Nitrogen heterocyclic compound and use thereof

Abstract

The present application provides a nitrogen heterocyclic compound or a pharmaceutically acceptable salt, solvate, hydrate, polymorphic substance, cocrystal, tautomer, stereoisomer or isotope compound thereof. The nitrogen heterocyclic compound has a structure represented by formula I. The nitrogen heterocyclic compound provided by the present application can be used for removing aging cells.

Description

Nitrogen heterocyclic compounds and their applications Technical Field

[0001] The present invention relates to the field of medicine, and in particular to a nitrogen heterocyclic compound capable of targeting and killing senescent cells, and its application in preventing or treating aging-related diseases. Background Art

[0002] As we age, senescent cells accumulate in our tissues and organs. These accumulated senescent cells are a key driver of aging and age-related diseases. On the one hand, the aging of some proliferating cells or stem cells can lead to a decline in the body's regenerative capacity, affecting the body's ability to recover and function properly. More importantly, senescent cells secrete a large number of inflammatory factors, known as the senescence-associated secretory phenotype (SASP), which creates a chronic inflammatory microenvironment, accelerates the aging process, and promotes the development of age-related diseases.

[0003] Given the relationship between senescent cells and disease, selective elimination of senescent cells is a promising therapeutic approach for treating aging-related diseases and improving the physiological functions of elderly individuals. The present disclosure addresses these needs and provides related advantages. Summary of the Invention

[0004] In order to solve at least one technical problem existing in the prior art, the present application provides a novel class of nitrogen heterocyclic compounds, which can selectively eliminate senescent cells.

[0005] In a first aspect, the present application provides a nitrogen heterocyclic compound or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer or isotope thereof, wherein the nitrogen heterocyclic compound has a structure shown in Formula I:

[0006] X1, X2, and X3 are each independently selected from CR g and N, and X1, X2, and X3 are not CR at the same time g ;

[0007] R a 、R b 、R c 、R d 、R e 、R f 、R g 、R h 、R i 、R j 、R kEach is independently selected from hydrogen, deuterium, a halogen-substituted or unsubstituted C1-C8 alkyl group, a halogen-substituted or unsubstituted C3-C8 cycloalkyl group, a halogen-substituted or unsubstituted C2-C8 alkenyl group, a halogen-substituted or unsubstituted C2-C8 alkynyl group, a halogen atom, a hydroxyl group, an amino group, a nitro group, a cyano group, a carboxyl group, an acyl group, and a halogen-substituted or unsubstituted C2-C8 alkoxy group;

[0008] Z is selected from O and N;

[0009] When Z is O, Y2 is absent, and Y1 is independently selected from hydrogen, deuterium, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, -R1-R2-R3, -R2-R3 or -R1-R3, wherein R1 is selected from substituted or unsubstituted C1-C 10 Alkylene, R2 is selected from -OC(O)- or -OC(O)-O-, and R3 is selected from substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C20 cycloalkyl, substituted or unsubstituted C2-C20 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted C1-C20 heteroaryl, or substituted or unsubstituted C2-C20 heteroalicyclic;

[0010] When Z is N, Y1 and Y2 are independently selected from hydrogen, deuterium, C1-C10 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C20 aryl, C1-C20 heteroaryl, C2-C20 heteroalicyclic, wherein C1-C10 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, wherein CH2 can be selected from -O-, -S-, -SO2-, -C(O)- and -NR 3-, the C1-C10 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C20 aryl, C1-C20 heteroaryl and C2-C20 heteroalicyclic groups are optionally replaced by halogen atoms, cyano groups, nitro groups, C6-C20 aryl, C1-C20 heteroaryl, C1-C10 alkoxy groups, C6-C20 aryloxy groups, C2-C20 heteroalicyclic groups, amino groups, hydroxyl groups, thiol groups, -substituted by one or more substituents in NR4R5; or

[0011] Y1 and Y2 together with the nitrogen atom to which they are attached constitute a heteroalicyclic group, preferably a C2-C20 heteroalicyclic group, which is optionally substituted by a halogen atom, a cyano group, a nitro group, a C6-C20 aryl group, a C1-C20 heteroaryl group, a C1-C10 alkoxy group, a C6-C20 aryloxy group, a C2-C20 heteroalicyclic group, an amino group, a hydroxyl group, a thiol group, -substituted by one or more substituents in NR4R5; or

[0012] Y1 is hydrogen or deuterium, and Y2 is selected from C1-C10 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C20 aryl, C1-C20 heteroaryl and C2-C20 heteroalicyclic group, wherein C1-C10 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, CH2 thereof may be replaced by one or more groups selected from -O-, -S-, -SO2-, -C(O)- and -NR3-, and the ... The C8 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C20 aryl, C1-C20 heteroaryl, or C2-C20 heteroalicyclic group is substituted with a halogen atom, a hydroxyl, a thiol, an amino, a nitro, a cyano, a carboxyl, an acyl, a C1-C10 alkoxy, a C6-C20 aryl, a C1-C20 heteroaryl, a C2-C20 heteroalicyclic group, a C1-C10 alkyl, a C2-C8 alkenyl, or a C2-C8 alkynyl group, and the substituents at at least two positions together constitute an aliphatic ring, a heteroalicyclic ring, an aromatic ring, or a heteroaromatic ring;

[0013] R4 and R5 are independently selected from hydrogen, deuterium, aryl, heteroaryl, C1-C8 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl and C2-C8 alkynyl, wherein the aryl and heteroaryl are optionally substituted with halogen atoms, hydroxyl, sulfhydryl, amino, nitro, cyano, carboxyl, acyl, alkoxy, aryl, heteroaryl, heteroalicyclic, C1-C10 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl or C2-C8 alkynyl, wherein the substituents at at least two positions together constitute an aliphatic ring, heteroalicyclic ring, aromatic ring or heteroaromatic ring;

[0014] Ring A is independently selected from substituted or unsubstituted aromatic or heteroaromatic rings;

[0015] Ring B is absent or independently selected from substituted or unsubstituted aromatic ring or heteroaromatic ring, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C6-C10 spirocycle, C6-C10 heterospirocycle, C6-C10 heterocondensed ring, C6-C10 heterocondensed ring;

[0016] L is absent or selected from C1-C6 alkylene, -C1-C6 alkylene-O- or -C1-C3 alkylene-O-C1-C3 alkylene-, wherein the alkylene is optionally substituted with a halogen atom, a hydroxyl group, a thiol group, an amino group, a nitro group, a cyano group, a carboxyl group, an acyl group, a C1-C10 alkoxy group, a C6-C20 aryl group, a C1-C20 heteroaryl group, a C2-C20 heteroalicyclic group, a C1-C10 alkyl group, a C3-C8 cycloalkyl group, a C2-C8 alkenyl group or a C2-C8 alkynyl group;

[0017] R is independently selected from an aromatic ring or a heteroaromatic ring, an aromatic ring and an aromatic heterocycle, a C3-C8 cycloalkane, a C3-C8 heterocycloalkane, a C6-C10 spirocycle, and a C6-C10 condensed cycloalkane; and the R is optionally substituted by a halogen atom, a hydroxyl group, a thiol group, an amino group, a nitro group, a cyano group, a carboxyl group, an acyl group, a C1-C10 alkoxy group, a C6-C20 aryl group, a C1-C20 heteroaryl group, a C2-C20 heteroalicyclic group, a C1-C10 alkyl group, a C3-C8 cycloalkyl group, a C2-C8 alkenyl group, or a C2-C8 alkynyl group.

[0018] In some embodiments, X3 is CR g .

[0019] In some embodiments, X1 is CR g , X2 is N.

[0020] In some embodiments, X1 is N, X2 is CR g .

[0021] In some embodiments, X3 is N, X1 and X2 are CR g .

[0022] In some embodiments, X1 is N, X2 and X3 are CR g .

[0023] In some embodiments, X2 is N, X1 and X3 are CR g。

[0024] In some embodiments, R a 、R b 、R c 、R d 、R e 、R f 、R g 、R h 、R i 、R j 、R k Each is independently selected from hydrogen, deuterium, halogen-substituted or unsubstituted C1-C6 chain alkyl, halogen-substituted or unsubstituted C3-C6 cycloalkyl, halogen-substituted or unsubstituted C2-C6 alkenyl, halogen-substituted or unsubstituted C2-C6 alkynyl, a halogen atom, a hydroxyl group, an amino group, a nitro group, a cyano group, a carboxyl group, a halogen-substituted or unsubstituted C2-C6 alkoxy group.

[0025] In some embodiments, R g It's hydrogen.

[0026] In some embodiments, R a 、R b 、R c 、R d 、R e、R f 、R g 、R h 、R i 、R j 、R k Each is independently selected from hydrogen, deuterium, halogen-substituted or unsubstituted C1-C6 chain alkyl, halogen-substituted or unsubstituted C3-C6 cycloalkyl, halogen atom, and C2-C6 alkoxy.

[0027] In some embodiments, R a 、R b 、R c 、R d 、R e 、R f 、R g 、R h 、R i 、R j 、R k All are hydrogen.

[0028] In some embodiments, Z is O, Y2 is absent, and Y1 is selected from hydrogen, deuterium, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, -R1-R2-R3, -R2-R3 or -R1-R3, wherein R1 is selected from substituted or unsubstituted C1-C 10 Alkylene, R2 is selected from -OC(O)- or -OC(O)-O-, and R3 is selected from substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C20 cycloalkyl, substituted or unsubstituted C2-C20 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted C1-C20 heteroaryl, or substituted or unsubstituted C2-C20 heteroalicyclic.

[0029] In some embodiments, Z is O, Y2 is absent, and Y1 is selected from hydrogen or deuterium.

[0030] In some embodiments, Z is O, Y2 is absent, and Y1 is selected from substituted or unsubstituted C1-C6 alkyl or substituted or unsubstituted C3-C 10 Cycloalkyl.

[0031] In some embodiments, Z is O, Y2 is absent, and Y1 is selected from -R1-R2-R3, -R2-R3, or -R1-R3.

[0032] In some embodiments, R1 is selected from substituted or unsubstituted C1-C6 alkylene, preferably substituted or unsubstituted C1-C3 alkylene, and more preferably methylene.

[0033] In some embodiments, R3 is selected from substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C2-C12 heteroaryl, or substituted or unsubstituted C1-C12 heteroalicyclic.

[0034] In some embodiments, R3 is selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C1-C10 heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C1-C10 heteroalicyclic.

[0035] In some embodiments, R3 is selected from the following groups:

[0036] In some embodiments, Z is N.

[0037] In some embodiments, Z is N, and Y1 and Y2 are independently selected from C1-C10 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C20 aryl, C1-C20 heteroaryl, C2-C20 heteroalicyclic, among which C1-C10 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, wherein CH2 can be replaced by one or more groups selected from -O-, -S-, -SO2-, -C(O)- and -NR3-.

[0038] In some embodiments, the C1-C10 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C20 aryl, C1-C20 heteroaryl and C2-C20 heteroalicyclic groups are optionally substituted by halogen atoms, cyano, nitro, C6-C20 aryl, C1-C20 heteroaryl, C1-C10 alkoxy, C6-C20 aryloxy, C2-C20 heteroalicyclic groups, amino, hydroxyl, thiol, -NR4R5 is substituted by one or more substituents.

[0039] In some embodiments, Y1 and Y2 together with the nitrogen atom to which they are attached constitute a heteroalicyclic group, preferably a C2-C20 heteroalicyclic group.

[0040] In some embodiments, Y1 is hydrogen, and Y2 is selected from C1-C10 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C20 aryl, C1-C20 heteroaryl and C2-C20 heteroalicyclic, wherein C1-C10 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, CH2 thereof may be replaced by one or more groups selected from -O-, -S-, -SO2-, -C(O)- and -NR3-, and the C1-C10 alkyl, The C3-C8 cycloalkyl group, C2-C8 alkenyl group, C2-C8 alkynyl group, C6-C20 aryl group, C1-C20 heteroaryl group, or C2-C20 heteroalicyclic group is substituted by a halogen atom, a hydroxyl group, a thiol group, an amino group, a nitro group, a cyano group, a carboxyl group, an acyl group, a C1-C10 alkoxy group, a C6-C20 aryl group, a C1-C20 heteroaryl group, a C2-C20 heteroalicyclic group, a C1-C10 alkyl group, a C2-C8 alkenyl group, or a C2-C8 alkynyl group, and the substituents at at least two positions together constitute an aliphatic ring, a heteroalicyclic ring, an aromatic ring, or a heteroaromatic ring.

[0041] In some embodiments, Y1 and Y2 together with the nitrogen atom to which they are attached constitute a C2-C20 heteroalicyclic group, such as a C2-C10 heteroalicyclic group, which optionally contains 1 or 2 additional heteroatoms selected from N or O in the ring.

[0042] In some embodiments, the C2-C20 heteroalicyclic group is optionally replaced by a halogen atom, a cyano group, a nitro group, a C6-C10 aryl group, a C1-C10 heteroaryl group, a C1-C6 alkoxy group, a C6-C10 aryloxy group, a C2-C10 heteroalicyclic group, an amino group, a hydroxyl group, a thiol group, a carbonyl group, a carboxyl group, an acyl group, -NR4R5 is substituted by one or more substituents.

[0043] In some embodiments, R4 and R5 are independently selected from hydrogen, C6-C10 aryl, C1-C10 heteroaryl, C1-C8 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl and C2-C8 alkynyl, wherein the aryl and heteroaryl are optionally substituted by halogen atoms, hydroxyl, sulfhydryl, amino, nitro, cyano, carboxyl, acyl, C1-C8 alkoxy, C6-C10 aryl, C1-C10 heteroaryl, C2-C10 heteroalicyclic, C1-C8 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl or C2-C8 alkynyl, and optionally, the substituents at at least two positions together constitute a C3-C10 alicyclic, C2-C10 heteroalicyclic, C6-C10 aromatic or C1-C10 heteroaromatic ring. In some embodiments, R4 and R5 are independently selected from hydrogen and C1-C6 alkyl.

[0044] In some embodiments, the C2-C20 heteroalicyclic group is optionally selected from a halogen atom, a hydroxyl group, a thiol group, an amino group, a nitro group, a cyano group, a C1-C10 alkoxy group, a C1-C10 alkyl group, a C3-C8 cycloalkyl group, a C2-C8 alkenyl group, a C2-C8 alkynyl group, Substituents are substituted, R4 and R5 are independently selected from hydrogen and C1-C6 alkyl.

[0045] In some embodiments, the C2-C8 heteroalicyclic group is optionally substituted by halogen, -NH2, -OH, -NO2, carbonyl, -CH2OH, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

[0046] In some embodiments, Y1 and Y2 together with the nitrogen atom to which they are attached constitute a C4-C20 heteroalicyclic group, and the C4-C20 heteroalicyclic group is selected from the following groups:

[0047] R' independently represents no substituent, a single substituent or multiple substituents, each substituent is independently selected from deuterium, hydroxyl, halogen, NH2, carboxyl (-COOH), C1-C6 alkyl, halogen-substituted C1-C6 alkyl, hydroxy-substituted C1-C6 chain alkyl, amino-substituted C1-C6 chain alkyl, morpholine-substituted C1-C6 chain alkyl, -COO-C1-C6 alkyl, cyano, C1-C6 alkoxy, C3-C6 cycloalkyl, halogen-substituted C3-C6 cycloalkyl, hydroxy-substituted C3-C6 cycloalkyl, phenyl, benzyl;

[0048] L2 is absent or C1-C6 alkylene, halogen, hydroxyl, C1-C6 alkoxy substituted C1-C6 alkylene, preferably methylene, ethylene, propylene;

[0049] R6 is H, deuterium, halogen, hydroxyl, NH2, carboxyl (-COOH), -CONH2, sulfonic acid (-SO3H), -SO2-C1-C6 alkyl, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, morpholine-substituted C1-C6 alkyl, -COO-C1-C6 alkyl, cyano, C1-C6 alkoxy, hydroxy-substituted C1-C6 alkyl, amino-substituted C1-C6 alkyl, C3-C6 cycloalkyl, halogen-substituted C3-C6 cycloalkyl, hydroxy-substituted C3-C6 cycloalkyl, phenyl or benzyl.

[0050] In some embodiments, Ring A is selected from pyridine, pyrimidine, pyridazine, quinoline, thiazole, imidazole, pyrrole, pyrazole, thiophene, thienofuran, thienothiazole, carbazolopyrrole, pyridopyrazole, pyridopyrrole, indole, azaindole, isoquinoline, anthracene, phenanthrene, benzofuran, benzothiophene, and indazole.

[0051] In some embodiments, ring A is a pyridine ring, a pyrimidine ring, or a pyridazine ring.

[0052] In some embodiments, Ring B is selected from the group consisting of pyrazole, pyrrole, imidazole, pyridine, pyrimidine, indole, indazole, tetrahydropyrrole piperidine, azetidine, cubane, pyridazine, quinoline, thiazole, imidazole, pyrrole, pyrazole, thiophene, thienofuran, thienothiazole, carbazolopyrrole, pyridopyrazole, pyridopyrrole, indole, azaindole, isoquinoline, anthracene, phenanthrene, benzofuran, benzothiophene, and indazole.

[0053] In some embodiments, the B ring is absent.

[0054] In some embodiments, Ring B is selected from the group consisting of:

[0055] In some embodiments, Ring B is selected from

[0056] In some embodiments, R is selected from phenyl, pyridine, pyrimidine, pyrazine, cycloalkyl, quinoline, isoquinoline, tetrahydroquinoline, tetrahydroisoquinoline, indole, indazole, cyclohexyl, cyclopentyl, cycloheptyl, oxaspiro[3.3]heptanyl, spiro[2.5]octanyl, and adamantyl.

[0057] In some embodiments, R is selected from the following groups:

[0058] In some embodiments, R is selected from the following groups:

[0059] In some embodiments, the structure of the compound is shown in Formula IA:

[0060] Wherein, the definitions of various symbols are the same as those described in the compound of formula I.

[0061] In some embodiments, the structure of the compound is shown in any one of Formulas I-1 to I-6:

[0062] In the above formulae, the definitions of the symbols are the same as those described for the compounds of formula I.

[0063] In some embodiments, the structure of the compound is shown in any one of Formulas I-7 to I-9:

[0064] In the above formulae, the definitions of the symbols are the same as those described for the compounds of formula I.

[0065] In some embodiments, the nitrogen heterocyclic compound is selected from the following compounds:

[0066] In some embodiments, the nitrogen heterocyclic compound is selected from the following compounds:

[0067] In some embodiments, the salt of the compound is an alkali metal salt, preferably a sodium salt.

[0068] In a second aspect, the present application provides a pharmaceutical composition comprising the compound described in the first aspect or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer or isotope compound thereof, and a pharmaceutically acceptable excipient.

[0069] In a third aspect, the present application provides a method for preventing or treating aging-related diseases, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of the first aspect or its pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer or isotope compound, or the pharmaceutical composition of the second aspect.

[0070] In some embodiments, the disease is selected from diseases associated with the accumulation of senescent cells, preferably selected from idiopathic pulmonary fibrosis, pulmonary fibrosis, liver fibrosis, renal fibrosis, viral-induced inflammation and tissue fibrosis and atrophy of the upper respiratory tract and lungs, cystic fibrosis, myelofibrosis, myocardial fibrosis, skin fibrosis, interstitial lung disease, fibrosing pancreatitis, retinopathy of prematurity, macular degeneration, diabetic macular edema, diabetic retinopathy, age-related macular degeneration, wet age-related macular degeneration, dry age-related macular degeneration, glaucoma, sickle cell retinopathy, ischemic arteritic neuropathy, keratitis sicca, Fuch's corneal dystrophy, presbyopia, cataracts, degenerative vitreous disorders including vitreomacular traction syndrome, macular hole, retinal tear, retinal detachment, proliferative vitreoretinopathy, osteoarthritis, herniated disc, osteoporosis, Alzheimer's disease, Parkinson's disease, atherosclerosis, chronic obstructive pulmonary disease. disease, diabetes, diabetic nephropathy, scars, superficial or flat scars, cord-like or contracture scars, webbed scars, depressed scars, atrophic scars, bridge-like and hypertrophic scars, hypertrophic scars, keloids, scar cancer, scleroderma, morphea, scleroderma zona, guttate scleroderma, acroscleroderma, diffuse scleroderma, CREST syndrome, acute coronary syndrome, myocardial infarction, stroke, hypertension, obesity, adipose tissue dysfunction, coronary artery disease, cerebrovascular disease The invention also includes one or more of: arthritis, periodontal disease, cancer treatment-related disabilities such as atrophy and fibrosis in various tissues, brain and heart damage, and treatment-related myelodysplastic syndrome, promyelocytic syndrome, ataxia-telangiectasia, Fanconi anemia, Friedreich's ataxia, dyskeratosis congenita, aplastic anemia, aneurysms, inflammatory bowel disease, lipoatrophy, renal transplant failure, sarcopenia, wound healing, alopecia, cardiomyocyte hypertrophy, glomerulosclerosis, and cancer.

[0071] In a fourth aspect, the present application provides the use of the compound described in the first aspect or its pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer or isotope compound, or the pharmaceutical composition described in the second aspect in the preparation of a drug for preventing or treating aging-related diseases.

[0072] In some embodiments, the disease is selected from diseases associated with the accumulation of senescent cells, preferably selected from idiopathic pulmonary fibrosis, pulmonary fibrosis, liver fibrosis, renal fibrosis, viral-induced inflammation and tissue fibrosis and atrophy of the upper respiratory tract and lungs, cystic fibrosis, myelofibrosis, myocardial fibrosis, skin fibrosis, interstitial lung disease, fibrosing pancreatitis, retinopathy of prematurity, macular degeneration, diabetic macular edema, diabetic retinopathy, age-related macular degeneration, wet age-related macular degeneration, dry age-related macular degeneration, glaucoma, sickle cell retinopathy, ischemic arteritic neuropathy, keratitis sicca, Fuch's corneal dystrophy, presbyopia, cataracts, degenerative vitreous disorders including vitreomacular traction syndrome, macular hole, retinal tear, retinal detachment, proliferative vitreoretinopathy, osteoarthritis, herniated disc, osteoporosis, Alzheimer's disease, Parkinson's disease, atherosclerosis, chronic obstructive pulmonary disease. disease, diabetes, diabetic nephropathy, scars, superficial or flat scars, cord-like or contracture scars, webbed scars, depressed scars, atrophic scars, bridge-like and hypertrophic scars, hypertrophic scars, keloids, scar cancer, scleroderma, morphea, scleroderma zona, guttate scleroderma, acroscleroderma, diffuse scleroderma, CREST syndrome, acute coronary syndrome, myocardial infarction, stroke, hypertension, obesity, adipose tissue dysfunction, coronary artery disease, cerebrovascular disease The invention also includes one or more of: arthritis, periodontal disease, cancer treatment-related disabilities such as atrophy and fibrosis in various tissues, brain and heart damage, and treatment-related myelodysplastic syndrome, promyelocytic syndrome, ataxia-telangiectasia, Fanconi anemia, Friedreich's ataxia, dyskeratosis congenita, aplastic anemia, aneurysms, inflammatory bowel disease, lipoatrophy, renal transplant failure, sarcopenia, wound healing, alopecia, cardiomyocyte hypertrophy, glomerulosclerosis, and cancer.

[0073] In a fifth aspect, the present application further provides a method for synthesizing the compound described in the first aspect, comprising:

[0074] The compound represented by formula II is reacted with the compound represented by formula III to obtain the compound represented by formula I.

[0075] X represents halogen, preferably chlorine, bromine or iodine, and the other symbols are defined as the same as those of the compound of formula I;

[0076] Alternatively, the compound represented by formula IV is reacted with the compound represented by formula V to obtain the compound represented by formula I,

[0077] The definitions of the symbols are the same as those of the compound of formula I;

[0078] Alternatively, the compound represented by formula VI is reacted with the compound represented by formula V to obtain the compound represented by formula VII; the compound represented by formula VII is converted into the compound represented by formula I,

[0079] The symbols are defined the same as those in the compound of formula I.

[0080] In a sixth aspect, the present application further provides an intermediate compound selected from the compounds represented by Formula II, Formula III, Formula IV, Formula VI or Formula VII:

[0081] X represents halogen, preferably chlorine, bromine or iodine, and the other symbols have the same definitions as those in the compound of formula I.

[0082] In a seventh aspect, the present application further provides an intermediate compound selected from any one of the following compounds: BRIEF DESCRIPTION OF THE DRAWINGS

[0083] FIG1 shows the effect of administration of compound RN001 in an oxygen-induced retinopathy (OIR) mouse model.

[0084] FIG2 shows the effect of administering compound RN001 in an imiquimod-induced psoriasis mouse model.

[0085] FIG3 shows the effect of administering compound RN001 in the bleomycin-induced scleroderma model.

[0086] FIG4 shows the effect of administering compound RN001 in an animal model of idiopathic pulmonary fibrosis.

[0087] FIG5 shows the effect of administering compound RN001 in an animal model of osteoarthritis.

[0088] FIG6 shows the effect of administering compound RN001 in a rabbit ear hypertrophic scar animal model. DETAILED DESCRIPTION

[0089] The present invention is described in detail below with reference to the examples. These examples are based on the present invention as a technical solution and provide detailed implementation plans and processes. However, the implementation plans provided herein are exemplary and intended to explain the present invention, and should not be construed as limiting the present invention. Conditions and methods not specified in the following examples were carried out conventionally.

[0090] definition

[0091] Term " alkyl " refers to aliphatic hydrocarbon group, can be the alkyl of branched or straight chain.According to structure, alkyl can be monovalent group or divalent group (i.e. alkylidene group).In the present invention, alkyl is preferably the alkyl with 1-8 carbon atom, more preferably has " low alkyl " of 1-6 carbon atom, even more preferably has the alkyl of 1-4 carbon atom.Typical alkyl includes but is not limited to methyl, ethyl, propyl group, butyl, amyl group, hexyl etc.It should be understood that " alkyl " mentioned in the application includes the alkyl of all configurations that may exist and conformation, for example " propyl group " mentioned in the application includes n-propyl and isopropyl, " butyl " includes n-butyl, isobutyl and tert-butyl, " amyl group " includes n-pentyl, isopropyl, neopentyl, tert-pentyl and penta-3-yl etc.

[0092] The term "alkoxy" refers to -O-alkyl, wherein alkyl is as defined herein. Typical alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and the like.

[0093] The term "cycloalkyl" refers to a monocyclic or polycyclic radical containing only carbon and hydrogen. Cycloalkyl includes a group having 3-12 ring atoms. According to structure, cycloalkyl can be a monovalent group or a divalent group (e.g., cycloalkylidene). In the present invention, cycloalkyl is preferably a cycloalkyl having 3-8 carbon atoms, more preferably a "low cycloalkyl" having 3-6 carbon atoms. The example of cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and adamantyl.

[0094] The term "aryl" refers to an aromatic ring in which each of the atoms forming the ring is a carbon atom. The aryl ring can be composed of five, six, seven, eight, nine, or more than nine atoms. An aryl group can be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, phenanthrenyl, anthracenyl, fluorenyl, and indenyl. Depending on the structure, an aryl group can be a monovalent group or a divalent group (i.e., an arylene group).

