TGF-β inhibitor compounds and their use

Abstract

This application relates to TGF-β inhibitor compounds and uses thereof. Specifically, this application discloses a compound of formula (I), or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer, or isomeric mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof. This application also relates to the use of said compound in medicine. [Formula 1] TIFF2025526716000074.tif35150

Description

[Technical Field]

[0001] This application provides a novel pharmaceutically active compound used for inhibiting fibroblast growth factor receptor (TGF). Furthermore, this application relates to compositions comprising the compound, and to the use of the compound and the composition in the manufacture of pharmaceuticals for treating TGF-related diseases or conditions. [Background technology]

[0002] Transforming growth factor-β (TGF-β) is a multifunctional cytokine involved in regulating cell proliferation, differentiation, and apoptosis through complex receptor signaling pathways on the cell surface. TGF-β belongs to the transforming growth factor-β superfamily (TGF-βs) along with various related proteins such as activins, inhibitors, and bone morphogenetic proteins.

[0003] TGF-β has three main cellular receptors: type I receptor (TGFβR1), type II receptor (TGFβR2), and type III receptor (TGFβR3). Type I and type II receptors are transmembrane serine kinases / transmembrane threonine kinases, and both transmit signals simultaneously. Type III receptor does not transmit signals; its function is primarily to transmit TGF-β to the type II receptor and indirectly influence signal transduction by providing ligands to the type II receptor. Three subtypes of TGF-β exist (TGFβ1, TGFβ2, and TGFβ3), and these, along with their receptors, are present in most cells. Each subtype expresses its characteristics in terms of tissue specificity and developmental regulation.

[0004] Related factors such as TGF-β and activators regulate a large number of cellular processes, such as cell cycle inhibition of epithelial cells and hematopoietic cells, control of mesenchymal cell proliferation and differentiation, inflammatory cell recruitment, immunosuppression, wound healing, and production of extracellular matrix. Studies have shown that abnormal TGF-β signaling is associated with many diseases, such as cancer, renal fibrosis, liver fibrosis, pulmonary fibrosis, viral infection, chronic nephritis, acute nephritis, diabetic nephropathy, osteoporosis, arthritis, wound healing, ulcers, corneal wounds, heart valve stenosis, congestive heart necrosis, nerve function damage, Alzheimer's syndrome, peritoneal or subcutaneous adhesions, arteriosclerosis, and tumor metastatic growth.

[0005] Therefore, it is desirable to develop new TGF-β inhibitors to prevent and / or treat multiple diseases related to this signaling pathway.

Summary of the Invention

[0006] A compound In a first aspect, the present application provides a compound of formula (I), or its isotope-labeled compound, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite.

Chemical Formula

[0007] Unless otherwise specified, the various technical terms used in this application should be interpreted in accordance with the meanings that a person skilled in the art would ordinarily understand. To avoid ambiguity, some terms are defined below.

[0008] Unless otherwise specified, the term "compound" as used in this specification, such as "compound of formula (I)" or "compound of the present application," includes any optical isomers, geometric isomers, tautomers, or mixtures of isomers thereof.

[0009] The term "optical isomer" refers to the fact that when a compound has one or more chiral centers, each chiral center can have either an R or S configuration, and the various isomers formed by this are optical isomers. Optical isomers include all diastereomers, enantiomers, meso compounds, racemates, or mixtures thereof. For example, optical isomers can be separated by chiral chromatography column or chiral synthesis.

[0010] The term "geometric isomer" means that when a compound has a double bond, it can have cis isomers, trans isomers, E isomers, and Z isomers. Geometric isomers include cis isomers, trans isomers, E isomers, Z isomers, or mixtures thereof.

[0011] The term "tautomer" refers to an isomer produced by the rapid movement of an atom at two positions within a molecule. Those skilled in the art will understand that tautomers can be converted into each other and, under certain conditions, can coexist in a balanced state.

[0012] Unless otherwise specified, the terms "compound of formula (I)" or "compound of the present application" as used herein also include isotope-labeled compounds in which one or more atoms in the compound are substituted with its isotopic atoms.

[0013] An example of an isotope included in the compound of this invention is a hydrogen isotope (for example, 2 H(D) and 3 H(T), isotopes of carbon (for example, 11 C, 13 C and 14 C) Isotopes of chlorine (for example, 36 Cl), fluorine isotopes (e.g., 18 F) Iodine isotopes (for example, 123 I and 125 I) Nitrogen isotopes (for example, 13 N and 15 N), oxygen isotopes (for example, 15 O, 17 O and 18 O), and sulfur isotopes (e.g., 35 Includes S)

[0014] The aforementioned isotope-labeled compounds (e.g., compounds containing radioactive isotopes) can be used in the study of pharmaceuticals and / or substrate tissue distribution. Considering the ease of introduction and the convenience of detection means, radioactive isotopes deuterium (i.e., D) and carbon-14 (i.e., 14 C) is particularly useful for that purpose.

[0015] Substitution with a relatively heavy isotope such as deuterium (i.e., D) can provide several therapeutic benefits and is therefore preferable in certain situations. These therapeutic benefits are brought about, for example, by greater metabolic stability (e.g., increased in vivo half-life or reduced dose requirements). Accordingly, in some embodiments, the compounds of the present application are isotope-labeled compounds, where H is optionally substituted with D at each occurrence.

[0016] Positron emission isotopes (for example, 11 C, 18 F, 15 O and 13 Substitution with N) can be used in positron emission topography (PET) studies to detect the occupancy status of substrate receptors.

[0017] The isotope-labeled compounds can generally be prepared by common techniques known to those skilled in the art, or by using a suitable isotope-labeled reagent instead of a conventionally used unlabeled reagent.

[0018] The compound of this application can exist as a pharmaceutically acceptable salt thereof.

[0019] The term "pharmaceutically acceptable" means that the corresponding compound, carrier, or molecule is suitable for administration to humans. Preferably, this term means that it can be used in mammals (preferably humans) as certified by regulatory bodies such as the CFDA (China), EMEA (Europe), and FDA (United States).

[0020] The aforementioned pharmaceutically acceptable salts include their acid addition salts and base addition salts. Suitable acid addition salts are formed by acids that form non-toxic salts. Examples include acetates, adipines, aspartates, benzoates, benzenesulfons, bicarbonates / carbonates, bisulfates / sulfates, borates, camphor sulfons, citrates, cyclohexaneamine sulfons, ethanedisulfons, formates, fumarates, glucoheptons, glucons, glucurons, hexafluorophosphates, 2-(4-hydroxybenzyl)benzoates, hydrogen chlorides / chlorides, hydrogen bromine compounds / brominateds, hydrogen iodides / iodides. This includes, but is not limited to, substances, 2-hydroxyethyl sulfonates, lactates, malates, maleates, malons, methanesulfons, methyl sulfates, naphthalenes, 2-naphthalenesulfons, nicotinates, nitrates, lactates, oxalates, hexadecanates, phosphates / hydrogen phosphates / dihydrogen phosphates, pyroglutamates, glucarates, stearates, salicylates, tannates, tartrates, toluenesulfonates, and trifluoroacetates. Suitable base addition salts are formed by alkalis that form non-toxic salts. Examples include, but are not limited to, aluminum, arginine, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, tristearin, and zinc salts. Hemisalts of acids and alkalis, such as sulfate hemisalts and calcium hemisalts, can be formed. For a description of appropriate salts, refer to *Handbook of Pharmaceutical Salts: Properties, Selection and Use by Stahl and Wermuth* (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds described herein are known to those skilled in the art.

[0021] Furthermore, the compounds of this application may exist in a non-solvated form and in a solvated form in a pharmaceutically acceptable solvent, such as water or ethanol. The compounds may exist in one or more crystalline states, i.e., polycrystalline form, or they may exist as amorphous solids. All of these forms are also included in the scope of this application.

[0022] This application further includes prodrugs of the compound of the present application. The term "prodrug" refers to a derivative that is converted to the compound of the present application in the body under physiological conditions such as enzymes and gastric acid, by reactions such as oxidation, reduction, and hydrolysis, which are respectively catalyzed by enzymes. Therefore, a derivative of the compound of the present application may be very small in quantity or have no pharmacological activity, but it can be converted to the compound of the present application having the desired activity in the body or when administered to the body.

[0023] This application further includes metabolites of the compounds of this application. The term “metabolite” means all molecules derived from any compound of this application in a cell or organism, preferably a human.

[0024] As used herein, the term “substitution” means that one or more (preferably 1 to 5, more preferably 1 to 3, most preferably 1 or 2) hydrogen atoms in the group are independently substituted with a corresponding number of substituents.

[0025] As used herein, the term "independent" means that if there is more than one chemical group or substituent, these chemical groups or substituents may be the same or different.

[0026] As used herein, the terms “optional” or “optionally” indicate whether the event described therein may or may not occur. For example, “optionally substituted” of a group means that the group may or may not be substituted.

[0027] The term "halogen" or "halo" refers to -F, -Cl, -Br, or -I.

[0028] As used herein, the term "alkyl" means saturated aliphatic hydrocarbons, including straight-chain and branched-chain hydrocarbons. In some embodiments, alkyl groups have 1 to 8, or 1 to 6, or 1 to 4, or 1 to 3 carbon atoms. For example, "C 1-8 The term "alkyl" refers to a linear or branched group of atoms having 1 to 8 carbon atoms. 1-8 The term "alkyl" is defined as "C 1-6 Alkyl," "C 1-3 This includes "alkyl" and "C1-4 alkyl," etc. Examples of alkyls include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, isopentyl, neopentyl, (R)-2-methylbutyl, (S)-2-methylbutyl, 3-methylbutyl, 2,3-dimethylpropyl, 2,3-dimethylbutyl, hexyl, etc. The alkyl group may be optionally substituted with one or more (e.g., 1 to 5) suitable substituents.

[0029] As used herein, the term “alkenyl” means an aliphatic hydrocarbon having at least one carbon-carbon double bond, and includes straight and branched chains having at least one carbon-carbon double bond. In some embodiments, alkenyls have 2 to 8 carbon atoms, 2 to 6 carbon atoms, 3 to 6 carbon atoms, or 2 to 4 carbon atoms. For example, “C 2-8The term "alkenyl" refers to a linear or branched unsaturated group of atoms (having at least one carbon-carbon double bond) with 2 to 8 carbon atoms. The double bond may or may not be a bonding site to another group. Alkenyls include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 2-methyl-2-propenyl, butenyl, pentenyl, 3-hexenyl, etc. The alkenyl group may be optionally substituted with one or more (e.g., 1 to 5) suitable substituents. If the compound of formula (I) contains an alkenyl group, the alkenyl group may exist in pure E form, pure Z form, or any mixture thereof.

[0030] As used herein, the term "alkynyl" means an aliphatic hydrocarbon having at least one carbon-carbon triple bond, and includes straight and branched chains having at least one carbon-carbon triple bond. In some embodiments, the alkynyl group has 2 to 8 carbon atoms, 2 to 6 carbon atoms, 3 to 6 carbon atoms, or 2 to 4 carbon atoms. For example, "C 2-8 The term "alkynyl" refers to a linear or branched unsaturated group of atoms with 2 to 8 carbon atoms (having at least one carbon-carbon triple bond). The triple bond may or may not be a bonding site with another group. Alkynnyls include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 2-methyl-2-propynyl, butynyl, pentynyl, 3-hexynyl, etc. The alkynyl group may be optionally substituted with one or more (e.g., 1 to 5) suitable substituents.

[0031] When used in this specification, "C 3-8 The term "alicyclic group" refers to an alicyclic group that has 3 to 8 carbon atoms forming a ring. 3-7 The term "alicyclic group" refers to an alicyclic group that has 3 to 7 carbon atoms forming a ring. 3-6The term "alicyclic group" refers to an alicyclic group having 3 to 6 carbon atoms forming a ring. The alicyclic group may also be a monocyclic ring. The definition of an alicyclic group also includes unsaturated non-aromatic alicyclic groups. Examples of alicyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclohexadienyl, cyclopentenyl, cycloheptenyl, and cyclooctenyl. The alicyclic group may be optionally substituted with one or more suitable substituents.

[0032] When used in this specification, "C 6-12 The term "dicycloalicyclic group" refers to an alkyl group having 6 to 12 carbon atoms forming a ring and possessing two rings. Dicycloalicyclic groups may be condensed and may include crosslinked bicyclic alicyclic group systems.

[0033] When used in this specification, "C 8―15 The term "tricycloalicyclic group" refers to an alkyl group having 8 to 15 carbon atoms forming a ring and possessing three rings. Tricycloalicyclic groups may be condensed or crosslinked.

[0034] As used herein, the term "n-membered heteroalicyclic group" refers to an alicyclic group having m carbon atoms forming a ring and (nm) heteroatoms forming a ring, wherein the heteroatoms are selected from O, S, and N. For example, the term "4-8 membered heteroalicyclic group" means that the substituents of the heteroalicyclic group contain a total of 4-8 ring atoms, at least one of which is a heteroatom. The term "4-6 membered heteroalicyclic group" means that the substituents of the heteroalicyclic group contain a total of 4-6 ring atoms, at least one of which is a heteroatom. The term "3-10 membered heteroalicyclic group" means that the substituents of the heteroalicyclic group contain a total of 3-10 ring atoms, at least one of which is a heteroatom. The term "n-membered dicycloheteroalkyl" refers to a dicycloheteroalkyl group having m carbon atoms forming a ring and (nm) heteroatoms forming a ring, wherein the heteroatoms are selected from O, S, and N.Examples of heteroalicyclic groups include azetidine, thietane, dihydrofuran, dihydrothiophene, tetrahydrothiophene, tetrahydrofuranil, tetrahydrotriazine, tetrahydropyrazolyl, tetrahydrooxazine, tetrahydropyrimidyl, octahydrobenzofuranil, octahydrobenzimidazol, octahydrobenzothiazole, imidazolidinil, pyrrolidinil, piperidinil, piperazinil, oxazolidinil, thiazolidinil, pyrazolidinil, thiomorpholinil, tetrahydropyranil, tetrahydrothiopyranil, tetrahydrothiazinyl, tetrahydrothiazinyl, tetrahydrothiazinine, tetrahydrooxazolyl, morpholinil, oxetanyl, and tetrahydro This includes, but is not limited to, tetrahydrodioxazine, oxazin, oxathiazin, quinuclidinyl, chromanyl, isochromanyl, dihydrobenzodioxinyl, benzodioxolyl, benzoxazine, dihydroindolyl, dihydrobenzofuranyl, tetrahydroquinolyl, isochromyl, dihydro-1H-isoindolyl, 2-azadicyclo[2.2.1]heptanoyl, 3-azadicyclo[3.1.0]hexyl, 3-azadicyclo[4.1.0]heptyl, oxepan, thiepan, azepan, etc. The heteroalicyclic group may be optionally substituted with one or more suitable substituents.

[0035] In this application, “aryl” means a 5- to 16-membered carbocyclic aromatic group having a ring with at least one conjugated π-electron system. Aryls may have conjugated or fused rings and may be unsubstituted or substituted as described. Examples of aryls include phenyl, naphthyl, anthracenyl, phenanthryl, azulenyl, biphenyl, etc. When used herein, the term “C” means a 5- to 16-membered carbocyclic aromatic group having a ring with at least one conjugated π-electron system. 5-16 "Aryl" refers to an aryl compound that has an aromatic ring containing 5 to 16 carbon atoms. Similarly, "C 5-8 The term "aryl" refers to an aryl group having an aromatic ring with 5, 6, 7, or 8 carbon atoms, such as phenyl.

