Tetrahydronaphthyridine STING inhibitor and medical application thereof

Abstract

The invention discloses a tetrahydronaphthyridine compound and medical application thereof.The structure of the tetrahydronaphthyridine compound is shown in the formula I. The tetrahydronaphthyridine compound is a potent STING inhibitor, has good pharmacokinetic properties and can be used for preparing a medicine for preventing and treating diseases. The compound as shown in the formula I or the pharmaceutically acceptable salt thereof can be used for preparing medicines for preventing or treating STING-mediated diseases.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of biological medicine, and particularly relates to tetrahydronaphthyridine STING inhibitors and medical uses thereof. BACKGROUND

[0002] The cGAS-STING signaling pathway plays an important role in mediating cytosolic DNA immune response. Cyclic GMP-AMP synthase (cGAS) is a DNA sensor that can recognize abnormal dsDNA in the cytoplasm. After recognizing dsDNA, cGAS forms a dimeric cGAS-DNA complex to synthesize 2',3'-cGAMP from ATP and GTP. As a second messenger, 2',3'-cGAMP specifically binds to the "V"-shaped pocket of the interferon-stimulated regulatory factor (STING) dimer, inducing the oligomerization and activation of STING protein. The activated STING is transferred from the endoplasmic reticulum to the Golgi apparatus and recruits TANK-binding kinase (TBK1), which in turn phosphorylates STING and recruits interferon regulatory factor 3 (IRF3), and then produces type I interferon (IFN) and other cytokines to produce immune inflammatory response. Abnormal 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 fatty liver disease, pneumonia, chronic nephritis, amyotrophic lateral sclerosis, psoriasis, and ischemic reperfusion injury. Therefore, STING inhibitors are expected to be used for the treatment of inflammatory and autoimmune diseases. However, the existing STING inhibitors are few in kind, weak in activity, and poor in drugability (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, and is difficult to be orally absorbed (Br J Pharmacol, 2021, 178, 4907-4922). So far, no STING inhibitor has been approved for marketing. In summary, there is a very urgent clinical need to develop new STING inhibitors. SUMMARY

[0003] The present application provides a tetrahydronaphthyridine compound with novel structure, which is a potent STING inhibitor, and thus can be used for preparing a medicament for preventing or treating a STING-mediated disease.

[0004] The present application also provides a preparation method and a pharmaceutical composition of the tetrahydronaphthyridine compound.

[0005] Technical scheme: In order to achieve the above-mentioned purpose, the present application provides a compound of formula I or a pharmaceutically acceptable salt thereof:

[0006]

[0007] wherein:

[0008] X is selected from CH or N;

[0009] only one of Y, Z and W is selected from N, and the other two are each independently selected from CR;

[0010] R is selected from H, halogen or C 1-4 alkyl;

[0011] R 1 and R 2 are each independently selected from 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 atom, wherein the heteroaryl is a 5-10 membered heteroaryl containing 1-2 oxygen, nitrogen or sulfur atoms, and the 5-10 membered heterocyclic ring is a heterocycloalkane ring or a heterocycloalkene ring containing 1-2 oxygen or nitrogen atoms;

[0012] R 3 Selected from: H, halogen or C 1-4 alkyl;

[0013] 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;

[0014] 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;

[0015] 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;

[0016] 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;

[0017] L 3 Selected from: O, S, NR e Or C1-3 alkyl;

[0018] R 6 selected from the group consisting of: optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C f substituted aryl, optionally substituted heteroaryl, optionally substituted C f substituted aryl, optionally substituted heteroaryl, optionally substituted C g substituted C 1-8 alkyl, optionally 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 atom;

[0019] R a , R b , R c and R d 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” 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 heterocycle by mutual bonding with carbon, nitrogen or oxygen atoms;

[0020] R e is selected from the group consisting of: H or C 1-6 alkyl;

[0021] 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 1-6Halogenated 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.

[0022] 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.

[0023] In some embodiments, the present invention provides a compound of formula II or a pharmaceutically acceptable salt thereof:

[0024]

[0025] in:

[0026] X is selected from: CH or N;

[0027] R is selected from: H, halogen, or C. 1-4 alkyl;

[0028] 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 1-4Alkyl), 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.

[0029] R 3 Selected from: H, halogen or C 1-4 alkyl;

[0030] 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;

[0031] 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;

[0032] 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 Rc substituted aryl or optionally substituted by 1 to 3 independently selected R c substituted heteroaryl, wherein the heteroaryl is a 5- to 10-membered heteroaryl comprising 1 to 2 heteroatoms independently selected from oxygen, nitrogen, or sulfur atoms;

[0033] L 2 selected from: carbonyl, -S(O) 1-2 , optionally substituted by 1 to 2 independently selected R d substituted C 1-4 alkyl or optionally substituted by 1 to 2 independently selected R d substituted C 3-8 cycloalkyl;

[0034] L 3 selected from: O, S, NR e or C 1-3 alkyl;

[0035] R 6 selected from: optionally substituted aryl, optionally substituted by 1 to 3 independently selected R f substituted aryl, optionally substituted by 1 to 3 independently selected R f substituted heteroaryl, optionally substituted by 1 to 3 independently selected R g substituted C 1-8 alkyl, optionally substituted by 1 to 3 independently selected R 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;

[0036] 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 independently selected R a , Rb R c R d by mutual bonding with carbon, nitrogen or oxygen atom to form 5-10 membered heterocyclic ring;

[0037] R e selected from H or C 1-6 alkyl;

[0038] R f and R g 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", -S(O) 1-2 (C 1-4 alkyl), aryl optionally substituted with 1-3 independently selected R a or heteroaryl optionally substituted with 1-3 independently selected R a or any two independently selected R f or R g by mutual bonding with carbon, nitrogen or oxygen atom to form 5-10 membered heterocyclic ring, wherein the heteroaryl is 5-10 membered heteroaryl containing 1-2 heteroatoms independently selected from oxygen, nitrogen or sulfur atom, and the 5-10 membered heterocyclic ring is a heterocycloalkane ring or a heterocycloalkene ring containing 1-2 heteroatoms independently selected from oxygen or nitrogen atom;

[0039] R' and R" are each independently selected from H or C 1-6 alkyl, or R' and R" are by mutual bonding with carbon, nitrogen or oxygen atom to form 5-6 membered heterocyclic ring, wherein the 5-6 membered heterocyclic ring is a heterocycloalkane ring or a heterocycloalkene ring containing 1 heteroatom independently selected from oxygen or nitrogen atom.

[0040] In certain embodiments, the present application provides a compound of Formulae I-II, or a pharmaceutically acceptable salt thereof, wherein: X is selected from CH.

[0041] In certain embodiments, the present application provides a compound of Formulae I-II, or a pharmaceutically acceptable salt thereof, selected from any one of Table 1:

[0042] Table 1. Structures and nomenclature of compounds

[0043]

[0044]

[0045]

[0046]

[0047]

[0048]

[0049]

[0050]

[0051] The compounds of the present application can be used as pharmaceutical salts. The salts can be acid salts of at least one of the following acids: galactaric acid, D-glucuronic acid, glycerophosphoric acid, hippuric acid, isethionic acid, lactobionic acid, maleic acid, 1,5-naphthalene disulfonic acid, naphthalene-2-sulfonic acid, pivalic acid, terephthalic acid, thiocyanic acid, cholic acid, n-dodecylsulfuric acid, 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, hydrobromic acid, methanesulfonic acid, nicotinic acid, nitric acid, orotic acid, oxalic acid, picric acid, L-pyroglutamic acid, saccharinic acid, salicylic acid, gentisic acid, p-toluenesulfonic acid, valeric acid, palmitic acid, succinic 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, undecylenic acid, ascorbic acid, camphoric acid, camphorsulfonic acid, dichloroacetic acid, ethanesulfonic acid, and the like. Alternatively, the salts can be salts of the compounds of the present application with metal (including sodium, potassium, calcium, and the like) ions or pharmaceutically acceptable amines (including ethylenediamine, tromethamine, and the like), ammonium ions, or choline.

[0052] The compounds of the present application can also be used in the form of stereoisomers, tautomers, prodrugs, deuterated derivatives, or solvates thereof.

[0053] The present application also provides methods for preparing the compounds of the present application. For example, representative compounds IIa can be prepared using the following synthetic routes. Alternatively, the compounds of the present application can be prepared according to the methods described in the examples or modifications thereof.

[0054] Synthetic routes:

[0055]

[0056] In the above synthetic routes, R 1 , R 2 and R 5 are defined in accordance with the definitions in formula I.

[0057] The compounds of the present application have strong STING inhibitory activity. Through systematic structure-activity relationship exploration, the present inventors unexpectedly found that the tetrahydro-1,7-naphthyridine compounds (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.) of the present application have strong STING inhibitory activity, and the IC 50 values of some compounds are less than 30 nM, while the activity of structurally similar tetrahydro-1,6-naphthyridine compounds (such as I-4, etc.) is very weak. Therefore, the compounds of the present application or pharmaceutically acceptable salts thereof can be used for preparing STING inhibitors, which can be used for preparing drugs for preventing or treating STING-mediated diseases.

[0058] The STING-mediated diseases are selected from infectious diseases, inflammatory diseases, autoimmune diseases, metabolic diseases, organ fibrosis diseases, cardiovascular and cerebrovascular diseases, respiratory system diseases, nervous system diseases, cancers or precancerous syndromes.

[0059] Among them, the infectious diseases include but are not limited to Mycobacterium tuberculosis infection, chlamydia infection, herpes virus (simplex herpes virus) infection, adenovirus infection, hepatitis B virus infection, orthomyxovirus infection and coronavirus infection, etc.

[0060] The inflammatory diseases and autoimmune diseases 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, neuromyotonia, CNS vasculitis, vasculitis, lymphangitis, phlebitis, cervicitis, endometritis, cystitis, epididymitis, orchitis, urethritis, dermatitis, atopic dermatitis, carbuncle, acne, inverse acne, hidradenitis suppurativa, skin pyogenic infection, tinea pedis, tinea corporis, hand eczema, alopecia areata, alopecia, urticaria, pruritus, keloid, appendicitis, myocarditis, parotitis, gingivitis, prostatitis, peritonitis, pleuritis, ulcerative colitis, Crohn's disease, systemic lupus erythematosus, familial chilblain lupus, lupus nephritis, Chagas disease, primary biliary cholangitis, primary sclerosing cholangitis, rheumatoid arthritis, ankylosing spondylitis, psoriasis, multiple sclerosis, systemic sclerosis, Sjogren's syndrome, Behcet's disease, STING-associated vasculitis with onset in infancy (SAVI), Aicardi-Goutieres syndrome, and retinal vasculopathy with cerebral leukodystrophy (RCVL), and the like.

[0061] The metabolic diseases include, but are not limited to, non-alcoholic steatohepatitis, alcoholic fatty liver disease, insulin resistance, metabolic syndrome, diabetic nephropathy, diabetic cardiomyopathy, diabetic eye disease, diabetic foot, polycystic kidney disease, polycystic ovary syndrome, hyperuricemia, gout, osteoporosis, and Duchenne muscular dystrophy, and the like.

[0062] The respiratory diseases include, but are not limited to, cough, asthma, tracheitis, bronchitis, pneumonia, respiratory distress syndrome, acute lung injury, pulmonary emphysema, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, cystic fibrosis lung disease, and rhinitis, and the like.

[0063] The organ fibrosis diseases include, but are not limited to, liver fibrosis, liver cirrhosis, pulmonary fibrosis, and renal fibrosis, and the like.

[0064] The cardiovascular and cerebrovascular diseases include, but are not limited to, atherosclerosis, peripheral vascular disease, coronary heart disease, angina pectoris, ischemia, cardiac ischemia, stroke, myocardial infarction, cardiomyopathy, heart failure, restenosis after angioplasty, ischemic encephalopathy, cerebral apoplexy, hemorrhagic encephalopathy, cerebral hemorrhage, cerebral edema, and cerebral infarction, and the like.

[0065] The nervous system diseases include, but are not limited to, Parkinson's disease, Alzheimer's disease, alpha-synucleinopathy, depression, amyotrophic lateral sclerosis, fibromyalgia syndrome, neuralgia, Down's syndrome, Hallervorden-Spatz disease, Huntington's disease, and Wilson's disease, and the like.

[0066] The cancer includes, but is 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 myelocytic leukemia, chronic lymphocytic leukemia, acute myelocytic leukemia, acute lymphocytic leukemia, multiple myeloma, malignant lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, and neuroblastoma, etc.

[0067] The compound of the present application or a pharmaceutically acceptable salt thereof can also be used for the preparation of an immunoadjuvant medicament.

[0068] The compound of the present application can be used alone or in combination with other therapeutic agents. As an immunomodulator, the compound of the present application can be used in monotherapy or in combination with other therapeutic agents to treat STING-mediated diseases.

[0069] The present application also provides a pharmaceutical composition for preventing or treating STING-mediated diseases, comprising at least one compound of the present application or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier or diluent.

[0070] The pharmaceutical composition is selected from the group consisting of capsule, powder, tablet, granule, pill, injection, syrup, oral liquid, inhalant, ointment, solution, cream, gel, powder, lotion, tincture, suppository, and patch, etc. in a pharmaceutically conventional preparation form.

[0071] Advantages: Compared with the prior art, the present application has the following advantages:

[0072] (1) The present application designs and synthesizes novel tetrahydronaphthyridine compounds, most of which have significantly better STING inhibitory activity than the positive control compound H-151, and the IC 50 values of some of which are less than 30 nM. The compounds of the present application can be orally absorbed and have a long oral half-life (T 1 / 2 , and are expected to be developed into drugs for treating STING-mediated diseases.