[0095] The term "heteroaryl" refers to an aromatic group that includes one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. The N-containing "heteroaryl" moiety refers to an aromatic group in which at least one skeletal atom on the ring is a nitrogen atom. Depending on the structure, a heteroaryl group can be a monovalent group or a divalent group (i.e., a heteroarylidene group). Examples of heteroaryl groups include, but are not limited to, pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolyl, isoquinolyl, indolyl, benzimidazolyl, benzofuranyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, isoindole, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, naphthyridinyl, and furopyridinyl.

[0096] As used herein, the term "alicyclic group" or "cycloalkyl" refers to a non-aromatic ring consisting of three or more carbon atoms, wherein two adjacent carbon atoms within the ring may have a single bond, a double bond, or a triple bond, and the number of rings may be one or more. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclohexenyl, cyclopentenyl, and cyclohexadienyl.

[0097] As used herein, the term "heterocycloalkyl" or "heteroalicyclic" or "heteroalicyclic" refers to a non-aromatic ring in which one or more of the atoms forming the ring is a heteroatom selected from nitrogen, oxygen and sulfur. A heterocycloalkyl group may be composed of three, four, five, six, seven, eight, nine or more atoms. A heterocycloalkyl group may be optionally substituted. Examples of heteroalicyclic groups include, but are not limited to, lactams, lactones, cyclic imines, cyclic thioimides, cyclic carbamates, tetrahydrothiopyran, 4H-pyran, tetrahydropyran, piperidine, 1,3-dioxin, 1,3-dioxane, 1,4-dioxin, 1,4-dioxane, piperazine, 1,3-oxathiinane, 1,4-oxathiinane, 1,4-oxathiinane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbital Acid, dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane, hexahydro-1,3,5-triazine, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, imidazolidine, pyrrolidone, pyrazoline, pyrazolidine, imidazoline, imidazolidine, 1,3-dioxole, 1,3-dioxolane, 1,3-dithiole, 1,3-dithiolane, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine and 1,3-oxathiolane. Depending on the structure, the heteroalicyclic group can be a monovalent group or a divalent group (i.e., a heterocycloalkylene group).

[0098] The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0099] The term "carbonyl" refers to an organic functional group composed of two atoms, carbon and oxygen, connected by a double bond (C=O).

[0100] The term "optionally" means that one or more of the subsequently described events may or may not occur, and includes both events that occur and events that do not occur.

[0101] The salts that may be formed by the compounds of the present invention also fall within the scope of the present invention. Unless otherwise indicated, the compounds of the present invention are understood to include their salts. The term "salt" as used herein refers to acidic or basic salts formed with inorganic or organic acids and bases. In addition, when the compound of the present invention contains a basic fragment, it includes but is not limited to pyridine or imidazole, and contains an acidic fragment, including but not limited to carboxylic acid, the zwitterions ("inner salts") that may be formed are included within the scope of the term "salt". Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, for example, in separation or purification steps during the preparation process. The compounds of the present invention may form salts, for example, compound I reacts with a certain amount, such as an equivalent amount, of an acid or base, salts out in a medium, or is obtained by freeze-drying in an aqueous solution.

[0102] The compounds of the present invention contain basic moieties, including but not limited to amines or pyridine or imidazole rings, which may form salts with organic or inorganic acids. Typical acids that can form salts include acetates (e.g., acetic acid or trihaloacetic acid, such as trifluoroacetic acid), adipates, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphor, camphorsulfonate, cyclopentanepropionate, diglycolate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide,

[0014] Examples of the present invention include, for example, hydroxyethylsulfonates, lactates, maleates, methanesulfonates, naphthalenesulfonates (e.g., 2-naphthalenesulfonate), nicotinates, nitrates, oxalates, pectinates, persulfates, phenylpropionates (e.g., 3-phenylpropionate), phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (e.g., with sulfuric acid), sulfonates, tartrates, thiocyanates, toluenesulfonates such as p-toluenesulfonate, dodecanoates, and the like.

[0103] Certain compounds of the present invention may contain acidic moieties, including but not limited to carboxylic acids, which may form salts with various organic or inorganic bases. Typical base-forming salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, and salts formed with organic bases (e.g., organic amines), such as benzathine, dicyclohexylamine, hepamine (salt formed with N,N-di(dehydroabietyl)ethylenediamine), N-methyl-D-glucamine, N-methyl-D-glucamide, tert-butylamine, and salts formed with amino acids such as arginine, lysine, and the like. Basic nitrogen-containing groups can react with halide quaternary ammonium salts, such as small molecular alkyl halides (such as chlorides, bromides and iodides of methyl, ethyl, propyl and butyl), dialkyl sulfates (such as dimethyl sulfate, diethyl sulfate, dibutyl sulfate and dipentyl sulfate), long chain halides (such as chlorides, bromides and iodides of decyl, dodecyl, tetradecyl and tetradecyl), aralkyl halides (such as benzyl and phenyl bromide), etc.

[0104] Prodrugs and solvates of the compounds of the present invention are also within the scope of this invention. The term "prodrug" herein refers to a compound that undergoes chemical transformation by metabolic or chemical processes to produce a compound, salt, or solvate of the present invention when treating a related disease. "Solvate" refers to a solvent addition form containing a stoichiometric or non-stoichiometric amount of solvent. Some compounds tend to capture a fixed molar ratio of solvent molecules in the crystalline solid state, thereby forming a solvate. If the solvent is water, the solvate formed is a hydrate; if the solvent is an alcohol, the solvate formed is an alcoholate. The combination of one or more water molecules with a molecule of a substance forms a hydrate, in which the water remains in its molecular state H2O. Non-limiting examples of solvates include ethanol solvates, acetone solvates, and the like.

[0105] The compounds, salts or solvates of the present invention may exist in tautomeric forms (such as amides and imino ethers). All such tautomers are part of the present invention.

[0106] All stereoisomers of the compounds (e.g., those that may exist due to asymmetric carbon atoms for various substitutions), including enantiomeric and diastereomeric forms, are contemplated by the present invention. Individual stereoisomers of the compounds of the present invention may not exist with other isomers (e.g., as a pure or substantially pure optical isomer having a particular activity), or may be mixtures, such as racemates, or mixtures with all other stereoisomers or portions thereof. The chiral centers of the present invention have either S or R configurations, as defined by the 1974 recommendations of the International Union of Pure and Applied Chemistry (IUPAC). Racemic forms can be resolved by physical methods, such as fractional crystallization, or by crystallization of diastereomers derived from them, or by separation by chiral column chromatography. Individual optical isomers can be obtained from the racemate by suitable methods, including but not limited to conventional methods, such as salt formation with an optically active acid followed by recrystallization.

[0107] The compounds of the present invention, obtained by sequential preparation, isolation, and purification, are described in the text to a concentration of 90% or greater by weight, for example, 95% or greater, or 99% or greater ("very pure" compounds). Such "very pure" compounds of the present invention are also considered part of the present invention.

[0108] All configurational isomers of the compounds of the present invention are encompassed, whether in mixture, pure or very pure form. The definition of the compounds of the present invention includes both cis (Z) and trans (E) olefin isomers, as well as cis and trans isomers of carbocyclic and heterocyclic rings.

[0109] Throughout the specification, groups and substituents may be chosen to provide stable fragments and compounds.

[0110] Specific functional groups and chemical term definitions are detailed below. For the purposes of this invention, chemical elements are referred to in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th The definitions of specific functional groups are consistent with those in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito, 1999, which is incorporated by reference in its entirety.

[0111] Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention encompasses all compounds, including their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, racemic mixtures, and other mixtures. Additionally, asymmetric carbon atoms may represent substituents, such as alkyl groups. All isomers and mixtures thereof are encompassed by the present invention.

[0112] According to the present invention, mixtures of isomers can contain various ratios of isomers. For example, mixtures containing only two isomers can have the following ratios: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0. All ratios of isomers are within the scope of the present invention. Similar ratios, as well as ratios for more complex mixtures of isomers, are readily understood by those skilled in the art and are also within the scope of the present invention.

[0113] The present invention also includes isotopically labeled compounds that are equivalent to the original compounds disclosed herein. However, in practice, it is common for one or more atoms to be replaced by atoms having a different atomic mass or mass number. Examples of isotopes of the compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine isotopes, such as 2 H. 3 H. 13 C. 11 C. 14 C. 15 N. 18 O. 17 O. 31 P. 32 P. 35 S. 18 F and 36 The compounds of the present invention, or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates thereof, which contain isotopes or other isotopic atoms of the above compounds are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, such as 3 H and 14 Radioisotopes of C are also included and are useful in tissue distribution experiments of drugs and substrates. 3 H and carbon-14, i.e. 14 C, their preparation and detection are relatively easy. It is the first choice among isotopes. In addition, heavier isotope substitutions such as deuterium, i.e. 2H, due to its excellent metabolic stability, has advantages in certain therapeutics, such as increasing half-life in vivo or reducing dosage, and therefore, may be preferred in some cases. Isotopically labeled compounds can be prepared using conventional methods by replacing readily available isotopically labeled reagents with non-isotopic reagents using the protocols disclosed in the examples.

[0114] If a synthesis of a specific enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, followed by separation of the resulting diastereomeric mixture and removal of the chiral auxiliary to obtain the pure enantiomer. Alternatively, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, diastereomeric salts can be formed with a suitable optically active acid or base, followed by separation by conventional means such as fractional crystallization or chromatography to obtain the pure enantiomer.

[0115] As described herein, the compounds of the present invention may be substituted with any number of substituents or functional groups to expand their scope. Generally, the term "substituted," whether preceding or following the term "optionally," in formulas of the present invention including substituents, refers to the replacement of a hydrogen radical with a substituent of the specified structure. When multiple positions in a particular structure are substituted with multiple substituents, the substituents may be the same or different at each position. The term "substituted," as used herein, includes all permissible substitutions in organic compounds. Broadly speaking, permissible substituents include acyclic, cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds. For example, heteroatoms such as nitrogen may be substituted with hydrogen or any of the permissible organic compounds described above to supplement their valences. Furthermore, the present invention is not intended to limit the permissible substitutions in any way to organic compounds. The present invention recognizes that combinations of substituents and variable groups are advantageous for providing stable compounds for the treatment of diseases. The term "stable" herein refers to a compound that is stable and maintains the structural integrity of the compound over a sufficient period of time to be tested, preferably over a sufficient period of time to be effective, as used herein for the above purposes.

[0116] Example 1 Synthesis of Compound RN001

[0117] The synthetic route is as follows

[0118] Step 1 Synthesis of Compound 1-2

[0119] Acetonitrile (4.0 mL) was added to a 25 mL single-necked flask, followed by the addition of compound 1-1 (200 mg, 0.72 mmol) and CDI (144 mg, 0.89 mmol) with stirring. The reaction mixture was stirred at room temperature for 0.5 hour, followed by the addition of DBU (CAS No. 6674-22-2) (172 mg, 1.14 mmol). After stirring at room temperature for 0.5 hour, 2-aminobenzothiazole (107 mg, 0.72 mmol) was added. The reaction mixture was then purged with nitrogen three times and stirred at 60°C for 4 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude product containing the target compound. Purification by column chromatography (mobile phase: ethyl acetate-petroleum ether, gradient: 0-50%) afforded the white compound 1-2 (108 mg, 0.26 mmol, yield 36.6%). MS (ESI) m / z = 411.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ12.26(s,1H),8.55(d,J=4.8Hz,1H),8.06(d,J=7.6Hz,1H),7.81(d,J=8.0Hz,1H),7.54(d,J=5.2H z,1H),7.48(t,J=7.2Hz,1H),7.36(t,J=7.2Hz,1H),5.00(s,2H),3.62(t,J=5.6Hz,2H),2.94(t,J=5.6Hz,2H),1.43(s,9H).

[0120] Step 2 Synthesis of Compound 1-3

[0121] To a 25 mL single-necked flask, 1,4-dioxane (3 mL) was added, followed by compound 1-2 (88 mg, 0.21 mmol) with stirring. A 4N 1,4-dioxane solution (3 mL) was then added under ice. The reaction mixture was stirred at room temperature for 3 hours, quenched with saturated sodium carbonate solution (30 mL), and extracted with methanol:dichloromethane (1 / 10, 50 mL). The organic phase was washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the target compound 1-3 as a white solid (60 mg, 0.19 mmol, 90.1% yield). MS (ESI) m / z = 311.0 [M+H] +

[0122] Step 3 Synthesis of Compound 1-4

[0123] To a 10 mL microwave tube was added N,N-dimethylformamide (0.4 mL), compound 1-3 (20 mg, 0.06 mmol), compound 3A (34.1 mg, 0.08 mmol), cesium carbonate (62.9 mg, 0.19 mmol), and bis(tri-tert-butylphosphine)palladium (4.62 mg, 0.01 mmol). Under nitrogen protection, the reaction solution was microwaved at 120°C for 5 hours. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phase was washed with saturated brine (15 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a crude product containing the target compound. Purification by column chromatography (mobile phase: methanol-dichloromethane, gradient: 0-10%) afforded the yellow compound 1-4 (23 mg, 0.01 mmol, yield 18.4%). MS (ESI) m / z = 716.4 [M+H] +

[0124] Step 4 Synthesis of compound RN001

[0125] To a 25 mL single-necked flask at 0°C, dichloromethane (1.0 mL), compound 1-4 (79 mg, 0.11 mmol), and trifluoroacetic acid (1.0 mL) were added sequentially and stirred at 25°C for 12 hours. The reaction solution was concentrated, and the brown target product RN001 (1.25 mg, 18.9 mol, 1.8% yield) was obtained by reverse-phase HPLC. MS (ESI) m / z = 660.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ12.30(br,1H),8.55(d,J=3.6Hz,1H),8.05(d,J=7.6Hz, 1H),7.81(d,J=8.0Hz,1H),7.60-7.53(m,2H),7.48(t,J=7.6Hz,1H),7.37(t,J=7. 6Hz,1H),7.29(s,1H),7.04(d,J=8.8Hz,1H),5.23(s,2H),3.94(t,J=5.6Hz,2H), 3.71(s,2H),3.05(t,J=5.6Hz,2H),2.12(s,3H),1.93(s,3H),1.69-1.49(m,12H).

[0126] Example 2 Synthesis of Compound RN003

[0127] The synthetic route is as follows:

[0128] Step 1 Synthesis of compound 3-2

[0129] Compound 3-1 (2.99 mL, 25.0 mmol), compound 1A (4.00 g, 19.2 mmol), potassium carbonate (7.97 g, 57.7 mmol), and potassium iodide (1.28 mL, 11.5 mmol) were dissolved in N,N-dimethylformamide (40 mL) and reacted at 90°C for 12 hours. After completion of the reaction, the mixture was diluted with water (50 mL), extracted with ethyl acetate (20 mL × 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound. Purification afforded compound 3-2 as a brown solid (253 mg, 0.85 mmol, 4.41% yield). MS (ESI) m / z = 299.2 [M+H] + . 1 H NMR (400MHz, CDCl3): δ7.76(s,1H),7.33–7.23(m,3H),7.11(d,J=7.2Hz,2H),5.31(s,2H),2.38(s,3H),1.30(s,12H)

[0130] Step 2 Synthesis of compound 3-3

[0131] Compound 2A (298 mg, 1.02 mmol), compound 3-2 (253 mg, 0.85 mmol), Pd(dppf)Cl2 (69.3 mg, 0.08 mmol), and potassium carbonate (351 mg, 2.55 mmol) were dissolved in 1,4-dioxane (2.5 mL) and H2O (0.5 mL) and reacted at 90°C for 2 hours. After completion, the reaction was concentrated under reduced pressure, diluted with water (10 mL), extracted with ethyl acetate (2 mL x 3), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude compound. Purification by column chromatography (mobile phase: ethyl acetate-petroleum ether, gradient: 0-5%) afforded compound 3-3 (161 mg, 0.42 mmol, yield 49.4%) as a white solid. MS (ESI) m / z = 384.2 [M+H] + . 1 H NMR (400MHz, CDCl3): δ7.57–7.51(m,2H),7.40(d,J=8.0Hz,1H),7.32(dd,J=1 2.0,7.2Hz,3H),7.22(d,J=6.8Hz,2H),5.34(s,2H),2.13(s,3H),1.33(s,9H).

[0132] Step 3 Synthesis of compound 3-4

[0133] Compound 1-3 (80 mg, 0.26 mmol), compound 3-3 (98.4 mg, 0.26 mmol), Pd(t-Bu3P)2 (26.3 mg, 0.05 mmol), and Cs2CO3 (252 mg, 0.77 mmol) were dissolved in N,N-dimethylformamide (0.8 mL) and reacted at 130°C for 2 hours. The reaction solution was diluted with H2O (8 mL), extracted with ethyl acetate (2 mL × 4), washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude compound. Purification afforded compound 3-4 (30 mg, 0.05 mmol, 17.8% yield) as a yellow solid. MS (ESI) m / z = 658.2 [M+H] + .

[0134] Step 4 Synthesis of compound RN003

[0135] Compound 3-4 (30 mg, 0.05 mmol) was dissolved in dichloromethane (5 mL), and TFA (0.1 mL, 1.34 mmol) was added. The reaction solution was stirred at 20°C for 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain a crude product, which was purified by preparative HPLC to afford compound RN003 (5.9 mg, 0.01 mmol, 21.4% yield) as a yellow solid. MS (ESI) m / z = 602.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ12.30(s,1H),8.55(d,J=4.8Hz,1H),8.05(d,J=8.0Hz,1H),7.81(d,J=8.0Hz,1H),7.60–7.53(m,2H),7.48(t,J=7. 6Hz,1H),7.37–7.25(m,5H),7.12(d,J=7.2Hz,2H),7.05(d,J=8.8Hz,1H),5.33(s,2H),5.23(s,2H),3.94(s,2H),3.05(s,2H),2.10(s,3H).

[0136] Example 3 Synthesis of Compound RN005

[0137] The synthetic route is as follows:

[0138] Step 1 Synthesis of compound 5-2

[0139] To a 100 mL single-necked flask, N,N-dimethylformamide (30 mL) was added, followed by the addition of compound 5-1 (1.95 mL, 15.87 mmol), compound 1A (3.30 g, 15.8 mmol), potassium carbonate (6.58 g, 47.61 mmol), and potassium iodide (2.63 g, 15.8 mmol) with stirring. The reaction mixture was purged with nitrogen three times and stirred at 80°C for 18 hours. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The organic phase was washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the white compound 5-2 (416 mg, 1.32 mmol, yield 8.29%). MS (ESI) m / z = 317.2 [M+H] +

[0140] Step 2 Synthesis of compound 5-3

[0141] Dioxane (3.0 mL) and H₂O (0.6 mL) were added to a single-necked flask, followed by the addition of compound 5-2 (366 mg, 1.16 mmol), compound 2A (336 mg, 1.16 mmol), potassium carbonate (479 mg, 3.47 mmol), and Pd(dppf)Cl₂ (84.70 mg, 0.12 mmol) with stirring. The reaction mixture was purged with nitrogen three times and stirred at 90°C for 3 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude product containing the target compound. Purification afforded compound 5-3 (246 mg, 0.62 mmol, 53.1% yield) as a yellow oil. MS (ESI) m / z = 402.2 [M+H] + ;

[0142] Step 3 Synthesis of compound 5-4

[0143] Compound 5-3 (77.3 mg, 0.19 mmol), compound 1-3 (30 mg, 0.10 mmol), cesium carbonate (157 mg, 0.48 mmol), and potassium iodide (48.13 mg, 0.29 mmol) were added to 0.5 mL of dimethyl sulfoxide. The reaction mixture was purged with nitrogen three times and stirred in a microwave oven at 150°C for 4 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (10 mL x 3). The organic phase was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound. Purification by column chromatography (mobile phase: methanol-dichloromethane, gradient: 0-10%) afforded the yellow compound 5-4 (10.0 mg, 0.01 mmol, 14.80%). MS (ESI) m / z = 676.2 [M+H]+

[0144] Step 4 Synthesis of compound RN005

[0145] At 0°C, dichloromethane (0.5 mL), compound 5-4 (10 mg, 0.03 mmol), and TFA (0.5 mL) were added sequentially to a single-necked flask and stirred at 25°C for 2 hours. The reaction solution was concentrated, and reverse-phase HPLC was used to obtain the brown target product RN005 (2.39 mg, 3.86 μmol, yield 28.3%). MS (ESI) m / z = 620.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6): δ12.9(s,1H),12.3(s,1H),8.56(d,J=4.8Hz,1H),8.06(d,J=7.6H z,1H),7.82(d,J=8.0Hz,1H),7.63-7.55(m,2H),7.50(t,J=8.0Hz,1H),7.43-7.33(m,3H), 7.11(td,J=8.8,2.4Hz,1H),7.06(d,J=8.8Hz,1H),6.95(d,J=7.6Hz,1H),6.91(d,J=9.6Hz ,1H),5.37(s,2H),5.23(s,2H),3.95(t,J=5.6Hz,2H),3.06(t,J=5.6Hz,2H),2.11(s,3H).

[0146] Example 4 Synthesis of Compound RN006

[0147] The synthetic route is as follows:

[0148] Step 1 Synthesis of Compound 6-2

[0149] Compound 6-1 (3.00 g, 15.8 mmol), compound 1A (3.30 g, 15.87 mmol), potassium iodide (2.63 g, 15.8 mmol), and potassium carbonate (6.58 g, 47.6 mmol) were added to N,N-dimethylformamide (30 mL). Stir at 80°C for 18 hours. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL x 2). The organic phase was washed with saturated brine (40 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound. Purification afforded compound 6-2 (450 mg, 1.42 mmol, 8.97% yield) as a yellow liquid. MS (ESI) m / z = 317.2 [M+H] +

[0150] Step 2 Synthesis of compound 6-3

[0151] Compound 6-2 (400 mg, 1.27 mmol), compound 2A (444 mg, 1.52 mmol), potassium carbonate (524 mg, 3.80 mmol), and Pd(dppf)Cl2 (92.5 mg, 0.13 mmol) were added to a mixture of dioxane (5 mL) and water (1 mL) and stirred at 90°C for 2 hours. Water (15 mL) was added to the reaction solution, and extraction was performed with ethyl acetate (20 mL x 2). The organic phase was washed with saturated brine (15 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the target compound 6-3 as a white solid (102 mg, 0.25 mmol, yield 20.0%). MS (ESI) m / z = 402.2 [M+H] +

[0152] Step 3 Synthesis of compound RN006

[0153] To a 10 mL microwave tube, N,N-dimethylformamide (0.7 mL), compound 6-3 (50 mg, 0.12 mmol), compound 1-3 (57.9 mg, 0.19 mmol), cesium carbonate (243 mg, 0.75 mmol), and potassium iodide (61.96 mg, 0.37 mmol) were added. Under nitrogen protection, the reaction solution was microwaved at 150°C for 12 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (10 mL x 2). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound. Reverse-phase HPLC yielded the brown target product RN006 (9 mg, 0.01 mmol, 10.7% yield). MS (ESI) m / z = 620.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.31(s,1H),8.56(d,J=4.8Hz,1H),8.06(d,J=7.6Hz,1 H),7.82(d,J=8.0Hz,1H),7.62-7.55(m,2H),7.52-7.45(m,1H),7.40-7.33(m,3 H),7.26-7.20(m,1H),7.19-7.13(m,1H),7.06(d,J=8.8Hz,1H),6.95-6.89(m,1 H),5.36(s,2H),5.23(s,2H),3.99-3.92(m,2H),3.09-3.01(m,2H),2.14(s,3H).

[0154] Example 5 Synthesis of Compound RN007

[0155] The synthetic route is as follows:

[0156] Step 1 Synthesis of Compound 7-2

[0157] Compound 7-1 (4.00 g, 19.2 mmol), compound 1A (2.39 mL, 19.2 mmol), potassium carbonate (7.97 g, 57.7 mmol), and potassium iodide (1.28 g, 7.69 mmol) were dissolved in N,N-dimethylformamide (40 mL) and reacted at 90°C for 12 hours. The reaction solution was diluted with H2O (50 mL), extracted with ethyl acetate (20 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound. Purification afforded compound 7-2 (1.05 g, 3.32 mmol, 17.3% yield) as a white solid. MS (ESI) m / z = 317.2 [M+H] + . 1 H NMR (400MHz, CDCl3): δ7.75 (s, 1H), 7.09 (dd, J = 8.4, 5.6Hz, 2H), 6.99 (t, J = 8.4Hz, 2H), 5.26 (s, 2H), 2.38 (s, 3H), 1.31 (s, 12H).

[0158] Step 2 Synthesis of compound 7-3

[0159] Compound 2A (462 mg, 1.58 mmol), compound 7-2 (500 mg, 1.58 mmol), Pd(dppf)Cl2 (116 mg, 0.16 mmol), and potassium carbonate (656 mg, 4.74 mmol) were dissolved in dioxane (5 mL) and H2O (1 mL) and reacted at 100°C for 12 hours. The reaction solution was concentrated under reduced pressure, diluted with H2O (15 mL), extracted with ethyl acetate (5 mL × 3), washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude compound. Purification by column chromatography (mobile phase: ethyl acetate-petroleum ether, gradient: 0-8%) afforded compound 7-3 (332 mg, 0.83 mmol, yield 52.2%) as a white solid. MS (ESI) m / z = 402.2 [M+H] + . 1 H NMR (400MHz, CDCl3): δ7.57-7.49(m,2H),7.40(d,J=8.4Hz,1H),7.23-7.18(m,2H),7.06-6.99(m,2H),5.30(s,2H),2.13(s,3H),1.33(s,9H).

[0160] Step 3 Synthesis of compound 7-4

[0161] Compound 1-3 (92.68 mg, 0.30 mmol), compound 7-3 (100 mg, 0.25 mmol), potassium iodide (0.08 mL, 0.75 mmol), and cesium carbonate (486 mg, 1.49 mmol) were dissolved in dimethyl sulfoxide (1 mL) and reacted at 150°C under microwave conditions for 12 hours. The reaction solution was filtered, concentrated, and purified to obtain a yellow solid compound 7-4 (7 mg, 0.01 mmol, yield 4.14%). MS (ESI) m / z = 676.2 [M+H] + .

[0162] Step 4 Synthesis of compound RN007

[0163] Compound 7-4 (30 mg, 0.05 mmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (1.5 mL, 20.1 mmol) was added. The reaction mixture was stirred at 20°C for 6 hours. The reaction mixture was directly drained to obtain a crude product. HPLC (mobile phase: acetonitrile-water (0.1% FA), gradient: 90-95%) was used to purify the crude product to obtain compound RN007 (3.3 mg, 0.01 mmol, yield 51.4%) as a yellow solid. MS (ESI) m / z = 620.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ12.30 (br, 1H), 8.56 (d, J = 4.4Hz, 1H), 8.13 (s, 1H), 8.05(d,J=7.6Hz,1H),7.81(d,J=8.0Hz,1H),7.59-7.54(m,2H),7.49(t,J=7. 6Hz,1H),7.40-7.34(m,2H),7.21-7.14(m,4H),7.05(d,J=8.8Hz,1H),5.32(s ,2H),5.23(s,2H),3.94(5,J=5.6Hz,2H),3.05(t,J=5.6Hz,2H),2.10(s,3H).

