 hour. 3'-Nitro-2,2,2-trifluoroacetophenone (9a) (0.30 g, 1.36 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with water, extracted with ethyl acetate, and the organic phase was dried and concentrated in vacuo. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate:petroleum ether=1:35) to obtain the target compound, 1-nitro-3-trifluoropropenylbenzene (9b). 1 H NMR (400 MHz, CDCl3) δ 8.30-8.36 (m, 1H), 8.29-8.24 (m, 1H), 7.79 (d, J =8.0Hz, 1H), 7.60 (t, J =8.0 Hz, 1H), 6.14 (d, J =0.8 Hz, 1H), 5.90-5.94 (m, 1H).

[0090] The remaining steps were carried out by referring to the methods of steps 3 to 5 of Example 7 to obtain the target compound, 8-chloro-N-(3-(1-(trifluoromethyl)propyl)phenyl)quinolin-2-amine (Compound 9). LCMS(ESI) calculation for C 19 H 14 ClF3N2[M+H] + m / z 363.08, found 363.00 1H NMR (400 MHz, DMSO-d6) δ 9.81 (s, 1H), 8.72 (s, 1H), 8.14 (d, J =8.8Hz, 1H), 7.86 (dd, J =8.0, 1.2Hz, 1H), 7.81-7.72 (m, 2H), 7.35 (t, J =8.0Hz, 1H), 7.29 (t, J =8.0Hz, 1H), 7.14 (d, J =8.8Hz, 1H), 7.08 (d, J =7.6Hz, 1H), 1.39-1.33 (m, 2H), 1.15-1.20 (m, 2H).

[0091] Example 9: 8-chloro-6-fluoro-N-(5-(1-(trifluoromethyl)cyclopropyl)pyridin-2-yl)quinolin-2-amine (Compound 10) JPEG2026503131000023.jpg54169 Step 1: (2E)-N-(2-chloro-4-fluorophenyl)-3-phenyl-2-propenamide 2-Chloro-4-fluoroaniline (10a) (5.00 g, 0.03 mol) and KCO (14.22 g, 0.10 mol) were added to water (26 mL) at room temperature under nitrogen gas protection. At 0°C, a solution of (2E)-3-phenyl-2-propenoyl chloride (10b) (5.71 g, 0.03 mol) in acetone (36 ml) was added dropwise, and the reaction was completed at 25°C for 2 hours. Water was added to the mixture, and the mixture was filtered to obtain the crude product of the target compound (2E)-N-(2-chloro-4-fluorophenyl)-3-phenyl-2-propenamide (10c). 1 H NMR (400 MHz, DMSO-d6) δ 9.77 (s, 1H), 7.88 (dd, J = 9.0, 6.0 Hz, 1H), 7.68-7.57 (m, 3H), 7.54 (dd, J = 8.6, 2.8 Hz, 1H), 7.50-7.40 (m, 3H), 7.29-7.24(m, 1H), 7.06 (d, J = 15.8 Hz, 1H).

[0092] Step 2: 8-chloro-6-fluoroquinolin-2(1H)-one At room temperature under nitrogen gas protection, (2E)-N-(2-chloro-4-fluorophenyl)-3-phenyl-2-propenamide (10c) (3.00 g, 0.01 mol) and AlCl (8.72 g, 0.07 mol) were added to chlorobenzene (10 ml), and the reaction was completed at 130 °C for 4 hours. Water was added to the mixture, and the mixture was filtered to obtain the crude product of the target compound 8-chloro-6-fluoroquinolin-2(1H)-one (10d). 1 H NMR (400 MHz, DMSO-d6) δ 11.16 (s, 1H), 7.94 (d, J = 9.6 Hz, 1H), 7.74 (dd, J = 8.6, 2.8 Hz, 1H), 7.63 (dd, J = 8.8, 2.8 Hz, 1H), 6.68 (d, J = 9.6 Hz, 1H).

[0093] Step 3: 2,8-Dichloro-6-fluoroquinoline At room temperature under nitrogen gas protection, 8-chloro-6-hydroxy-1H-quinolin-2-one (10d) (4.20 g, 0.02 mol) was added to POCl3 (30 mL) and the reaction was completed at 110 °C for 4 hours. Water was added to the mixture, which was then filtered to give the crude target compound 2,8-dichloro-6-fluoroquinoline (10e). 1 H NMR (400 MHz, DMSO-d6) δ 8.53 (d, J = 8.6 Hz, 1H), 8.14-8.13 (m, 1H), 7.93 (dd, J = 8.8, 2.8 Hz, 1H), 7.77 (d, J = 8.6 Hz, 1H).

[0094] Step 4: 8-chloro-6-fluoro-N-(5-(1-(trifluoromethyl)cyclopropyl)pyridin-2-yl)quinolin-2-amine At room temperature under nitrogen gas protection, 5-(1-(trifluoromethyl)cyclopropyl)pyridin-2-amine (2e) (0.06 g, 0.30 mmol), 2,8-dichloro-6-fluoroquinoline (10e) (0.08 g, 0.36 mmol), palladium acetate (3.33 mg, 0.01 mmol), bis(2-diphenylphosphinophenyl)ether (8.00 mg, 0.01 mmol), and sodium tert-butoxide (0.09 g, 0.89 mmol) were added to ultra-dry toluene (30 mL). The reaction mixture was stirred under a nitrogen gas atmosphere at 105°C for 10 hours to complete the reaction. The reaction mixture was allowed to cool to room temperature, then filtered through diatomaceous earth, and the filtrate was concentrated in vacuo. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 3:1) to obtain the target compound 8-chloro-6-fluoro-N-(5-(1-(trifluoromethyl)cyclopropyl)pyridin-2-yl)quinolin-2-amine (Compound 10). LCMS(ESI) calculation for C 18 H 12 ClF4N3[M+H] + m / z 382, ​​found 382.0. 1 H NMR (400 MHz, DMSO-d6) δ 10.49 (s, 1H), 8.96 (d, J =8.8Hz, 1H), 8.38 (d, J =2.4Hz, 1H), 8.21 (d, J =9.0Hz, 1H), 7.92-7.87 (m, 2H), 7.68 (dd, J =8.8, 2.8Hz, 1H), 7.54 (d, J =8.8Hz, 1H), 1.37-1.34 (m, 2H), 1.19-1.17 (m, 2H).

[0095] Example 10: 8-chloro-N-(2-(1-(trifluoromethyl)cyclopropyl)pyrimidin-5-yl)quinolin-2-amine (Compound 11) JPEG2026503131000024.jpg42169 The target compound, 8-chloro-N-(2-(1-(trifluoromethyl)cyclopropyl)pyrimidin-5-yl)quinolin-2-amine (Compound 11), was obtained by referring to the production methods in Steps 1 to 5 of Example 6. LCMS(ESI) calculation for C 17 H 12 ClF3N4[M+H] + m / z 364.07, found 364.95. 1 H NMR (400 MHz, DMSO-d6) δ 10.15 (s,1H), 9.54 (s, 2H), 8.25 (d, J =8.9 Hz, 1H), 7.88-7.77 (m, 2H), 7.36 (t, J =7.8 Hz, 1H), 7.21 (d,J =8.9 Hz, 1H), 1.52-1.48 (m, 4H).