[0073] (2) The compounds of the present application are designed ingeniously, have simple structures, and are easy to obtain raw materials. The synthesis process is simple, safe and environmentally friendly, and easy to scale up. DETAILED DESCRIPTION

[0074] The present application is specifically illustrated below by examples. The following examples are intended to better illustrate the present application, and are not intended to limit the scope of the present application. Various changes and modifications can be made to the present application without departing from the spirit and scope of the present application.

[0075] Unless otherwise specified, the starting materials used in the examples of the present application are known products, which can be obtained by purchasing commercially available products.

[0076] The structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). The NMR determination is performed by using a (Bruker) nuclear magnetic instrument, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3) or deuterated methanol (CD3OD) as the solvent, and tetramethylsilane (TMS) as the internal standard.

[0077] Silica gel column chromatography generally uses silica gel 200-300 mesh silica gel from Qingdao Haizhuan Chemical Factory as the carrier.

[0078] The known starting materials of the present application can be synthesized by using or according to the methods known in the art, or can be purchased from companies such as Lianyuan, Bide Pharmaceutical, Aladdin, and An'eg.

[0079] Example 1

[0080] 1-(5-Fluoro-1H-indol-3-yl)-3-(7-(4-(trifluoromethyl)benzyl)-5,6,7,8-tetrahydro-1,7- naphthyridin-3-yl)urea (Compound I-1)

[0081]

[0082] Synthesis of Intermediate A-1

[0083] 7-(tert-Butoxycarbonyl)-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carboxylic acid (CAS: 1245645-20-8) (339 mg, 1.22 mmol) was added to tetrahydrofuran (5 mL), triethylamine (185 mg, 1.83 mmol) was added, and then diphenyl phosphorazide (403 mg, 1.46 mmol) was slowly added dropwise. The mixture was stirred at room temperature overnight. After the reaction was completed, the solvent was evaporated under reduced pressure, diluted with water (3 mL), extracted with ethyl acetate (3 mL x 3), and the combined organic phases were washed with saturated brine (5 mL x 1), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 8:1) to obtain Intermediate A-1 (white solid, 341 mg). 1 H NMR (300 MHz, CDCl3) δ 9.02 (d, J = 2.1 Hz, 1H), 8.07 (d, J = 2.1 Hz, 1H), 4.76 (s, 2H), 3.73 (t, J = 5.8 Hz, 2H), 2.93 (t, J = 5.8 Hz, 2H), 1.51 (s, 9H). HRMS (ESI) calcd for C 14 H 17 N5O3[M+H] + 304.1404, found 304.1403.

[0084] Synthesis of intermediate A-2

[0085] The above intermediate A-1 and benzyl alcohol (138 mg, 1.28 mmol) were added to toluene (4 mL) and reacted at 100 °C for 6 h. After the reaction was completed, the solvent was removed by evaporation under reduced pressure, and the residue was slurried with petroleum ether (5 mL) and filtered to obtain intermediate A-2 (white solid, 408 mg).

[0086] Synthesis of intermediate A-3

[0087] Intermediate A-2 (100 mg, 0.26 mmol) was added to ethyl acetate (1 mL), and 4 M hydrogen chloride ethyl acetate solution (2 mL) was slowly added under ice bath conditions, and the mixture was slowly warmed to room temperature and reacted for 5 h. After the reaction was completed, the solvent was removed by evaporation under reduced pressure to obtain intermediate A-3 (98.8 mg, white solid). 1 H NMR (300 MHz, DMSO-d6) δ 10.16 (s, 1H), 9.63 (s, 2H), 8.51 (d, J = 2.4 Hz, 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 = 6.1 Hz, 2H). HRMS (ESI) calcd for C 16 H 17 N3O2[M+H] + 284.1394, found 284.1393.

[0088] Synthesis of intermediate A-4

[0089] 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 at room temperature overnight. After the reaction was completed, the mixture was diluted with water (3 mL) and extracted with ethyl acetate (3 mL x 3), and the combined organic phase was washed with saturated brine (5 mL x 1), dried over anhydrous sodium sulfate, and the solvent was removed by evaporation under reduced pressure to obtain intermediate A-4 (110 mg, light yellow solid). 1H NMR (300 MHz, CDC13) δ 8.21 (d, J = 2.5 Hz, 1H), 7.82 (s, 1H), 7.57 (t, J = 7.7 Hz, 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 = 5.7 Hz, 2H), 2.76 (t, J = 5.8 Hz, 2H). HRMS (ESI) calcd for C 24 H 21 F4N3O2[M+H] + 460.1643, found 460.1641.

[0090] Synthesis of Intermediate A-5

[0091] Intermediate A-4 (110 mg), 10% palladium on carbon (11 mg) were added to methanol (2 mL), replaced with hydrogen gas for three times, stirred at room temperature for 8 hours. After the reaction was completed, the reaction mixture was filtered, and the filtrate was evaporated under reduced pressure to give Intermediate A-5 (light yellow solid, 45 mg). 1 H NMR (400 MHz, CDC13) δ 7.90 (d, J = 2.7 Hz, 1H), 7.57 (t, J = 7.6 Hz, 1H), 7.29 (t, J = 11.3 Hz, 2H), 6.79 (d, J = 2.6 Hz, 1H), 3.76 (s, 2H), 3.66 (s, 2H), 2.84 (t, J = 5.9 Hz, 2H), 2.73 (t, J = 5.8 Hz, 2H). HRMS (ESI) calcd for C 16 H 15 F4N3[M+H] + 326.1275, found 326.1273.

[0092] Synthesis of Intermediate A-6

[0093] Intermediate A-6 (16.2 g) was dissolved in N,N-dimethylformamide (DMF) (140 mL), trifluoroacetic anhydride (TFAA) (62 g, 296 mmol) was added slowly under ice-bath condition, stirred at room temperature overnight. After the reaction was completed, water (500 mL) was added, a pink solid was precipitated, filtered, dried to give Intermediate A-6 (white solid, 16.2 g), which was used directly in the next step.

[0094] Synthesis of Intermediate A-7

[0095] The crude intermediate A-6 (16.2 g) was dissolved in 20% NaOH (120 mL) solution, stirred at 100 °C for 2.5 h. After the reaction was completed, insoluble impurities were removed by suction filtration, 6N HC1 solution was added to the filtrate under ice bath condition, the pH was adjusted to 3, a large amount of yellow solid was precipitated, suction filtered and dried to give intermediate A-7 (yellow solid, 12.5 g).

[0096] Synthesis of intermediate A-8

[0097] Intermediate A-7 (10.6 g, 59.4 mmol) was dissolved in dichloromethane (DCM) (120 mL), triethylamine (TEA) (18 mL, 132 mmol) was added, stirred at room temperature for 15 min, diphenyl phosphorazide (DPPA) (16 g, 59.4 mmol) was added, and the reaction was allowed to proceed overnight. After the reaction was completed, 1N HC1 solution (200 mL) was added, dichloromethane (100 mL x 3) was used for extraction, the organic phase was combined, washed with saturated brine (200 mL x 1), dried over anhydrous sodium sulfate, and the solvent was removed by evaporation 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).

[0098] Synthesis of compound I-1

[0099] Intermediate A-8 (30.6 mg, 0.15 mmol) was added to toluene (3 mL), the system was moved into an oil bath, and the reaction was allowed to proceed at 100 °C for 3 h. After cooling to room temperature, intermediate A-5 (45 mg, 0.15 mmol) was added, and the reaction was allowed to proceed overnight. White solid was precipitated, and the solvent was removed by evaporation under reduced pressure. Dichloromethane / methanol = 20:1 (3 mL) was added to the residue for trituration, stirred at room temperature for 2 h, suction filtered, and the filter cake was dried to give compound I-1 (yellow solid, 51 mg). 1 H NMR (300 MHz, DMSO-d6) δ 10.91 (s, 1H), 8.64 (s, 1H), 8.55 (s, 1H), 8.34 (d, J = 2.4 Hz, 1H), 7.84 - 7.72 (m, 2H), 7.56 (d, J = 2.5 Hz, 1H), 7.51 (d, J = 12.1 Hz, 1H), 7.45 (d, J = 8.1 Hz, 1H), 7.35 (dd, J = 8.8, 4.5 Hz, 1H), 7.23 (dd, J = 9.9, 2.6 Hz, 1H), 6.95 (td, J = 9.2, 2.6 Hz, 1H), 3.80 (s, 2H), 3.57 (s, 2H), 2.85 (t, J = 5.7 Hz, 2H), 2.71 (t, J = 5.7 Hz, 2H). HRMS (ESI) calcd for C 25 H 20F5N5O [M+H] + 502.1661, found 502.1660.

[0100] Example 2

[0101] 1-(5-Fluoro-1H-indol-3-yl)-3-(7-(4-((trifluoromethyl)thio)benzyl)-5,6,7,8- tetrahydro-1,7-naphthyridin-3-yl)urea (Compound I-2)

[0102]

[0103] Compound I-2 was prepared according to the procedure of Reference Example 1, replacing 3-fluoro-4-trifluoromethylbenzyl bromide with 4- trifluoromethylbenzyl bromide. 1 H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 8.63 (s, 1H), 8.54 (s, 1H), 8.32 (d, J = 2.5 Hz, 1H), 7.78 (d, J = 2.4 Hz, 1H), 7.71 (d, J = 8.1 Hz, 2H), 7.62 - 7.51 (m, 3H), 7.34 (dd, J = 8.8, 4.5 Hz, 1H), 7.23 (dd, J = 9.8, 2.6 Hz, 1H), 6.95 (td, J = 9.1, 2.5 Hz, 1H), 3.76 (s, 2H), 3.52 (s, 2H), 2.84 (t, J = 5.8 Hz, 2H), 2.70 (t, J = 5.9 Hz, 2H). HRMS (ESI) calcd for C 25 H 21 F4N5OS [M+H] + 516.1476, found 516.1489.

[0104] Example 3

[0105] 1-(5-Fluoro-1H-indol-3-yl)-3-(7-(4-(trifluoromethyl)benzyl)-5,6,7,8-tetrahydro- 1,7-naphthyridin-3-yl)urea (Compound I-3)

[0106]

[0107] Compound I-3 was prepared according to the procedure of Reference Example 1, replacing 3-fluoro-4-trifluoromethylbenzyl bromide with 4- trifluoromethylbenzyl bromide. 1H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 8.64 (s, 1H), 8.56 (s, 1H), 8.33 (d, J = 2.5 Hz, 1H), 7.78 (s, 1H), 7.73 (d, J = 8.0 Hz, 2H), 7.62 (d, J = 8.0 Hz, 2H), 7.56 (d, J = 2.5 Hz, 1H), 7.34 (dd, J = 8.8, 4.5 Hz, 1H), 7.23 (dd, J = 9.8, 2.6 Hz, 1H), 6.95 (td, J = 9.2, 2.6 Hz, 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

[0108] Example 4

[0109] 1-(5-Fluoro-1H-indol-3-yl)-3-(6-(4-((trifluoromethyl)thio)benzyl)-5,6,7,8- tetrahydro-1,6-naphthyridin-2-yl)urea (Compound I-4)

[0110]

[0111]

[0112] Synthesis of Intermediate A-9

[0113] tert-Butyl 2-amino-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (CAS: 1149333-40-3) (74.8 mg, 0.3 mmol) was added to ethyl acetate (1 mL), 4M hydrogen chloride ethyl acetate solution (3 mL) was added slowly under ice bath condition, slowly warmed to room temperature, reaction for 5 hours. After reaction was completed, the solvent was evaporated under reduced pressure to give Intermediate A-9 (57 mg, white solid), which was used directly in the next step without purification.

[0114] Synthesis of Intermediate A-10

[0115] Intermediate A-9 (57 mg, 0.26 mmol), 4-trifluoromethylthiobenzyl bromide (70.5 mg, 0.26 mmol), potassium carbonate (108 mg, 0.78 mmol) were added into N,N-dimethylformamide (3 mL) and stirred at room temperature overnight. After the reaction was completed, water (3 mL) was added for dilution, and ethyl acetate (3 mL x 3) was extracted. The combined organic phase was washed with saturated brine (5 mL x 1), dried over anhydrous sodium sulfate, and the solvent was removed by evaporation under reduced pressure to obtain intermediate A-10 (81 mg, light yellow solid), which was used directly in the next step without further purification.

[0116] Synthesis of compound I-4

[0117] Compound I-4 was prepared according to the method of Example 1, by replacing intermediate A-5 with intermediate A-10. 1 H NMR (300 MHz, DMSO-d6) δ 10.91 (s, 1H), 10.85 (s, 1H), 9.50 (s, 1H), 7.71 (d, J = 8.0 Hz, 2H), 7.65 (d, J = 2.5 Hz, 1H), 7.56 (d, J = 8.1 Hz, 2H), 7.44 (d, J = 8.4 Hz, 1H), 7.37 (dd, J = 8.9, 4.5 Hz, 1H), 7.19 (dd, J = 9.7, 2.5 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 6.97 (td, J = 9.2, 2.5 Hz, 1H), 3.78 (s, 2H), 3.53 (s, 2H), 2.97 (t, J = 5.8 Hz, 2H), 2.85 (t, J = 5.6 Hz, 2H). HRMS (ESI) calcd for C 25 H 21 F4N5OS[M+H] + 516.1476, found 516.1487.

[0118] Example 5

[0119] 1-(5-Fluoro-1H-indol-3-yl)-3-(7-(3,4,5-trifluorobenzyl)-5,6,7,8-tetrahydro-1,7- naphthyridin-3-yl)urea (Compound I-5)

[0120]

[0121] Compound I-5 was prepared according to the method of Example 1, by replacing 3-fluoro-4-trifluoromethylbenzyl bromide with 3,4,5-trifluorobenzyl bromide. 1H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 8.65 (s, 1H), 8.57 (s, 1H), 8.34 (d, J = 2.5 Hz, 1H), 7.77 (d, J = 2.4 Hz, 1H), 7.56 (d, J = 2.5 Hz, 1H), 7.37 - 7.28 (m, 3H), 7.24 (dd, J = 9.9, 2.6 Hz, 1H), 6.95 (td, J = 9.2, 2.6 Hz, 1H), 3.68 (s, 2H), 3.54 (s, 2H), 2.83 (t, J = 5.8 Hz, 2H), 2.68 (t, J = 5.8 Hz, 2H). HRMS (ESI) calcd for C 24 H 19 F4N5O [M+H] + 470.1598, found 470.1595.