[0164] Example 6 Synthesis of Compound RN008

[0165] The synthetic route is as follows:

[0166] Step 1 Synthesis of compound 8-2

[0167] To a 250 mL three-necked flask, dioxane (80 mL), water (80 mL), compound 8-1 (6.9 g, 23.6 mmol, 1.1 eq), cesium carbonate (20.8 g, 63.8 mmol, 3 eq), compound 1A (7.6 g, 21.3 mmol, 1 eq), and [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium dichloride (1.0 g, 1.53 mmol, 0.07 mmol) were added. The atmosphere was purged with nitrogen and the reaction was carried out at 90°C for 14 h. The reaction mixture was cooled and concentrated under reduced pressure. 100 mL of water was added, and the mixture was extracted three times with 100 mL of ethyl acetate. The ethyl acetate layers were combined and washed twice with 50 mL of saturated sodium chloride. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Column chromatography revealed a pure point at a dichloromethane:methanol ratio of 5:1. The mixture was concentrated under reduced pressure and dried to afford compound 8-2 (3.6 g, 34.5% yield).

[0168] Step 2 Synthesis of compound 8-3

[0169] Compound 8-2 (2.8 g), acetonitrile (7 mL), and concentrated hydrochloric acid (7 mL) were added sequentially to a 100 mL three-necked flask and reacted at 40°C for 4 h. TLC monitoring (dichloromethane:methanol = 10:1) indicated the completion of the reaction, with the precipitation of a large amount of white solid. 7 mL of acetonitrile was added and filtered, and the filter cake was washed with 10 mL of acetonitrile and dried to afford compound 8-3 (2.1 g, 85.9% yield).

[0170] Step 3 Synthesis of compound 8-4

[0171] To a 100 mL single-necked flask, 8-3 (2.0 g, 5.19 mmol, 1.0 eq), 20 mL of N,N-dimethylformamide, N,N-diisopropylethylamine (2.68 g, 20.77 mmol, 4 eq), and TBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate) (2.0 g, 6.23 mmol, 1.2 eq) were added. The atmosphere was purged with nitrogen and stirred at room temperature for 30 min. 2-(piperidin-4-yl)-ethan-1-ol (0.74 g, 5.71 mmol, 1.1 eq) was then added and allowed to react at 40°C for 4 h. The reaction was complete when monitored by TLC (dichloromethane:methanol = 10:1). The reaction mixture was added with 100 mL of purified water and washed three times with 100 mL of ethyl acetate. The combined ethyl acetate was washed three times with 50 mL of saturated sodium chloride and concentrated under reduced pressure to obtain an oil. The residue was purified by column chromatography (dichloromethane:methanol=15:1) and concentrated under reduced pressure to give compound 8-4 (2.22 g, yield 86.2%).

[0172] Step 4 Synthesis of compound 8-6

[0173] Compound 8-5 (250 mg, 0.906 mmol, 1 eq), 6 mL N,N-dimethylformamide, diisopropylethylamine (350 mg, 2.70 mmol, 3 eq), TBTU (2-(1H-benzotriazol L-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate) (347 mg, 1.08 mmol, 1.2 eq) were added to a 25 mL single-necked flask, the atmosphere was replaced with nitrogen, and the reaction was carried out under magnetic stirring for 30 min. 2-Aminobenzothiazole (147 mg, 0.99 mmol, 1.1 eq) was added and the reaction was carried out at room temperature for 8 h. The reaction of the raw materials was monitored by TLC (dichloromethane: methanol = 20:1), and the mixture was concentrated under reduced pressure to obtain a crude product of compound 8-6.

[0174] Step 5 Synthesis of compound 8-7

[0175] To the crude solid compound 8-6, 4 mL of acetonitrile and 2 mL of concentrated hydrochloric acid were added and reacted at room temperature for 1.5 h. After completion of the reaction, the mixture was monitored by TLC. The mixture was added to 30 mL of aqueous sodium bicarbonate solution, extracted with ethyl acetate, washed with saturated sodium chloride, concentrated under reduced pressure, and purified by column chromatography to obtain a white solid compound 8-7 (210 mg, total yield of two steps was 74.5%).

[0176] Step 6 Synthesis of compound RN008

[0177] Compound 8-7 (150 mg, 0.483 mmol, 1 eq), compound 8-4 (240 mg, 0.483 mmol, 1 eq), cesium carbonate (394 mg, 1.61 mmol, 2.5 eq), and bis(tri-tert-butylphosphine)palladium (50 mg, 0.097 mmol, 0.2 eq) were added to a 10 mL microwave tube. The mixture was purged with nitrogen and microwaved at 130°C for 3 h. The mixture was then filtered, the filter cake was rinsed with methanol, and concentrated under reduced pressure. RN008 (14.8 mg, 3.9% yield) was isolated by column chromatography as a white solid. MS (ESI) m / z = 771.4 [M+H] + . 1HNMR (400MHz, DMSO-d6) δ13.13(s,1H),8.83(s,1H),8.65(s,1H),8.05(d,J=7.9Hz,1H),7.81(d,J=8.0Hz ,1H),7.57–7.45(m,2H),7.38(t,J=7.6Hz,1H),7.21(s,1H),6.96(d,J=8.9Hz,1H),5.04(s,2H),4.24(d, J=12.5Hz,1H),3.88(p,J=6.6Hz,2H),3.71(d,J=2.8Hz,2H),3.27(t,J=6.4Hz,2H),3.12(d,J=13.1Hz,2H ),3.07–3.00(m,2H),2.74–2.59(m,2H),2.15(s,3H),1.92(s,3H),1.72–1.30(m,16H),1.27–1.09(m,3H).

[0178] Example 7 Synthesis of Compound RN009

[0179] The synthetic route is as follows:

[0180] Step 1 Synthesis of Compound 9-2A

[0181] At room temperature, compound 9-1A (5 g, 18.99 mmol), DMA (50 mL), tetrazole (2.66 g, 37.98 mmol), and compound 9-3A (9.47 g, 37.98 mmol) were added sequentially to a 50 mL three-necked flask. The reaction system was stirred under nitrogen for 2 h, then cooled to -10°C and slowly added dropwise with 30% hydrogen peroxide (4.6 mL, 40 mmol). The mixture was stirred at room temperature for 2 h, then cooled to -10°C and quenched with 0.5 M sodium thiosulfate solution. The reaction mixture was extracted with ethyl acetate (300 mL x 2) and concentrated to afford compound 9-2A (1 g, 57.8% yield).

[0182] Step 2 Synthesis of Compound 1A

[0183] At room temperature, compound 9-2A (2 g, 4.39 mmol), ethanol (20 mL), and palladium on carbon (10% palladium loading, 200 mg) were added sequentially to a 100 mL pressure-resistant glass bottle. The reaction system was stirred under a hydrogen atmosphere (30 psi) for 2 h. The reaction mixture was filtered and concentrated to obtain compound 1A (1.2 g, 85.0% yield).

[0184] Step 3 Synthesis of compound 9-1

[0185] To a 5 mL brown bottle, compound RN001 (9 mg, 13.7 μmol), 0.5 mL of N,N-dimethylformamide, and N,N-diisopropylethylamine (2.6 mg, 20.5 μmol, 1.5 eq) were added. The mixture was stirred at room temperature, the atmosphere was purged with nitrogen, and TBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate) (6.6 mg, 20.5 μmol, 1.5 eq) was added and allowed to react at room temperature for 30 min. Compound 1A (6.6 mg, 20.5 μmol, 1.5 eq) was added and allowed to react at room temperature for 2.5 h. The reaction was complete upon TLC (dichloromethane:methanol = 20:1). The reaction solution was added to 4 mL of ice water and extracted twice with 2 mL of ethyl acetate. The combined ethyl acetate layers were washed twice with 2 mL of saturated brine, dried over sodium sulfate, and filtered and concentrated under reduced pressure to afford compound 9-1 (15 mg) as a white solid.

[0186] Step 2 Synthesis of compound RN009

[0187] The solid compound 9-1 was added to a 5 mL brown bottle, dissolved in 1 mL of ethyl acetate, and then 0.2 mL of a 2 M hydrogen chloride ethyl acetate solution was added. A white solid gradually precipitated and was separated by preparative chromatography to obtain a yellow compound RN009 (0.73 mg). MS (ESI) m / z = 850.9 [M+H] +.1 HNMR (400MHz, DMSO-d6): δ8.53(s,1H),8.03(d,J=7.9Hz,1H),7.79(d,J=7.9Hz ,1H),7.57–7.41(m,3H),7.34(s,1H),7.22(s,1H),6.94(d,J=9.1Hz,1H),5.18 (s,2H),4.26(d,J=12.2Hz,2H),3.90(s,2H),3.70(s,2H),3.52(s,2H),3.04(s ,2H),2.32(s,2H),2.15(s,3H),1.91(s,3H),1.69–1.41(m,14H),1.23(s,5H).

[0188] Example 8 Synthesis of Compound RN002

[0189] The synthetic route is as follows:

[0190] Step 1 Synthesis of Compound 2-2

[0191] Compound 2-1 (3.00 g, 14.4 mmol), compound 1A (3.54 mL, 28.8 mmol), and CMBP (CAS: 157141-27-0) (4.87 g, 20.2 mmol) were dissolved in toluene (30 mL). After nitrogen displacement, the reaction mixture was allowed to react at 90°C for 12 hours. After completion of the reaction, the mixture was diluted with water (20 mL), extracted with ethyl acetate (5 mL × 3), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Purification afforded compound 2-2 (316 mg, 7.20% yield) as a brown solid. MS (ESI) m / z = 305.2 [M+H] + . 1 H NMR (400MHz, CDCl3): δ7.70 (s, 1H), 3.86 (d, J = 7.2Hz, 2H), 2.42 (d, J = 6.4Hz, 3H), 1.92 (dd, J = 7.2, 3. 6Hz,1H),1.75–1.57(m,6H),1.29(d,J=13.6Hz,12H),1.20(d,J=8.0Hz,2H),0.99(t,J=12.0Hz,2H).

[0192] Step 2 Synthesis of Compound 2-3

[0193] Compound 2-2 (365 mg, 1.25 mmol), tert-butyl 3-bromo-6-chloropicolinate (316 mg, 1.04 mmol), Pd(dppf)Cl2 (84.8 mg, 0.10 mmol), and K2CO3 (431 mg, 3.12 mmol) were dissolved in dioxane (3 mL) / H2O (0.6 mL) and reacted at 90°C for 2 hours. The reaction solution was concentrated under reduced pressure, diluted with H2O (10 mL), extracted with ethyl acetate (5 mL × 3), washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The product was purified by reverse phase column chromatography (mobile phase: ethyl acetate-petroleum ether, gradient: 0-5%) to afford compound 2-3 (361 mg, yield 89.1%) as a white solid. MS (ESI) m / z = 390.2 [M+H] + . 1H NMR (400MHz, CDCl3) δ7.55(d,J=8.0Hz,1H),7.46(s,1H),7.41(d,J=8.0Hz,1H),3.91(d,J=7.2Hz,2H),2.18(s, 3H),1.93(ddd,J=11.2,7.6,3.6Hz,1H),1.79–1.64(m,6H),1.40(s,9H),1.20–1.10(m,2H),1.06–0.98(m,2H).

[0194] Step 3 Synthesis of Compound 2-4

[0195] Compound 3A (80 mg, 0.26 mmol), compound 2-3 (167 mg, 0.43 mmol), Pd(t-Bu3P)2 (39.9 mg, 0.08 mmol), and Cs2CO3 (252 mg, 0.77 mmol) were dissolved in N,N-dimethylformamide (0.8 mL) and reacted at 130°C for 2 hours. The reaction solution was diluted with H2O (8 mL), extracted with ethyl acetate (3 mL x 4), washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude compound. Purification afforded compound 2-4 (33.2 mg, 19.5% yield) as a yellow solid. MS (ESI) m / z = 664.4 [M+H] + .

[0196] Step 4 Synthesis of compound RN002

[0197] Compound 2-4 (30 mg, 0.05 mmol) was dissolved in dichloromethane, and TFA (0.1 mL, 1.34 mmol) was added. The reaction mixture was stirred at 20°C for 2 hours. The reaction mixture was directly drained to obtain the crude product, which was purified to obtain compound RN002 (5.7 mg, 20.7% yield) as a yellow solid. MS (ESI) m / z = 608.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.55(d,J=4.4Hz,1H),8.05(d,J=8.0Hz,1H),7.81(d, J=8.0Hz,1H),7.57–7.45(m,3H),7.40–7.30(m,2H),6.99(d,J=8.8Hz,1H),5.2 1(t,2H),3.92(t,J=5.6Hz,2H),3.85(d,J=7.2Hz,2H),3.04(t,2H),2.13(s,3H ),1.84–1.75(m,1H),1.74–1.31(m,6H),1.29–1.17(m,2H),1.02–0.89(m,2H).

[0198] Example 9 Synthesis of Compound RN004

[0199] The synthetic route is as follows:

[0200] Step 1 Synthesis of compound 4-2

[0201] Toluene (40 mL) and H₂O (0.5 mL) were added to a 100 mL single-necked flask. Compound 4-1 (5.02 mL, 38.4 mmol), 3-methylpyrazole-4-boronic acid pinacol ester (4.0 g, 19.2 mmol), and CMBP (7.06 mL, 26.9 mmol) were then added sequentially with stirring. The reaction mixture was purged with nitrogen three times and stirred at 90°C for 18 hours. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The organic phase was washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The white compound 4-2 (418 mg, 6.39% yield) was obtained by reverse synthesis. MS (ESI) m / z = 341.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ7.47(s,1H),3.93(d,J=7.2Hz,2H),2.37(d,J=4.4Hz,3H),2.08-1.46(m,9H),1.24(s,12H).

[0202] Step 2 Synthesis of compound 4-3

[0203] To a 25 mL single-necked flask, dioxane (4.0 mL) and H₂O (0.8 mL) were added, followed by the addition of compound 4-2 (368 mg, 1.08 mmol), tert-butyl 3-bromo-6-chloropicolinate (314 mg, 1.08 mmol), K₂CO₃ (448 mg, 3.24 mmol), and Pd(dppf)Cl₂ (79.1 mg, 0.11 mmol) with stirring. The reaction mixture was purged with nitrogen three times and stirred at 90°C for 2 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (10 mL x 3). The organic phase was washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude product containing the target compound. Purification afforded compound 4-3 as a yellow oil (169 mg, 27.2% yield). MS (ESI) m / z = 426.2 [M+H] +

[0204] Step 3 Synthesis of compound 4-4

[0205] Compound 4-3 (80 mg, 0.19 mmol), compound 4 (58.5 mg, 0.19 mmol), Cs2CO3 (307 mg, 0.94 mmol), and KI (93.9 mg, 0.57 mmol) were added to 0.5 mL of dimethyl sulfoxide. The reaction mixture was purged with nitrogen three times and stirred in a microwave oven at 150°C for 2 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound (mobile phase: methanol-dichloromethane, gradient: 0-10%). Purification afforded the yellow compound 4-4 (7.0 mg, yield 5.32%). MS (ESI) m / z = 700.4 [M+H] + ;

[0206] Step 4 Synthesis of compound RN004

[0207] At 0°C, dichloromethane (0.5 mL), compound 4-4 (7 mg, 0.01 mmol), and TFA (0.5 mL) were added sequentially to a single-necked flask and stirred at 25°C for 2 hours. The reaction solution was concentrated, and the brown target product RN004 (1.45 mg, 22.4% yield) was obtained by reverse phase reaction. MS (ESI) m / z = 644.2 [M+H] + ; 1H NMR (400MHz, DMSO-d6): δ12.86(s,1H),12.31(s,1H),8.56(d,J=4.8Hz,1H),8.06(d,J=8.1 Hz,1H),7.82(d,J=8.1Hz,1H),7.59–7.52(m,2H),7.49(t,J=7.7Hz,1H),7.37(t,J=7.7Hz,1 H),7.31(s,1H),7.05(d,J=8.8Hz,1H),5.23(s,2H),3.98–3.94(m,4H),3.06(t,J=5.5Hz,2H ),2.14(s,3H),2.04–1.95(m,3H),1.87–1.68(m,2H),1.66–1.58(m,2H),1.32–1.19(m,2H).

[0208] The example compounds in the following Table 1 were prepared by the same methods as in the above examples using commercially available compounds or referring to the preparation methods of the intermediate compounds shown.

[0209] Table 1

[0210] Table 1

[0211] Example 10 Synthesis of Compound RN018

[0212] The synthetic route is as follows:

[0213] Step 1 Synthesis of compound RN018

[0214] To a 5 mL brown bottle, compound RN001 (9 mg, 13.7 μmol), N,N-dimethylformamide (1 mL), potassium carbonate (10 mg), and chloromethyl isobutyrate (3 mg) were added. The atmosphere was purged with nitrogen and the reaction was allowed to react at room temperature for 8 h. Completion of the reaction was monitored by TLC (dichloromethane:methanol = 20:1). The reaction solution was added to 4 mL of ice water and extracted twice with 2 mL of ethyl acetate. The ethyl acetate layers were combined, washed twice with 2 mL of saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford an oil. Preparative liquid separation afforded RN018 (1.5 mg, 14.5% yield) as a white solid. MS (ESI) m / z = 760.4 [M+H] + . 1H NMR (400MHz, DMSO-d6): δ12.32(s,1H),8.56(d,J=4.9Hz,1H),8.05(d,J=7.2Hz,1H),7.82(d,J=8.0Hz, 1H),7.61(d,J=8.8Hz,1H),7.57(d,J=4.9Hz,1H),7.53–7.44(m,1H),7.41–7.33(m,1H),7.24(s,1H),7 .13(d,J=8.9Hz,1H),5.74(s,2H),5.22(s,2H),3.95(t,J=5.9Hz,2H),3.72(s,2H),3.05(t,J=5.8Hz,2 H),2.11(s,3H),2.00(q,J=7.0Hz,1H),1.93(s,3H),1.72–1.39(m,12H),1.05(dd,J=12.7,6.9Hz,6H).

[0215] The example compounds in Table 2 below were prepared by the same methods as in the above examples using commercially available compounds or referring to the preparation methods of the intermediate compounds shown.

[0216] Table 2

[0217] Example 11 Synthesis of Compound RN019

[0218] The synthetic route is as follows:

[0219] Step 1 Synthesis of Compound 19-9

[0220] Compound 19-7 (200 mg, 446.12 μmol, 1 eq) and compound 19-8 (263.37 mg, 892.24 μmol, 2 eq) were dissolved in 1 mL of dioxane and 0.2 mL of water. 1,1-Bis(diphenylphosphino)ferrocenepalladium chloride (16.32 mg, 22.31 μmol, 0.05 eq) and potassium carbonate (184.97 mg, 1.34 mmol, 3 eq) were then added. The reaction mixture was stirred at 90°C for 16 hours under nitrogen. 5 mL of water was added to the reaction mixture, followed by extraction twice with 5 mL of ethyl acetate. The organic phase was washed with 5 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain compound 19-9 (200 mg, 83.54% yield) as a white solid. 1H NMR: δ8.57(br d,J=4.1Hz,1H),7.51-7.41(m,1H),7.34(br d,J=4.6Hz,1H),6.84(br d,J=8.6Hz,1H),5.77(br d,J=17.6Hz,1H),5.09(s,2H),4.46-4.21(m,4H),4.06(s,5H),3.07(br s,2H),1.60(s,9H),1.51(d,J=4.3Hz,9H)

[0221] Step 2 Synthesis of Compound 19-10

[0222] Compound 19-9 (150 mg, 279.53 μmol, 1 eq) was dissolved in 10 mL of methanol, followed by the addition of wet palladium on carbon (150.00 mg, 140.95 μmol, 10%, 5.04 e-1 eq). The atmosphere was then replaced with argon three times. The reaction mixture was stirred at 25°C under 15 psi for 16 hours. LCMS monitoring indicated complete reaction of the starting material with product formation. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to afford compound 19-10 (150 mg, crude) as a yellow solid.

[0223] Step 3 Synthesis of compound 19-11

[0224] Compound 19-10 (150 mg, 278.48 μmol, 1 eq) was dissolved in 2 mL of methanol and 1 mL of water, followed by the addition of monohydrate and lithium hydroxide (23.37 mg, 556.96 μmol, 2 eq). The reaction mixture was stirred at 25°C for 1 hour. LCMS monitoring indicated complete reaction of the starting material and formation of the product. The reaction mixture was adjusted to pH 6 with 1 M hydrochloric acid. The mixture was then concentrated under reduced pressure to afford compound 19-11 (146 mg, 278.30 μmol, crude) as a yellow solid.

[0225] Step 4 Synthesis of compound 19-13

[0226] Compound 19-11 (136 mg, 259.24 μmol, 1 eq) and 1,3-benzothiazol-2-amine (101.24 mg, 674.03 μmol, 2.6 eq) were dissolved in 2 mL of N,N-dimethylformamide. Then, N,N-diisopropylethylamine (167.53 mg, 1.30 mmol, 225.78 μL, 5 eq) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-B]pyridinium cation 1-oxidohexafluorophosphate (197.14 mg, 518.48 μmol, 2 eq) were added. The reaction mixture was stirred at 25°C for 1 hour. LCMS monitoring indicated that the starting materials had reacted completely and the product had formed. The reaction mixture was filtered, and the filtrate was purified by preparative liquid chromatography to afford compound 19-13 (28 mg, 16.44% yield) as a white solid.

[0227] Step 5 Synthesis of Compound 19-14

[0228] Compound 19-13 (28 mg, 42.63 μmol, 1 eq) was dissolved in 2 mL of dichloromethane, followed by the addition of trifluoroacetic acid (145.83 mg, 1.28 mmol, 95.00 μL, 30 eq). The reaction mixture was stirred at 25°C for 1 hour. Monitoring indicated that the starting material had reacted completely and the product had formed. The reaction mixture was concentrated under reduced pressure to yield compound 19-14 (26 mg, crude) as a brown solid.

[0229] Step 6 Synthesis of compound RN019

[0230] Compound 19-14 (20 mg, 39.95 μmol, 1 eq) and 1-adamantanecarboxaldehyde (19.69 mg, 119.86 μmol, 3 eq) were dissolved in 2 mL of methanol and 2 mL of N,N-dimethylformamide. Triethylamine (12.13 mg, 119.86 μmol, 16.68 μL, 3 eq) and sodium cyanoborohydride (5.02 mg, 79.91 μmol, 2 eq) were then added sequentially. The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was quenched by the addition of 1 mL of ethanol and then filtered. The filtrate was purified by preparative liquid chromatography to afford RN019 hydrochloride (3.27 mg, 9.18% yield) as a yellow solid. 1H NMR: (400MHz, DMSO-d6): δ12.49-12.11(m,1H),10.30-10.12(m,1H),9.62-9.46(m,1H),8.56(d,J =4.6Hz,1H),8.13-8.03(m,1H),7.89(d,J=9.0Hz,1H),7.83(d,J=8.1Hz,1H),7.59-7.53(m,1H),7 .50(t,J=7.7Hz,1H),7.43-7.30(m,1H),7.24-7.09(m,1H),5.24(s,2H),4.09-3.98(m,1H),3.97- 3.88(m,2H),3.87-3.74(m,2H),3.28-3.10(m,2H),3.09-2.99(m,4H),2.30-2.02(m,2H),1.97(br d,J=2.9Hz,3H),1.75-1.57(m,12H).

[0231] Example 12 Synthesis of compounds RN013 and RN014

[0232] The synthetic route is as follows:

[0233] Step 1 Synthesis of compound 13-3

[0234] [(3R,5S,7s)-adamantan-1-yl]methanol (10 g, 60.15 mmol, 1 eq) was dissolved in 100 mL of toluene. Vinyl acetate (15.53 g, 180.44 mmol, 16.70 mL, 3 eq), potassium carbonate (3.82 g, 36.09 mmol, 0.6 eq), and 1,5-cyclooctadiene iridium chloride dimer (404.01 mg, 601.47 μmol, 0.01 eq) were added. The reaction mixture was stirred at 110°C for 16 hours. TLC indicated the formation of new spots and complete reaction of the starting material. The reaction mixture was quenched with 200 mL of saturated sodium carbonate solution and extracted twice with 200 mL of ethyl acetate. The combined organic phases were washed with 200 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography to afford compound 13-3 (7.61 g, 65.80% yield). 1H NMR: (400MHz, CDCl3): δ6.41(dd,J=6.8,14.4Hz,1H),4.06(dd,J=1.8,14.3Hz,1H),3.85(dd,J=1.8,6.8Hz,1H),3.16(s,2H),1.91(br s,3H),1.70-1.64(m,3H),1.61-1.56(m,3H),1.49(d,J=2.4Hz,6H)

[0235] Step 2 Synthesis of compound 13-5

[0236] Compound 13-3 (3 g, 15.60 mmol, 1 eq) was dissolved in 30 mL of toluene. 2-Vinyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.40 g, 15.60 mmol, 2.65 mL, 1 eq) and Grubbs' second-generation catalyst (1.32 g, 1.56 mmol, 0.1 eq) were added. The reaction mixture was stirred at 110°C for 16 hours. TLC showed the formation of new spots. The reaction mixture was post-processed and purified by column chromatography to obtain compound 13-5 (2.13 g, 42.90% yield) as a yellow oil. 1 H NMR (400MHz, CDCl3): δ7.06 (d, J = 14.4Hz, 1H), 4.41 (d, J = 14.3Hz, 1H), 3.33 (s, 2H), 1.98 (br s,3H),1.75-1.70(m,3H),1.68-1.64(m,3H),1.55(d,J=2.4Hz,6H),1.25(s,12H)

[0237] Step 3 Synthesis of compound 13-7

[0238] Compound 13-6 (1.95 g, 6.67 mmol, 1 eq) was dissolved in 20 mL of dichloromethane, and trifluoroacetic acid (15.35 g, 134.62 mmol, 10 mL, 20.18 eq) was added. The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated to obtain a crude product, which was dissolved in 30 mL of dichloromethane and the pH was adjusted to 9 with saturated sodium bicarbonate solution. The product was extracted five times with 50 mL of a 1:1 mixture of dichloromethane and methanol. The combined organic phases were dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain compound 13-7 (1.06 g, 82.67% yield) as a yellow oil.

[0239] Step 4 Synthesis of compound 13-8

[0240] Compound 13-7 (1.06 g, 5.51 mmol, 1 eq) was dissolved in 10 mL of dimethyl sulfoxide, and potassium fluoride (1.60 g, 27.57 mmol, 5 eq) and tert-butyl 3-bromo-6-chloropyridine-2-carboxylate (3.23 g, 11.03 mmol, 2 eq) were added. The reaction mixture was stirred at 100°C for 16 hours. The reaction mixture was poured into 30 mL of water and extracted twice with 30 mL of ethyl acetate. The combined organic phases were washed with 50 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography to afford compound 13-8 (1.51 g, 61.08% yield) as a yellow oil.

