TGF-β inhibitor compounds and uses thereof

Abstract

The present application relates to TGF-β inhibitor compounds and uses thereof. Specifically, the present application provides a compound of formula (I) or formula (II), 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. The present application also provides the use of the compound in medicine. [Formula 1] TIFF2025526717000069.tif44153

Description

[Technical Field]

[0001] This application provides novel pharmaceutically active compounds for use in inhibiting fibroblast growth factor receptors (TGFs). This application further relates to compositions comprising the compounds and the use of the compounds and compositions in the manufacture of medicaments 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 cell surface receptor signaling pathways. TGF-β belongs to the transforming growth factor β superfamily (TGF-βs) along with various related proteins such as activins, inhibins, and bone morphogenetic proteins.

[0003] TGF-β has three major cellular receptors: type I receptor (TGFβRl), type II receptor (TGFβR2), and type III receptor (TGFβR3). Type I and type II receptors are transmembrane serine kinases / transmembrane threonine kinases, and both simultaneously transduce signals. Type III receptors do not transduce signals, but their function is primarily to transmit TGF-β to type II receptors and indirectly influence signal transduction by providing ligands to type II receptors. There are three subtypes of TGF-β (TGF-βl, TGF-β2, and TGF-β3), which are present in most cells along with their receptors. Each subtype is expressed in a tissue-specific and developmentally regulated manner.

[0004] TGF-β and related factors, such as activators, regulate numerous cellular processes, including cell cycle inhibition of epithelial cells and hematopoietic cells, control of mesenchymal cell proliferation and differentiation, inflammatory cell recruitment, immunosuppression, wound healing, and extracellular matrix production. Studies have shown that abnormal TGF-β signaling is associated with many diseases, including cancer, renal fibrosis, liver fibrosis, pulmonary fibrosis, viral infection, chronic nephritis, acute nephritis, diabetic nephropathy, osteoporosis, arthritis, wound healing, ulcers, corneal wounds, valvular stenosis, hyperemic cardiac necrosis, nerve function damage, Alzheimer's syndrome, peritoneal or subcutaneous adhesions, arteriosclerosis, and tumor metastasis 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] (1) Compound In a first aspect, the present application provides 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: [ka] (wherein n=1, 2, 3; L is (C=O), (O=S=O), ((C=O)-CH), CH or a connecting bond; R1 is H, halogen, -OH, -NO2, -CN, -SF5, -SH, -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkyl halides, 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 Dicycloaliphatic groups, 6- to 12-membered dicycloheteroalicyclic groups, C 8―158-15-membered tricycloaliphatic group, 8-15-membered tricycloheteroaliphatic group, C 5-8 Aryl, 5-10 membered heteroaryl, C 7-11 Dicycloaryl, 7-11 membered dicycloheteroaryl, -C 1-4 Alkyl-(C 3-7 alicyclic group), -C 1-4 Alkyl-(3- to 10-membered heteroalicyclic group), -C 1-4 Alkyl-(C 6-12 Dicycloaliphatic group), -C 1-4 Alkyl-(6- to 12-membered dicycloheteroalicyclic group), -C 1-4 Alkyl-(C 8―15 -membered tricycloaliphatic group), -C 1-4 Alkyl-(8- to 15-membered tricycloheteroalicyclic group), -C 1-4 Alkyl-(C 5-8 aryl), -C 1-4 Alkyl-(5-10 membered heteroaryl), -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 wherein said -SC is selected from 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkyl halides, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-7Alicyclic group, 3- to 10-membered heteroalicyclic group, C 6-12 Dicycloaliphatic groups, 6- to 12-membered dicycloheteroalicyclic groups, C 8―15 8-15-membered tricycloaliphatic group, 8-15-membered tricycloheteroaliphatic group, C 5-8 Aryl, 5-10 membered heteroaryl, C 7-11 Dicycloaryl, 7-11 membered dicycloheteroaryl, -C 1-4 Alkyl-(C 3-7 alicyclic group), -C 1-4 Alkyl-(3- to 10-membered heteroalicyclic group), -C 1-4 Alkyl-(C 6-12 Dicycloaliphatic group), -C 1-4 Alkyl-(6- to 12-membered dicycloheteroalicyclic group), -C 1-4 Alkyl-(C 8―15 -membered tricycloaliphatic group), -C 1-4 Alkyl-(8- to 15-membered tricycloheteroalicyclic group), -C 1-4 Alkyl-(C 5-8 aryl) and -C 1-4 Alkyl-(5-10 membered heteroaryl) is 0, 1, 2, 3 or 4 R 1a are optionally substituted with R 1a are halogens, -OH, -NO2, -CN, -SF5, -SH, -SC 1-4 Alkyl, oxo, C 1-4 Alkyl, C 1-4 Alkyl halides, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, 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 )(R14 ), -C(=O)-R 15 , -C(=O)-OR 15 , -OC(=O)R 15 , -N(R 13 )(S(=O)2R 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 For each occurrence, H, C 1-6 Alkyl, C 1-6 Alkyl halides, C 3-7 Alicyclic group, 3- to 10-membered heteroalicyclic group, C 5-8 Aryl, 5-7 membered heteroaryl, C 7-11 Dicycloaryl, 7-11 membered dicycloheteroaryl, -C 1-4 Alkyl-(C 3-7 alicyclic group), -C 1-4 Alkyl-(3- to 10-membered heteroalicyclic group), -C 1-4 Alkyl-(C 6-12 Dicycloaliphatic group), -C 1-4 Alkyl-(6- to 12-membered dicycloaliphatic group), -C 1-4 Alkyl-(C 8-15 -membered tricycloaliphatic group), -C 1-4 Alkyl-(8- to 15-membered tricycloaliphatic group), -C 1-4 Alkyl-(C 5-8 aryl) and -C 1-4 alkyl-(5-10 membered heteroaryl), where each option within the group is selected from halogen, —OH, —NH2, —NH(CH3), —N(CH3)2, —CN, —NO2, —SF5, —SH, —SC 1-4 Alkyl, oxo, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Alicyclic group, 3- to 10-membered heteroalicyclic group, C 5-8Aryl, 5-7 membered heteroaryl, C 7-11 Dicycloaryl, 7-11 membered 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 halides, C 1-4 Alkoxy and C 1-4 optionally substituted with 0, 1, 2, 3, or 4 substituents each independently selected from the group consisting of halogenated alkoxy, or R 10 and R 11 form a 3- to 14-membered ring together with the atoms to which they are connected, or R 13 and R 14 form a 3- to 14-membered ring together with the atoms connected to them; The number of R2 is 1, 2, 3 or 4, and each R2 is independently H, halogen, -CN, -OH, -NO2, -NR7R8, C 1-4 Alkyl, C 1-4 Alkyl halides, C 1-4 Alkoxy, C 3-6 selected from alicyclic groups and 4- to 6-membered heteroalicyclic groups; The number of R3 is 1, 2 or 3, and each R3 is independently H, halogen, -CN, -OH, -NO2, -NR7R8, C 1-4 Alkyl, C 1-4 Alkyl halides, C 1-4 Alkoxy, C 3-6 selected from alicyclic groups and 4- to 6-membered heteroalicyclic groups; R7 and R8 are H, C, 1-6 Alkyl, C 1-4 Alkyl halides, C 1-4 alkoxy, or together with R7, R8 and the N atom connected thereto, form a 3- to 6-membered ring; 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 and R5 are H, halogen, -CN, -OH, -NO2, C 1-6 Alkyl, C 1-6 Alkyl halides, C 1-6 or R4 and R5 together with the atoms connected thereto form a 3- to 8-membered ring.