[0096] Example 11: 8-chloro-N-(6-methyl-5-(1-(trifluoromethyl)cyclopropyl)pyridin-2-yl)quinolin-2-amine (Compound 12) JPEG2026503131000025.jpg47169 The target compound, 8-chloro-N-(6-methyl-5-(1-(trifluoromethyl)cyclopropyl)pyridin-2-yl)quinolin-2-amine (Compound 12), was obtained by referring to the production methods in Steps 1 to 5 of Example 2. LCMS(ESI) calculation for C 19 H 15 ClF3N3[M+H] + m / z 378.10, found 378.0. 1H NMR (400 MHz, DMSO-d6) δ 10.39 (s,1H), 8.90 (d, J =8.6Hz, 1H), 8.20 (d, J =9.0Hz, 1H), 7.77-7.83 (m, 3H), 7.47 (d, J =8.9Hz, 1H), 7.34 (t, J =7.8Hz, 1H), 2.55 (s, 3H), 1.43-1.46 (m, 2H), 1.18-1.23 (m, 2H).

[0097] Example 12: 8-chloro-N-(4-methyl-5-(1-(trifluoromethyl)cyclopropyl)pyridin-2-yl)quinolin-2-amine (Compound 13) JPEG2026503131000026.jpg51169 The target compound, 8-chloro-N-(4-methyl-5-(1-(trifluoromethyl)cyclopropyl)pyridin-2-yl)quinolin-2-amine (Compound 13), was obtained by referring to the production methods in Steps 1 to 5 of Example 2. LCMS(ESI) calculation for C 19 H 15 ClF3N3[M+H] + m / z 378, found 378.0. 1 H NMR (400 MHz, DMSO-d6) δ 9.03 (s,1H), 8.27 (s,1H), 8.22 (d, J =9.2Hz, 1H), 7.82-7.74 (m, 2H), 7.45 (t, J =7.6Hz, 1H), 7.35 (t, J =7.6Hz, 1H), 2.49 (s, 3H), 1.46-1.39 (m, 2H), 1.26-1.18 (m, 2H).

[0098] Example 13: 8-chloro-N-(5-(1-(trifluoromethyl)cyclopropyl)pyrazin-2-yl)quinolin-2-amine (Compound 14) JPEG2026503131000027.jpg47169 The target compound, 8-chloro-N-(5-(1-(trifluoromethyl)cyclopropyl)pyrazin-2-yl)quinolin-2-amine (Compound 14), was obtained by referring to the production methods in Steps 1 to 5 of Example 6. LCMS(ESI) calculation for C 17 H 12 ClF3N4[M+H] + m / z 365.07, found 364.7. 1 H NMR (400 MHz, DMSO-d6) δ 10.75 (s, 1H), 10.26 (d, J =1.4Hz, 1H), 8.50 (s, 1H), 8.30 (d, J =8.9Hz, 1H), 7.82-7.88 (m, 2H), 7.50 (d, J =8.9Hz, 1H), 7.39 (t, J =7.8Hz, 1H), 1.42-1.45 (m, 2H), 1.36-1.39 (m, 2H).

[0099] Example 14: 8-chloro-N-(4-fluoro-5-(1-(trifluoromethyl)cyclopropyl)pyridin-2-yl)quinolin-2-amine (Compound 15) JPEG2026503131000028.jpg42169 Step 1: 2-chloro-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine At room temperature under a nitrogen gas atmosphere, 2-chloro-4-fluoropyridine (15a) (10.00 g, 76.00 mmol), bis(pinacolato)diboron (9.65 g, 38.00 mmol), 6,6'-di-tert-butyl-2,2'-bipyridine (0.20 g, 0.70 mmol), and methoxy(cyclooctadiene)iridium(I) dimer (0.25 g, 0.30 mmol) were added to a tetrahydrofuran solution (120 mL), and the mixture was stirred at 80°C for 16 hours. After concentration, the crude product was purified by silica gel column chromatography (eluent: ethyl acetate:petroleum ether=1:4) to obtain the target compound, 2-chloro-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (15b). LCMS(ESI) calculation for C 11 H 14 BClFNO2[M+H] + m / z 258.08, found 258.00

[0100] The remaining steps were carried out by referring to the methods of steps 1 to 5 of Example 2 to obtain the target compound, 8-chloro-N-(4-fluoro-5-(1-((trifluoromethyl))cyclopropyl)pyridin-2-yl)quinolin-2-amine (Compound 15). LCMS(ESI) calculation for C 18 H 12 ClF4N3[M+H] + m / z 382.07, found 381.90. 1 H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 9.05 (d, J =14.0Hz, 1H), 8.42 (d, J =13.2Hz, 1H), 8.27 (d, J =9.2Hz, 1H), 7.78-7.92 (m, 2H), 7.45 (d, J =8.8Hz, 1H), 7.39 (t, J =8.0Hz, 1H), 1.38-1.48 (m, 2H), 1.21-1.26 (m, 2H).

[0101] (Example 15) 8-chloro-2-((3-(1-(trifluoromethyl)cyclopropyl)phenyl)amino)quinoline-6-carbonitrile (Compound 16) JPEG2026503131000029.jpg35169 At room temperature, 6-cyano-2,8-dichloroquinoline (0.05 g, 0.22 mmol), 3-(1-(trifluoromethyl)cyclopropyl)aniline (9d) (0.06 g, 0.29 mmol), cesium carbonate (0.15 g, 0.45 mmol), Xantphos (0.01 g, 0.02 mmol), and palladium acetate (2.50 mg, 0.01 mmol) were dissolved in dioxane (5 mL), and the mixture was stirred at 80°C under a nitrogen atmosphere for 2 hours. The reaction mixture was diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate:petroleum ether=10:1) to obtain the target compound, 8-chloro-2-((3-(1-(trifluoromethyl)cyclopropyl)phenyl)amino)quinoline-6-carbonitrile (Compound 16). LCMS(ESI) calculation for C 20 H 13 ClF3N3[M+H] + m / z 388.08, found 387.90. 1 H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 8.71 (s, 1H), 8.35 (s, 1H), 8.19 (s, 2H), 7.85 (d, J =7.6Hz, 1H), 7.40-7.37 (m, 1H), 7.25 (d, J =8.8Hz, 1H), 7.15 (d, J =6.0Hz, 1H), 1.38-1.34 (m, 2H), 1.19-1.14 (m, 2H).

[0102] Example 16: 8-chloro-6-fluoro-N-(4-(1-(trifluoromethyl)cyclopropyl)pyridin-2-yl)quinolin-2-amine (Compound 17) JPEG2026503131000030.jpg38169 The target compound, 8-chloro-6-fluoro-N-(4-(1-(trifluoromethyl)cyclopropyl)pyridin-2-yl)quinolin-2-amine (Compound 17), was obtained by referring to the preparation method of Example 15. LCMS(ESI) calculation for C 18 H 12 ClF4N3[M+H] + m / z 382.07, found 381.9. 1 H NMR (400 MHz, DMSO-d6) δ 10.46 (s, 1H), 9.23 (s, 1H), 8.32 (d, J =5.1Hz, 1H), 8.21 (d, J =9.0Hz, 1H), 7.89 (dd, J =8.7, 2.7Hz, 1H), 7.68 (dd, J =8.9, 2.7Hz, 1H), 7.48 (d, J =8.9Hz, 1H), 7.12 (d, J =4.9Hz, 1H), 1.46-1.43 (m, 2H), 1.29-1.26 (m, 2H).