[0241] Step 5 Synthesis of Compound 13-9

[0242] Compound 13-8 (300 mg, 669.18 μmol, 1 eq) was dissolved in 3 mL of dioxane and 0.6 mL of water. 4,4,5,5-tetramethyl-2-[(1E)-2-{[(3R,5S,7s)-adamantan-1-yl]methoxy}vinyl]-1,3,2-dioxaborolane (563 mg, 1.77 mmol, 2.64 eq), potassium carbonate (277.45 mg, 2.01 mmol, 3 eq), and 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (48.96 mg, 66.92 μmol, 0.1 eq) were added. The reaction mixture was stirred at 100°C under a nitrogen atmosphere for 2 hours. The reaction solution was poured into 30 mL of water and extracted twice with 30 mL of ethyl acetate. The combined organic phases were washed with 50 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography to obtain compound 13-9 (302 mg, yield 80.63%) as a yellow oil.

[0243] Step 6 Synthesis of compound 13-10

[0244] Compound 13-9 (200 mg, 357.34 μmol, 1 eq) was dissolved in 5 mL of tetrahydrofuran, and wet palladium on carbon (100.00 mg, 10% palladium content) was added. The reaction mixture was stirred at 25°C under a 15 psi hydrogen atmosphere for 16 hours. The reaction mixture was filtered and concentrated, and the residue was purified by column chromatography to afford the yellow compound 13-10 (141 mg, 70.25% yield).

[0245] Step 7 Synthesis of compound 13-11

[0246] Compound 13-10 (141 mg, 251.02 μmol, 1 eq) was dissolved in a mixture of 1 mL of tetrahydrofuran, 1 mL of methanol, and 1 mL of water. Lithium hydroxide monohydrate (21.07 mg, 502.04 μmol, 2 eq) was added, and the reaction mixture was stirred at 25°C under a nitrogen atmosphere for 1 hour. The reaction mixture was adjusted to pH 7 with 0.5 mol / L hydrochloric acid and then lyophilized to obtain compound 13-11 (121 mg, crude) as a yellow solid.

[0247] Step 8 Synthesis of compound RN013

[0248] Compound 13-11 (60 mg, 109.55 μmol, 1 eq) was dissolved in 1 mL of N,N-dimethylformamide. N,N-diisopropylethylamine (70.79 mg, 547.76 μmol, 95.41 μL, 5 eq) and 1,3-benzothiazol-2-amine (32.91 mg, 219.10 μmol, 2 eq) were added, followed by HATU (124.97 mg, 328.66 μmol, 3 eq). The reaction mixture was stirred at 25°C for 2 hours. LCMS showed complete consumption of the starting material. The reaction mixture was poured into 10 mL of water and extracted twice with 10 mL of ethyl acetate. The combined organic phases were washed with 10 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography to afford RN013 (20 mg, 26.85% yield) as a yellow oil.

[0249] Step 9 Synthesis of compound RN014

[0250] Compound RN013 (48 mg, 70.60 μmol, 1 eq) was dissolved in 1 mL of dichloromethane, and trifluoroacetic acid (1.54 g, 13.46 mmol, 1 mL, 190.68 eq) was added. The reaction mixture was stirred at 25°C for 2 hours. 3 mL of N,N-dimethylformamide was added, and the pH was adjusted to 8 with DIEA. The reaction mixture was then purified by preparative liquid phase to afford RN014 (24.11 mg, 54.75% yield) as an off-white solid. 1H NMR: (400MHz, DMSO-d6): δ8.53(d,J=4.8Hz,1H),8.05(d,J=7.9Hz,1H),7.81(d,J=8.0Hz,1H),7.52 (d,J=4.8Hz,1H),7.50-7.42(m,2H),7.39-7.33(m,1H),6.83(d,J=8.6Hz,1H),5.14(s,2H),3.88(br t,J=5.7Hz,2H),3.47(br s,2H),3.01(br t,J=5.5Hz,2H),2.93(s,2H),2.80(br t,J=6.9Hz,2H),1.89(br s,3H),1.70-1.61(m,3H),1.61-1.54(m,3H),1.45(d,J=1.6Hz,6H)

[0251] Example 13 Synthesis of Compound RN020

[0252] The synthetic route is as follows:

[0253] Step 1 Synthesis of Compound 20-2

[0254] Compound 20-1 (200 mg, 1.21 mmol, 214.36 μL, 1 eq) was dissolved in ethyl formate (1.84 g, 24.87 mmol, 2 mL, 20.55 eq). The reaction mixture was stirred at 60°C under a nitrogen atmosphere for 16 hours, then the solvent was removed by spin drying. The residue was dissolved in 4 mL of tetrahydrofuran and cooled to 0°C. Lithium aluminum tetrahydride (2.5 M, 1.45 mL, 3 eq) was added dropwise at 0°C, and the reaction mixture was slowly warmed to room temperature. The reaction mixture was stirred at 80°C under a nitrogen atmosphere for 16 hours. TLC (petroleum ether:ethyl acetate = 4:1) showed the formation of new spots. The reaction mixture was quenched with 20 mL of ice water at 0°C, followed by the addition of 20 mL of 2N sodium hydroxide solution and extraction with 30 mL of ethyl acetate twice. The combined organic phases were washed with 50 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to afford compound 20-2 (91 mg, 41.94% yield) as a yellow oil. 1 H NMR: δ2.42(s,3H),2.22(s,2H),1.97(br s,3H),1.76-1.69(m,3H),1.68-1.61(m,3H),1.53(br s,6H).

[0255] Step 2 Synthesis of Compound 20-5

[0256] Compound 20-3 (2.7 g, 9.70 mmol, 1 eq) was dissolved in 40 mL of N,N-dimethylformamide. N,N-diisopropylethylamine (3.76 g, 29.10 mmol, 5.07 mL, 3 eq) and compound 20-3 (1.75 g, 11.64 mmol, 1.2 eq) were added. HATU (5.53 g, 14.55 mmol, 1.5 eq) was then added portionwise at 0–5°C. The reaction mixture was stirred at 25°C for 2 hours. LCMS analysis indicated 75% product formation. The reaction mixture was poured into 50 mL of water and filtered. The residue was washed twice with 30 mL of ethyl acetate and then dried to afford compound 20-5 (2.19 g, 54.99% yield) as a yellow solid.

[0257] Step 3 Synthesis of compound 20-6

[0258] Compound 20-5 (1.82 g, 4.43 mmol, 1 eq) was dissolved in 10 mL of dichloromethane, and trifluoroacetic acid (15.35 g, 134.62 mmol, 10 mL, 30.36 eq) was added. The reaction mixture was stirred at 25°C for 1 hour. LCMS monitoring indicated 99% product formation. The reaction mixture was concentrated to obtain a crude product, which was then poured into 40 mL of saturated aqueous sodium bicarbonate solution. The mixture was filtered, and the filter cake was concentrated to afford compound 20-6 (1.01 g, 73.40% yield) as a yellow solid.

[0259] Step 4 Synthesis of Compound 20-8

[0260] Compound 20-6 (N-(1,3-benzothiazol-2-yl)-5,6,7,8-tetrahydro-2,7-naphthyridine-1-carboxamide) (1.01 g, 3.25 mmol, 1 eq) was dissolved in 15 mL of dimethyl sulfoxide. Cesium carbonate (4.24 g, 13.02 mmol, 4 eq) and compound 20-7 tert-butyl 3-bromo-6-chloropyridine-2-carboxylate (2.86 g, 9.76 mmol, 3 eq) were added. The reaction mixture was stirred at 95°C for 16 hours. LCMS monitoring indicated 36% product formation. The reaction solution was poured into 30 mL of water, and the pH was adjusted to 7 with 1N hydrochloric acid. The mixture was then filtered, and the filtrate was extracted twice with 30 mL of ethyl acetate. The combined organic phases were washed with 30 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography to obtain yellow solid compound 20-8 (1.02 g, yield 55.33%).

[0261] Step 5 Synthesis of Compound 20-9

[0262] Compound 20-8 (1 g, 1.77 mmol, 1 eq) was dissolved in 10 mL of tetrahydrofuran, and triethylamine (357.26 mg, 3.53 mmol, 491.42 μL, 2 eq) and 2-(trimethylsilyl)ethoxymethyl chloride (441.47 mg, 2.65 mmol, 468.66 μL, 1.5 eq) were added. The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was poured into 50 mL of water and extracted twice with 50 mL of dichloromethane. The combined organic phases were washed with 100 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography to afford Compound 20-9 (0.97 g, 78.86% yield) as a yellow oil.

[0263] Step 6 Synthesis of compound 20-11

[0264] Compound 20-9 (150.00 mg, 215.29 μmol, 1 eq) was dissolved in 2 mL of dioxane and 0.5 mL of water. Compound 20-10 (2-[(1E)-2-ethoxyvinyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane) (127.93 mg, 645.88 μmol, 3 eq), potassium carbonate (89.27 mg, 645.88 μmol, 3 eq), and 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (15.75 mg, 21.53 μmol, 0.1 eq) were added. The reaction mixture was stirred at 95°C under a nitrogen atmosphere for 2 hours. The reaction solution was poured into 10 mL of water and extracted twice with 10 mL of ethyl acetate. The combined organic phases were washed with 10 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography to obtain compound 20-11 (128 mg, yield 86.43%) as a yellow oil.

[0265] Step 7 Synthesis of Compound 20-12

[0266] Compound 20-11 (128.00 mg, 186.07 μmol, 1 eq) was dissolved in 2 mL of dichloromethane, and trifluoroacetic acid (1.54 g, 13.46 mmol, 1 mL, 72.35 eq) was added. The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was concentrated to give compound 20-12 (88.1 mg, crude) as a brown oil.

[0267] Step 8 Synthesis of compound RN020

[0268] Compound 20-12 (88.10 mg, 186.06 μmol, 1 eq) was dissolved in 2 mL of dichloromethane. Triethylamine (94.14 mg, 930.30 μmol, 129.49 μL, 5 eq) and compound 20-2 (40.03 mg, 223.27 μmol, 1.2 eq) were added, and the reaction mixture was stirred at 25°C for 1 hour. Sodium triacetoxyborohydride (78.87 mg, 372.12 μmol, 2 eq) was then added, and the reaction mixture was stirred at 25°C under a nitrogen atmosphere for 1 hour. 3 mL of N,N-dimethylformamide was added to the reaction mixture, and the mixture was filtered. The filtrate was purified by preparative liquid chromatography to afford RN020 (18.11 mg, 14.73% yield) as a yellow solid. MS (ESI) m / z = 637.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ8.54(d,J=4.8Hz,1H),8.05(d,J=7.6Hz,1H),7.81(d,J=8.1Hz ,1H),7.58-7.45(m,3H),7.41-7.32(m,1H),6.94(d,J=8.8Hz,1H),5.16(s,2H),3.89(br t,J=5.7Hz,2H),3.01(br t,J=5.6Hz,2H),2.80-2.75(m,2H),2.69-2.65(m,2H),2.36(s,3H),2.16(s,2H),1.75(br s,3H),1.54-1.48(m,3H),1.47-1.41(m,3H),1.30(br s,6H).

[0269] Example 14 Synthesis of Compound RN021

[0270] The synthetic route is as follows:

[0271] Step 1 Synthesis of Compound 21-3

[0272] Compound 21-1 (300 mg, 669.18 μmol, 1 eq) and compound 21-2 (339.72 mg, 2.01 mmol, 3 eq) were dissolved in 3 mL of N,N-dimethylformamide, followed by the addition of cesium carbonate (654.10 mg, 2.01 mmol, 3 eq) and 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (97.93 mg, 133.84 μmol, 0.2 eq). The reaction mixture was stirred at 100°C under nitrogen for 16 hours. The starting materials reacted completely, and the product was formed. 10 mL of water was added to the reaction mixture, followed by extraction with 10 mL of ethyl acetate twice. The organic phase was washed with 10 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography to afford compound 21-3 (230 mg, 64.05% yield) as a yellow solid.

[0273] Step 2 Synthesis of Compound 21-4

[0274] Compound 21-3 (230 mg, 428.61 μmol, 1 eq) was dissolved in 5 mL of methanol, followed by the addition of wet palladium on carbon (115 mg, 108.06 μmol, 10% purity). The atmosphere was then replaced with argon three times. The reaction mixture was stirred at 25°C under 15 psi for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to afford compound 21-4 (175 mg, 75.80% yield) as a yellow solid.

[0275] Step 3 Synthesis of compound 21-5

[0276] Compound 21-4 (175 mg, 324.90 μmol, 1 eq) was dissolved in 1 mL of methanol and 1 mL of water. Water and lithium hydroxide (27.27 mg, 649.79 μmol, 2 eq) were then added. The reaction mixture was stirred at 25°C for 1 hour. The pH of the reaction mixture was adjusted to 8 with 1 M hydrochloric acid solution. The mixture was then concentrated under reduced pressure to yield compound 21-5 (170 mg, crude) as a yellow solid.

[0277] Step 4 Synthesis of Compound 21-7

[0278] Compound 21-5 (150 mg, 285.93 μmol, 1 eq) and 1,3-benzothiazol-2-amine (51.54 mg, 343.11 μmol, 1.2 eq) were dissolved in 2 mL of tetrahydrofuran. N,N-diisopropylethylamine (184.77 mg, 1.43 mmol, 249.02 μL, 5 eq) and 2-chloro-1-methylpyridinium iodide (219.15 mg, 857.78 μmol, 3 eq) were then added. The reaction mixture was stirred at 60°C for 16 hours. 10 mL of water was added to the reaction mixture, and the mixture was extracted twice with 10 mL of ethyl acetate. The organic phase was washed with 10 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain the yellow compound 21-7 (110 mg, 167.48 μmol, yield: 58.57%).

[0279] Step 5 Synthesis of Compound 21-8

[0280] Compound 21-7 (100 mg, 152.26 μmol, 1 eq) was dissolved in 2 mL of dichloromethane, followed by the addition of trifluoroacetic acid (3.07 g, 26.92 mmol, 2 mL, 176.84 eq). The reaction mixture was stirred at 25°C for 2 hours. LCMS monitoring indicated complete reaction of the starting material and formation of the product. The reaction mixture was concentrated under reduced pressure to afford compound 21-8 (76 mg, crude) as a brown solid.

[0281] Step 6 Synthesis of compound RN021

[0282] Compound 21-8 (76 mg, 151.83 μmol, 1 eq) and 1-adamantanecarboxaldehyde (62.34 mg, 379.57 μmol, 2.5 eq) were dissolved in 2 mL of N,N-dimethylformamide. Triethylamine (46.09 mg, 455.48 μmol, 63.40 μL, 3 eq) and sodium cyanoborohydride (19.08 mg, 303.65 μmol, 2 eq) were then added sequentially. The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was quenched by the addition of 0.5 mL of ethanol and then filtered. The filtrate was purified by preparative liquid chromatography to afford compound RN021 (2.51 mg, 2.47% yield) as a yellow solid.

[0283] Example 15 Synthesis of Compound RN022

[0284] The synthetic route is as follows:

[0285] Step 1 Synthesis of Compound 22-3

[0286] To a 25 mL single-necked flask, dioxane (5 mL) and water (0.5 mL) were added, followed by the addition of compound 22-1 (300 mg, 1.11 mmol), compound 22-2 (395 mg, 1.11 mmol), Pd(dppf)Cl2 (71.6 mg, 0.11 mmol), and cesium carbonate (1.08 g, 3.33 mmol) with stirring. The reaction mixture was purged with nitrogen three times and stirred at 70°C for 18 hours. After completion, the reaction was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude product containing the target compound. Purification afforded compound 22-3 (59 mg, 12.6% yield) as a colorless oil. MS (ESI) m / z = 420.2 [M+H] + .

[0287] Step 2 Synthesis of compound RN022

[0288] To a 25 mL three-necked flask, dimethyl sulfoxide (1 mL) was added, followed by the addition of compound 22-3 (50 mg, 0.12 mmol), compound 2A (N-(benzo[d][1,3]thiazol-2-yl)-5,6,7,8-tetrahydropyrido[3,4-c]pyridine-1-carboxamide) (36.9 mg, 0.12 mmol), cesium carbonate (193 mg, 0.60 mmol), and potassium iodide (59.2 mg, 0.36 mmol) with stirring. The reaction mixture was purged with nitrogen three times and stirred at 130°C for 18 hours. The reaction mixture was filtered, and the filtrate was reversed to afford RN022 as a white solid (2.22 mg, 2.8% yield). MS (ESI) m / z = 666.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ = 12.30 (br, 1H), 8.60 (d, J = 4.8Hz, 1H), 8.05 (d, J = 7.6Hz ,1H),7.82(d,J=8.0Hz,1H),7.61(d,J=4.8Hz,1H),7.49(t,J=7.6Hz,1H),7.45(s, 1H),7.37(t,J=7.6Hz,1H),5.15(s,2H),3.81(t,J=4.8Hz,2H),3.73(s,2H),3.12 (t,J=5.6Hz,2H),2.16(s,3H),1.93(s,3H),1.70-1.61(m,3H),1.60-1.49(m,9H).

[0289] Example 16 Synthesis of Compounds RN023 and RN024

[0290] The synthetic route is as follows:

[0291] Step 1 Synthesis of Compound 23-2

[0292] Compound 23-1 (1.00 g, 3.70 mmol) and compound 1A (1.27 g, 3.70 mmol) were dissolved in dioxane (10 mL) and water (1 mL). Cesium carbonate (3.61 g, 11.0 mmol) and Pd(dtbpf)Cl2 (0.24 g, 0.37 mmol) were added to the reaction solution, and the reaction mixture was allowed to react at 70°C for 18 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, diluted with water (30 mL), extracted with ethyl acetate (30 mL × 3), washed with saturated brine (10 mL), dried, and concentrated to obtain the crude product. Purification (mobile phase: ethyl acetate-petroleum ether, gradient: 0-20%) afforded compound 23-2 (424 mg, 1.04 mmol, yield 28.2%) as a yellow solid. MS (ESI) m / z = 406.2 [M+H] + .

[0293] Step 2 Synthesis of compound RN023

[0294] Compound 23-2 (50 mg, 0.12 mmol), compound 2A (57.3 mg, 0.18 mmol), cesium carbonate (200 mg, 0.62 mmol), and potassium iodide (61.3 mg, 0.37 mmol) were dissolved in dimethyl sulfoxide (1.5 mL) and reacted at 100°C for 16 hours. The reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 2). The mixture was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. Prep-TLC purification (dichloromethane:methanol = 10:1) afforded compound RN023 as a white solid (20 mg, yield 23.8%). MS (ESI) m / z = 680.2 [M+H] + .

[0295] Step 3 Synthesis of compound RN024

[0296] Compound RN023 (20 mg, 0.03 mmol) and lithium hydroxide monohydrate (6.17 mg, 0.15 mmol) were dissolved in tetrahydrofuran (0.3 mL), methanol (0.05 mL), and water (0.1 mL) and reacted at 25°C for 3 hours. The mixture was concentrated and the reaction was reversed to afford compound RN024 (1.02 mg, 5.32% yield) as a white solid. MS (ESI) m / z = 652.2 [M+H] + . 1H NMR (400MHz, DMSO-d6): δ12.31(s,1H),8.60(d,J=4.8Hz,1H),8.06(t,J=3.6Hz,2H) ,7.82(d,J=8.0Hz,1H),7.73(s,1H),7.61(d,J=4.8Hz,1H),7.49(d,J=7.8Hz,1H),7 .37(t,J=7.8Hz,1H),5.15(s,2H),3.84(t,J=6.0Hz,2H),3.80(s,2H),3.12(t,J=5. 2Hz, 2H), 1.93 (s, 3H), 1.64 (d, J = 11.6Hz, 3H), 1.54 (d, J = 10.8Hz, 3H), 1.47 (s, 6H).

[0297] Example 17 Synthesis of Compounds RN025 and RN026

[0298] The synthetic route is as follows:

[0299] Step 1 Synthesis of Compound 25-2

[0300] At 0°C, under nitrogen, anhydrous toluene (300 mL), 3-methylpyrazole-4-boronic acid pinacol ester (30 g, 144 mmol), and 1-adamantane methanol (33.5 g, 201 mmol) were added to a 500 mL single-necked flask. The reaction mixture was purged with nitrogen three times and stirred at 100°C for 12 hours. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (200 mL x 2). The organic phase was washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound. Purification afforded the white compound 25-2 (2.5 g, 4.87% yield). MS (ESI) m / z = 357.2 [M+H] + . 1 H NMR (400MHz, CDCl3): δ7.69(s,1H),3.71(s,2H),2.42(s,3H),1.97(s,3H),1.74-1.55(m,12H),1.31(s,12H).

[0301] Step 2 Synthesis of compound 25-3

[0302] To a 100 mL single-necked flask were added 1,4-dioxane (20 mL), water (2.0 mL), tert-butyl 3-bromo-6-chloropicolinate (1.72 g, 5.87 mmol), compound 25-2 (1.9 g, 5.33 mmol), Pd(dppf)Cl2 (0.34 g, 0.53 mmol), and cesium carbonate (5.21 g, 16.0 mmol). The reaction mixture was purged with nitrogen three times and stirred at 90°C for 12 hours. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a crude product containing the target compound. Purification afforded the yellow compound 25-3 (858 mg, 36.4% yield). MS (ESI) m / z = 442.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ7.85(d,J=8.0Hz,1H),7.66(d,J=8.0Hz,1H),7.36(s ,1H),3.77(s,2H),2.17(s,3H),1.93(s,3H),1.72-1.53(m,12H),1.36(s,9H).

[0303] Step 3 Synthesis of compound 25-5

[0304] To a 25 mL single-necked flask, N,N-dimethylformamide (3.0 mL) was added, followed by the addition of compound 25-4 (300 mg, 1.08 mmol), N,N-diisopropylethylamine (0.54 mL, 3.23 mmol), and HATU (614 mg, 1.62 mmol) with stirring. The reaction mixture was stirred at room temperature for 0.5 hours, followed by the addition of 2-aminobenzothiazole (194 mg, 1.29 mmol). The reaction mixture was purged with nitrogen three times and stirred at 40°C for 5 hours. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (10 mL x 3). The organic phase was washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude product containing the target compound. The crude product was purified by slurrying with ethyl acetate (15 mL) to afford the white compound 25-5 (350 mg, 79.1% yield). MS (ESI) m / z = 411.1 [M+H] + . 1H NMR (400MHz, DMSO-d6): δ13.09(s,1H),8.78(s,1H),8.57(s,1H),8.05(d,J=7.6Hz,1H),7.80(d,J=7.6Hz,1H ),7.49(d,J=7.2Hz,1H),7.37(t,J=7.6Hz,1H),4.78(s,2H),3.62(s,2H),2.89(t,J=4.0Hz,2H),1.41(s,9H).

[0305] Step 4 Synthesis of compound 25-6

[0306] To a 25 mL single-necked flask, 1,4-dioxane (5 mL) was added, followed by the addition of compound 25-5 (260 mg, 0.63 mmol) with stirring. A 4N hydrogen chloride solution in 1,4-dioxane (10 mL) was then added under ice. The reaction mixture was stirred at room temperature for 3 hours, quenched with saturated sodium carbonate solution (10 mL), and extracted with n-butanol (20 mL x 3). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield a white solid containing the target compound 25-6 (130 mg, 66.1% yield). MS (ESI) m / z = 311.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ13.09(s,1H),8.78(s,1H),8.57(s,1H),8.05(d,J=7.6Hz,1H),7.80(d,J=7.6 Hz,1H),7.49(d,J=7.2Hz,1H),7.37(t,J=7.6Hz,1H),4.78(s,2H),3.62(s,2H),2.89(t,J=4.0Hz,2H).

[0307] Step 5 Synthesis of compound RN025

[0308] To a 10 mL microwave tube was added N,N-dimethylformamide (3.0 mL), compound 25-6 (84.2 mg, 0.27 mmol), 25-3 (80 mg, 0.18 mmol), cesium carbonate (206 mg, 0.63 mmol), and bis(tri-tert-butylphosphine)palladium (18.5 mg, 0.04 mmol). Under nitrogen protection, the reaction solution was microwaved at 120°C for 2 hours. Water (15 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound (mobile phase: methanol / dichloromethane, gradient: 0-8%). Purification afforded the yellow compound RN025 (106 mg, yield 69.5%). MS (ESI) m / z = 716.3 [M+H] +

[0309] Step 6 Synthesis of compound RN026

[0310] To a 25 mL single-necked flask at 0°C, dichloromethane (2.0 mL), compound RN025 (79 mg, 0.11 mmol), and trifluoroacetic acid (2.0 mL) were added sequentially and stirred at 25°C for 4 hours. The reaction solution was concentrated, and the white target product RN026 (6.35 mg, 8.72% yield) was obtained by reverse synthesis. MS (ESI) m / z = 660.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ13.09(br,1H),12.83(br,1H),8.80(s,1H),8.60(s,1H),8.05(d,J =7.6Hz,1H),7.81(d,J=8.4Hz,1H),7.54(d,J=8.8Hz,1H),7.49(t,J=7.9Hz,1H),7.37(t,J= 7.2Hz,1H),7.28(s,1H),7.03(d,J=8.8Hz,1H),5.02(s,2H),3.94(t,J=5.6Hz,2H),3.71(s, 2H),3.01(t,J=5.6Hz,2H),2.11(s,3H),1.93(s,3H),1.68-1.61(m,3H),1.60-1.50(m,9H).

[0311] Example 18 Synthesis of Compound RN027

[0312] The synthetic route is as follows:

[0313] Step 1 Synthesis of compound RN027

[0314] Compound 27-1 (200 mg, 0.644 mmol, 1 eq), compound 27-2 (320 mg, 0.644 mmol, 1 eq), cesium carbonate (525 mg, 1.61 mmol, 2.5 eq), and bis(tri-tert-butylphosphine)palladium (66 mg, 0.129 mmol, 0.2 eq) were added to a 10 mL microwave tube. The mixture was purged with nitrogen and microwaved at 130°C for 3 h. The mixture was then filtered, the filter cake was rinsed with methanol, and the mixture was concentrated under reduced pressure. Column chromatography was performed to obtain compound RN027 (5.75 mg) as a white solid. MS (ESI) m / z = 771.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ13.13(s,1H),8.83(s,1H),8.65(s,1H),8.05(d,J=7.9Hz,1H),7.81(d,J=8.0Hz ,1H),7.57–7.45(m,2H),7.38(t,J=7.6Hz,1H),7.21(s,1H),6.96(d,J=8.9Hz,1H),5.04(s,2H),4.24(d, J=12.5Hz,1H),3.88(p,J=6.6Hz,2H),3.71(d,J=2.8Hz,2H),3.27(t,J=6.4Hz,2H),3.12(d,J=13.1Hz,2H ),3.07–3.00(m,2H),2.74–2.59(m,2H),2.15(s,3H),1.92(s,3H),1.72–1.30(m,16H),1.27–1.09(m,3H).