[0007] In a second aspect, the present application provides a compound of formula (II), 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: [ka] (wherein m=0 or 1; R1 is C 5-16 aryl, 5- to 16-membered heteroaryl, 5-16 Aryl and 5- to 16-membered heteroaryl are each 1, 2, 3, or 4 R 1b are optionally substituted with R 1b are halogens, -OH, -NO2, -CN, -SF5, -SH, and -SC, respectively. 1-4 Alkyl, oxo, C 1-4 Alkyl, C 1-4 Alkyl halides, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, 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)2R 14 ), -S(=O)2-N(R 13 )(R 14 ), -SR 15 and -OR 15 are independently selected from; R 13 , R 14 and R 15 For each occurrence, H, C 1-6 Alkyl, C 1-6 Alkyl halides, C 3-7 Alicyclic group, 3- to 10-membered heteroalicyclic group, C 5-8 Aryl, 5-7 membered heteroaryl, C 7-11 Dicycloaryl, 7-11 membered dicycloheteroaryl, -C 1-4 Alkyl-(C 3-7 alicyclic group), -C 1-4 Alkyl-(3- to 10-membered heteroalicyclic group), -C 1-4 Alkyl-(C 6-12 Dicycloaliphatic group), -C 1-4 Alkyl-(6- to 12-membered dicycloaliphatic group), -C 1-4 Alkyl-(C 8-15 -membered tricycloaliphatic group), -C 1-4 Alkyl-(8- to 15-membered tricycloaliphatic group), -C 1-4 Alkyl-(C 5-8 aryl) and -C 1-4 alkyl-(5-10 membered heteroaryl), where each option within the group is selected from halogen, —OH, —NH2, —NH(CH3), —N(CH3)2, —CN, —NO2, —SF5, —SH, —SC 1-4 Alkyl, oxo, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Alicyclic group, 3- to 10-membered heteroalicyclic group, C 5-8Aryl, 5-7 membered heteroaryl, C 7-11 Dicycloaryl, 7-11 membered 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 halides, C 1-4 Alkoxy and C 1-4 optionally substituted with 0, 1, 2, 3, or 4 substituents each independently selected from the group consisting of halogenated alkoxy, or R 13 and R 14 form a 3- to 14-membered ring together with the atoms connected to them; The number of R2 is 1, 2, 3 or 4, and each R2 is H, halogen, -CN, -OH, -NO2, -NR7R8, C 1-4 Alkyl, C 1-4 Alkyl halides, C 1-4 Alkoxy, C 3-6 R7 and R8 are independently selected from an alicyclic group and a 4- to 6-membered heteroalicyclic group, 1-6 Alkyl, C 1-4 Alkyl halides, C 1-4 or form a 3- to 6-membered ring together with R7, R8 and the N atom connected thereto. DETAILED DESCRIPTION OF THE INVENTION

[0008] Unless otherwise specified, various technical terms used herein should be interpreted according to the meanings that are commonly understood by those skilled in the art. To avoid any ambiguity, certain terms are defined below.

[0009] Unless otherwise specified, the term "compound" as used herein, such as "compound of formula (I)," "compound of formula (II)," or "compound of the present application," also includes any optical isomer, geometric isomer, tautomer, or mixture of isomers thereof.

[0010] The term "optical isomer" means that when a compound has one or more chiral centers, each chiral center can have an R or S configuration, and the various isomers formed thereby are optical isomers. Optical isomers include all diastereomers, enantiomers, meso forms, racemates, or mixtures thereof. For example, optical isomers can be separated by chiral chromatography columns or chiral synthesis.

[0011] The term "geometric isomer" means that when a compound has a double bond, the compound exists as cis, trans, E, and Z isomers. Geometric isomers include cis, trans, E, Z isomers or mixtures thereof.

[0012] The term "tautomer" refers to an isomer formed by the rapid displacement 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 that under certain conditions, they can reach a state of equilibrium and coexist.

[0013] Unless otherwise specified, the terms "compound of formula (I)," "compound of formula (II)," "compound of the present application," and the like used herein also include isotopically labeled compounds in which one or more atoms in the compound are replaced with their isotope atoms.

[0014] Examples of isotopes that may be present in compounds of this application include isotopes of hydrogen (e.g., 2 H(D) and 3 H(T)), isotopes of carbon (e.g., 11 C. 13 C and 14 C), isotopes of chlorine (e.g., 36 Cl), isotopes of fluorine (e.g., 18 F), isotopes of iodine (e.g., 123 I and 125 I), isotopes of nitrogen (e.g., 13 N and 15 N), isotopes of oxygen (e.g., 15O. 17 O and 18 O), and isotopes of sulfur (e.g., 35 S).

[0015] The isotopically labeled compounds (e.g., compounds containing radioactive isotopes) can be used in drug and / or substrate tissue distribution studies. Due to their ease of introduction and convenient means of detection, the radioactive isotopes deuterium (i.e., D) and carbon-14 (i.e., 14 C) is particularly useful for this purpose.

[0016] Substitution with heavier isotopes such as deuterium (i.e., D) can provide several therapeutic advantages and is therefore preferred in certain circumstances. The therapeutic advantages may result, for example, from greater metabolic stability (e.g., increased in vivo half-life or reduced dose requirements). Thus, in some embodiments, the compounds of the present application are isotopically labeled compounds, where H, at each occurrence, is optionally replaced with D.

[0017] Positron-emitting isotopes (e.g., 11 C. 18 F, 15 O and 13 N) can be used in Positron Emission Topography (PET) studies to detect substrate receptor occupancy.

[0018] Such isotopically labeled compounds may generally be prepared by conventional techniques known to those skilled in the art, or by substituting an appropriate isotopically labeled reagent for a conventionally used non-labeled reagent.

[0019] The compounds of the present application can exist as their pharmaceutically acceptable salts.

[0020] The term "pharmaceutically acceptable" means that the corresponding compound, carrier, or molecule is suitable for administration to humans. Preferably, this term refers to those that can be used in mammals (preferably humans) as approved by regulatory agencies such as CFDA (China), EMEA (Europe), and FDA (USA).

