Tetrahydronaphthyridine sting inhibitor and pharmaceutical use thereof

Abstract

Disclosed in the present invention are a tetrahydronaphthyridine compound and a pharmaceutical use thereof. The structure of the tetrahydronaphthyridine compound is as shown in formula I. The compound in the present invention is a potent STING inhibitor and exhibits favorable pharmacokinetic properties. The compound of formula I or a pharmaceutically acceptable salt thereof in the present invention can be used for preparing a drug for preventing or treating STING-mediated diseases.

Description

Tetrahydronaphthylidine STING inhibitors and their pharmaceutical uses Technical Field

[0001] This invention belongs to the field of biomedicine, specifically relating to tetrahydronaphthidine STING inhibitors and their pharmaceutical uses. Background Technology

[0002] The cGAS-STING signaling pathway plays a crucial role in mediating cytoplasmic DNA immune responses. Circular GMP-AMP synthase (cGAS) is a DNA sensor that recognizes abnormal dsDNA in the cytoplasm. Upon recognition of dsDNA, cGAS forms a dimer cGAS-DNA complex, which synthesizes 2',3'-cGAMP using ATP and GTP. 2',3'-cGAMP, acting as a second messenger, specifically binds to the "V"-shaped pocket formed by the interferon-stimulated regulatory factor (STING) dimer, inducing oligomerization activation of the STING protein. Activated STING translocates from the endoplasmic reticulum to the Golgi apparatus and recruits TANK-binding kinase 1 (TBK1). TBK1, in turn, phosphorylates STING and recruits interferon regulatory factor 3 (IRF3), leading to the production of type I interferon (IFN) and other cytokines, thereby generating an immune inflammatory response. Aberrant activation of the STING pathway can lead to the development of various inflammatory and autoimmune diseases (Nature Immunology, 2017, 18(7):716-724), such as AGS syndrome, systemic lupus erythematosus, Bloom syndrome, SAVI disease, sepsis, Parkinson's disease, non-alcoholic steatohepatitis, pneumonia, chronic nephritis, amyotrophic lateral sclerosis, psoriasis, and ischemia-reperfusion injury. Therefore, STING inhibitors hold promise for the treatment of inflammatory and autoimmune diseases. However, existing STING inhibitors are few in number, have weak activity, and poor drug-like properties (Cell Reports 2018, 25, 3405–3421; ACS Med. Chem. Lett. 2019, 10(1), 92-97; Nature 2018, 559, 269-273; EP3556362; PNAS 2021, 118(24):e2105465118; WO2021138434). For example, the STING palmitoylation inhibitor H-151 (Nature 2018, 559, 269-273; EP3556362) has weak activity and poor metabolic stability, making it difficult to absorb orally (Bri J Pharmacol, 2021, 178, 4907-4922). To date, no STING inhibitor has been approved for marketing. In conclusion, there is a very urgent clinical need to develop novel STING inhibitors. Summary of the Invention

[0003] Objective of the Invention: To address the problems existing in the prior art, this invention provides a novel tetrahydronaphthidine compound, which is a potent STING inhibitor and can therefore be used to prepare drugs for the prevention or treatment of STING-mediated diseases. This invention also provides a method for preparing the said tetrahydronaphthidine compound and pharmaceutical compositions thereof.

[0004] The present invention also provides a method for preparing the tetrahydronaphthidine compounds and a pharmaceutical composition thereof.

[0005] Technical solution: To achieve the above objectives, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof:

[0006] in:

[0007] X is selected from: CH or N;

[0008] Of Y, Z, and W, only one is selected from N, and the other two are each independently selected from CR;

[0009] R is selected from: H, halogen, or C. 1-4 alkyl;

[0010] R 1 and R 2 Each is independently selected from: H, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-8 cycloalkyl, C 3-8 Halogenated cycloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkylthio, C 1-4 Haloalkylthio groups, -S(O) 1-2 (C 1-4 Alkyl), OH, NR'R", CN, NO2, -C(=O)(C 1-4 Alkyl), -C(=O)O(C 1-4 Alkyl), -C(=O)OH, -(C 0-3 alkyl)-heteroaryl, -(C 0-3 alkyl)-5 to 10-membered heterocyclic groups, R a Substituted aryl or R a Substituted heteroaryl, or R 1 and R 2 By bonding with carbon, nitrogen or oxygen atoms to form a 5- to 10-membered heterocycle, wherein the heteroaryl group is a 5- to 10-membered heteroaryl group containing 1 to 2 independently selected oxygen, nitrogen or sulfur atoms, and the 5- to 10-membered heterocycle is a heterocyclic alkane ring or a heterocyclic alkene ring containing 1 to 2 independently selected oxygen or nitrogen atoms.

[0011] R3 Selected from: H, halogen or C 1-4 alkyl;

[0012] R 4 Selected from: H, R which is arbitrarily chosen by 1 to 3 independent selections a Replacement C 1-10 Alkyl groups, optionally with 1 to 3 independently selected R groups a Replacement C 3-8 cycloalkyl, optionally with 1 to 3 independently selected R a Substituted aryl group, optionally selected by 1 to 3 independently chosen R a Substituted heteroaryl, -L 1 -R 5 or -L 2 -L 3 -R 6 The heteroaryl group is a 5- to 10-membered heteroaryl group comprising 1 to 2 independently selected oxygen, nitrogen, or sulfur atoms;

[0013] L 1 Selected from: carbonyl, -S(O) 1-2 Optionally selected by 1 to 2 independent R b Replacement C 1-4 Alkyl groups or optionally 1 to 2 independently selected R groups b Replacement C 3-8 cycloalkyl;

[0014] R 5 Selected from: R, which is arbitrarily chosen by 1 to 3 independent selections c Replacement C 1-8 Alkyl groups, optionally with 1 to 3 independently selected R groups c Replacement C 3-8 cycloalkyl, optionally with 1 to 3 independently selected R c Substituted aryl group or optionally 1 to 3 independently selected R groups c Substituted heteroaryl groups, wherein the heteroaryl group is a 5- to 10-membered heteroaryl group comprising 1 to 2 independently selected oxygen, nitrogen, or sulfur atoms;

[0015] L 2 Selected from: carbonyl, -S(O) 1-2 Optionally selected by 1 to 2 independent R d Replacement C 1-4 Alkyl groups or optionally 1 to 2 independently selected R groups d Replacement C 3-8 cycloalkyl;

[0016] L 3 Selected from: O, S, NR e Or C 1-3 alkyl;

[0017] R 6 Selected from: R, which is arbitrarily chosen by 1 to 3 independent selections f Substituted aryl group, optionally selected by 1 to 3 independently chosen R f Substituted heteroaryl groups, optionally selected by 1 to 3 independently chosen R groups g Replacement C 1-8 Alkyl groups, optionally with 1 to 3 independently selected R groups g Replacement C 3-8 Cycloalkyl, wherein the heteroaryl group is a 5- to 10-membered heteroaryl group comprising 1 to 2 independently selected oxygen, nitrogen, or sulfur atoms;

[0018] R a R b R c and R d Each is independently selected from: H, halogen, CN, OH, NR'R", C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, C 3-8 Halogenated cycloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1- 6-alkylthio, C 1-6 Haloalkylthio group, C 2-6 alkynyl group, C 2-6 alkenyl, -C(=O)(C 1-4 Alkyl), -C(=O)O(C 1- 4-alkyl), -C(=O)OH, -C(=O)NR'R” or -S(O) 1-2 (C 1-4 Alkyl group, or any two independently chosen R groups a R b R c Or R d It forms 5- to 10-membered heterocycles by bonding with carbon, nitrogen, or oxygen atoms;

[0019] R e Selected from: H or C 1-6 alkyl;

[0020] R f and R g Each is independently selected from: H, halogen, CN, OH, NR'R", C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, C 3-8 Halogenated cycloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C1-6 Alkylthio, C 1-6 Haloalkylthio group, C 2-6 alkynyl group, C 2-6 alkenyl, -C(=O)(C 1-4 Alkyl), -C(=O)O(C 1-4 Alkyl groups, -C(=O)OH, -C(=O)NR'R”, -S(O) 1-2 (C 1-4 Alkyl groups, optionally with 1 to 3 independently selected R groups a Substituted aryl group or optionally 1 to 3 independently selected R groups a Substituted heteroaryl groups, or any two independently chosen R groups f Or R g By bonding with carbon, nitrogen or oxygen atoms to form a 5- to 10-membered heterocycle, wherein the heteroaryl group is a 5- to 10-membered heteroaryl group containing 1 to 2 independently selected oxygen, nitrogen or sulfur atoms, and the 5- to 10-membered heterocycle is a heterocyclic alkane ring or a heterocyclic alkene ring containing 1 to 2 independently selected oxygen or nitrogen atoms.

[0021] R' and R” are each independently selected from: H or C 1-6 Alkyl groups, or R' and R" form 5- to 6-membered heterocycles by bonding with carbon, nitrogen, or oxygen atoms, wherein the 5- to 6-membered heterocycle is a heterocyclic alkane ring or a heterocyclic alkene ring containing one independent oxygen or nitrogen atom.

[0022] In some embodiments, the present invention provides a compound of formula II or a pharmaceutically acceptable salt thereof:

[0023] in:

[0024] X is selected from: CH or N;

[0025] R is selected from: H, halogen, or C. 1-4 alkyl;

[0026] R 1 and R 2 Each is independently selected from: H, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-8 cycloalkyl, C 3-8 Halogenated cycloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkylthio, C 1-4 Haloalkylthio groups, -S(O) 1-2 (C 1-4 Alkyl), OH, NR'R", CN, NO2, -C(=O)(C 1-4 Alkyl), -C(=O)O(C1-4 Alkyl), -C(=O)OH, -(C 0-3 alkyl)-heteroaryl, -(C 0-3 alkyl)-5 to 10-membered heterocyclic groups, R a Substituted aryl or R a Substituted heteroaryl, or R 1 and R 2 By bonding with carbon, nitrogen or oxygen atoms to form a 5- to 10-membered heterocycle, wherein the heteroaryl group is a 5- to 10-membered heteroaryl group containing 1 to 2 independently selected oxygen, nitrogen or sulfur atoms, and the 5- to 10-membered heterocycle is a heterocyclic alkane ring or a heterocyclic alkene ring containing 1 to 2 independently selected oxygen or nitrogen atoms.

[0027] R 3 Selected from: H, halogen or C 1-4 alkyl;

[0028] R 4 Selected from: R, which is arbitrarily chosen by 1 to 3 independent selections a Replacement C 1-10 Alkyl groups, optionally with 1 to 3 independently selected R groups a Replacement C 3-8 cycloalkyl, optionally with 1 to 3 independently selected R a Substituted aryl group, optionally selected by 1 to 3 independently chosen R a Substituted heteroaryl, -L 1 -R 5 or -L 2 -L 3 -R 6 The heteroaryl group is a 5- to 10-membered heteroaryl group comprising 1 to 2 independently selected oxygen, nitrogen, or sulfur atoms;

[0029] L 1 Selected from: carbonyl, -S(O) 1-2 Optionally selected by 1 to 2 independent R b Replacement C 1-4 Alkyl groups or optionally 1 to 2 independently selected R groups b Replacement C 3-8 cycloalkyl;

[0030] R 5 Selected from: R, which is arbitrarily chosen by 1 to 3 independent selections c Replacement C 1-8 Alkyl groups, optionally with 1 to 3 independently selected R groups c Replacement C 3-8 cycloalkyl, optionally with 1 to 3 independently selected R c Substituted aryl group or optionally 1 to 3 independently selected R groups cSubstituted heteroaryl groups, wherein the heteroaryl group is a 5- to 10-membered heteroaryl group comprising 1 to 2 independently selected oxygen, nitrogen, or sulfur atoms;

[0031] L 2 Selected from: carbonyl, -S(O) 1-2 Optionally selected by 1 to 2 independent R d Replacement C 1-4 Alkyl groups or optionally 1 to 2 independently selected R groups d Replacement C 3-8 cycloalkyl;

[0032] L 3 Selected from: O, S, NR e Or C 1-3 alkyl;

[0033] R 6 Selected from: R, which is arbitrarily chosen by 1 to 3 independent selections f Substituted aryl group, optionally selected by 1 to 3 independently chosen R f Substituted heteroaryl groups, optionally selected by 1 to 3 independently chosen R groups g Replacement C 1-8 Alkyl groups, optionally with 1 to 3 independently selected R groups g Replacement C 3-8 Cycloalkyl, wherein the heteroaryl group is a 5- to 10-membered heteroaryl group comprising 1 to 2 independently selected oxygen, nitrogen, or sulfur atoms;

[0034] R a R b R c and R d Each is independently selected from: H, halogen, CN, OH, NR'R", C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, C 3-8 Halogenated cycloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1- 6-alkylthio, C 1-6 Haloalkylthio group, C 2-6 alkynyl group, C 2-6 alkenyl, -C(=O)(C 1-4 Alkyl), -C(=O)O(C 1- 4-alkyl), -C(=O)OH, -C(=O)NR'R” or -S(O) 1-2 (C 1-4 Alkyl group, or any two independently chosen R groups a R b R c Or R dIt forms 5- to 10-membered heterocycles by bonding with carbon, nitrogen, or oxygen atoms;

[0035] R e Selected from: H or C 1-6 alkyl;

[0036] R f and R g Each is independently selected from: H, halogen, CN, OH, NR'R", C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, C 3-8 Halogenated cycloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkylthio, C 1-6 Haloalkylthio group, C 2-6 alkynyl group, C 2-6 alkenyl, -C(=O)(C 1-4 Alkyl), -C(=O)O(C 1-4 Alkyl groups, -C(=O)OH, -C(=O)NR'R”, -S(O) 1-2 (C 1-4 Alkyl groups, optionally with 1 to 3 independently selected R groups a Substituted aryl group or optionally 1 to 3 independently selected R groups a Substituted heteroaryl groups, or any two independently chosen R groups f Or R g By bonding with carbon, nitrogen or oxygen atoms to form a 5- to 10-membered heterocycle, wherein the heteroaryl group is a 5- to 10-membered heteroaryl group containing 1 to 2 independently selected oxygen, nitrogen or sulfur atoms, and the 5- to 10-membered heterocycle is a heterocyclic alkane ring or a heterocyclic alkene ring containing 1 to 2 independently selected oxygen or nitrogen atoms.

[0037] R' and R” are each independently selected from: H or C 1-6 Alkyl groups, or R' and R" form 5- to 6-membered heterocycles by bonding with carbon, nitrogen, or oxygen atoms, wherein the 5- to 6-membered heterocycle is a heterocyclic alkane ring or a heterocyclic alkene ring containing one independent oxygen or nitrogen atom.

[0038] In some embodiments, the present invention provides compounds of formula I-II or pharmaceutically acceptable salts thereof, wherein: X is selected from CH.