[0315] Example 19 Synthesis of Compound RN030

[0316] The synthetic route is as follows:

[0317] Step 1 Synthesis of Compound 30-2

[0318] Compound 30-1 (440 mg, 1.58 mmol) was dissolved in acetonitrile (5 mL), and CDI (0.28 mL, 2.21 mmol) was added and stirred for 0.5 h. DBU (0.38 mL, 2.53 mmol) was then added to the reaction mixture and stirred for 0.5 h. Compound 1A (332 mg, 2.21 mmol) was then added and the temperature was raised to 60°C with stirring for 12 h. The reaction mixture was concentrated under reduced pressure to remove the acetonitrile and extracted with a 10:1 mixture of dichloromethane and methanol (20 mL). The organic phase was washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product (mobile phase: dichloromethane-methanol, gradient: 0-10%). Purification afforded compound 30-2 (576 mg, 88.8% yield) as a yellow oil. MS (ESI) m / z = 411.1 [M+H] + .

[0319] Step 2 Synthesis of compound 30-3

[0320] Compound 30-2 (520 mg, 1.27 mmol) was dissolved in dioxane (1 mL) and 4N HCl / dioxane (1 mL, 4.00 mmol) was added. The reaction mixture was reacted at 20°C for 2 hours. The reaction mixture was concentrated under reduced pressure and used directly in the next step. Compound 30-3 (467 mg of crude hydrochloride) was obtained as a yellow solid. MS (ESI) m / z = 311.1 [M+H] + .

[0321] Step 3 Synthesis of compound 30-4

[0322] Compound 30-3 (467 mg, 1.50 mmol) and compound 3A (880 mg, 3.01 mmol) were dissolved in dimethyl sulfoxide (10 mL), and cesium carbonate (2450 mg, 7.52 mmol) and potassium iodide (749 mg, 4.51 mmol) were added. The reaction solution was stirred at 100°C for 48 hours. The reaction solution was diluted with water (100 mL), extracted with ethyl acetate (25 mL × 4), washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product compound 30-4 (198 mg, yield 23.2%). MS (ESI) m / z = 566.0 [M+H] + .

[0323] Step 4 Synthesis of compound 30-5

[0324] Compound 30-4 (90.0 mg, 0.16 mmol) and compound 4A (62.3 mg, 0.17 mmol) were dissolved in water (0.3 mL) and dioxane (1.2 mL). Pd2(dba)3 (14.5 mg, 0.02 mmol), meCgPPh (CAS: 97739-46-3) (9.00 mg, 0.03 mmol), and sodium bicarbonate (53.4 mg, 0.64 mmol) were added, and the reaction mixture was stirred at 120°C for 12 hours. The reaction mixture was filtered through a funnel, and the organic phase was concentrated to obtain the crude product. Purification afforded compound 30-5 (25.0 mg, 22.0% yield) as a yellow solid. MS (ESI) m / z = 716.0 [M+H] +

[0325] Step 5 Synthesis of compound RN030

[0326] Compound 5 (20.0 mg, 0.03 mmol) was dissolved in DCM (0.5 mL) and TFA (0.25 mL, 3.35 mmol) was added. The reaction mixture was stirred at 20°C for 6 hours. The reaction mixture was concentrated to give the crude product (mobile phase: acetonitrile-water (0.1% FA), gradient: 92-98%). Purification afforded the yellow solid product RN030 (5.70 mg, yield 30.9%). MS (ESI) m / z = 660.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ8.60(d,J=4.8Hz,1H),8.05(d,J=8.0Hz,1H),7.81(d, J=7.7Hz,1H),7.59(d,J=4.9Hz,1H),7.50(dd,J=16.0,8.2Hz,2H),7.37(t,J=7 .7Hz,1H),7.27(s,1H),7.04(d,J=8.5Hz,1H),4.97(s,2H),4.01(s,2H),3.70( s,2H),3.11(s,2H),2.10(s,3H),1.93(s,3H),1.59(dd,J=40.8,16.0Hz,12H).

[0327] Example 20 Synthesis of Compound RN031

[0328] The synthetic route is as follows:

[0329] Step 1: Synthesis of compound 31-2

[0330] Dissolve 3,5-dibromopyridine-4-carboxaldehyde (23.42 g, 88.41 mmol, 1 eq) in 250 mL of tetrahydrofuran, add 2-methylpropane-2-sulfenamide (12.86 g, 106.09 mmol, 1.2 eq) and tetraisopropoxytitanium (22.61 g, 79.57 mmol, 23.48 mL, 0.9 eq). The reaction mixture is stirred at 70°C for 16 hours. The reaction mixture is concentrated to give Compound 31-2 (32.54 g, crude) as a yellow solid. MS (ESI) m / z = 368.7 [M+H] +

[0331] Step 2: Synthesis of compound 31-3

[0332] 31-2 (32.54 g, 88.40 mmol, 1 eq) was dissolved in 350 mL of methanol. Sodium borohydride (1.17 g, 30.94 mmol, 0.35 eq) was added portionwise at 0-5°C under nitrogen. The reaction mixture was stirred at 25°C under nitrogen for 2 hours. The reaction mixture was quenched with 100 mL of methanol at 0-5°C and then filtered. The filter cake was washed twice with 100 mL of methanol. The filtrate was concentrated to obtain the crude product, which was purified by column chromatography to afford compound 31-3 (26.48 g, 80.93% yield) as a light yellow solid.

[0333] Step 3: Synthesis of compound 31-5

[0334] 31-3 (27.78 g, 75.06 mmol, 1 eq) was dissolved in 300 mL of dioxane and 60 mL of water. 31-4 (15.61 g, 78.81 mmol, 1.05 eq) and potassium phosphate (31.87 g, 150.12 mmol, 2 eq) were added. The atmosphere was then purged with nitrogen three times before the addition of 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (5.49 g, 7.51 mmol, 0.1 eq). The reaction mixture was stirred at 90°C under nitrogen for 2 hours. The reaction mixture was poured into 500 mL of water and extracted twice with 500 mL of ethyl acetate. The combined organic phases were washed with 500 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography to afford compound 31-5 (21.64 g, 79.80% yield) as an orange oil. MS (ESI) m / z = 363.0 [M+H] + .

[0335] Step 4: Synthesis of compound 31-6

[0336] 31-5 (21.64 g, 59.90 mmol, 1 eq) was dissolved in 150 mL of trifluoroacetic acid. Triethylsilane (109.20 g, 939.14 mmol, 150 mL, 15.68 eq) was added dropwise at 0-5°C under nitrogen. The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was concentrated to give compound 31-6 (12.76 g, crude) as a brown oil. MS (ESI) m / z = 215.0 [M+H] + .

[0337] Step 5: Synthesis of compound 31-7

[0338] 31-6 (12.76 g, 59.89 mmol, 1 eq) was dissolved in 150 mL of dichloromethane. Triethylamine (24.24 g, 239.54 mmol, 33.34 mL, 4 eq) was added, followed by the addition of di-tert-butyl dicarbonate (26.14 g, 119.77 mmol, 27.52 mL, 2 eq) in portions at 0°C under nitrogen. The reaction mixture was stirred at 25°C under nitrogen for 2 hours. The reaction mixture was poured into 100 mL of water and extracted twice with 100 mL of dichloromethane. The combined organic phases were washed with 100 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography to afford compound 31-7 (3.32 g, 17.70% yield) as a yellow oil. MS (ESI) m / z = 314.9 [M+H] + .

[0339] Step 6: Synthesis of compound 31-8

[0340] Compound 31-7 (3.32 g, 10.60 mmol, 1 eq) was dissolved in 30 mL of methanol and 30 mL of dimethyl sulfoxide. Triethylamine (3.22 g, 31.80 mmol, 4.43 mL, 3 eq) and 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (1.16 g, 1.59 mmol, 0.15 eq) were added. The reaction mixture was stirred at 80°C under 50 psi of carbon dioxide for 16 hours. The reaction mixture was poured into 300 mL of water and filtered. The filtrate was extracted twice with 100 mL of ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography to afford compound 31-8 (2.21 g, 71.32% yield) as a yellow oil. MS (ESI) m / z = 293.2 [M+H] + .

[0341] Step 7: Synthesis of compound 31-9

[0342] 31-8 was dissolved in 10 mL of dichloromethane and trifluoroacetic acid (15.35 g, 134.62 mmol, 10 mL, 39.35 eq) was added. The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated to obtain a crude product, which was dissolved in 50 mL of dichloromethane and 10 mL of water was added. The pH was adjusted to 9 with sodium carbonate and extracted five times with 30 mL of a 10:1 mixture of chloroform and isopropanol. The combined organic phases were dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain compound 31-9 (651 mg, crude) as a yellow oil. MS (ESI) m / z = 193.1 [M+H] + .

[0343] Step 8: Synthesis of compound 31-11

[0344] 31-9 (651 mg, 3.39 mmol, 1 eq) was dissolved in 10 mL of dimethyl sulfoxide, and N,N-diisopropylethylamine (1.31 g, 10.16 mmol, 1.77 mL, 3 eq) and compound 31-10 (3.23 g, 11.03 mmol, 2 eq) were added. The reaction mixture was stirred at 100°C for 16 hours. The reaction mixture was poured into 30 mL of water and extracted three times with 30 mL of ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography to afford compound 31-11 (1.36 g, 89.57% yield) as an orange oil.

[0345] Step 9: Synthesis of compound 31-13

[0346] Compound 31-11 (200 mg, 446.12 μmol, 1 eq) was dissolved in 4 mL of dioxane and 0.4 mL of water. Compound 31-12 (442.12 mg, 892.24 μmol, 2 eq), potassium carbonate (184.97 mg, 1.34 mmol, 3 eq), and 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (32.64 mg, 44.61 μmol, 0.1 eq) were added. The reaction mixture was stirred at 100°C under nitrogen for 2 hours. The reaction mixture was poured into 10 mL of water and extracted twice with 10 mL of ethyl acetate. The combined organic phases were washed with 10 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography to afford compound 31-13 (261 mg, 96.28% yield) as a yellow oil. MS (ESI) m / z = 608.2 [M+H] + .

[0347] Step 10: Synthesis of Compounds 31-14

[0348] Compound 31-13 (261 mg, 429.54 μmol, 1 eq) was dissolved in a mixture of 1 mL of tetrahydrofuran, 1 mL of methanol, and 1 mL of water. Lithium hydroxide monohydrate (36.05 mg, 859.09 μmol, 2 eq) was added and the reaction mixture was stirred at 25°C under nitrogen for 1 hour. The pH of the reaction mixture was adjusted to 7 with 1 M hydrochloric acid and then dried to give compound 31-14 (275 mg, crude product). MS (ESI) m / z = 594.2 [M+H] + .

[0349] Step 11: Synthesis of Compound 31-16

[0350] Compound 31-14 (76.54 mg, 509.61 μmol, 1.1 eq) was dissolved in 5 mL of acetonitrile, and N-methylimidazole (190.18 mg, 2.32 mmol, 184.64 μL, 5 eq) and 1,3-benzothiazol-2-amine (275 mg, 463.28 μmol, 1 eq) were added. The reaction mixture was stirred at 25°C for 10 minutes, followed by the addition of N,N,N,N-tetramethylchloroformamidine hexafluorophosphate (389.96 mg, 1.39 mmol, 3 eq). The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was poured into 10 mL of water and extracted twice with 10 mL of ethyl acetate. The combined organic phases were washed with 10 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography to afford compound 31-16 (35 mg, 9.96% yield). MS (ESI) m / z = 726.3 [M+H] +

[0351] Step 11: Synthesis of RN031

[0352] 31-16 (32 mg, 42.19 μmol, 1 eq) was dissolved in 1 mL of dichloromethane, and trifluoroacetic acid (1.54 g, 13.46 mmol, 1 mL, 319.06 eq) was added. The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated to obtain the crude product, which was then purified by preparative liquid chromatography to afford RN031 (21.97 mg, 76.83% yield) as a yellow solid. MS (ESI) m / z = 670.2 [M+H] + . 1H NMR (400MHz, DMSO-d6): δ = 8.80 (s, 1H), 8.58 (s, 1H), 8.02 (d, J = 7.6Hz, 1H), 7.78 (d, J = 8.0Hz, 1H), 7.68-7.62 (m, 1H), 7.61 -7.50(m,3H),7.50-7.44(m,1H),7.40(s,1H),7.38-7.26(m,2H),7.01(d,J=8.8Hz,1H),5.44(s,2H),5.04(s,2H),3.94(br t,J=5.8Hz,2H),3.00(br t,J=5.6Hz,2H),2.11(s,3H)

[0353] Example 21 Synthesis of Compound RN032

[0354] The synthetic route is as follows:

[0355] Step 1: Synthesis of compound 32-2

[0356] Compound 19-7 (3.00 g, 6.69 mmol, 1.00 eq) and compound 32-1 (4.41 g, 12.1 mmol, 1.80 eq) were dissolved in 60 mL of dioxane and 12 mL of water. 1,1-Bis(diphenylphosphino)ferrocenepalladium chloride (979 mg, 1.34 mmol, 0.2 eq) and cesium carbonate (4.36 g, 13.4 mmol, 2.00 eq) were added. The reaction mixture was stirred at 100°C under nitrogen for 3 hours. The reaction mixture was poured into 40 mL of water and extracted twice with 40 mL of ethyl acetate. The combined organic phases were washed with 40 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain compound 32-2 (3.0 g, 64.8% yield) as a yellow oil. MS (ESI) m / z = 608.1 [M+H] + .

[0357] Step 2: Synthesis of compound 32-3

[0358] 32-2 (2.20 g, 3.62 mmol, 1.00 eq) was dissolved in 10 mL of methanol, 10 mL of tetrahydrofuran, and 10 mL of water, and lithium hydroxide monohydrate (456 mg, 10.9 mmol, 3.00 eq) was added. The reaction mixture was stirred at 25°C for 3 hours. The pH of the reaction mixture was adjusted to 6-7 with 1 M hydrochloric acid. The reaction mixture was dried to give compound 32-3 (2.15 g, crude) as a black solid. MS (ESI) m / z = 594.0 [M+H] + .

[0359] Step 3: Synthesis of compound 32-4

[0360] 32-3 (2.15 g, 3.62 mmol, 1.00 eq) and 1,3-benzothiazol-2-amine (544 mg, 3.62 mmol, 1.00 eq) were dissolved in 20 mL of tetrahydrofuran, and N,N-diisopropylethylamine (2.34 g, 18.1 mmol, 5.00 eq) and 2-chloro-1-methylpyridinium iodide (4.63 g, 18.1 mmol, 5.00 eq) were added. The reaction mixture was stirred at 60°C for 16 hours. The reaction mixture was poured into 20 mL of water and extracted twice with 20 mL of ethyl acetate. The combined organic phases were washed with 20 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain compound 32-4 (2.0 g, 65.6% yield) as a brown solid. MS (ESI) m / z = 726.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ12.34(s,1H),8.55(d,J=4.9Hz,1H),8.05(d,J=7.5Hz,1H),7.81(d,J=8.0Hz,1H),7.7 0-7.65(m,3H),7.57-7.49(m,3H),7.40-7.35(m,3H),7.04(d,J=8.9Hz,1H),5.44(s,2H),5.21(s,2H),3.93(br t,J=5.8Hz,2H),3.05(br t,J=5.8Hz,2H),2.09(s,3H),1.35(s,9H).

[0361] Step 4: Synthesis of compound RN032

[0362] Compound 32-4 (2.0 g, 2.76 mmol, 1.00 eq) was dissolved in 10 mL of dichloromethane, and trifluoroacetic acid (23.0 g, 202 mmol, 15 mL, 73.3 eq) was added. The reaction mixture was stirred at 25°C for 16 hours. The dichloromethane and trifluoroacetic acid were removed by nitrogen evaporation. The crude product was diluted with 5 mL of dimethylformamide, and the pH was adjusted to 7-8 with N,N-diisopropylethylamine. The product was then purified by preparative liquid phase chromatography to afford an off-white solid, compound RN032 (318 mg, 16.82% yield). MS (ESI) m / z = 670.0 [M+H] + . 1H NMR (400MHz, DMSO-d6): δ8.55(d,J=4.9Hz,1H), 8.05(d,J=7.9Hz,1H), 7.81(d,J=7.9Hz, 1H),7.68-7.63(m,1H),7.61-7.53(m,3H),7.51-7.45(m,3H),7.39-7.33(m,2H),6.91(br d,J=8.8Hz,1H),5.43(s,2H),5.19(s,2H),3.93(br t,J=5.8Hz,2H),3.05-3.02(m,2H),2.14(s,3H).

[0363] The example compounds in the following Table 3 were prepared by the same methods as in the above examples, using commercially available compounds or referring to the preparation methods of the intermediate compounds shown.

[0364] Table 3

[0365] Example 22 Synthesis of Compound RN042

[0366] The synthetic route is as follows:

[0367] Step 1: Synthesis of compound RN042

[0368] RN032 (25.0 mg, 37.3 μmol, 1.00 eq) was dissolved in 1 mL of dimethylformamide, and potassium iodide (6.20 mg, 37.3 μmol, 1.00 eq) and potassium carbonate (10.3 mg, 74.7 μmol, 2.00 eq) were added. The reaction mixture was stirred at 25°C for 10 minutes. 2-Methylpropyl chloromethyl ester (5.10 mg, 37.3 μmol, 1.00 eq) was then added, and the reaction mixture was stirred at 25°C for 4 hours. The reaction mixture was filtered, and the filtrate was purified by preparative liquid chromatography to obtain RN042 (3.5 mg, 11.9% yield) as an off-white solid. MS (ESI) m / z = 770.0 [M+H] + . 1H NMR (400MHz, DMSO-d6): δ12.29(br s,1H),8.55(d,J=4.8Hz,1H),8.07-8.00(m,1H),7.81(d,J=8.1Hz,1H),7.68-7.45(m,6H) ,7.40-7.31(m,3H),7.13(d,J=8.9Hz,1H),5.74(s,2H),5.45(s,2H),5.22(s,2H),3.94(br t,J=5.7Hz,2H),3.04(br t,J=5.6Hz,2H),2.48-2.40(m,1H),2.09(s,3H),0.99(d,J=7.0Hz,6H).

[0369] Example 22 Synthesis of Compound RN043

[0370] The structure of compound RN043 is as follows:

[0371] According to the same synthetic method as Example RN042, an off-white solid compound RN043 (7 mg, yield 16.8%) was prepared.

[0372] MS (ESI) m / z = 784.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ12.30 (br s,1H),8.54(d,J=4.8Hz,1H),8.04(d,J=7.9Hz,1H),7.81(d,J=8.0Hz,1H),7.68-7.63(m,1H),7.61-7.53(m,4H),7.48(t,J=7.6Hz,1H),7.42(br d,J=7.6Hz,1H),7.39-7.31(m,2H),7.14(d,J=8.9Hz,1H),6.73(q,J=5.4Hz,1H),5.45(s,2H),5.31-5.17(m,2H),3.94(br t,J=5.8Hz,2H),3.04(br t,J=5.5Hz,2H),2.39(td,J=7.0,13.9Hz,1H),2.09(s,3H),1.21(d,J=5.4Hz,3H),0.96(dd,J=3.3,6.9Hz,6H).

[0373] Example 23 Synthesis of Compound RN044

[0374] The synthetic route is as follows:

[0375] Step: Synthesis of compound RN044

[0376] Compound RN001 (30 mg, 45.47 μmol, 1 eq) was dissolved in 1 mL of N,N-dimethylformamide, and N,N-diisopropylethylamine (17.63 mg, 136.41 μmol, 23.76 μL, 3 eq) and 1-methylpiperazine (6.83 mg, 68.20 μmol, 7.57 μL, 1.5 eq) were added. The reaction mixture was stirred at 25°C for 10 minutes, followed by the addition of HATU (25.93 mg, 68.20 μmol, 1.5 eq). The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was purified by preparative liquid chromatography to afford compound RN044 (9.5 mg, 27.91% yield) as a yellow solid. MS (ESI) m / z = 742.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ=12.42-12.20(m,1H),8.55(d,J=4.9Hz,1H),8.04(d,J=7.5Hz,1H),7.81(d,J=7.9Hz,1H) ,7.58-7.53(m,2H),7.52-7.44(m,1H),7.41-7.32(m,1H),7.22(s,1H),6.97(d,J=8.9Hz,1H),5.21(s,2H),3.90(br t,J=5.8Hz,2H),3.72(s,2H),3.41(br s,2H),3.05(br t,J=5.6Hz,2H),2.94(br s,2H),2.19-2.09(m,5H),2.01(s,3H),1.93(br s,5H),1.70-1.62(m,3H),1.59-1.51(m,9H).

[0377] The example compounds in the following Table 4 were prepared by the same methods as in the above examples using commercially available compounds or referring to the preparation methods of the intermediate compounds shown.

[0378] Table 4

[0379] Example 24 Synthesis of Compound RN052

[0380] The synthetic route is as follows:

[0381] Step 1: Synthesis of compound 52-2

[0382] Compound 4 (400 mg, 1.29 mmol) was dissolved in DMSO (3 mL), and compound 52-1 (699 mg, 1.93 mmol) and triethylamine (0.89 mL, 6.44 mmol) were added. Under N2 protection, the reaction solution was stirred at 100°C for 18 hours. The reaction solution was extracted with water (20 mL) and DCM (15 mL × 2). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to obtain compound 52-2 (598 mg, yield 58.3%) as a brown oil. MS (ESI) m / z = 636.2 [M+H] +

[0383] Step 2: Synthesis of compound 52-3

[0384] Compound 52-2 (598 mg, 0.75 mmol) was dissolved in THF (5 mL), and triethylamine (0.31 mL, 2.26 mmol) and SEM-Cl (0.20 mL, 1.13 mmol) were added. The reaction solution was stirred at 40°C for 1 hour. The reaction solution was extracted with water (30 mL) and dichloromethane (10 mL × 3). The organic phase was separated, washed with saturated brine (20 mL), dried over sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by preparative thin-layer chromatography to obtain a brown solid compound 52-3 (682 mg, yield 70.9%). MS (ESI) m / z = 766.4 [M+H] +

[0385] Step 3: Synthesis of compound 52-4

[0386] Compound 52-3 (650 mg, 0.51 mmol) was dissolved in ethanol (10 mL) and platinum / carbon (99.3 mg) was added under nitrogen. The suspension was degassed and flushed with hydrogen three times. The mixture was stirred at 50°C under hydrogen (15 Psi) for 18 hours. LCMS showed that the reaction was complete. The suspension was filtered through celite, the filtrate was concentrated, and the residue was purified by preparative thin-layer chromatography to give compound 52-4 (195 mg, yield 33.4%) as a brown oil. MS (ESI) m / z = 768.4 [M+H] +

[0387] Step 4: Synthesis of compound 52-5

[0388] Compound 52-4 (195 mg, 0.17 mmol) was dissolved in THF solution (1 mL), and TBAF·THF (0.34 mL, 0.34 mmol, 1 M) was added. Under N2 protection, the reaction solution was stirred at 25°C for 1 hour. LCMS showed that the reaction was complete. The reaction mixture was extracted with 10 mL of water and DCM (5 mL × 3). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue, which gave compound 52-5 (102 mg, yield 59.6%) as a brown oil. MS (ESI) m / z = 654.3 [M+H] +

[0389] Step 5: Synthesis of compound 52-6

[0390] Compound 52-5 (100 mg, 0.10 mmol) and triethylamine (0.04 mL, 0.30 mmol) were dissolved in DCM (1 mL) solution, and MsCl (14.8 mg, 0.13 mmol) was added at 0°C under nitrogen protection. The reaction solution was stirred at 25°C for 1 hour. LCMS showed that the reaction was complete. The reaction mixture was extracted between 10 mL of water and DCM (5 mL×2). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by preparative thin-layer chromatography to obtain compound 52-6 (43 mg, yield 38.4%) as a brown oil. MS (ESI) m / z=732.2[M+H] +

[0391] Step 5: Synthesis of compound 52-8

[0392] Compound 52-6 (38 mg, 0.05 mmol), compound 52-7 (15.0 mg, 0.08 mmol), and cesium carbonate (50.7 mg, 0.16 mmol) were mixed with DMF (0.6 mL), degassed, and flushed with nitrogen three times. The mixture was stirred at 50°C under nitrogen for 1 hour. LCMS showed the reaction was complete. The reaction mixture was diluted with water (5 mL), extracted with ethyl acetate (5 mL × 3), washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The residue was purified by preparative thin-layer chromatography to obtain compound 52-8 (8.00 mg, 22.0% yield) as a yellow solid.

[0393] Step: Synthesis of compound RN052

[0394] Compound 52-8 (8.00 mg, 0.01 mmol) was dissolved in a mixed solvent of ethanol (0.3 mL) and water (0.3 mL), and lithium hydroxide monohydrate (1.44 mg, 0.03 mmol) was added. The mixture was stirred at 25°C for 2 hours. LCMS showed that the reaction was complete. The mixture was concentrated. The crude product was purified by Prep-HPLC to obtain compound RN052 (0.96 mg, 12.5% ​​yield) as a white solid. MS (ESI) m / z = 671.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ8.56(s,1H),8.33(s,1H),8.03(d,J=7.6Hz,1H),7.8 0(d,J=8.0Hz,1H),7.57(s,1H),7.47(t,J=7.6Hz,1H),7.35(t,J=7.6Hz,1H),7 .25-7.28(m,1H),7.19(d,J=6.8Hz,1H),7.11-7.13(m,1H),5.06(s,2H),4.09( s,2H),3.76(s,2H),3.19(s,2H),3.08(s,2H),2.21(s,6H),1.97–2.04(m,4H).

[0395] Example 25 Synthesis of Compound RN053

[0396] The synthetic route is as follows:

[0397] Step 1: Synthesis of compound 53-2

[0398] Benzyl alcohol (5 g, 46.24 mmol, 4.79 mL, 1 eq) and vinyl acetate (11.94 g, 138.71 mmol, 12.84 mL, 3 eq) were dissolved in 50 mL of toluene. Potassium carbonate (2.94 g, 27.74 mmol, 0.6 eq) and 1,5-cyclooctadiene iridium chloride dimer (310.58 mg, 462.37 μmol, 0.01 eq) were added. The reaction mixture was stirred at 120°C for 2 hours. The reaction mixture was added with 5 mL of water and extracted twice with 5 mL of ethyl acetate. The combined organic phases were washed with 10 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to afford Compound 53-2 (3.9 g, 62.86% yield) as a yellow oil. 1H NMR (400MHz, CDCl3): δ7.34-7.16 (m, 5H), 6.49 (dd, J=6.8, 14.3Hz, 1H), 4.68 (s, 2H), 4.23 (dd, J=2.1, 14.3Hz, 1H), 4.00 (dd, J=2.1, 6.8Hz, 1H).