[0021] The pharmaceutically acceptable salts include the acid addition salts and base addition salts thereof. Suitable acid addition salts are formed with acids which form non-toxic salts. Examples include acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate / carbonate, hydrogensulfate / sulfate, borate, camphorsulfonate, citrate, cyclohexanaminesulfonate, ethanedisulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, 2-(4-hydroxybenzyl)benzoate, hydrogen chloride / chloride, hydrogen bromide / bromide, hydrogen iodide / iodide. Examples of suitable base addition salts include, but are not limited to, 2-hydroxyethylsulfonate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthalene, 2-naphthalenesulfonate, nicotinate, nitrate, lactate, oxalate, hexadecanoate, phosphate / hydrogenphosphate / dihydrogenphosphate, pyroglutamate, glucarate, stearate, salicylate, tannate, tartrate, toluenesulfonate, and trifluoroacetate. Suitable base addition salts are formed with 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. Acid and alkali hemisalts, such as sulfate hemisalts and calcium hemisalts, can also be formed. For a description of suitable salts, see 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.

[0022] The compounds of the present application can also exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, etc. The compounds may also exist in one or more crystalline states, i.e., polycrystalline forms, or they may exist as amorphous solids. All of these forms are included within the scope of the present application.

[0023] The present application further includes prodrugs of the compounds of the present application. The term "prodrug" refers to a derivative that is converted into the compounds of the present application in vivo under physiological conditions such as enzymes, gastric acid, etc., for example, by reactions such as oxidation, reduction, hydrolysis, etc., each of which is carried out under enzyme catalysis. Therefore, some derivatives of the compounds of the present application themselves have very little or no pharmacological activity, but can be converted into the compounds of the present application having the desired activity when administered to or in the body.

[0024] The present application further includes metabolites of the compounds of the present application. The term "metabolite" means any molecule derived in a cell or organism, preferably a human, from any compound of the present application.

[0025] As used herein, the term "substituted" means that one or more (preferably 1 to 5, more preferably 1 to 3, and most preferably 1 or 2) hydrogen atoms in a group are independently replaced with a corresponding number of substituents.

[0026] As used herein, the term "independent" means that when there are more than one chemical groups or substituents, these chemical groups or substituents may be the same or different.

[0027] As used herein, the terms "optionally" or "optionally" indicate that the event described thereby may or may not occur. For example, a group being "optionally substituted" means that the group may be unsubstituted or may be substituted.

[0028] The term "halogen" or "halo" means -F, -Cl, -Br, or -I.

[0029] As used herein, the term "alkyl" means a saturated aliphatic hydrocarbon, including straight and branched chains. In some embodiments, an alkyl group has 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" means a straight or branched chain group of atoms having from 1 to 8 carbon atoms. 1-8 The term "alkyl" is defined as "C 1-6 Alkyl," "C 1-3 Examples of alkyl 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, and the like. An alkyl group may be optionally substituted with one or more (e.g., 1 to 5) suitable substituents.

[0030] As used herein, the term "alkenyl" refers to an aliphatic hydrocarbon having at least one carbon-carbon double bond, including straight and branched chains having at least one carbon-carbon double bond. In some embodiments, alkenyl 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 2-8The term "alkenyl" refers to a straight or branched chain unsaturated group (having at least one carbon-carbon double bond) of 2 to 8 carbon atoms. The double bond may not be the point of attachment to another group, or it may be the point of attachment to another group. Alkenyl includes, but is not limited to, vinyl, 1-propenyl, 2-propenyl, 2-methyl-2-propenyl, butenyl, pentenyl, 3-hexenyl, and the like. An alkenyl group may be optionally substituted with one or more (e.g., 1 to 5) suitable substituents. When a compound of formula (I) contains an alkenyl group, the alkenyl group may exist in the pure E form, the pure Z form, or any mixture thereof.

[0031] As used herein, the term "alkynyl" refers to an aliphatic hydrocarbon having at least one carbon-carbon triple bond, including straight and branched chains having at least one carbon-carbon triple bond. In some embodiments, alkynyl groups 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 2-8 The term "alkynyl" means a straight or branched chain unsaturated group (having at least one carbon-carbon triple bond) of 2 to 8 carbon atoms. The triple bond may or may not be the point of attachment to another group. Alkynyl includes, but is not limited to, ethynyl, 1-propynyl, 2-propynyl, 2-methyl-2-propynyl, butynyl, pentynyl, 3-hexynyl, and the like. An alkynyl group may be optionally substituted with one or more (e.g., 1 to 5) suitable substituents.

[0032] As used herein, "C 3-8 The term "alicyclic group" means an alicyclic group having 3 to 8 carbon atoms forming a ring. 3-7 The term "alicyclic group" means an alicyclic group having 3 to 7 carbon atoms forming a ring. 3-6The term "alicyclic group" means an alicyclic group having 3 to 6 carbon atoms forming the ring. The alicyclic group may be a monocyclic ring. The definition of alicyclic group also includes unsaturated non-aromatic alicyclic groups. Examples of alicyclic groups are, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclohexadienyl, cyclopentenyl, cycloheptenyl, and cyclooctenyl. An alicyclic group may be optionally substituted with one or more suitable substituents.

[0033] As used herein, "C 6-12 The term "dicycloaliphatic" refers to an alkyl having 6 to 12 carbon atoms forming the ring and having two rings. Dicycloaliphatic groups may be fused or may include bridged bicyclic alicyclic systems.

[0034] As used herein, "C 8―15 The term "membered tricycloaliphatic group" means an alkyl having 8 to 15 carbon atoms forming the ring and having three rings. Tricycloaliphatic groups may be fused or bridged.

[0035] As used herein, the term "n-membered heteroalicyclic group" refers to an alicyclic group having m ring-forming carbon atoms and (nm) ring-forming heteroatoms, wherein the heteroatoms are selected from O, S, and N. For example, the term "4- to 8-membered heteroalicyclic group" means that the substituents of the heteroalicyclic group contain a total of 4 to 8 ring atoms, at least one of which is a heteroatom. The term "4- to 6-membered heteroalicyclic group" means that the substituents of the heteroalicyclic group contain a total of 4 to 6 ring atoms, at least one of which is a heteroatom. The term "3- to 10-membered heteroalicyclic group" means that the substituents of the heteroalicyclic group contain a total of 3 to 10 ring atoms, at least one of which is a heteroatom. The term "n-membered dicycloheteroalkyl" refers to a dicycloheteroalkyl having m ring-forming carbon atoms and (nm) ring-forming heteroatoms, wherein the heteroatoms are selected from O, S, and N.Examples of heteroalicyclic groups include azetidine, thietane, dihydrofuran, dihydrothiophene, tetrahydrothiophene, tetrahydrofuranyl, tetrahydrotriazine, tetrahydropyrazolyl, tetrahydrooxazine, tetrahydropyrimidyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, octahydrobenzothiazole, imidazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiazinyl, tetrahydrothiadiazine, tetrahydrooxazolyl, morpholinyl, oxetanyl, tetrahydro Examples of heteroalicyclic groups include, but are 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. Heteroalicyclic groups may be optionally substituted with one or more suitable substituents.