[0039] In some embodiments, the present invention provides compounds of formula I-II or pharmaceutically acceptable salts thereof, said compounds being selected from any one of those in Table 1:

[0040] Table 1. Structure and Nomenclature of Compounds

[0041] The compounds of this invention can be used as pharmaceutical salts. The salt may be an acid salt of at least one of the following acids: galactoside, D-glucuronic acid, glycerophosphate, hippuric acid, hydroxyethanesulfonic acid, lactobionic acid, maleic acid, 1,5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, neopentanoic acid, terephthalic acid, thiocyanate, cholic acid, dodecyl sulfate, benzenesulfonic acid, citric acid, D-glucose, glycolic acid, lactic acid, malic acid, malonic acid, mandelic acid, phosphoric acid, propionic acid, hydrochloric acid, sulfuric acid, tartaric acid, succinic acid, formic acid, hydroiodic acid, hydrogen... Bromic acid, methanesulfonic acid, nicotinic acid, nitric acid, orotic acid, oxalic acid, picric acid, L-pyroglutamic acid, saccharinic acid, salicylic acid, gentian acid, p-toluenesulfonic acid, valeric acid, palmitic acid, sebacic acid, stearic acid, lauric acid, acetic acid, adipic acid, carbonic acid, benzenesulfonic acid, ethanedisulfonic acid, ethylsuccinic acid, fumaric acid, 3-hydroxynaphthalene-2-carboxylic acid, 1-hydroxynaphthalene-2-carboxylic acid, oleic acid, undecenoic acid, ascorbic acid, camphoric acid, camphorsulfonic acid, dichloroacetic acid, ethanesulfonic acid, etc. Alternatively, the salts described can also be salts formed by the compounds of this invention with metal ions (including sodium, potassium, calcium, etc.) or pharmaceutically acceptable amines (including ethylenediamine, tromethamine, etc.), ammonium ions, or choline.

[0042] The compounds of the present invention may also be used in the form of their stereoisomers, tautomers, prodrugs, deuterated derivatives or solvates.

[0043] This invention also provides methods for preparing the compounds of the invention. For example, representative compound IIa can be prepared using the following synthetic route. Alternatively, the compounds of the invention can be prepared using the methods described in the examples or improved methods.

[0044] Synthesis route:

[0045] In the above synthetic route, R 1 R 2 and R 5 The definition is consistent with the definition in Equation I.

[0046] The compounds of this invention possess potent STING inhibitory activity. Through systematic structure-activity relationship studies, the inventors unexpectedly discovered that the tetrahydro-1,7-naphthidine compounds of this invention (such as I-1, I-2, I-8, I-14, I-15, I-16, I-18, I-21, I-26, I-30, I-31, I-33, I-36, I-37, I-38, etc.) possess potent STING inhibitory activity, and the IC50 of some compounds...50 The activity is less than 30 nM, while structurally similar tetrahydro-1,6-naphthidine compounds (such as I-4) have very weak activity. Therefore, the compounds of the present invention or their pharmaceutically acceptable salts can be used to prepare STING inhibitors, and further to prepare drugs for the prevention or treatment of STING-mediated diseases.

[0047] The diseases mediated by STING are selected from: infectious diseases, inflammatory diseases, autoimmune diseases, metabolic diseases, organ fibrosis diseases, cardiovascular and cerebrovascular diseases, respiratory diseases, nervous system diseases, cancer or precancerous syndromes.

[0048] The infectious diseases mentioned include, but are not limited to, Mycobacterium tuberculosis infection, Chlamydia infection, herpes simplex virus infection, adenovirus infection, hepatitis B virus infection, orthomyxovirus infection, and coronavirus infection.

[0049] The inflammatory and autoimmune diseases mentioned include, but are not limited to, osteoarthritis, acute and chronic infectious arthritis, keratitis, scleritis, conjunctivitis, enteritis, hepatitis, cholecystitis, pancreatitis, gastritis, nephritis, chronic kidney disease, IgA nephropathy, meningitis, neuromuscular rigidity, CNS vasculitis, vasculitis, lymphangitis, phlebitis, cervicitis, endometritis, cystitis, epididymitis, orchitis, urethritis, dermatitis, atopic dermatitis, carbuncles, acne, atypical acne, hidradenitis suppurativa, purulent skin infections, tinea pedis, tinea corporis, hand eczema, alopecia areata, hair loss, urticaria, pruritus, and scars. Patients with lumps, appendicitis, myocarditis, mumps, gingivitis, prostatitis, peritonitis, pleurisy, ulcerative colitis, Crohn's disease, systemic lupus erythematosus, familial frostbite lupus, lupus nephritis, Chagas disease, primary biliary cholangitis, primary sclerosing cholangitis, rheumatoid arthritis, ankylosing spondylitis, psoriasis, multiple sclerosis, systemic sclerosis, Sjögren's syndrome, Behcet's disease, STING-associated vasculitis (SAVI) with infancy, Aicardi-Goutières syndrome, and retinal vascular disease with cerebral protein dystrophy (RCVL), etc.

[0050] The metabolic diseases mentioned include, but are not limited to, non-alcoholic steatohepatitis, alcoholic fatty liver disease, insulin resistance, metabolic syndrome, diabetic nephropathy, diabetic cardiomyopathy, diabetic retinopathy, diabetic foot, polycystic kidney disease, polycystic ovary syndrome, hyperuricemia, gout, osteoporosis, and Duchenne muscular dystrophy.

[0051] The respiratory diseases mentioned include, but are not limited to, cough, asthma, tracheitis, bronchitis, pneumonia, acute respiratory distress syndrome, acute lung injury, emphysema, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, cystic fibrosis, and rhinitis.

[0052] The organ fibrosis diseases mentioned include, but are not limited to, liver fibrosis, cirrhosis, pulmonary fibrosis, and renal fibrosis.

[0053] The cardiovascular and cerebrovascular diseases mentioned include, but are not limited to, atherosclerosis, peripheral vascular disease, coronary heart disease, angina pectoris, ischemia, myocardial ischemia, stroke, myocardial infarction, cardiomyopathy, heart failure, restenosis after angioplasty, ischemic encephalopathy, stroke, hemorrhagic encephalopathy, cerebral hemorrhage, cerebral edema, and cerebral infarction.

[0054] The neurological diseases mentioned include, but are not limited to, Parkinson's disease, Alzheimer's disease, alpha-common protein disease, depression, amyotrophic lateral sclerosis, fibromyalgia syndrome, neuralgia, Down syndrome, Hallewarden-Scholes disease, Huntington's disease, and Wilson's disease.

[0055] The cancers mentioned include, but are not limited to, liver cancer, kidney cancer, cervical cancer, lung cancer, skin cancer, uterine cancer, adenocarcinoma, prostate cancer, sarcoma, osteosarcoma, thyroid cancer, non-small cell lung cancer, esophageal cancer, chronic myeloid leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, acute lymphocytic leukemia, multiple myeloma, malignant lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, and neuroblastoma.

[0056] The compounds of the present invention or their pharmaceutically acceptable salts can also be used to prepare immunoadjuvant drugs.

[0057] The compounds of this invention can be used alone or in combination with other therapeutic agents. As immunomodulators, the compounds of this invention can be used as monotherapy or in combination with other therapeutic agents to treat STING-mediated diseases.

[0058] The present invention also provides a pharmaceutical composition for the prevention or treatment of STING-mediated diseases, comprising at least one compound of the present invention or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier or diluent.

[0059] The pharmaceutical composition is selected from conventional pharmaceutical formulations such as capsules, powders, tablets, granules, pills, injections, syrups, oral liquids, inhalers, ointments, solutions, creams, gels, powders, lotions, tinctures, suppositories, or patches.

[0060] Beneficial effects: Compared with the prior art, the present invention has the following advantages:

[0061] (1) This invention designs and synthesizes novel tetrahydronaphthidine compounds, most of which exhibit significantly better STING inhibitory activity than the positive control compound H-151, and some compounds show higher IC50 values. 50The value is less than 30 nM. The compounds of this invention are orally absorbed and have a relatively long oral half-life (T0). 1 / 2 This drug holds promise for development into a treatment for STING-mediated diseases.

[0062] (2) The compounds of the present invention are ingeniously designed, have simple structures, use cheap and readily available raw materials, and have simple, safe and environmentally friendly synthesis processes, making them easy to scale up for production. Detailed Implementation

[0063] The present invention will be specifically illustrated below through examples. These examples are provided to better illustrate the invention and are not intended to limit its scope. Various changes and modifications can be made to the invention without departing from its spirit and scope.

[0064] Unless otherwise specified, the starting materials used in the embodiments of the present invention are all known products and can be obtained by purchasing commercially available products.

[0065] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR determination was performed using a Bruker NMR spectrometer with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), or deuterated methanol (CD3OD) as the solvent and tetramethylsilane (TMS) as the internal standard.

[0066] Silica gel column chromatography typically uses 200-300 mesh silica gel from the Qingdao Marine Chemical Plant branch as the carrier.

[0067] The known starting materials of this invention can be synthesized using or according to methods known in the art, or can be purchased from companies such as Leyan, Bid Pharmaceutical, Aladdin, and Anaiji.

[0068] Example 1

[0069] 1-(5-Fluoro-1H-indol-3-yl)-3-(7-(4-(trifluoromethyl)benzyl)-5,6,7,8-tetrahydro-1,7-naphthidin-3-yl)urea (Compound I-1)

[0070] Synthesis of intermediate A-1

[0071] 7-(tert-butoxycarbonyl)-5,6,7,8-tetrahydro-1,7-naphthyl-3-carboxylic acid (CAS: 1245645-20-8) (339 mg, 1.22 mmol) was added to tetrahydrofuran (5 mL), followed by triethylamine (185 mg, 1.83 mmol), and then diphenyl azidophosphate (403 mg, 1.46 mmol) was slowly added dropwise. The mixture was stirred overnight at room temperature. After the reaction was complete, the solvent was removed by vacuum distillation, the mixture was diluted with water (3 mL), extracted with ethyl acetate (3 mL x 3), the organic phases were combined, washed with saturated brine (5 mL x 1), dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 8:1) to give intermediate A-1 (white solid, 341 mg). 1 H NMR(300MHz, CDCl3)δ9.02(d,J=2.1Hz,1H),8.07(d,J=2.1Hz,1H),4.76(s,2H),3.73(t,J=5.8Hz,2H),2.93(t,J=5.8Hz,2H),1.51(s,9H).HRMS(ESI)calcd for C 14 H 17 N5O3[M+H] + 304.1404, found 304.1403.

[0072] Synthesis of intermediate A-2

[0073] All of the above intermediates A-1 and benzyl alcohol (138 mg, 1.28 mmol) were added to toluene (4 mL), and the reaction was carried out at 100 °C for 6 hours. After the reaction was completed, the solvent was removed by vacuum distillation, and the residue was added to petroleum ether (5 mL), stirred into a slurry, and filtered to obtain intermediate A-2 (white solid, 408 mg).

[0074] Synthesis of intermediate A-3

[0075] Intermediate A-2 (100 mg, 0.26 mmol) was added to ethyl acetate (1 mL), and 4 M ethyl hydrochloride solution (2 mL) was slowly added under ice bath conditions. The mixture was slowly brought to room temperature and reacted for 5 hours. After the reaction was completed, the solvent was removed by vacuum distillation to obtain intermediate A-3 (98.8 mg, white solid). 1H NMR (300MHz, DMSO-d6) δ10.16 (s, 1H), 9.63 (s, 2H), 8.51 (d, J = 2.4Hz, 1H), 7.83 (s, 1H), 7.51–7. 17(m,5H),5.18(s,2H),4.26–4.13(m,2H),3.37(s,2H),3.03(t,J=6.1Hz,2H).HRMS(ESI)calcd for C 16 H 17 N3O2[M+H] + 284.1394, found 284.1393.

[0076] Synthesis of intermediate A-4

[0077] Intermediate A-3 (89 mg, 0.25 mmol), 3-fluoro-4-trifluoromethylbenzyl bromide (64 mg, 0.25 mmol), and potassium carbonate (104 mg, 0.75 mmol) were added to N,N-dimethylformamide (3 mL) and stirred overnight at room temperature. After the reaction was complete, the mixture was diluted with water (3 mL), extracted with ethyl acetate (3 mL x 3), the organic phases were combined, washed with saturated brine (5 mL x 1), dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation to give intermediate A-4 (110 mg, pale yellow solid). 1 H NMR (300MHz, CDCl3) δ8.21(d,J=2.5Hz,1H),7.82(s,1H),7.57(t,J=7.7Hz,1H),7.45–7.29(m,6H),7.26(s,1H),6 .73(s,1H),5.23(s,2H),3.76(s,2H),3.70(s,2H),2.92(t,J=5.7Hz,2H),2.76(t,J=5.8Hz,2H).HRMS(ESI)calcd for C 24 H 21 F4N3O2[M+H] + 460.1643, found 460.1641.

[0078] Synthesis of intermediate A-5

[0079] All intermediate A-4 (110 mg) and 10% palladium on carbon (11 mg) were added to methanol (2 mL), purged three times with hydrogen, and stirred at room temperature for 8 hours. After the reaction was complete, the mixture was filtered, and the solvent was removed from the filtrate under reduced pressure to obtain intermediate A-5 (pale yellow solid, 45 mg). 1H NMR (400MHz, CDCl3) δ7.90(d,J=2.7Hz,1H),7.57(t,J=7.6Hz,1H),7.29(t,J=11.3Hz,2H),6.79(d,J =2.6Hz,1H),3.76(s,2H),3.66(s,2H),2.84(t,J=5.9Hz,2H),2.73(t,J=5.8Hz,2H).HRMS(ESI)calcd for C 16 H 15 F4N3[M+H] + 326.1275, found 326.1273.

[0080] Synthesis of intermediate A-6

[0081] 5-Fluoroindole (10 g, 74 mmol) was dissolved in N,N-dimethylformyl (DMF) (140 mL), and trifluoroacetic anhydride (TFAA) (62 g, 296 mmol) was slowly added under ice bath conditions, with stirring at room temperature overnight. After the reaction was complete, water (500 mL) was added, and a pink solid precipitated. The solid was filtered, dried, and yielded intermediate A-6 (white solid, 16.2 g). The crude product was used directly in the next reaction step.

[0082] Synthesis of intermediate A-7

[0083] The crude intermediate A-6 (16.2 g) was dissolved in 20% NaOH (120 mL) solution and stirred at 100 °C for 2.5 hours. After the reaction was completed, insoluble impurities were removed by filtration. 6N HCl solution was added to the filtrate under ice bath conditions to adjust the pH to 3, resulting in the precipitation of a large amount of yellow solid. The solid was filtered and dried to obtain intermediate A-7 (yellow solid, 12.5 g).

[0084] Synthesis of intermediate A-8

[0085] Intermediate A-7 (10.6 g, 59.4 mmol) was dissolved in dichloromethane (DCM) (120 mL), and triethylamine (TEA) (18 mL, 132 mmol) was added. The mixture was stirred at room temperature for 15 minutes, and diphenyl azidophosphate (DPPA) (16 g, 59.4 mmol) was added. The reaction was allowed to proceed overnight. After the reaction was complete, 200 mL of 1N HCl solution was added, and the mixture was extracted with dichloromethane (100 mL x 3). The organic phases were combined, washed with saturated brine (200 mL x 1), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 2:1) to give intermediate A-8 (gray solid, 7.1 g).

[0086] Synthesis of compound I-1

[0087] Intermediate A-8 (30.6 mg, 0.15 mmol) was added to toluene (3 mL), and the system was transferred to an oil bath and reacted at 100 °C for 3 hours. After cooling to room temperature, intermediate A-5 (45 mg, 0.15 mmol) was added, and the reaction was allowed to proceed overnight. A white solid precipitated, and the solvent was removed by vacuum evaporation. The residue was slurried with dichloromethane / methanol in a ratio of 20:1 (3 mL), stirred at room temperature for 2 hours, filtered, and the filter cake was dried to obtain compound I-1 (yellow solid, 51 mg). 1 H NMR(300MHz,DMSO-d6)δ10.91(s,1H),8.64(s,1H),8.55(s,1H),8.34(d,J=2.4Hz,1H), 7.84–7.72(m,2H),7.56(d,J=2.5Hz,1H),7.51(d,J=12.1Hz,1H),7.45(d,J=8.1Hz,1H) ,7.35(dd,J=8.8,4.5Hz,1H),7.23(dd,J=9.9,2.6Hz,1H),6.95(td,J=9.2,2.6Hz,1H), 3.80(s,2H),3.57(s,2H),2.85(t,J=5.7Hz,2H),2.71(t,J=5.7Hz,2H).HRMS(ESI)calcd for C 25 H 20 F5N5O[M+H] + 502.1661, found 502.1660.