[0122] Example 6

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

[0124]

[0125] Compound I-6 was prepared according to the procedure of Reference Example 1, substituting 3-(trifluoromethoxy)benzyl bromide for 3-fluoro-4- trifluoromethylbenzyl bromide. 1 H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 8.65 (s, 1H), 8.57 (s, 1H), 8.34 (d, J = 2.5 Hz, 1H), 7.77 (d, J = 2.4 Hz, 1H), 7.56 (d, J = 2.5 Hz, 1H), 7.37 - 7.28 (m, 3H), 7.24 (dd, J = 9.9, 2.6 Hz, 1H), 6.95 (td, J = 9.2, 2.6 Hz, 1H), 3.68 (s, 2H), 3.54 (s, 2H), 2.83 (t, J = 5.8 Hz, 2H), 2.68 (t, J = 5.8 Hz, 2H). HRMS (ESI) calcd for C 25 H 21 F4N5O2 [M+H] + 500.1704, found 500.1704.

[0126] Example 7

[0127] 1-(7-(4-(1,1-difluoroethyl)benzyl)-5,6,7,8-tetrahydro-1,7-naphthyridin-3-yl)-3-(5- fluoro-1H-indol-3-yl)urea (Compound I-7)

[0128]

[0129] Synthesis of Intermediate A-11

[0130] Intermediate A-11 was prepared according to the procedure described in WO 2007 / 040605. To a solution of 4-(1,1-difluoroethyl)benzoic acid (93 mg, 0.5 mmol) in anhydrous tetrahydrofuran (3 mL), 1M borane tetrahydrofuran complex (1.5 mL, 1.5 mmol) was added slowly under ice-bath condition. The reaction mixture was allowed to warm up to room temperature slowly and stirred for 3 hours. After completion of the reaction, methanol (1 mL) was added dropwise to quench the reaction. The solvent was removed under reduced pressure, diluted with water (3 mL) and extracted with ethyl acetate (3 mL x 3). The organic phase was combined, washed with saturated brine (5 mL x 1), dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to give intermediate A-11 (colorless oily liquid, 80 mg) which was used directly in the next step.

[0131] Synthesis of Intermediate A-12

[0132] To a solution of intermediate A-11 (80 mg, 0.3 mmol) in dichloromethane (3 mL), triphenylphosphine (170 mg, 0.65 mmol) and N-bromosuccinimide (116 mg, 0.65 mmol) were added portionwise under ice-bath condition. The reaction mixture was allowed to warm up to room temperature slowly and stirred for 3 hours. After completion of the reaction, the solvent was removed under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 20:1) to give intermediate A-12 (colorless oily liquid, 91 mg).

[0133] Synthesis of Compound I-7

[0134] Compound I-7 was prepared according to the procedure described in Example 1 by replacing 3-fluoro-4-trifluoromethylbenzyl bromide with A-12. 1 HNMR (300 MHz, DMSO-d6) δ 10.90 (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, 4.5 Hz, 1H), 7.25 (dd, J = 9.8, 2.6 Hz, 1H), 6.95 (td, J = 9.2, 2.6 Hz, 1H), 3.74 (s, 2H), 3.53 (s, 2H), 2.84 (s, 2H), 2.71 (s, 2H), 1.98 (t, J = 18.8 Hz, 3H). HRMS (ESI) calcd for C 26 H24 F3N5O [M+H] + 480.2006, found 480.2002.

[0135] Example 8

[0136] 1-(5-Fluoro-1H-indol-3-yl)-3-(7-(4-(trifluoromethyl)phenethyl)-5,6,7,8-tetrahydro- 1,7-naphthyridin-3-yl)urea (Compound I-8)

[0137]

[0138] Compound I-8 was prepared according to the procedure of Reference Example 1 by replacing 3-fluoro-4-trifluoromethylbenzyl bromide with 4- trifluoromethylphenethyl bromide. 1 H NMR (300 MHz, DMSO-d6) δ 10.88 (s, 1H), 8.70 (s, 1H), 8.60 (s, 1H), 8.35 (s, 1H), 7.76 (s, 1H), 7.65 (d, J = 8.0 Hz, 2H), 7.61 - 7.47 (m, 3H), 7.33 (dd, J = 8.8, 4.5 Hz, 1H), 7.23 (dd, J = 9.9, 2.5 Hz, 1H), 6.93 (td, J = 9.2, 2.6 Hz, 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.

[0139] Example 9

[0140] 1-(5-Fluoro-1H-indol-3-yl)-3-(7-(3-(4-(trifluoromethyl)phenyl)propyl)-5,6,7,8- tetrahydro-1,7-naphthyridin-3-yl)urea (Compound I-9)

[0141]

[0142] Intermediate A-13 was prepared according to the procedure of Reference Example 7 by replacing 4-(1,1 -difluoroethyl)benzoic acid with 3-(4- trifluoromethylphenyl)propanoic acid. Compound I-9 was prepared according to the procedure of Reference Example 1 by replacing 3-fluoro-4- trifluoromethylbenzyl bromide with Intermediate A-13. 1H NMR (300 MHz, DMSO-d6) δ 10.90 (s, 1H), 8.74 (d, J = 31.1 Hz, 2H), 8.37 (s, 1H), 7.79 (s, 1H), 7.66 (d, J = 8.0 Hz, 2H), 7.56 (d, J = 2.5 Hz, 1H), 7.49 (d, J = 8.0 Hz, 2H), 7.35 (dd, J = 8.8, 4.5 Hz, 1H), 7.27 (dd, J = 9.9, 2.5 Hz, 1H), 6.95 (td, J = 9.2, 2.5 Hz, 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.

[0143] Example 10

[0144] 1-(5-Fluoro-1H-indol-3-yl)-3-(7-(4-(trifluoromethoxy)benzyl)-5,6,7,8-tetrahydro-1,7- naphthyridin-3-yl)urea (Compound I-10)

[0145]

[0146] Compound I-10 was prepared according to the procedure of Reference Example 1, substituting 4-trifluoromethoxybenzyl bromide for 3-fluoro-4-trifluoromethylbenzyl bromide. 1 H NMR (300 MHz, DMSO-d6) δ 10.89 (s, 1H), 8.79 (d, J = 32.7 Hz, 2H), 8.53 - 8.18 (m, 1H), 7.83 (s, 1H), 7.69 - 7.18 (m, 7H), 6.95 (td, J = 9.2, 2.6 Hz, 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.

[0147] Example 11

[0148] 1-(5-Fluoro-1H-indol-3-yl)-3-(7-(3-fluoro-5-(trifluoromethyl)benzyl)-5,6,7,8-tetrahydro- 1,7-naphthyridin-3-yl)urea (Compound I-11)

[0149]

[0150] Compound I-11 was prepared according to the procedure of Example 1, substituting 3-fluoro-5-(trifluoromethyl)benzyl bromide for 3-fluoro-4- trifluoromethylbenzyl bromide. 1 H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 8.62 (s, 1H), 8.54 (s, 1H), 8.32 (d, J = 2.5 Hz, 1H), 7.76 (d, J = 2.4 Hz, 1H), 7.55 (d, J = 2.5 Hz, 1H), 7.34 (dd, J = 8.9, 4.5 Hz, 1H), 7.28 (d, J = 8.1 Hz, 2H), 7.26 - 7.18 (m, 4H), 6.95 (td, J = 9.2, 2.5 Hz, 1H), 3.63 (s, 2H), 3.49 (s, 2H), 2.81 (t, J = 5.9 Hz, 2H), 2.68 (t, J = 6.1 Hz, 2H), 1.22 (s, 3H), 1.20 (s, 3H). HRMS (ESI) calcd for C 25 H 20 F5N5O [M+H] + 502.1661, found 502.1660.

[0151] Example 12

[0152] 1-(5-Fluoro-1H-indol-3-yl)-3-(7-(4-isopropylbenzyl)-5,6,7,8-tetrahydro-1,7- naphthyridin-3-yl)urea (Compound I-12)

[0153]

[0154] Compound I-12 was prepared according to the procedure of Example 1, substituting 4-isopropylbenzyl bromide for 3-fluoro-4-trifluoromethylbenzyl bromide. 1 H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 8.62 (s, 1H), 8.54 (s, 1H), 8.32 (d, J = 2.5 Hz, 1H), 7.76 (d, J = 2.4 Hz, 1H), 7.55 (d, J = 2.5 Hz, 1H), 7.34 (dd, J = 8.9, 4.5 Hz, 1H), 7.28 (d, J = 8.1 Hz, 2H), 7.26 - 7.18 (m, 4H), 6.95 (td, J = 9.2, 2.5 Hz, 1H), 3.63 (s, 2H), 3.49 (s, 2H), 2.81 (t, J = 5.9 Hz, 2H), 2.68 (t, J = 6.1 Hz, 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.

[0155] Example 13

[0156] 1-(5-Fluoro-1H-indol-3-yl)-3-(7-(4-(tert-butyl)benzyl)-5,6,7,8-tetrahydro-1,7- naphthyridin-3-yl)urea (Compound I-13)

[0157]

[0158] Compound I-13 was prepared according to the procedure of Reference Example 1, replacing 3-fluoro-4-trifluoromethylbenzyl bromide with 4-tert-butylbenzyl bromide. 1 H NMR (300 MHz, DMSO-d6) δ 10.90 (s, 1H), 8.63 (s, 1H), 8.55 (s, 1H), 8.32 (d, J = 2.4 Hz, 1H), 7.77 (d, J = 2.4 Hz, 1H), 7.55 (d, J = 2.5 Hz, 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 = 5.9 Hz, 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.

[0159] Example 14

[0160] 1-(7-(3-(tert-Butyl)benzyl)-5,6,7,8-tetrahydro-1,7-naphthyridin-3-yl)-3-(5-fluoro-1H- indol-3-yl)urea (Compound I-14)

[0161]

[0162]

[0163] Intermediate A-14 was prepared according to the procedure of Reference Example 7, replacing 4-(1,1-difluoroethyl)benzoic acid with 3-tert-butylbenzoic acid. Compound I-14 was prepared according to the procedure of Reference Example 1, replacing 3-fluoro-4- trifluoromethylbenzyl bromide with Intermediate A-14. 1H NMR (400 MHz, DMSO-d6) δ 10.86 (d, J = 2.6 Hz, 1H), 8.58 (s, 1H), 8.50 (s, 1H), 8.28 (d, J = 2.4 Hz, 1H), 7.72 (d, J = 2.4 Hz, 1H), 7.51 (d, J = 2.5 Hz, 1H), 7.36 - 7.10 (m, 6H), 6.91 (td, J = 9.2, 2.5 Hz, 1H), 3.64 (s, 2H), 3.48 (s, 2H), 2.77 (t, J = 6.0 Hz, 2H), 2.64 (t, J = 5.8 Hz, 2H), 1.25 (s, 9H). HRMS (ESI) calcd for C 28 H 30 FN5O[M+H] + 472.2507, found 472.2507.

[0164] Example 15

[0165] 1-(5-Fluoro-1H-indol-3-yl)-3-(7-(3-fluoro-4-(trifluoromethoxy)benzyl)-5,6,7,8- tetrahydro-1,7-naphthyridin-3-yl)urea (Compound I-15)

[0166]

[0167] Following the procedure of Example 7, intermediate A-15 was prepared by replacing 4-(1,1 -difluoroethyl)benzoic acid with 3-fluoro-4-(trifluoromethoxy)benzoic acid. Following the procedure of Example 1, Compound I-15 was prepared by replacing 3-fluoro-4-trifluoromethylbenzyl bromide with intermediate A-15. 1 H NMR (400 MHz, DMSO-d6) δ 10.86 (d, J = 2.6 Hz, 1H), 8.58 (s, 1H), 8.50 (s, 1H), 8.28 (d, J = 2.4 Hz, 1H), 7.72 (d, J = 2.4 Hz, 1H), 7.51 (d, J = 2.5 Hz, 1H), 7.36 - 7.10 (m, 6H), 6.91 (td, J = 9.2, 2.5 Hz, 1H), 3.64 (s, 2H), 3.48 (s, 2H), 2.77 (t, J = 6.0 Hz, 2H), 2.64 (t, J = 5.8 Hz, 2H), 1.25 (s, 9H). HRMS (ESI) calcd for C 25 H 20 F5N5O2[M+H] + 518.1610, found 518.1607.

[0168] Example 16

[0169] 1-(5-Fluoro-1H-indol-3-yl)-3-(7-(2-fluoro-4-(trifluoromethyl)benzyl)-5,6,7,8- tetrahydro-1,7-naphthyridin-3-yl)urea (Compound I-16)

[0170]

[0171] Compound I-16 was prepared according to the procedure of Example 1, substituting 2-fluoro-4-(trifluoromethyl)benzyl bromide for 3-fluoro-4- trifluoromethylbenzyl bromide. 1 H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 8.63 (s, 1H), 8.54 (s, 1H), 8.34 (d, J = 2.5 Hz, 1H), 7.77 (d, J = 2.2 Hz, 1H), 7.74 (d, J = 7.5 Hz, 1H), 7.68 (dd, J = 10.1, 1.8 Hz, 1H), 7.61 (dd, J = 8.4, 1.8 Hz, 1H), 7.55 (d, J = 2.5 Hz, 1H), 7.34 (dd, J = 8.8, 4.5 Hz, 1H), 7.24 (dd, J = 9.8, 2.6 Hz, 1H), 6.99 - 6.91 (m, 1H), 3.83 (s, 2H), 3.59 (s, 2H), 2.84 (t, J = 5.5 Hz, 2H), 2.73 (t, J = 5.7 Hz, 2H). HRMS (ESI) calcd for C 25 H 20 F5N5O [M+H] + 502.1661, found 502.1661.