[0103] (Example 17) 8-chloro-6-fluoro-N-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)quinolin-2-amine (Compound 18) JPEG2026503131000031.jpg42169 The target compound, 8-chloro-6-fluoro-N-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)quinolin-2-amine (Compound 18), was obtained by referring to the preparation method of Example 15. LCMS(ESI) calculation for C 19 H 13 ClF4N2[M+H] + m / z 381.07, found 380.90. 1H NMR (400 MHz, DMSO-d6) δ 9.83 (s, 1H), 8.17 (d, J =8.8Hz, 2H), 8.13 (d, J =9.2Hz, 1H), 7.83 (dd, J =8.4, 2.8Hz, 1H), 7.63 (dd, J =9.2, 2.8Hz, 1H), 7.43 (d, J =8.4Hz, 2H), 7.20 (d, J =8.8Hz, 1H), 1.28-1.33 (m, 2H), 1.08-1.14 (m, 2H).

[0104] (Example 18) 8-chloro-2-((5-(1-(trifluoromethyl)cyclopropyl)pyridin-2-yl)amino)quinoline-6-carbonitrile (Compound 19) JPEG2026503131000032.jpg31169 At room temperature under nitrogen gas protection, 5-(1-(trifluoromethyl)cyclopropyl)pyridin-2-amine (2e) (0.04 g, 0.20 mmol), 2,8-dichloroquinoline-6-carbonitrile (0.02 g, 0.10 mmol), palladium acetate (2.22 mg, 0.01 mmol), bis(2-diphenylphosphinophenyl)ether (5.33 mg, 0.01 mmol), and sodium tert-butoxide (0.06 g, 0.59 mmol) were added to ultra-dry toluene (40 mL). The reaction mixture was stirred at 90°C for 2 hours under a nitrogen gas atmosphere to complete the reaction. The reaction mixture was allowed to cool to room temperature, then filtered through diatomaceous earth, and the filtrate was concentrated in vacuo. The crude product was purified by reverse phase chromatography (eluent: acetonitrile:water (0.05% aqueous ammonia)) to give the target compound, 8-chloro-2-((5-(1-(trifluoromethyl)cyclopropyl)pyridin-2-yl)amino)quinoline-6-carbonitrile (compound 19). LCMS(ESI) calculation for C 19 H 12 ClF3N4[M+H] + m / z 389, found 388.9. 1H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 8.97 (d, J =8.8Hz, 1H), 8.41 (dd, J =12.0, 1.6Hz, 2H), 8.29 (d, J =9.0Hz, 1H), 8.24 (d, J =1.6Hz, 1H), 7.96 (dd, J =8.6, 2.2Hz, 1H), 7.60 (d, J =9.0Hz, 1H), 1.39-1.36 (m, 2H), 1.24-1.21 (m, 2H).

[0105] (Example 19) 8-chloro-2-((4-(1-(trifluoromethyl)cyclopropyl)phenyl)amino)quinoline-6-carbonitrile (Compound 20) JPEG2026503131000033.jpg42169 The target compound, 8-chloro-2-((4-(1-(trifluoromethyl)cyclopropyl)phenyl)amino)quinoline-6-carbonitrile (Compound 20), was obtained by following the preparation method of Example 15. LCMS(ESI) calculation for C 20 H 13 ClF3N3[M+H] + m / z 388.08, found 388.00. 1 H NMR (400 MHz, DMSO-d6) δ10.20 (s, 1H), 8.35 (d, J =2.0Hz, 1H), 8.24-8.15 (m, 4H), 7.47 (d, J =8.4Hz, 2H), 7.26 (d, J =8.8Hz, 1H), 1.33-1.30 (m, 2H), 1.13-1.10 (m, 2H).

[0106] Example 20: 8-chloro-6-(methylsulfonyl)-N-(4-(1-(trifluoromethyl)cyclopropyl)phenylquinolin-2-amine (Compound 21) JPEG2026503131000034.jpg43169 The target compound, 8-chloro-6-(methylsulfonyl)-N-(4-(1-(trifluoromethyl)cyclopropyl)phenylquinolin-2-amine (Compound 21), was obtained by following the preparation method of Example 15. LCMS(ESI) calculation for C 20 H 16 ClF3N2O2S [M+H] + m / z 441.06, found 441.00. 1 H NMR (400 MHz, CDCl3) δ 8.20-8.19 (m, 2H), 8.04 (d, J =9.2Hz, 1H), 7.80 (s, 2H), 7.52 (d, J =8.4Hz, 2H), 7.08 (d, J =8.4Hz, 1H), 3.14 (s,3H), 1.37-1.32 (m,2H), 1.06-1.02 (m,2H).

[0107] (Example 21) 8-chloro-N-(4-(1,1-difluoro-2-methylpropan-2-yl)phenyl)quinolin-2-amine (Compound 22) JPEG2026503131000035.jpg40169 Step 1: 2-(4-((diphenylmethylene)amino)phenyl)-2-methylpropionitrile At room temperature under nitrogen gas protection, 2-(4-bromophenyl)-2-methylpropionitrile (22a) (0.50 g, 2.23 mmol), benzophenone imine (0.49 g, 2.68 mmol), Pd(dba) (0.04 g, 0.04 mmol), BINAP (0.08 g, 0.13 mmol), and sodium tert-butoxide (0.32 g, 3.35 mmol) were added to a toluene solution (8 mL), and the mixture was stirred at 90 °C under nitrogen gas atmosphere for 17 h. After cooling to room temperature, the reaction mixture was filtered through diatomaceous earth and the filtrate was concentrated in vacuo. The crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate=9:1) to obtain the target compound, 2-(4-((diphenylmethylene)amino)phenyl)-2-methylpropionitrile (22b). LCMS(ESI) calculation for C 23 H 20 N2[M+H] + m / z 325, found 325.2.

[0108] Step 2: 2-(4-aminophenyl)-2-methylpropionitrile At room temperature, 2-(4-((diphenylmethylene)amino)phenyl)-2-methylpropionitrile (22b) (0.70 g, 2.16 mmol) was dissolved in ethyl acetate (3.5 mL), and a solution of ethyl acetate and hydrochloric acid (4 M, 7 mL) was added. The solution was allowed to react at room temperature for 15 minutes to complete the reaction. After extraction with ethyl acetate, the pH of the aqueous phase was adjusted to 9 by adding saturated sodium bicarbonate solution, extracted with dichloromethane, dried, filtered, and concentrated to give the crude target compound 2-(4-aminophenyl)-2-methylpropionitrile (22c). LCMS(ESI) calculation for C 10 H 12 N2[M+H] + m / z 161, found 161.0.