[0399] Step 2: Synthesis of compound 53-3

[0400] Compound 53-2 (1 g, 7.45 mmol, 1 eq) and 2-vinyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.15 g, 7.45 mmol, 1.26 mL, 1 eq) were dissolved in 10 mL of toluene. Grubbs' second-generation catalyst (632.74 mg, 745.30 μmol, 0.1 eq) was added, and the reaction mixture was stirred at 100°C under nitrogen for 16 hours. The reaction mixture was purified directly by column chromatography without further treatment to obtain compound 53-3 (531 mg, 27.39% yield) as a yellow oil. MS (ESI) m / z = 281.1 [M+H] +

[0401] Step 3: Synthesis of compound 53-4

[0402] Compound 13-8 (400 mg, 892.24 μmol, 1 eq) was dissolved in 2 mL of dioxane and 0.5 mL of water. Compound 53-3 (464.21 mg, 1.78 mmol, 2 eq), potassium carbonate (369.95 mg, 2.68 mmol, 3 eq), and 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (65.29 mg, 89.22 μmol, 0.1 eq) were added. The reaction mixture was stirred at 100°C under nitrogen for 2 hours. The reaction mixture was poured into 30 mL of water and extracted twice with 30 mL of ethyl acetate. The combined organic phases were washed with 30 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography to afford compound 53-4 (286 mg, 63.91% yield) as a yellow oil. MS (ESI) m / z = 502.5 [M+H] +

[0403] Step 4: Synthesis of compound 53-5

[0404] Compound 53-4 (286 mg, 570.21 μmol, 1 eq) was dissolved in 5 mL of tetrahydrofuran, and wet palladium on carbon (100 mg, 93.97 μmol, 10% purity, 1.65 e-1 eq) was added. The reaction mixture was stirred at 25°C under a 15 psi hydrogen atmosphere for 16 hours. The reaction mixture was filtered and concentrated, and the residue was purified by column chromatography to obtain compound 53-5 (242 mg, 84.28% yield) as a yellow oil. MS (ESI) m / z = 504.1 [M+H] +

[0405] Step 5: Synthesis of compound 53-6

[0406] Compound 53-5 (242 mg, 480.55 μmol, 1 eq) was dissolved in a mixture of 2 mL of methanol and 2 mL of water. Lithium hydroxide monohydrate (40.33 mg, 961.10 μmol, 2 eq) was added, and the reaction mixture was stirred at 25°C for 1 hour. The pH of the reaction mixture was adjusted to 1 with 0.5 M hydrochloric acid, then extracted three times with 20 mL of dichloromethane. The combined organic phases were dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to afford compound 53-6 (219 mg, 93.09% yield) as a yellow solid. MS (ESI) m / z = 490.1 [M+H] +

[0407] Step 6: Synthesis of compound 53-7

[0408] Compound tert-butyl 1,3-benzothiazol-2-amine (128.25 mg, 853.83 μmol, 2 eq) was dissolved in 4 mL of N,N-dimethylformamide. N,N-diisopropylethylamine (275.87 mg, 2.13 mmol, 371.79 μL, 5 eq) and compound 53-6 (209 mg, 426.91 μmol, 1 eq) were added, followed by HATU (486.97 mg, 1.28 mmol, 3 eq). The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was poured into 10 mL of water and extracted twice with 10 mL of ethyl acetate. The combined organic phases were washed with 10 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography to afford compound 53-7 (149 mg, 56.13% yield) as a yellow oil. MS (ESI) m / z = 622.3 [M+H] + .

[0409] Step 7: Synthesis of compound RN053

[0410] Compound 53-7 (139 mg, 223.56 μmol, 1 eq) was dissolved in 1.5 mL of dichloromethane, and trifluoroacetic acid (2.30 g, 20.19 mmol, 1.5 mL, 90.33 eq) was added. The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated to obtain a crude product, which was purified by preparative liquid chromatography to afford RN053 (10.16 mg, 7.64% yield) as an off-white solid. MS (ESI) m / z = 566.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ = 8.53 (d, J = 4.8Hz, 1H), 8.05 (d, J = 7.6Hz, 1H), 7.81 (d, J = 8.0Hz, 1H), 7.55-7.45(m,3H),7.40-7.21(m,6H),6.84(d,J=8.6Hz,1H),5.14(s,2H),4.44(s,2H),3.89(br t,J=5.7Hz,2H),3.59-3.56(m,2H),3.01(br t,J=5.5Hz,2H),2.88(br t,J=7.0Hz,2H).

[0411] Example 26 Synthesis of Compound RN054

[0412] The synthetic route is as follows:

[0413] Step 1: Synthesis of compound 54-3

[0414] At 20°C, under N₂ protection, EtMgBr (5.4 mL, 2 M) was added dropwise to a solution of compound 54-1 (3.1 g, 9.84 mmol) in DCM (62 mL). After 30 minutes, compound 54-2 (1.8 g, 11.80 mmol) was added, and the mixture was stirred at 20°C for 18 hours. After completion, the reaction was quenched with saturated NH₄Cl (30 mL) and extracted with DCM (30 mL x 3). The organic layer was separated, washed with saturated sodium chloride solution, and concentrated to afford the crude product (mobile phase: methanol (0.1% ammonia)-dichloromethane, gradient: 0-6%), affording compound 54-3 (1.9 g, 46.0% yield) as a pale yellow oil. MS (ESI) m / z = 338.2 [M+H] +

[0415] Step 2: Synthesis of compound 54-4

[0416] Compound 54-3 (2.1 g, 6.22 mmol) was dissolved in TFA (15 mL) at room temperature, followed by the addition of Et3SiH3 (15 mL). The mixture was stirred at 80°C under N2 protection for 18 hours. After completion of the reaction, the reaction was quenched with saturated NaHCO3 until the pH reached ~8 and extracted with DCM (30 mL x 3). The organic layer was separated, washed with saturated sodium chloride solution, and concentrated to afford the crude product (mobile phase: methanol (0.1% ammonia)-dichloromethane, gradient: 0-10%), yielding compound 54-4 (1.72 g, 68.8% yield) as a white solid. MS (ESI) m / z = 322.2 [M+H] +

[0417] Step 3: Synthesis of compound 54-5

[0418] Compound 54-4 (1.5 g, 4.67 mmol) was dissolved in EtOH (15 mL) at room temperature, followed by the addition of EtONa (3.8 g, 56.01 mmol). The mixture was stirred at 80°C under N₂ protection for 18 hours. After completion of the reaction, the reaction was quenched with saturated NaHCO₃ to a pH of ~8 and extracted with EtOAc (100 mL x 3). The organic layer was separated, washed with saturated sodium chloride solution, and concentrated to afford the crude product (mobile phase: methanol (0.1% ammonia)-dichloromethane, gradient: 0-10%), yielding compound 54-5 (664 mg, 66.4% yield) as a yellow solid. MS (ESI) m / z = 215.2 [M+H] +

[0419] Step 4: Synthesis of compound 54-6

[0420] At room temperature, compound 54-5 (664 mg, 3.10 mmol) was dissolved in DMSO (8 mL), and tert-butyl 6-chloro-3-fluoropyridine-3-carboxylate (1.1 g, 4.65 mmol), KI (1.2 g, 6.20 mmol), and Cs2CO3 (3.0 g, 9.30 mmol) were added. The mixture was stirred at 80°C for 2 hours under N2 protection. After the reaction, water (50 mL) was added for dilution, and the mixture was extracted with EtOAc (50 mL x 3). The organic layer was separated, washed with saturated sodium chloride solution, and concentrated. The crude product was slurried with EtOAc (5 mL) at 25°C to give compound 54-6 (350 mg, yield 26.6%) as a white solid. MS (ESI) m / z = 426.0 [M+H] +

[0421] Step 5: Synthesis of compound 54-7

[0422] At room temperature, compound 54-6 (330 mg, 0.78 mmol) was dissolved in DMSO (3.5 mL), and methyl 5,6,7,8-tetrahydropyrido[3,4-c]pyridine-1-carboxylate (179.6 mg, 0.93 mmol) and KF (226.1 mg, 3.89 mmol) were added. The mixture was stirred at 100°C under N2 protection for 24 hours. After completion of the reaction, the mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The organic layer was separated, washed with saturated sodium chloride solution, and concentrated to obtain the crude product. The crude product was purified by preparative TLC (DCM:MeOH = 10:1) to afford compound 54-7 (160 mg, 35.5% yield) as a white solid. MS (ESI) m / z = 582.4 [M+H] +

[0423] Step 6: Synthesis of compound 54-8

[0424] At room temperature, compound 54-7 (160 mg, 0.28 mmol) was dissolved in THF (0.7 mL), H2O (0.7 mL), and MeOH (0.7 mL). LiOH.H2O (23.1 mg, 0.55 mmol) was added, and the mixture was stirred at 30°C under N2 protection for 5 hours. The reaction solution was concentrated to obtain a yellow solid compound 54-8 (169 mg, 0.30 mmol, crude product), which was used directly in the next reaction without further purification. MS (ESI) m / z = 568.4 [M+H] +

[0425] Step 7: Synthesis of compound 54-9

[0426] Compound 54-8 (149 mg, 0.26 mmol) was dissolved in DMF (3 mL), followed by the addition of DIEA (204.3 mg, 1.58 mmol), HATU (500.8 mg, 1.32 mmol), and benzo[2,1-d][1,3]thiazol-2-amine (59.3 mg, 0.40 mmol). The mixture was stirred at 30°C for 16 hours under N2 protection. The reaction mixture was diluted with water (20 mL), adjusted to pH ~3 with 0.5N HCl, and extracted with EtOAc (30 mL x 3). The organic layer was separated, washed with brine, and concentrated. The crude product was purified by preparative TLC (DCM:MeOH = 10:1) to afford compound 54-9 (80 mg, 21.8% yield) as a yellow solid. MS (ESI) m / z = 700.4 [M+H] +

[0427] Step 8: Synthesis of compound RN054

[0428] To a solution of compound 54-9 (70 mg, 0.10 mmol) in DCM (1 mL) was added TFA (1 mL). Under nitrogen, the reaction mixture was stirred at 25°C for 4 hours. After completion of the reaction, the reaction mixture was concentrated. The crude product was purified by Prep-HPLC to obtain RN054 as a white solid (19.59 mg, yield: 30.3%). MS (ESI) m / z = 644.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ12.30(s,1H),8.57(d,J=4.8Hz,1H),8.15(s,0.06H,HCOOH),8.05(d,J=7.8H z,1H),7.81(d,J=8.0Hz,1H),7.64(d,J=9.0Hz,1H),7.58(d,J=4.9Hz,1H),7.48(t,J=7.7Hz,1H),7.44 (s,1H),7.36(t,J=7.6Hz,1H),7.08(d,J=9.0Hz,1H),5.27(s,2H),3.98(t,J=5.7Hz,2H),3.07(t,J=5. 5Hz,2H),2.36(d,J=6.5Hz,2H),2.04–1.93(m,2H),1.90(s,3H),1.84–1.67(m,5H),1.29–1.15(m,2H).

[0429] The example compounds listed in Table 5 below were prepared by the same methods as in the above examples, using commercially available compounds or referring to the preparation methods of the intermediate compounds shown.

[0430] Table 5

[0431] Example 27 Synthesis of Compound RN061

[0432] The synthetic route is as follows:

[0433] Step 1: Synthesis of compound 61-2

[0434] Compound 61-1 (2.00 g, 8.42 mmol) was dissolved in tert-butanol (40 mL), pyridine (4.76 mL, 58.9 mmol) was added, and then p-toluenesulfonyl chloride (3.85 mL, 20.2 mmol) was added dropwise at 20°C. Under nitrogen protection, the reaction was carried out at 50°C for 6 hours. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography to obtain compound 61-2 (1.50 g, yield 60.6%) as a colorless oil. MS (ESI) m / z = 293.0 [M+H] +

[0435] Step 2: Synthesis of compound 61-3

[0436] Compound 61-2 (690 mg, 2.35 mmol) was dissolved in dioxane (10 mL), and water (1 mL) and compound 25-2 (600 mg, 1.68 mmol), Pd(dtbpf)Cl2 (108 mg, 0.17 mmol), and cesium carbonate (2.74 g, 8.42 mmol) were added. Under N2 protection, the mixture was reacted at 60°C for 12 hours. The reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography to obtain compound 61-3 (493 mg, 66.0% yield) as a brown solid. MS (ESI) m / z = 443.2 [M+H] +

[0437] Step 3: Synthesis of compound 61-4

[0438] Methyl 5,6,7,8-tetrahydropyridinium[3,4-c]pyridine-1-carboxylate (120 mg, 0.62 mmol) was dissolved in DMSO (2.5 mL), and compound 61-3 (276 mg, 0.62 mmol) and potassium fluoride (108 mg, 1.87 mmol) were added. Under N2 protection, the reaction was carried out at 90°C for 4 hours. The reaction solution was added to ice-cold water (8 mL), the precipitate was filtered, and vacuum dried. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to obtain compound 61-4 (51 mg, yield 13.6%) as a light yellow gum. MS (ESI) m / z = 599.4 [M+H] +

[0439] Step 4: Synthesis of compound 61-5

[0440] Compound 61-4 (51 mg, 0.09 mmol) was dissolved in a mixed solvent of methanol (0.3 mL), tetrahydrofuran (0.3 mL), and water (0.3 mL), and lithium hydroxide monohydrate (10.7 mg, 0.26 mmol) was added. The mixture was allowed to react at 25°C for 2 hours. The reaction solution was concentrated to obtain compound 61-5 (49.8 mg, crude product) as a pale yellow solid. MS (ESI) m / z = 585.4 [M+H] +

[0441] Step 5: Synthesis of compound 61-6

[0442] Compound 61-5 (40 mg, 0.07 mmol) was dissolved in DMF (0.8 mL), and benzo[d][1,3]thiazol-2-amine (11.3 mg, 0.08 mmol), DIEA (26.5 mg, 0.21 mmol), and HATU (53.2 mg, 0.14 mmol) were added. Under N2 protection, the mixture was reacted at 25°C for 4 hours. The reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (5 mL x 2). The organic layer was washed with water (3 mL) and saturated brine (3 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a residue. The residue was purified to obtain compound 61-6 (29 mg, yield 59.1%) as a yellow oil. MS (ESI) m / z = 359 [M / 2+H] +

[0443] Step 6: Synthesis of compound RN061

[0444] Compound 61-6 (29 mg, 0.04 mmol) was dissolved in dichloromethane (0.3 mL) and trifluoroacetic acid (0.3 mL) was added. The reaction mixture was reacted at 25°C for 2 hours and concentrated to obtain a residue. The residue was purified by preparative HPLC to obtain compound RN061 (2.75 mg, 10.2% yield) as a pale yellow solid. MS (ESI) m / z = 661.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ8.56(s,1H),8.43(s,1H),8.15(s,1H),8.05(d,J=5.6Hz,1H),7.81(d,J=8.4Hz,1H),7.46-7.56(m, 3H),7.37(t,J=7.2Hz,1H),5.27(s,2H),3.95(s,2H),3.73(s,2H),3.08(s,2H),2.32(s,3H),1.93(s,3H),1.53-1.66m,12H).

[0445] Example 28 Synthesis of Compound RN062

[0446] The synthetic route is as follows:

[0447] Step 1: Synthesis of compound 62-1

[0448] Compound 21-1 (976 mg, 2.19 mmol) was dissolved in CH3CN (10 mL), followed by the addition of Pd(dppf)Cl2.CH2Cl2 (178.6 mg, 0.22 mmol), TEA (0.97 mL, 7.00 mmol), and HBPin (4.8 mL, 32.80 mmol). The mixture was stirred at 80°C for 40 minutes. MeOH (5 mL) and water (30 mL) were added to the reaction solution, which was then extracted with EtOAc (30 mL x 3). The organic layer was separated, washed with saturated NaCl solution, and concentrated. The residue was purified by silica gel column chromatography to afford 62-1 (1.03 g, 1.67 mmol, 76.37% yield) as a yellow oil. MS (ESI) m / z = 496.2 [M+H] +

[0449] Step 2: Synthesis of compound 62-3

[0450] Compound 62-2 (10 g, 104.03 mmol) was dissolved in CH3CN (100 mL), and NIS (28.1 g, 124 mmol) was added. The mixture was stirred at 80°C for 12 hours under N2 protection. The reaction was concentrated to remove CH3CN, then diluted with water (100 mL) and extracted with EtOAc (200 mL × 3). The organic layer was separated, further washed with saturated aqueous Na2CO3 solution, and concentrated. The residue was slurried with EtOAc (100 mL) at 25°C and filtered to obtain compound 62-3 (12.0 g, 51.9% yield) as a yellow solid. MS (ESI) m / z = 222.8 [M+H] +

[0451] Step 3: Synthesis of compound 62-4

[0452] Compound 62-3 (2.5 g, 11.26 mmol) was dissolved in DMF (25 mL). NaH (0.90 g, 22.52 mmol) was then added at 0°C and stirred at room temperature for 30 minutes. 1-(Bromomethyl)tricyclo[3.3.1.13,7]decane (3.1 g, 13.51 mmol) was then added to the reaction mixture. The reaction was stirred at 130°C for 18 hours under nitrogen. Saturated NH4Cl (100 mL) was added to the reaction mixture, and the mixture was extracted with EtOAc (100 mL × 3). The mixture was separated, washed with saturated NaCl solution, concentrated, and then slurried with EtOAc (20 mL) at 25°C. After filtration, compound 62-4 (1.11 g, 23.2% yield) was obtained as a yellow solid. MS (ESI) m / z = 371.0 [M+H] +

[0453] Step 4: Synthesis of compound 62-5

[0454] Compound 62-1 (1.34 g, 2.70 mmol) was dissolved in dioxane (10 mL) and H₂O (2.5 mL). Compound 62-4 (1.0 g, 2.70 mmol), Pd₂(dba)₃ (0.25 g, 0.27 mmol), meCgPPh (0.32 g, 1.08 mmol), and K₃PO₄ (1.72 g, 8.11 mmol) were then added. Under N₂ protection, the mixture was stirred at 90°C for 2 hours. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The organic layer was separated, washed with saturated brine (50 mL), and concentrated. The residue was purified by prep-HPLC and concentrated to afford compound 62-5 (300 mg, 16.9% yield) as a yellow solid. MS (ESI) m / z = 612.4 [M+H] +

[0455] Step 5: Synthesis of compound 62-6

[0456] Compound 62-5 (300 mg, 0.49 mmol) was dissolved in THF (2 mL), MeOH (2 mL), and water (2 mL), followed by the addition of LiOH.H2O (41.1 mg, 0.98 mmol). Under N2 protection, the reaction was stirred at 30°C for 4 hours. After concentration, compound 62-6 (314 mg, crude product) was obtained as a yellow solid, which was used directly in the next reaction without further purification. MS (ESI) m / z = 598.4 [M+H] +

[0457] Step 6: Synthesis of compound 62-7

[0458] Compound 62-6 (314 mg, 0.53 mmol) was dissolved in DMF (3 mL), followed by the addition of DIEA (340.6 mg, 2.64 mmol), HATU (400.8 mg, 1.05 mmol), and benzo[d][1,3]thiazol-2-amine (79.2 mg, 0.53 mmol). Under N2 protection, the reaction was stirred at 25°C for 1 hour. The reaction was diluted with water (20 mL) and extracted with EtOAc (3 mL x 3). The organic layer was separated and washed with 0.5N HCl solution, then separated, washed with saturated sodium chloride solution, and concentrated. The residue was purified by column chromatography to afford compound 62-7 (137 mg, 35.7% yield) as a yellow solid. MS (ESI) m / z = 730.2 [M+H] +

[0459] Step 7: Synthesis of compound RN062

[0460] Compound 62-7 (137 mg, 0.19 mmol) was dissolved in DCM (2 mL), and TFA (2 mL) was added. The mixture was stirred at 25°C for 5 hours under N2 protection. The reaction mixture was concentrated and then purified by prep-HPLC to obtain compound RN062 as a white solid (3.28 mg, 2.6% yield). MS (ESI) m / z = 674.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ12.29(s,1H),8.56(d,J=4.8Hz,1H),8.15(s,1H),8.06(d,J=7.6H z,1H),7.82(d,J=8.0Hz,1H),7.68(d,J=8.7Hz,1H),7.57(d,J=4.9Hz,1H),7.49(t,J=7.7Hz ,1H),7.37(t,J=7.6Hz,1H),7.02(d,J=8.8Hz,1H),5.22(s,2H),3.95(t,J=5.6Hz,2H),3.5 7(s,2H),3.06(t,J=5.8Hz,2H),2.31(s,3H),2.08(s,3H),1.96(s,3H),1.69–1.49(m,12H).

[0461] Example 29 Synthesis of Compound RN063

[0462] The synthetic route is as follows:

[0463] Step 1: Synthesis of compound 63-2

[0464] Compound 63-1 (5.00 g, 31.0 mmol) was dissolved in dimethyl sulfoxide (100 mL), and compound 63-2 (10.3 g, 46.5 mmol) and cuprous iodide (1.18 g, 6.21 mmol) were added. After fully replacing the nitrogen atmosphere, cesium carbonate (30.3 g, 93.1 mmol) and 1,10-phenanthroline (5.60 g, 31.0 mmol) were added. The reaction mixture was stirred at 110°C for 16 hours. After completion of the reaction, the mixture was quenched with water (100 mL), extracted with dichloromethane (100 mL x 2), washed with water (200 mL), washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. The mother liquor was concentrated in vacuo and purified by silica gel column chromatography to obtain compound 63-2 (1.20 g, 15.2% yield) as a white solid.

[0465] Step 2: Synthesis of compound 63-3

[0466] Compound 63-2 (1.20 g, 4.70 mmol), Pd(dppf)Cl2 (385 mg, 0.47 mmol), pinacol diboronate (1.55 g, 6.12 mmol), and potassium acetate (1.02 g, 10.3 mmol) were dissolved in 1,4-dioxane (12 mL). After nitrogen displacement, the reaction solution was stirred at 100°C for 16 hours. The reaction solution was concentrated in vacuo, extracted with dichloromethane (30 mL x 2), washed with water (50 mL x 2), washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate. Purification by silica gel column chromatography afforded compound 63-3 as a yellow oil (680 mg, yield 47.8%). MS (ESI) m / z = 303.2 [M+H] +

[0467] Step 3: Synthesis of compound 63-4

[0468] Under nitrogen, compound 63-3 (680 mg, 2.25 mmol), compound 3A (790 mg, 2.70 mmol), Pd(dtbpf)Cl2 (145 mg, 0.23 mmol), and cesium carbonate (2.20 g, 6.75 mmol) were dissolved in dioxane (7 mL) and water (0.7 mL) and reacted at 100°C for 18 hours. After completion of the reaction, the reaction solution was added with water (30 mL) and extracted with ethyl acetate (30 mL x 2). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by silica gel column chromatography to afford the product 63-4 as a white solid (410 mg, 47.2% yield). MS (ESI) m / z = 388.2 [M+H] +

[0469] Step 4: Synthesis of compound 63-5

[0470] Under nitrogen, compound 63-4 (350 mg, 2.91 mmol), compound 13-7 (211 mg, 1.09 mmol), Pd(t-Bu3P)2 (46.4 mg, 0.09 mmol), and cesium carbonate (886 mg, 2.72 mmol) were dissolved in N,N-dimethylformamide (4 mL) and reacted at 110°C for 3 hours. After completion of the reaction, the reaction solution was added with water (30 mL) and extracted with dichloromethane (20 mL × 2). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by silica gel column chromatography to obtain compound 63-5 (220 mg, 44.8% yield) as a white solid. MS (ESI) m / z = 544.2 [M+H] +

[0471] Step 5: Synthesis of compound 63-6

[0472] Compound 63-5 (200 mg, 0.37 mmol) and lithium hydroxide monohydrate (30.99 mg, 0.74 mmol) were dissolved in methanol (2 mL), tetrahydrofuran (2 mL), and water (2 mL) and reacted at 25°C for 3 hours. After vacuum concentration, a white crude product, compound 63-6 (220 mg), was obtained. MS (ESI) m / z = 530.2 [M+H] +

[0473] Step 6: Synthesis of compound 63-7

[0474] Compound 63-6 (180 mg, 0.34 mmol), 2-aminobenzothiazole (56.4 mg, 0.38 mmol), HATU (285 mg, 0.75 mmol), and DIEA (132 mg, 1.02 mmol) were dissolved in N,N-dimethylformamide (2 mL) and reacted at 30°C for 2 hours. After completion of the reaction, the reaction solution was added with water (20 mL) and extracted with ethyl acetate (20 mL x 2). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by silica gel column chromatography to obtain compound 63-7 (60 mg, yield 26.7%) as a yellow oil. MS (ESI) m / z = 662.2 [M+H] +

[0475] Step 7: Synthesis of compound RN063

[0476] Compound 63-7 (40 mg, 0.06 mmol) was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred at 25°C for 2 hours. After completion of the reaction, the reaction mixture was concentrated. The crude product was purified by Prep-HPLC to obtain RN063 (6.3 mg, 17.2% yield) as a white solid. MS (ESI) m / z = 606.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ8.56(s,1H),8.06(d,J=7.9Hz,1H),7.82(d,J=8.1Hz,1H),7.64(s,1H),7.61–7.51(m,4H),7.50–7.41(m ,1H),7.37(tt,J=8.3,2.1Hz,3H),7.00(d,J=8.8Hz,1H),5.23(s,2H),3.95(t,J=5.8Hz,2H),3.06(t,J=5.4Hz,2H),2.23(s,3H).

[0477] The example compounds in the following Table 6 were prepared by the same methods as in the above examples using commercially available compounds or referring to the preparation methods of the intermediate compounds shown.

[0478] Table 6

[0479] Example 30 Synthesis of Compound RN071

[0480] The synthetic route is as follows:

[0481] Step 1: Synthesis of compound 71-2

[0482] Compound 71-1 (3.10 g, 17.7 mmol), ethyl acetate (E)-2-cyano-3-ethoxyacrylate (3.00 g, 17.7 mmol), and sodium carbonate (1.88 g, 17.7 mmol) were dissolved in ethanol (30 mL). The mixture was heated to 80°C with stirring under N2 protection for 5 hours, then cooled to 25°C and allowed to stand for 12 hours. The reaction solution was concentrated under reduced pressure to remove the solvent, and the crude product was purified by column chromatography to obtain compound 71-2 (3.80 g, 82.0% yield) as a yellow solid. MS (ESI) m / z = 262.2 [M+H] + . 1H NMR (400MHz, DMSO-d6): δ7.65(s,1H),7.45–7.38(m,2H),7.11–7.02(m,2H),6.17(s,2H),4.21(q,J=7.1Hz,2H),3.81(s,3H),1.26(t,J=7.1Hz,3H).

[0483] Step 2: Synthesis of compound 71-3

[0484] Compound 71-2 (3.8 g, 14.5 mmol) and formamide (38 mL) were mixed and heated to 180°C under N2 protection with stirring for 18 hours. LCMS indicated the reaction was complete. The suspension was filtered. The crude product was purified by recrystallization from ethanol / water = 10 / 1 (22 mL) at 25°C to afford compound 71-3 (2.23 g, 63.3% yield). MS (ESI) m / z = 243.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ12.37(s,1H),8.28(s,1H),8.16(s,1H),7.94–7.84(m,2H),7.16–7.08(m,2H),3.82(s,3H).

[0485] Step 3: Synthesis of compound 71-4

[0486] Compound 71-3 (1.00 g, 4.13 mmol) was dissolved in phosphorus trichloride (10 mL). The mixture was stirred at 100°C for 2 hours. LCMS showed that the reaction was complete. The reaction mixture was extracted with ice water (100 mL) and dichloromethane (100 mL). The organic phase was washed with saturated aqueous sodium chloride solution (80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 71-4 (700 mg, yield 65.1%) as a pale yellowish-white solid. MS (ESI) m / z = 261.0 [M+H] + .