[0172] Example 17

[0173] 1-(5-Fluoro-1H-indol-3-yl)-3-(7-(2-(4-fluorophenoxy)ethyl)-5,6,7,8-tetrahydro-1,7- naphthyridin-3-yl)urea (Compound I-17)

[0174]

[0175] Intermediate A-17 was prepared according to the procedure of Example 7, substituting 2-(4-fluorophenoxy)acetic acid for 4-(1,1 -difluoroethyl)benzoic acid. Compound I-17 was then prepared according to the procedure of Example 1, substituting Intermediate A-17 for 3-fluoro-4-trifluoromethylbenzyl bromide. 1H NMR (400 MHz, DMSO-d6) δ 10.86 (d, J = 2.6 Hz, 1H), 8.58 (s, 1H), 8.49 (s, 1H), 8.31 (d, J = 2.5 Hz, 1H), 7.73 (d, J = 2.4 Hz, 1H), 7.52 (d, J = 2.5 Hz, 1H), 7.32 (dd, J = 8.9, 4.5 Hz, 1H), 7.20 (dd, J = 9.9, 2.6 Hz, 1H), 7.14 - 7.04 (m, 2H), 6.98 - 6.87 (m, 3H), 4.13 (t, J = 5.7 Hz, 2H), 3.63 (s, 2H), 2.88 (t, J = 5.8 Hz, 2H), 2.82 - 2.74 (m, 4H). HRMS (ESI) calcd for C 25 H 23 F2N5O2[M+H] + 464.1893, found 464.1893.

[0176] Example 18

[0177] 1-(5-Fluoro-1H-indol-3-yl)-3-(7-(4-(trifluoromethoxy)phenethyl)-5,6,7,8- tetrahydro-1,7-naphthyridin-3-yl)urea (Compound I-18)

[0178]

[0179] Following the procedure of Example 7, intermediate A-18 was prepared by replacing 4-(1,1 -difluoroethyl)benzoic acid with 2-(4-(trifluoromethoxy)phenyl)acetic acid. Following the procedure of Example 1, Compound I-18 was prepared by replacing 3-fluoro-4-trifluoromethylbenzyl bromide with intermediate A-18. 1 H NMR (400 MHz, DMSO-d6) δ 10.88 (s, 1H), 8.68 (s, 1H), 8.59 (s, 1H), 8.35 (d, J = 2.5 Hz, 1H), 7.76 (d, J = 2.4 Hz, 1H), 7.66 (d, J = 8.5 Hz, 2H), 7.56 (d, J = 2.5 Hz, 1H), 7.34 (dd, J = 8.8, 4.5 Hz, 1H), 7.25 (dd, J = 9.8, 2.5 Hz, 1H), 7.17 (d, J = 8.6 Hz, 2H), 6.95 (td, J = 9.2, 2.6 Hz, 1H), 4.28 (t, J = 5.7 Hz, 2H), 3.67 (s, 2H), 2.95 (t, J = 5.6 Hz, 2H), 2.85 - 2.76 (m, 4H). HRMS (ESI) calcd for C 26 H 23F4N5O2 [M+H] + 514.1861, found 514.1861.

[0180] Example 19

[0181] 1-(7-(4-(Diifluoromethoxy)benzyl)-5,6,7,8-tetrahydro-1,7-naphthyridin-3-yl)-3-(5- fluoro-1 H-indol-3-yl)urea (Compound I-20)

[0182]

[0183] Following the procedure of Example 7, intermediate A-19 was prepared by replacing 4-(1,1 -difluoroethyl)benzoic acid with 2-(4-(trifluoromethyl)phenoxy)acetic acid. Following the procedure of Example 1, Compound I-19 was prepared by replacing 3-fluoro-4- trifluoromethylbenzyl bromide with intermediate A-19. 1 H NMR (400 MHz, DMSO-d6) d 10.86 (s, 1 H), 8.59 (s, 1 H), 8.51 (s, 1 H), 8.31 (d, J = 2.5 Hz, 1 H), 7.72 (d, J = 2.5 Hz, 1 H), 7.52 (d, J = 2.5 Hz, 1 H), 7.41 - 7.36 (m, 2H), 7.32 (dd, J = 8.8, 4.5 Hz, 1 H), 7.28 - 7.18 (m, 3H), 6.92 (td, J = 9.2, 2.6 Hz, 1 H), 3.58 (s, 2H), 2.86 (t, J = 7.5 Hz, 2H), 2.77 (t, J = 5.6 Hz, 2H), 2.75 - 2.69 (m, 4H). HRMS (ESI) calcd for C 26 H 23 F4N5O2 [M+H] + 514.1861, found 514.1861.

[0184] Example 20

[0185] 1-(7-(4-(Diifluoromethoxy)benzyl)-5,6,7,8-tetrahydro-1,7-naphthyridin-3-yl)-3-(5- fluoro-1 H-indol-3-yl)urea (Compound I-20)

[0186]

[0187] Following the procedure of Example 7, intermediate A-20 was prepared by replacing 4-(1,1 -difluoroethyl)benzoic acid with 4-(difluoromethoxy)benzoic acid. Following the procedure of Example 1, Compound I-20 was prepared by replacing 3-fluoro-4- trifluoromethylbenzyl bromide with intermediate A-20.1 H NMR (300 MHz, DMSO-d6) δ 10.90 (s, 1H), 8.64 (s, 1H), 8.56 (s, 1H), 8.32 (d, J = 2.4 Hz, 1H), 7.77 (s, 1H), 7.55 (d, J = 2.5 Hz, 1H), 7.43 (d, J = 8.2 Hz, 2H), 7.34 (dd, J = 8.9, 4.5 Hz, 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.

[0188] Example 21

[0189] 1-(5-Fluoro-1H-indol-3-yl)-3-(7-(4-fluoro-3-(trifluoromethyl)benzyl)-5,6,7,8- tetrahydro-1,7-naphthyridin-3-yl)urea (Compound I-21)

[0190]

[0191] Compound I-21 was prepared according to the procedure of Reference Example 1, replacing 3-fluoro-4-trifluoromethylbenzyl bromide with 4-fluoro-3- (trifluoromethyl)benzyl bromide. 1 H NMR (400 MHz, DMSO-d6) δ 10.88 (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, 4.5 Hz, 1H), 7.27 (dd, J = 9.8, 2.6 Hz, 1H), 6.95 (td, J = 9.2, 2.6 Hz, 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.

[0192] Example 22

[0193] 1 -(5-Fluoro- 1 H-indol-3-yl)-3-(7-(3-(trifluoromethyl)benzyl)-5,6,7,8- tetrahydro- 1,7-naphthyridin-3-yl)urea (Compound I-22)

[0194]

[0195] Compound I-22 was prepared according to the procedures of Example 1 by replacing 3-fluoro-4-trifluoromethylbenzyl bromide with 3- trifluoromethylbenzyl bromide. 1 H NMR (300 MHz, DMSO-d6) δ 10.91 (s, 1H), 8.63 (s, 1H), 8.55 (s, 1H), 8.33 (d, J = 2.4 Hz, 1H), 7.77 (d, J = 2.4 Hz, 1H), 7.74 - 7.59 (m, 4H), 7.56 (d, J = 2.5 Hz, 1H), 7.35 (dd, J = 8.9, 4.5 Hz, 1H), 7.23 (dd, J = 9.9, 2.6 Hz, 1H), 6.95 (td, J = 9.2, 2.6 Hz, 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 25 H 21 F4N5O [M+H] + 484.1755, found 484.1752.

[0196] Example 23

[0197] 1 -(7-(3-( 1, 1 -difluoroethyl)benzyl)-5,6,7,8-tetrahydro- 1,7-naphthyridin-3-yl)-3-(5- fluoro- 1 H-indol-3-yl)urea (Compound I-23)

[0198]

[0199] Intermediate A-21 was prepared according to the procedures of Example 7 by replacing 4-(1,1 -difluoroethyl)benzoic acid with 3-(1,1 - difluoroethyl)benzoic acid. Compound I-23 was prepared according to the procedures of Example 1 by replacing 3-fluoro-4-trifluoromethylbenzyl bromide with Intermediate A-21. 1H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 8.62 (s, 1H), 8.53 (s, 1H), 8.33 (d, J = 2.4 Hz, 1H), 7.77 (d, J = 2.4 Hz, 1H), 7.60 - 7.44 (m, 5H), 7.34 (dd, J = 8.8, 4.5 Hz, 1H), 7.23 (dd, J = 9.9, 2.6 Hz, 1H), 6.95 (td, J = 9.1, 2.6 Hz, 1H), 3.75 (s, 2H), 3.53 (s, 2H), 2.82 (d, J = 6.0 Hz, 2H), 2.71 (d, J = 5.7 Hz, 2H), 1.98 (t, J = 18.9 Hz, 3H). HRMS (ESI) calcd for C 26 H 24 F3N5O [M+H] + 480.2006, found 480.2004.

[0200] Example 24

[0201] 1-(7-(3,4-Difluorobenzyl)-5,6,7,8-tetrahydro-1,7-naphthyridin-3-yl)-3-(5-fluoro-1H- indol-3-yl)urea (Compound I-24)

[0202]

[0203] Compound I-24 was prepared according to the procedure of Reference Example 1, replacing 3-fluoro-4-trifluoromethylbenzyl bromide with 3,4-difluorobenzyl bromide. 1 H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 8.62 (s, 1H), 8.53 (s, 1H), 8.33 (d, J = 2.4 Hz, 1H), 7.77 (d, J = 2.4 Hz, 1H), 7.60 - 7.44 (m, 5H), 7.34 (dd, J = 8.8, 4.5 Hz, 1H), 7.23 (dd, J = 9.9, 2.6 Hz, 1H), 6.95 (td, J = 9.1, 2.6 Hz, 1H), 3.75 (s, 2H), 3.53 (s, 2H), 2.82 (d, J = 6.0 Hz, 2H), 2.71 (d, J = 5.7 Hz, 2H), 1.98 (t, J = 18.9 Hz, 3H). HRMS (ESI) calcd for C 24 H 20 F3N5O [M+H] + 452.1693, found 452.1691.

[0204] Example 25

[0205] 1-(7-(3-(Difluoromethoxy)benzyl)-5,6,7,8-tetrahydro-1,7-naphthyridin-3-yl)-3-(5-fluoro- 1H-indol-3-yl)urea (Compound I-25)

[0206]

[0207] Compound I-25 was prepared according to the procedure of Example 1 by replacing 3-fluoro-4-trifluoromethylbenzyl bromide with 3-(difluoromethoxy)benzyl bromide. 1 H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 8.73 (s, 1H), 8.65 (s, 1H), 8.35 (s, 1H), 7.78 (s, 1H), 7.56 (d, J = 2.5 Hz, 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, 2.5 Hz, 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.

[0208] Example 26

[0209] 1-(7-(3-chloro-4-(trifluoromethoxy)benzyl)-5,6,7,8-tetrahydro-1,7-naphthyridin-3-yl)-3-(5-fluoro-1H-indol-3-yl)urea (Compound I-26)

[0210]

[0211] Synthesis of Intermediate A-21

[0212] Intermediate A-21 was prepared according to the procedure of Example 1 by replacing 3-fluoro-4-trifluoromethylbenzyl bromide with 3-chloro-4- trifluoromethoxybenzyl bromide.

[0213] Synthesis of Intermediate A-22

[0214] Intermediate A-21 (178 mg, 0.5 mmol) was added to glacial acetic acid (0.5 mL), and 33% hydrobromic acid in acetic acid (6 mL) was added dropwise. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, 2N NaOH was slowly added under ice bath conditions to adjust the pH to about 8. The organic phase was extracted with ethyl acetate (3 mL x 3), washed with saturated brine (5 mL x 1), dried over anhydrous sodium sulfate, and the solvent was removed by reduced pressure evaporation. The residue was purified by column chromatography (dichloromethane / methanol = 30:1) to obtain Intermediate A-22 (yellow oily liquid, 114 mg).

[0215] Synthesis of compound 1-26

[0216] Compound 1-26 was prepared according to the procedure of Example 1 by replacing intermediate A-5 with intermediate A-22. 1 H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 8.65 (s, 1H), 8.56 (s, 1H), 8.34 (d, J = 2.4 Hz, 1H), 7.78 (d, J = 2.5 Hz, 1H), 7.68 (d, J = 2.0 Hz, 1H), 7.59 - 7.52 (m, 2H), 7.49 (dd, J = 8.4, 1.9 Hz, 1H), 7.35 (dd, J = 8.9, 4.5 Hz, 1H), 7.24 (dd, J = 9.8, 2.6 Hz, 1H), 6.95 (td, J = 9.1, 2.6 Hz, 1H), 3.73 (s, 2H), 3.53 (s, 2H), 2.83 (t, J = 5.9 Hz, 2H), 2.70 (t, J = 5.8 Hz, 2H). HRMS (ESI) calcd for C 25 H 20 ClF4N5O2[M+H] + 534.1314, found 534.1303.