[0036] In this application, "heteroaryl" means a 5-16 member aromatic group having a ring with at least one conjugated π-electron system and containing 1-4 heteroatoms such as N, O, or S. Heteroaryls may have conjugated or fused rings and may be unsubstituted or substituted as described. Examples of heteroaryls include thienyl, furanyl, pyrrolyl, pyrazolyl, imidazoyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyridizinyl, pyrimidinyl group, pyrazinyl, triazinyl, indolyl, isoindolyl, indolizinyl, and benzofuranyl. Contains furanyl, benzothienyl, indazolyl, benzimidazoyl, benzthiazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl.

[0037] As used herein, the term "n-membered heteroaryl" means a heteroaryl having m carbon atoms forming an aromatic ring and (nm) heteroatoms forming an aromatic ring, wherein the heteroatoms are selected from O, S, and N. For example, 5- to 7-membered heteroaryls include, but are not limited to, furyl, thienyl, pyrrolyl, thiazolyl, pyrazolyl, imidazolyl, pyridyl, pyranyl, pyridadinyl, pyrimidinyl, and pyrazinyl. Heteroaryls may be optionally substituted with one or more suitable substituents.

[0038] When used in this specification, "C 7-11 The term "dicycloaryl" refers to a dicycloaryl molecule having 7 to 11 carbon atoms, such as naphthyl and indenyl. Dicycloaryl molecules may be optionally substituted with one or more suitable substituents.

[0039] As used herein, the term "n-membered dicycloheteroaryl" means a dicycloheteroaryl having m carbon atoms forming an aromatic biring and (nm) heteroatoms forming an aromatic biring, wherein the heteroatoms are selected from O, S, and N. For example, 7- to 11-membered dicycloheteroaryls include, but are not limited to, quinoline, isoquinoline, indolyl, purine, and benzothiazole groups. Dicycloheteroaryls may be optionally substituted with one or more suitable substituents.

[0040] As used herein, the term "11-15 member tricyclo" includes, but is not limited to, acridine. The 11-15 member tricyclo may be optionally substituted with one or more suitable substituents.

[0041] As used herein, the term "alkyl halide" means an alkyl group having one or more halogen substituents (at most an alkyl perhalide, i.e., each hydrogen atom of the alkyl group is substituted with a halogen atom). For example, "C 1-6The term "alkyl halide" refers to a C with one or more halogen substituents. 1-6 This refers to alkyl groups (at most alkyl perhalides, meaning that each hydrogen atom of the alkyl group is substituted with a halogen atom). Another example is "C 1-4 The term "alkyl halide" refers to a C with one or more halogen substituents. 1-4 This means alkyl group (at most an alkyl perhalide, that is, each hydrogen atom of the alkyl group is substituted with a halogen atom). 1-3 The term "alkyl halide" refers to a C with one or more halogen substituents. 1-3 This means alkyl group (at most an alkyl perhalide, that is, each hydrogen atom of the alkyl group is substituted with a halogen atom). 1-2 The term "alkyl halide" refers to a C with one or more halogen substituents. 1-2 This refers to alkyl groups (i.e., methyl or ethyl) (at most alkyl perhalides, i.e., each hydrogen atom of the alkyl group is substituted with a halogen atom). For example, the term "C1 alkyl halide" refers to a methyl group having one, two, or three halogen substituents. Examples of alkyl halides include CF3, C2F5, CHF2, CH2F, CH2CF3, CH2Cl, etc.

[0042] As used herein, the term "alkoxy" means an alkyl group bonded to an oxygen atom by a single bond. The bonding site between the alkoxy and the molecule is the oxygen atom. Alkoxy can be represented as alkyl-O-. 1-6 The term "alkoxy" refers to a linear or branched alkoxy group containing 1 to 6 carbon atoms. 1-6 The term "alkoxy" is defined as "C 1-3 The term "alkoxy" is included. Alkoxy includes, but is not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, hexyloxy, etc. Alkoxy may be optionally substituted with one or more suitable substituents.

[0043] As used herein, the term "3- to 14-membered ring" means a saturated or unsaturated ring system having 3 to 14 ring-forming atoms.

[0044] In this specification, ranges of numbers relating to the number of substituents, carbon atoms, and ring atoms correspond to listing all integers within that range one by one, and the range is simply a simplified notation. For example, "4-6 members" refers to 4, 5, or 6 members, "5-7 members" refers to 5, 6, or 7 members, "7-11 members" refers to 7, 8, 9, 10, or 11 members, "4-8 members" refers to 4, 5, 6, 7, or 8 members, "3-10 members" refers to 3, 4, 5, 6, 7, 8, 9, or 10 members, and "3-14 members" refers to 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 members, and "C 1-3 " refers to one carbon atom (C1), two carbon atoms (C2), or three carbon atoms (C3), and "C 1-4 " refers to one carbon atom (C1), two carbon atoms (C2), three carbon atoms (C3), or four carbon atoms (C4), and "C 3-6 " refers to a carbon atom with 3 carbon atoms (C3), 4 carbon atoms (C4), 5 carbon atoms (C5), or 6 carbon atoms (C6), and "C 3-8 " refers to a carbon atom with 3 carbon atoms (C3), 4 carbon atoms (C4), 5 carbon atoms (C5), 6 carbon atoms (C6), 7 carbon atoms (C7), or 8 carbon atoms (C8). 5-7 " refers to a carbon atom with 5 carbon atoms (C5), 6 carbon atoms (C6), or 7 carbon atoms (C7), and "C 7-11 " refers to 7 carbon atoms (C7), 8 carbon atoms (C8), 9 carbon atoms (C9), 10 carbon atoms (C 10 ) or 11 carbon atoms (C 11 This indicates that the range of numbers related to the number of substituents, the number of carbon atoms, and the number of ring atoms also includes any one of its subranges, and each subrange is also considered to be disclosed herein.

[0045] In the above formula (I), R1 may be any substituent common in organic chemistry and is not particularly limited.

[0046] In some embodiments, R1 is C 1-6 It is an alkyl group, and for example, R1 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, isopentyl, neopentyl, (R)-2-methylbutyl, (S)-2-methylbutyl, 3-methylbutyl, 2,3-dimethylpropyl, 2,3-dimethylbutyl, and hexyl.

[0047] In some embodiments, R1 is C 3-7 It is an alicyclic group, and for example, R1 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclohexadienyl, cyclopentenyl, and cycloheptenyl.

[0048] In some embodiments, R1 is a 3- to 10-membered heteroalicyclic group, for example, R1 is azetidine, thietan, dihydrofuran, dihydrothiophene, tetrahydrothiophene, tetrahydrofuranil, tetrahydrotriazine, tetrahydropyrazolyl, tetrahydrooxazine, tetrahydropyrimidyl, octahydrobenzofuranil, octahydrobenzimidazol, octahydrobenzothiazole, imidazolidinil, pyrrolidinil, piperidinil, piperazinil, oxazolidinil, thiazolidinil, pyrazolidinil, thiazolidinil, thiazolidinil, thiazolidinil, thiazolidinil, thiazolidinil Selected from omorpholinil, tetrahydropyranil, tetrahydrothiopyranil, tetrahydrothiadinil, tetrahydrothiadiazine, tetrahydrooxazolyl, morpholinil, oxetanil, tetrahydrodioxazine, oxazine, oxathiadinil, quinuclidinil, chromanil, isochromanil, dihydrobenzodioxanil, benzodioxol, benzoxazine, dihydroindolyl, dihydrobenzofuranil, tetrahydroquinolyl, isochroman, dihydro-1H-isoindolyl, oxepane, thiepan, and azepan.

[0049] In some embodiments, R1 is H, halogen, -OH, -NO2, -CN, -SF5, or -SH.

[0050] In some embodiments, R1 is -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkyl halogens, C 1-6 Alkoxy, C 1-6 Alkoxy halogens, C 2-8 Alkenil, C 2-8 Selected from Alkinyl.

[0051] In some embodiments, R1 is C 5-8 Aryl (e.g., phenyl), 5-10 member heteroaryl (e.g., furyl, thienyl, pyrrolyl, thiazolyl, pyrazolyl, imidazolyl, pyridyl, pyranyl, pyridadinyl, pyrimidinyl, pyrazinyl, etc.), -C 1-4 Alkyl-(C 5-8 Ariel), -C 1-4 Selected from alkyl-(5-10 member heteroaryl).

[0052] In some embodiments, R1 is -N(R 10 )(R 11 ), -N(R 10 )(C(=O)R 11 ), -N(R 10 )(C(=O)-OR 11 ), -N(R 12 )(C(=O)-N(R 10 )(R 11 )), -C(=O)-N(R 10 )(R 11 ), -C(=O)-R 12 , -C(=O)-OR 12 -OC(=O)R 12 , -N(R 10 )(S(=O)2R 11 ), -S(=O)2-N(R 10 )(R 11 ), -SR 12 and -OR 12 Selected from, here, R 10, R 11 and R 12 Each time it appears, H, C 1-6 Alkyl, C 1-6 Alkyl halogens, C 3-7 Alicyclic group, 3-10 membered heteroalicyclic group, C 5-8 Aryl, 5-7 member heteroaryl, C 7-11 Dicycloaryl, 7-11 member dicycloheteroaryl, -C 1-4 Alkyl-(C 3-7 alicyclic group), -C 1-4 Alkyl-(3-10 member heteroalicyclic group), -C 1-4 Alkyl-(C 6-12 (Dicycloalicyclic group), -C 1-4 Alkyl-(6-12 member dicycloalicyclic group), -C 1-4 Alkyl-(C 8-15 (member tricycloalicyclic group), -C 1-4 Alkyl-(8-15 member tricycloalicyclic group), -C 1-4 Alkyl-(C 5-8 Aryl) and -C 1-4 Each is independently selected from alkyl-(5-10 member heteroaryl), where each option within the group is halogen, -OH, -NH2, -NH(CH3), -N(CH3)2, -CN, -NO2, -SF5, -SH, -SC 1-4 Alkyl, oxo, C 1-4 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-7 Alicyclic group, 3-10 membered heteroalicyclic group, C 5-8 Aryl, 5-7 member heteroaryl, C 7-11 Dicycloaryl, 7-11 member dicycloheteroaryl, C 1-4 Hydroxyalkyl, -SC 1-4 Alkyl, -C(=O)H, -C(=O)-C 1-4 Alkyl, -C(=O)-OC 1-4 Alkyl, -C(=O)-NH2, -C(=O)-N(C 1-4 Alkyl)2, C 1-4 Alkyl halogens, C 1-4 Alkoxy and C 1-4It is optionally substituted with 0, 1, 2, 3, or 4 substituents independently selected from the group consisting of halogenated alkoxys, or R 10 and R 11 These, together with the atoms to which they are bonded, form a 3- to 14-membered ring.

[0053] In some embodiments, R1 is -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkyl halogens, C 1-6 Alkoxy, C 1-6 Alkoxy halogens, C 2-8 Alkenil, C 2-8 Alkinyl, C 3-7 Alicyclic group, 3-10 membered heteroalicyclic group, C 6-12 Dicycloalicyclic group, 6-12 member dicycloheteroalicyclic group, C 5-8 Aryl, 5-10 member heteroaryl, C 7-11 Selected from dicycloaryls and 7-11 member dicycloheteraryls, where the -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkyl halogens, C 1-6 Alkoxy, C 1-6 Alkoxy halogens, C 2-8 Alkenil, C 2-8 Alkinyl, C 3-7 Alicyclic group, 3-10 membered heteroalicyclic group, C 6-12 Dicycloalicyclic group, 6-12 member dicycloheteroalicyclic group, C 5-8 Aryl, 5-10 member heteroaryl, C 7-11 Dicycloaryls and 7-11 member dicycloheteroaryls are unsubstituted or have 1, 2, 3, or 4 R members, respectively. 1a Replaced with R 1a These are independently halogen, -OH, -NH2, -NH(CH3), -N(CH3)2, -CN, -NO2, -SF5, -SH, and -SC 1-4 Alkyl, oxo, C 1-4 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-7Alicyclic group, 3-10 membered heteroalicyclic group, C 5-8 Aryl, 5-7 member heteroaryl, C 7-11 Bicycloaryl, 7-11 member bicycloheteroaryl, C 1-4 Hydroxyalkyl, -SC 1-4 Alkyl, -C(=O)H, -C(=O)-C 1-4 Alkyl, -C(=O)-OC 1-4 Alkyl, -C(=O)-NH2, -C(=O)-N(C 1-4 Alkyl)2, C 1-4 Alkyl halogens, C 1-4 Alkoxy and C 1-4 Selected from alkoxy halogens.

[0054] Any exemplary group listed in R1 above should be understood to be arbitrarily substituted. That is, any group listed in R1 above can be arbitrarily replaced with 0, 1, 2, 3, or 4 R depending on the situation. 1a It may be replaced with R 1a These are halogen, -OH, -NO2, -CN, -SF5, -SH, and -SC 1-4 Alkyl, oxo, C 1-4 Alkyl, C 1-4 Alkyl halogens, C 1-4 Alkoxy, C 1-4 Alkoxy halogens, C 2-8 Alkenil, C 2-8 Alkinyl, C 3-7 Alicyclic group, 3-10 membered heteroalicyclic group, C 5-8 Aryl, 5-7 member heteroaryl, -N(R 13 )(R 14 ), -N(R 13 )(C(=O)R 14 ), -N(R 13 )(C(=O)-OR 14 ), -N(R 15 )(C(=O)-N(R 13 )(R 14 )), -C(=O)-N(R 13 )(R 14 ), -C(=O)-R 15 , -C(=O)-OR 15 -OC(=O)R15 , -N(R 13 )(S(=O)2R 14 ), -S(=O)2-N(R 13 )(R 14 ), -SR 15 and -OR 15 Selected independently from, where R 13 , R 14 and R 15 Each time it appears, H, C 1-6 Alkyl, C 1-6 Alkyl halogens, C 3-7 Alicyclic group, 3-10 membered heteroalicyclic group, C 5-8 Aryl, 5-7 member heteroaryl, C 7-11 Dicycloaryl, 7-11 member dicycloheteroaryl, -C 1-4 Alkyl-(C 3-7 alicyclic group), -C 1-4 Alkyl-(3-10 member heteroalicyclic group), -C 1-4 Alkyl-(C 6-12 (Dicycloalicyclic group), -C 1-4 Alkyl-(6-12 member dicycloalicyclic group), -C 1-4 Alkyl-(C 8-15 (member tricycloalicyclic group), -C 1-4 Alkyl-(8-15 member tricycloalicyclic group), -C 1-4 Alkyl-(C 5-8 Aryl) and -C 1-4 Each is independently selected from alkyl-(5-10 member heteroaryl), where each option within the group is halogen, -OH, -NH2, -NH(CH3), -N(CH3)2, -CN, -NO2, -SF5, -SH, -SC 1-4 Alkyl, oxo, C 1-4 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-7 Alicyclic group, 3-10 membered heteroalicyclic group, C 5-8 Aryl, 5-7 member heteroaryl, C 7-11 Dicycloaryl, 7-11 member dicycloheteroaryl, C 1-4 Hydroxyalkyl, -SC 1-4 Alkyl, -C(=O)H, -C(=O)-C 1-4Alkyl, -C(=O)-OC 1-4 Alkyl, -C(=O)-NH2, -C(=O)-N(C 1-4 Alkyl)2, C 1-4 Alkyl halogens, C 1-4 Alkoxy and C 1-4 It is optionally substituted with 0, 1, 2, 3, or 4 substituents independently selected from the group consisting of halogenated alkoxys, or R 13 and R 14 These atoms, together with the atoms linked to them, form 3- to 14-membered rings.