[0088] Example 2

[0089] 1-(5-Fluoro-1H-indol-3-yl)-3-(7-(4-((trifluoromethyl)thio)benzyl)-5,6,7,8-tetrahydro-1,7-naphthid-3-yl)urea (compound I-2)

[0090] Following the method of Example 1, 3-fluoro-4-trifluoromethylbenzyl bromide was replaced with 4-trifluoromethylthiobenzyl bromide to prepare compound I-2. 1H NMR (400MHz, DMSO-d6) δ10.91(s,1H),8.63(s,1H),8.54(s,1H),8.32(d,J=2.5Hz ,1H),7.78(d,J=2.4Hz,1H),7.71(d,J=8.1Hz,2H),7.62–7.51(m,3H),7.34(dd,J =8.8,4.5Hz,1H),7.23(dd,J=9.8,2.6Hz,1H),6.95(td,J=9.1,2.5Hz,1H),3.76( s,2H),3.52(s,2H),2.84(t,J=5.8Hz,2H),2.70(t,J=5.9Hz,2H).HRMS(ESI)calcd for C 25 H 21 F4N5OS[M+H] + 516.1476, found 516.1489.

[0091] Example 3

[0092] 1-(5-Fluoro-1H-indol-3-yl)-3-(7-(4-(trifluoromethyl)benzyl)-5,6,7,8-tetrahydro-1,7-naphthidin-3-yl)urea (compound I-3)

[0093] Following the method of Example 1, 3-fluoro-4-trifluoromethylbenzyl bromide was replaced with 4-trifluoromethylbenzyl bromide to prepare compound I-3. 1 H NMR (400MHz, DMSO-d6) δ10.91(s,1H),8.64(s,1H),8.56(s,1H),8.33(d,J=2.5H z,1H),7.78(s,1H),7.73(d,J=8.0Hz,2H),7.62(d,J=8.0Hz,2H),7.56(d,J=2.5H z,1H),7.34(dd,J=8.8,4.5Hz,1H),7.23(dd,J=9.8,2.6Hz,1H),6.95(td,J=9.2, 2.6Hz,1H),3.79(s,2H),3.54(s,2H),2.84(s,2H),2.70(s,2H).HRMS(ESI)calcd for C 25 H 21 F4N5O[M+H] + 484.1755, found 484.1768

[0094] Example 4

[0095] 1-(5-Fluoro-1H-indol-3-yl)-3-(6-(4-((trifluoromethyl)thio)benzyl)-5,6,7,8-tetrahydro-1,6-naphthid-2-yl)urea (compound I-4)

[0096] Synthesis of intermediate A-9

[0097] 74.8 mg (0.3 mmol) of 2-amino-7,8-dihydro-1,6-naphthyl-6(5H)-carboxylic acid tert-butyl ester (CAS: 1149333-40-3) was added to ethyl acetate (1 mL), and 3 mL of 4M ethyl hydrochloride solution was slowly added under ice bath conditions. The mixture was then slowly brought to room temperature and reacted for 5 hours. After the reaction was complete, the solvent was removed by vacuum distillation to obtain intermediate A-9 (57 mg, white solid), which was used directly in the next reaction without purification.

[0098] Synthesis of intermediate A-10

[0099] Intermediate A-9 (57 mg, 0.26 mmol), 4-trifluoromethylthiobenzyl bromide (70.5 mg, 0.26 mmol), and potassium carbonate (108 mg, 0.78 mmol) were added to N,N-dimethylformamide (3 mL) and stirred overnight at room temperature. After the reaction was complete, the mixture was diluted with water (3 mL), extracted with ethyl acetate (3 mL x 3), and the organic phases were combined, washed with saturated brine (5 mL x 1), dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation to obtain intermediate A-10 (81 mg, pale yellow solid), which was used directly in the next reaction without further purification.

[0100] Synthesis of compound I-4

[0101] Following the method of Example 1, intermediate A-5 was replaced with intermediate A-10 to obtain compound I-4. 1H NMR(300MHz,DMSO-d6)δ10.91(s,1H),10.85(s,1H),9.50(s,1H),7.71(d,J=8.0Hz,2H), 7.65(d,J=2.5Hz,1H),7.56(d,J=8.1Hz,2H),7.44(d,J=8.4Hz,1H),7.37(dd,J=8.9,4.5 Hz,1H),7.19(dd,J=9.7,2.5Hz,1H),7.12(d,J=8.4Hz,1H),6.97(td,J=9.2,2.5Hz,1H), 3.78(s,2H),3.53(s,2H),2.97(t,J=5.8Hz,2H),2.85(t,J=5.6Hz,2H).HRMS(ESI)calcd for C 25 H 21 F4N5OS[M+H] + 516.1476, found 516.1487.

[0102] Example 5

[0103] 1-(5-fluoro-1H-indol-3-yl)-3-(7-(3,4,5-trifluorobenzyl)-5,6,7,8-tetrahydro-1,7-naphthid-3-yl)urea (compound I-5)

[0104] Following the method of Example 1, 3-fluoro-4-trifluoromethylbenzyl bromide was replaced with 3,4,5-trifluorobenzyl bromide to prepare compound I-5. 1 H NMR (400MHz, DMSO-d6) δ10.90(s,1H),8.65(s,1H),8.57(s,1H),8.34(d,J=2.5Hz,1H),7.77(d,J=2.4Hz,1H),7.56(d,J=2.5Hz,1H),7.37–7.28(m,3 H),7.24(dd,J=9.9,2.6Hz,1H),6.95(td,J=9.2,2.6Hz,1H),3.68(s,2H),3.54(s,2H),2.83(t,J=5.8Hz,2H),2.68(t,J=5.8Hz,2H).HRMS(ESI)calcd for C 24 H 19 F4N5O[M+H] + 470.1598, found 470.1595.

[0105] Example 6

[0106] 1-(5-Fluoro-1H-indol-3-yl)-3-(7-(3-(trifluoromethoxy))benzyl)-5,6,7,8-tetrahydro-1,7-naphthidin-3-yl)urea (compound I-6)

[0107] Following the method of Example 1, 3-fluoro-4-trifluoromethylbenzyl bromide was replaced with 3-(trifluoromethoxy)benzyl bromide to prepare compound I-6. 1 H NMR (300MHz, DMSO-d6) δ10.91(s,1H),8.63(s,1H),8.55(s,1H),8.34(d,J=2.4H z,1H),7.78(d,J=2.4Hz,1H),7.56(d,J=2.5Hz,1H),7.53–7.46(m,1H),7.42(d,J =7.6Hz,1H),7.40–7.30(m,2H),7.26(m,2H),6.95(td,J=9.2,2.6Hz,1H),3.75(s ,2H),3.54(s,2H),2.83(t,J=5.8Hz,2H),2.69(t,J=5.7Hz,2H).HRMS(ESI)calcd for C 25 H 21 F4N5O2[M+H] + 500.1704, found 500.1704.

[0108] Example 7

[0109] 1-(7-(4-(1,1-difluoroethyl)benzyl)-5,6,7,8-tetrahydro-1,7-naphthid-3-yl)-3-(5-fluoro-1H-indol-3-yl)urea (compound I-7)

[0110] Synthesis of intermediate A-11

[0111] 4-(1,1-difluoroethyl)benzoic acid (93 mg, 0.5 mmol) was added to anhydrous tetrahydrofuran (3 mL). Under ice bath conditions, 1 M boranetetrahydrofuran complex (1.5 mL, 1.5 mmol) was slowly added to the above reaction solution. The mixture was slowly brought to room temperature and stirred for 3 hours. After the reaction was completed, methanol (1 mL) was slowly added dropwise to quench the reaction. The solvent was then removed under reduced pressure, diluted with water (3 mL), extracted with ethyl acetate (3 mL x 3), and the organic phases were combined. The mixture was washed with saturated brine (5 mL x 1), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain intermediate A-11 (colorless oily liquid, 80 mg). The crude product was used directly in the next reaction.

[0112] Synthesis of intermediate A-12

[0113] All crude intermediate A-11 was added to dichloromethane (3 mL), and triphenylphosphine (170 mg, 0.65 mmol) and N-bromosuccinimide (116 mg, 0.65 mmol) were added sequentially in an ice bath. The mixture was slowly heated to room temperature and reacted for 3 hours. After the reaction was complete, the solvent was removed by vacuum distillation, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 20:1) to give intermediate A-12 (colorless oily liquid, 91 mg).

[0114] Synthesis of compound I-7

[0115] Following the method of Example 1, 3-fluoro-4-trifluoromethylbenzyl bromide was replaced with A-12 to prepare compound I-7. 1 H NMR (300MHz, DMSO-d6) δ10.90(s,1H),8.71(s,1H),8.62(s,1H),7.78(s,1H),7.61–7.44(m,5H),7.34(dd,J=8.8,4.5Hz,1H),7.25(dd,J= 9.8,2.6Hz,1H),6.95(td,J=9.2,2.6Hz,1H),3.74(s,2H),3.53(s,2H),2.84(s,2H),2.71(s,2H),1.98(t,J=18.8Hz,3H).HRMS(ESI)calcd for C 26 H 24 F3N5O[M+H] + 480.2006, found 480.2002.

[0116] Example 8

[0117] 1-(5-fluoro-1H-indol-3-yl)-3-(7-(4-(trifluoromethyl)phenethyl)-5,6,7,8-tetrahydro-1,7-naphthidin-3-yl)urea (compound I-8)

[0118] Following the method of Example 1, 3-fluoro-4-trifluoromethylbenzyl bromide was replaced with 4-trifluoromethylphenylethyl bromide to prepare compound I-8. 1H NMR (300MHz, DMSO-d6) δ10.88(s,1H),8.70(s,1H),8.60(s,1H),8.35(s,1H),7.76(s,1H),7.65(d,J=8.0Hz,2H),7.61–7.47(m,3H),7 .33(dd,J=8.8,4.5Hz,1H),7.23(dd,J=9.9,2.5Hz,1H),6.93(td,J=9.2,2.6Hz,1H),3.65(s,2H),3.10–2.59(m,8H).HRMS(ESI)calcd for C 26 H 23 F4N5O[M+H] + 498.1911, found 498.1911.

[0119] Example 9

[0120] 1-(5-Fluoro-1H-indol-3-yl)-3-(7-(3-(4-(trifluoromethyl)phenyl)propyl)-5,6,7,8-tetrahydro-1,7-naphthid-3-yl)urea (compound I-9)

[0121] Following the method of Example 7, 4-(1,1-difluoroethyl)benzoic acid was replaced with 3-(4-trifluoromethylphenyl)propionic acid to prepare intermediate A-13. Then, following the method of Example 1, 3-fluoro-4-trifluoromethylbenzyl bromide was replaced with intermediate A-13 to prepare compound I-9. 1 H NMR(300MHz,DMSO-d6)δ10.90(s,1H),8.74(d,J=31.1Hz,2H),8.37(s,1H),7.79(s ,1H),7.66(d,J=8.0Hz,2H),7.56(d,J=2.5Hz,1H),7.49(d,J=8.0Hz,2H),7.35(dd ,J=8.8,4.5Hz,1H),7.27(dd,J=9.9,2.5Hz,1H),6.95(td,J=9.2,2.5Hz,1H),3.60 (s,1H),3.21(s,1H),3.07–2.60(m,7H),2.42(s,1H),1.91(s,2H)HRMS(ESI)calcd for C 27 H 25 F4N5O[M+H] + 512.2068, found 512.2067.

[0122] Example 10

[0123] 1-(5-Fluoro-1H-indol-3-yl)-3-(7-(4-(trifluoromethoxy)benzyl)-5,6,7,8-tetrahydro-1,7-naphthid-3-yl)urea (Compound I-10)

[0124] Following the method of Example 1, 3-fluoro-4-trifluoromethylbenzyl bromide was replaced with 4-trifluoromethoxybenzyl bromide to prepare compound I-10. 1 H NMR(300MHz,DMSO-d6)δ10.89(s,1H),8.79(d,J=32.7Hz,2H),8.53–8.18(m,1H),7.83(s,1H),7.6 9–7.18(m,7H),6.95(td,J=9.2,2.6Hz,1H),3.94–3.42(m,4H),3.12–2.59(m,4H)HRMS(ESI)calcd for C 25 H 21 F4N5O2[M+H] + 500.1704, found 500.1704.

[0125] Example 11

[0126] 1-(5-fluoro-1H-indol-3-yl)-3-(7-(3-fluoro-5-(trifluoromethyl)benzyl)-5,6,7,8-tetrahydro-1,7-naphthidin-3-yl)urea (compound I-11)

[0127] Following the method of Example 1, 3-fluoro-4-trifluoromethylbenzyl bromide was replaced with 3-fluoro-5-(trifluoromethyl)benzyl bromide to prepare compound I-11. 1 H NMR (300MHz, DMSO-d6) δ10.89(s,1H),8.75(d,J=30.9Hz,2H),8.36(s,1H),7.79(s,1H),7.70–7.52(m,4H),7.34(dd,J=8.8,4.5Hz ,1H),7.27(dd,J=9.9,2.5Hz,1H),6.95(td,J=9.2,2.6Hz,1H),3.83(s,2H),3.60(s,2H),2.80(d,J=38.2Hz,4H).HRMS(ESI)calcd for C 25 H 20 F5N5O[M+H] + 502.1661, found 502.1660.

[0128] Example 12

[0129] 1-(5-Fluoro-1H-indol-3-yl)-3-(7-(4-isopropylbenzyl)-5,6,7,8-tetrahydro-1,7-naphthid-3-yl)urea (compound I-12)

[0130] Following the method of Example 1, 3-fluoro-4-trifluoromethylbenzyl bromide was replaced with 4-isopropylbenzyl bromide to prepare compound I-12. 1 H NMR(400MHz,DMSO-d6)δ10.90(s,1H),8.62(s,1H),8.54(s,1H),8.32(d,J=2.5Hz,1H) ,7.76(d,J=2.4Hz,1H),7.55(d,J=2.5Hz,1H),7.34(dd,J=8.9,4.5Hz,1H),7.28(d,J=8 .1Hz,2H),7.26–7.18(m,4H),6.95(td,J=9.2,2.5Hz,1H),3.63(s,2H),3.49(s,2H),2 .81(t,J=5.9Hz,2H),2.68(t,J=6.1Hz,2H),1.22(s,3H),1.20(s,3H).HRMS(ESI)calcd for C 27 H 28 FN5O[M+H] + 458.2351, found 458.2350.

[0131] Example 13

[0132] 1-(5-Fluoro-1H-indol-3-yl)-3-(7-(4-(tert-butyl)benzyl)-5,6,7,8-tetrahydro-1,7-naphthidin-3-yl)urea (compound I-13)

[0133] Following the method of Example 1, 3-fluoro-4-trifluoromethylbenzyl bromide was replaced with 4-tert-butylbenzyl bromide to prepare compound I-13. 1H NMR (300MHz, DMSO-d6) δ10.90(s,1H),8.63(s,1H),8.55(s,1H),8.32(d,J=2.4Hz,1H),7.77(d,J=2.4Hz,1H),7.55(d,J=2.5Hz,1H),7.40–7. 32(m,3H),7.31–7.21(m,3H),6.99–6.90(m,1H),3.64(s,2H),3.49(s,2H),2.81(d,J=5.9Hz,2H),2.68(t,2H),1.29(s,9H).HRMS(ESI)calcd for C 28 H 30 FN5O[M+H] + 472.2507, found 472.2505.