[0217] Example 27

[0218] 1-(7-(4-bromo-3-fluorobenzyl)-5,6,7,8-tetrahydro-1,7-naphthyridin-3-yl)-3-(5-fluoro-1H- indol-3-yl)urea (Compound 1-27)

[0219]

[0220] Compound 1-27 was prepared according to the procedure of Example 26 by replacing 3-chloro-4-trifluoromethoxybenzyl bromide with 3-fluoro-4-bromobenzyl bromide. 1 H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 8.65 (s, 1H), 8.56 (s, 1H), 8.34 (d, J = 2.4 Hz, 1H), 7.78 (d, J = 2.5 Hz, 1H), 7.68 (d, J = 2.0 Hz, 1H), 7.59 - 7.52 (m, 2H), 7.49 (dd, J = 8.4, 1.9 Hz, 1H), 7.35 (dd, J = 8.9, 4.5 Hz, 1H), 7.24 (dd, J = 9.8, 2.6 Hz, 1H), 6.95 (td, J = 9.1, 2.6 Hz, 1H), 3.73 (s, 2H), 3.53 (s, 2H), 2.83 (t, J = 5.9 Hz, 2H), 2.70 (t, J = 5.8 Hz, 2H). HRMS (ESI) calcd for C 24 H20 BrF2N5O[M+H] + 512.0892, found 512.0880.

[0221] Example 28

[0222] 1-(5-Fluoro-1H-indol-3-yl)-3-(7-(2-(4-(trifluoromethoxy)phenoxy)ethyl)- 5,6,7,8-tetrahydro-1,7-naphthyridin-3-yl)urea (Compound I-28)

[0223]

[0224] Following the procedure of Example 7, intermediate A-23 was prepared by replacing 4-(1,1-difluoroethyl)benzoic acid with 2-(4-(trifluoromethoxy)phenoxy)acetic acid. Following the procedure of Example 1, Compound I-28 was prepared by replacing 3-fluoro-4-trifluoromethylbenzyl bromide with intermediate A-23. 1 H NMR (300 MHz, DMSO-d6) δ 10.90 (s, 1H), 8.65 (s, 1H), 8.56 (s, 1H), 8.34 (d, J = 2.4 Hz, 1H), 7.77 (d, J = 2.4 Hz, 1H), 7.56 (d, J = 2.5 Hz, 1H), 7.39 - 7.26 (m, 3H), 7.24 (dd, J = 9.9, 2.5 Hz, 1H), 7.13 - 7.06 (m, 2H), 6.95 (td, J = 9.2, 2.6 Hz, 1H), 4.21 (t, J = 5.6 Hz, 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.

[0225] Example 29

[0226] 1-(7-(3,5-Difluorobenzyl)-5,6,7,8-tetrahydro-1,7-naphthyridin-3-yl)-3-(5-fluoro- 1H-indol-3-yl)urea (Compound I-29)

[0227]

[0228] Following the procedure of Example 1, Compound I-29 was prepared by replacing 3-fluoro-4-trifluoromethylbenzyl bromide with 3,5-difluorobenzyl bromide. 1H NMR (400 MHz, DMSO-d6) δ 10.89 (d, J = 2.6 Hz, 1H), 8.61 (s, 1H), 8.52 (s, 1H), 8.34 (d, J = 2.5 Hz, 1H), 7.77 (d, J = 2.4 Hz, 1H), 7.55 (d, J = 2.5 Hz, 1H), 7.35 (dd, J = 8.8, 4.5 Hz, 1H), 7.23 (dd, J = 9.8, 2.5 Hz, 1H), 7.18 - 7.06 (m, 3H), 6.95 (td, J = 9.2, 2.6 Hz, 1H), 3.72 (s, 2H), 3.55 (s, 2H), 2.84 (t, J = 5.8 Hz, 2H), 2.70 (t, J = 5.8 Hz, 2H). HRMS (ESI) calcd for C 24 H 20 F3N5O [M+H] + 452.1693, found 452.1687.

[0229] Example 30

[0230] 1-(5-Fluoro-1H-indol-3-yl)-3-(7-(4-fluoro-3-(trifluoromethoxy)benzyl)-5,6,7,8- tetrahydro-1,7-naphthyridin-3-yl)urea (Compound 1-30)

[0231]

[0232] Compound 1-30 was prepared according to the procedure of Example 1, replacing 3-fluoro-4-trifluoromethylbenzyl bromide with 3-trifluoromethoxy-4-fluorobenzyl bromide. 1 H NMR (400 MHz, DMSO-d6) δ 10.89 (d, J = 2.6 Hz, 1H), 8.61 (s, 1H), 8.52 (s, 1H), 8.34 (d, J = 2.5 Hz, 1H), 7.77 (d, J = 2.4 Hz, 1H), 7.55 (d, J = 2.5 Hz, 1H), 7.35 (dd, J = 8.8, 4.5 Hz, 1H), 7.23 (dd, J = 9.8, 2.5 Hz, 1H), 7.18 - 7.06 (m, 3H), 6.95 (td, J = 9.2, 2.6 Hz, 1H), 3.72 (s, 2H), 3.55 (s, 2H), 2.84 (t, J = 5.8 Hz, 2H), 2.70 (t, J = 5.8 Hz, 2H). HRMS (ESI) calcd for C 25 H 20 F5N5O2 [M+H] + 518.1610, found 518.1598.

[0233] Example 31

[0234] 1-(7-(3,5-difluoro-4-(trifluoromethyl)benzyl)-5,6,7,8-tetrahydro-1,7- naphthyridin-3-yl)-3-(5-fluoro-1H-indol-3-yl)urea (Compound I-31)

[0235]

[0236] Compound I-31 was prepared according to the procedure of Example 1 by replacing 3-fluoro-4-trifluoromethylbenzyl bromide with 3,5-difluoro-4- trifluoromethylbenzyl bromide. 1 H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 8.64 (s, 1H), 8.55 (s, 1H), 8.34 (d, J = 2.4 Hz, 1H), 7.78 (d, J = 2.5 Hz, 1H), 7.56 (d, J = 2.6 Hz, 1H), 7.41 (d, J = 11.3 Hz, 2H), 7.35 (dd, J = 8.9, 4.5 Hz, 1H), 7.23 (dd, J = 9.9, 2.7 Hz, 1H), 6.95 (td, J = 9.2, 2.5 Hz, 1H), 3.80 (s, 2H), 3.59 (s, 2H), 2.85 (t, J = 5.1 Hz, 2H), 2.71 (t, J = 5.8 Hz, 2H). HRMS (ESI) calcd for C 25 H 19 F6N5O [M+H] + 520.1567, found 520.1556.

[0237] Example 32

[0238] 1-(5-Fluoro-1H-indol-3-yl)-3-(7-(3-fluoro-5-(trifluoromethoxy)benzyl)-5,6,7,8- tetrahydro-1,7-naphthyridin-3-yl)urea (Compound I-32)

[0239]

[0240] Compound I-32 was prepared according to the procedure of Example 1 by replacing 3-fluoro-4-trifluoromethylbenzyl bromide with 3-fluoro-5- trifluoromethoxybenzyl bromide. 1H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 8.61 (s, 1H), 8.52 (s, 1H), 8.34 (d, J = 2.4 Hz, 1H), 7.76 (d, J = 2.4 Hz, 1H), 7.56 (d, J = 2.5 Hz, 1H), 7.35 (dd, J = 8.8, 4.5 Hz, 1H), 7.31 - 7.26 (m, 2H), 7.23 (dd, J = 9.9, 2.5 Hz, 1H), 7.20 - 7.17 (m, 1H), 7.12 - 7.06 (m, 2H), 6.95 (td, J = 9.1, 2.6 Hz, 1H), 3.53 (s, 2H), 2.82 (t, J = 5.8 Hz, 2H), 2.69 - 2.58 (m, 4H), 2.49 - 2.44 (m, 2H), 1.88 - 1.77 (m, 2H). HRMS (ESI) calcd for C 25 H 20 F5N5O2[M+H] + 518.1610, found 518.1560.

[0241] Example 33

[0242] 1-(7-(3-(4-(diifluoromethoxy)phenyl)propyl)-5,6,7,8-tetrahydro-1,7-naphthyridin-3-yl)-3-(5- fluoro-1 H-indol-3-yl)urea (Compound 1-33)

[0243]

[0244] Following the procedure of Example 7, intermediate A-24 was prepared by replacing 4-(1,1 -difluoroethyl)benzoic acid with 3-(4-(difluoromethoxy)phenyl)propanoic acid. Following the procedure of Example 1, Compound 1-33 was prepared by replacing 3-fluoro-4- trifluoromethylbenzyl bromide with intermediate A-24. 1 H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 8.61 (s, 1H), 8.52 (s, 1H), 8.34 (d, J = 2.4 Hz, 1H), 7.76 (d, J = 2.4 Hz, 1H), 7.56 (d, J = 2.5 Hz, 1H), 7.35 (dd, J = 8.8, 4.5 Hz, 1H), 7.31 - 7.26 (m, 2H), 7.23 (dd, J = 9.9, 2.5 Hz, 1H), 7.20 - 7.17 (m, 1H), 7.12 - 7.06 (m, 2H), 6.95 (td, J = 9.1, 2.6 Hz, 1H), 3.53 (s, 2H), 2.82 (t, J = 5.8 Hz, 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 26F3N5O2 [M+H] + 510.2111, found 510.2102.

[0245] Example 34

[0246] 1-(5-Fluoro-1H-indol-3-yl)-3-(7-(4-(trifluoromethyl)benzyl)-5,6,7,8-tetrahydro- 2,7-naphthyridin-3-yl)urea (Compound I-34)

[0247]

[0248] Compound I-34 was prepared according to the procedure of Example 4, replacing 2-amino-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylic acid tert-butyl ester with 6-amino-3,4-dihydro-2,7-naphthyridine-2(1 H)-carboxylic acid tert-butyl ester (CAS: 1393561-07-3), 4-trifluoromethylthiobenzyl bromide with 4-trifluoromethylbenzyl bromide. 1 H NMR (300 MHz, DMSO-d6) δ 10.92 (s, 1H), 10.36 (s, 1H), 9.29 (s, 1H), 8.07 (s, 1H), 7.73 (d, J = 8.0 Hz, 2H), 7.66 - 7.57 (m, 4H), 7.36 (dd, J = 8.8, 4.5 Hz, 1H), 7.25 (s, 1H), 7.19 (dd, J = 9.7, 2.5 Hz, 1H), 6.96 (td, J = 9.2, 2.5 Hz, 1H), 3.78 (s, 2H), 3.55 (s, 2H), 2.84 (t, J = 5.5 Hz, 2H), 2.71 (t, J = 5.8 Hz, 2H). HRMS (ESI) calcd for C 25 H 21 F4N5O [M+H] + 484.1755, found 484.1748.

[0249] Example 35

[0250] 1-(5-Fluoro-1H-indol-3-yl)-3-(7-(4-(trifluoromethoxy)benzyl)-5,6,7,8-tetrahydro- 2,7-naphthyridin-3-yl)urea (Compound I-35)

[0251]

[0252] Compound I-35 was prepared according to the procedure of Example 34, replacing 4-trifluoromethylbenzyl bromide with 4-trifluoromethoxybenzyl bromide. 1H NMR (300 MHz, DMSO-d6) δ 10.92 (s, 1H), 10.37 (s, 1H), 9.29 (s, 1H), 8.07 (s, 1H), 7.61 (d, J = 2.5 Hz, 1H), 7.50 (d, J = 8.5 Hz, 2H), 7.40 - 7.30 (m, 3H), 7.25 (s, 1H), 7.19 (dd, J = 9.6, 2.5 Hz, 1H), 6.96 (td, J = 9.2, 2.5 Hz, 1H), 3.70 (s, 2H), 3.53 (s, 2H), 2.83 (t, J = 5.8 Hz, 2H), 2.68 (t, J = 5.4 Hz, 2H). HRMS (ESI) calcd for C 25 H 21 F4N5O2[M+H] + 500.1704, found 500.1697.

[0253] Example 36

[0254] 1 -(5-Chloro- 1 H-indol-3-yl)-3-(7-(3-(trifluoromethoxy)benzyl)-5,6,7,8- tetrahydro- 1,7-naphthyridin-3-yl)urea (Compound I-36)

[0255]

[0256] Compound I-36 was prepared according to the procedure of Example 6, substituting 5-fluoroindole for 5-fluoroindole. 1 H NMR (300 MHz, DMSO-d6) δ 10.92 (s, 1H), 10.37 (s, 1H), 9.29 (s, 1H), 8.07 (s, 1H), 7.61 (d, J = 2.5 Hz, 1H), 7.50 (d, J = 8.5 Hz, 2H), 7.40 - 7.30 (m, 3H), 7.25 (s, 1H), 7.19 (dd, J = 9.6, 2.5 Hz, 1H), 6.96 (td, J = 9.2, 2.5 Hz, 1H), 3.70 (s, 2H), 3.53 (s, 2H), 2.83 (t, J = 5.8 Hz, 2H), 2.68 (t, J = 5.4 Hz, 2H). HRMS (ESI) calcd for C 25 H 21 ClF3N5O2[M+H] + 516.1409, found 516.1407.

[0257] Example 37

[0258] 1 -(5-chloro- 1 H-indol-3-yl)-3-(7-(4-(trifluoromethoxy)benzyl)-5,6,7,8- tetrahydro- 1,7-naphthyridin-3-yl)urea (Compound 1-37)

[0259]

[0260] Compound 1-37 was prepared according to the procedure of Example 10, substituting 5-fluoroindole with 5-chloroindole. 1 HNMR (300 MHz, DMSO-d6) δ 11.00 (s, 1H), 8.63 (s, 1H), 8.58 (s, 1H), 8.33 (d, J = 2.5 Hz, 1H), 7.77 (d, J = 2.4 Hz, 1H), 7.55 (d, J = 2.3 Hz, 2H), 7.51 (d, J = 8.6 Hz, 2H), 7.40 - 7.31 (m, 3H), 7.10 (dd, J = 8.6, 2.1 Hz, 1H), 3.72 (s, 2H), 3.52 (s, 2H), 2.83 (t, J = 5.8 Hz, 2H), 2.69 (t, J = 5.7 Hz, 2H) HRMS (ESI) calcd for C 25 H 21 ClF3N5O2[M+H] + 516.1409, found 516.1408.