[0055] In some preferred embodiments, R1 is selected from methyl, ethyl, propyl, isopropyl, and cyclobutyl. The methyl, ethyl, propyl, isopropyl, or cyclobutyl may be optionally substituted with 0, 1, or 2 substituents independently selected from the group consisting of methyl, ethyl, cyclopentyl, cyclopropyl, -CN, -OH, morpholinyl, and piperidinyl, and the substituents may be optionally substituted with 0, 1, or 2 substituents independently selected from the group consisting of methyl, ethyl, cyclopentyl, cyclopropyl, -CN, and -OH. For example, in some preferred embodiments, R1 is selected from (1-hydroxycyclopropyl)ethyl, 3-hydroxycyclobutyl, 2-cyanoethyl, 2-hydroxyethyl, 2-cyano-1-cyclopentylethyl, 1-cyanopropane, 2-morpholinoethyl, ethyl, and (1-methylpiperidine-4-yl)methyl.

[0056] In some preferred embodiments, R1 is selected from halogens, for example, F.

[0057] In some preferred embodiments, R1 is selected from piperazinyl, morpholinyl, pyrrolidinyl, piperidinyl and azetidine, and the piperazinyl, morpholinyl, pyrrolidinyl, piperidinyl and azetidine may be optionally substituted with 0, 1 or 2 substituents independently selected from the group consisting of methyl, ethyl, cyclopentyl, cyclopropyl, -CN, and -OH. In some preferred embodiments, R1 is selected from methyl, ethyl, propyl, isopropyl, and cyclobutyl, and the methyl, ethyl, propyl, isopropyl, or cyclobutyl may be optionally substituted with 0, 1 or 2 substituents independently selected from the group consisting of methyl, ethyl, cyclopentyl, cyclopropyl, -CN, -OH, morpholinyl and piperidinyl, and the substituents may further be optionally substituted with 0, 1 or 2 substituents independently selected from the group consisting of methyl, ethyl, cyclopentyl, cyclopropyl, -CN, and -OH.

[0058] In some preferred embodiments, R1 is selected from piperazinyl, morpholinyl, pyrrolidinyl, piperidinyl, and azetidine. For example, in some preferred embodiments, R1 is selected from 3,5-dimethylpiperazinyl, morpholinyl, 3-hydroxypyrrolidinyl, 4-methylpiperazinyl, 4-ethylpiperazinyl, 4-hydroxypiperidinyl, 1-methylpiperidinyl, 1-ethylpiperidine-4-yl, and 1-methylazetidine-3-yl.

[0059] In some preferred embodiments, R1 is selected from H, methyl, ethyl, n-propyl, isopropyl, butyl, methoxy, ethoxy, hydroxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, morpholinomethyl, hydroxycyclobutyl, hydroxycyclohexyl, cyanoethoxy, cyanomethyl, pyridine-3-yl, 1-methyl-1H-pyrazole-4-yl, 1-methyl-1H-pyrazole-3-yl, 4-methylpiperazine-1-yl, 1-methylpiperidine-4-yl, morpholinyl, pyrrolidine-3-yl, 3-hydroxypyrrolidine-1-yl, and 3-cyanopyrrolidine-1-yl.

[0060] In some preferred embodiments, R1 is H, halogen, -OH, -NO2, -CN, -SF5, -SH, -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkyl halogens, C 1-6 Alkoxy, C 1-6 Alkoxy halogens, C 3-6 Alicyclic group, 4-6 member heteroalicyclic group, C 5-8 Aryl, 5-10 member heteroaryl, -C 1-4 Alkyl-(C 3-7 alicyclic group), -C 1-4 Alkyl-(3-10 member heteroalicyclic group), -C 1-4 Alkyl-(C 5-8 Ariel), -C 1-4 Alkyl-(5-10 member heteroaryl),-N(R 10 )(R 11 ) is selected from, where -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkyl halogens, C 1-6 Alkoxy, C 1-6 Alkoxy halogens, C 3-6 Alicyclic group, 4-6 member heteroalicyclic group, C 5-8 Aryl, 5-10 member heteroaryl, -C 1-4 Alkyl-(C 3-7 alicyclic group), -C 1-4 Alkyl-(3-10 member heteroalicyclic group), -C1-4 Alkyl-(C 5-8 Ariel), -C 1-4 Each alkyl-(5-10 member heteroaryl) can have 0, 1, 2, 3, or 4 R atoms. 1a Replaced with R 1a These are halogen, -OH, -NO2, -CN, oxo, C 1-4 Alkyl, C 1-4 Alkyl halogens, C 1-4 Alkoxy, C 1-4 Alkoxy halogens, C 3-7 Alicyclic group, 3-10 membered heteroalicyclic group, C 5-8 Independently selected from aryls and 5- to 7-membered heteroaryls; and R 10 , R 11 and R 12 Each time it appears, H, C 1-6 Alkyl, C 1-6 Alkyl halogens, C 3-7 Alicyclic groups and 3- to 10-membered heteroalicyclic groups are independently selected, where each option within the group is halogen, -OH, -NH2, oxo, or C. 1-4 Alkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkyl halogens, C 1-4 Alkoxy and C 1-4 It is optionally substituted with 0, 1, 2, 3, or 4 substituents independently selected from the group consisting of halogenated alkoxys, or R 10 and R 11 These, together with the atoms linked to them, form a 3- to 8-membered ring. R1 consists of H, halogen, -OH, -NO2, -CN, -SF5, -SH, and -SC. 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkyl halogens, C 1-6 Alkoxy, C 1-6 Alkoxy halogens, C 3-6 Alicyclic group, 4-6 member heteroalicyclic group, C 5-8 Aryl, 5-10 member heteroaryl, -C 1-4 Alkyl-(C 3-7 alicyclic group), -C 1-4 Alkyl-(3-10 member heteroalicyclic group), -C1-4 Alkyl-(C 5-8 Ariel), -C 1-4 Alkyl-(5-10 member heteroaryl),-N(R 10 )(R 11 ) is selected from, where -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkyl halogens, C 1-6 Alkoxy, C 1-6 Alkoxy halogens, C 3-6 Alicyclic group, 4-6 member heteroalicyclic group, C 5-8 Aryl, 5-10 member heteroaryl, -C 1-4 Alkyl-(C 3-7 alicyclic group), -C 1-4 Alkyl-(3-10 member heteroalicyclic group), -C 1-4 Alkyl-(C 5-8 Ariel), -C 1-4 Each alkyl-(5-10 member heteroaryl) can have 0, 1, 2, 3, or 4 R atoms. 1a It may be replaced with R 1a These are halogen, -OH, -NO2, -CN, oxo, C 1-4 Alkyl, C 1-4 Alkyl halogens, C 1-4 Alkoxy, C 1-4 Alkoxy halogens, C 3-7 Alicyclic group, 3-10 membered heteroalicyclic group, C 5-8 Independently selected from aryls and 5- to 7-membered heteroaryls; and R 10 , R 11 and R 12 Each time it appears, H, C 1-6 Alkyl, C 1-6 Alkyl halogens, C 3-7 Alicyclic groups and 3- to 10-membered heteroalicyclic groups are independently selected, where each option within the group is halogen, -OH, -NH2, oxo, or C. 1-4 Alkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkyl halogens, C 1-4 Alkoxy and C 1-4It is optionally substituted with 0, 1, 2, 3, or 4 substituents independently selected from the group consisting of halogenated alkoxys, or R 10 and R 11 These atoms, together with the atoms linked to them, form a 3- to 8-membered ring.

[0061] In some preferred embodiments, R1 is selected from H, halogen, -OH, methyl, ethyl, propyl, butyl, pentyl, hexyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, pyrrolyl, morpholinyl, pyridyl, and pyrazolyl, where each of methyl, ethyl, propyl, butyl, pentyl, hexyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, pyrrolyl, morpholinyl, pyridyl, and pyrazolyl, each of which may be one or two R 1a It is replaced by and R 1a These are halogen, -OH, -NO2, -CN, oxo, C 1-4 Alkyl, C 1-4 Alkyl halides, and C 1-4 It is independently selected from alkoxy halogens.

[0062] In some preferred embodiments, R1 is selected from H, methyl, methylpiperazinyl, pyrrolidinyl, methylpiperazinyl, hydroxycyclobutyl, methylpyrazolyl, hydroxyethyl, hydroxypropyl, methylpiperizinyl, morpholinyl, and hydroxypyrrolidinyl.

[0063] It should be understood that any embodiment of R1 described above can be arbitrarily combined with any embodiment of R2, R3, L, n, and ring A described above or below.

[0064] In equation (I) above, R2 is H, halogen, -CN, -OH, -NO2, -NR7R8, C 1-4 Alkyl, C 1-4 Alkyl halogens, C 1-4 Alkoxy, C 3-6 Alicyclic groups and 4- to 6-membered heteroalicyclic groups can be selected.

[0065] In some embodiments, R2 is H.

[0066] In some embodiments, R2 is a halogen, for example, selected from F, Cl, Br, and I.

[0067] In some embodiments, R2 is -CN.

[0068] In some embodiments, R2 is -NO2.

[0069] In some embodiments, R2 is C 1-3 Alkyl or C 1-3 The alkyl halide is selected from methyl, ethyl, propyl, and isopropyl, for example, in which R2 is optionally substituted with one or more halogen atoms (e.g., fluorine, chlorine, bromine, iodine).

[0070] In some embodiments, R2 is C 1-3 It is an alkoxy, and for example, R2 is selected from methoxy, ethoxy, propoxy, and isopropoxy.

[0071] In some embodiments, R2 is C 3-6 It is an alicyclic group, and for example, R2 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclohexenyl.

[0072] In some embodiments, R2 is a 4- to 6-membered heteroalicyclic group, for example, R2 is selected from oxetanyl, oxetanyl, azethinyl, tetrahydrofuranil, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranil, tetrahydrothiopyranil, piperidinyl, morpholinil, and piperazinyl.

[0073] In some embodiments, R2 is -NR7R8, where R7 and R8 are, in each instance, H, C 1-3 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, etc.), C 1-3 Alkyl halides (e.g., methyl, ethyl, propyl, isopropyl halides substituted with one or more halogen atoms selected from fluorine, chlorine, bromine, or iodine), C 1-3 They are independently selected from alkoxys (e.g., methoxy, ethoxy, propoxy, isopropoxy) or together with R7, R8 and the N atoms linked to them, they form a 3- to 6-membered ring (e.g., pyrrole, pyridine, pyrimidine, imidazole, pyrazole, pyrrolidine, hexahydropyridine, etc.).

[0074] It should be understood that any embodiment of R2 described above can be arbitrarily combined with any embodiment of R1, R3, L, n, and ring A described above or below.

[0075] In equation (I) above, R3 is H, halogen, -CN, -OH, -NO2, -NR7R8, C 1-4 Alkyl, C 1-4 Alkyl halogens, C 1-4 Alkoxy, C 3-6 Alicyclic groups and 4- to 6-membered heteroalicyclic groups can be selected.

[0076] In some embodiments, R3 is H.

[0077] In some embodiments, R3 is a halogen, for example, selected from F, Cl, Br, and I.

[0078] In some embodiments, R3 is -CN.

[0079] In some embodiments, R3 is -NO2.

[0080] In some embodiments, R3 is C 1-3 Alkyl or C 1-3 The alkyl halide is selected from methyl, ethyl, propyl, and isopropyl, for example, where R3 is optionally substituted with one or more halogen atoms (e.g., fluorine, chlorine, bromine, iodine).

[0081] In some embodiments, R3 is C 1-3 It is an alkoxy, and for example, R3 is selected from methoxy, ethoxy, propoxy, and isopropoxy.

[0082] In some embodiments, R3 is C 3-6 It is an alicyclic group, and for example, R3 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclohexenyl.

[0083] In some embodiments, R3 is a 4- to 6-membered heteroalicyclic group, for example, R3 is selected from oxetanil, thioxetanil, azetidinil, tetrahydrofuranil, tetrahydrothiophenyl, pyrrolidinil, tetrahydropyranil, tetrahydrothiopyranil, piperidinil, morpholinil, and piperazinil.

[0084] In some embodiments, R3 is -NR7R8, where R7 and R8 are, in each instance, H, C 1-3 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, etc.), C 1-3 Alkyl halides (e.g., methyl, ethyl, propyl, isopropyl halides substituted with one or more halogen atoms selected from fluorine, chlorine, bromine, or iodine), C 1-3Each is independently selected from alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy), or forms a 3- to 6-membered ring (e.g., pyrrole, pyridine, pyrimidine, imidazole, pyrazole, pyrrolidine, hexahydropyridine, etc.) together with R7, R8 and the N atom to which they are attached.

[0085] It should be understood that any embodiment of R3 above can be arbitrarily combined with any embodiment of R1, R2, L, n and ring A above or below.

[0086] In some embodiments, R3 and R2 may be the same. For example, both R3 and R2 are halogen, e.g., Cl, and also, for example, both R3 and R2 are methyl. In one preferred embodiment, both R3 and R2 are Cl. In one preferred embodiment, both R3 and R2 are H.

[0087] In some other embodiments, R3 and R2 may be different.

[0088] In the formula (I) as described above, L may be (C=O), (O=S=O), ((C=O)-CH2), CH2 or a linking bond.

[0089] In some embodiments, L is (C=O).

[0090] In some embodiments, L is (O=S=O).

[0091] In some embodiments, L is ((C=O)-CH2).

[0092] In some embodiments, L is CH2.

[0093] In some embodiments, L is a linking bond (i.e., R1 and the N atom are directly linked by a covalent bond).

[0094] It should be understood that any embodiment of the above L can be arbitrarily combined with any embodiment of the above or below R1, R2, R3, ring A and n.

[0095] In the formula (I) as described above, n is 1, 2 or 3.

[0096] In some embodiments, n is 1.

[0097] In some embodiments, n is 2.

[0098] In some embodiments, n is 3.

[0099] It should be understood that any embodiment of the above n can be arbitrarily combined with any embodiment of the above or below R1, R2, R3, L and ring A.

[0100] In the above formula (I), ring A is a nitrogen-containing aromatic ring, and satisfies 1) G1 = NR4, G2 = CR5; or 2) G1 = CR4, G2 = NR5; or 3) G1 = CR4, G2 = O or S, where R4, R5 are each independently selected from H, halogen, -CN, -OH, -NO2, C 1-6 alkyl, C 1-6 halogenated alkyl, C 1-6 alkoxy (R4, R5 may be the same or different); or R4, R5 together with the atoms to which they are attached form a 3- to 8-membered ring.

[0101] Therefore, the compound of formula (I) in the present application can have one of the following structures.