[0109] Step 3: 2-(4-((8-chloroquinolin-2-yl)amino)phenyl)-2-methylpropionitrile A solution of 2-(4-aminophenyl)-2-methylpropionitrile (22c) (0.20 g, 1.25 mmol), 2,8-dichloroquinoline (0.30 g, 1.50 mmol), palladium acetate (0.01 g, 0.06 mmol), Xantphos (0.03 g, 0.06 mmol), and cesium carbonate (1.22 g, 3.74 mmol) in 1,4-dioxane (120 mL) was added at room temperature under nitrogen gas protection, and the mixture was stirred at 90°C for 3 hours under nitrogen gas atmosphere. After cooling to room temperature, the reaction mixture was filtered through diatomaceous earth and the filtrate was concentrated in vacuo. The crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate=3:1) to obtain the target compound, 2-(4-((8-chloroquinolin-2-yl)amino)phenyl)-2-methylpropionitrile (22d). LCMS(ESI) calculation for C 19 H 16 ClN3[M+H] + m / z 322, found 322.1.

[0110] Step 4: 2-(4-((8-chloroquinolin-2-yl)amino)phenyl)-2-methylpropane At −78° C. under nitrogen gas protection, 2-(4-((8-chloroquinolin-2-yl)amino)phenyl)-2-methylpropionitrile (22d) (0.10 g, 0.31 mmol) was dissolved in ultra-dry dichloromethane (2.5 mL), and DIBAL-H (1 M, 0.4 mL, 0.37 mmol) was added dropwise. After the dropwise addition was completed, the mixture was stirred at -78°C for 2 hours to allow the reaction to proceed, and then the temperature was raised to room temperature and the reaction was completed by stirring for 2 hours. The reaction was quenched with 1 M aqueous hydrochloric acid (1.2 mL) under ice bath. Dichloromethane was added to the mixture, which was then extracted, washed, dried, filtered and concentrated. The crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate=3:1) to obtain the target compound 2-(4-((8-chloroquinolin-2-yl)amino)phenyl)-2-methylpropane (22e). LCMS(ESI) calculation for C 19 H 17 ClNO [M+H] + m / z 325, found 324.9.

[0111] Step 5: 8-chloro-N-(4-(1,1-difluoro-2-methylpropan-2-yl)phenyl)quinolin-2-amine 2-(4-((8-chloroquinolin-2-yl)amino)phenyl)-2-methylpropane (22e) (0.08 g, 0.26 mmol) was dissolved in dichloromethane (8 mL) at room temperature. The temperature was lowered to -20°C, and DAST (0.11 g, 0.65 mmol) was added dropwise. The reaction mixture was stirred at -20°C for 10 minutes, then warmed to room temperature and reacted for 2 hours to complete the reaction. The reaction mixture was quenched with water, adjusted to pH 8-9 with saturated sodium bicarbonate solution, extracted with ethyl acetate, washed, dried, filtered and concentrated. The crude product was purified by reverse phase chromatography (eluent: acetonitrile / water (0.05% aqueous ammonia)) to obtain the target compound, 8-chloro-N-(4-(1,1-difluoro-2-methylpropan-2-yl)phenyl)quinolin-2-amine (Compound 22). LCMS(ESI) calculation for C 19 H 17 ClF2N2[M+H] + m / z 347, found 346.9. 1 H NMR (400 MHz, DMSO-d6) δ 9.84 (s,1H), 8.23 ​​(d,J =8.4Hz,2H), 8.15 (d, J =9.2Hz, 1H), 7.89-7.65 (m, 2H), 7.39 (d, J =8.4Hz, 2H), 7.29 (t, J =7.8Hz, 1H), 7.17 (d,J =8.8Hz, 1H), 5.48 (dd, J =44.8, 17.6Hz, 1H), 1.38 (d,J =21.6Hz,3H), 1.28 (d, J =22.0Hz, 3H).

[0112] Example 22: 8-chloro-N-(6-(1-(trifluoromethyl)cyclopropyl)pyridazin-3-yl)quinolin-2-amine (Compound 23) JPEG2026503131000036.jpg47169 The target compound, 8-chloro-N-(6-(1-(trifluoromethyl)cyclopropyl)pyridazin-3-yl)quinolin-2-amine (Compound 23), was obtained by following the production methods in Steps 1 to 5 of Example 6. LCMS(ESI) calculation for C 17 H 12 ClF3N4[M+H] + m / z 365.07, found 365.0. 1 H NMR (400 MHz, DMSO-d6) δ 11.03 (s,1H), 9.30 (d, J =9.4Hz, 1H), 8.30 (d, J =8.9Hz, 1H), 7.82-7.90 (m, 3H), 7.54 (d, J =8.9Hz, 1H), 7.39 (t, J =7.8Hz, 1H), 1.42-1.50 (m, 4H).

[0113] Example 23: 8-chloro-N-(5-(1-(trifluoromethyl)cyclopropyl)pyrimidin-2-yl)quinolin-2-amine (Compound 24) JPEG2026503131000037.jpg21169 Step 1: 2-chloro-5-(3,3,3-trifluoro-1-propen-2-yl)pyrimidine (2-Chloropyrimidin-5-yl)boronic acid (24a) (8.00 g, 50.63 mmol), 2-bromo-3,3,3-trifluoro-1-propene (13.29 g, 75.95 mmol), Pd(dba) (2.32 g, 2.53 mmol), tricyclohexylphosphine (1.42 g, 5.06 mmol), and potassium phosphate (21.47 g, 101.26 mmol) were added together to a mixture of dioxane and water at room temperature under nitrogen gas protection. The reaction was completed at 80°C for 2 hours. After cooling to room temperature, the mixture was filtered through diatomaceous earth and concentrated. The residue was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate=10:1) to obtain the target compound, 2-chloro-5-(3,3,3-trifluoro-1-propen-2-yl)pyrimidine (24b). 1 H NMR (400 MHz, CDCl3) δ 8.71 (s, 2H), 6.25-6.16 (m, 1H), 5.99-5.92 (m, 1H).

[0114] Step 2: 2-chloro-5-(1-(trifluoromethyl)cyclopropyl)pyrimidine At 0°C under nitrogen gas protection, NaHMDS (2 M in THF, 8.5 mL, 16.93 mmol) was added dropwise to a solution of 2-chloro-5-(3,3,3-trifluoro-1-propen-2-yl)pyrimidine (24b) (2.20 g, 10.58 mmol) and diphenyl(methyl)sulfonium tetrafluoroborate (3.96 g, 13.75 mmol) in anhydrous tetrahydrofuran. The mixture was stirred at room temperature for 3 hours to complete. After the reaction was completed, the reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate=10:1) to obtain the target compound, 2-chloro-5-(1-(trifluoromethyl)cyclopropyl)pyrimidine (24c). 1 H NMR (400 MHz, DMSO-d6) δ 8.75 (d, J =1.3Hz,2H), 1.30-1.24 (m, 2H), 1.16 (t, J =6.1Hz, 2H).