[0261] Example 38

[0262] 1 -(5-chloro- 1 H-indol-3-yl)-3-(7-(4-(trifluoromethoxy)benzyl)-5,6,7,8- tetrahydro- 1,7-naphthyridin-3-yl)urea (Compound 1-37)

[0263]

[0264] Compound 1-38 was prepared according to the procedure of Example 15, substituting 5-fluoroindole with 5-chloroindole. 1HNMR (300 MHz, DMSO-d6) δ 11.00 (s, 1H), 8.63 (s, 1H), 8.58 (s, 1H), 8.33 (d, J = 2.5 Hz, 1H), 7.77 (d, J = 2.4 Hz, 1H), 7.55 (d, J = 2.3 Hz, 2H), 7.51 (d, J = 8.6 Hz, 2H), 7.40 - 7.31 (m, 3H), 7.10 (dd, J = 8.6, 2.1 Hz, 1H), 3.72 (s, 2H), 3.52 (s, 2H), 2.83 (t, J = 5.8 Hz, 2H), 2.69 (t, J = 5.7 Hz, 2H). HRMS (ESI) calcd for C 25 H 20 ClF4N5O2[M+H] + 534.1314, found 534.1314.

[0265] Example 39

[0266] 1-(5-Chloro-1H-indol-3-yl)-3-(7-(3-fluoro-5-(trifluoromethoxy)benzyl)-5,6,7,8- tetrahydro-1,7-naphthyridin-3-yl)urea (Compound 1-39)

[0267]

[0268] Compound 1-39 was prepared according to the procedure described in Reference Example 32, replacing 5-fluoroindole with 5-chloroindole. 1 HNMR (400 MHz, DMSO-d6) δ 11.00 (d, J = 2.5 Hz, 1H), 8.63 (s, 1H), 8.59 (s, 1H), 8.34 (d, J = 2.4 Hz, 1H), 7.78 (d, J = 2.4 Hz, 1H), 7.55 (d, J = 2.3 Hz, 2H), 7.37 (d, J = 8.7 Hz, 1H), 7.34 - 7.24 (m, 3H), 7.10 (dd, J = 8.6, 2.1 Hz, 1H), 3.77 (s, 2H), 3.56 (s, 2H), 2.84 (t, J = 5.9 Hz, 2H), 2.70 (t, J = 6.0 Hz, 2H). HRMS (ESI) calcd for C 25 H 20 ClF4N5O2[M+H] + 534.1314, found 534.1315.

[0269] Example 40

[0270] 1 -(5-Fluoro- 1 H-indol-3-yl)-3-(7-(2-(4-(trifluoromethoxy)phenyl)acetyl)- 5,6,7,8-tetrahydro- 1,7-naphthyridin-3-yl)urea (Compound I-40)

[0271]

[0272]

[0273] Synthesis of Intermediate A-25

[0274] Intermediate A-3 (178 mg, 0.5 mmol) and triethylamine (152 mg, 1.5 mmol) were added to dichloromethane (3 mL), followed by addition of 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 reaction was allowed to proceed at room temperature for 5 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, the residue was diluted with water (3 mL), extracted with ethyl acetate (3 mL x 3), the organic phases were combined and washed with 1 N HCI (3 mL x 1), water (3 mL x 1) and saturated brine (5 mL x 1) in turn, dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol = 80: 1) to give Intermediate A-25 (yellow oily liquid, 180 mg).

[0275] Synthesis of Intermediate A-26

[0276] Intermediate A-25 (180 mg) and 10% palladium-carbon (18 mg) were added to methanol (3 mL), the hydrogen gas was replaced three times and the reaction was allowed to proceed at room temperature for 8 hours. After completion of the reaction, the mixture was filtered under suction and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol = 20: 1) to give Intermediate A-26 (white solid, 118 mg).

[0277] Synthesis of Compound I-40

[0278] Compound I-40 was prepared according to the method described in Reference Example 1, replacing Intermediate A-5 with Intermediate A-26. 1H NMR (400 MHz, DMSO-d6) δ 10.91 (d, J = 2.5 Hz, 1H), 8.69 (s, 1H), 8.56 (d, J = 3.5 Hz, 1H), 8.42 (dd, J = 15.6, 2.4 Hz, 1H), 7.83 (dd, J = 8.5, 2.4 Hz, 1H), 7.56 (d, J = 2.4 Hz, 1H), 7.43 - 7.26 (m, 5H), 7.24 (dd, J = 9.9, 2.5 Hz, 1H), 6.95 (td, J = 9.2, 2.5 Hz, 1H), 4.65 (d, J = 35.3 Hz, 2H), 3.90 (d, J = 2.1 Hz, 2H), 3.76 (dt, J = 18.0, 5.8 Hz, 2H), 2.86 - 2.73 (m, 2H). HRMS (ESI) calcd for C 26 H 21 F4N5O3 [M+H] + 528.1653, found 528.1654.

[0279] Example 41

[0280] 1-(5-Fluoro-1H-indol-3-yl)-3-(7-(2-(4-(trifluoromethoxy)phenoxy)acetyl)- 5,6,7,8-tetrahydro-1,7-naphthyridin-3-yl)urea (Compound I-41)

[0281]

[0282] Compound I-41 was prepared according to the procedure of Example 40, replacing 2-(4-(trifluoromethoxy)phenyl)acetic acid with 2-(4- (trifluoromethoxy)phenoxy)acetic acid. 1 H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 8.73 - 8.66 (m, 1H), 8.61 - 8.53 (m, 1H), 8.50 - 8.37 (m, 1H), 7.85 (dd, J = 19.4, 2.8 Hz, 1H), 7.56 (d, J = 2.5 Hz, 1H), 7.43 - 7.19 (m, 4H), 7.04 (dd, J = 8.9, 5.2 Hz, 2H), 6.95 (td, J = 9.1, 2.6 Hz, 1H), 5.06 - 3.85 (m, 2H), 4.73 - 4.52 (m, 2H), 3.75 (dt, J = 24.1, 5.7 Hz, 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.

[0283] Example 42

[0284] 1-(5-Fluoro-1H-indol-3-yl)-3-(7-(2-(4-(trifluoromethoxy)phenyl)acetyl)- 5,6,7,8-tetrahydro-1,7-naphthyridin-3-yl)urea (Compound I-42)

[0285]

[0286] Compound I-42 was prepared according to the procedure of Example 40, replacing 2-(4-(trifluoromethoxy)phenyl)acetic acid with 3-(4- (trifluoromethoxy)phenyl)propanoic acid. 1 H NMR (300 MHz, DMSO-d6) δ 10.91 (d, J = 2.6 Hz, 1H), 8.68 (s, 1H), 8.55 (d, J = 2.7 Hz, 1H), 8.42 (dd, J = 9.1, 2.4 Hz, 1H), 7.82 (dd, J = 6.9, 2.4 Hz, 1H), 7.56 (d, J = 2.5 Hz, 1H), 7.44 - 7.30 (m, 3H), 7.31 - 7.20 (m, 3H), 6.95 (td, J = 9.2, 2.5 Hz, 1H), 4.59 (s, 2H), 3.70 (q, J = 6.4 Hz, 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.

[0287] Example 43

[0288] 1-(5-Fluoro-1H-indol-3-yl)-3-(7-(4-(trifluoromethoxy)benzoyl)-5,6,7,8- tetrahydro-1,7-naphthyridin-3-yl)urea (Compound I-43)

[0289]

[0290] Compound I-43 was prepared according to the procedure of Example 40, replacing 2-(4-(trifluoromethoxy)phenyl)acetic acid with 4- trifluoromethoxybenzoic acid. 1H NMR (400 MHz, DMSO-d6) δ 10.91 (d, J = 2.6 Hz, 1H), 8.71 (s, 1H), 8.56 (s, 1H), 8.50 - 8.34 (m, 1H), 7.86 (s, 1H), 7.63 (d, J = 8.2 Hz, 2H), 7.56 (d, J = 2.5 Hz, 1H), 7.48 (d, J = 7.8 Hz, 2H), 7.35 (dd, J = 8.9, 4.5 Hz, 1H), 7.23 (dd, J = 9.8, 2.6 Hz, 1H), 6.95 (td, J = 9.2, 2.6 Hz, 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.

[0291] Example 44

[0292] 1-(5-Fluoro-1H-indol-3-yl)-3-(7-(2-(4-(trifluoromethyl)phenoxy)acetyl)- 5,6,7,8-tetrahydro-1,7-naphthyridin-3-yl)urea (Compound I-44)

[0293]

[0294] Compound I-44 was prepared according to the procedure described in Reference Example 40 by replacing 2-(4-(trifluoromethoxy)phenyl)acetic acid with 2-(4-(trifluoromethyl)phenoxy)acetic acid. 1H NMR (300 MHz, DMSO-d6) δ 10.92 (d, J = 2.6 Hz, 1H), 8.71 (s, 1H), 8.58 (d, J = 4.2 Hz, 1H), 8.44 (dd, J = 22.5, 2.4 Hz, 1H), 7.85 (dd, J = 14.8, 2.4 Hz, 1H), 7.64 (dd, J = 9.1, 2.9 Hz, 2H), 7.56 (d, J = 2.5 Hz, 1H), 7.35 (dd, J = 8.9, 4.5 Hz, 1H), 7.24 (dd, J = 9.9, 2.5 Hz, 1H), 7.13 (dd, J = 8.8, 2.4 Hz, 2H), 6.95 (td, J = 9.2, 2.6 Hz, 1H), 5.11 (s, 2H), 4.63 (d, J = 26.2 Hz, 2H), 3.72 (t, J = 5.8 Hz, 2H), 2.95 (t, J = 5.7 Hz, 1H), 2.79 (t, J = 5.1 Hz, 1H). HRMS (ESI) calcd for C 26 H 21 F4N5O3[M+H] + 528.1653, found 528.1648.

[0295] Example 45

[0296] 1-(5-Fluoro-1H-indol-3-yl)-3-(7-(2-(4-(trifluoromethyl)thio)phenoxy)acetyl)- 5,6,7,8-tetrahydro-1,7-naphthyridin-3-yl)urea (Compound I-45)

[0297]

[0298] Compound I-45 was prepared according to the procedure described in Reference Example 40 by replacing 2-(4-(trifluoromethoxy)phenyl)acetic acid with 2-(4- (trifluoromethylthio)phenoxy)acetic acid. 1H NMR (400 MHz, DMSO-d6) δ 10.90 (d, J = 2.6 Hz, 1H), 8.69 (s, 1H), 8.55 (d, J = 4.5 Hz, 1H), 8.44 (dd, J = 28.1, 2.4 Hz, 1H), 7.84 (dd, J = 19.7, 2.5 Hz, 1H), 7.67 - 7.58 (m, 2H), 7.56 (d, J = 2.4 Hz, 1H), 7.35 (dd, J = 8.8, 4.5 Hz, 1H), 7.23 (dd, J = 9.8, 2.5 Hz, 1H), 7.09 (dd, J = 9.0, 3.8 Hz, 2H), 6.95 (td, J = 9.2, 2.6 Hz, 1H), 5.08 (s, 2H), 4.62 (d, J = 31.7 Hz, 2H), 3.72 (t, J = 5.7 Hz, 3H), 2.94 (t, J = 5.9 Hz, 1H), 2.79 (t, J = 5.9 Hz, 1H). HRMS (ESI) calcd for C 26 H 21 F4N5O3S [M+H] + 560.1374, found 560.1368.

[0299] Example 46

[0300] 1-(5-Fluoro-1H-indol-3-yl)-3-(7-(5-(trifluoromethyl)pyridin-2-yl)-5,6,7,8- tetrahydro-1,7-naphthyridin-3-yl)urea (Compound I-46)

[0301]

[0302] Synthesis of Intermediate A-27

[0303] 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 into N,N-dimethylformamide (3 mL) and reacted at 100 °C for 3 h. After the reaction was completed, the residue was diluted with water (3 mL) and extracted with ethyl acetate (3 mL x 3). The combined organic phase was washed with water (3 mL x 1) and saturated brine (5 mL x 1) successively, dried over anhydrous sodium sulfate to give the crude product of Intermediate A-27 (white solid, 294 mg).

[0304] Synthesis of Compound I-46

[0305] According to the method of Example 1, Intermediate A-4 was replaced by Intermediate A-27 to give Compound I-46: 1H NMR (400 MHz, DMSO-d6) δ 10.89 (d, J = 2.6 Hz, 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 = 2.5 Hz, 1H), 7.35 (dd, J = 8.8, 4.5 Hz, 1H), 7.24 (dd, J = 9.8, 2.5 Hz, 1H), 7.05 (d, J = 9.1 Hz, 1H), 6.95 (td, J = 9.2, 2.6 Hz, 1H), 4.75 (s, 2H), 3.95 (t, J = 5.8 Hz, 2H), 2.92 (t, J = 5.8 Hz, 2H). HRMS (ESI) calcd for C 23 H 18 F4N6O [M+H] + 471.1551, found 471.1547.

[0306] Example 47

[0307] 1-(5-Fluoro-1H-indol-3-yl)-3-(7-(3-(4-(trifluoromethyl)phenyl)propionyl)- 5,6,7,8-tetrahydro-1,7-naphthyridin-3-yl)urea (Compound I-47)

[0308]

[0309] Compound I-47 was prepared according to the procedure of Example 40, replacing 2-(4-(trifluoromethoxy)phenyl)acetic acid with 2-(4-(trifluoromethyl)phenyl)propanoic acid. 1 H NMR (400 MHz, DMSO-d6) δ 10.89 (d, J = 2.6 Hz, 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 = 2.5 Hz, 1H), 7.35 (dd, J = 8.8, 4.5 Hz, 1H), 7.24 (dd, J = 9.8, 2.5 Hz, 1H), 7.05 (d, J = 9.1 Hz, 1H), 6.95 (td, J = 9.2, 2.6 Hz, 1H), 4.75 (s, 2H), 3.95 (t, J = 5.8 Hz, 2H), 2.92 (t, J = 5.8 Hz, 2H). HRMS (ESI) calcd for C 27 H23 F4N5O2[M+H] + 526.1861, found 526.1854.