Chemical formula

[0102]

Chemical formula

[0103]

Chemical formula

[0104]

Chemical formula

[0105] The embodiments and preferred options of R1, R2, R3, ring A, L, n, etc. shown in the general formula (I) are the same for the general formulas (I-1), (I-2), (I-3), and (I-4).

[0106] In some specific embodiments, the compound of formula (I) of the present application is selected from the compounds shown in the corresponding examples. II. Method for producing the compound

[0107] The compound of formula (I) of the present application can be synthesized by those skilled in the art by conventional organic synthesis methods based on the specific structure of the compound.

[0108] In addition, those skilled in the art can obtain a synthesis method for obtaining other compounds by appropriately adjusting the reaction raw materials and reaction conditions by referring to the synthesis routes of the specific compounds in the specific examples of the present application. III. Use of the compound and composition containing the compound

[0109] Experiments have shown that the compound of formula (I) of the present invention can inhibit TGF-β activity, i.e., it can be used as a TGF-β inhibitor. Specifically, the compound of formula (I) of the present invention can be used to suppress the TGF-β1 receptor (TGFβRl), i.e., as a TGF-β1 inhibitor.

[0110] In a second embodiment, the present application provides a pharmaceutical composition comprising the aforementioned compound of the present application, or an isotope-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a pharmaceutically acceptable salt thereof, a prodrug thereof, or a metabolite thereof, and one or more pharmaceutically acceptable carriers, adjuvants or excipients.

[0111] The pharmaceutical compositions of this application can be prepared by methods well known in the pharmaceutical field and can be administered in various ways, depending on whether the treatment is local or systemic and on the site of treatment. Administration may be local (including ophthalmic and mucosal administration, including intranasal, vaginal, and rectal administration), pulmonary (e.g., administration by inhalation or blowing of powder or aerosol (including administration by nebulizer), intratracheal, intranasal, epidermal, and transdermal administration), ocular, oral, or extra-gastrointestinal. Methods for ocular administration may include local administration (ophthalmic solution), which is injected subconjunctivally, periorbitally, or intravitreously, or introduced by a balloon catheter or ophthalmic implant placed in the conjunctival sac by surgical means. Extra-gastrointestinal administration includes intravenous, intra-arterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion, or intracranial (e.g., intrasacral or intracerebral) administration. Extra-gastrointestinal administration may be in the form of a single injection dose or can be carried out, for example, by a continuous infusion pump. Topical pharmaceutical compositions and preparations may include transdermal patches, ointments, lotions, creams, gels, drips, suppositories, sprays, liquids, and powders.

[0112] When a solid carrier is used, the formulation may be in the form of a tablet, a powder or granule encapsulated in a hard capsule, or a troche or lozenge. The solid carrier may contain conventional excipients such as binders, fillers, tableting lubricants, disintegrants, and wetting agents. If necessary, the tablets may be film-coated using conventional techniques. When a liquid carrier is used, the formulation may be in the form of a syrup, emulsion, ointment, softgel capsule, sterile carrier for injection, aqueous or non-aqueous liquid suspension, or a dry product that can be reconstituted with water or another suitable carrier before use. The liquid formulation may contain conventional additives such as suspending agents, emulsifiers, wetting agents, non-aqueous carriers (including edible oils), preservatives, and flavorings and / or colorings. For extra-gastrointestinal administration, the carrier usually contains at least mostly sterile water, but physiological saline, glucose solution, etc., may also be used. An injectable suspension may be used, in which case conventional suspending agents may be used. Conventional preservatives, buffers, etc., may be added to the extra-gastrointestinal dosage form. The pharmaceutical composition is prepared by conventional techniques suitable for the desired formulation containing an appropriate amount of the active ingredient (i.e., the compound of the present application).

[0113] Compositions suitable for extra-gastrointestinal injection may include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, as well as sterile powders for sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers, diluents, and solvents include water, ethanol, polyols (such as propylene glycol, polyethylene glycol, and glycerol), suitable mixtures thereof, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate).

[0114] These compositions may further contain various excipients, such as preservatives, humectants, emulsifiers, and dispersants. Various antimicrobial and antifungal agents (e.g., parabens, chlorobutanol, phenol, sorbic acid, etc.) may be used to ensure the inhibition of microbial activity. Furthermore, isotonic agents, such as sugars and sodium chloride, may be included. The absorption of injectable pharmaceutical dosage forms can be delayed by the use of absorption-delaying reagents (e.g., aluminum monostearate and gelatin).

[0115] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inactive excipient (or carrier) (e.g., sodium citrate or dicalcium phosphate), which may further include the following: (a) Fillers or mixtures (e.g., starch, lactose, sucrose, glucose, mannitol, and silicic acid), (b) Binders (e.g., carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic), (c) Humectants (e.g., glycerol), (d) Disintegrants (e.g., agar - agar, calcium carbonate, potato or tapioca starch, alginic acid, certain synthetic silicates, sodium carbonate), (e) Solution barriers (e.g., paraffin), (f) Absorption enhancers (e.g., quaternary ammonium compounds), (i) Wetting agents (e.g., cetyl alcohol and glycerol monostearate), (h) Adsorbents (e.g., kaolin and bentonite), and (i) Lubricants (e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate) or mixtures thereof.

[0116] Similar solid compositions can be used as fillers for flexible and rigid gel capsules, for example, using lactose and high molecular weight polyethylene glycol as excipients.

[0117] Solid dosage forms (e.g., tablets, sugar-coated tablets, capsules, pills, and granules) can be prepared with coatings and shells (e.g., enteric coatings and others known in the art). It may also contain light-shielding agents and may further contain active compounds or compositions of various active compounds that release the active compound or various active compounds with a delay at specific sites in the intestinal tract. Examples of usable coating compositions are polymers and waxes. The active ingredient may further be in a microencapsulated form and, where appropriate, may contain one or more of the aforementioned excipients.

[0118] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, dispersions, syrups, and elixirs. Additives to the active compound may include inert diluents commonly used in the art (e.g., water or other solvents), solubilizers, and emulsifiers (e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide), oils (specifically, cottonseed oil, peanut oil, corn oil, olive oil, castor oil, sesame oil), glycerin, tetrahydrofuranol, polyethylene glycol, and fatty acid esters of sorbitan or mixtures thereof.

[0119] In addition to these inert diluents, the composition may further contain, for example, wetting agents, emulsifiers and suspending agents, flavoring agents, seasoning agents, and fragrance agents.

[0120] In addition to the active compound, the suspension may also contain suspending agents such as ethoxylated isooctadecanol, polyoxylated ethylene sorbitol, sorbitan ester, microcrystalline fiber, aluminum metahydroxide, bentonite, agar-agar and astragalus gel, or mixtures thereof.

[0121] Topical dosage forms of the compounds of this application include ointments, powders, sprays, and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and necessary preservatives, buffers, or propellants. Ophthalmic formulations, ophthalmic ointments, powders, and solutions are also included within the scope of this application.

[0122] The amount of the compound of this application in a pharmaceutical composition and dosage form can be appropriately determined by a person skilled in the art as needed. For example, the compound of this application may be present in a therapeutically effective amount in a pharmaceutical composition or dosage form.

[0123] In a third aspect, the present application relates to the use of the compound of formula (I) of the present application, or its isotope-labeled compound, or its optical isomers, geometric isomers, tautomers or isomeric mixtures, or its pharmaceutically acceptable salts, prodrugs or metabolites, or its metabolites, or the pharmaceutical composition thereof, in the manufacture of pharmaceuticals for the treatment of TGF-β (particularly TGF-β1) related diseases or conditions.

[0124] In a fourth embodiment, the present application further provides a method for treating TGF-β (particularly TGF-β1) related diseases or conditions, the method comprising administering to a patient in need a therapeutically effective amount of the compound of formula (I) of the present application, or an isotope-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a pharmaceutically acceptable salt thereof, a prodrug thereof, or a metabolite thereof, or the pharmaceutical composition thereof, where the patient is preferably a mammal, more preferably a human patient. The route of administration may be oral, topical (including, but not limited to, external application, spraying, etc.), extra-gastrointestinal (including subcutaneous, intramuscular, cortical, and intravenous), bronchial, or nasal. The dose is a therapeutically effective dose and can be determined by a person skilled in the art as required by practical needs.

[0125] In this application, "TGF-β (especially TGF-β1) related diseases or conditions" may include cancer, viral infections, chronic nephritis, acute nephritis, diabetic nephropathy, osteoporosis, arthritis, wound healing, scarring, ulcers, corneal wounds, valvular stenosis, congestive cardiac necrosis, neurological disorders, Alzheimer's syndrome, peritoneal or subcutaneous adhesions, arteriosclerosis, dermatofibrosis and skin aging due to fat loss, bone disorders or chondrocyte disorders, hypophosphatemic disorders and organ fibrosis, especially hepatocellular carcinoma, breast cancer, bladder cancer, colorectal cancer, melanoma, mesothelioma, lung cancer, prostate cancer, fascicular adenocarcinoma, testicular cancer, thyroid cancer, squamous cell carcinoma, glioblastoma, neuroblastoma, uterine cancer, rhabdomyosarcoma, renal fibrosis, hepatic fibrosis, pulmonary fibrosis, skin scarring, dermatofibrosis and skin aging due to fat loss, etc.

[0126] In some embodiments, the TGF-β-related disease or condition is cancer. The compounds of the present invention are used, for example, to inhibit the proliferation, metastasis, etc., of cancer cells.

[0127] Similar cancers include bladder cancer, breast cancer, cervical cancer, colorectal cancer, small intestine cancer, colon cancer, rectal cancer, anal cancer, endometrial cancer, head and neck cancers (e.g., cancers of the throat, larynx, nasopharynx, oropharynx, lips and oral cavity), kidney cancer, liver cancers (e.g., hepatocellular carcinoma, cholangiocarcinoma), lung cancers (e.g., adenocarcinoma, small cell lung cancer and non-small cell lung cancer, small cell carcinoma and non-small cell carcinoma, bronchial cancer, bronchial adenocarcinoma, pleuroblastoma), ovarian cancer, prostate cancer, testicular cancer, uterine cancer, esophageal cancer, gallbladder cancer, pancreatic cancer (e.g., exocrine pancreatic carcinoma), thyroid cancer, parathyroid cancer, skin cancers (e.g., squamous cell carcinoma, Kaposi's sarcoma, Merkel cell carcinoma), and brain cancers (e.g., astrocytoma, neural tube germ cell tumor, subependymal tumor, neuroectodermal tumor, pineal tumor).

[0128] Other exemplary cancers include hematopoietic malignancies, such as leukemia or lymphoma, multiple myeloma, chronic lymphocytic lymphoma, adult T-cell leukemia, B-cell lymphoma, cutaneous T-cell lymphoma, acute myeloid leukemia, Hodgkin or non-Hodgkin lymphoma, myeloproliferative neoplasms (e.g., polycythemia vera, essential thrombocytosis and essential myelofibrosis), vatestasone macroglobulinemia, pilosarcocyte lymphoma, chronic myeloid lymphoma, acute lymphoblastic lymphoma, AIDS-related lymphoma and Burkitt lymphoma.

[0129] Other exemplary cancers include eye tumors, glioblastoma, melanoma, rhabdomyosarcoma, lymphosarcoma, and osteosarcoma.

[0130] In some preferred embodiments, the TGF-β-related disease or condition is selected from hepatocellular carcinoma, breast cancer, bladder cancer, colorectal cancer, melanoma, mesothelioma, lung cancer, prostate cancer, membrane cancer, testicular cancer, thyroid cancer, squamous cell carcinoma, glioblastoma, neuroblastoma, uterine cancer, and rhabdomyosarcoma.

[0131] In some other embodiments, the TGF-β-related disorder or condition is selected from skeletal disorders and chondrocyte disorders. Such skeletal and chondrocyte disorders include, but are not limited to, cartilage hypoplasia, chondrodysplasia, dwarfism, fatal chondrodysplasia (TD) (clinical forms TD I and TD II), Apert syndrome, Crouzon syndrome, Jackson-Weiss syndrome, Beare-Stevenson cutis gyrate syndrome, Pfeiffer syndrome, and craniosynostosis.

[0132] In some other embodiments, the TGF-β-related disorder or condition is a hypophosphatemic disorder. The hypophosphatemic disorder includes, for example, X-linked hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets, and tumor-induced osteromalacia.

[0133] In some other embodiments, the TGF-β-related disease or condition is selected from fibrotic diseases. Exemplary fibrotic diseases include cirrhosis, glomerulonephritis, pulmonary fibrosis, systemic fibrosis, rheumatoid arthritis, and wound healing.

[0134] In some preferred embodiments, the TGF-β-related disease or condition is a skin disease, particularly skin scarring, dermatofibrosis, and skin aging due to fat loss.

[0135] The present application will be further described below with reference to specific examples. [Examples]

[0136] The examples described herein are for illustrative purposes only and are used to illustrate various aspects and embodiments of the present invention, and are not intended to limit the scope of protection of the present invention in any way.

[0137] Unless otherwise specified, all reactant raw materials are commercially available. The instruments and equipment used in the synthesis experiments and product analysis / detection are all common instruments and equipment commonly used in organic synthesis. Unless otherwise specified, the reaction conditions and detection conditions are all commonly used in organic synthesis and pharmaceuticals.

[0138] Example 1: 1-(2-(4-(2-(6-methylpyridine-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-yl)pyridine-2-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-yl)ethane-1-one [ka]

[0139] Synthetic route of compound 1: [ka]

[0140] Synthesis method: Synthesis of intermediate 1-b:2-bromo-1-(6-methylpyridine-2-yl)ethane-1-one

[0141] Starting material 1-a (2.0 g, 14.8 mmol) was dissolved in 40 ml of acetonitrile, and p-toluenesulfonic acid (3.8 g, 22.2 mmol) was added. The temperature was then raised to 80°C, and NBS (2.6 g, 14.8 mmol) was added in multiple portions over 2 hours. The mixture was then reacted at 80°C for 3 hours. After monitoring the completion of the reaction by TLC, saturated sodium bicarbonate solution was added to the reaction mixture to quench it. The mixture was extracted twice with EA, the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to obtain 1.8 g of intermediate 1-b. The yield was 57.2%. LC-MS m / z(ESI)[M+H] + The calculated value for C8H9BrNO is 214.1, and the measured value is also 214.1.

[0142] Synthesis of intermediate 1-c:2-(6-methylpyridine-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole

[0143] Intermediate 1-b (800.0 mg, 3.7 mmol) was dissolved in 40 ml of toluene, sodium bicarbonate (942.4 mg, 11.2 mmol) and 2-aminopyrrolidine hydrochloride (896.4 mg, 7.5 mmol) were added, and the mixture was heated to 80°C and reacted overnight. The reaction was monitored by TLC to confirm completion of the starting materials, water was added to the reaction mixture to quench it, and the mixture was extracted twice by DCM. The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column to obtain 313.8 mg of intermediate 1-c, with a yield of 41.9%. LC-MS m / z(ESI)[M+H] ++ :C 12 H 14 The calculated value for N3 is 200.1, and the measured value is 200.2.