[0134] Example 14

[0135] 1-(7-(3-(tert-butyl)benzyl)-5,6,7,8-tetrahydro-1,7-naphthidin-3-yl)-3-(5-fluoro-1H-indole-3-yl)urea (compound I-14)

[0136] Following the method of Example 7, 4-(1,1-difluoroethyl)benzoic acid was replaced with 3-tert-butylbenzoic acid to prepare intermediate A-14. Then, following the method of Example 1, 3-fluoro-4-trifluoromethylbenzyl bromide was replaced with intermediate A-14 to prepare compound I-14. 1 H NMR (400MHz, DMSO-d6) δ10.86(d,J=2.6Hz,1H),8.58(s,1H),8.50(s,1H),8.28(d,J=2.4Hz,1H),7.72(d,J=2.4Hz,1H),7.51(d,J=2.5Hz,1H),7.3 6–7.10(m,6H),6.91(td,J=9.2,2.5Hz,1H),3.64(s,2H),3.48(s,2H),2.77(t,J=6.0Hz,2H),2.64(t,J=5.8Hz,2H),1.25(s,9H).HRMS(ESI)calcd for C 28 H 30 FN5O[M+H] + 472.2507, found 472.2507.

[0137] Example 15

[0138] 1-(5-Fluoro-1H-indol-3-yl)-3-(7-(3-Fluoro-4-(trifluoromethoxy)benzyl)-5,6,7,8-tetrahydro-1,7-naphthidin-3-yl)urea (Compound I-15)

[0139] Following the method of Example 7, 4-(1,1-difluoroethyl)benzoic acid was replaced with 3-fluoro-4-(trifluoromethoxy)benzoic acid to prepare intermediate A-15. Then, following the method of Example 1, 3-fluoro-4-trifluoromethylbenzyl bromide was replaced with intermediate A-15 to prepare compound I-15. 1 H NMR (400MHz, DMSO-d6) δ10.90(s,1H),8.61(s,1H),8.52(s,1H),8.33(d,J=2.5Hz,1H),7.78(d,J=2.4Hz,1H),7.61–7.47(m,3H),7.39–7.32(m,2H) ,7.23(dd,J=9.8,2.6Hz,1H),6.95(td,J=9.2,2.5Hz,1H),3.74(s,2H),3.55(s,2H),2.84(t,J=5.9Hz,2H),2.70(t,J=5.8Hz,2H).HRMS(ESI)calcd for C 25 H 20 F5N5O2[M+H] + 518.1610, found 518.1607.

[0140] Example 16

[0141] 1-(5-fluoro-1H-indol-3-yl)-3-(7-(2-fluoro-4-(trifluoromethyl)benzyl)-5,6,7,8-tetrahydro-1,7-naphthid-3-yl)urea (compound I-16)

[0142] Following the method of Example 1, 3-fluoro-4-trifluoromethylbenzyl bromide was replaced with 2-fluoro-4-(trifluoromethyl)benzyl bromide to prepare compound I-16. 1H NMR (400MHz, DMSO-d6) δ10.89(s,1H),8.63(s,1H),8.54(s,1H),8.34(d,J=2.5Hz,1H),7.77(d ,J=2.2Hz,1H),7.74(d,J=7.5Hz,1H),7.68(dd,J=10.1,1.8Hz,1H),7.61(dd,J=8.4,1.8Hz,1H ),7.55(d,J=2.5Hz,1H),7.34(dd,J=8.8,4.5Hz,1H),7.24(dd,J=9.8,2.6Hz,1H),6.99–6.91( m,1H),3.83(s,2H),3.59(s,2H),2.84(t,J=5.5Hz,2H),2.73(t,J=5.7Hz,2H).HRMS(ESI)calcd for C 25 H 20 F5N5O[M+H] + 502.1661, found 502.1661.

[0143] Example 17

[0144] 1-(5-Fluoro-1H-indol-3-yl)-3-(7-(2-(4-fluorophenoxy)ethyl)-5,6,7,8-tetrahydro-1,7-naphthidin-3-yl)urea (Compound I-17)

[0145] Following the method of Example 7, 4-(1,1-difluoroethyl)benzoic acid was replaced with 2-(4-fluorophenoxy)acetic acid to prepare intermediate A-17. Then, following the method of Example 1, 3-fluoro-4-trifluoromethylbenzyl bromide was replaced with intermediate A-17 to prepare compound I-17. 1 H NMR(400MHz,DMSO-d6)δ10.86(d,J=2.6Hz,1H),8.58(s,1H),8.49(s,1H),8.31(d, J=2.5Hz,1H),7.73(d,J=2.4Hz,1H),7.52(d,J=2.5Hz,1H),7.32(dd,J=8.9,4.5Hz, 1H),7.20(dd,J=9.9,2.6Hz,1H),7.14–7.04(m,2H),6.98–6.87(m,3H),4.13(t,J= 5.7Hz,2H),3.63(s,2H),2.88(t,J=5.8Hz,2H),2.82–2.74(m,4H).HRMS(ESI)calcd for C 25 H 23 F2N5O2[M+H]+ 464.1893, found 464.1893.

[0146] Example 18

[0147] 1-(5-fluoro-1H-indol-3-yl)-3-(7-(4-(trifluoromethoxy)phenethyl)-5,6,7,8-tetrahydro-1,7-naphthid-3-yl)urea (compound I-18)

[0148] Following the method of Example 7, 4-(1,1-difluoroethyl)benzoic acid was replaced with 2-(4-(trifluoromethoxy)phenyl)acetic acid to prepare intermediate A-18. Then, following the method of Example 1, 3-fluoro-4-trifluoromethylbenzyl bromide was replaced with intermediate A-18 to prepare compound I-18. 1 H NMR (400MHz, DMSO-d6) δ10.88(s,1H),8.68(s,1H),8.59(s,1H),8.35(d,J=2.5Hz,1H),7. 76(d,J=2.4Hz,1H),7.66(d,J=8.5Hz,2H),7.56(d,J=2.5Hz,1H),7.34(dd,J=8.8,4.5Hz, 1H),7.25(dd,J=9.8,2.5Hz,1H),7.17(d,J=8.6Hz,2H),6.95(td,J=9.2,2.6Hz,1H),4.28 (t,J=5.7Hz,2H),3.67(s,2H),2.95(t,J=5.6Hz,2H),2.85–2.76(m,4H).HRMS(ESI)calcd for C 26 H 23 F4N5O2[M+H] + 514.1861, found 514.1859.

[0149] Example 19

[0150] 1-(5-fluoro-1H-indol-3-yl)-3-(7-(2-(4-(trifluoromethyl)phenoxy)ethyl)-5,6,7,8-tetrahydro-1,7-naphthid-3-yl)urea (compound I-19)

[0151] Following the method of Example 7, 4-(1,1-difluoroethyl)benzoic acid was replaced with 2-(4-(trifluoromethyl)phenoxy)acetic acid to prepare intermediate A-19. Then, following the method of Example 1, 3-fluoro-4-trifluoromethylbenzyl bromide was replaced with intermediate A-19 to prepare compound I-19. 1H NMR (400MHz, DMSO-d6) δ10.86(s,1H),8.59(s,1H),8.51(s,1H),8.31(d,J=2.5H z,1H),7.72(d,J=2.5Hz,1H),7.52(d,J=2.5Hz,1H),7.41–7.36(m,2H),7.32(dd, J=8.8,4.5Hz,1H),7.28–7.18(m,3H),6.92(td,J=9.2,2.6Hz,1H),3.58(s,2H), 2.86(t,J=7.5Hz,2H),2.77(t,J=5.6Hz,2H),2.75–2.69(m,4H).HRMS(ESI)calcd for C 26 H 23 F4N5O2[M+H] + 514.1861, found 514.1861.

[0152] Example 20

[0153] 1-(7-(4-(difluoromethoxy)benzyl)-5,6,7,8-tetrahydro-1,7-naphthid-3-yl)-3-(5-fluoro-1H-indole-3-yl)urea (compound I-20)

[0154] Following the method of Example 7, 4-(1,1-difluoroethyl)benzoic acid was replaced with 4-(difluoromethoxy)benzoic acid to prepare intermediate A-20. Then, following the method of Example 1, 3-fluoro-4-trifluoromethylbenzyl bromide was replaced with intermediate A-20 to prepare compound I-20. 1 H NMR (300MHz, DMSO-d6) δ10.90(s,1H),8.64(s,1H),8.56(s,1H),8.32(d,J=2.4Hz,1H),7.77(s,1H),7.55(d,J=2.5Hz,1H),7.43(d,J=8.2Hz, 2H),7.34(dd,J=8.9,4.5Hz,1H),7.26–7.14(m,4H),7.00–6.90(m,1H),3.67(s,2H),3.50(s,2H),2.82(s,2H),2.68(s,2H).HRMS(ESI)calcd for C 25 H 22 F3N5O2[M+H] + 482.1798, found 482.1798.

[0155] Example 21

[0156] 1-(5-fluoro-1H-indol-3-yl)-3-(7-(4-fluoro-3-(trifluoromethyl)benzyl)-5,6,7,8-tetrahydro-1,7-naphthidin-3-yl)urea (compound I-21)

[0157] Following the method of Example 1, 3-fluoro-4-trifluoromethylbenzyl bromide was replaced with 4-fluoro-3-(trifluoromethyl)benzyl bromide to prepare compound I-21. 1 H NMR (400MHz, DMSO-d6) δ10.88(s,1H),8.76(s,1H),8.67(s,1H),8.36(s,1H),7.78(s,3H),7.64-7.45(m,2H),7.34(dd,J=8.9,4.5Hz ,1H),7.27(dd,J=9.8,2.6Hz,1H),6.95(td,J=9.2,2.6Hz,1H),3.76(s,2H),3.55(s,2H),2.84(s,2H),2.71(s,2H).HRMS(ESI)calcd for C 25 H 20 F5N5O[M+H] + 502.1661, found 502.1661.

[0158] Example 22

[0159] 1-(5-Fluoro-1H-indol-3-yl)-3-(7-(3-(trifluoromethyl)benzyl)-5,6,7,8-tetrahydro-1,7-naphthid-3-yl)urea (Compound I-22)

[0160] Following the method of Example 1, 3-fluoro-4-trifluoromethylbenzyl bromide was replaced with 3-trifluoromethylbenzyl bromide to obtain compound I-22. 1 H NMR (300MHz, DMSO-d6) δ10.91(s,1H),8.63(s,1H),8.55(s,1H),8.33(d,J=2.4 Hz,1H),7.77(d,J=2.4Hz,1H),7.74-7.59(m,4H),7.56(d,J=2.5Hz,1H),7.35(d d,J=8.9,4.5Hz,1H),7.23(dd,J=9.9,2.6Hz,1H),6.95(td,J=9.2,2.6Hz,1H),3 .79(s,2H),3.54(s,2H),2.93-2.78(m,2H),2.76-2.64(m,2H).HRMS(ESI)calcd for C 25H 21 F4N5O[M+H] + 484.1755, found 484.1752.

[0161] Example 23

[0162] 1-(7-(3-(1,1-difluoroethyl)benzyl)-5,6,7,8-tetrahydro-1,7-naphthid-3-yl)-3-(5-fluoro-1H-indole-3-yl)urea (compound I-23)

[0163] Following the method of Example 7, 4-(1,1-difluoroethyl)benzoic acid was replaced with 3-(1,1-difluoroethyl)benzoic acid to prepare intermediate A-21. Then, following the method of Example 1, 3-fluoro-4-trifluoromethylbenzyl bromide was replaced with intermediate A-21 to prepare compound I-23. 1 H NMR (400MHz, DMSO-d6) δ10.89(s,1H),8.62(s,1H),8.53(s,1H),8.33(d,J=2.4Hz ,1H),7.77(d,J=2.4Hz,1H),7.60-7.44(m,5H),7.34(dd,J=8.8,4.5Hz,1H),7.23( dd,J=9.9,2.6Hz,1H),6.95(td,J=9.1,2.6Hz,1H),3.75(s,2H),3.53(s,2H),2.8 2(d,J=6.0Hz,2H),2.71(d,J=5.7Hz,2H),1.98(t,J=18.9Hz,3H).HRMS(ESI)calcd for C 26 H 24 F3N5O[M+H] + 480.2006, found 480.2004.

[0164] Example 24

[0165] 1-(7-(3,4-difluorobenzyl)-5,6,7,8-tetrahydro-1,7-naphthid-3-yl)-3-(5-fluoro-1H-indole-3-yl)urea (compound I-24)

[0166] Following the method of Example 1, 3-fluoro-4-trifluoromethylbenzyl bromide was replaced with 3,4-difluorobenzyl bromide to prepare compound I-24. 1H NMR(400MHz,DMSO-d6)δ10.88(s,1H),8.78(s,1H),8.39(s,1H),7.81(s,1H),7.60–7.39(m,3H),7.38–7 .25(m,3H),7.25–7.12(m,1H),7.00–6.89(m,1H),4.07–3.42(m,4H),3.14–2.59(m,4H).HRMS(ESI)calcd for C 24 H 20 F3N5O[M+H] + 452.1693, found 452.1691.

[0167] Example 25

[0168] 1-(7-(3-(difluoromethoxy)benzyl)-5,6,7,8-tetrahydro-1,7-naphthid-3-yl)-3-(5-fluoro-1H-indole-3-yl)urea (compound I-25)

[0169] Following the method of Example 1, 3-fluoro-4-trifluoromethylbenzyl bromide was replaced with 3-(difluoromethoxy)benzyl bromide to prepare compound I-25. 1 H NMR (400MHz, DMSO-d6) δ10.90(s,1H),8.73(s,1H),8.65(s,1H),8.35(s,1H),7.78(s,1H),7.56(d,J=2.5Hz,1H),7.46–7.31(m,3H),7.31 –7.23(m,3H),7.08–7.06(m,1H),6.95(td,J=9.1,2.5Hz,1H),3.71(s,2H),3.53(s,2H),2.84(s,2H),2.76–2.63(m,2H).HRMS(ESI)calcd for C 25 H 22 F3N5O2[M+H] + 482.1798, found 482.1790.

[0170] Example 26

[0171] 1-(7-(3-chloro-4-(trifluoromethoxy)benzyl)-5,6,7,8-tetrahydro-1,7-naphthidin-3-yl)-3-(5-fluoro-1H-indole-3-yl)urea (compound I-26)

[0172] Synthesis of intermediate A-21

[0173] Following the method of Example 1, 3-fluoro-4-trifluoromethylbenzyl bromide was replaced with 3-chloro-4-trifluoromethoxybenzyl bromide to prepare intermediate A-21.

[0174] Synthesis of intermediate A-22

[0175] Intermediate A-21 (178 mg, 0.5 mmol) was added to a solution of glacial acetic acid (0.5 mL), followed by dropwise addition of a 33% hydrobromic acid-acetic acid solution (6 mL). The mixture was stirred at room temperature for 1 hour. After the reaction was complete, 2N NaOH was slowly added under ice bath conditions to adjust the pH to approximately 8. The mixture was extracted with ethyl acetate (3 mL x 3), and the organic phases were combined, washed with saturated brine (5 mL x 1), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol = 30:1) to obtain intermediate A-22 (yellow oily liquid, 114 mg).