[0115] Step 3: 8-chloro-N-(5-(1-(trifluoromethyl)cyclopropyl)pyrimidin-2-yl)quinolin-2-amine 8-Chloroquinolin-2-amine (0.05 g, 0.28 mmol), 2-chloro-5-(1-(trifluoromethyl)cyclopropyl)pyrimidine (24c) (0.05 g, 0.23 mmol), Pd(dba) (0.03 g, 0.03 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.02 g, 0.03 mmol), and cesium carbonate (0.18 g, 0.56 mmol) were dissolved in dioxane at room temperature under nitrogen gas protection. The reaction was completed by stirring at 110°C for 4 hours. After cooling to room temperature, the mixture was filtered through diatomaceous earth and concentrated. The residue was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by high-performance liquid chromatography (ZORBAX ECLIPES PLUS C18, 1.8 μm, 4.6*50 mm, eluted with 5% to 95% MeCN / HO containing 0.1% FA) to obtain the target compound, 8-chloro-N-(5-(1-(trifluoromethyl)cyclopropyl)pyrimidin-2-yl)quinolin-2-amine (Compound 24). LCMS(ESI) calculation for C 17 H 13 ClF3N4[M+H] + m / z 365.08, found 364.95. 1 H NMR (400 MHz, DMSO-d6) δ 10.44 (s, 1H), 8.68 (s, 2H), 8.50 (d, J =9.0Hz, 1H), 8.39 (d, J =9.1Hz, 1H), 7.86 (dd, J =12.2, 4.6Hz, 2H), 7.41 (t, J =7.8Hz, 1H), 1.39-1.37 (m, 2H), 1.26-1.21 (m, 2H).

[0116] Example 24: (2S,3S,4S,5R,6R)-6-((8-chloroquinolin-2-yl)(4-(1-(trifluoromethyl)cyclopropyl)phenyl)amino)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid (Compound 25) JPEG2026503131000038.jpg96169 Step 1: (2R,3R,4S,5S,6S)-5-(carboxyoxy)-2-((8-chloroquinolin-2-yl)(4-(1-(trifluoromethyl)cyclopropyl)phenyl)amino)-6-(methoxycarbonyl)-3,4-diacetyloxytetrahydro-2H-pyran At room temperature under nitrogen gas protection, 8-chloro-N-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)quinolin-2-amine (compound 4) (0.50 g, 1.38 mmol) and cadmium carbonate (0.15 g, 0.90 mmol) were added to toluene (20 mL). The mixture was refluxed at 140° C. for 12 hours, and (2R,3R,4S,5S,6S)-2-bromo-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triol triacetate (1.05 g, 2.64 mmol) was added. Water was separated at 140°C and the reaction was completed for 24 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: dichloromethane:methanol=20:1) to obtain the target compound (2R,3R,4S,5S,6S)-5-(carboxyoxy)-2-((8-chloroquinolin-2-yl)(4-(1-(trifluoromethyl)cyclopropyl)phenyl)amino)-6-(methoxycarbonyl)-3,4-diacetyloxytetrahydro-2H-pyran (25a). LCMS(ESI) calculation for C 31 H 28 ClF3N2O 10 [M+H] + m / z 681.14, found 681.10.

[0117] Step 2: (2S,3S,4S,5R,6R)-6-((8-chloroquinolin-2-yl)(4-(1-(trifluoromethyl)cyclopropyl)phenyl)amino)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid Lithium hydroxide monohydrate (0.45 g, 10.74 mmol) was dissolved in water (15 mL) at room temperature, hydrogen peroxide (1 mL) was added, and the mixture was stirred at room temperature for 10 minutes. (2R,3R,4S,5S,6S)-5-(carboxyoxy)-2-((8-chloroquinolin-2-yl)(4-(1-(trifluoromethyl)cyclopropyl)phenyl)amino)-6-(methoxycarbonyl)-3,4-diacetyloxytetrahydro-2H-pyran (25a) (0.30 g, 0.44 mmol) was dissolved in tetrahydrofuran (15 mL), and the prepared lithium hydroxide / hydrogen peroxide mixed solution was slowly added dropwise at room temperature. The mixture was stirred at room temperature for 2 hours and then completed. The reaction mixture was quenched with saturated sodium thiosulfate, adjusted to pH 3 with diluted hydrochloric acid, extracted with ethyl acetate, and the organic phase was washed with water, filtered, dried and concentrated. The crude product was purified by high-performance liquid chromatography (ZORBAX ECLIPES PLUS C18, 1.8 μm, 4.6*50 mm, eluted with 5% to 95% MeCN / HO containing 0.1% FA) to obtain the target compound (2S,3S,4S,5R,6R)-6-((8-chloroquinolin-2-yl)(4-(1-(trifluoromethyl)cyclopropyl)phenyl)amino)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid (compound 25). LCMS (ESI) calculation for C 31 H 28 ClF3N2O 10 [M + H] + m / z 539.11, found 539.04.

[0118] Pharmacological activity test: Regulation and control of miR-124 expression by quinoline derivatives in a PBMC in vitro model A. Materials and Methods 1. Test materials 1) Human PBMC cells 2) PHA-L 3) IL-2 4) mirVana® miRNA Extraction Kit 5)TaqMan Advanced miRNA cDNA Synthesis Kit 6)Taqman Fast Gene Expression Master Mix 7)TaqMan Advanced miRNA Assay (mir191) 8)TaqMan Advanced miRNA Assay (mir124)

[0119] 2. Test method Resuscitate human PBMC cells and place the cell suspension in a 75 cm2 tube containing 13 mL of medium. 2 The cells were transferred to a culture flask. The cells were cultured overnight in a 37°C, 5% CO2 incubator. The cell suspension was then collected in an Erlenmeyer flask and centrifuged at 1200 rpm for 5 minutes. The supernatant was discarded and the cells were resuspended in 1 mL of fresh medium. The cell mass was then gently blown away and the cells were collected in 4 x 10 6 The cells were seeded into a 6-well plate at a density of 1000 cells / mL, and 5 μg / mL of PHA-L and 10 ng / mL of IL-2 were added to each well, followed by incubation in an incubator for 48 hours. 5 μM of a test compound was added to each well of a 6-well plate, and 0.1% DMSO was added to blank control wells, followed by incubation at 37° C. for 24 hours. Cells were harvested, and total RNA was isolated and extracted according to the steps of the mirVana® miRNA extraction kit. cDNA was prepared according to the steps of the TaqMan Advanced miRNA cDNA Synthesis kit, and qPCR testing was performed using miR-191 as an internal reference gene. The qPCR reaction system is as shown in Table 1.

[0120] That is, RNA sample → poly(A) tailing reaction → adapter ligation reaction → reverse transcription (RT) reaction → miR amplification reaction → qPCR test.

[0121] [Table 1]

[0122] The qPCR reaction procedure was 50°C for 2 minutes, 95°C for 20 seconds, 95°C for 1 second, and 60°C for 20 seconds, followed by 40 cycles.

[0123] 3. Data analysis The relative gene expression level was calculated using the formula ΔCt = Ct(miR-124) - Ct(miR-191). Relative miRNA expression level = 2- ΔCt is.

[0124] 4. Test results The relative expression levels of miR-124 obtained by measurement for each test compound are shown in Table 2.

[0125] [Table 2]

[0126] As can be seen from the results in Table 2, the compounds of the present invention can upregulate the expression level of miR-124 in PBMCs.