[0144] Synthesis of intermediate 1-d:3-bromo-2-(6-methylpyridine-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole

[0145] Intermediate 1-c (313.8 mg, 1.6 mmol) was dissolved in 20 ml of DCM, and NBS (279.5 mg, 1.6 mmol) was added in multiple portions over 5 minutes at room temperature. The reaction was immediately monitored by TLC to ensure complete reaction of the starting materials. The reaction mixture was quenched with water, extracted twice with DCM, the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to obtain 289.7 mg of intermediate 1-d, with a yield of 66.4%. LC-MS m / z(ESI)[M+H] + :C 12 H 13 The calculated value for N3Br is 278.0, and the measured value is also 278.0.

[0146] Synthesis of intermediate 1-1:2-(4-bromopyridine-2-yl)-3a,4,6,6a-tetrahydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate tert-butyl

[0147] 2-Aldehyde-4-bromopyridine (0.8 g, 4.3 mmol) was dissolved in 30 ml of tert-butanol. 3,4-Diaminopyrrolidine-1-carboxylate tert-butyl (1.1 g, 5.6 mmol), iodine (1.6 g, 6.5 mmol), and potassium carbonate (1.2 g, 8.6 mmol) were added, and the mixture was heated to 70°C and reacted for 3 hours. After the reaction was complete, the mixture was cooled to room temperature, the reaction was quenched with 5% aqueous sodium thiosulfate solution, and EA was added for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain 1.4 g of intermediate 1-1, with a yield of 88.9%. LC-MS m / z(ESI)[M+H] + :C 15 H 20 The calculated value for BrN4O2 is 367.1, and the measured value is also 367.1.

[0148] Synthesis of intermediate 1-2:2-(4-bromopyridine-2-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate tert-butyl

[0149] Intermediate 1-1 (1.4 g, 3.8 mmol) was dissolved in 20 ml of DMSO, and IBX (2.1 g, 7.6 mmol) was added. The mixture was heated to 50°C and reacted overnight. After the reaction was complete, the mixture was cooled to room temperature, saturated sodium bicarbonate solution was added to quench the reaction, EA was added for extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain 1.2 g of intermediate 1-2. The yield was 84.7%. LC-MS m / z(ESI)[M+H] + :C 15 H 18 The calculated value for BrN4O2 is 365.1, and the measured value is also 365.1.

[0150] Synthesis of intermediate 1-3: 2-(4-bromopyridine-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrro[3,4-d]imidazole-5(1H)-carboxylate tert-butyl

[0151] Intermediate 1-2 (1.2 g, 3.2 mmol) was dissolved in 20 ml of THF, cooled to 0°C, NaH (60%) (0.2 g, 4.9 mmol) was added, and the mixture was stirred for 0.5 hours. SEMCl (0.8 g, 4.9 mmol) was then added. After the addition was complete, the mixture was heated to room temperature and stirred. After the reaction was complete, water was added to quench the reaction, EA was added for extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain 1.2 g of intermediate 1-3. The yield was 75.2%. LC-MS m / z(ESI)[M+H] + :C 21 H 32 The calculated value for BrN4O3Si is 495.1, and the measured value is also 495.1.

[0152] Intermediate 1-4: Synthesis of (2-(5-(tert-butoxycarbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-yl)pyridine-4-yl)boronic acid

[0153] Intermediate 1-3 (200.0 mg, 0.4 mmol) was dissolved in 10 ml of dioxane, and pinacol bisboronic acid (207.5 mg, 0.8 mmol) and Pd(dppf)Cl2 (29.7 mg, 0.04 mmol) were added. The mixture was then purged with nitrogen gas, potassium acetate (120.5 mg, 1.2 mmol) was added, the mixture was again purged with nitrogen gas, and the temperature was raised to 80°C and the reaction was allowed to proceed overnight. The reaction mixture was cooled to room temperature to obtain the crude product of intermediate 1-4, which was then used in the next reaction.

[0154] Synthesis of intermediate 1-5: 2-(4-(2-(6-methylpyrridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-yl)pyrridin-2-yl)-1-(2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate tert-butyl

[0155] 2 ml of water and potassium carbonate (111.6 mg, 0.8 mmol) were added to the reaction flask containing intermediates 1-4. Then, intermediate 1-d (114.1 mg, 0.8 mmol) and Pd(dppf)Cl2 (29.7 mg, 0.04 mmol), dissolved in 10 ml of dioxane, were added. The flask was purged with nitrogen gas, and the temperature was raised to 100°C and the reaction was allowed to proceed overnight. The reaction mixture was cooled to room temperature, concentrated, and purified by silica gel column chromatography to obtain 86.5 mg of intermediate 1-5, with a yield of 35.2%. LC-MS m / z(ESI)[M+H] + :C 33 H 44 The calculated value for N7O3Si is 614.3, and the measured value is also 614.3.

[0156] Synthesis of intermediate 1-6:2-(4-(2-(6-methylpyrrolo-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-yl)pyrrolo-2-yl)-1-(2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole

[0157] Intermediates 1-5 (60.0 mg, 0.1 mmol) were dissolved in 10 ml of DCM, zinc bromide (44.1 mg, 0.2 mmol) was added, the mixture was purged with nitrogen gas, and the reaction was allowed to proceed overnight at room temperature. After concentrating the reaction mixture and removing the solvent, it was dissolved in 20 ml of THF, and then washed once each with saturated sodium bicarbonate solution and saturated saline solution. The mixture was concentrated to obtain 46.4 mg of crude intermediate 1-6, with a yield of 92.8%. LC-MS m / z(ESI)[M+H] + :C 28 H 36 The calculated value for N7OSi is 514.3, and the measured value is also 514.3.

[0158] Synthesis of intermediate 1-7: 1-(2-(4-(2-(6-methylpyridine-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-yl)pyridine-2-yl)-1-(2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-yl)ethane-1-one

[0159] Intermediate 1-6 (46.4 mg, 0.1 mmol) was dissolved in 10 ml of DCM, triethylamine (18.4 mg, 0.2 mmol) was added at room temperature, followed by acetyl chloride (14.2 mg, 0.2 mmol), and the mixture was stirred at room temperature for 0.5 hours. After the reaction was complete, water was added to quench the mixture, DCM was added for extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified on a preparation plate to obtain 27.4 mg of intermediate 1-7, with a yield of 54.8%. LC-MS m / z(ESI)[M+H] + :C 30 H 38 The calculated value for N7O2Si is 556.3, and the measured value is also 556.3.

[0160] Synthesis of Compound 1: 1-(2-(4-(2-(6-methylpyridine-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-yl)pyridine-2-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-yl)ethane-1-one

[0161] Intermediate 1-7 (27.4 mg, 0.1 mmol) was dissolved in 4 ml of methanol, 2 ml of concentrated hydrochloric acid was added, and the mixture was reacted at 50°C for 3 hours. The mixture was concentrated, dissolved in 5 ml of methanol, 0.5 ml of aqueous ammonia was added, and the mixture was concentrated again. Further purification was performed using a reversed-phase silica gel column to obtain 6.2 mg of the final product, with a yield of 29.6%. LC-MS m / z(ESI)[M+H] + :C 24 H 24 The calculated value for N7O is 426.2, and the measured value is also 426.2.

[0162] Example 2: 2-(4-(2-(6-methylpyridine-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-yl)pyridine-2-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole [ka]

[0163] Synthetic route of compound 2: [ka]

[0164] Synthesis method: Synthesis of Compound 2: 2-(4-(2-(6-methylpyrridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-yl)pyrridin-2-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole

[0165] Intermediates 1-5 (36.5 mg, 0.1 mmol) were dissolved in 4 ml of methanol, 2 ml of concentrated hydrochloric acid was added, and the mixture was reacted at 50°C for 3 hours. The mixture was concentrated, dissolved in 5 ml of methanol, 0.5 ml of aqueous ammonia was added, and the mixture was concentrated again. Further purification was performed using a reversed-phase silica gel column to obtain 4.1 mg of the final product, with a yield of 17.9%. LC-MS m / z(ESI)[M+H] + :C 22 H 22 The calculated value for N7 is 384.2, and the measured value is also 384.2.

[0166] Example 3: 5-methyl-2-(4-(2-(6-methylpyridine-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-yl)pyridine-2-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole [ka]

[0167] Synthetic route of compound 3: [ka]

[0168] Synthesis method: Synthesis of compound 3: 5-methyl-2-(4-(2-(6-methylpyridine-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-yl)pyridine-2-yl)-1,4,5,6-tetrahydropyrrole[3,4-d]imidazole

[0169] Intermediate 1-6 (50.0 mg, 0.1 mmol) and 30% formaldehyde aqueous solution (11.7 mg, 0.4 mmol) were dissolved in 5 ml of DCM, stirred at room temperature for 0.5 hours, cooled to 0°C, sodium triacetylborohydride (82.8 mg, 0.4 mmol) was added, and the mixture was reacted at room temperature for 2 hours. Water was added to quench the mixture, and the mixture was extracted with DCM. The organic phase was combined, washed with saturated brine, and concentrated. The concentrate was dissolved in 4 ml of methanol, 2 ml of concentrated hydrochloric acid was added, and the mixture was reacted at 50°C for 2 hours. The concentrate was then dissolved in 5 ml of methanol, 0.5 ml of aqueous ammonia was added, and the mixture was concentrated. The mixture was purified on a preparation plate, and 3.2 mg of the final product was obtained, with a yield of 8.3%.

[0170] 1 H NMR(400MHz,CD3OD) δ8.61(d,J=4.0Hz,1H),8.14(s,1H),7.74-7.70(m,1H),7.54(d,J=8.0Hz,1H),7.43-7.41(m,1H),7.19(d,J= 8.0Hz,1H),4.59(s,4H),4.27-4.23(m,2H),3.21(s,3H),3.07-3.03(m,2H),2.79-2.72(m,2H),2.36(s,3H).

[0171] Example 4: (4-methylpiperazine-1-yl)(2-(4-(2-(6-methylpyridine-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-yl)pyridine-2-yl)-4,6-dihydropyrolo[3,4-d]imidazole-5(1H)-yl)ketone (MDI-980) [ka]

[0172] Synthetic route of compound 4: [ka]

[0173] Synthesis method: Synthesis of Compound 4: (4-methylpiperazine-1-yl)(2-(4-(2-(6-methylpyridine-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-yl)pyridine-2-yl)-4,6-dihydropyrolo[3,4-d]imidazole-5(1H)-yl)ketone

[0174] Intermediates 1-6 (40.0 mg, 0.1 mmol) were dissolved in 10 ml of DCM. Triphosgene (23.1 mg, 0.1 mmol) was added to the system, the system was cooled to 0°C, triethylamine (80.8 mg, 0.8 mmol) was added dropwise, and the mixture was reacted for 0.5 hours. N-methylpiperidine (8.0 mg, 0.1 mmol) was added to the system, and the mixture was heated to room temperature and reacted. After the reaction was complete, water was added to quench the mixture, and the mixture was extracted with DCM. The organic phases were combined, washed with saturated brine, and concentrated. The concentrate was dissolved in 4 ml of methanol, 2 ml of concentrated hydrochloric acid was added, and the mixture was reacted at 50°C for 2 hours. The concentrate was then concentrated, dissolved in 5 ml of methanol, 0.5 ml of aqueous ammonia was added, and the mixture was concentrated. The mixture was purified on a preparation plate, and 2.2 mg of the final product was obtained, with a yield of 5.5%. LC-MS m / z(ESI)[M+H] + :C 28 H 32 The calculated value for N9O is 510.3, and the measured value is also 510.3.

[0175] Example 6: (2-(4-(4-(6-methylpyridine-2-yl)-1H-imidazole-5-yl)pyridine-2-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-yl)(pyrrolidine-1-yl)ketone [ka]

[0176] Synthetic route of compound 6: [ka]

[0177] Synthesis method Synthesis of intermediate 6-1:2-(1H-imidazole 4-yl)-6-methylpyridine

[0178] Intermediate 1-b (0.8 g, 3.7 mmol) was dissolved in 30 ml of ethylene glycol, formamidine acetate (2.0 g, 18.7 mmol) was added, and the mixture was reacted at 130°C for 2 hours under the protection of nitrogen gas. After cooling to room temperature, water was added to adjust the pH to 10, the mixture was extracted with EA, washed with saturated saline solution, dried over anhydrous sodium sulfate, and concentrated to obtain 400.0 mg of intermediate 6-1. LC-MS m / z(ESI)[M+H] + :C9H 10 The calculated value for N3 is 160.1, and the measured value is also 160.1.

[0179] Synthesis of intermediate 6-2:2-methyl-6-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-yl)pyridine

[0180] Intermediate 6-1 (400.0 mg, 2.5 mmol) was dissolved in 10 ml of THF, NaH (120.0 mg, 3.0 mmol, 60%) was added, and the mixture was reacted at 0°C for 0.5 hours. SEMCl (628.4 mg, 3.8 mmol) was added, and the mixture was reacted at room temperature for 2 hours. Saturated ammonium chloride solution was added to quench the mixture, extracted with EA, washed with saturated saline solution, dried over anhydrous sodium sulfate, concentrated, and passed through a column to obtain 140.0 mg of intermediate 6-2, with a yield of 19.3%.

[0181] Synthesis of intermediate 6-3:2-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole4-yl)-6-methylpyridine

[0182] Intermediate 6-2 (140.0 mg, 0.5 mmol) was dissolved in 10 ml of DCM, and NBS (77.5 mg, 0.4 mmol) was added in multiple portions. The mixture was reacted at room temperature for 10 minutes. The mixture was quenched with saturated sodium bicarbonate solution, extracted with DCM, washed with saturated saline solution, dried over anhydrous sodium sulfate, concentrated, and passed through a column to obtain 90.0 mg of intermediate 6-3, with a yield of 50.5%. LC-MS m / z(ESI)[M+H] + :C 15 H 23The calculated value for BrN3OSi is 368.1, and the measured value is also 368.1.

[0183] Synthesis of intermediate 6-4:2-(4-(4-(6-methylpyridine-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-yl)pyridine-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate tert-butyl

[0184] Intermediate 1-3 (300.0 mg, 0.6 mmol) was dissolved in 10 ml of 1,4-dioxane, potassium acetate (178.0 mg, 1.8 mmol) and pinacol bisboronic acid (184.0 mg, 0.7 mmol) were added, and under the protection of nitrogen gas, Pd(dppf)Cl2 (45.0 mg, 0.1 mmol) was added and the mixture was reacted overnight at 85°C. Intermediate 6-3 (90.0 mg, 0.2 mmol), potassium acetate (178.0 mg, 1.8 mmol), 1 ml of H2O, and Pd(dppf)Cl2 (45.0 mg, 0.1 mmol) were added and the mixture was reacted at 100°C for 6 hours. The mixture was filtered and concentrated to obtain 50.0 mg of intermediate 6-4, with a yield of 11.5%.

[0185] Intermediate 6-5: Synthesis of (2-(4-(4-(6-methylpyridine-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-yl)pyridine-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-yl)(pyrroridine-1-yl)ketone

[0186] Intermediate 6-4 (50.0 mg, 0.1 mmol) was dissolved in 10 ml of DCM, and under the protection of nitrogen gas, ZnBr2 (32.0 mg, 0.1 mmol) was added and the mixture was reacted overnight at room temperature. Triethylamine (1 ml) was added and the mixture was reacted at room temperature for 0.5 hours. Pyrrolidine-1-carbonyl chloride (10.0 mg, 0.1 mmol) was added and the mixture was reacted at room temperature for 2 hours. Water was added, the mixture was extracted with DCM, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated and purified to obtain 20.0 mg of intermediate 6-5, with a yield of 42.9%. LC-MS m / z(ESI)[M+H] + :C 36 H 53 The calculated value for N8O3Si2 is 701.4, and the measured value is also 701.4.