[0176] Synthesis of compound I-26

[0177] Following the method of Example 1, intermediate A-5 was replaced with intermediate A-22 to obtain compound I-26. 1 H NMR(400MHz,DMSO-d6)δ10.90(s,1H),8.65(s,1H),8.56(s,1H),8.34(d,J=2.4Hz,1H),7 .78(d,J=2.5Hz,1H),7.68(d,J=2.0Hz,1H),7.59–7.52(m,2H),7.49(dd,J=8.4,1.9Hz,1 H),7.35(dd,J=8.9,4.5Hz,1H),7.24(dd,J=9.8,2.6Hz,1H),6.95(td,J=9.1,2.6Hz,1H) ,3.73(s,2H),3.53(s,2H),2.83(t,J=5.9Hz,2H),2.70(t,J=5.8Hz,2H).HRMS(ESI)calcd for C 25 H 20 ClF4N5O2[M+H] + 534.1314, found 534.1303.

[0178] Example 27

[0179] 1-(7-(4-bromo-3-fluorobenzyl)-5,6,7,8-tetrahydro-1,7-naphthid-3-yl)-3-(5-fluoro-1H-indole-3-yl)urea (compound I-27)

[0180] Following the method of Example 26, 3-chloro-4-trifluoromethoxybenzyl bromide was replaced with 3-fluoro-4-bromobenzyl bromide to prepare compound I-27. 1 H NMR(300MHz,DMSO-d6)δ10.90(s,1H),8.62(s,1H),8.54(s,1H),8.33(d,J=2 .4Hz,1H),7.77(d,J=2.4Hz,1H),7.73–7.63(m,1H),7.55(d,J=2.5Hz,1H),7 .43–7.30(m,2H),7.26–7.13(m,2H),6.95(td,J=9.2,2.6Hz,1H),3.69(s,2H ),3.54(s,2H),2.83(t,J=5.2Hz,2H),2.69(t,J=5.8Hz,2H).HRMS(ESI)calcd for C 24 H 20 BrF₂N₅O[M+H] + 512.0892, found 512.0880.

[0181] Example 28

[0182] 1-(5-Fluoro-1H-indol-3-yl)-3-(7-(2-(4-(trifluoromethoxy)phenoxy)ethyl)-5,6,7,8-tetrahydro-1,7-naphthid-3-yl)urea (compound I-28)

[0183] Following the method of Example 7, 4-(1,1-difluoroethyl)benzoic acid was replaced with 2-(4-(trifluoromethoxy)phenoxy)acetic acid to prepare intermediate A-23. Then, following the method of Example 1, 3-fluoro-4-trifluoromethylbenzyl bromide was replaced with intermediate A-23 to prepare compound I-28. 1 H NMR (300MHz, DMSO-d6) δ10.90(s,1H),8.65(s,1H),8.56(s,1H),8.34(d,J=2. 4Hz,1H),7.77(d,J=2.4Hz,1H),7.56(d,J=2.5Hz,1H),7.39–7.26(m,3H),7.24 (dd,J=9.9,2.5Hz,1H),7.13–7.06(m,2H),6.95(td,J=9.2,2.6Hz,1H),4.21( t,J=5.6Hz,2H),3.67(s,2H),2.98–2.87(m,1H),2.81(s,4H).HRMS(ESI)calcd for C 26 H 23 F4N5O3[M+H]+ 530.1810, found 530.1797.

[0184] Example 29

[0185] 1-(7-(3,5-difluorobenzyl)-5,6,7,8-tetrahydro-1,7-naphthid-3-yl)-3-(5-fluoro-1H-indole-3-yl)urea (compound I-29)

[0186] Following the method of Example 1, 3-fluoro-4-trifluoromethylbenzyl bromide was replaced with 3,5-difluorobenzyl bromide to prepare compound I-29. 1 H NMR (400MHz, DMSO-d6) δ10.89(d,J=2.6Hz,1H),8.61(s,1H),8.52(s,1H),8.34(d,J =2.5Hz,1H),7.77(d,J=2.4Hz,1H),7.55(d,J=2.5Hz,1H),7.35(dd,J=8.8,4.5Hz,1 H),7.23(dd,J=9.8,2.5Hz,1H),7.18–7.06(m,3H),6.95(td,J=9.2,2.6Hz,1H),3.7 2(s,2H),3.55(s,2H),2.84(t,J=5.8Hz,2H),2.70(t,J=5.8Hz,2H).HRMS(ESI)calcd for C 24 H 20 F3N5O[M+H] + 452.1693, found 452.1687.

[0187] Example 30

[0188] 1-(5-fluoro-1H-indol-3-yl)-3-(7-(4-fluoro-3-(trifluoromethoxy)benzyl)-5,6,7,8-tetrahydro-1,7-naphthid-3-yl)urea (compound I-30)

[0189] Following the method of Example 1, 3-fluoro-4-trifluoromethylbenzyl bromide was replaced with 3-trifluoromethoxy-4-fluorobenzyl bromide to prepare compound I-30. 1H NMR (400MHz, DMSO-d6) δ10.90(s,1H),8.62(s,1H),8.53(s,1H),8.33(d,J=2.5H z,1H),7.77(d,J=2.4Hz,1H),7.58–7.52(m,2H),7.51–7.44(m,2H),7.35(dd,J=8 .9,4.5Hz,1H),7.23(dd,J=9.9,2.6Hz,1H),6.95(td,J=9.2,2.5Hz,1H),3.73(s ,2H),3.54(s,2H),2.82(t,J=5.8Hz,2H),2.69(t,J=5.7Hz,2H).HRMS(ESI)calcd for C 25 H 20 F5N5O2[M+H] + 518.1610, found 518.1598.

[0190] Example 31

[0191] 1-(7-(3,5-difluoro-4-(trifluoromethyl)benzyl)-5,6,7,8-tetrahydro-1,7-naphthidin-3-yl)-3-(5-fluoro-1H-indole-3-yl)urea (compound I-31)

[0192] Following the method of Example 1, 3-fluoro-4-trifluoromethylbenzyl bromide was replaced with 3,5-difluoro-4-trifluoromethylbenzyl bromide to obtain compound I-31. 1 H NMR (400MHz, DMSO-d6) δ10.90(s,1H),8.64(s,1H),8.55(s,1H),8.34(d,J=2.4Hz, 1H),7.78(d,J=2.5Hz,1H),7.56(d,J=2.6Hz,1H),7.41(d,J=11.3Hz,2H),7.35(dd ,J=8.9,4.5Hz,1H),7.23(dd,J=9.9,2.7Hz,1H),6.95(td,J=9.2,2.5Hz,1H),3.80 (s,2H),3.59(s,2H),2.85(t,J=5.1Hz,2H),2.71(t,J=5.8Hz,2H).HRMS(ESI)calcd for C 25 H 19 F6N5O[M+H] + 520.1567, found 520.1556.

[0193] Example 32

[0194] 1-(5-fluoro-1H-indol-3-yl)-3-(7-(3-fluoro-5-(trifluoromethoxy)benzyl)-5,6,7,8-tetrahydro-1,7-naphthid-3-yl)urea (compound I-32)

[0195] Following the method of Example 1, 3-fluoro-4-trifluoromethylbenzyl bromide was replaced with 3-fluoro-5-trifluoromethoxybenzyl bromide to prepare compound I-32. 1 H NMR (400MHz, DMSO-d6) δ10.90(s,1H),8.63(s,1H),8.54(s,1H),8.34(d,J=2.4Hz,1H),7.78(d,J=2.4Hz,1H),7.55(d,J=2.5Hz,1H),7.40–7.26( m,4H),7.23(dd,J=9.9,2.5Hz,1H),6.95(td,J=9.2,2.6Hz,1H),3.77(s,2H),3.56(s,2H),2.87–2.81(m,2H),2.73–2.66(m,2H)HRMS(ESI)calcd for C 25 H 20 F5N5O2[M+H] + 518.1610, found 518.1560.

[0196] Example 33

[0197] 1-(7-(3-(4-(difluoromethoxy)phenyl)propyl)-5,6,7,8-tetrahydro-1,7-naphthidin-3-yl)-3-(5-fluoro-1H-indole-3-yl)urea (compound I-33)

[0198] Following the method of Example 7, 4-(1,1-difluoroethyl)benzoic acid was replaced with 3-(4-(difluoromethoxy)phenyl)propionic acid to prepare intermediate A-24. Then, following the method of Example 1, 3-fluoro-4-trifluoromethylbenzyl bromide was replaced with intermediate A-24 to prepare compound I-33. 1H NMR (400MHz, DMSO-d6) δ10.89(s,1H),8.61(s,1H),8.52(s,1H),8.34(d,J=2.4Hz,1H),7.76(d, J=2.4Hz,1H),7.56(d,J=2.5Hz,1H),7.35(dd,J=8.8,4.5Hz,1H),7.31–7.26(m,2H),7.23(dd,J= 9.9,2.5Hz,1H),7.20–7.17(m,1H),7.12–7.06(m,2H),6.95(td,J=9.1,2.6Hz,1H),3.53(s,2H), 2.82(t,J=5.8Hz,2H),2.69–2.58(m,4H),2.49–2.44(m,2H),1.88–1.77(m,2H).HRMS(ESI)calcd for C 27 H 26 F3N5O2[M+H] + 510.2111, found 510.2102.

[0199] Example 34

[0200] 1-(5-Fluoro-1H-indol-3-yl)-3-(7-(4-(trifluoromethyl)benzyl)-5,6,7,8-tetrahydro-2,7-naphthidin-3-yl)urea (compound I-34)

[0201] Referring to the method in Example 4, 2-amino-7,8-dihydro-1,6-naphthyl-6(5H)-carboxylic acid tert-butyl ester was replaced with 6-amino-3,4-dihydro-2,7-naphthyl-2(1H)-carboxylic acid tert-butyl ester (CAS: 1393561-07-3), and 4-trifluoromethylthiobenzyl bromide was replaced with 4-trifluoromethylbenzyl bromide to obtain compound I-34. 1 H NMR(300MHz,DMSO-d6)δ10.92(s,1H),10.36(s,1H),9.29(s,1H),8.07(s,1H ),7.73(d,J=8.0Hz,2H),7.66–7.57(m,4H),7.36(dd,J=8.8,4.5Hz,1H),7.25 (s,1H),7.19(dd,J=9.7,2.5Hz,1H),6.96(td,J=9.2,2.5Hz,1H),3.78(s,2H ),3.55(s,2H),2.84(t,J=5.5Hz,2H),2.71(t,J=5.8Hz,2H).HRMS(ESI)calcd for C 25 H 21F4N5O[M+H] + 484.1755, found 484.1748.

[0202] Example 35

[0203] 1-(5-Fluoro-1H-indol-3-yl)-3-(7-(4-(trifluoromethoxy)benzyl)-5,6,7,8-tetrahydro-2,7-naphthidin-3-yl)urea (Compound I-35)

[0204] Following the method of Example 34, 4-trifluoromethylbenzyl bromide was replaced with 4-trifluoromethoxybenzyl bromide to prepare compound I-35. 1 H NMR(300MHz,DMSO-d6)δ10.92(s,1H),10.37(s,1H),9.29(s,1H),8.07(s,1 H),7.61(d,J=2.5Hz,1H),7.50(d,J=8.5Hz,2H),7.40–7.30(m,3H),7.25(s ,1H),7.19(dd,J=9.6,2.5Hz,1H),6.96(td,J=9.2,2.5Hz,1H),3.70(s,2H) ,3.53(s,2H),2.83(t,J=5.8Hz,2H),2.68(t,J=5.4Hz,2H).HRMS(ESI)calcd for C 25 H 21 F4N5O2[M+H] + 500.1704, found 500.1697.

[0205] Example 36

[0206] 1-(5-chloro-1H-indol-3-yl)-3-(7-(3-(trifluoromethoxy)benzyl)-5,6,7,8-tetrahydro-1,7-naphthidin-3-yl)urea (compound I-36)

[0207] Following the method of Example 6, 5-fluoroindole was replaced with 5-chloroindole to prepare compound I-36. 1HNMR(300MHz,DMSO-d6)δ11.00(d,J=2.6Hz,1H),8.63(s,1H),8.59(s,1H),8.33(d, J=2.4Hz,1H),7.77(d,J=2.4Hz,1H),7.55(d,J=2.3Hz,2H),7.53–7.45(m,1H),7.45– 7.39(m,1H),7.39–7.33(m,2H),7.32–7.24(m,1H),7.10(dd,J=8.6,2.1Hz,1H),3.7 5(s,2H),3.54(s,2H),2.83(t,J=5.9Hz,2H),2.70(t,J=5.2Hz,2H).HRMS(ESI)calcd for C 25 H 21 ClF3N5O2[M+H] + 516.1409, found 516.1407.

[0208] Example 37

[0209] 1-(5-chloro-1H-indol-3-yl)-3-(7-(4-(trifluoromethoxy)benzyl)-5,6,7,8-tetrahydro-1,7-naphthidin-3-yl)urea (compound I-37)

[0210] Following the method of Example 10, 5-fluoroindole was replaced with 5-chloroindole to prepare compound I-37. 1 HNMR(300MHz,DMSO-d6)δ11.00(s,1H),8.63(s,1H),8.58(s,1H),8.33(d,J=2.5 Hz,1H),7.77(d,J=2.4Hz,1H),7.55(d,J=2.3Hz,2H),7.51(d,J=8.6Hz,2H),7.40 -7.31(m,3H),7.10(dd,J=8.6,2.1Hz,1H),3.72(s,2H),3.52(s,2H),2.83(t,J=5.8Hz,2H),2.69(t,J=5.7Hz,2H)HRMS(ESI)calcd for C 25 H 21 ClF3N5O2[M+H] + 516.1409, found 516.1408.

[0211] Example 38

[0212] 1-(5-chloro-1H-indol-3-yl)-3-(7-(3-fluoro-4-(trifluoromethoxy)benzyl)-5,6,7,8-tetrahydro-1,7-naphthidin-3-yl)urea (compound I-38)

[0213] Following the method of Example 15, 5-fluoroindole was replaced with 5-chloroindole to prepare compound I-38. 1 HNMR (300MHz, DMSO-d6) δ11.00(s,1H),8.63(s,1H),8.58(s,1H),8.33(d,J=2.5Hz,1H),7.77(d,J=2.4Hz,1H),7.55(d,J=2.3Hz,2H),7.51(d,J=8 .6Hz,2H),7.40–7.31(m,3H),7.10(dd,J=8.6,2.1Hz,1H),3.72(s,2H),3.52(s,2H),2.83(t,J=5.8Hz,2H),2.69(t,J=5.7Hz,2H).HRMS(ESI)calcd for C 25 H 20 ClF4N5O2[M+H] + 534.1314, found 534.1314.

[0214] Example 39

[0215] 1-(5-chloro-1H-indol-3-yl)-3-(7-(3-fluoro-5-(trifluoromethoxy)benzyl)-5,6,7,8-tetrahydro-1,7-naphthidin-3-yl)urea (compound I-39)

[0216] Following the method of Example 32, 5-fluoroindole was replaced with 5-chloroindole to prepare compound I-39. 1 HNMR(400MHz,DMSO-d6)δ11.00(d,J=2.5Hz,1H),8.63(s,1H),8.59(s,1H), 8.34(d,J=2.4Hz,1H),7.78(d,J=2.4Hz,1H),7.55(d,J=2.3Hz,2H),7.37(d ,J=8.7Hz,1H),7.34–7.24(m,3H),7.10(dd,J=8.6,2.1Hz,1H),3.77(s,2H) ,3.56(s,2H),2.84(t,J=5.9Hz,2H),2.70(t,J=6.0Hz,2H).HRMS(ESI)calcd for C 25 H 20ClF4N5O2[M+H] + 534.1314, found 534.1315.