[0310] Example 48

[0311] 1-(5-Fluoro-1H-indol-3-yl)-3-(7-(2-(4-(trifluoromethyl)phenyl)acetyl)- 5,6,7,8-tetrahydro-1,7-naphthyridin-3-yl)urea (Compound I-48)

[0312]

[0313] Compound I-48 was prepared according to the procedure described in Reference Example 40, by replacing 2-(4-(trifluoromethoxy)phenyl)acetic acid with 2-(4-(trifluoromethyl)phenyl)acetic acid. 1 H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 8.68 (s, 1H), 8.55 (d, J = 4.5 Hz, 1H), 8.42 (dd, J = 15.9, 2.4 Hz, 1H), 7.83 (dd, J = 9.2, 2.4 Hz, 1H), 7.71 - 7.60 (m, 2H), 7.56 (s, 1H), 7.48 (dd, J = 14.2, 7.9 Hz, 2H), 7.35 (dd, J = 8.8, 4.5 Hz, 1H), 7.24 (dd, J = 9.9, 2.4 Hz, 1H), 6.95 (td, J = 9.2, 2.6 Hz, 1H), 4.65 (d, J = 34.7 Hz, 2H), 3.97 (s, 2H), 3.76 (dt, J = 17.2, 5.9 Hz, 2H), 2.80 (dt, J = 15.0, 5.8 Hz, 2H). HRMS (ESI) calcd for C 26 H 21 F4N5O2[M+H] + 512.1704, found 512.1699.

[0314] Example 49

[0315] 1-(5-Fluoro-1H-indol-3-yl)-3-(7-((4-(trifluoromethoxy)phenethyl)sulfonyl)- 5,6,7,8-tetrahydro-1,7-naphthyridin-3-yl)urea (Compound I-49)

[0316]

[0317] Synthesis of Intermediate A-28

[0318] Intermediate A-28 was prepared according to the following procedure. Intermediate A-29 was prepared according to the following procedure. Intermediate A-29 (178 mg, 0.5 mmol), intermediate A-4 (178 mg, 0.5 mmol), triethylamine (0.1 mL, 0.7 mmol) were added to dichloromethane, and intermediate A-28 was added slowly. The reaction was stirred at room temperature for 5 hours. After the reaction was completed, the solvent was removed by evaporation under reduced pressure, and the residue was diluted with water (3 mL) and extracted with ethyl acetate (3 mL x 3). The combined organic phase was washed with 1 N HC1 (3 mL x 1), water (3 mL x 1), and saturated brine (5 mL x 1) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol = 80: 1) to give intermediate A-29 (white solid, 198 mg).

[0319] Synthesis of intermediate A-29

[0320] Intermediate A-28 was prepared according to the following procedure. Intermediate A-29 was prepared according to the following procedure. Intermediate A-29 (178 mg, 0.5 mmol), intermediate A-4 (178 mg, 0.5 mmol), triethylamine (0.1 mL, 0.7 mmol) were added to dichloromethane, and intermediate A-28 was added slowly. The reaction was stirred at room temperature for 5 hours. After the reaction was completed, the solvent was removed by evaporation under reduced pressure, and the residue was diluted with water (3 mL) and extracted with ethyl acetate (3 mL x 3). The combined organic phase was washed with 1 N HC1 (3 mL x 1), water (3 mL x 1), and saturated brine (5 mL x 1) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol = 80: 1) to give intermediate A-29 (white solid, 198 mg).

[0321] Synthesis of compound I-49

[0322] Compound I-49 was prepared according to the method of Example 1, replacing intermediate A-4 with intermediate A-29. 1 H NMR (400 MHz, DMSO-d6) δ 10.90 (d, J = 2.6 Hz, 1H), 8.69 (s, 1H), 8.55 (s, 1H), 8.42 (d, J = 2.5 Hz, 1H), 7.84 (d, J = 2.4 Hz, 1H), 7.55 (d, J = 2.5 Hz, 1H), 7.45 (d, J = 8.6 Hz, 2H), 7.34 (dd, J = 8.9, 4.5 Hz, 1H), 7.29 (d, J = 8.2 Hz, 2H), 7.23 (dd, J = 9.9, 2.6 Hz, 1H), 6.95 (td, J = 9.2, 2.5 Hz, 1H), 4.38 (s, 2H), 3.51 (td, J = 8.2, 7.1, 4.4 Hz, 4H), 3.09 - 2.99 (m, 2H), 2.89 (t, J = 5.9 Hz, 2H). HRMS (ESI) calcd for C 26 H23 F4N5O4S [M+H] + 578.1480, found 578.1472.

[0323] Example 50

[0324] 1-(5-Fluoro-1H-indol-3-yl)-3-(7-((4-(trifluoromethoxy)benzyl)sulfonyl)- 5,6,7,8-tetrahydro-1,7-naphthyridin-3-yl)urea (Compound I-50)

[0325]

[0326] Compound I-50 was prepared according to the procedure of Example 49, replacing 1-(2-bromoethyl)-4-(trifluoromethoxy)benzene with 4- trifluoromethoxybenzyl bromide. 1 H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 8.70 (s, 1H), 8.56 (s, 1H), 8.40 (d, J = 2.4 Hz, 1H), 7.82 (d, J = 2.4 Hz, 1H), 7.60 - 7.51 (m, 3H), 7.40 - 7.31 (m, 3H), 7.23 (dd, J = 9.9, 2.5 Hz, 1H), 6.95 (td, J = 9.2, 2.6 Hz, 1H), 4.61 (s, 2H), 4.31 (s, 2H), 3.42 (t, J = 5.8 Hz, 2H), 2.82 (t, J = 5.9 Hz, 2H). HRMS (ESI) calcd for C 25 H 21 F4N5O4S [M+H] + 564.1323, found 564.1315.

[0327] Example 51

[0328] 1-(5-Fluoro-1H-indol-3-yl)-3-(7-((4-(trifluoromethyl)benzyl)sulfonyl)- 5,6,7,8-tetrahydro-1,7-naphthyridin-3-yl)urea (Compound I-51)

[0329]

[0330] Compound I-51 was prepared according to the procedure of Example 49, replacing 1-(2-bromoethyl)-4-(trifluoromethoxy)benzene with 4- trifluoromethylbenzyl bromide. 1H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 8.70 (s, 1H), 8.56 (s, 1H), 8.40 (d, J = 2.4 Hz, 1H), 7.83 (d, J = 2.4 Hz, 1H), 7.74 (d, J = 8.1 Hz, 2H), 7.66 (d, J = 8.0 Hz, 2H), 7.55 (d, J = 2.5 Hz, 1H), 7.35 (dd, J = 8.8, 4.5 Hz, 1H), 7.23 (dd, J = 9.9, 2.6 Hz, 1H), 6.95 (td, J = 9.2, 2.6 Hz, 1H), 4.70 (s, 2H), 4.33 (s, 2H), 3.44 (t, J = 5.9 Hz, 2H), 2.84 (t, J = 5.8 Hz, 2H). HRMS (ESI) calcd for C 25 H 21 F4N5O3S [M+H] + 548.1374, found 548.1368.

[0331] Example 52

[0332] 1-(5-Fluoro-1H-indol-3-yl)-3-(7-((4-(trifluoromethoxy)phenyl)sulfonyl)- 5,6,7,8-tetrahydro-1,7-naphthyridin-3-yl)urea (Compound I-52)

[0333]

[0334] Compound I-52 was prepared according to the procedure described in Reference Example 49, by replacing intermediate A-28 with 4-trifluoromethoxybenzenesulfonyl chloride. 1 H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 8.69 (s, 1H), 8.56 (s, 1H), 8.40 (d, J = 2.4 Hz, 1H), 8.03 - 7.94 (m, 2H), 7.78 (d, J = 2.4 Hz, 1H), 7.62 (d, J = 8.3 Hz, 2H), 7.54 (d, J = 2.5 Hz, 1H), 7.34 (dd, J = 8.8, 4.5 Hz, 1H), 7.22 (dd, J = 9.8, 2.6 Hz, 1H), 6.94 (td, J = 9.2, 2.6 Hz, 1H), 4.19 (s, 2H), 3.38 (t, J = 5.9 Hz, 4H), 2.87 (t, J = 6.0 Hz, 2H). HRMS (ESI) calcd for C 24 H 19 F4N5O4S [M+H] + 550.1167, found 550.1160.

[0335] Example 53

[0336] 1-(5-Fluoro-1H-indol-3-yl)-3-(7-((1s,4s)-4-(trifluoromethyl)cyclohexane-1- carbonyl)-5,6,7,8-tetrahydro-1,7-naphthyridin-3-yl)urea (Compound I-53)

[0337]

[0338] Compound I-53 was prepared according to the procedure of Example 40, replacing 2-(4-(trifluoromethoxy)phenyl)acetic acid with trans-4-(trifluoromethyl)cyclohexanecarboxylic acid. 1 H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 8.68 (s, 1H), 8.55 (d, J = 5.7 Hz, 1H), 8.43 (dd, J = 24.9, 2.4 Hz, 1H), 7.82 (dd, J = 22.0, 2.6 Hz, 1H), 7.56 (d, J = 2.5 Hz, 1H), 7.35 (dd, J = 8.9, 4.5 Hz, 1H), 7.24 (dd, J = 9.9, 2.6 Hz, 1H), 6.95 (td, J = 9.2, 2.6 Hz, 1H), 4.62 (d, J = 49.7 Hz, 2H), 3.74 (dt, J = 23.6, 5.9 Hz, 2H), 2.87 (t, J = 5.8 Hz, 1H), 2.76 (q, J = 7.7, 6.0 Hz, 2H), 2.28 (p, J = 9.4 Hz, 1H), 1.89 (d, J = 10.8 Hz, 2H), 1.77 (t, J = 15.7 Hz, 2H), 1.55 - 1.32 (m, 4H). HRMS (ESI) calcd for C 25 H 25 F4N5O2[M+H] + 504.2017, found 504.2014.

[0339] Example 54

[0340] 1-(5-Fluoro-1H-indol-3-yl)-3-(7-(6-(trifluoromethyl)pyridazin-3-yl)-5,6,7,8- tetrahydro-1,7-naphthyridin-3-yl)urea (Compound I-54)

[0341]

[0342] Compound I-54 was prepared according to the procedure of Example 46, replacing 2- fluoro-5-trifluoromethylpyridine with 2-fluoro-5-trifluoromethylpyridazine. 1H NMR (400 MHz, DMSO-d6) δ 10.90 (d, J = 2.6 Hz, 1H), 8.73 (s, 1H), 8.58 (s, 1H), 8.46 (d, J = 2.5 Hz, 1H), 7.88 (d, J = 2.4 Hz, 1H), 7.84 (d, J = 9.7 Hz, 1H), 7.56 (d, J = 2.5 Hz, 1H), 7.52 (d, J = 9.7 Hz, 1H), 7.35 (dd, J = 8.9, 4.5 Hz, 1H), 7.24 (dd, J = 9.8, 2.5 Hz, 1H), 6.95 (td, J = 9.2, 2.5 Hz, 1H), 4.85 (s, 2H), 4.04 (t, J = 5.8 Hz, 2H), 2.97 (t, J = 5.8 Hz, 2H). HRMS (ESI) calcd for C 22 H 17 F4N7O [M+H] + 472.1503, found 472.1500.

[0343] Example 55

[0344] 1-(5-Fluoro-1H-indol-3-yl)-3-(7-(5-(trifluoromethyl)pyrimidin-2-yl)-5,6,7,8- tetrahydro-1,7-naphthyridin-3-yl)urea (Compound I-55)

[0345]

[0346] Compound I-55 was prepared according to the procedure described in Reference Example 46, by replacing 2-fluoro-5-trifluoromethylpyridine with 2-fluoro-5- trifluoromethylpyrimidine. 1 H NMR (400 MHz, DMSO-d6) δ 10.90 (d, J = 2.6 Hz, 1H), 8.73 (s, 1H), 8.58 (s, 1H), 8.46 (d, J = 2.5 Hz, 1H), 7.88 (d, J = 2.4 Hz, 1H), 7.84 (d, J = 9.7 Hz, 1H), 7.56 (d, J = 2.5 Hz, 1H), 7.52 (d, J = 9.7 Hz, 1H), 7.35 (dd, J = 8.9, 4.5 Hz, 1H), 7.24 (dd, J = 9.8, 2.5 Hz, 1H), 6.95 (td, J = 9.2, 2.5 Hz, 1H), 4.85 (s, 2H), 4.04 (t, J = 5.8 Hz, 2H), 2.97 (t, J = 5.8 Hz, 2H). HRMS (ESI) calcd for C 22 H 17 F4N7O [M+H] + 472.1503, found 472.1500.

[0347] Example 56

[0348] 1-(5-Fluoro-1H-indol-3-yl)-3-(7-(5-(trifluoromethyl)pyrazin-2-yl)-5,6,7,8- tetrahydro-1,7-naphthyridin-3-yl)urea (Compound I-56)

[0349]

[0350] Compound I-56 was prepared according to the procedure described in Reference Example 46 by replacing 2-fluoro-5-trifluoromethylpyridine with 2-fluoro-5- trifluoromethylpyrazine. 1 H NMR (400 MHz, DMSO-d6) δ 10.90 (d, J = 2.6 Hz, 1H), 8.70 (s, 1H), 8.55 (d, J = 2.3 Hz, 2H), 8.53 (d, J = 1.5 Hz, 1H), 8.46 (d, J = 2.5 Hz, 1H), 7.87 (d, J = 2.4 Hz, 1H), 7.56 (d, J = 2.5 Hz, 1H), 7.35 (dd, J = 8.8, 4.5 Hz, 1H), 7.23 (dd, J = 9.8, 2.6 Hz, 1H), 6.95 (td, J = 9.2, 2.6 Hz, 1H), 4.82 (s, 2H), 4.01 (t, J = 5.8 Hz, 2H), 2.96 (t, J = 5.9 Hz, 2H). HRMS (ESI) calcd for C 22 H 17 F4N7O [M+H] + 472.1503, found 472.1499.