[0187] Synthesis of Compound 6: (2-(4-(4-(6-methylpyridine-2-yl)-1H-imidazole-5-yl)pyridine-2-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-yl)(pyrrolidine-1-yl)ketone

[0188] Intermediate 6-5 (20.0 mg, 0.03 mmol) was dissolved in 2 ml of methanol, 1 ml of hydrochloric acid was added, and the mixture was reacted at 50°C for 3 hours. The mixture was concentrated, and the base was adjusted by adding aqueous ammonia. The mixture was then concentrated and purified to obtain 4.7 mg of product, with a yield of 37.4%. LC-MS m / z(ESI)[M+H] + :C 24 H 25 The calculated value for N8O is 441.2, and the measured value is also 441.2.

[0189] Example 7: (4-methylpiperazine-1-yl)(2-(4-(3-(6-methylpyridine-2-yl)-1H-pyrazole-4-yl)pyridine-2-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-yl)ketone [ka]

[0190] Synthetic route of compound 7: [ka]

[0191] Synthesis method: Synthesis of intermediate 7-1:2-methyl-6-(1H-pyrazole-3-yl)pyridine

[0192] 1.0 g, 7.4 mmol of 1-(6-methylpyridine-2-yl)ethane-1-one was dissolved in 10 ml of DMF-DMA and stirred at 110°C for 20 hours. The reaction mixture was cooled to room temperature and concentrated to a yellow solid. The solid was dissolved in 8 ml of ethanol, 4 ml of hydrazine hydrate was added, and the mixture was reacted at 90°C for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted twice with EA to combine the organic phases. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a total of 1.1 g of crude intermediate 7-1, with a yield of 90.2%.

[0193] Synthesis of intermediate 7-2:2-methyl-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-yl)pyridine

[0194] Intermediate 7-1 (1.1 g, 6.7 mmol) was dissolved in 10 ml of DCM, p-toluenesulfonic acid (1.3 g, 6.7 mmol) was added, and DHP (0.7 ml, 8.0 mmol) was added dropwise at room temperature. The mixture was reacted at room temperature for 2 hours. Water was added to the reaction mixture, extracted twice with DCM, the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to obtain a total of 1.6 g of intermediate 7-2, with a yield of 95.5%.

[0195] 1 H NMR(400MHz,CDCl3) δ 7.79(d,J=7.8Hz,1H),7.70-7.67(m,1H),7.63-7.59(m,1H),7.08(d,J=7.5Hz,1H),6.96(d,J=2.5Hz,1H),5 .51-5.48(m,1H),4.15-4.11(m,1H),3.77-3.72(m,1H),2.62(s,3H),2.16-2.11(m,3H),1.77-1.71(m,3H).

[0196] Synthesis of intermediate 7-3:2-(4-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-yl)-6-methylpyridine

[0197] Intermediate 7-2 (250.0 mg, 1.0 mmol) was dissolved in 10 ml of DCM, p-NBS (274.3 mg, 1.5 mmol) was added, and the mixture was stirred at room temperature for 15 minutes to terminate the reaction. Water was added to the reaction mixture, and it was extracted twice with DCM to combine the organic phases. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to obtain a total of 223.2 mg of intermediate 7-3, with a yield of 67.4%.

[0198] 1 H NMR(400MHz, CDCl3) δ7.77-7.74(m,2H),7.66(t,J=7.7Hz,1H),7.15(d,J=7.8Hz,1H),5.51-5.48(m,1H),4. 12-4.08(m,1H),3.77-3.69(m,1H),2.67(s,3H),2.17-2.00(m,3H),1.74-1.64(m,3H).

[0199] Synthesis of intermediate 7-4:2-(4-(3-(6-methylpyridine-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-yl)pyridine-2-yl)-1-(2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate tert-butyl

[0200] 2-(4-bromopyridine-2-yl)-1-(2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5-(1H)-carboxylate tert-butyl (300.0 mg, 0.6 mmol) and pinacol bisboronic acid (184.5 mg, 0.7 mmol) were dissolved in 8 ml of dioxane. Potassium acetate (118.9 mg, 1.2 mmol) and Pd(dppf)Cl2 (45.0 mg, 0.1 mmol) were added to the solution, the mixture was purged with nitrogen gas, and the mixture was reacted at 90°C for 16 hours. The reaction mixture was cooled to room temperature, and intermediate 7-3 (195.1 mg, 0.6 mmol) and potassium carbonate (251.1 mg, 1.8 mmol) were added to the reaction mixture. Pd(dppf)Cl2 (45.0 mg, 0.1 mmol) was added, 2 ml of water was added, the mixture was purged with nitrogen gas, and the reaction was carried out at 100°C for 24 hours. The reaction mixture was filtered, water was added to the filtrate, and the mixture was extracted twice with EA. The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to obtain a total of 203.6 mg of intermediate 7-4, with a yield of 50.8%.

[0201] 1 H NMR(400MHz, CDCl3) δ8.38(t,J=5.7Hz,1H),8.32-8.27(m,1H),8.03(d,J=5.2Hz,1H),7.58(t,J=7.7Hz,1H),7. 46-7.43(m,1H),7.23-7.20(m,1H),7.11(d,J=7.7Hz,1H),6.07-6.02(m,2H),5.51-5.47(m, 1H),4.61-4.44(m,4H),4.13-4.10(m,1H),3.73(t,J=10.8Hz,1H),3.62-3.54(m,2H),2.53( s,3H),2.22-2.07(m,3H),1.72-1.64(m,3H),1.53(s,9H),0.95-0.85(m,2H),-0.06(s,9H).

[0202] Synthesis of intermediate 7-5: 2-(4-(3-(6-methylpyridine-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-yl)pyridine-2-yl)-1-(2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole

[0203] Intermediate 7-4 (65.0 mg, 0.1 mmol) was dissolved in 10 ml of DCM, ZnBr2 (110.9 mg, 0.5 mmol) was added, and the mixture was stirred at room temperature. After the reaction was complete, aqueous ammonia was added to quench the mixture, DCM was added for extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a total of 55.1 mg of intermediate 7-5, with a yield of 99.7%.

[0204] Intermediate 7-6: Synthesis of (4-methylpiperazine-1-yl)(2-(4-(3-(6-methylpyridine-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-yl)pyridine-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-yl)ketone

[0205] Intermediate 7-5 (55.0 mg, 0.1 mmol) and triphosgene (29.2 mg, 0.1 mmol) were dissolved in 10 ml of DCM, cooled to 0°C, and triethylamine (99.5 mg, 0.1 mmol) was added to the solution. The mixture was reacted for 5 minutes, and N-methylpiperazine (19.7 mg, 0.2 mmol) was added to the system. The mixture was heated to room temperature and stirred. After the reaction was complete, water was added to quench the mixture, extracted with DCM, the organic phases were combined, washed with saturated brine, and concentrated. The mixture was purified by silica gel column chromatography, yielding a total of 35.2 mg of intermediate 7-6, with a yield of 51.9%.

[0206] Synthesis of Compound 7: (4-methylpiperazine-1-yl)(2-(4-(3-(6-methylpyridine-2-yl)-1H-pyrazole-4-yl)pyridine-2-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-yl)ketone

[0207] Intermediate 7-6 (35.2 mg, 0.1 mmol) was dissolved in 4 ml of methanol, 2 ml of concentrated hydrochloric acid was added, and the mixture was reacted at 45°C for 6 hours. The mixture was concentrated, dissolved in 5 ml of methanol, and 0.5 ml of aqueous ammonia was added to adjust the alkalinity. The mixture was concentrated and purified to obtain 5.0 mg of the final product, with a yield of 20.8%. LC-MS m / z(ESI)[M+H]+:C 25 H 28 The calculated value for N9O is 470.2, and the measured value is also 470.2.

[0208] Examples 9 to 11 The following examples were prepared using appropriate starting materials according to the synthesis route of Example 1.

[0209] [Table 1] TIFF0007845739000019.tif80151

[0210] Examples 12 to 13 The following examples were prepared using appropriate starting materials according to the synthesis route of Example 3.

[0211] [Table 2]

[0212] Examples 14 to 15 The following examples were prepared using appropriate starting materials according to the synthesis route of Example 4.

[0213] [Table 3]

[0214] Examples 22 to 23 The compounds in each of the following examples were prepared using appropriate starting materials according to the synthesis route of Example 7.

[0215] [Table 4]

[0216] Examples 25 to 26 The compounds in each of the following examples were prepared using appropriate starting materials according to the synthesis route of Example 3.

[0217] [Table 5]

[0218] Examples 27 to 34 The compounds in each of the following examples were prepared using appropriate starting materials according to the synthesis route of Example 4.

[0219] [Table 6] TIFF0007845739000025.tif165151TIFF0007845739000026.tif155149TIFF0007845739000027.tif176153

[0220] Examples 37 to 60 The compounds in each of the following examples were prepared using appropriate starting materials according to the synthesis route of Example 7.

[0221] [Table 7] TIFF0007845739000029.tif162151TIFF0007845739000030.tif167151TIFF0007845739000031.t if155149TIFF0007845739000032.tif151149TIFF0007845739000033.tif151150TIFF00078457390 00034.tif159149TIFF0007845739000035.tif160150TIFF0007845739000036.tif157149TIFF000 7845739000037.tif165151TIFF0007845739000038.tif170150TIFF0007845739000039.tif161152

[0222] Example 61: (4-methylpiperazine-1-yl)(2-(4-(2-(6-methylpyridine-2-yl)-5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazin-3-yl)pyridine-2-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-yl)ketone [ka]

[0223] Synthetic route of compound 61: [ka]

[0224] Synthesis method: Synthesis of intermediate 61-1:2-(6-methylpyridine-2-yl)-5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazine

[0225] 2-Bromo-1-(6-methylpyridine-2-yl)ethane-1-one (500.0 mg, 2.3 mmol), morpholine-3-imine hydrochloride (318.0 mg, 2.3 mmol), and sodium carbonate (1.2 g, 11.7 mmol) were dissolved in 10 ml of DMF and heated to 80°C and reacted overnight. After the reaction was complete, water was added to quench the mixture, extracted twice with EA, the organic phase was combined, washed with saturated saline, concentrated, and purified by silica gel column to obtain a total of 282.0 mg of intermediate 61-1, with a yield of 56.1%. LC-MS m / z(ESI)[M+H]+:C 12 H14 The calculated value for N3O is 216.1, and the measured value is also 216.1.

[0226] 1 H NMR(400MHz,CDCl3) δ7.70(d,J=8.0Hz,1H),7.62-7.58(m,2H),7.03(d,J=8.0Hz,1H),4.94(s,2H),4.11(s,4H),2.58(s,3H).

[0227] Synthesis of intermediate 61-2:3-iodo-2-(6-methylpyridine-2-yl)-5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazine

[0228] Intermediate 61-1 (20.0 mg, 0.1 mmol) and NIS (48.2 mg, 0.3 mmol) were dissolved in 1 ml of DMF and reacted at 60°C for 4 hours. After the reaction was complete, water was added to quench the mixture, extracted twice with EA, the organic phase was combined, washed with saturated saline, concentrated, and purified to obtain a total of 23.0 mg of intermediate 61-2, with a yield of 72.6%. LC-MS m / z(ESI)[M+H]+:C 12 H 13 The calculated value for IN3O is 342.0, and the measured value is also 342.0.

[0229] 1 H NMR(400MHz, CDCl3) δ7.76(d,J=8.0Hz,1H),7.63(t,J=8.0Hz,1H),7.09(d,J=8.0Hz,1H),4.92(s,2H),4.14(t,J=4.0Hz,2H),3.96(t,J=8.0Hz,1H),2.64(s,3H).

[0230] Synthesis of intermediate 61-3: 2-(4-(2-(6-methylpyridine-2-yl)-5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazin-3-yl)pyridine-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate tert-butyl

[0231] 2-(4-bromopyridine-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5-(1H)-carboxylate tert-butyl (76.3 mg, 0.2 mmol) was dissolved in 10 ml of 1,4-dioxane, and potassium acetate (20.1 mg, 0.2 mmol), pinacol bisboronic acid (58.6 mg, 0.2 mmol), and Pd(dppf)Cl2 (7.5 mg, 0.01 mmol) were added. The mixture was reacted overnight at 100°C under the protection of nitrogen gas. The mixture was cooled to room temperature, and intermediate 61-2 (35.0 mg, 0.1 mmol), potassium carbonate (28.4 mg, 0.2 mmol), 2 ml of H2O, and Pd-127 (7.8 mg, 0.01 mmol) were added. The mixture was reacted at 100°C for 5 hours under the protection of nitrogen gas, cooled to room temperature, water was added, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified to obtain 42.0 mg of intermediate 61-3, with a yield of 65.0%. LC-MS m / z(ESI)[M+H]+:C 33 H 44 The calculated value for N7O4Si is 630.3, and the measured value is also 630.3.

[0232] Synthesis of intermediate 61-4: 2-(6-methylpyridine-2-yl)-3-(2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-yl)pyridine-4-yl)-5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazine

[0233] Intermediate 61-3 (42.0 mg, 0.1 mmol) was dissolved in 10 ml of DCM, zinc bromide (60.3 mg, 0.3 mmol) was added, and the mixture was reacted overnight at room temperature. Saturated sodium bicarbonate solution was added and the mixture was stirred for 10 minutes. The mixture was extracted with DCM, washed once with saturated saline solution, dried over anhydrous sodium sulfate, and concentrated. A crude product of intermediate 61-4 of 35.0 mg was obtained, with a yield of 99.1%.

[0234] Intermediate 61-5: Synthesis of (4-methylpiperazine-1-yl)(2-(4-(2-(6-methylpyridine-2-yl)-5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazin-3-yl)pyridine-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-yl)ketone

[0235] Intermediate 61-4 (35.0 mg, 0.1 mmol) was dissolved in 10 ml of DCM, cooled to 0°C, triphosgene (24.5 mg, 0.1 mmol) was added, and the mixture was reacted for 5 minutes. Triethylamine (66.9 mg, 0.7 mmol) was added dropwise, and the mixture was reacted for 0.5 hours. N-methylpiperidine (7.9 mg, 0.1 mmol) was added to the system, and the mixture was heated to room temperature and reacted. After the reaction was complete, water was added to quench the mixture, extracted with DCM, the organic phase was combined, washed with saturated brine, and concentrated and purified to obtain 31.0 mg of intermediate 61-5, with a yield of 71.5%.

[0236] Synthesis of Compound 61: (4-methylpiperazine-1-yl)(2-(4-(2-(6-methylpyridine-2-yl)-5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazine-3-yl)pyridine-2-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-yl)ketone

[0237] Intermediate 61-5 (31.0 mg, 0.05 mmol) was dissolved in 4 ml of methanol, 2 ml of concentrated hydrochloric acid was added, and the mixture was reacted at 50°C for 2 hours. The mixture was concentrated, dissolved in 5 ml of methanol, and 0.5 ml of aqueous ammonia was added to adjust the alkalinity. The mixture was concentrated and purified on a preparation plate to obtain 4.6 mg of the final product, with a yield of 18.5%. LC-MS m / z(ESI)[M+H]+:C 28 H 32 The calculated value for N9O2 is 526.3, and the measured value is also 526.3.