[0127] Pharmacological activity test: Modulation and control of macrophage IL-6 and TNF-α secretion by quinoline derivatives 1. Test method 1) Induction of macrophages Mouse bone marrow cells were isolated from the femur and tibia bone marrow of 6-8 week-old C75BL / 6 mice raised under SPF conditions, and 1.5*10 6The cells were seeded into a 6-well plate at a density of 2 mL / well, 50 ng / mL of M-CSF was added to each well, and the cells were cultured in a CO2 incubator for 3 days. On the third day, the medium was replaced with fresh medium containing 100 ng / mL M-CSF, and the cells were cultured for another 3 days. On day 6, the supernatant was aspirated, the cells were washed once with DPBS, 1 mL of DPBS was added, and the macrophages were collected with a cell scraper and centrifuged at 400 g for 10 minutes. The supernatant was discarded, and the cells were resuspended in fresh culture medium containing 50 ng / mL of M-CSF. 4 The cells were seeded into a 96-well plate at a density of 200 μL / well and cultured overnight in a CO 2 incubator. 0, 3, 5, and 10 μM of the test compound were added (0.1% DMSO was added to the 0 well), and the cells were cultured in a CO2 incubator for a total of 1 hour. 200 ng / ml of LPS was then added and the cells were cultured for a total of 6 hours. The cell supernatant was then collected, and the secretion levels of IL-6 and TNF-α were detected using an ELISA kit.

[0128] 2. Test results Tests were conducted on selected examples and compared with the test results of ABX-464. The test results are shown in Tables 3 and 4.

[0129] [Table 3]

[0130] [Table 4]

[0131] The results in Tables 3 and 4 show that the compounds of the present invention can effectively inhibit the secretion of IL-6 and TNF-α by mouse macrophages, and have better inhibitory effects than the ABX-464 compound.

[0132] Pharmacological activity test: CYP enzyme inhibition study 1. Examination process The inhibitors, probe substrates and reaction times for each isoenzyme are shown in Table 5. Commercially available mixed human liver microsomes were used, where the liver microsomal concentrations of diclofenac, dextromethorphan, and midazolam were 0.1 mg / mL, and the liver microsomal concentrations of phenacetin, bupropion, amodiaquine, mephenytoin, and testosterone were 0.2 mg / mL. The probe substrate, specific inhibitor, and test compound (ABX464, compound 18) were diluted to the corresponding concentrations to prepare working solutions for use. A mixed solution containing liver microsomes, MgCl2, substrate, specific inhibitor, and test compound was prepared, and 50 μL of 4 mM NADP solution was added to initiate the reaction. The reaction time was as shown in the table. After the incubation period, 600 μL of iced ACN working solution containing IS was added to terminate the reaction. The mixture was mixed, centrifuged, and then subjected to LC-MS / MS detection.

[0133] [Table 5]

[0134] At different concentrations of the test compound or positive inhibitor, the residual activity rate is obtained by comparing the amount of a characteristic metabolite of the probe substrate produced with the amount produced in the absence of the test compound or positive inhibitor. When the metabolite production level significantly decreased at the highest concentration set point, the half maximal inhibitory concentration (IC) was calculated using the log(inhibitor) vs. response -- variable slope equation in GraphPad Prism software. 50 ) was calculated. Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*Hillslope)) X: Log (concentration of test compound or positive inhibitor), Y: residual activity rate, Top and Bottom: The theoretical maximum and minimum remaining activity rates, respectively. Hillslope: Slope coefficient or rate of incline.

[0135] When the maximum concentration is set, if no significant decrease in the amount of metabolites produced is observed (residual enzyme activity rate > 50%), the half maximal inhibitory concentration (IC 50 ) cannot be calculated accurately, and IC 50 was reported to be greater than the highest concentration tested.

[0136] 2. Test results [Table 6]

[0137] The results in Table 6 show that compound 18 is significantly superior to ABX464 in terms of CYP1A2 inhibition.

[0138] Pharmacological activity test: In vivo drug efficacy evaluation in mice 1. Examination process In this study, male C57BL / 6 mice (Jiangsu Jisui Pharmaceutical Biotechnology Co., Ltd.) were used and allowed to drink water containing 3% DSS ad libitum to establish a colitis model. The grouping and administration information are shown in the table below.

[0139] [Table 7]

[0140] After the mice had completed the adaptation feeding, they were randomly divided into four groups based on their body weight: normal control group, DSS enteritis model group, compound 18-10 mg / kg group, and ABX464-40 mg / kg group. The day of group division was designated as D0. From D0 to D8, mice in each group (G2 to G4) were given 3% DSS-containing water, which was replaced every 3 days. From D9 to D11, mice in each group (G2 to G4) were given normal water and orally administered the corresponding solvent and drug for 11 consecutive days from D0 to D11. From D0 to D11, mice in group (G1) were given normal feed and water, and blank solvent for 11 consecutive days. From D0 to D11, the body weight of the mice was observed and recorded daily, the diarrhea score and bloody stool score were measured daily, and the DAI value was calculated. On D11, the mice were euthanized, and the colon tissues were collected, measured, weighed, and photographed. The colon tissues were subjected to HE staining and pathological analysis.

[0141] Statistical analysis: Independent sample T test was adopted. # indicates P<0.05 compared to the normal control group, ## indicates P<0.01 compared to the normal control group, and ### indicates P<0.001 compared to the normal control group. * indicates P<0.05 compared with the model control group, ** indicates P<0.01 compared with the model control group, and *** indicates P<0.001 compared with the model control group.

[0142] 2. Test results: 1) Body weight: The changes in body weight of mice in each group during the drug efficacy period are shown in FIG.

[0143] 2) DAI score: The changes in DAI score of mice in each group during the drug efficacy period are shown in FIG.

[0144] 3) Colon length and colon weight. [Table 8]

[0145] 4) Pathological score [Table 9]

[0146] 5) Conclusion Compared with the normal control group, the mice in the DSS enteritis model group had significantly lower body weight, significantly higher DAI scores, significantly shorter colon lengths, and significantly higher pathology scores, suggesting that the enteritis model was successfully established. Compared with the DSS colitis model control group, mice in the compound 18-10 mg / kg group showed a significant increase in body weight, the DAI scores of the compound 18-10 mg / kg group and the ABX464-40 mg / kg group were significantly decreased, the colon length and colon weight of mice in the compound 18-10 mg / kg group and the ABX464-40 mg / kg group were significantly increased, and the colon pathology scores of mice in the compound 18-10 mg / kg group and the ABX464-40 mg / kg group were significantly decreased. This suggests that both compound 18 and ABX464 significantly reduced enteritis disease and pathology scores, reduced intestinal shortening due to enteritis, and increased intestinal weight.