[0036] As used herein, "aryl" refers to a 5- to 16-membered carbocyclic aromatic group having at least one ring with a conjugated π-electron system. Aryl may have conjugated or fused rings and may be unsubstituted or substituted as described. Examples of aryl include phenyl, naphthyl, anthracenyl, phenanthryl, azulenyl, biphenyl, and the like. As used herein, the term "C 5-16 "Aryl" means an aryl having an aromatic ring containing 5 to 16 carbon atoms. 5-8 The term "aryl" means an aryl having an aromatic ring with 5, 6, 7 or 8 carbon atoms, for example, phenyl.

[0037] As used herein, "heteroaryl" refers to a 5- to 16-membered aromatic group having at least one ring with a conjugated π-electron system and containing 1 to 4 heteroatoms such as N, O, or S. Heteroaryls can have conjugated or fused rings and can be unsubstituted or substituted as described. Examples of heteroaryl include thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolyl, isoindolyl, indolizinyl, and benzofuranyl. furanyl, benzothienyl, indazolyl, benzimidazolyl, benzthiazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl.

[0038] As used herein, the term "n-membered heteroaryl" refers to a heteroaryl having m carbon atoms forming an aromatic ring and (nm) heteroatoms forming the 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, pyridazinyl, pyrimidinyl, and pyrazinyl. Heteroaryls may be optionally substituted with one or more suitable substituents.

[0039] As used herein, "C 7-11 The term "dicycloaryl" means a dicycloaryl having 7 to 11 carbon atoms, for example, naphthyl, indenyl, etc. A dicycloaryl may be optionally substituted with one or more suitable substituents.

[0040] As used herein, the term "n-membered dicycloheteroaryl" refers to a dicycloheteroaryl having m carbon atoms forming an aromatic bicyclic ring and (nm) heteroatoms forming an aromatic bicyclic ring, 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, benzothiazole groups, etc. Dicycloheteroaryls may be optionally substituted with one or more suitable substituents.

[0041] As used herein, the term "11- to 15-membered tricyclo" includes, but is not limited to, acridine, etc. The 11- to 15-membered tricyclo may be optionally substituted with one or more suitable substituents.

[0042] As used herein, the term "halogenated alkyl" refers to an alkyl group having one or more halogen substituents (at most a perhalogenated alkyl, i.e., every hydrogen atom of the alkyl group is replaced with a halogen atom). For example, "C 1-6The term "halogenated alkyl" refers to a C alkyl group having one or more halogen substituents. 1-6 It refers to an alkyl group (which may be at most a perhalogenated alkyl group, i.e., each hydrogen atom of the alkyl group is replaced with a halogen atom). Another example is "C 1-4 The term "halogenated alkyl" refers to a C alkyl group having one or more halogen substituents. 1-4 "C" means an alkyl group (which may be at most a perhalogenated alkyl group, i.e., each hydrogen atom of the alkyl group is replaced with a halogen atom). 1-3 The term "halogenated alkyl" refers to a C alkyl group having one or more halogen substituents. 1-3 "C" means an alkyl group (which may be at most a perhalogenated alkyl group, i.e., each hydrogen atom of the alkyl group is replaced with a halogen atom). 1-2 The term "halogenated alkyl" refers to a C alkyl group having one or more halogen substituents. 1-2 It refers to an alkyl group (i.e., methyl or ethyl) that is at most a perhalogenated alkyl, i.e., each hydrogen atom of the alkyl group is replaced with a halogen atom. By way of further example, the term "C1 halogenated alkyl" refers to a methyl group having one, two, or three halogen substituents. Examples of halogenated alkyl groups include CF3, C2F5, CHF2, CH2F, CH2CF3, CH2Cl, and the like.

[0043] As used herein, the term "alkoxy" refers to an alkyl bonded to an oxygen atom by a single bond. The bond between the alkoxy and the molecule is the oxygen atom. The alkoxy can be represented as alkyl-O-. 1-6 The term "alkoxy" means a straight or branched chain alkoxy group containing 1 to 6 carbon atoms. 1-6 The term "alkoxy" is defined as "C 1-3 The term "alkoxy" includes, but is not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, hexyloxy, and the like. An alkoxy may be optionally substituted with one or more suitable substituents.

[0044] As used herein, the term "3- to 14-membered ring" means a saturated or unsaturated ring system having 3 to 14 atoms forming the ring.

[0045] In this specification, numerical ranges relating to the number of substituents, the number of carbon atoms, and the number of ring atoms are equivalent to listing all integers within the range one by one, and the ranges are merely abbreviated notations. For example, "4 to 6-membered" indicates 4, 5, or 6-membered, "5 to 7-membered" indicates 5, 6, or 7-membered, "7 to 11-membered" indicates 7, 8, 9, 10, or 11-membered, "4 to 8-membered" indicates 4, 5, 6, 7, or 8-membered, "3 to 10-membered" indicates 3, 4, 5, 6, 7, 8, 9, or 10-membered, "3 to 14-membered" indicates 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14-membered, and "C 1-3 " indicates one carbon atom (C1), two carbon atoms (C2) or three carbon atoms (C3), and "C 1-4 " indicates one carbon atom (C1), two carbon atoms (C2), three carbon atoms (C3) or four carbon atoms (C4), and "C 3-6 " indicates three carbon atoms (C3), four carbon atoms (C4), five carbon atoms (C5) or six carbon atoms (C6), and "C 3-8 " indicates 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), and "C 5-7 " indicates five carbon atoms (C5), six carbon atoms (C6) or seven carbon atoms (C7), and "C 7-11 " is a molecule with seven carbon atoms (C7), eight carbon atoms (C8), nine carbon atoms (C9), and ten carbon atoms (C 10 ) or 11 carbon atoms (C 11 ) and the like. Thus, numerical ranges relating to the number of substituents, the number of carbon atoms, and the number of ring atoms also include any one of the subranges, and each subrange is also considered to be disclosed herein. (1) Compound of formula (I)

[0046] In the above formula (I), R1 may be any substituent commonly used in organic chemistry and is not particularly limited.

[0047] In some embodiments, R is C 1-6 alkyl, 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, hexyl.

[0048] In some embodiments, R is C 3-7 It is an alicyclic group, for example, R1 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclohexadienyl, cyclopentenyl, cycloheptenyl.