[0238] Example 62: (4-methylpiperazine-1-yl)(2-(4-(2-(6-methylpyridine-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-yl)pyridine-2-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-yl)ketone [ka]

[0239] Synthetic route of compound 62: [ka]

[0240] Synthesis method: Synthesis of intermediate 62-1:3-(6-methylpyridine-2-yl)-3-oxopropionate ethyl

[0241] Ethyl acetate (874.3 mg, 9.9 mmol) was dissolved in 10 ml of toluene, sodium ethoxide (450.0 mg, 6.6 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Methyl 6-methylpicolinate (500.0 mg, 3.3 mmol) was added, and the mixture was stirred at 95°C for 16 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, and acetic acid was added to adjust the pH to 7. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a total of 530.3 mg of crude intermediate 62, with a yield of 77.3%. LC-MS m / z(ESI)[M+H]+:C 11 H 13 The calculated value for NO3 is 208.1, and the measured value is 208.2.

[0242] Synthesis of intermediate 62-2:3-(6-methylpyridine-2-yl)-3-((2-oxopyrrolidine-1-yl)imino)propionate ethyl

[0243] Intermediate 62-1 (430.0 mg, 2.1 mmol) was dissolved in 10 ml of pyridine, and 2-iminopyrrolidine hydrochloride (275.2 mg, 2.3 mmol) was added. The reaction was allowed to proceed at room temperature for 16 hours to terminate the reaction. The reaction mixture was concentrated to remove the pyridine, water was added to the concentrate, and the mixture was extracted twice with ethyl acetate to combine the organic phases. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a total of 580.1 mg of crude intermediate 62-2, with a yield of 96.6%.

[0244] Synthesis of intermediate 62-3:2-(6-methylpyridine-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxylic acid

[0245] Intermediate 62-2 (580.0 mg, 2.0 mmol) was dissolved in 10 ml of toluene, sodium ethoxide (272.7 mg, 4.0 mmol) was added, and the mixture was stirred at 100°C for 15 hours. The reaction mixture was cooled to room temperature, water was added to the reaction mixture, and the mixture was stirred for 20 minutes. The pH was adjusted to 4 with concentrated hydrochloric acid, and the mixture was extracted twice with dichloromethane:isopropanol = 10:1. The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a total of 340.2 mg of crude intermediate 62-3, with a yield of 69.4%. LC-MS m / z(ESI)[M+H]+:C 13 H 13 The calculated value for N3O2 is 244.1, and the measured value is also 244.1.

[0246] Synthesis of intermediate 62-4:3-bromo-2-(6-methylpyridine-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole

[0247] Intermediate 62-3 (340.0 mg, 1.4 mmol) was dissolved in 10 ml of DMF, NBS (272.1 mg, 1.5 mmol) was added, and the mixture was stirred at room temperature for 16 hours to terminate the reaction. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to obtain a total of 350.1 mg of intermediate 62-4, with a yield of 90.0%. LC-MS m / z(ESI)[M+H]+:C 12 H 12 The calculated value for BrN3 is 278.0, and the measured value is also 278.0.

[0248] Synthesis of intermediate 62-5: 2-(4-(2-(6-methylpyridine-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-yl)pyridine-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydroxypyrrolo[3,4-d]imidazole-5(1H)-carboxylate tert-butyl

[0249] 2-(4-bromopyridine-2-yl)-1-(2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5-(1H)-carboxylate tert-butyl (106.9 mg, 0.2 mmol) and pinacol bisboronic acid (109.6 mg, 0.4 mmol) were dissolved in 8 ml of dioxane. Potassium acetate (42.3 mg, 0.4 mmol) and Pd(dppf)Cl2 (16.0 mg, 0.02 mmol) were added to the solution, the mixture was purged with nitrogen gas, and the mixture was reacted at 90°C for 16 hours. The reaction mixture was cooled to room temperature, intermediate 62-4 (60.0 mg, 0.2 mmol) was dissolved in 4 ml of dioxane, and added to the reaction mixture along with potassium carbonate (89.2 mg, 0.6 mmol). Pd(dppf)Cl2 (16.0 mg, 0.02 mmol) was added, 3 ml of water was added, the mixture was purged with nitrogen gas, and the reaction was carried out at 100°C for 20 hours. The reaction mixture was filtered, water was added to the filtrate, and the mixture was extracted twice with ethyl acetate. The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to obtain a total of 70.6 mg of intermediate 62-5, with a yield of 52.9%. LC-MS m / z(ESI)[M+H]+:C 33 H 43 The calculated value for N7O3Si is 614.3, while the measured value is 614.5.

[0250] Synthesis of intermediate 62-6: 2-(4-(2-(6-methylpyridine-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-yl)pyridine-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole

[0251] Intermediate 62-5 (26.0 mg, 0.04 mmol) was dissolved in 5 ml of dichloromethane, zinc bromide (38.0 mg, 0.17 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched by adding aqueous ammonia, extracted with dichloromethane, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a total of 16.3 mg of crude intermediate 62-6, with a yield of 73.5%.

[0252] Intermediate 62-7: Synthesis of (4-methylpiperazine-1-yl)(2-(4-(2-(6-methylpyridine-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-yl)pyridine-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydro-pyrrolo[3,4-d]imidazole-5(1H)-yl)ketone

[0253] N-methylpiperazine (6.2 mg, 0.06 mmol) was dissolved in 5 ml of dichloromethane, cooled to 0°C, triphosgene (18.4 mg, 0.06 mmol) was added, and triethylamine (62.9 mg, 0.6 mmol) was slowly added to the reaction mixture. The mixture was reacted for 5 minutes, and a solution of 62-6 (16.3 mg, 0.03 mmol) in dichloromethane was added to the reaction mixture. The mixture was heated to room temperature and stirred. After the reaction was complete, water was added to quench the reaction, and the mixture was extracted with dichloromethane. The organic phases were combined, washed with saturated brine, and concentrated. The mixture was purified by silica gel column chromatography, and 15.2 mg of intermediate 62-7 was obtained, with a yield of 37.7%.

[0254] Synthesis of Compound 62: (4-methylpiperazine-1-yl)(2-(4-(2-(6-methylpyridine-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-yl)pyridine-2-yl)-4,6-dihydro-pyrrolo[3,4-d]imidazole-5(1H)-yl)ketone

[0255] Intermediate 62-7 (15.2 mg, 0.02 mmol) was dissolved in 4 ml of methanol, 2 ml of concentrated hydrochloric acid was added, and the mixture was reacted at 45°C for 1 hour. The mixture was concentrated, dissolved in 5 ml of methanol, and 0.5 ml of aqueous ammonia was added to adjust the alkalinity. The mixture was concentrated and purified on a silica gel plate to obtain 5.3 mg of the final product, with a yield of 44.4%. LC-MS m / z(ESI)[M+H]+:C 28 H 31 The calculated value for N9O is 510.3, and the measured value is also 510.3.

[0256] Example 63: 2-(4-(2-(6-methylpyridine-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-yl)pyridine-2-yl)-5-(methylsulfonyl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine [ka]

[0257] Synthetic route of compound 63: [ka]

[0258] Synthesis method: Synthesis of intermediate 63-2:3-bromobenzidinemethyl

[0259] Intermediate 63-1 (5.0 g, 27.5 mmol) was dissolved in 50 ml of methanol, sodium methoxide (3.0 g, 55.4 mmol) was added to the reaction mixture, and the mixture was reacted at room temperature for 16 hours. The reaction mixture was concentrated to remove methanol, water was added to the concentrate, and the mixture was extracted twice with ethyl acetate. The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 4.8 g of crude intermediate 63-2, with a yield of 81.4%.

[0260] Synthesis of intermediate 63-3:3-bromobenzimidazole hydrochloride

[0261] Intermediate 63-2 (4.8 g, 22.3 mmol) was dissolved in 40 ml of ethanol, and NH4Cl (3.6 g, 67.2 mmol) was added. The reaction was carried out at 80°C for 2 hours. After the reaction was complete, the mixture was concentrated to obtain 3.2 g of intermediate 63-3, with a yield of 57.1%.

[0262] Synthesis of intermediate 63-4: 2-(4-bromopyridine-2-yl)-3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate tert-butyl

[0263] Intermediate 63-3 (3.2 g, 13.6 mmol) was dissolved in 40 ml of toluene, and N-Boc-3-bromo-4-oxopiperidine (7.5 g, 27.2 mmol) and sodium bicarbonate (3.4 g, 40.8 mmol) were added. The mixture was heated to 80°C and reacted overnight. After cooling the following day, the reaction was monitored by TLC, indicating that the starting materials had reacted completely. The reaction mixture was quenched with water, extracted twice with EA, the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to obtain 2.9 g of intermediate 63-4, with a yield of 56.6%. LC-MS m / z(ESI)[M+H] + :C 16 H 20 The calculated value for BrN4O2 is 379.1, and the measured value is 379.0.

[0264] Synthesis of intermediate 63-5: 2-(4-bromopyridine-2-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)-3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate tert-butyl

[0265] Intermediate 63-4 (2.9 g, 7.6 mmol) was dissolved in 30 ml of THF, cooled to 0°C, NaH (60%) (0.6 g, 15.2 mmol) was added, and the mixture was stirred for 0.5 hours. SEMCl (1.9 g, 11.4 mmol) was then added. After the addition was complete, the mixture was heated to room temperature and stirred. After the reaction was complete, water was added to quench the reaction, EA was added for extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain 2.7 g of intermediate 63-5. The yield was 68.8%. LC-MS m / z(ESI)[M+H] + :C 22 H 34 The calculated value for BrN4O3Si is 509.2, while the measured value is 509.1.

[0266] Intermediate 63-6: Synthesis of (2-(5-(tert-butoxycarbonyl)-3-((2-(trimethylsilyl)ethoxy)methyl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-2-yl)pyridine-4-yl)boronic acid

[0267] Intermediate 63-5 (2.7 g, 5.2 mmol) was dissolved in 30 ml of DME, and bisboronic acid pinacol ester (2.6 g, 10.4 mmol) and dibromlodimethoxyethane (393.3 mg, 0.5 mmol) were added. The mixture was purged with nitrogen gas, potassium acetate (1.6 g, 15.6 mmol) was added, the mixture was again purged with nitrogen gas, and the temperature was raised to 90°C and the reaction was allowed to proceed overnight. The next day, the reaction mixture was cooled to room temperature, concentrated, and purified by silica gel column chromatography to obtain 1.2 g of intermediate 63-6, with a yield of 48.1%. LC-MS m / z(ESI)[M+H] + :C 22 H 36 The calculated value for BN4O5Si is 475.3, and the measured value is also 475.3.

[0268] Synthesis of intermediate 63-7: 2-(4-(2-(6-methylpyridine-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-yl)pyridine-2-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)-3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate tert-butyl

[0269] 3-Bromo-2-(6-methylpyridine-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (100.0 mg, 0.4 mmol) was dissolved in 10 ml of DME and 1 ml of water. Intermediate 63-6 (256.5 mg, 0.5 mmol), sodium carbonate (76.2 mg, 0.7 mmol), and dibromlodimethoxyethane (27.2 mg, 0.04 mmol) were added, the mixture was purged with nitrogen gas, and the temperature was raised to 80°C and the reaction was allowed to proceed overnight. Water was added, the mixture was extracted, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain 89.4 mg of intermediate 63-7, with a yield of 39.6%. LC-MS m / z(ESI)[M+H] + :C 34 H 46 The calculated value for N7O3Si is 628.3, and the measured value is also 628.3.

[0270] Synthesis of intermediate 63-8: 2-(4-(2-(6-methylpyridine-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-yl)pyridine-2-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine

[0271] Intermediate 63-7 (89.4 mg, 0.2 mmol) was dissolved in 10 ml of DCM, zinc bromide (128.3 mg, 0.6 mmol) was added, the mixture was purged with nitrogen gas, and the reaction was allowed to proceed overnight at room temperature. After the reaction was complete the following day, 0.5 ml of aqueous ammonia was added to the reaction solution, followed by water, and DCM was added for two extractions to combine the organic phases. The mixture was then washed once each with saturated sodium bicarbonate solution and saturated brine, and after concentration, 75.0 mg of the crude product of intermediate 63-8 was obtained, with a yield of 100%.

[0272] Synthesis of intermediate 63-9: (2-(4-(2-(6-methylpyridine-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-yl)pyridine-2-yl)-5-(methylsulfonyl)-3-((2-(trimethylsilyl)ethoxy)methyl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine

[0273] Intermediate 63-8 (32.0 mg, 0.1 mmol) was dissolved in 5 ml of DCM, triethylamine (20.2 mg, 0.2 mmol) was added, methanesulfonyl chloride (8.3 mg, 0.1 mmol) was added, and the mixture was reacted at room temperature for 1 hour. Water was added to the reaction mixture, extracted with DCM, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 33.0 mg of crude intermediate 63-9, with a yield of 89.9%.

[0274] Synthesis of compound 63: 2-(4-(2-(6-methylpyridine-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-yl)pyridine-2-yl)-5-(methylsulfonyl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine

[0275] Intermediate 63-9 (33.0 mg, 0.1 mmol) was dissolved in 2 ml of methanol, 1 ml of concentrated hydrochloric acid was added, and the mixture was reacted at 50°C for 2 hours. The mixture was concentrated, dissolved in 5 ml of methanol, 0.5 ml of aqueous ammonia was added, the mixture was concentrated, and the solution was purified to obtain 5.2 mg of the final product. The yield was 20.1%. LC-MS m / z(ESI)[M+H]+ :C 24 H 26 The calculated value for N7O2S is 476.2, and the measured value is also 476.2.

[0276] Example 64 The compounds in the following examples were prepared using appropriate starting materials according to the synthesis route of Example 1.

[0277] [Table 8]

[0278] Examples 65 to 74 The compounds in each of the following examples were prepared using appropriate starting materials according to the synthesis route of Example 62.

[0279] [Table 9] TIFF0007845739000048.tif161150TIFF0007845739000049.tif172149TIFF0007845739000050.tif173152TIFF0007845739000051.tif175151

[0280] Examples 75 to 76 The compounds in each of the following examples were prepared using appropriate starting materials according to the synthesis route of Example 63.