[0217] Example 40

[0218] 1-(5-Fluoro-1H-indol-3-yl)-3-(7-(2-(4-(trifluoromethoxy)phenyl)acetyl)-5,6,7,8-tetrahydro-1,7-naphthid-3-yl)urea (compound I-40)

[0219] Synthesis of intermediate A-25

[0220] Intermediate A-3 (178 mg, 0.5 mmol) and triethylamine (152 mg, 1.5 mmol) were added to dichloromethane (3 mL), followed by 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (105 mg, 0.55 mmol) and 1-hydroxybenzotriazole (HOBt) (74 mg, 0.55 mmol). After stirring for 5 minutes, 2-(4-(trifluoromethoxy)phenyl)acetic acid (121 mg, 0.55 mmol) was added, and the mixture was reacted at room temperature for 5 hours. After the reaction was completed, the solvent was removed by vacuum distillation, the residue was diluted with water (3 mL), extracted with ethyl acetate (3 mL x 3), the organic phases were combined and washed successively with 1N HCl (3 mL x 1), water (3 mL x 1) and saturated brine (5 mL x 1), dried over anhydrous sodium sulfate, the solvent was removed by vacuum distillation, and the residue was purified by column chromatography (dichloromethane / methanol = 80:1) to give intermediate A-25 (yellow oily liquid, 180 mg).

[0221] Synthesis of intermediate A-26

[0222] All intermediate A-25 (180 mg) and 10% palladium on carbon (18 mg) were added to methanol (3 mL), purged three times with hydrogen, and stirred at room temperature for 8 hours. After the reaction was complete, the mixture was filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was purified by column chromatography (dichloromethane / methanol = 20:1) to give intermediate A-26 (white solid, 118 mg).

[0223] Synthesis of compound I-40

[0224] Following the method of Example 1, intermediate A-5 was replaced with intermediate A-26 to obtain compound I-40. 1H NMR (400MHz, DMSO-d6) δ10.91(d,J=2.5Hz,1H),8.69(s,1H),8.56(d,J=3.5Hz,1H),8.42 (dd,J=15.6,2.4Hz,1H),7.83(dd,J=8.5,2.4Hz,1H),7.56(d,J=2.4Hz,1H),7.43–7.26( m,5H),7.24(dd,J=9.9,2.5Hz,1H),6.95(td,J=9.2,2.5Hz,1H),4.65(d,J=35.3Hz,2H), 3.90(d,J=2.1Hz,2H),3.76(dt,J=18.0,5.8Hz,2H),2.86–2.73(m,2H).HRMS(ESI)calcd for C 26 H 21 F4N5O3[M+H] + 528.1653, found 528.1654.

[0225] Example 41

[0226] 1-(5-Fluoro-1H-indol-3-yl)-3-(7-(2-(4-(trifluoromethoxy)phenoxy)acetyl)-5,6,7,8-tetrahydro-1,7-naphthidin-3-yl)urea (compound I-41)

[0227] Following the method of Example 40, 2-(4-(trifluoromethoxy)phenyl)acetic acid was replaced with 2-(4-(trifluoromethoxy)phenoxy)acetic acid to obtain compound I-41. 1 H NMR(400MHz,DMSO-d6)δ10.91(s,1H),8.73–8.66(m,1H),8.61–8.53(m,1H),8.50–8.3 7(m,1H),7.85(dd,J=19.4,2.8Hz,1H),7.56(d,J=2.5Hz,1H),7.43–7.19(m,4H),7.04( dd,J=8.9,5.2Hz,2H),6.95(td,J=9.1,2.6Hz,1H),5.06–3.85(m,2H),4.73–4.52(m,2H ),3.75(dt,J=24.1,5.7Hz,2H),2.99–2.91(m,1H),2.84–2.75(m,1H).HRMS(ESI)calcd for C 26 H 21 F4N5O4[M+H] + 544.1602, found 544.1600.

[0228] Example 42

[0229] 1-(5-Fluoro-1H-indol-3-yl)-3-(7-(2-(4-(trifluoromethoxy)phenyl)propionyl)-5,6,7,8-tetrahydro-1,7-naphthidin-3-yl)urea (compound I-42)

[0230] Following the method of Example 40, 2-(4-(trifluoromethoxy)phenyl)acetic acid was replaced with 3-(4-(trifluoromethoxy)phenyl)propionic acid to prepare compound I-42. 1 H NMR (300MHz, DMSO-d6) δ10.91(d,J=2.6Hz,1H),8.68(s,1H),8.55(d,J=2.7Hz,1 H),8.42(dd,J=9.1,2.4Hz,1H),7.82(dd,J=6.9,2.4Hz,1H),7.56(d,J=2.5Hz,1 H),7.44–7.30(m,3H),7.31–7.20(m,3H),6.95(td,J=9.2,2.5Hz,1H),4.59(s,2 H),3.70(q,J=6.4Hz,2H),2.94–2.83(m,2H),2.84–2.72(m,4H).HRMS(ESI)calcd for C 27 H 23 F4N5O3[M+H] + 542.1810, found 542.1809.

[0231] Example 43

[0232] 1-(5-Fluoro-1H-indol-3-yl)-3-(7-(4-(trifluoromethoxy)benzoyl)-5,6,7,8-tetrahydro-1,7-naphthid-3-yl)urea (compound I-43)

[0233] Following the method of Example 40, 2-(4-(trifluoromethoxy)phenyl)acetic acid was replaced with 4-trifluoromethoxybenzoic acid to obtain compound I-43. 1H NMR(400MHz,DMSO-d6)δ10.91(d,J=2.6Hz,1H),8.71(s,1H),8.56(s,1H),8.50–8.3 4(m,1H),7.86(s,1H),7.63(d,J=8.2Hz,2H),7.56(d,J=2.5Hz,1H),7.48(d,J=7.8H z,2H),7.35(dd,J=8.9,4.5Hz,1H),7.23(dd,J=9.8,2.6Hz,1H),6.95(td,J=9.2,2. 6Hz,1H),4.85–4.42(m,2H),3.90(s,1H),3.59(s,1H),2.89(s,2H).HRMS(ESI)calcd for C 25 H 19 F4N5O3[M+H] + 514.1497, found 514.1498.

[0234] Example 44

[0235] 1-(5-Fluoro-1H-indol-3-yl)-3-(7-(2-(4-(trifluoromethyl)phenoxy)acetyl)-5,6,7,8-tetrahydro-1,7-naphthid-3-yl)urea (compound I-44)

[0236] Following the method of Example 40, 2-(4-(trifluoromethoxy)phenyl)acetic acid was replaced with 2-(4-(trifluoromethyl)phenoxy)acetic acid to obtain compound I-44. 1 H NMR (300MHz, DMSO-d6) δ10.92(d,J=2.6Hz,1H),8.71(s,1H),8.58(d,J=4.2Hz,1H),8.44(dd,J=22.5,2.4Hz ,1H),7.85(dd,J=14.8,2.4Hz,1H),7.64(dd,J=9.1,2.9Hz,2H),7.56(d,J=2.5Hz,1H),7.35(dd,J=8.9,4.5 Hz,1H),7.24(dd,J=9.9,2.5Hz,1H),7.13(dd,J=8.8,2.4Hz,2H),6.95(td,J=9.2,2.6Hz,1H),5.11(s,2H), 4.63(d,J=26.2Hz,2H),3.72(t,J=5.8Hz,2H),2.95(t,J=5.7Hz,1H),2.79(t,J=5.1Hz,1H).HRMS(ESI)calcd for C 26 H21 F4N5O3[M+H] + 528.1653, found 528.1648.

[0237] Example 45

[0238] 1-(5-Fluoro-1H-indol-3-yl)-3-(7-(2-(4-(trifluoromethyl)thio)phenoxy)acetyl)-5,6,7,8-tetrahydro-1,7-naphthid-3-yl)urea (compound I-45)

[0239] Following the method of Example 40, 2-(4-(trifluoromethoxy)phenyl)acetic acid was replaced with 2-(4-(trifluoromethylthio)phenoxy)acetic acid to obtain compound I-45. 1 H NMR (400MHz, DMSO-d6) δ10.90(d,J=2.6Hz,1H),8.69(s,1H),8.55(d,J=4.5Hz,1H),8.44(dd,J=28.1,2.4 Hz,1H),7.84(dd,J=19.7,2.5Hz,1H),7.67–7.58(m,2H),7.56(d,J=2.4Hz,1H),7.35(dd,J=8.8,4.5Hz,1 H),7.23(dd,J=9.8,2.5Hz,1H),7.09(dd,J=9.0,3.8Hz,2H),6.95(td,J=9.2,2.6Hz,1H),5.08(s,2H),4. 62(d,J=31.7Hz,2H),3.72(t,J=5.7Hz,3H),2.94(t,J=5.9Hz,1H),2.79(t,J=5.9Hz,1H).HRMS(ESI)calcd for C 26 H 21 F4N5O3S[M+H] + 560.1374, found 560.1368.

[0240] Example 46

[0241] 1-(5-Fluoro-1H-indol-3-yl)-3-(7-(5-(trifluoromethyl)pyridin-2-yl)-5,6,7,8-tetrahydro-1,7-naphthidin-3-yl)urea (compound I-46)

[0242] Synthesis of intermediate A-27

[0243] Intermediate A-3 (178 mg, 0.5 mmol), 2-fluoro-5-trifluoromethylpyridine (91 mg, 0.55 mmol), and potassium carbonate (207 mg, 1.5 mmol) were added to N,N-dimethylformamide (3 mL), and the mixture was reacted at 100 °C for 3 hours. After the reaction was complete, the residue was diluted with water (3 mL), extracted with ethyl acetate (3 mL x 3), and the organic phases were combined and washed successively with water (3 mL x 1) and saturated brine (5 mL x 1), and dried over anhydrous sodium sulfate to give crude intermediate A-27 (white solid, 294 mg).

[0244] Synthesis of compound I-46

[0245] Following the method of Example 1, intermediate A-4 was replaced with intermediate A-27 to obtain compound I-46: 1 H NMR(400MHz,DMSO-d6)δ10.89(d,J=2.6Hz,1H),8.69(s,1H),8.55(s,1H),8.49 –8.42(m,2H),7.88–7.79(m,2H),7.56(d,J=2.5Hz,1H),7.35(dd,J=8.8,4.5Hz, 1H),7.24(dd,J=9.8,2.5Hz,1H),7.05(d,J=9.1Hz,1H),6.95(td,J=9.2,2.6Hz, 1H),4.75(s,2H),3.95(t,J=5.8Hz,2H),2.92(t,J=5.8Hz,2H).HRMS(ESI)calcd for C 23 H 18 F4N6O[M+H] + 471.1551, found 471.1547.

[0246] Example 47

[0247] 1-(5-Fluoro-1H-indol-3-yl)-3-(7-(3-(4-(trifluoromethyl)phenyl)propionyl)-5,6,7,8-tetrahydro-1,7-naphthidin-3-yl)urea (compound I-47)

[0248] Following the method of Example 40, 2-(4-(trifluoromethoxy)phenyl)acetic acid was replaced with 2-(4-(trifluoromethyl)phenyl)propionic acid to obtain compound I-47. 1H NMR (400MHz, DMSO-d6) δ10.89(d,J=2.6Hz,1H),8.70(s,1H),8.57(d,J=4.8Hz,1H),8.41(dd,J=9.4,2.4Hz ,1H),7.81(dd,J=10.1,2.4Hz,1H),7.63(d,J=8.1Hz,1H),7.59(d,J=8.1Hz,1H),7.55(d,J=2.5Hz,1H),7.5 3–7.44(m,2H),7.34(dd,J=8.9,4.5Hz,1H),7.24(dd,J=9.9,2.5Hz,1H),6.94(td,J=9.1,2.5Hz,1H),4.58( s,2H),3.70(q,J=5.8Hz,2H),3.01–2.88(m,2H),2.86–2.77(m,3H),2.74(t,J=5.8Hz,1H).HRMS(ESI)calcd for C 27 H 23 F4N5O2[M+H] + 526.1861, found 526.1854.

[0249] Example 48

[0250] 1-(5-fluoro-1H-indol-3-yl)-3-(7-(2-(4-(trifluoromethyl)phenyl)acetyl)-5,6,7,8-tetrahydro-1,7-naphthidin-3-yl)urea (compound I-48)

[0251] Following the method of Example 40, 2-(4-(trifluoromethoxy)phenyl)acetic acid was replaced with 2-(4-(trifluoromethyl)phenyl)acetic acid to obtain compound I-48. 1H NMR (400MHz, DMSO-d6) δ10.90(s,1H),8.68(s,1H),8.55(d,J=4.5Hz,1H),8.42(dd,J=15.9,2.4Hz ,1H),7.83(dd,J=9.2,2.4Hz,1H),7.71–7.60(m,2H),7.56(s,1H),7.48(dd,J=14.2,7.9Hz,2H),7. 35(dd,J=8.8,4.5Hz,1H),7.24(dd,J=9.9,2.4Hz,1H),6.95(td,J=9.2,2.6Hz,1H),4.65(d,J=34. 7Hz,2H),3.97(s,2H),3.76(dt,J=17.2,5.9Hz,2H),2.80(dt,J=15.0,5.8Hz,2H).HRMS(ESI)calcd for C 26 H 21 F4N5O2[M+H] + 512.1704, found 512.1699.

[0252] Example 49

[0253] 1-(5-Fluoro-1H-indol-3-yl)-3-(7-((4-(trifluoromethoxy)phenethyl)sulfonyl)-5,6,7,8-tetrahydro-1,7-naphthid-3-yl)urea (compound I-49)

[0254] Synthesis of intermediate A-28

[0255] 1-(2-bromoethyl)-4-(trifluoromethoxy)benzene (1.35 g, 5 mmol) and thiourea (380 mg, 5 mmol) were added to ethanol (15 mL). After reacting at 80 °C for 4 hours, the mixture was cooled to room temperature, and the solvent was removed by vacuum distillation. The residue was dissolved in acetonitrile (15 mL), and N-chlorosuccinimide (2.68 g, 20 mmol) was added. 2N HCl solution (1.15 mL) was added dropwise under ice bath conditions, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the solvent was removed by vacuum distillation, and the residue was diluted with water (8 mL). The mixture was extracted with ethyl acetate (15 mL × 3), and the organic phases were combined. The organic phases were washed with saturated brine (10 mL × 1), dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation to give intermediate A-28 (yellow oily liquid, 1.0 g).

[0256] Synthesis of intermediate A-29

[0257] Intermediate A-3 (178 mg, 0.5 mmol) and triethylamine were added to dichloromethane, followed by the slow addition of intermediate A-28. The reaction was carried out at room temperature for 5 hours. After the reaction was complete, the solvent was removed by vacuum distillation, and the residue was diluted with water (3 mL), extracted with ethyl acetate (3 mL x 3), and the organic phases were combined. The residue was washed successively with 1N HCl (3 mL x 1), water (3 mL x 1), and saturated brine (5 mL x 1), dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The residue was purified by column chromatography (dichloromethane / methanol = 80:1) to give intermediate A-29 (white solid, 198 mg).