[0351] Example 57

[0352] 1-(7-(5-Chloropyrimidin-2-yl)-5,6,7,8-tetrahydro-1,7-naphthyridin-3-yl)-3-(5-fluoro- 1H-indol-3-yl)urea (Compound I-57)

[0353]

[0354] Compound I-57 was prepared according to the procedure described in Reference Example 46 by replacing 2-fluoro-5-trifluoromethylpyridine with 2-fluoro-5-chloropyrimidine. 1H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 8.72 (s, 1H), 8.54 (s, 1H), 8.48 (d, J = 2.4 Hz, 1H), 7.89 (d, J = 2.4 Hz, 1H), 7.56 (d, J = 2.5 Hz, 1H), 7.35 (dd, J = 8.8, 4.5 Hz, 1H), 7.23 (dd, J = 9.9, 2.6 Hz, 1H), 6.95 (td, J = 9.2, 2.6 Hz, 1H), 4.71 (s, 2H), 3.90 (t, J = 5.9 Hz, 2H), 3.02 (t, J = 5.9 Hz, 2H). HRMS (ESI) calcd for C 21 H 17 ClFN7O [M+H] + 438.1240, found 438.1238.

[0355] Example 58

[0356] 1-(5-Fluoro-1H-indol-3-yl)-3-(7-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)- 5,6,7,8-tetrahydro-1,7-naphthyridin-3-yl)urea (Compound I-58)

[0357]

[0358] Compound I-58 was prepared according to the procedure described in Reference Example 46, by replacing 2-fluoro-5-trifluoromethylpyridine with 2-bromo-5- (trifluoromethyl)-1,3,4-thiadiazole. 1 H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 8.72 (s, 1H), 8.54 (s, 1H), 8.48 (d, J = 2.4 Hz, 1H), 7.89 (d, J = 2.4 Hz, 1H), 7.56 (d, J = 2.5 Hz, 1H), 7.35 (dd, J = 8.8, 4.5 Hz, 1H), 7.23 (dd, J = 9.9, 2.6 Hz, 1H), 6.95 (td, J = 9.2, 2.6 Hz, 1H), 4.71 (s, 2H), 3.90 (t, J = 5.9 Hz, 2H), 3.02 (t, J = 5.9 Hz, 2H). HRMS (ESI) calcd for C 20 H 15 F4N7OS [M+H] + 478.1068, found 478.1067.

[0359] Example 59

[0360] 1 -(5-Fluoro- 1 H-indol-3-yl)-3-(7-(6-(trifluoromethyl)pyrazin-2-yl)-5,6,7,8- tetrahydro- 1,7-naphthyridin-3-yl)urea (Compound I-59)

[0361]

[0362] Compound I-59 was prepared according to the procedure described in Reference Example 46, by replacing 2-fluoro-5-trifluoromethylpyridine with 2-chloro-6- (trifluoromethyl)pyrazine. 1 H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 8.71 (s, 1H), 8.56 (s, 1H), 8.47 (d, J = 2.5 Hz, 1H), 8.39 (d, J = 6.3 Hz, 1H), 7.88 (d, J = 2.4 Hz, 1H), 7.56 (d, J = 2.5 Hz, 1H), 7.35 (dd, J = 8.8, 4.5 Hz, 1H), 7.24 (dd, J = 9.9, 2.5 Hz, 1H), 7.18 (d, J = 6.3 Hz, 1H), 6.95 (td, J = 9.1, 2.6 Hz, 1H), 4.78 (s, 2H), 3.97 (s, 2H), 2.94 (t, J = 5.9 Hz, 2H). HRMS (ESI) calcd for C 22 H 17 F4N7O [M-H] + 470.1352, found 470.1361.

[0363] Example 60

[0364] 1 -(7-(4-Cyano-5-(trifluoromethyl)pyridin-2-yl)-5,6,7,8-tetrahydro- 1,7-naphthyridin-3- yl)-3-(5-fluoro- 1 H-indol-3-yl)urea (Compound I-60)

[0365]

[0366] Compound I-60 was prepared according to the procedure described in Reference Example 46, by replacing 2-fluoro-5-trifluoromethylpyridine with 2-chloro-5- (trifluoromethyl)isonicotinonitrile. 1H NMR (400 MHz, DMSO-d6) δ 10.95 (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 = 2.5 Hz, 1H), 7.36 (dd, J = 8.9, 4.5 Hz, 1H), 7.30 (dd, J = 9.9, 2.5 Hz, 1H), 6.96 (td, J = 9.1, 2.6 Hz, 1H), 5.01 (s, 2H), 4.02 (t, J = 5.8 Hz, 2H), 3.04 (t, J = 5.8 Hz, 2H). HRMS (ESI) calcd for C 24 H 17 F4N7O[M-H] + 494.1352, found 494.1362.

[0367] Example 61

[0368] Evaluation of the inhibitory activity of compounds on the STING signaling pathway of THP1-Dual cells

[0369] Principle of experiment: THP1-Dual is a commercial dual reporter gene detection cell for NF-κB and IRF signaling pathways. Among them, the transcriptional activity of the IRF signaling pathway can be evaluated by detecting the secreted luciferase. At the same time, this cell expresses cGAS and STING protein, and the introduction of exogenous 2’,3’-cGAMP can directly activate the STING signaling pathway, thereby enhancing the transcriptional activity of IRF. Therefore, by activating the STING-IRF signaling pathway in the cell by transfecting exogenous 2’,3’-cGAMP, after adding compounds to interfere with the STING signaling pathway, the inhibitory activity of the compounds on STING can be evaluated by detecting the secreted luciferase.

[0370] Experimental reagents and materials: heat-inactivated serum (Biological Industries), 1640 medium (Biological Industries), penicillin-streptomycin double antibody (Biological Industries), THP1-Dual TM Cells (InvivoGen), 2’,3’-cGAMP (Targetmol, prepared as a 1 mg / mL stock solution), Opti-MEM (Gibco), Lipo6000 (Beyotime), QUANTI-Luc TM (InvivoGen).

[0371] Experimental method: (1) Cell plating: well-grown THP1-Dual cells were centrifuged, resuspended and counted. The cell suspension was mixed with the previously prepared 2', 3'-cGAMP working solution (for example: 2 μg of 2', 3'-cGAMP storage solution was mixed with 4 μL of Lipo6000 in 0.5 mL of Opti-MEM, and the mixture was allowed to stand at room temperature for 10 min to obtain a 2', 3'-cGAMP solution with a concentration of 2 μg / mL and a cell concentration of 400,000 cells / mL. 100 μL of the solution was added to the 96-well plate as the experimental well; and the control well was added with the corresponding cell solution without 2', 3'-cGAMP. (2) Cell administration: the test compound was prepared into a 10 mM storage solution, which was diluted with the culture medium to obtain a drug solution with a test concentration, and 100 μL of the drug solution was sequentially added to the experimental well, and 100 μL of the culture medium was added to the control well and the model well. After incubation in the incubator for 16-18 h, detection was performed. (3) Detection: the QUANTI-Luc TM The powder was prepared into a detection solution with purified water according to the instructions, and the detection solution was divided and stored at 4°C. 10 μL of the detection solution was added to a white non-transparent 384-well plate. The 96-well plate with cultured cells was taken out and centrifuged at 1000 rpm for 1 min with a microplate centrifuge, and then 4 μL of supernatant was sequentially taken and added to the 96-well plate with the detection solution. The chemiluminescence was detected by using an enzyme-labeled instrument. (4) Data processing: the inhibition rate of the compound at a fixed concentration was calculated according to the following formula: the inhibition rate of the compound at a certain concentration = 1- (the chemiluminescence value of the compound well at a certain concentration-the chemiluminescence value of the control well) / (the chemiluminescence value of the model well-the chemiluminescence value of the control well) x 100%; and then a curve was fitted according to the inhibition rates of the compound at different concentrations to calculate the half inhibitory concentration (IC 50 value) of the compound. Experimental results: the inhibition activity of the compound on the 2', 3'-cGAMP stimulated activation of the THP-1 Dual cell STING signal pathway is shown in Table 2.

[0372] The test results (Table 2) show that the tetrahydro-1,7-naphthyridine compounds (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.) of the present application have strong STING inhibitory activity on the 2', 3'-cGAMP stimulated activation of the THP-1 Dual cell, and the IC 50 value of some compounds is less than 30 nM. Surprisingly, the tetrahydro-1,6-naphthyridine compounds (such as I-4, etc.) have weak activity.

[0373] Table 2. Test results of the inhibition activity of the compound on the THP-1 Dual cell STING

[0374]

[0375]

[0376]

[0377]

[0378]

[0379]

[0380]

[0381]

[0382] Example 62

[0383] Pharmacokinetic evaluation of the compound in rats

[0384] Experimental animals: 3 male SD rats, SPF level, from Beijing Vantoll Life.

[0385] Experimental method: 3 rats in the oral administration group were administered orally at a dose of 20 mg / kg. The rats were fasted for 12 hours before oral administration, and fed 4 hours after administration. After oral administration, the rats were taken blood from the orbit about 0.2 mL at 0.25, 0.5, 1, 2, 4, 6, 8, 24 hours, respectively, and ethylenediamine tetraacetate disodium salt was added quickly after blood collection. After blood collection, the blood was placed on ice. All samples were centrifuged at 18000g for 7 minutes in a low-temperature centrifuge, and plasma was separated. The content of the compound in the plasma was detected by LC-MS / MS, and the relevant pharmacokinetic parameters were calculated according to the blood drug concentration data at different time points. The experimental results are shown in Table 3.

[0386] The experimental results show that compounds I-2, I-10, I-15, etc. have a long oral half-life (T 1 / 2 ) and a high oral exposure (AUC), indicating that the above-mentioned compounds have good pharmacokinetic properties. Other compounds of the present application also have good pharmacokinetic properties.

[0387] Table 3. Pharmacokinetic parameters of the compound in rats

[0388]

[0389]

[0390] Example 63

[0391] Tablets

[0392] The compound I-1 (50 g) prepared in Example 1, hydroxypropyl methylcellulose E (150 g), starch (200 g), povidone K30 (appropriate amount), and magnesium stearate (1 g) were mixed, granulated, and tableted.

[0393] In addition, the compounds prepared in Examples 1 to 57 can be formulated into capsules, powders, tablets, granules, pills, injections, syrups, oral solutions, inhalants, ointments, solutions, creams, gels, powders, lotions, tinctures, suppositories, or patches according to the conventional formulation methods of Pharmacopoeia 2015 edition by using different pharmaceutical excipients.

Claims

1. A compound of Formula I: ###0001### or a pharmaceutically acceptable salt thereof, wherein: X is selected from CH or N; Y, Z and W are independently selected from N, CR1, or CR2R3; and R1 and R2 are independently selected from H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, C1-C6 alkylsulfonamide, C1-C6 haloalkylsulfonamide, C1-C6 alkylamino, C1-C6 haloalkylamino, C1-C6 alkylcarbonyl, C1-C6 haloalkylcarbonyl, C1-C6 alkoxycarbonyl, C1-C6 haloalkoxycarbonyl, C1-C6 alkylaminocarbonyl, C1-C6 haloalkylaminocarbonyl, C1-C6 alkylcarbonyloxy, C1-C6 haloalkylcarbonyloxy, C1-C6 alkylcarbonylamino, C1-C6 haloalkylcarbonylamino, C1-C6 alkylcarbonylaminocarbonyl, C1-C6 haloalkylcarbonylaminocarbonyl, C1-C6 alkylcarbonylaminosulfonyl, C1-C6 haloalkylcarbonylaminosulfonyl, C1-C6 alkylsulfonylaminocarbonyl, C1-C6 haloalkylsulfonylaminocarbonyl, C1-C6 alkylsulfonylaminosulfonyl, C1-C6 haloalkylsulfonylaminosulfonyl, C1-C6 alkylcarbonylaminosulfonyl, C1-C6 haloalkylcarbonylaminosulfonyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylsulfonamide, C1-C6 haloalkylsulfonamide, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, C1-C6 alkylamino, C1-C6 haloalkylamino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylsulfonamide, C1-C6 haloalkylsulfonamide, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, C1-C6 alkylamino, C1-C6 haloalkylamino, C1-C6 alkylcarbonyl, C1-C6 haloalkylcarbonyl, C1-C6 alkoxycarbonyl, C1-C6 haloalkoxycarbonyl, C1-C6 alkylaminocarbonyl, C1-C6 haloalkylaminocarbonyl, C1-C6 alkylcarbonyloxy, C1-C6 haloalkylcarbonyloxy, C1-C6 alkylcarbonylamino, C1-C6 haloalkylcarbonylamino, C1-C6 alkylcarbonylaminocarbonyl, C1-C6 haloalkylcarbonylaminocarbonyl, C1-C6 alkylcarbonylaminosulfonyl, C1-C6 haloalkylcarbonylaminosulfonyl, C1-C6 alkylsulfonylaminocarbony ​ ​ ​ 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. ​ ​ ​ 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 ​ ​ 4. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, wherein ​ ​ ​ 7. Use according to claim 6, characterized in that, ​ ​ 9. A pharmaceutical composition for preventing or treating a STING-mediated disease, characterized by, ​ 10. Pharmaceutical composition according to claim 9, characterized in that ​

Images