[0487] Step 4: Synthesis of compound 71-5

[0488] Compound 71-4 (700 mg, 2.69 mmol), 3-(dimethylamino)propylamine (0.41 mL, 3.22 mmol) and triethylamine (0.82 mL, 5.91 mmol) were dissolved in tetrahydrofuran (10 mL) and stirred at 25°C under a N2 atmosphere for 18 hours. LCMS showed that the reaction was complete. The reaction mixture was extracted with water (20 mL) and ethyl acetate (20 mL). The organic phase was washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 71-5 (790 mg, 2.42 mmol, yield 90.1%) as a white solid. MS (ESI) m / z = 327.2 [M+H] + .

[0489] Step 5: Synthesis of compound 71-6

[0490] Compound 71-5 (400 mg, 1.23 mmol) was dissolved in sulfolane (5 mL), trimethylsilyl iodide (1.75 mL, 12.2 mmol) was added, and the mixture was stirred at 80°C for 5 hours. LCMS showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure to remove the solvent. The crude product was purified by reverse-phase high-performance liquid chromatography to obtain compound 71-6 (157 mg, 41.0% yield) as a pale yellowish-white solid. MS (ESI) m / z = 313.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ8.45(t,J=5.7Hz,1H),8.31(d,J=10.3Hz,2H),8.17(s,1H),7.88– 7.82(m,2H),6.93–6.87(m,2H),3.56(q,J=6.6Hz,2H),2.63(t,J=7.4Hz,2H),2.40(s,6H).

[0491] Step 6: Synthesis of compound 71-8

[0492] Compound 71-7 (3.50 g, 12.9 mmol) was dissolved in tetrahydrofuran (24 mL) and a mixture of KOH (1.09 g, 19.4 mmol) / H2O (24 mL) was added dropwise at 0°C. The mixture was stirred at 20°C for 2 hours. LCMS showed that the reaction was complete. The mixture was diluted with water (50 mL) and then extracted with MTBE (10 mL×3). The aqueous phase was acidified with 6N hydrochloric acid to pH=1, and a light yellow solid precipitated. The solid was filtered and washed with water (5 mL). The crude product was slurried with 15 mL of water for 30 minutes, filtered and dried under vacuum to give compound 71-8 (2.80 g, yield 89.2%) as a light yellow oil. MS (ESI) m / z=239.9[MH]-

[0493] Step 7: Synthesis of compound 71-9

[0494] Compound 71-8 (3.50 g, 14.4 mmol) was dissolved in tetrahydrofuran (70 mL), and Boc2O (7.64 mL, 33.2 mmol) and DMAP (0.35 g, 2.89 mmol) were added. The mixture was stirred at 65°C for 16 hours. The reaction solution was diluted with water (30 mL), and the organic layer was separated. The aqueous phase was extracted with ethyl acetate (15 mL), and the organic phases were combined. The product was washed with water (10 mL) and saturated brine (10 mL x 2), and dried over anhydrous sodium sulfate. The crude product was isolated and purified to give Compound 71-9 (3.70 g, 85.8% yield) as a white solid.

[0495] Step 8: Synthesis of compound 71-10

[0496] Compound 71-9 (1.00 g, 3.35 mmol) was dissolved in dioxane (12 mL) / water (1.2 mL). (6E)-2,2,3,3-tetramethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-4-oxo-3-silahept-6-ene (1.50 g, 5.02 mmol), cesium carbonate (2.73 g, 8.37 mmol), and Pd(dtbpf)Cl2 (0.22 g, 0.33 mmol) were added. The mixture was stirred at 70°C under nitrogen for 1.5 hours. LCMS indicated the reaction was complete. The mixture was concentrated, diluted with water (15 mL), and extracted with ethyl acetate (10 mL x 3). The product was washed with water (5 mL) and brine (5 mL), and then dried over anhydrous sodium sulfate. Concentration and purification gave compound 71-10 (522 mg, 39.9% yield) as a light yellow oil. MS (ESI) m / z = 412.0 [M+Na] + . 1 H NMR (400MHz, CDCl3): δ7.46(dt,J=2.0,16.0Hz,1H),6.16(dt,J=4.8,16.0Hz,1H),4.33(dd,J=1.6,4.8Hz,1H),1.60(s,9H),0.93(s,9H),0.10(s,6H).

[0497] Step 9: Synthesis of compound 71-11

[0498] Compound 71-10 (520 mg, 1.33 mmol) was dissolved in tetrahydrofuran (7 mL), and TBAF (2.67 mL, 2.67 mmol, 1 M in tetrahydrofuran) was added. Under N2 protection, the mixture was stirred at 25°C for 2 hours. LCMS showed that the reaction was complete. The mixture was concentrated, diluted with water (15 mL), extracted with ethyl acetate (10 mL × 3), washed with water (5 mL) and brine (5 mL), and dried over anhydrous sodium sulfate. The crude product was concentrated and purified to give compound 71-11 (264 mg, 71.9% yield) as a yellow oil. MS (ESI) m / z = 220.0 [M-tBu+H] +

[0499] Step 10: Synthesis of compound 71-12

[0500] Compound 71-11 (264 mg, 0.96 mmol) was dissolved in DMSO (4 mL), and compound 13-7 (220 mg, 1.15 mmol) and DIEA (0.50 mL, 2.87 mmol) were added. Under N2 protection, the mixture was reacted at 100°C for 16 hours. LCMS showed that the reaction was complete. The reaction solution was diluted with H2O (25 mL), extracted with ethyl acetate (10 mL × 3), washed with H2O (5 mL) and saturated brine (5 mL), and dried over anhydrous sodium sulfate. The crude product was concentrated and purified to obtain compound 71-12 (309 mg, 74.8% yield) as a yellow solid. MS (ESI) m / z = 432.2 [M+H] +

[0501] Step 11: Synthesis of compound 71-13

[0502] Compound 71-12 (309 mg, 0.72 mmol) was dissolved in a methanol (10 mL) / tetrahydrofuran (2 mL) mixed solvent, and platinum dioxide (56.9 mg, 0.25 mmol) was added. The mixture was stirred at 25°C for 12 hours while passing hydrogen gas (15 psi). LCMS showed that the reaction was complete. The reactants were filtered and concentrated to give compound 71-13 (262 mg, 84.4% yield) as a yellow solid. The crude product was used directly in the next step without further purification. MS (ESI) m / z = 434.2 [M+H] +

[0503] Step 12: Synthesis of Compound 71-14

[0504] To a dichloromethane solution (5 mL) containing compound 71-13 (260 mg, 0.60 mmol) was added triethylamine (0.25 mL, 1.80 mmol) and MsCl (0.07 mL, 0.90 mmol) at 0°C. The reaction mixture was stirred at 25°C under nitrogen for 2 hours. LCMS showed that the reaction was complete. The reaction mixture was diluted with water (10 mL), extracted with dichloromethane (10 mL × 3), washed with water (5 mL) and saturated brine (5 mL), and dried over anhydrous sodium sulfate. The concentrated crude product was purified by column chromatography to obtain compound 71-14 (256 mg, 83.4% yield) as a yellow solid. MS (ESI) m / z = 512.2 [M+H] +

[0505] Step 13: Synthesis of compound 71-15

[0506] Compound 71-14 (256 mg, 0.50 mmol) was dissolved in DMF solution (4 mL), and potassium carbonate (207 mg, 1.50 mmol) and compound 71-6 (390 mg, 1.25 mmol) were added. Under N2 protection, the reaction solution was stirred at 90°C for 12 hours. LCMS showed that the reaction was complete. The reaction solution was added dropwise to ice-cold H2O (15 mL) with stirring, stirred for 10 minutes, and then filtered. The crude product was purified by preparative column chromatography to obtain compound 71-15 (216 mg, yield 59.3%) as a yellow solid. MS (ESI) m / z = 728.4 [M+H] +

[0507] Step 14: Synthesis of Compound 71-16

[0508] Compound 71-15 (60 mg, 0.08 mmol) was dissolved in a mixture of methanol (0.2 mL) / tetrahydrofuran (0.2 mL) / H₂O (0.2 mL), and lithium hydroxide monohydrate (6.92 mg, 0.16 mmol) was added. Under N₂ protection, the reaction solution was stirred at 30°C for 2 hours. LCMS showed that the reaction was complete, and the product was concentrated to give compound 71-16 (58.8 mg, crude product). This product was used directly in the next step without further purification. MS (ESI) m / z = 714.4 [M+H] +

[0509] Step 15: Synthesis of Compound 71-17

[0510] Compound 71-16 (58.8 mg, 0.08 mmol) was dissolved in DMF solution (1.5 mL), and 2-benzothiazolamine (13.6 mg, 0.09 mmol), NMI (20.2 mg, 0.25 mmol), and TCFH (115 mg, 0.41 mmol) were added. Under N2 protection, the mixture was stirred at 25°C for 2 hours. LCMS showed that the reaction was complete. The reaction solution was diluted with water (10 mL), extracted with ethyl acetate (5 mL × 3), washed with water (3 mL) and saturated brine (5 mL), and dried over anhydrous sodium sulfate. The crude product was purified by column chromatography to obtain compound 71-17 (26 mg, yield 37.3%) as a yellow oil. MS (ESI) m / z = 846.4 [M+H] +

[0511] Step 16: Synthesis of compound RN-071

[0512] Compound 71-17 (16 mg, 0.02 mmol) was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (1 mL) was added. The mixture was stirred at 25°C for 3 hours under nitrogen. LCMS indicated the reaction was complete, and the reaction solution was concentrated. The crude product was purified by preparative HPLC to obtain compound RN071 (3.03 mg, 20.2% yield) as a pale yellow solid. MS (ESI) m / z = 790.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ8.55(s,1H),8.47(s,1H),8.26-8.31(m,3H),7.98( d,J=8.8Hz,2H),7.79(d,J=7.2Hz,1H),7.56(s,1H),7.47(s,1H),7.35(s,1H) ,7.06(d,J=7.2Hz,2H),5.07(s,2H),4.04(s,2H),3.77(s,2H),3.54(s,2H),3 .23(s,2H),3.07(s,2H),2.42(s,2H),2.23(s,6H),2.05(s,2H),1.79(s,2H).

[0513] Example 31 Synthesis of Compound RN072

[0514] The structure of compound RN072:

[0515] The same method as Example RN019 was used to prepare yellow solid compound RN072 (2.16 mg, yield 2.00%).

[0516] MS (ESI) m / z = 663.4 [M+H]+ . 1 H NMR (400MHz, DMSO-d6): δ = 8.54 (d, J = 4.8Hz, 1H), 8.05 (d, J = 8.0Hz, 1H), 7.81 (d, J = 8.0Hz, 1H) ,7.70(d,J=8.8Hz,1H),7.55(d,J=5.0Hz,1H),7.51-7.44(m,1H),7.41-7.29(m,1H),6.95(br d,J=9.0Hz,1H),5.17(br d,J=5.0Hz,2H),3.94-3.82(m,2H),3.59-3.49(m,1H),3.03(br t,J=5.3Hz,2H),2.85-2.70(m,1H),2.42-2.35(m,4H),2.22-1.99(m,2H),1.94(br s,3H),1.72-1.41(m,12H),0.66(d,J=6.3Hz,3H).

[0517] Example 32 Synthesis of Compound RN073

[0518] The synthetic route is as follows:

[0519] Step 1: Synthesis of compound 73-2

[0520] Compound 73-1 (5.00 g, 59.4 mmol) was dissolved in DMSO (150 mL), and 1-bromomethyladamantane (8.02 mL, 47.5 mmol) and cesium carbonate (48.4 g, 148 mmol) were added. The reaction mixture was stirred at 90°C for 16 hours. After completion of the reaction, the mixture was diluted with water (1.5 L) and extracted with ethyl acetate (150 mL x 3). The organic phase was concentrated to obtain a crude white solid (488 mg, 1.26 mmol, 2.12% yield), which was used directly in the next reaction. MS (ESI) m / z = 233.2 [M+H] +

[0521] Step 2: Synthesis of compound 73-3

[0522] Compound 73-2 (200 mg, 0.86 mmol) was dissolved in DMSO (2 mL) and tert-butyl 3-fluoro-6-chloropicolinate (197 mg, 0.86 mmol), cesium carbonate (841 mg, 2.58 mmol), and potassium iodide (142 mg, 0.86 mmol) were added. The reaction mixture was stirred at 80°C for 2 hours. The reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (10 mL × 2), washed with saturated brine (5 mL), dried, and concentrated. The crude product was purified by prep-HPLC (0.1% TFA, ACN:H2O = 70% to 93%) to obtain compound 73-3 (45 mg, yield 13.4%) as a white solid. MS (ESI) m / z = 388.2 [M- t Bu+H] +

[0523] Step 3: Synthesis of compound 73-4

[0524] Compound 20-6 (80.0 mg, 0.26 mmol) was dissolved in DMF (3 mL), and compound 73-3 (136 mg, 0.31 mmol), cesium carbonate (251 mg, 0.77 mmol), and Pd(t-Bu3P)2 (13.1 mg, 0.03 mmol) were added. The reaction mixture was stirred at 130°C under microwave conditions for 6 hours. After completion of the reaction, the mixture was diluted with water (10 mL), extracted with ethyl acetate (5 mL × 2), washed with water (3 mL), washed with saturated brine (3 mL), and dried over anhydrous sodium sulfate. The crude product was purified by preparative purification to obtain compound 73-4 (44.0 mg, yield 23.8%) as a yellow oil. MS (ESI) m / z = 716.4 [M+H] +

[0525] Step 4: Synthesis of compound RN073

[0526] Compound 73-4 (34.0 mg, 0.05 mmol) was dissolved in dichloromethane (0.8 mL) and trifluoroacetic acid (0.8 mL) was added. The reaction mixture was stirred at 25°C for 2 hours. After completion of the reaction, the reaction mixture was concentrated. The crude product was purified by Prep-HPLC to obtain the white solid product RN073 (11.5 mg, 37.1% yield). MS (ESI) m / z = 660.4 [M+H] + . 1H NMR (400MHz, DMSO-d6): δ8.57(d,J=4.8Hz,1H),8.05(d,J=7.6Hz,1H),7.81(d,J=8.4Hz,1H),7.58(d,J=4.8Hz,2H),7.48(t,J=7.6Hz,1H),7.3 4-7.39(m,2H),7.02(d,J=9.2Hz,1H),5.26(s,2H),3.97(s,2H),3.07( s,2H),2.17(s,2H),1.89(s,6H),1.61-1.64(m,3H),1.50-1.57(m,9H).

[0527] Example 33 Synthesis of Compound RN074

[0528] The synthetic route is as follows:

[0529] Step 1: Synthesis of compound 74-1

[0530] Compound RN001 (50 mg, 75.78 μmol, 1 eq) was dissolved in 1 mL of N,N-dimethylformamide, and N,N-diisopropylethylamine (DIEA) (29.38 mg, 227.34 μmol, 39.60 μL, 3 eq) and 2-(piperidin-4-yl)ethan-1-ol (14.69 mg, 113.67 μmol, 1.5 eq) were added. The reaction mixture was stirred at 25°C for 10 minutes, followed by the addition of HTAU (43.22 mg, 113.67 μmol, 1.5 eq). The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was poured into 10 mL of water and extracted twice with 10 mL of ethyl acetate. The combined organic phases were washed with 10 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography to afford Compound 74-1 (51 mg, 87.29% yield) as a yellow solid. MS (ESI) m / z = 771.2 [M+H] +

[0531] Step 2: Synthesis of compound RN074

[0532] To a solution of phosphorus oxychloride (12.73 mg, 83.01 μmol, 7.74 μL, 1.6 eq) in 0.5 mL of pyridine was added dropwise under nitrogen at -15°C. The reaction mixture was stirred at -15°C for 2 hours. The reaction was carefully quenched with 0.5 mL of water at -5°C, and the mixture was stirred at -5°C for 1 hour. The reaction mixture was basified to pH = 10 with 4 M NaOH and concentrated to obtain the crude product. 3 mL of dimethyl sulfoxide and 1 mL of pyridine were added to the crude product, and the mixture was filtered. The filter cake was washed twice with 5 mL of water and then lyophilized to obtain compound RN074 (1.12 mg, 2.35% yield) as a yellow solid. MS (ESI) m / z = 851.1 [M-2Na+H] + . 1 H NMR (400MHz, DMSO-d6): δ = 8.32 (br d, J = 3.8Hz, 1H), 7.72 (br s, 1H), 7.57-7.42 (m, 2H), 7.29-7.16 (m, 3H), 7.12-7.01 (m, 1H), 6.79 (br d,J=8.0Hz,1H),4.90(br s,2H),4.29-4.20(m,1H),3.91-3.82(m,2H),3.69(br s,2H),3.50(br s,2H),3.11-3.06(m,2H),2.95(br d,J=5.6Hz,2H),2.13(br s,3H),1.91(br d,J=2.4Hz,3H),1.67-1.62(m,3H),1.57-1.48(m,11H),1.40-1.33(m,2H) ,1.25-1.19(m,2H),0.73(ddd,J=2.7,6.0,10.3Hz,1H),0.62-0.35(m,1H).

[0533] Example 34 Synthesis of Compound RN075

[0534] The structure of compound RN075 is as follows:

[0535] The same method as in Example 33 was used to obtain yellow solid compound RN075 (2.33 mg, yield 2.12%). MS (ESI) m / z = 837.2 [M-2Na+H] + . 1H NMR (400MHz, DMSO-d6): δ = 8.31 (br d, J = 4.8Hz, 1H), 7.69 (br d, J = 7.5Hz, 1H), 7.48 (br d, J = 8.8Hz, 2H), 7.25-7.07 (m, 3H), 7.03 (br t,J=7.4Hz,1H),6.86(br d,J=8.6Hz,1H),5.17-4.94(m,1H),4.84(br d,J=17.4Hz,1H),4.19(br d,J=11.6Hz,1H),3.99(br dd,J=6.1,7.9Hz,1H),3.86-3.75(m,1H),3.74-3.63(m,2H),3.12-2.78(m,5H),2.66-2.55(m,1H),2.12(s,3H),1.91(br s,3H),1.68-1.59(m,3H),1.58-1.30(m,13H),0.80-0.67(m,1H),0.41(br dd,J=1.5,11.5Hz,1H)

[0536] Example 35 Synthesis of Compound RN076

[0537] The synthetic route is as follows:

[0538] Step 1: Synthesis of compound 76-1

[0539] Compound RN051 (40 mg, 51.23 μmol, 1 eq) was dissolved in 2 mL of dichloromethane. [Di(tert-butyloxy)phosphanyl]diethylamine (63.86 mg, 256.13 μmol, 5 eq) and tetrazole (14.35 mg, 204.90 μmol, 18.17 μL, 4 eq) were added. The reaction mixture was stirred at 25°C for 1 hour. Hydrogen peroxide (0.2 g, 1.76 mmol, 169.49 μL, 30% purity, 34.44 eq) was then added dropwise to the mixture. The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was poured into 10 mL of water and extracted twice with 10 mL of dichloromethane. The combined organic phases were dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography to afford 76-1 (46 mg, 92.29% yield) as a yellow oil.

[0540] Step 2: Synthesis of compound RN076

[0541] Compound 76-1 (43 mg, 44.19 μmol, 1 eq) was dissolved in ethyl acetate hydrochloride (2 M, 3 mL, 135.77 eq), and the reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated to obtain a crude product, which was then purified by preparative liquid chromatography to obtain a crude product. The crude product was dissolved in 1 mL of methanol, the pH was adjusted to 7-8 with 0.5 M sodium hydroxide solution, and then lyophilized to obtain a yellow solid compound RN076 (2.44 mg, yield 5.60%). MS (ESI) m / z = 861.1 [M-2Na+H] + . 1 H NMR (400MHz, DMSO-d6): δ = 8.40 (d, J = 4.8Hz, 1H), 7.84 (br d,J=7.8Hz,1H),7.69-7.55(m,4H),7.52(d,J=8.8Hz,1H),7.40-7.26(m, 4H),7.23-7.12(m,1H),6.86(d,J=8.8Hz,1H),5.53-5.38(m,2H),5.03(br s,2H),4.25(br d,J=12.3Hz,1H),3.93-3.81(m,2H),3.52(br s,1H),3.14-3.06(m,2H),2.98(br t,J=5.3Hz,2H),2.65-2.58(m,1H),2.45-2.38(m,1H),2.14(s,3H),1.52(br d,J=11.1Hz,1H),1.46-1.36(m,1H),1.32(br d,J=12.0Hz,1H),1.16(td,J=6.1,12.4Hz,2H),0.77-0.62(m,1H),0.56-0.37(m,1H).

[0542] Example 36 Synthesis of Compound RN077

[0543] The structure of compound RN077 is as follows:

[0544] The same method as Example RN076 was used to prepare yellow solid compound RN077 (6.92 mg, yield 17.97%).

[0545] MS (ESI) m / z = 823.4 [M-2Na+H] + . 1H NMR (400MHz, DMSO-d6): δ = 8.55 (d, J = 4.8Hz, 1H), 8.06 (d, J = 7.9Hz, 1H), 7.81 (d, J = 8.0Hz, 1H), 7.59-7.53 (m, 2H), 7.52-7.44 (m ,1H),7.42-7.30(m,1H),7.24(s,1H),6.96(d,J=8.9Hz,1H),5.28-5.12(m,2H),4.31-4.24(m,1H),3.93-3.88(m,2H),3.71(br s,2H),3.19-3.09(m,3H),3.05(br t,J=5.6Hz,2H),2.97-2.91(m,1H),2.16(s,3H),1.93(br s,3H),1.73-1.41(m,15H),1.35-1.25(m,1H).

[0546] Example 37 Synthesis of Compound RN078

[0547] The structure of compound RN078 is as follows:

[0548] The same method as Example RN001 was used to obtain a white solid compound RN078 (24 mg, yield 42.60%). MS (ESI) m / z = 718.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ = 8.56 (br d,J=4.6Hz,1H),8.05(d,J=7.6Hz,1H),7.81(d,J=8.0Hz,1H),7.61-7.44(m,3H),7.41-7.29(m,2H),6.99(d,J=8.8Hz,1H),5.21(s,2H),3.94(br t,J=5.8Hz,2H),3.77(s,2H),3.58(s,3H),3.06(br t,J=5.6Hz,2H),2.13(s,3H),2.04(br s,2H),1.79-1.65(m,6H),1.62-1.41(m,6H).

[0549] Example 38 Synthesis of Compound RN079

[0550] The synthetic route is as follows:

[0551] Step 1: Synthesis of compound RN079

[0552] Compound RN078 (16 mg, 22.29 μmol, 1 eq) was dissolved in a mixture of 1 mL of methanol, 1 mL of tetrahydrofuran, and 1 mL of water. Lithium hydroxide monohydrate (2.81 mg, 66.87 μmol, 3 eq) and aqueous sodium hydroxide solution (0.3 mL, 20% purity) were added, and the reaction mixture was stirred at 25°C for 3 hours. The reaction mixture was concentrated to obtain a crude product, which was then purified by preparative liquid chromatography to afford compound RN079 (6.62 mg, 41.30% yield) as a yellow solid. MS (ESI) m / z = 704.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ = 8.55 (d, J = 4.8Hz, 1H), 8.05 (d, J = 7.8Hz, 1H), 7.81 (d, J = 8.0Hz, 1H), 7.55 (d,J=4.8Hz,1H),7.52-7.42(m,2H),7.41-7.29(m,2H),6.90(d,J=8.8Hz,1H),5.19(s,2H),3.92(br t,J=5.6Hz,2H),3.76(s,2H),3.05(br t,J=5.7Hz,2H),2.14(s,3H),2.03(br s,2H),1.75-1.61(m,6H),1.58-1.41(m,6H).

[0553] Test Example 1 Senescent Cell Activity Data

[0554] This test case used a human non-small cell lung cancer cell line (A549 cells). These cells were senescent by induction with etoposide (10 μM). The effects of the target compounds on senescent cell viability were examined, thereby evaluating the compound's specific killing effect on senescent cells.

[0555] Briefly, senescent cells were plated (96-well plate). Compounds (at a concentration of 1 μM) were added for 72 h, and then Cell viability was detected using Luminescent Cell Viability Assay Kit (Promega), and the results are shown in Table 7. Table 7 summarizes the cytotoxicity (IC 50 ).

[0556] Table 7

[0557] Note: In the table, A represents less than 0.2 μM; B represents: 0.2-1.0 μM; C represents: 1-10 μM.

[0558] Test Example 2: SPR data of target proteins BCL-2 and BCL-XL

[0559] In order to investigate the effects of the nitrogen heterocyclic compound of Formula I on the affinity and selectivity of the target protein, an SPR experiment was performed.

[0560] SPR assays were performed on a Biacore 8K instrument (GE Healthcare). Target proteins were immobilized on NTA chips (Catlog BR100532) at 25°C using a loading buffer of 50 mM Tris-HCl, 150 mM NaCl, pH 8.0, 0.005% Tween-20, and 1 mM TCEP. Target proteins (BCL-2 10 μg / mL, BCL-XL 20 μg / mL) were thawed and diluted in loading buffer. The parameters under "Ligand" were set to: contact time = 200 s, flow rate = 2 μL / min; BCL-2 and BCL-XL proteins were covalently coupled to a density of 2000-4000 Ru (response units). All SPR kinetic analysis experiments were performed at 25°C in an assay buffer containing 50 mM Tris-HCl, 150 mM NaCl, pH 8.0, 0.005% Tween-20, 1 mM TCEP, and 5% DMSO. Click "1. Method," set the parameters in "Startup," select "Wash 1," and choose the assay buffer as the solution. Set the parameters in "Single Cycle Kinetics" by selecting "Analyte," contact time = 70 s, dissociation time = 1800 s, and flow rate = 30 μL / min. Select the ligand-immobilized channel and define the gradient concentration of the analyte and the plate position. Background from the reference channel and blanks was subtracted from the raw data before data analysis using Biacore 8K Evaluation Software. Sensorgrams recorded at different compound concentrations in the single-cycle experiment were fitted using a 1:1 interaction model.

[0561] The test results are shown in Table 8. It can be seen that compared with compound A-1331852 (CAS No. 1430844-80-6), the inhibitor described in the present application has higher affinity and better selectivity for the target protein BCL-XL.

[0562] Table 8

[0563] Test Example 3 Kinetic Solubility Data

[0564] To 485 μL of 100 mM phosphate buffered saline (PBS), 15 μL of a 10 mM compound stock solution was added. The mixture was shaken at 1100 rpm for 1 hour at room temperature. The solution was filtered, and the compound concentration in the resulting filtrate / supernatant was determined by LC-MS / MS. The compound concentration was calculated by comparison with a standard calibration curve.

[0565] The test results are shown in Table 9. The kinetic solubility of the inhibitor described in the present application is significantly improved (ie, the value is increased) compared with that of compound A-1331852.