Claims

1. A quinoline-derived compound having the structural formula as shown in Formula I, or a pharmaceutically acceptable salt thereof. where: A １ , A ２ , A ３ , A ４ and A ５ are each independently N or C—R １ is selected from, where A １ , A ２ , A ３ , A ４ and A ５ At the same time, N does not exceed two, R １ represents hydrogen, deuterium, halogen, cyano group, amino group, hydroxy group, nitro group, C １ ~C ３ Alkyl group, C １ ~C ３ Alkanoyl group, C １ ~C ３ Alkylsulfonyl group, C １ ~C ３ Alkylamine group, C １ ~C ３ Alkyl phosphate group, C １ ~C ３ Alkylaminosulfonyl group, aminosulfonyl group, C １ ~C ３ an alkoxy group and a phosphate group, wherein said C １ ~C ３ Alkyl group, C １ ~C ３ Alkanoyl group, C １ ~C ３ Alkylsulfonyl group, C １ ~C ３ Alkylamine group, C １ ~C ３ Alkyl phosphate group, C １ ~C ３ Alkylaminosulfonyl group, C １ ~C ３ The alkoxy groups are each independently selected from the group consisting of C １ ~C ３ Alkyl group, C １ ~C ６ Alkoxy group, C ３ ~C ７ Cycloalkyl group, C ３ ~C ６ substituted with one or more identical or different substituents selected from heterocycloalkyl groups, deuterium, halogen, cyano groups, amino groups, hydroxy groups, and nitro groups; R ２ are selected from hydrogen, alkyl groups, cycloalkyl groups, and heterocycloalkyl groups, wherein the alkyl groups, cycloalkyl groups, and heterocycloalkyl groups are each independently substituted with one or more of the same or different substituents selected from halogen, hydroxy groups, carboxy groups, ester groups, alkyl groups, alkoxy groups, deuterium, haloalkyl groups, haloalkoxy groups, nitro groups, amino groups, and cyano groups; R ３ and R ４ are each independently a cyano group, a hydroxy group, C １ ~C ３ Alkyl group, C １ ~C ３ Alkanoyl group, C １ ~C ３ alkylamine groups, and C １ ~C ３ alkoxy groups, wherein said C １ ~C ３ Alkyl group, C １ ~C ３ Alkanoyl group, C １ ~C ３ alkylamine groups, and C １ ~C ３ the alkoxy groups are each independently substituted with one or more of the same or different substituents selected from halogen, hydroxy, carboxy, ester, alkyl, alkoxy, deuterium, haloalkyl, haloalkoxy, nitro, amino, and cyano groups; or R ３ and R ４ are connected to each other, C ３ ~C ６ Cycloalkyl group or C ３ ~C ６ constitutes a heterocycloalkyl group, R ５ represents deuterium, halogen, amino group, hydroxy group, nitro group, C １ ~C ６ Alkyl group, C １ ~C ６ Haloalkyl group, C １ ~C ６ Alkanoyl group, C １ ~C ６ Alkylsulfonyl group, C １ ~C ６ Alkylamine group, C １ ~C ６ Alkyl phosphate group, C １ ~C ６ Alkylaminosulfonyl group, aminosulfonyl group, and C １ ~C ６ alkoxy groups, R ３ , R ４ and R ５ cannot simultaneously be an alkyl group or a cycloalkyl group, Each R ６ are the same or different and each independently represent hydrogen, deuterium, a halogen, a cyano group, a hydroxy group C １ ~C ３ Alkyl group, C １ ~C ３ Alkoxy group, C １ ~C ３ Alkanoyl group, C １ ~C ３ Alkylamine group, C １ ~C ３ Alkylsulfonyl group, C １ ~C ３ Alkyl phosphate group, C １ ~C ３ Alkylaminosulfonyl group, aminosulfonyl group, C ３ ~C ７ Cycloalkyl group, C ３ ~C ６ Heterocycloalkyl group, C ２ ~C ６ Alkenyl group, C ２ ~C ６ an alkynyl group, a phosphate group, wherein １ ~C ３ Alkyl group, C １ ~C ３ Alkoxy group, C １ ~C ３ Alkanoyl group, C １ ~C ３ Alkylamine group, C １ ~C ３ Alkylsulfonyl group, C １ ~C ３ Alkyl phosphate group, C １ ~C ３ Alkylaminosulfonyl group, C ３ ~C ７ Cycloalkyl group, C ３ ~C ６ Heterocycloalkyl group, C ２ ~C ６ Alkenyl group, C ２ ~C ６ Each alkynyl group is independently selected from the group consisting of C １ ~C ６ Alkyl group, C １ ~C ６ Alkoxy group, C ３ ~C ７ Cycloalkyl group, C ３ ~C ６ optionally substituted with one or more of the same or different substituents selected from heterocycloalkyl groups, deuterium, halogen, cyano groups, amino groups, hydroxy groups, and nitro groups; n=1, 2 or 3.

2. The quinoline derivative compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the structural formula is as shown in Formula I-1. where: Each R ７ are the same or different and each independently represent a hydrogen atom, a halogen atom, an amino group, a hydroxy group, a nitro group, C １ ~C ３ Alkyl group, C １ ~C ３ Haloalkyl group, C １ ~C ３ Alkanoyl group, C １ ~C ３ Alkylsulfonyl group, C １ ~C ３ Alkylamine group, C １ ~C ３ Alkyl phosphate group, C １ ~C ３ Alkylaminosulfonyl group, aminosulfonyl group, and C １ ~C ３ alkoxy groups, p=1, 2 or 3; A １ , A ２ , A ３ , A ４ , A ５ , R ２ , R ３ , R ４ , R ６ is as defined in claim 1.

3. The quinoline derivative compound or a pharmaceutically acceptable salt thereof according to claim 1, having a structural formula as shown in Formula I-2.

4. The R ２ is hydrogen or C ３ ~C ８ heterocycloalkyl group, wherein said C ３ ~C ８ 2. The quinoline-derived compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the heterocycloalkyl group is optionally substituted with one or more of the same or different substituents selected from a hydroxy group and a carboxy group.

5. The quinoline derivative compound or a pharmaceutically acceptable salt thereof according to claim 1, having a structural formula as shown in formula I-3, formula I-4 or formula I-5.

6.

7.

8. The quinoline derivative compound or a pharmaceutically acceptable salt thereof according to claim 5, wherein the structural formula is as shown in Formula I-7 or Formula I-8. where: R ８ represents deuterium, halogen, cyano group, amino group, hydroxy group, nitro group, C １ ~C ６ Alkyl group, C １ ~C ６ Haloalkyl group, C １ ~C ６ Alkanoyl group, C １ ~C ６ Alkylsulfonyl group, C １ ~C ６ Alkylamine group, C １ ~C ６ Alkyl phosphate group, C １ ~C ６ Alkylaminosulfonyl group, aminosulfonyl group, and C １ ~C ６ alkoxy groups, Each R ９ are the same or different and each independently represent hydrogen, deuterium, a halogen, a cyano group, a hydroxy group, C １ ~C ３ Alkyl group, C １ ~C ３ Alkoxy group, C １ ~C ３ Alkanoyl group, C １ ~C ３ Alkylamine group, C １ ~C ３ Alkylsulfonyl group, C １ ~C ３ Alkyl phosphate group, C １ ~C ３ Alkylaminosulfonyl group, aminosulfonyl group, C ３ ~C ７ Cycloalkyl group, C ３ ~C ６ Heterocycloalkyl group, C ２ ~C ６ Alkenyl group, C ２ ~C ６ an alkynyl group, a phosphate group, wherein １ ~C ３ Alkyl group, C １ ~C ３ Alkoxy group, C １ ~C ３ Alkanoyl group, C １ ~C ３ Alkylamine group, C １ ~C ３ Alkylsulfonyl group, C １ ~C ３ Alkyl phosphate group, C １ ~C ３ Alkylaminosulfonyl group, C ３ ~C ７ Cycloalkyl group, C ３ ~C ６ Heterocycloalkyl group, C ２ ~C ６ Alkenyl group, C ２ ~C ６ Each alkynyl group is independently selected from the group consisting of C １ ~C ６ Alkyl group, C １ ~C ６ Alkoxy group, C ３ ~C ７ Cycloalkyl group, C ３ ~C ６ optionally substituted with one or more of the same or different substituents selected from heterocycloalkyl groups, deuterium, halogen, cyano groups, amino groups, hydroxy groups, and nitro groups; r=0, 1 or 2; A １ , A ２ , A ３ , A ４ , A ５ , R ２ , R ５ , R ６ is as defined in claim 1.