[0258] Synthesis of compound I-49

[0259] Compound I-49 was prepared by replacing intermediate A-4 with intermediate A-29, following the method described in Example 1. 1 H NMR (400MHz, DMSO-d6) δ10.90(d,J=2.6Hz,1H),8.69(s,1H),8.55(s,1H),8.42(d,J=2.5Hz,1H ),7.84(d,J=2.4Hz,1H),7.55(d,J=2.5Hz,1H),7.45(d,J=8.6Hz,2H),7.34(dd,J=8.9,4.5Hz, 1H),7.29(d,J=8.2Hz,2H),7.23(dd,J=9.9,2.6Hz,1H),6.95(td,J=9.2,2.5Hz,1H),4.38(s,2 H),3.51(td,J=8.2,7.1,4.4Hz,4H),3.09–2.99(m,2H),2.89(t,J=5.9Hz,2H).HRMS(ESI)calcd for C 26 H 23 F4N5O4S[M+H] + 578.1480, found 578.1472.

[0260] Example 50

[0261] 1-(5-Fluoro-1H-indol-3-yl)-3-(7-((4-(trifluoromethoxy)benzyl)sulfonyl)-5,6,7,8-tetrahydro-1,7-naphthid-3-yl)urea (compound I-50)

[0262] Following the method of Example 49, 1-(2-bromoethyl)-4-(trifluoromethoxy)benzene was replaced with 4-trifluoromethoxybenzyl bromide to prepare compound I-50. 1H NMR (400MHz, DMSO-d6) δ10.90(s,1H),8.70(s,1H),8.56(s,1H),8.40(d,J=2.4Hz,1H),7.82(d,J=2.4Hz,1H),7.60–7.51(m,3H),7.40–7.31(m,3H) ,7.23(dd,J=9.9,2.5Hz,1H),6.95(td,J=9.2,2.6Hz,1H),4.61(s,2H),4.31(s,2H),3.42(t,J=5.8Hz,2H),2.82(t,J=5.9Hz,2H).HRMS(ESI)calcd for C 25 H 21 F4N5O4S[M+H] + 564.1323, found 564.1315.

[0263] Example 51

[0264] 1-(5-Fluoro-1H-indol-3-yl)-3-(7-((4-(trifluoromethyl)benzyl)sulfonyl)-5,6,7,8-tetrahydro-1,7-naphthid-3-yl)urea (compound I-51)

[0265] Following the method of Example 49, 1-(2-bromoethyl)-4-(trifluoromethoxy)benzene was replaced with 4-trifluoromethylbenzyl bromide to prepare compound I-51. 1 H NMR(400MHz,DMSO-d6)δ10.90(s,1H),8.70(s,1H),8.56(s,1H),8.40(d,J=2.4Hz,1H), 7.83(d,J=2.4Hz,1H),7.74(d,J=8.1Hz,2H),7.66(d,J=8.0Hz,2H),7.55(d,J=2.5Hz,1H ),7.35(dd,J=8.8,4.5Hz,1H),7.23(dd,J=9.9,2.6Hz,1H),6.95(td,J=9.2,2.6Hz,1H), 4.70(s,2H),4.33(s,2H),3.44(t,J=5.9Hz,2H),2.84(t,J=5.8Hz,2H).HRMS(ESI)calcd for C 25 H 21 F4N5O3S[M+H] + 548.1374, found 548.1368.

[0266] Example 52

[0267] 1-(5-Fluoro-1H-indol-3-yl)-3-(7-((4-(trifluoromethoxy)phenyl)sulfonyl)-5,6,7,8-tetrahydro-1,7-naphthidin-3-yl)urea (compound I-52)

[0268] Following the method of Example 49, intermediate A-28 was replaced with 4-trifluoromethoxybenzenesulfonyl chloride to prepare compound I-52. 1 H NMR (400MHz, DMSO-d6) δ10.90(s,1H),8.69(s,1H),8.56(s,1H),8.40(d,J=2.4Hz,1 H),8.03–7.94(m,2H),7.78(d,J=2.4Hz,1H),7.62(d,J=8.3Hz,2H),7.54(d,J=2.5H z,1H),7.34(dd,J=8.8,4.5Hz,1H),7.22(dd,J=9.8,2.6Hz,1H),6.94(td,J=9.2,2. 6Hz,1H),4.19(s,2H),3.38(t,J=5.9Hz,4H),2.87(t,J=6.0Hz,2H).HRMS(ESI)calcd for C 24 H 19 F4N5O4S[M+H] + 550.1167, found 550.1160.

[0269] Example 53

[0270] 1-(5-Fluoro-1H-indol-3-yl)-3-(7-((1s,4s)-4-(trifluoromethyl)cyclohexane-1-carbonyl)-5,6,7,8-tetrahydro-1,7-naphthid-3-yl)urea (compound I-53)

[0271] Following the method of Example 40, 2-(4-(trifluoromethoxy)phenyl)acetic acid was replaced with trans-4-(trifluoromethyl)cyclohexylcarboxylic acid to prepare compound I-53. 1H NMR (400MHz, DMSO-d6) δ10.90(s,1H),8.68(s,1H),8.55(d,J=5.7Hz,1H),8.43(dd,J=24.9,2.4Hz,1H),7.82(dd ,J=22.0,2.6Hz,1H),7.56(d,J=2.5Hz,1H),7.35(dd,J=8.9,4.5Hz,1H),7.24(dd,J=9.9,2.6Hz,1H),6.95(td,J= 9.2,2.6Hz,1H),4.62(d,J=49.7Hz,2H),3.74(dt,J=23.6,5.9Hz,2H),2.87(t,J=5.8Hz,1H),2.76(q,J=7.7,6.0H z,2H),2.28(p,J=9.4Hz,1H),1.89(d,J=10.8Hz,2H),1.77(t,J=15.7Hz,2H),1.55–1.32(m,4H).HRMS(ESI)calcd for C 25 H 25 F4N5O2[M+H] + 504.2017, found 504.2014.

[0272] Example 54

[0273] 1-(5-Fluoro-1H-indol-3-yl)-3-(7-(6-(trifluoromethyl)pyridazin-3-yl)-5,6,7,8-tetrahydro-1,7-naphthidin-3-yl)urea (compound I-54)

[0274] Following the method of Example 46, 2-fluoro-5-trifluoromethylpyridine was replaced with 2-fluoro-5-trifluoromethylpyridazine to prepare compound I-54. 1 H NMR (400MHz, DMSO-d6) δ10.90(d,J=2.6Hz,1H),8.73(s,1H),8.58(s,1H),8.46(d,J=2. 5Hz,1H),7.88(d,J=2.4Hz,1H),7.84(d,J=9.7Hz,1H),7.56(d,J=2.5Hz,1H),7.52(d,J =9.7Hz,1H),7.35(dd,J=8.9,4.5Hz,1H),7.24(dd,J=9.8,2.5Hz,1H),6.95(td,J=9.2, 2.5Hz,1H),4.85(s,2H),4.04(t,J=5.8Hz,2H),2.97(t,J=5.8Hz,2H).HRMS(ESI)calcd for C22 H 17 F4N7O[M+H] + 472.1503, found 472.1500.

[0275] Example 55

[0276] 1-(5-Fluoro-1H-indol-3-yl)-3-(7-(5-(trifluoromethyl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-1,7-naphthidin-3-yl)urea (Compound I-55)

[0277] Following the method of Example 46, 2-fluoro-5-trifluoromethylpyridine was replaced with 2-fluoro-5-trifluoromethylpyrimidine to obtain compound I-55. 1 H NMR(400MHz,DMSO-d6)δ10.90(d,J=2.6Hz,1H),8.77(d,J=0.9Hz,2H),8.70(s,1H ),8.55(s,1H),8.45(d,J=2.4Hz,1H),7.86(d,J=2.4Hz,1H),7.56(d,J=2.5Hz,1H ),7.35(dd,J=8.8,4.5Hz,1H),7.23(dd,J=9.9,2.6Hz,1H),6.95(td,J=9.2,2.5H z,1H),4.92(s,2H),4.12(t,J=5.8Hz,2H),2.92(t,J=5.9Hz,2H).HRMS(ESI)calcd for C 22 H 17 F4N7O[M+H] + 472.1503, found 472.1500.

[0278] Example 56

[0279] 1-(5-fluoro-1H-indol-3-yl)-3-(7-(5-(trifluoromethyl)pyrazin-2-yl)-5,6,7,8-tetrahydro-1,7-naphthidin-3-yl)urea (compound I-56)

[0280] Following the method of Example 46, 2-fluoro-5-trifluoromethylpyridine was replaced with 2-fluoro-5-trifluoromethylpyrazine to obtain compound I-56. 1H NMR(400MHz,DMSO-d6)δ10.90(d,J=2.6Hz,1H),8.70(s,1H),8.55(d,J=2.3Hz,2H), 8.53(d,J=1.5Hz,1H),8.46(d,J=2.5Hz,1H),7.87(d,J=2.4Hz,1H),7.56(d,J=2.5H z,1H),7.35(dd,J=8.8,4.5Hz,1H),7.23(dd,J=9.8,2.6Hz,1H),6.95(td,J=9.2,2. 6Hz,1H),4.82(s,2H),4.01(t,J=5.8Hz,2H),2.96(t,J=5.9Hz,2H).HRMS(ESI)calcd for C 22 H 17 F4N7O[M+H] + 472.1503, found 472.1499.

[0281] Example 57

[0282] 1-(7-(5-chloropyrimidin-2-yl)-5,6,7,8-tetrahydro-1,7-naphthidin-3-yl)-3-(5-fluoro-1H-indole-3-yl)urea (compound I-57)

[0283] Following the method of Example 46, 2-fluoro-5-trifluoromethylpyridine was replaced with 2-fluoro-5-chloropyrimidine to obtain compound I-57. 1 H NMR(400MHz,DMSO-d6)δ10.90(d,J=2.6Hz,1H),8.70(s,1H),8.57(s,1H),8.49 (s,2H),8.43(d,J=2.4Hz,1H),7.85(d,J=2.5Hz,1H),7.56(d,J=2.5Hz,1H),7. 34(dd,J=8.9,4.5Hz,1H),7.24(dd,J=9.8,2.5Hz,1H),6.95(td,J=9.2,2.6Hz, 1H),4.81(s,2H),4.02(t,J=5.8Hz,2H),2.88(t,J=5.9Hz,2H).HRMS(ESI)calcd for C 21 H 17 ClFN7O[M+H] + 438.1240, found 438.1238.

[0284] Example 58

[0285] 1-(5-Fluoro-1H-indol-3-yl)-3-(7-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)-5,6,7,8-tetrahydro-1,7-naphthidin-3-yl)urea (compound I-58)

[0286] Following the method of Example 46, 2-fluoro-5-trifluoromethylpyridine was replaced with 2-bromo-5-(trifluoromethyl)-1,3,4-thiadiazole to prepare compound I-58. 1 H NMR (400MHz, DMSO-d6) δ10.89(s,1H),8.72(s,1H),8.54(s,1H),8.48(d,J=2.4Hz,1H),7.89(d,J=2.4Hz,1H),7.56(d,J=2.5Hz,1H),7.35(dd,J=8. 8,4.5Hz,1H),7.23(dd,J=9.9,2.6Hz,1H),6.95(td,J=9.2,2.6Hz,1H),4.71(s,2H),3.90(t,J=5.9Hz,2H),3.02(t,J=5.9Hz,2H).HRMS(ESI)calcd for C 20 H 15 F4N7OS[M+H] + 478.1068, found 478.1067.

[0287] Example 59

[0288] 1-(5-fluoro-1H-indol-3-yl)-3-(7-(6-(trifluoromethyl)pyrazin-2-yl)-5,6,7,8-tetrahydro-1,7-naphthidin-3-yl)urea (compound I-59)

[0289] Following the method of Example 46, 2-fluoro-5-trifluoromethylpyridine was replaced with 2-chloro-6-(trifluoromethyl)pyrazine to prepare compound I-59. 1H NMR (400MHz, DMSO-d6) δ10.90(s,1H),8.71(s,1H),8.56(s,1H),8.47(d,J=2.5Hz, 1H),8.39(d,J=6.3Hz,1H),7.88(d,J=2.4Hz,1H),7.56(d,J=2.5Hz,1H),7.35(dd, J=8.8,4.5Hz,1H),7.24(dd,J=9.9,2.5Hz,1H),7.18(d,J=6.3Hz,1H),6.95(td,J= 9.1,2.6Hz,1H),4.78(s,2H),3.97(s,2H),2.94(t,J=5.9Hz,2H).HRMS(ESI)calcd for C 22 H 17 F4N7O[MH] + 470.1352, found 470.1361.

[0290] Example 60

[0291] 1-(7-(4-cyano-5-(trifluoromethyl)pyridin-2-yl)-5,6,7,8-tetrahydro-1,7-naphthidin-3-yl)-3-(5-fluoro-1H-indole-3-yl)urea (compound I-60)

[0292] Following the method of Example 46, 2-fluoro-5-trifluoromethylpyridine was replaced with 2-chloro-5-(trifluoromethyl)isocyanonitrile to prepare compound I-60. 1 H NMR(400MHz,DMSO-d6)δ10.95(s,1H),9.23(s,1H),8.88(s,1H),8.77(s,1H ),8.67(s,1H),8.09(s,1H),7.78(s,1H),7.57(d,J=2.5Hz,1H),7.36(dd,J =8.9,4.5Hz,1H),7.30(dd,J=9.9,2.5Hz,1H),6.96(td,J=9.1,2.6Hz,1H),5.01(s,2H),4.02(t,J=5.8Hz,2H),3.04(t,J=5.8Hz,2H).HRMS(ESI)calcd for C 24 H 17 F4N7O[MH] + 494.1352, found 494.1362.

[0293] Example 61

[0294] Evaluation of the inhibitory activity of the compound on the STING signaling pathway in THP1-Dual cells

[0295] Experimental Principle: THP1-Dual is a commercially available dual reporter gene assay cell line for the NF-κB and IRF signaling pathways. The transcriptional activity of the IRF signaling pathway can be evaluated by detecting secreted luciferase. This cell line also expresses cGAS and STING proteins; the introduction of exogenous 2',3'-cGAMP directly activates the STING signaling pathway, thereby enhancing IRF transcriptional activity. Therefore, exogenous 2',3'-cGAMP is used to activate the intracellular STING-IRF signaling pathway. After adding compounds to intervene in the STING signaling pathway, the inhibitory activity of the compounds on STING is evaluated by detecting secreted luciferase.

[0296] Experimental reagents and materials: heat-inactivated serum (Biological Industries), 1640 medium (Biological Industries), penicillin-streptomycin dual antibody (Biological Industries), THP1-Dual TM Cells (InvivoGen), 2',3'-cGAMP (Targetmol, stock solution prepared at 1 mg / mL), Opti-MEM (Gibco), Lipo6000 (Beyotime), QUANTI-Luc TM (InvivoGen).