[0566] Table 9

[0567] Efficacy of Test Example 4 in an animal model of hyperoxia-induced retinopathy

[0568] The effects of compound RN001 were studied in the oxygen-induced retinopathy (OIR) mouse model, which is somewhat indicative of an in vivo model of retinopathy of prematurity (ROP), diabetic retinopathy, and wet age-related macular degeneration.

[0569] From postnatal day 7 (P7) to day 12 (P12), C57Bl / 6 mouse pups and their CD1 foster mothers were exposed to a hyperoxic environment (75% O2). At P12, the animals were intravitreally injected with 1 μL of a test composition (200 μM compound) prepared in 1% DMSO, 10% Tween 80, 20% PEG-400 and returned to room air until day 17 (P17). At P17, the eyes were enucleated and the retinas dissected for vascular staining. To determine the area of ​​avascularity or neovascularization, the retinas were flattened and stained with isolectin B4 (IB4).

[0570] Figure 1 shows that intravitreal (IVT) administration of RN001 resulted in statistically significant improvements in avascular zone and vascular proliferation.

[0571] Efficacy of Test Example 5 in an animal model of psoriasis induced by topical imiquimod application

[0572] The effects of compound RN001 were investigated in an imiquimod-induced psoriasis mouse model, which is indicative of age-related skin diseases.

[0573] Take a healthy male Balb / c mouse and remove the hair in the middle of the back (2 × 3 cm) 2The next day, animals without skin damage after hair removal were selected for modeling. The normal control group received no special treatment. All other animals, except those in the normal control group, were treated with imiquimod (Sichuan Mingxin Pharmaceutical Co., Ltd.) for modeling. 5% imiquimod (Sichuan Mingxin Pharmaceutical Co., Ltd.) was applied daily with a brush for six consecutive days. In addition to imiquimod, the drug group also received daily application of 1 mg / kg of compound RN001. After photography and erythema and scaling were completed on the seventh day, samples were fixed, paraffin-embedded, and stained with hematoxylin and eosin (HE) for comparison with the normal control group to determine model establishment and improvement after drug administration.

[0574] FIG2 shows that skin application of RN001 resulted in a decrease in erythema and scaling scores, and a decrease in skin epidermal thickness as measured by HE staining.

[0575] Efficacy of Test Example 6 in Bleomycin-induced Scleroderma Animal Model

[0576] The effect of compound RN001 was studied in a bleomycin-induced model of scleroderma, either localized or diffuse.

[0577] Male C57BL / 6J mice were depilated mid-back. The next day, animals without skin damage after depilation were grouped for modeling. A normal control group received no special treatment. All other mice received a subcutaneous injection of 0.075 mg of bleomycin for four consecutive weeks. In addition to the subcutaneous bleomycin injection, the drug group also received daily application of 1 mg / kg of the compound RN001. Four weeks after modeling, skin samples were obtained, fixed, paraffin-embedded, and stained with H&E and Masson staining. The stained sections were scanned and analyzed for changes in dermal thickness and collagen content.

[0578] Figure 3 shows that skin application of RN001 resulted in a significant improvement in dermal thickness and a reduction in the deposition of skin collagen fibers as determined by Masson staining.

[0579] Efficacy of Test Example 7 in an animal model of idiopathic pulmonary fibrosis

[0580] This example uses an idiopathic pulmonary fibrosis animal model to test the effects of the disclosed compounds on idiopathic pulmonary fibrosis.

[0581] In simple terms, anesthetized 6-week-old SD rats were fixed on a foam board with medical tape. First, the skin on the tracheal surface was cut open with surgical scissors to fully expose the trachea. A microinjection needle of 100 microliters of a certain volume of bleomycin (BLM 5mg / kg) solution drawn according to the rat's weight was inserted into the trachea through the mouth for administration. After giving the BLM solution, the foam board was immediately rotated and shaken so that the BLM medicinal solution was evenly distributed in the lung tissue as much as possible, and then the skin on the tracheal surface was sutured with surgical sutures. After the 7th day of modeling, the compound solution of the present invention was given according to the rat's weight, and intraperitoneal injection (IP) was performed (5mg / kg) for 3 consecutive weeks. At the 28th day, mice were euthanized by carbon dioxide, and lung tissue was taken, and left alveolar lavage fluid was collected for white blood cell (WBC) counting. Hydroxyproline (HYP) was detected in the right lung tissue portion, and the remaining lung tissue was subjected to pathological H&E staining and Masson staining.

[0582] Figure 4 shows that intraperitoneal (IP) administration of RN001 resulted in statistically significant improvements in WBC, HYP, and pathology scores in the IPF model.

[0583] Efficacy of Test Example 8 in an animal model of osteoarthritis

[0584] This example uses an osteoarthritis animal model to test the effects of the compounds of the present disclosure on osteoarthritis.

[0585] An osteoarthritis animal model was constructed by the following steps. The mice were anesthetized with isoflurane and fixed. The hair on the right hind limb of the mice was shaved, the skin was wiped and disinfected with alcohol, and the skin at the joint was cut. Under an optical microscope, the inner side of the right knee joint with the knee flexed was cut longitudinally with a blade. The patellar ligament was not cut. The patellar ligament was pulled to one side and compression was continuously applied with a sterile cotton swab to stop bleeding. The joint cavity was fully exposed and physiological saline was added in time to prevent the joint cavity from drying out. The excess muscle tissue was gently separated with blunt forceps to expose the meniscus ligament and the anterior cruciate ligament was searched deep in the joint cavity. The anterior cruciate ligament was cut open with micro-scissors, and the wound was disinfected with penicillin solution. The muscles were sutured with sterilized needles and thread, and finally the skin tissue was sutured. The efficacy of the drug was determined by intra-articular injection. At the end of the experiment, the plantar pain threshold was tested and the bone joints were stained with safranin and fast green.

[0586] FIG5 shows that intra-articular administration of RN001 resulted in statistically significant improvements in plantar mechanical pain threshold and pathological scores of safranin fast green staining in an osteoarthritis (OA) model.

[0587] Efficacy of Test Example 9 in Rabbit Ear Hypertrophic Scar Model

[0588] This example uses a rabbit ear hypertrophic scar animal model to test the effect of the disclosed compounds on hypertrophic scars. Briefly, six male New Zealand white rabbits, 3 months old, were selected. After the New Zealand rabbits were anesthetized with sodium pentobarbital, four circular full-thickness wounds with a diameter of 10 mm were made on the ventral surface of each ear by removing the epidermis, dermis and perichondrium to the exposed cartilage. The rabbits were randomly divided into a control group and an RN001 experimental group. On the 14th day after surgery, after the wound was completely re-epithelialized, the compound solution (150 μM, 100 μL, 10% DMSO + 90% saline) or the negative control solution (100 μL, 10% DMSO + 90% saline) was taken and the solution was injected from the edge of the wound into the center of each lesion, once a week, for a total of 4 injections. The improvement of scar formation by the drug was evaluated by SEI (scar hyperplasia index).

[0589] FIG6 shows that administration of RN001 resulted in a statistically significant improvement in the scar hyperplasia index in the rabbit ear hypertrophic scar model.

Claims

1. A nitrogen heterocyclic compound or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer or isotope compound thereof, wherein the nitrogen heterocyclic compound has a structure shown in Formula I: in, X1, X2, and X3 are each independently selected from CR g and N, and X1, X2, and X3 are not CR at the same time g ; R a , R b , R c , R d , R e , R f , R g , R h , R i , R j , R k Each is independently selected from hydrogen, deuterium, halogen-substituted or unsubstituted C1-C8 alkyl, halogen-substituted or unsubstituted C3-C8 cycloalkyl, halogen-substituted or unsubstituted C2-C8 alkenyl, halogen-substituted or unsubstituted C2-C8 alkynyl, a halogen atom, a hydroxyl group, an amino group, a nitro group, a cyano group, a carboxyl group, an acyl group, a halogen-substituted or unsubstituted C2-C8 alkoxy group; Z is selected from O and N; When Z is O, Y2 is absent, and Y1 is independently selected from hydrogen, deuterium, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, -R1-R2-R3, -R2-R3 or -R1-R3, wherein R1 is selected from substituted or unsubstituted C1-C 10 Alkylene, R2 is selected from -OC(O)- or -OC(O)-O-, and R3 is selected from substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C20 cycloalkyl, substituted or unsubstituted C2-C20 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted C1-C20 heteroaryl, substituted or unsubstituted C2-C20 heteroalicyclic; When Z is N, Y1 and Y2 are independently selected from hydrogen, deuterium, C1-C10 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C20 aryl, C1-C20 heteroaryl, C2-C20 heteroalicyclic, wherein C1-C10 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, wherein CH2 can be selected from -O-, -S-, -SO2-, -C(O)- and -NR 3-, the C1-C10 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C20 aryl, C1-C20 heteroaryl and C2-C20 heteroalicyclic groups are optionally replaced by halogen atoms, cyano, nitro, C6-C20 aryl, C1-C20 heteroaryl, C1-C10 alkoxy, C6-C20 aryloxy, C2-C20 heteroalicyclic groups, amino, hydroxyl, thiol, - substituted by one or more substituents in NR4R5; or Y1 and Y2 together with the N atom to which they are connected constitute a heteroalicyclic group, preferably a C2-C20 heteroalicyclic group, which is optionally substituted by halogen atoms, cyano, nitro, C6-C20 aryl, C1-C20 heteroaryl, C1-C10 alkoxy, C6-C20 aryloxy, C2-C20 heteroalicyclic group, amino, hydroxyl, thiol, - substituted by one or more substituents in NR4R5; or Y1 is hydrogen or deuterium, and Y2 is selected from C1-C10 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C20 aryl, C1-C20 heteroaryl and C2-C20 heteroalicyclic group, wherein C1-C10 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, CH2 in which can be selected from -O-, -S-, -SO2-, -C(O)- and -NR3-One or more groups replaced, the C1-C10 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, wherein CH2 can be selected from -O-, -S-, -SO2-, -C(O)- and -NR3-One or more groups replaced, the C1-C10 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, wherein CH2 in C8 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C20 aryl, C1-C20 heteroaryl, C2-C20 heteroalicyclic group is substituted by halogen atoms, hydroxyl, thiol, amino, nitro, cyano, carboxyl, acyl, C1-C10 alkoxy, C6-C20 aryl, C1-C20 heteroaryl, C2-C20 heteroalicyclic group, C1-C10 alkyl, C2-C8 alkenyl or C2-C8 alkynyl, and the substituents at at least two positions together constitute an aliphatic ring, a heteroalicyclic ring, an aromatic ring or a heteroaromatic ring; R4 and R5 are independently selected from hydrogen, deuterium, aryl, heteroaryl, C1-C8 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl and C2-C8 alkynyl, wherein the aryl and heteroaryl are optionally substituted by halogen atoms, hydroxyl, sulfhydryl, amino, nitro, cyano, carboxyl, acyl, alkoxy, aryl, heteroaryl, heteroalicyclic, C1-C10 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl or C2-C8 alkynyl, wherein the substituents at at least two positions together constitute an aliphatic ring, a heteroalicyclic ring, an aromatic ring or a heteroaromatic ring; Ring A is independently selected from substituted or unsubstituted aromatic or heteroaromatic rings; Ring B is absent or independently selected from substituted or unsubstituted aromatic or heteroaromatic rings, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C6-C10 spiro, C6-C10 heterospiro, C6-C10 heterocondensed ring, C6-C10 heterocondensed ring; L is absent or selected from C1-C6 alkylene, -C1-C6 alkylene-O- or -C1-C3 alkylene-O-C1-C3 alkylene-, wherein the alkylene is optionally substituted by a halogen atom, a hydroxyl, a thiol, an amino, a nitro, a cyano, a carboxyl, an acyl, a C1-C10 alkoxy, a C6-C20 aryl, a C1-C20 heteroaryl, a C2-C20 heteroalicyclic, a C1-C10 alkyl, a C3-C8 cycloalkyl, a C2-C8 alkenyl or a C2-C8 alkynyl; R is independently selected from an aromatic ring or a heteroaromatic ring, an aromatic ring and an aromatic heterocycle, a C3-C8 cycloalkane, a C3-C8 heterocycloalkane, a C6-C14 spirocycle, and a C6-C14 condensed cycloalkane; and R is optionally substituted by a halogen atom, a hydroxyl, a thiol, an amino group, a nitro group, a cyano group, a carboxyl group, an acyl group, a C1-C10 alkoxy group, a C6-C20 aryl group, a C1-C20 heteroaryl group, a C2-C20 heteroalicyclic group, a C1-C10 alkyl group, a C3-C8 cycloalkyl group, a C2-C8 alkenyl group, or a C2-C8 alkynyl group.

2. The compound according to claim 1, characterized in that X3 is CR g ; Or, X3 is N, X1 and X2 are CR g ; Or, X1 is N, X2 and X3 are CR g ; Or, X2 is N, X1 and X3 are CR g .

3. The compound according to claim 1 or 2, characterized in that R a , R b , R c , R d , R e , R f , R g , R h , R i , R j , R k Each is independently selected from hydrogen, deuterium, halogen-substituted or unsubstituted C1-C6 alkyl, halogen-substituted or unsubstituted C3-C6 cycloalkyl, halogen-substituted or unsubstituted C2-C6 alkenyl, halogen-substituted or unsubstituted C2-C6 alkynyl, a halogen atom, a hydroxyl group, an amino group, a nitro group, a cyano group, a carboxyl group, a halogen-substituted or unsubstituted C2-C6 alkoxy group; Preferably, R a , R b , R c , R d , R e , R f , R g , R h , R i , R j , R k Each is independently selected from hydrogen, deuterium, halogen-substituted or unsubstituted C1-C6 alkyl, halogen-substituted or unsubstituted C3-C6 cycloalkyl, halogen atom, C2-C6 alkoxy; Preferably, R a , R b , R c , R d , R e , R f , R g , R h , R i , R j , R k All are hydrogen.

4. The compound according to any one of claims 1 to 3, characterized in that Z is O, Y2 is absent, and Y1 is selected from hydrogen, deuterium, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, -R1-R2-R3, -R2-R3 or -R1-R3, wherein R1 is selected from substituted or unsubstituted C1-C 10 Alkylene, R2 is selected from -OC(O)- or -OC(O)-O-, and R3 is selected from substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C20 cycloalkyl, substituted or unsubstituted C2-C20 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted C1-C20 heteroaryl, substituted or unsubstituted C2-C20 heteroalicyclic.

5. The compound according to any one of claims 1 to 4, characterized in that Z is O, Y2 is absent, and Y1 is selected from hydrogen or deuterium; or Z is O, Y2 is absent, and Y1 is selected from substituted or unsubstituted C1-C6 alkyl or substituted or unsubstituted C3-C 10 Cycloalkyl; or Z is O, Y2 is absent, and Y1 is selected from -R1-R2-R3, -R2-R3 or -R1-R3.

6. The compound according to any one of claims 1 to 5, characterized in that R1 is selected from substituted or unsubstituted C1-C6 alkylene, preferably substituted or unsubstituted C1-C3 alkylene, more preferably methylene; R3 is selected from substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C2-C12 heteroaryl or substituted or unsubstituted C1-C12 heteroalicyclic group; preferably, R3 is selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C1-C10 heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C1-C10 heteroalicyclic group; Preferably, R3 is selected from the following groups:

7. The compound according to any one of claims 1 to 6, characterized in that Z is N, Y1 and Y2 are independently selected from C1-C10 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C20 aryl, C1-C20 heteroaryl, C2-C20 heteroalicyclic, wherein C1-C10 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, wherein CH2 may be replaced by one or more groups selected from -O-, -S-, -SO2-, -C(O)- and -NR3-, The C1-C10 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C20 aryl, C1-C20 heteroaryl and C2-C20 heteroalicyclic groups are optionally substituted with halogen atoms, cyano, nitro, C6-C20 aryl, C1-C20 heteroaryl, C1-C10 alkoxy, C6-C20 aryloxy, C2-C20 heteroalicyclic groups, amino, hydroxyl, thiol, - substituted by one or more substituents in NR4R5; or Y1 and Y2 together with the N atom to which they are connected constitute a heteroalicyclic group, preferably a C2-C20 heteroalicyclic group; or Y1 is hydrogen, and Y2 is selected from C1-C10 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C20 aryl, C1-C20 heteroaryl and C2-C20 heteroalicyclic group, wherein C1-C10 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, CH2 in which may be selected from -O-, -S-, -SO2-, -C(O)- and -NR3- One or more groups replaced, the C1-C10 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, wherein CH2 can be selected from -O-, -S-, -SO2-, -C(O)- and -NR3-One or more groups replaced, the C1-C10 alkyl, C3-C8 The cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C20 aryl, C1-C20 heteroaryl, C2-C20 heteroalicyclic group is substituted by a halogen atom, a hydroxyl, a thiol, an amino group, a nitro group, a cyano group, a carboxyl group, an acyl group, a C1-C10 alkoxy group, a C6-C20 aryl, a C1-C20 heteroaryl, a C2-C20 heteroalicyclic group, a C1-C10 alkyl group, a C2-C8 alkenyl group or a C2-C8 alkynyl group, and the substituents at at least two positions together constitute an aliphatic ring, a heteroalicyclic ring, an aromatic ring or a heteroaromatic ring.

8. The compound according to any one of claims 1 to 7, characterized in that Y1 and Y2 together with the N atom to which they are attached constitute a C2-C20 heteroalicyclic group, such as a C2-C10 heteroalicyclic group, wherein the ring of the C2-C20 heteroalicyclic group optionally contains 1 or 2 additional heteroatoms selected from N or O, The C2-C20 heteroalicyclic group is optionally substituted by a halogen atom, a cyano group, a nitro group, a C6-C10 aryl group, a C1-C10 heteroaryl group, a C1-C6 alkoxy group, a C6-C10 aryloxy group, a C2-C10 heteroalicyclic group, an amino group, a hydroxyl group, a thiol group, a carbonyl group, a carboxyl group, an acyl group, -NR4R5 is substituted by one or more substituents, R4 and R5 are independently selected from hydrogen, C6-C10 aryl, C1-C10 heteroaryl, C1-C8 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl and C2-C8 alkynyl, and the aryl and heteroaryl are optionally substituted by halogen atoms, hydroxyl, sulfhydryl, amino, nitro, cyano, carboxyl, acyl, C1-C8 alkoxy, C6-C10 aryl, C1-C10 heteroaryl, C2-C10 heteroalicyclic, C1-C8 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl or C2-C8 alkynyl, and optionally, the substituents at at least two positions together constitute a C3-C10 alicyclic, C2-C10 heteroalicyclic, C6-C10 aromatic or C1-C10 heteroaromatic ring; For example, the C2-C20 heteroalicyclic group is optionally selected from a halogen atom, a hydroxyl group, a thiol group, an amino group, a nitro group, a cyano group, a C1-C10 alkoxy group, a C1-C10 alkyl group, a C3-C8 cycloalkyl group, a C2-C8 alkenyl group, a C2-C8 alkynyl group, Substituents are substituted, R4 and R5 are independently selected from hydrogen and C1-C6 alkyl; For example, the C2-C8 heteroalicyclic group is optionally substituted by a group selected from halogen, -NH2, -OH, -NO2, carbonyl, -CH2OH, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

9. The compound according to any one of claims 1 to 8, characterized in that Y1 and Y2 together with the N atom to which they are connected constitute a C4-C20 heteroalicyclic group, and the C4-C20 heteroalicyclic group is selected from the following groups: R' independently represents no substituent, a single substituent or multiple substituents, each substituent is independently selected from deuterium, hydroxyl, halogen, NH2, carboxyl (-COOH), C1-C6 alkyl, halogen-substituted C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, amino-substituted C1-C6 alkyl, morpholine-substituted C1-C6 alkyl, -COO-C1-C6 alkyl, cyano, C1-C6 alkoxy, C3-C6 cycloalkyl, halogen-substituted C3-C6 cycloalkyl, hydroxy-substituted C3-C6 cycloalkyl, phenyl, benzyl; L2 is absent or C1-C6 alkylene, halogen, hydroxyl, C1-C6 alkoxy substituted C1-C6 alkylene, preferably methylene, ethylene, propylene; R6 is H, deuterium, halogen, hydroxyl, NH2, carboxyl (-COOH), -CONH2, sulfonic acid (-SO3H), -SO2-C1-C6 alkyl, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, morpholine-substituted C1-C6 alkyl, -COO-C1-C6 alkyl, cyano, C1-C6 alkoxy, hydroxy-substituted C1-C6 alkyl, amino-substituted C1-C6 alkyl, C3-C6 cycloalkyl, halogen-substituted C3-C6 cycloalkyl, hydroxy-substituted C3-C6 cycloalkyl, phenyl or benzyl.

10. The compound according to any one of claims 1 to 9, characterized in that Ring A is selected from pyridine, pyrimidine, pyridazine, quinoline, thiazole, imidazole, pyrrole, pyrazole, thiophene, thienofuran, thienothiazole, carbazolepyrrole, pyridopyrazole, pyridopyrrole, indole, azaindole, isoquinoline, anthracene, phenanthrene, benzofuran, benzothiophene, indazole; Preferably, the A ring is a pyridine ring, a pyrimidine ring or a pyridazine ring.

11. The compound according to any one of claims 1 to 10, characterized in that The structure of the compound is shown in Formula IA, or in any one of Formulas I-1 to I-9: In the above formulae, the definitions of the symbols are the same as those in any one of claims 1 to 11.

12. The compound according to any one of claims 1 to 11, characterized in that The B ring is selected from the group consisting of pyrazole, pyrrole, imidazole, pyridine, pyrimidine, indole, indazole, tetrahydropyrrole, piperidine, azetidine, cubane, pyridazine, quinoline, thiazole, imidazole, pyrrole, pyrazole, thiophene, thienofuran, thienothiazole, carbazole pyrrole, pyridopyrazole, pyridopyrrole, indole, azaindole, isoquinoline, anthracene, phenanthrene, benzofuran, benzothiophene, and indazole; Preferably B is selected from the following groups: R is selected from phenyl, pyridine, pyrimidine, pyrazine, cycloalkyl, quinoline, isoquinoline, tetrahydroquinoline, tetrahydroisoquinoline, indole, indazole, cyclohexyl, cyclopentyl, cycloheptyl, oxaspiro[3.3]heptyl, spiro[2.5]octyl, adamantyl; Preferably R is selected from the following groups:

13. The compound according to claim 1, characterized in that The compound or its pharmaceutically acceptable salt is selected from:

14. The compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer or isotope thereof, characterized in that: The salt of the compound is an alkali metal salt, preferably a sodium salt.

15. A pharmaceutical composition comprising the compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer or isotope compound thereof, and a pharmaceutically acceptable excipient.

16. A method for preventing or treating a disease associated with aging, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer or isotope thereof, or a pharmaceutical composition according to claim 15.

17. The method according to claim 16, characterized in that The disease is selected from the group consisting of diseases associated with the accumulation of senescent cells, and the disease is preferably selected from the group consisting of idiopathic pulmonary fibrosis, pulmonary fibrosis, liver fibrosis, renal fibrosis, viral inflammation and tissue fibrosis and atrophy of the upper respiratory tract and lungs, cystic fibrosis, myelofibrosis, myocardial fibrosis, skin fibrosis, interstitial lung disease, fibrosing pancreatitis, retinopathy of prematurity, macular degeneration, diabetic macular edema, diabetic retinopathy, age-related macular degeneration, wet age-related macular degeneration, dry age-related macular degeneration, glaucoma, sickle cell retinopathy, ischemic arteritic neuropathy, keratitis sicca, Fuch's corneal dystrophy, presbyopia, cataracts, degenerative vitreous disorders, including vitreomacular traction syndrome, macular holes, retinal tears, retinal detachment, proliferative vitreoretinopathy, osteoarthritis, intervertebral disc herniation, osteoporosis, Alzheimer's disease, Parkinson's disease, atherosclerosis, chronic obstructive pulmonary disease, diabetes , diabetic nephropathy, scars, superficial scars or flat scars, cord-like scars or contracture scars, webbed scars, depressed scars, atrophic scars, bridge-like scars and hypertrophic scars, hypertrophic scars, keloids, scar cancer, scleroderma, morphea, scleroderma bands, guttate scleroderma, acroscleroderma, diffuse scleroderma, CREST syndrome, acute coronary syndrome, myocardial infarction, stroke, hypertension, obesity, fat dysfunction, coronary artery disease, cerebrovascular disease, One or more of periodontal disease, cancer treatment-related disabilities such as atrophy and fibrosis in various tissues, brain and heart damage and treatment-related myelodysplastic syndrome, promyeloid syndrome, ataxia-telangiectasia, Fanconi anemia, Friedreich's ataxia, dyskeratosis congenita, aplastic anemia, aneurysm, inflammatory bowel disease, lipoatrophy, renal transplant failure, sarcopenia, wound healing, alopecia, cardiomyocyte hypertrophy, glomerulosclerosis, and cancer.

18. Use of the compound according to any one of claims 1 to 14 or its pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer or isotope compound, or the pharmaceutical composition according to claim 15 in the preparation of a medicament for preventing or treating aging-related diseases.

19. The use according to claim 15, wherein: The disease is selected from the group consisting of diseases associated with the accumulation of senescent cells, and the disease is preferably selected from the group consisting of idiopathic pulmonary fibrosis, pulmonary fibrosis, liver fibrosis, renal fibrosis, viral inflammation and tissue fibrosis and atrophy of the upper respiratory tract and lungs, cystic fibrosis, myelofibrosis, myocardial fibrosis, skin fibrosis, interstitial lung disease, fibrosing pancreatitis, retinopathy of prematurity, macular degeneration, diabetic macular edema, diabetic retinopathy, age-related macular degeneration, wet age-related macular degeneration, dry age-related macular degeneration, glaucoma, sickle cell retinopathy, ischemic arteritic neuropathy, keratitis sicca, Fuch's corneal dystrophy, presbyopia, cataracts, degenerative vitreous disorders, including vitreomacular traction syndrome, macular holes, retinal tears, retinal detachment, proliferative vitreoretinopathy, osteoarthritis, intervertebral disc herniation, osteoporosis, Alzheimer's disease, Parkinson's disease, atherosclerosis, chronic obstructive pulmonary disease, diabetes , diabetic nephropathy, scars, superficial scars or flat scars, cord-like scars or contracture scars, webbed scars, depressed scars, atrophic scars, bridge-like scars and hypertrophic scars, hypertrophic scars, keloids, scar cancer, scleroderma, morphea, scleroderma bands, guttate scleroderma, acroscleroderma, diffuse scleroderma, CREST syndrome, acute coronary syndrome, myocardial infarction, stroke, hypertension, obesity, fat dysfunction, coronary artery disease, cerebrovascular disease, One or more of periodontal disease, cancer treatment-related disabilities such as atrophy and fibrosis in various tissues, brain and heart damage and treatment-related myelodysplastic syndrome, promyeloid syndrome, ataxia-telangiectasia, Fanconi anemia, Friedreich's ataxia, dyskeratosis congenita, aplastic anemia, aneurysm, inflammatory bowel disease, lipoatrophy, renal transplant failure, sarcopenia, wound healing, alopecia, cardiomyocyte hypertrophy, glomerulosclerosis, and cancer.

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