[0049] In some embodiments, R1 is a 3-10 membered heteroalicyclic group, e.g., R1 is selected from the group consisting of azetidine, thietane, dihydrofuran, dihydrothiophene, tetrahydrothiophene, tetrahydrofuranyl, tetrahydrotriazine, tetrahydropyrazolyl, tetrahydrooxazine, tetrahydropyrimidyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, octahydrobenzothiazole, imidazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, thiazolidinyl, and thiazolidinyl. morpholinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiazinyl, tetrahydrothiadiazine, tetrahydrooxazolyl, morpholinyl, oxetanyl, tetrahydrodioxazine, oxazine, oxathiazine, quinuclidinyl, chromanyl, isochromanyl, dihydrobenzodioxanyl, benzodioxole, benzoxazine, dihydroindolyl, dihydrobenzofuranyl, tetrahydroquinolyl, isochroman, dihydro-1H-isoindolyl, oxepane, thiepane, azepane.

[0050] In some embodiments, R1 is H, halogen, -OH, -NO2, -CN, -SF5, or -SH.

[0051] In some embodiments, R1 is -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkyl halides, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-8 Alkenyl, C 2-8 alkynyl.

[0052] In some embodiments, R is C 5-8 Aryl (e.g., phenyl), 5- to 10-membered heteroaryl (e.g., furyl, thienyl, pyrrolyl, thiazolyl, pyrazolyl, imidazolyl, pyridyl, pyranyl, pyridazinyl, pyrimidinyl, pyrazinyl, etc.), -C 1-4 Alkyl-(C 5-8 aryl), -C 1-4 alkyl-(5-10 membered heteroaryl).

[0053] 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 12where R 10 , R 11 and R 12 For each occurrence, H, C 1-6 Alkyl, C 1-6 Alkyl halides, C 3-7 Alicyclic group, 3- to 10-membered heteroalicyclic group, C 5-8 Aryl, 5-7 membered heteroaryl, C 7-11 Dicycloaryl, 7-11 membered dicycloheteroaryl, -C 1-4 Alkyl-(C 3-7 alicyclic group), -C 1-4 Alkyl-(3- to 10-membered heteroalicyclic group), -C 1-4 Alkyl-(C 6-12 Dicycloaliphatic group), -C 1-4 Alkyl-(6- to 12-membered dicycloaliphatic group), -C 1-4 Alkyl-(C 8-15 -membered tricycloaliphatic group), -C 1-4 Alkyl-(8- to 15-membered tricycloaliphatic group), -C 1-4 Alkyl-(C 5-8 aryl) and -C 1-4 alkyl-(5-10 membered heteroaryl), where each option within the group is selected from halogen, —OH, —NH2, —NH(CH3), —N(CH3)2, —CN, —NO2, —SF5, —SH, —SC 1-4 Alkyl, oxo, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Alicyclic group, 3- to 10-membered heteroalicyclic group, C 5-8 Aryl, 5-7 membered heteroaryl, C 7-11 Dicycloaryl, 7-11 membered 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 halides, C 1-4 Alkoxy and C 1-4optionally substituted with 0, 1, 2, 3, or 4 substituents each independently selected from the group consisting of halogenated alkoxy, or R 10 and R 11 form a 3- to 14-membered ring together with the atoms to which they are attached.

[0054] In some embodiments, R1 is -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkyl halides, 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 Dicycloaliphatic groups, 6- to 12-membered dicycloheteroalicyclic groups, C 5-8 Aryl, 5-10 membered heteroaryl, C 7-11 dicycloaryl, 7- to 11-membered dicycloheteroaryl, wherein said -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkyl halides, 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 Dicycloaliphatic groups, 6- to 12-membered dicycloheteroalicyclic groups, C 5-8 Aryl, 5-10 membered heteroaryl, C 7-11 Dicycloaryl and 7- to 11-membered dicycloheteroaryl are unsubstituted or optionally each substituted with 1, 2, 3, or 4 R 1a and R 1a are independently halogen, -OH, -NH2, -NH(CH3), -N(CH3)2, -CN, -NO2, -SF5, -SH, -SC 1-4 Alkyl, oxo, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7Alicyclic group, 3- to 10-membered heteroalicyclic group, C 5-8 Aryl, 5-7 membered heteroaryl, C 7-11 Bicycloaryl, 7-11 membered 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 halides, C 1-4 Alkoxy and C 1-4 halogenated alkoxy.

[0055] It should be understood that any of the exemplary groups listed for R above are optionally substituted, i.e., any of the groups listed for R above can be optionally substituted with 0, 1, 2, 3, or 4 R, depending on the context. 1a and R 1a are halogens, -OH, -NO2, -CN, -SF5, -SH, -SC 1-4 Alkyl, oxo, C 1-4 Alkyl, C 1-4 Alkyl halides, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, 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)R15 , -N(R 13 )(S(=O)2R 14 ), -S(=O)2-N(R 13 )(R 14 ), -SR 15 and -OR 15 are independently selected from, where R 13 , R 14 and R 15 For each occurrence, H, C 1-6 Alkyl, C 1-6 Alkyl halides, C 3-7 Alicyclic group, 3- to 10-membered heteroalicyclic group, C 5-8 Aryl, 5-7 membered heteroaryl, C 7-11 Dicycloaryl, 7-11 membered dicycloheteroaryl, -C 1-4 Alkyl-(C 3-7 alicyclic group), -C 1-4 Alkyl-(3- to 10-membered heteroalicyclic group), -C 1-4 Alkyl-(C 6-12 Dicycloaliphatic group), -C 1-4 Alkyl-(6- to 12-membered dicycloaliphatic group), -C 1-4 Alkyl-(C 8-15 -membered tricycloaliphatic group), -C 1-4 Alkyl-(8- to 15-membered tricycloaliphatic group), -C 1-4 Alkyl-(C 5-8 aryl) and -C 1-4 alkyl-(5-10 membered heteroaryl), where each option within the group is selected from halogen, —OH, —NH2, —NH(CH3), —N(CH3)2, —CN, —NO2, —SF5, —SH, —SC 1-4 Alkyl, oxo, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Alicyclic group, 3- to 10-membered heteroalicyclic group, C 5-8 Aryl, 5-7 membered heteroaryl, C 7-11 Dicycloaryl, 7-11 membered 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 halides, C 1-4 Alkoxy and C 1-4 optionally substituted with 0, 1, 2, 3, or 4 substituents each independently selected from the group consisting of halogenated alkoxy, or R 13 and R 14 form a 3- to 14-membered ring together with the atoms to which they are connected.

[0056] In some preferred embodiments, R is selected from methyl, ethyl, propyl, isopropyl, and cyclobutyl. The methyl, ethyl, propyl, isopropyl, and cyclobutyl are optionally substituted with zero, one, or two substituents independently selected from the group consisting of methyl, ethyl, cyclopentyl, cyclopropyl, -CN, -OH, morpholinyl, and piperidinyl, and the substituents are optionally substituted with zero, one, or two substituents independently selected from the group consisting of methyl, ethyl, cyclopentyl, cyclopropyl, -CN, and -OH. For example, in some preferred embodiments, R is selected from (1-hydroxycyclopropyl)ethyl, 3-hydroxycyclobutyl, 2-cyanoethyl, 2-hydroxyethyl, 2-cyano-1-cyclopentylethyl, 1-cyanopropane, 2-morpholinoethyl, ethyl, and (1-methylpiperidin-4-yl)methyl.