[0297] Experimental methods: (1) Cell seeding: Centrifuge, resuspend and count THP1-Dual cells in good growth condition. Mix the cell suspension with the pre-prepared 2',3'-cGAMP working solution (e.g., mix 2 μg of 2',3'-cGAMP stock solution with 4 μL of Lipo6000 in 0.5 mL of Opti-MEM and let stand at room temperature for 10 min before use) to prepare a culture medium solution with a 2',3'-cGAMP concentration of 2 μg / mL and a cell concentration of 400,000 cells / mL. Add 100 μL to a 96-well plate as the experimental wells; and add the corresponding cell solution without 2',3'-cGAMP to the control wells. (2) Cell drug delivery: Prepare a 10 mM stock solution of the test compound, and dilute it with culture medium in a gradient to the test concentration. Add 100 μL of the drug solution to the experimental wells, and add 100 μL of culture medium to the control wells and model wells. After incubating in an incubator for 16–18 hours, the samples were tested. (3) Detection: QUANTI-Luc was placed in an incubator for 16–18 hours. TMThe powder was prepared into a detection solution with purified water according to the instructions, aliquoted and stored at 4℃. 10 μL of the detection solution was added to a white, opaque 384-well plate. The 96-well plate containing cultured cells was taken out, centrifuged at 1000 rpm for 1 min using a microplate centrifuge, and 4 μL of the supernatant was taken and added to the 96-well plate containing the detection solution. Chemiluminescence was detected using an ELISA reader. (4) Data processing: The inhibition rate of the compound at a fixed concentration was calculated using the following formula: Inhibition rate of a compound at a certain concentration = 1 - (Chemiluminescence value of the compound well at a certain concentration - chemiluminescence value of the control well) / (Chemiluminescence value of the model well - chemiluminescence value of the control well) × 100%; then, the half-maximal inhibitory rate (IC50) of the compound was calculated by fitting the curve based on the inhibition rate of the compound at each concentration. 50 (Value). Experimental results: The inhibitory activity of the compound on the STING signaling pathway in THP-1Dual cells activated by 2',3'-cGAMP stimulation is shown in Table 2.

[0298] The test results (Table 2) show that the tetrahydro-1,7-naphthidine compounds of the present invention (such as I-1, I-2, I-8, I-14, I-15, I-16, I-18, I-21, I-26, I-30, I-31, I-33, I-36, I-37, I-38, etc.) have strong STING inhibitory activity against 2',3'-cGAMP-stimulated THP-1Dual cells. The IC50 values ​​of some compounds are also shown. 50 The value is less than 30 nM. Surprisingly, tetrahydro-1,6-naphthidine compounds (such as I-4) have very weak activity.

[0299] Table 2. Results of the assay for the inhibitory activity of compounds against STING in THP-1 Dual cells

[0300] Example 62

[0301] Pharmacokinetic evaluation of the compound in rats

[0302] Experimental animals: 3 male SD rats, SPF grade, obtained from Beijing Vital River.

[0303] Experimental Methods: Three rats were used in the oral administration group, with an oral dose of 20 mg / kg. Rats were fasted for 12 hours before oral administration and fed 4 hours after administration. Approximately 0.2 mL of blood was collected from the orbital sinus at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after oral administration. Dipotassium ethylenediaminetetraacetate (EDTA) was added immediately after blood collection for anticoagulation, and the collected blood was placed on ice. All samples were centrifuged at 18000g for 7 minutes in a low-temperature centrifuge to separate plasma. The content of compounds in the plasma was detected by LC-MS / MS, and relevant pharmacokinetic parameters were calculated based on the blood drug concentration data at different time points. The experimental results are shown in Table 3.

[0304] Experimental results show that compounds I-2, I-10, and I-15 have relatively long oral half-lives (T0). 1 / 2 The high oral exposure (AUC) and high concentration of oral toxicities suggest that the above compounds have favorable pharmacokinetic properties. Other compounds of the present invention also exhibit favorable pharmacokinetic properties.

[0305] Table 3. Pharmacokinetic parameters of the compounds in rats

[0306] Example 63

[0307] tablet

[0308] The compound I-1 (50g) obtained in Example 1, hydroxypropyl methylcellulose E (150g), starch (200g), appropriate amount of povidone K30 and magnesium stearate (1g) were mixed, granulated and compressed into tablets.

[0309] In addition, according to the conventional formulation method of the 2015 edition of the Pharmacopoeia, the compounds obtained in Examples 1 to 57 can be compounded with different pharmaceutical excipients to produce capsules, powders, tablets, granules, pills, injections, syrups, oral liquids, inhalants, ointments, solutions, creams, gels, powders, lotions, tinctures, suppositories, or patches.

Claims

1. A compound of Formula I: ###00001### I or a pharmaceutically acceptable salt thereof. wherein: X is selected from: CH or N; only one of Y, Z and W is selected from N, and the other two are each independently selected from CR; R is selected from: H, halogen or C 1-4 alkyl; R 1 and R 2 are each independently selected from the group consisting of: H, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkylthio, C 1-4 haloalkylthio, -S(O) 1-2 (C 1-4 alkyl), OH, NR’R”, CN, NO2, -C(=O)(C 1-4 alkyl), -C(=O)O(C 1-4 alkyl), -C(=O)OH, -(C 0-3 alkyl)-heteroaryl, -(C 0-3 alkyl)-5-10 membered heterocyclyl, R a substituted aryl, or R a substituted heteroaryl, or R 1 and R 2 form a 5-10 membered heterocyclic ring by mutual bonding with carbon, nitrogen or oxygen atoms, wherein the heteroaryl is a 5-10 membered heteroaryl containing 1-2 atoms independently selected from oxygen, nitrogen or sulfur atoms, and the 5-10 membered heterocyclic ring is a heterocycloalkane ring or a heterocycloalkene ring containing 1-2 atoms independently selected from oxygen or nitrogen atoms; R 3 selected from: H, halogen or C 1-4 alkyl; R 4 Selected from: H, R which is arbitrarily chosen by 1 to 3 independent selections a Replacement C 1-10 Alkyl groups, optionally with 1 to 3 independently selected R groups a Replacement C 3-8 cycloalkyl, optionally with 1 to 3 independently selected R a Substituted aryl group, optionally selected by 1 to 3 independently chosen R a Substituted heteroaryl, -L 1 -R 5 or -L 2 -L 3 -R 6 The heteroaryl group is a 5- to 10-membered heteroaryl group comprising 1 to 2 independently selected oxygen, nitrogen, or sulfur atoms; L 1 Selected from: carbonyl, -S(O) 1-2 Optionally selected by 1 to 2 independent R b Replacement C 1-4 Alkyl groups or optionally 1 to 2 independently selected R groups b Replacement C 3-8 cycloalkyl; R 5 Selected from: R, which is arbitrarily chosen by 1 to 3 independent selections c Replacement C 1-8 Alkyl groups, optionally with 1 to 3 independently selected R groups c Replacement C 3-8 cycloalkyl, optionally with 1 to 3 independently selected R c Substituted aryl group or optionally 1 to 3 independently selected R groups c Substituted heteroaryl groups, wherein the heteroaryl group is a 5- to 10-membered heteroaryl group comprising 1 to 2 independently selected oxygen, nitrogen, or sulfur atoms; L 2 selected from: carbonyl, -S(O) 1-2 , optionally substituted C d 1-2 independently selected R 1-4 alkyl or optionally substituted C d 1-2 independently selected R 3-8 cycloalkyl; L 3 selected from: O, S, NR e or C 1-3 alkyl; R 6 substituted aryl, optionally substituted with 1 to 3 independently selected R f substituted aryl, optionally substituted with 1 to 3 independently selected R f substituted heteroaryl, optionally substituted with 1 to 3 independently selected R g substituted C 1-8 substituted C g substituted C 3-8 cycloalkyl, wherein the heteroaryl is a 5- to 10-membered heteroaryl comprising 1 to 2 heteroatoms independently selected from oxygen, nitrogen, or sulfur. R a , R b , R c and R d are each independently selected from H, halogen, CN, OH, NR'R", C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, C 1-6 haloalkylthio, C 2-6 alkynyl, C 2-6 alkenyl, -C(=O)(C 1-4 alkyl), -C(=O)O(C 1-4 alkyl), -C(=O)OH, -C(=O)NR'R" or -S(O) 1-2 (C 1-4 alkyl), or any two independent R a , R b , R c or R d form a 5- to 10-membered heterocyclic ring by mutual bonding with carbon, nitrogen or oxygen atoms; R e selected from: H or C 1-6 alkyl; R f and R g are each independently selected from the group consisting of: H, halogen, CN, OH, NR’R”, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, C 1-6 haloalkylthio, C 2-6 alkynyl, C 2-6 alkenyl, -C(=O)(C 1-4 alkyl), -C(=O)O(C 1-4 alkyl), -C(=O)OH, -C(=O)NR’R”, -S(O) 1-2 (C 1-4 alkyl), aryl optionally substituted with 1 to 3 independently selected R a or heteroaryl optionally substituted with 1 to 3 independently selected R a or R f or R g form a 5- to 10-membered heterocyclic ring by mutual bonding with carbon, nitrogen or oxygen atoms, wherein the heteroaryl is a 5- to 10-membered heteroaryl containing 1 to 2 atoms independently selected from oxygen, nitrogen or sulfur atoms, and the 5- to 10-membered heterocyclic ring is a heterocycloalkane ring or a heterocycloalkene ring containing 1 to 2 atoms independently selected from oxygen or nitrogen atoms; R' and R" are each independently selected from: H or C 1-6 alkyl, or R' and R" are linked to each other by a bond to a carbon, nitrogen or oxygen atom to form a 5- to 6-membered heterocyclic ring, wherein the 5- to 6-membered heterocyclic ring is a heterocycloalkane ring or a heterocycloalkene ring comprising 1 heteroatom independently selected from oxygen or nitrogen.

2. The compound according to claim 1, which is a compound of formula II: ###0001### or a pharmaceutically acceptable salt thereof. wherein: X is selected from: CH or N; R is selected from: H, halogen or C 1-4 alkyl; R 1 and R 2 are each independently selected from the group consisting of: H, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkylthio, C 1-4 haloalkylthio, -S(O) 1-2 (C 1-4 alkyl), OH, NR’R”, CN, NO2, -C(=O)(C 1-4 alkyl), -C(=O)O(C 1-4 alkyl), -C(=O)OH, -(C 0-3 alkyl)-heteroaryl, -(C 0-3 alkyl)-5-10 membered heterocyclyl, R a substituted aryl or R a substituted heteroaryl, or R 1 and R 2 form a 5-10 membered heterocyclic ring by mutual bonding with carbon, nitrogen or oxygen atoms, wherein the heteroaryl is a 5-10 membered heteroaryl containing 1-2 atoms independently selected from oxygen, nitrogen or sulfur atoms, and the 5-10 membered heterocyclic ring is a heterocycloalkane ring or a heterocycloalkene ring containing 1-2 atoms independently selected from oxygen or nitrogen atoms; R 3 selected from: H, halogen or C 1-4 alkyl; R 4 selected from: optionally substituted C a substituted C 1-10 alkyl, optionally substituted with 1 to 3 independently selected R a substituted C 3-8 cycloalkyl, optionally substituted with 1 to 3 independently selected R a substituted aryl, optionally substituted with 1 to 3 independently selected R a substituted heteroaryl, -L 1 -R 5 or -L 2 -L 3 -R 6 wherein the heteroaryl is a 5- to 10-membered heteroaryl comprising 1 to 2 heteroatoms independently selected from oxygen, nitrogen, or sulfur atoms; L 1 selected from: carbonyl, -S(O) 1-2 , optionally substituted with 1-2 independently selected R b substituted C 1-4 alkyl or optionally substituted with 1-2 independently selected R b substituted C 3-8 cycloalkyl; R 5 Selected from: R, which is arbitrarily chosen by 1 to 3 independent selections c Replacement C 1-8 Alkyl groups, optionally with 1 to 3 independently selected R groups c Replacement C 3-8 cycloalkyl, optionally with 1 to 3 independently selected R c Substituted aryl group or optionally 1 to 3 independently selected R groups c Substituted heteroaryl groups, wherein the heteroaryl group is a 5- to 10-membered heteroaryl group comprising 1 to 2 independently selected oxygen, nitrogen, or sulfur atoms; L 2 selected from: carbonyl, -S(O) 1-2 , optionally substituted with 1-2 independently selected R d substituted C 1-4 alkyl or optionally substituted with 1-2 independently selected R d substituted C 3-8 cycloalkyl; L 3 selected from: O, S, NR e or C 1-3 alkyl; R 6 substituted aryl, optionally substituted with 1 to 3 independently selected R f substituted aryl, optionally substituted with 1 to 3 independently selected R f substituted heteroaryl, optionally substituted with 1 to 3 independently selected R g substituted C 1-8 substituted C g substituted C 3-8 cycloalkyl, wherein the heteroaryl is a 5- to 10-membered heteroaryl comprising 1 to 2 heteroatoms independently selected from oxygen, nitrogen, or sulfur atoms; R a , R b , R c and R d are each independently selected from H, halogen, CN, OH, NR'R", C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, C 1-6 haloalkylthio, C 2-6 alkynyl, C 2-6 alkenyl, -C(=O)(C 1-4 alkyl), -C(=O)O(C 1-4 alkyl), -C(=O)OH, -C(=O)NR'R" or -S(O) 1-2 (C 1-4 alkyl), or any two independent selected R a , R b , R c or R d form a 5- to 10-membered heterocyclic ring by mutual bonding with carbon, nitrogen or oxygen atoms; R e selected from: H or C 1-6 alkyl; R f and R g each independently is selected from the group consisting of H, halogen, CN, OH, NR’R”, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, C 1-6 haloalkylthio, C 2-6 alkynyl, C 2-6 alkenyl, -C(=O)(C 1-4 alkyl), -C(=O)O(C 1-4 alkyl), -C(=O)OH, -C(=O)NR’R”, -S(O) 1-2 (C 1-4 alkyl), aryl optionally substituted with 1 to 3 independently selected R a , or heteroaryl optionally substituted with 1 to 3 independently selected R a , or any two independently selected R f or R g form a 5- to 10-membered heterocyclic ring by interlinking with carbon, nitrogen or oxygen atoms, wherein the heteroaryl is a 5- to 10-membered heteroaryl containing 1 to 2 atoms independently selected from oxygen, nitrogen or sulfur atoms, and the 5- to 10-membered heterocyclic ring is a heterocycloalkane ring or a heterocycloalkene ring containing 1 to 2 atoms independently selected from oxygen or nitrogen atoms; R' and R" are each independently selected from: H or C 1-6 alkyl, or R' and R" are linked to each other by a bond to a carbon, nitrogen or oxygen atom to form a 5- to 6-membered heterocyclic ring, wherein the 5- to 6-membered heterocyclic ring is a heterocycloalkane ring or a heterocycloalkene ring comprising 1 heteroatom independently selected from oxygen or nitrogen.

3. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-2, wherein wherein: X is selected from CH.

4. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, wherein The compound is selected from any one of the following:

5. Use of a compound of any one of claims 1-2, or a pharmaceutically acceptable salt thereof, in the manufacture of a STING inhibitor.

6. Use of a compound of any one of claims 1-2, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for preventing or treating a STING-mediated disease.

7. Use according to claim 6, characterized in that, The STING-mediated disease is selected from: an infectious disease, an inflammatory disease, an autoimmune disease, a metabolic disease, an organ fibrosis disease, a cardiovascular and cerebrovascular disease, a respiratory system disease, a nervous system disease, a cancer or a precancerous syndrome.

8. Use of a compound of any one of claims 1-2, or a pharmaceutically acceptable salt thereof, in the manufacture of an immunoadjuvant medicament.

9. A pharmaceutical composition for preventing or treating a STING-mediated disease, characterized by, which comprises a compound of any one of claims 1-2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

10. Pharmaceutical composition according to claim 9, characterized in that The pharmaceutical composition is preferably selected from a capsule, a powder, a tablet, a granule, a pill, an injection, a syrup, an oral solution, an inhalant, an ointment, a solution, a cream, a gel, a powder, a lotion, a tincture, a suppository or a patch.

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