9.

10. The quinoline-derived compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein the quinoline-derived compound is any compound selected from the following:

11. A method for producing a quinoline-derived compound or a pharmaceutically acceptable salt thereof, which is used to produce the compound of claim 1, and comprises the following steps: where: A １ , A ２ , A ３ , A ４ and A ５ are each independently N or C—R １ is selected from, where A １ , A ２ , A ３ , A ４ and A ５ At the same time, N does not exceed two, R １ represents hydrogen, deuterium, halogen, cyano group, amino group, hydroxy group, nitro group, C １ ~C ３ Alkyl group, C １ ~C ３ Alkanoyl group, C １ ~C ３ Alkylsulfonyl group, C １ ~C ３ Alkylamine group, C １ ~C ３ Alkyl phosphate group, C １ ~C ３ Alkylaminosulfonyl group, aminosulfonyl group, C １ ~C ３ an alkoxy group and a phosphate group, wherein said C １ ~C ３ Alkyl group, C １ ~C ３ Alkanoyl group, C １ ~C ３ Alkylsulfonyl group, C １ ~C ３ Alkylamine group, C １ ~C ３ Alkyl phosphate group, C １ ~C ３ Alkylaminosulfonyl group, C １ ~C ３ The alkoxy groups are each independently selected from the group consisting of C １ ~C ３ Alkyl group, C １ ~C ６ Alkoxy group, C ３ ~C ７ Cycloalkyl group, C ３ ~C ６ substituted with one or more identical or different substituents selected from heterocycloalkyl groups, deuterium, halogen, cyano groups, amino groups, hydroxy groups, and nitro groups; R ２ are selected from hydrogen, alkyl groups, cycloalkyl groups, and heterocycloalkyl groups, wherein the alkyl groups, cycloalkyl groups, and heterocycloalkyl groups are each independently substituted with one or more of the same or different substituents selected from halogen, hydroxy groups, carboxy groups, alkyl groups, alkoxy groups, deuterium, haloalkyl groups, haloalkoxy groups, nitro groups, amino groups, and cyano groups; R ３ and R ４ are each independently a cyano group, a hydroxy group, C １ ~C ３ Alkyl group, C １ ~C ３ Alkanoyl group, C １ ~C ３ alkylamine groups, and C １ ~C ３ alkoxy groups, or R ３ and R ４ are connected to each other, C ３ ~C ６ Cycloalkyl group or C ３ ~C ６ constitutes a heterocycloalkyl group, R ５ represents deuterium, halogen, amino group, hydroxy group, nitro group, C １ ~C ６ Alkyl group, C １ ~C ６ Haloalkyl group, C １ ~C ６ Alkanoyl group, C １ ~C ６ Alkylsulfonyl group, C １ ~C ６ Alkylamine group, C １ ~C ６ Alkyl phosphate group, C １ ~C ６ Alkylaminosulfonyl group, aminosulfonyl group, and C １ ~C ６ alkoxy groups, R ３ , R ４ and R ５ cannot simultaneously be an alkyl group or a cycloalkyl group, Each R ６ are the same or different and each independently represent hydrogen, deuterium, a halogen, a cyano group, a hydroxy group C １ ~C ３ Alkyl group, C １ ~C ３ Alkoxy group, C １ ~C ３ Alkanoyl group, C １ ~C ３ Alkylamine group, C １ ~C ３ Alkylsulfonyl group, C １ ~C ３ Alkyl phosphate group, C １ ~C ３ Alkylaminosulfonyl group, aminosulfonyl group, C ３ ~C ７ Cycloalkyl group, C ３ ~C ６ Heterocycloalkyl group, C ２ ~C ６ Alkenyl group, C ２ ~C ６ an alkynyl group, a phosphate group, wherein １ ~C ３ Alkyl group, C １ ~C ３ Alkoxy group, C １ ~C ３ Alkanoyl group, C １ ~C ３ Alkylamine group, C １ ~C ３ Alkylsulfonyl group, C １ ~C ３ Alkyl phosphate group, C １ ~C ３ Alkylaminosulfonyl group, C ３ ~C ７ Cycloalkyl group, C ３ ~C ６ Heterocycloalkyl group, C ２ ~C ６ Alkenyl group, C ２ ~C ６ Each alkynyl group is independently selected from the group consisting of C １ ~C ６ Alkyl group, C １ ~C ６ Alkoxy group, C ３ ~C ７ Cycloalkyl group, C ３ ~C ６ optionally substituted with one or more of the same or different substituents selected from heterocycloalkyl groups, deuterium, halogen, cyano groups, amino groups, hydroxy groups, and nitro groups; n=1, 2 or 3.

12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

13. Use of the compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof in the manufacture of a drug for the prevention and / or treatment of inflammatory diseases or a drug for the treatment of cancer.

14. 14. The application of claim 13, wherein the inflammatory disease is selected from autoimmune-related inflammatory diseases, inflammatory diseases of the central nervous system (CNS), inflammatory diseases of the joints, inflammatory diseases of the gastrointestinal tract, inflammatory diseases of the skin, other inflammatory diseases associated with epithelial cells, cancer-related inflammation, irritant-related inflammation, and injury-related inflammation.

15. 14. The application of claim 13, wherein the inflammatory disease is selected from inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, Alzheimer's disease, Parkinson's disease, osteoarthritis, atherosclerosis, ankylosing spondylitis, psoriasis, dermatitis, systemic lupus erythematosus, Sjogren's syndrome, bronchitis, asthma and inflammation associated with colon cancer.

16. 16. The application of claim 15, wherein the inflammatory bowel disease is ulcerative colitis (UC) or Crohn's disease (CD).

17. 14. The application of claim 13, wherein the cancer is selected from leukemia, lymphoma, macroglobulinemia, heavy chain disease, sarcoma, carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, cystadenocarcinoma, medullary carcinoma, bronchial carcinoma, liver cancer, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, uterine cancer, testicular cancer, lung cancer, bladder cancer, glioma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, schwannoma, neurofibroma, retinoblastoma, melanoma, skin cancer, kidney cancer, nasopharyngeal cancer, gastric cancer, esophageal cancer, head and neck cancer, colorectal cancer, small intestine cancer, gallbladder cancer, childhood tumors, urothelial carcinoma, ureteral tumor, thyroid cancer, bone tumor, neuroblastoma, brain tumor, and myeloma.

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