[0057] In some preferred embodiments, R1 is selected from halogen, for example, F.

[0058] In some preferred embodiments, R is selected from piperazinyl, morpholinyl, pyrrolidinyl, piperidinyl, and azetidine, each of which is optionally substituted with zero, one, or two substituents independently selected from the group consisting of methyl, ethyl, cyclopentyl, cyclopropyl, -CN, and -OH. In some preferred embodiments, R is selected from methyl, ethyl, propyl, isopropyl, and cyclobutyl, each of which is optionally substituted with zero, one, or two substituents independently selected from the group consisting of methyl, ethyl, cyclopentyl, cyclopropyl, -CN, -OH, morpholinyl, and piperidinyl, each of which is optionally substituted with zero, one, or two substituents independently selected from the group consisting of methyl, ethyl, cyclopentyl, cyclopropyl, -CN, and -OH.

[0059] 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-ethylpiperidin-4-yl, and 1-methylazetidin-3-yl.

[0060] 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, pyridin-3-yl, 1-methyl-1H-pyrazol-4-yl, 1-methyl-1H-pyrazol-3-yl, 4-methylpiperazin-1-yl, 1-methylpiperidin-4-yl, morpholinyl, pyrrolidin-3-yl, 3-hydroxypyrrolidin-1-yl, 3-cyanopyrrolidin-1-yl.

[0061] 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 halides, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Alicyclic groups, 4- to 6-membered heteroalicyclic groups, C 5-8 Aryl, 5-10 membered heteroaryl, -C 1-4 Alkyl-(C 3-7 alicyclic group), -C 1-4 Alkyl-(3- to 10-membered heteroalicyclic group), -C 1-4 Alkyl-(C 5-8 aryl), -C 1-4 Alkyl-(5-10 membered heteroaryl), -N(R 10 )(R 11 ) wherein said -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkyl halides, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Alicyclic groups, 4- to 6-membered heteroalicyclic groups, C 5-8 Aryl, 5-10 membered heteroaryl, -C 1-4 Alkyl-(C 3-7 alicyclic group), -C 1-4 Alkyl-(3- to 10-membered heteroalicyclic group), -C1-4 Alkyl-(C 5-8 aryl), -C 1-4 Each alkyl-(5- to 10-membered heteroaryl) optionally has 0, 1, 2, 3, or 4 R 1a and R 1a is halogen, -OH, -NO2, -CN, oxo, C 1-4 Alkyl, C 1-4 Alkyl halides, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-7 Alicyclic group, 3- to 10-membered heteroalicyclic group, C 5-8 aryl, 5- to 7-membered heteroaryl; and R 10 , R 11 and R 12 For each occurrence, H, C 1-6 Alkyl, C 1-6 Alkyl halides, C 3-7 alicyclic group, and 3- to 10-membered heteroalicyclic group, wherein each option within the group is selected from halogen, —OH, —NH2, oxo, C 1-4 Alkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkyl halides, C 1-4 Alkoxy and C 1-4 optionally substituted with 0, 1, 2, 3, or 4 substituents each independently selected from the group consisting of halogenated alkoxy, or R 10 and R 11 form a 3- to 8-membered ring together with the atoms connected to them. R1 is H, halogen, -OH, -NO2, -CN, -SF5, -SH, -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkyl halides, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Alicyclic groups, 4- to 6-membered heteroalicyclic groups, C 5-8 Aryl, 5-10 membered heteroaryl, -C 1-4 Alkyl-(C 3-7 alicyclic group), -C 1-4 Alkyl-(3- to 10-membered heteroalicyclic group), -C1-4 Alkyl-(C 5-8 aryl), -C 1-4 Alkyl-(5-10 membered heteroaryl), -N(R 10 )(R 11 ) wherein said -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkyl halides, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Alicyclic groups, 4- to 6-membered heteroalicyclic groups, C 5-8 Aryl, 5-10 membered heteroaryl, -C 1-4 Alkyl-(C 3-7 alicyclic group), -C 1-4 Alkyl-(3- to 10-membered heteroalicyclic group), -C 1-4 Alkyl-(C 5-8 aryl), -C 1-4 Each alkyl-(5- to 10-membered heteroaryl) optionally has 0, 1, 2, 3, or 4 R 1a and R 1a is halogen, -OH, -NO2, -CN, oxo, C 1-4 Alkyl, C 1-4 Alkyl halides, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-7 Alicyclic group, 3- to 10-membered heteroalicyclic group, C 5-8 aryl, 5- to 7-membered heteroaryl; and R 10 , R 11 and R 12 For each occurrence, H, C 1-6 Alkyl, C 1-6 Alkyl halides, C 3-7 alicyclic group, and 3- to 10-membered heteroalicyclic group, wherein each option within the group is selected from halogen, —OH, —NH2, oxo, C 1-4 Alkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkyl halides, C 1-4 Alkoxy and C 1-4optionally substituted with 0, 1, 2, 3, or 4 substituents each independently selected from the group consisting of halogenated alkoxy, or R 10 and R 11 form a 3- to 8-membered ring together with the atoms to which they are connected.

[0062] In some preferred embodiments, 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, wherein 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 are each optionally preceded by one or two R 1a and R 1a is halogen, -OH, -NO2, -CN, oxo, C 1-4 Alkyl, C 1-4 Alkyl halides, and C 1-4 halogenated alkoxy.

[0063] In some preferred embodiments, R1 is selected from H, methyl, methylpiperazinyl, pyrrolidinyl, methylpiperazinyl, hydroxycyclobutyl, methylpyrazolyl, hydroxyethyl, hydroxypropyl, methylpiperidinyl, morpholinyl, hydroxypyrrolidinyl.

[0064] It should be understood that any of the above embodiments of R1 can be combined in any way with any of the above or below embodiments of R2, R3, L, n, and ring A.

[0065] In formula (I) as above, R2 is H, halogen, -CN, -OH, -NO2, -NR7R8, C 1-4 Alkyl, C 1-4 Alkyl halides, C 1-4 Alkoxy, C 3-6 It can be selected from alicyclic groups and 4- to 6-membered heteroalicyclic groups.

[0066] In some embodiments, R2 is H.

[0067] In some embodiments, R2 is halogen, eg, R2 is selected from F, Cl, Br, and I.

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

[0069] In some embodiments, R2 is -NO2.

[0070] In some embodiments, R2 is C 1-3 Alkyl or C 1-3 Halogenated alkyl, for example, R2 is selected from methyl, ethyl, propyl, isopropyl, optionally substituted with one or more halogen atoms (eg, fluorine, chlorine, bromine, iodine).

[0071] In some embodiments, R2 is C 1-3 Alkoxy, for example, R2 is selected from methoxy, ethoxy, propoxy, isopropoxy.