[0281] [Table 10]

[0282] Example 77: Detection of compound activity 1. Reagents and consumables

[0283] [Table 11]

[0284] 2. Experimental Method 2.1 Preparation of 1x kinase reaction buffer

[0285] [Table 12]

[0286] 2.2 Kinase reaction conditions:

[0287] [Table 13]

[0288] 2.3 Steps for measuring activity: The principle of the activity test is that the TGFβR1 phosphorylation substrate TGFβR1 tide consumes ATP. In this experiment, the kinase activity test was measured using the ADP-Glo ​​method, and the IC50 value was measured to evaluate the inhibitory ability of the test compound on human TGFβR1. In the experiment, DSM was used as the negative control and LY364947 was used as the positive control. The specific experimental steps are as follows: The compound was diluted four-fold with DMSO on a dilution plate to a final starting concentration of 10 μM, with 10 concentration gradient points. The compound was diluted 50-fold in kinase reaction buffer and shaken for 20 minutes. Kinase was prepared using enzyme reaction buffer, and 2 μl of kinase was added to each well of the reaction plate. 1 μl of the compound diluted in buffer was added to each well, the plate was sealed with seal film, centrifuged at 1000 g for 30 seconds, and left at room temperature for 10 minutes. A TGFβR1 tide and ATP solution was prepared using enzyme reaction buffer, and 2 μl of the TGFβR1 tide / ATP solution was added to the reaction plate. The plate, sealed with seal film, was centrifuged at 1000 g for 30 seconds and allowed to react at room temperature for 60 minutes. 4 μl of ADP-Glo ​​was transferred to a 384 reaction plate, centrifuged at 1000 rpm / min for 1 minute, and incubated at 25°C for 40 minutes. 8 μl of detection solution was transferred to a 384 reaction plate, centrifuged at 1000 rpm / min for 1 minute, and incubated at 25°C for 40 minutes. The RLU (Relative luminescence unit) signal was read using a BMG microplate reader, and the signal intensity was used to represent the kinase activity.

[0289] 3. Data Analysis 3.1 The inhibition rate is calculated as follows: Compound inhibition rate (%inh) = 100% - (compound - positive control) / (negative control - positive control) * 100%

[0290] 3.2 The IC50 was calculated to create an inhibition curve for the compound. The IC50 (half-inhibitory concentration) of the compounds was obtained using the following nonlinear fitting equation, and the data was analyzed using Graphpad 7.0 software. Y=Bottom+(Top-Bottom) / (1+10^((LogIC50-X)*Hill Slope)) X: Compound concentration log value Y: Inhibition rate (%inhibition)

[0291] 3.3 Report Secondary Examination 3.3.1 After one experimenter has finished writing the report, another experimenter will perform a re-examination to ensure the accuracy of the data analysis. 3.3.2 Data is derived from BMG and analyzed manually. 3.3.2.1 The ratio is converted to a suppression rate, and IC50 is calculated from Prism GraphPad 7.0 using the suppression rate. 3.3.2.2 The accuracy of the results was verified by recalculating IC50 as a ratio.

[0292] 3.4 Quality Control Z factor>0.5, S / B>2. Positive control IC 50 This is within three times the historical average.

[0293] 4. Activity test results

[0294] [Table 14] TIFF0007845739000057.tif70149

[0295] As can be seen from the above results, the compound of this application exhibits a TGFβR1 inhibitory effect equivalent to or greater than that of the positive control LY364947, and therefore can be used for the treatment of TGF-β (especially TGF-β1) related diseases or conditions.

[0296] While specific embodiments of the present invention have been illustrated and described, this does not mean that these embodiments illustrate and describe all possible forms of the present application. More precisely, the words used in the specification of the present invention are descriptive words and not limiting. It will be apparent to those skilled in the art that various other changes and modifications can be made without departing from the general scope of this disclosure. Accordingly, the appended claims are intended to include all such changes and modifications within the scope of the present invention.

Claims

1. A compound of formula (I), or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof. 【Chemistry 1】 (In the formula, n = 1, 2, 3; L is (C=O), (O=S=O), ((C=O)-CH ２ ), CH ２ or linked; R １ is H, halogen, -OH, -NO ２ , -CN, -SF ５ , -SH, -S-C １－４ alkyl, C １－６ alkyl, C １－６ halogenated alkyl, C １－６ alkoxy, C １－６ halogenated alkoxy, C ２－８ alkenyl, C ２－８ alkynyl, C ３－７ alicyclic group, 3- to 10-membered heteroalicyclic group, C ６－１２ dicyclic alicyclic group, 6- to 12-membered dicyclic heteroalicyclic group, C[[ID=​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​-OC(=O)R １２ , -N(R １０ ) (S (=O) ２ R １１ ), -S (=O) ２ -N(R) １０ ) (Caution １１ ), -SR １２ and -OR １２ Selected from, where -S-C １－４ Alkyl, C １－６ Alkyl, C １－６ Alkyl halogens, C １－６ Alkoxy, C １－６ Alkoxy halogenated compounds, C ２－８ Alkenil, C ２－８ Alkinyl, C ３－７ Alicyclic group, 3-10 membered heteroalicyclic group, C ６－１２ Dicycloalicyclic group, 6-12 membered dicycloheteroalicyclic group, C ８―１５ Member tricycloalicyclic group, 8-15 member tricycloheteroalicyclic group, C ５－８ Aryl, 5-10 member heteroaryl, C ７－１１ Dicycloaryl, 7-11 member dicycloheteroaryl, -C １－４ Alkyl-(C) ３－７ alicyclic group), -C １－４ Alkyl-(3-10 membered heteroalicyclic group), -C １－４ Alkyl-(C) ６－１２ Dicycloalicyclic group), -C １－４ Alkyl-(6-12 membered dicycloheteroalicyclic group), -C １－４ Alkyl-(C) ８―１５ (member tricycloalicyclic group), -C １－４ Alkyl-(8-15 member tricycloheteroalicyclic group), -C １－４ Alkyl-(C) ５－８ Aryl) and -C １－４ Alkyl- (5-10 member heteroaryl) has 0, 1, 2, 3 or 4 R １ａ Each is arbitrarily substituted, R １ａ These are halogen, -OH, -NO ２ -CN, -SF ５ , -SH, -S-C １－４ Alkyl, oxo, C １－４ Alkyl, C １－４ alkyl halide, C １－４ alkoxy, C １－４ haloalkoxy, C ２－８ alkenyl, C ２－８ alkynyl, C ３－７ alicyclic group, 3- to 10-membered heteroalicyclic group, C ５－８ aryl, 5- to 7-membered heteroaryl, -N(R １３ )(R １４ ), -N(R １３ )(C(=O)R １４ ), -N(R １３ )(C(=O)-OR １４ ), -N(R １５ )(C(=O)-N(R １３ )(R １４ )), -C(=O)-N(R １３ )(R １４ ), -C(=O)-R １５ ), -C(=O)-OR １５ ), -OC(=O)R １５ ), -N(R １３ )(S(=O) ２ R １４ ), -S(=O) ２ -N(R １３ )(R １４ ), -SR １５ and -OR １５ are independently selected from; R １０ , R １１ , R １２ , R １３ , R １４ and R １５ Each time it appears, H, C １－６ Alkyl, C １－６ Alkyl halogens, C ３－７ Alicyclic group, 3-10 membered heteroalicyclic group, C ５－８ Aryl, 5-7 member heteroaryl, C ７－１１ Dicycloaryl, 7-11 member dicycloheteroaryl, -C １－４ Alkyl-(C) ３－７ alicyclic group), -C １－４ Alkyl-(3-10 membered heteroalicyclic group), -C １－４ Alkyl-(C) ６－１２ Dicycloalicyclic group), -C １－４ Alkyl-(6-12 membered dicycloalicyclic group), -C １－４ Alkyl-(C) ８－１５ (member tricycloalicyclic group), -C １－４ Alkyl-(8-15 member tricycloalicyclic group), -C １－４ Alkyl-(C) ５－８ Aryl) and -C １－４ Each is independently selected from the group consisting of alkyl-(5-10 member heteroaryl), where each option within the group is halogen, -OH, -NH ２ ,-NH(CH ３ ), -N(CH ３ ) ２ -CN, -NO ２ , -SF ５ , -SH, -S-C １－４ Alkyl, oxo, C １－４ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－７ Alicyclic group, 3-10 membered heteroalicyclic group, C ５－８ Aryl, 5-7 member heteroaryl, C ７－１１ Dicycloaryl, 7-11 member dicycloheteroaryl, C １－４ Hydroxyalkyl, -S-C １－４ Alkyl, -C(=O)H, -C(=O)-C １－４ Alkyl, -C(=O)-O-C １－４ Alkyl, -C(=O)-NH ２ , -C(=O)-N(C １－４ Alkyl) ２ , C １－４ Alkyl halogens, C １－４ Alkoxy and C １－４ It is optionally substituted with 0, 1, 2, 3, or 4 substituents independently selected from the group consisting of alkoxy halogens, or R １０ and R １１ These, together with the atoms linked to them, form a 3- to 14-membered ring, or R １３ and R １４ These, together with the atoms linked to them, form a 3- to 14-membered ring; R ２ The number of each R is 1, 2, 3, or 4, and each R ２ These are independently H, halogen, -CN, -OH, and -NO. ２ , -NR ７ R ８ , C １－４ Alkyl, C １－４ Alkyl halogens, C １－４ Alkoxy, C ３－６ Selected from alicyclic groups and 4-6 membered heteroalicyclic groups; R ３ The number of each R is 1, 2, or 3, and each R ３ These are independently H, halogen, -CN, -OH, and -NO. ２ , -NR ７ R ８ , C １－４ Alkyl, C １－４ Alkyl halogens, C １－４ Alkoxy, C ３－６ Selected from alicyclic groups and 4-6 membered heteroalicyclic groups; R ７ and R ８ Each time it appears, H, C １－６ Alkyl, C １－４ Alkyl halogens, C １－４ Each alkoxy is independently selected, or R ７ , R ８ and together with the N atoms linked to them, they form a 3- to 6-membered ring; Ring A is a nitrogen-containing aromatic ring, and 1) G1 = NR ４ G2 = CR ５ ; or 2) G1 = CR ４ G2 = NR ５ ; or 3) G1 = CR ４ , G2 = O or S, where R ４ , R ５ H, halogen, -CN, -OH, -NO ２ , C １－６ Alkyl, C １－６ Alkyl halogens, C １－６ Each alkoxy is independently selected, or R ４ , R ５ These atoms, together with the atoms linked to them, form a 3- to 8-membered ring.

2. The compound of formula (I) is the compound according to claim 1, having one of the following structures, or an isotope-labeled compound thereof, or an optical isomer, geometric isomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof. 【Chemistry 2】 (In the formula, n, L, R １ , R ２ , R ３ , R ４ , R ５ (This is as described in claim 1.) 【Transformation 3】 (In the formula, n, L, R １ , R ２ , R ３ , R ４ , R ５ (This is as described in claim 1.) 【Chemistry 4】 (In the formula, n, L, R １ , R ２ , R ３ , R ４ (This is as described in claim 1.) 【Transformation 5】 (In the formula, n, L, R １ , R ２ , R ３ The following is described in claim 1. Ring B is a 3- to 8-membered ring containing one N atom, and R ａ H, halogen, -CN, -OH, -NO ２ , C １－６ Alkyl, C １－６ Alkyl halogens, C １－６ (Selected from alkoxy.)

3. n = 1 or 2 A compound according to claim 1, or an isotope-labeled compound thereof, or an optical isomer, geometric isomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

4. R ２ and R ３ H, CH ３ , independently selected from F, Cl and Br, A compound according to claim 1, or an isotope-labeled compound thereof, or an optical isomer, geometric isomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

5. R １ H, halogen, -OH, -NO ２ -CN, -SF ５ , -SH, -S-C １－４ Alkyl, C １－６ Alkyl, C １－６ Alkyl halogens, C １－６ Alkoxy, C １－６ Alkoxy halogenated compounds, C ３－６ Alicyclic group, 4-6 member heteroalicyclic group, C ５－８ Aryl, 5-10 member heteroaryl, -C １－４ Alkyl-(C) ３－７ alicyclic group), -C １－４ Alkyl-(3-10 membered heteroalicyclic group), -C １－４ Alkyl-(C) ５－８ Aryl), -C １－４ Alkyl-(5-10 member heteroaryl),-N(R １０ ) (Caution １１ ) is selected from, where the -S-C １－４ Alkyl, C １－６ Alkyl, C １－６ Alkyl halogens, C １－６ Alkoxy, C １－６ Alkoxy halogenated compounds, C ３－６ Alicyclic group, 4-6 member heteroalicyclic group, C ５－８ Aryl, 5-10 member heteroaryl, -C １－４ Alkyl-(C) ３－７ alicyclic group), -C １－４ Alkyl-(3-10 membered heteroalicyclic group), -C １－４ Alkyl-(C) ５－８ Aryl), -C １－４ Each alkyl- (5-10 member heteroaryl) can have 0, 1, 2, 3, or 4 R atoms. １ａ Replaced with R １ａ These are halogen, -OH, -NO ２ ,-CN, oxo, C １－４ Alkyl, C １－４ Alkyl halogens, C １－４ Alkoxy, C １－４ Alkoxy halogenated compounds, C ３－７ Alicyclic group, 3-10 membered heteroalicyclic group, C ５－８ Independently selected from aryls and 5- to 7-membered heteroaryls; Furthermore, R １０ , R １１ and R １２ Each time it appears, H, C １－６ Alkyl, C １－６ Alkyl halogens, C ３－７ Each is independently selected from the group consisting of alicyclic groups and 3- to 10-membered heteroalicyclic groups, where each option within the group is halogen, -OH, -NH ２ , oxo, C １－４ Alkyl, C １－４ Hydroxyalkyl, C １－４ Alkyl halogens, C １－４ Alkoxy and C １－４ It is optionally substituted with 0, 1, 2, 3, or 4 substituents independently selected from the group consisting of alkoxy halogens, or R １０ and R １１ These, together with the atoms linked to them, form a 3- to 8-membered ring. A compound according to claim 1, or an isotope-labeled compound thereof, or an optical isomer, geometric isomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

6. R １ R is selected from H, halogen, -OH, methyl, ethyl, propyl, butyl, pentyl, hexyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, pyrrolyl, morpholinyl, pyridyl, and pyrazolyl, where each R is optionally one or two １ａ It is replaced by and R １ａ These are halogen, -OH, -NO ２ ,-CN, oxo, C １－４ Alkyl, C １－４ Alkyl halides, and C １－４ Independently selected from alkoxy halogens, A compound according to claim 5, or an isotope-labeled compound thereof, or an optical isomer, geometric isomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

7. The compound is selected from the following compounds 1-4, 6-7, 9-15, 22-23, 25-34, 37-76, as described in claim 1, or an isotope-labeled compound thereof, or an optical isomer, geometric isomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof. 【Transformation 6】 【Transformation 7】 【Transformation 8】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】

8. A compound according to claim 1, or an isotope-labeled compound thereof, or an optical isomer, geometric isomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, One or more pharmaceutically acceptable carriers, adjuvants, or excipients, A pharmaceutical composition containing the following:

9. The use of the compound described in claim 1, or an isotope-labeled compound thereof, or an optical isomer, geometric isomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described in claim 8, in the manufacture of a pharmaceutical for treating a TGF-β related disease or disorder.

10. The use according to claim 9, wherein the TGF-β-related diseases and conditions are selected from cancer, viral infection, chronic nephritis, acute nephritis, diabetic nephropathy, osteoporosis, arthritis, wound healing, scarring, ulcers, corneal wounds, valvular stenosis, congestive cardiac necrosis, neurological dysfunction, Alzheimer's syndrome, peritoneal or subcutaneous adhesions, arteriosclerosis, dermatofibrosis and skin aging due to fat loss, skeletal disorders or chondrocyte disorders, hypophosphatemic disorders and organ fibrosis.

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