[0072] In some embodiments, R2 is C 3-6 It is an alicyclic group, for example, R2 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl.

[0073] In some embodiments, R2 is a 4-6 membered heteroalicyclic group, for example, R2 is selected from oxetanyl, oxetanyl, azetinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, and piperazinyl.

[0074] In some embodiments, R2 is -NR7R8, where R7 and R8, at each occurrence, are selected from the group consisting of H, C, 1-3 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, etc.), C 1-3 halogenated alkyl (e.g., methyl, ethyl, propyl, isopropyl substituted with one or more halogen atoms selected from fluorine, chlorine, bromine, iodine); 1-3 or R7, R8 and the N atom connected thereto form a 3- to 6-membered ring (e.g., pyrrole, pyridine, pyrimidine, imidazole, pyrazole, pyrrolidine, hexahydropyridine, etc.).

[0075] It should be understood that any of the above embodiments of R2 can be combined in any way with any of the above or below embodiments of R1, R3, L, n and ring A.

[0076] In formula (I) as above, R3 is H, halogen, -CN, -OH, -NO2, -NR7R8, C 1-4 Alkyl, C 1-4 Alkyl halides, C 1-4 Alkoxy, C 3-6 It can be selected from alicyclic groups and 4- to 6-membered heteroalicyclic groups.

[0077] In some embodiments, R3 is H.

[0078] In some embodiments, R3 is halogen, eg, R3 is selected from F, Cl, Br, and I.

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

[0080] In some embodiments, R3 is -NO2.

[0081] In some embodiments, R3 is C 1-3 Alkyl or C 1-3 Halogenated alkyl, for example, R3 is selected from methyl, ethyl, propyl, isopropyl, optionally substituted with one or more halogen atoms (eg, fluorine, chlorine, bromine, iodine).

[0082] In some embodiments, R3 is C 1-3 Alkoxy, for example, R3 is selected from methoxy, ethoxy, propoxy, isopropoxy.

[0083] In some embodiments, R3 is C 3-6 It is an alicyclic group, for example, R3 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl.

[0084] In some embodiments, R3 is a 4-6 membered heteroalicyclic group, for example, R3 is selected from oxetanyl, thioxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, and piperazinyl.

[0085] In some embodiments, R3 is -NR7R8, where R7 and R8, at each occurrence, are selected from the group consisting of H, C, 1-3 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, etc.), C 1-3 halogenated alkyl (e.g., methyl, ethyl, propyl, isopropyl substituted with one or more halogen atoms selected from fluorine, chlorine, bromine, iodine); 1-3or R7, R8 and the N atom connected thereto form a 3- to 6-membered ring (e.g., pyrrole, pyridine, pyrimidine, imidazole, pyrazole, pyrrolidine, hexahydropyridine, etc.).

[0086] It should be understood that any of the above embodiments of R3 can be combined in any way with any of the above or below embodiments of R1, R2, L, n and ring A.

[0087] In some embodiments, R3 and R2 can be the same. For example, R3 and R2 are both halogen, such as Cl, or, for example, R3 and R2 are both methyl. In one preferred embodiment, R3 and R2 are both Cl. In one preferred embodiment, R3 and R2 are both H.

[0088] In some other embodiments, R3 and R2 may be different.

[0089] In formula (I) as above, L may be (C=O), (O=S=O), ((C=O)-CH2), CH2 or a connecting bond.

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

[0091] In some embodiments, L is (O=S=O).

[0092] In some embodiments, L is ((C=O)-CH2).

[0093] In some embodiments, L is CH2.

[0094] In some embodiments, L is a connecting bond (ie, R1 and the N atom are directly linked by a covalent bond).

[0095] It should be understood that any of the above embodiments of L can be combined in any way with any of the above or below embodiments of R1, R2, R3, ring A and n.

[0096] In formula (I) as above, n is 1, 2 or 3.

[0097] In some embodiments, n is 1.

[0098] In some embodiments, n is 2.

[0099] In some embodiments, n is 3.

[0100] It should be understood that any of the above n embodiments can be combined in any way with any of the above or below mentioned embodiments of R1, R2, R3, L and ring A.

[0101] 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 and R5 are H, halogen, -CN, -OH, -NO2, C 1-6 Alkyl, C 1-6 Alkyl halides, C 1-6 alkoxy (R4 and R5 may be the same or different); or R4 and R5 together with the atoms connected thereto form a 3- to 8-membered ring.

[0102] Thus, compounds of formula (I) herein may have one of the following structures: [ka] (In the formula, n, L, R1, R2, R3, R4, and R5 are as defined above.)

[0103] [ka] (In the formula, n, L, R1, R2, R3, R4, and R5 are as defined above.)

[0104] [ka] (In the formula, n, L, R1, R2, R3, and R4 are as defined above.)

[0105] [ka] (wherein n, L, R1, R2, and R3 are as defined above. Ring B is a 3- to 8-membered ring containing one N atom, and R a H, halogen, -CN, -OH, -NO2, C 1-6 Alkyl, C 1-6 Alkyl halides, C 1-6 alkoxy.

[0106] The embodiments and preferred options of R1, R2, R3, ring A, L, n, etc. shown in the above general formula (I) also apply to general formulas (I-1), (I-2), (I-3), and (I-4).

[0107] In some specific embodiments, the compound of formula (I) of the present application is selected from the compounds shown in each corresponding example. (2) Compound of formula (II)

[0108] In some embodiments of the compound of Formula (II), R is C 6-12 Aryl (preferably C 6-10 aryl), 5- to 12-membered heteroaryl (preferably 5- to 10-membered heteroaryl), 6-12 Aryl (preferably C 6-10 aryl), 5- to 12-membered heteroaryl (preferably 5- to 10-membered heteroaryl) can be substituted with 1, 2, 3, or 4 R 1b are optionally substituted with R 1b are halogens, -OH, -NO2, -CN, -SF5, -SH, and -SC, respectively. 1-4 Alkyl, oxo, C1-4 Alkyl, C 1-4 Alkyl halides, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, 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)2R 14 ), -S(=O)2-N(R 13 )(R 14 ), -SR 15 and -OR 15 and preferably, R 1b are halogens, -OH, -NO2, -CN, -SF5, -SH, and -SC, respectively. 1-4 Alkyl, oxo, C 1-4 Alkyl, C 1-4 Alkyl halides, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, 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, and most preferably halogen, —OH, —NO2, —CN, —SF5, —SH, —SC 1-4 Alkyl, oxo, C 1-4 Alkyl, C 1-4 Alkyl halides, C 1-4Alkoxy is selected from:

[0109] In formula (II) as above, R1 can be any C 5-16 It may be an aryl or a 5- to 16-membered heteroaryl, and examples thereof include substituted or unsubstituted phenyl, naphthyl, anthryl, phenanthryl, azulenyl, biphenyl, thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolyl, and isopropyl. isoindolyl, indolizinyl, benzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, purine, quinolidinyl, quinolyl, isoquinolyl, cinnolyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and when the above groups are substituted, the substituents are selected from 1, 2, 3, or 4 R 1b where R 1b are halogens, -OH, -NO2, -CN, -SF5, -SH, and -SC, respectively. 1-4 Alkyl, oxo, C 1-4 Alkyl, C 1-4 Alkyl halides, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-7 are independently selected from an alicyclic group, a 3- to 10-membered heteroalicyclic group, and preferably R 1b are halogens, -OH, -NO2, -CN, -SF5, -SH, and -SC, respectively. 1-4 Alkyl, oxo, C 1-4 Alkyl, C 1-4 Alkyl halides, C 1-4 Alkoxy is selected from:

[0110] In some preferred embodiments, R in formula (II) is selected from substituted or unsubstituted indazolyl, benzimidazolyl, indolyl, isoindole, triazolopyridyl, imidazopyridyl, benzoxazole, benzothiazole, tetrahydropyrroloimidazole, and when R is substituted, the substituents are 1, 2, 3, or 4 R as defined above. 1b and preferably one or two R 1b and each R 1b is halogen, -OH, -NO2, -CN, oxo, C 1-4 Alkyl, C 1-4 Alkyl halides and C 1-4 alkoxy.

[0111] In some preferred embodiments, R in formula (II) is selected from substituted or unsubstituted indazolyl, benzimidazolyl, indolyl, isoindole, triazolopyridyl, imidazopyridyl, benzoxazole, benzothiazole, tetrahydropyrroloimidazole, or pyrazolopyridyl, and when R is substituted, the substituents are 1, 2, 3, or 4 R as defined above. 1b and preferably one or two R 1b and each R 1b is halogen, -OH, -NO2, -CN, oxo, C 1-4 Alkyl, C 1-4 Alkyl halides and C 1-4 alkoxy.

[0112] In formula (II), m may be 0 or 1 (preferably 0).

[0113] In the above formula (II), the number of R2 is 1, 2, 3 or 4, and each R2 is H, halogen, -CN, -OH, -NO2, -NR7R8, C 1-4 Alkyl, C 1-4 Alkyl halides, C 1-4 Alkoxy, C 3-6R7 and R8 are independently selected from an alicyclic group and a 4- to 6-membered heteroalicyclic group, 1-6 Alkyl, C 1-4 Alkyl halides, C 1-4 or form a 3- to 6-membered ring together with R7, R8 and the N atom connected thereto.

[0114] In some preferred embodiments, the number of R2 is 1, 2, 3, or 4, and each R2 is H, halogen, —CN, —OH, —NO2, —NR7R8, C 1-4 Alkyl, C 1-4 Alkyl halides, C 1-4 alkoxy, wherein R7 and R8 are independently selected from H, C 1-6 Alkyl, C 1-4 Alkyl halides, C 1-4 or form a 3- to 6-membered ring together with R7, R8 and the N atom connected thereto.

[0115] In some preferred embodiments, R2 in formula (II) is selected from H, CH3, F, Cl, and Br.

[0116] The options and preferred options for R1, R2 and m in the above formula (II) can be arbitrarily combined, and any combination thereof is within the scope of the present disclosure.

[0117] In some specific embodiments, the compound of formula (II) of the present application is selected from the compounds shown in each corresponding example. (ii) Method for manufacturing the compound

[0118] The compounds of formula (I) and formula (II) of the present invention can be synthesized by a person skilled in the art using conventional organic synthesis methods based on the specific structures of the compounds.

[0119] Furthermore, those skilled in the art can obtain synthesis methods for obtaining other compounds by appropriately adjusting the reaction raw materials and reaction conditions with reference to the synthesis routes for the specific compounds in the specific examples of the present application. 3. Use of the compound and compositions containing the compound

[0120] Experiments have shown that the compounds of formula (I) and formula (II) of the present invention can inhibit the activity of TGF-β, i.e., can be used as TGF-β inhibitors. Specifically, the compounds of formula (I) and formula (II) of the present invention can be used to suppress TGF-β type I receptor (TGFβR1), i.e., can be used as TGF-β1 inhibitors.

[0121] In a third aspect, the present application provides pharmaceutical compositions, which comprise the aforementioned compounds of the present application, or isotopically labeled compounds thereof, or optical isomers, geometric isomers, tautomers or isomeric mixtures thereof, or pharmaceutically acceptable salts thereof, prodrugs thereof, or metabolites thereof, and one or more pharmaceutically acceptable carriers, adjuvants or excipients.

[0122] The pharmaceutical compositions of the present application can be prepared by methods well known in the pharmaceutical art and can be administered in a variety of ways, depending on the desired local or systemic treatment and on the area to be treated. Administration can be topical (including ophthalmic and mucosal administration, including intranasal, vaginal, and rectal), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including nebulizer administration, intratracheal, intranasal, epidermal, and transdermal), ophthalmic, oral, or parenteral. Ophthalmic administration methods can include topical administration (eye drops), subconjunctival, periocular, or intravitreal injection, or by a balloon catheter or ophthalmic insert surgically placed in the conjunctival sac. Parenteral administration can include intravenous, intraarterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion, or intracranial (e.g., intrasheath or intracerebral) administration. Parenteral administration can be in the form of a single injection dose or can be achieved, for example, by a continuous infusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, plasters, lotions, creams, gels, drops, suppositories, sprays, liquids and powders.

[0123] When a solid carrier is used, the formulation may be in the form of a tablet, placed in a hard capsule in powder or granular form, or in the form of a troche or lozenge. Solid carriers may contain conventional excipients such as binders, fillers, tableting lubricants, disintegrants, wetting agents, and the like. If necessary, tablets may be film-coated by conventional techniques. When a liquid carrier is used, the formulation may be in the form of a syrup, emulsion, ointment, softgel capsule, sterile injectable carrier, aqueous or non-aqueous liquid suspension, or a dry product that can be reconstituted with water or other suitable carrier before use. Liquid formulations may contain conventional additives such as suspending agents, emulsifiers, wetting agents, non-aqueous carriers (including edible oils), preservatives, and flavorings and / or colorants. For parenteral administration, the carrier usually comprises at least mostly sterile water, although saline, glucose solution, and the like may also be used. Injectable suspensions may also be used, in which case conventional suspending agents may be used. Conventional preservatives, buffers, and the like may also be added to parenteral dosage forms. Pharmaceutical compositions are prepared by conventional techniques appropriate to the desired formulation containing appropriate amounts of the active ingredient (ie, the compound of the present application).

[0124] Compositions suitable for parenteral 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 (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate).

[0125] These compositions may further contain various excipients, such as preservatives, wetting agents, emulsifying agents, and dispersing agents. To ensure the prevention of microbial action, various antibacterial and antifungal agents (e.g., parabens, chlorobutanol, phenol, sorbic acid, etc.) may be used. Furthermore, isotonic agents, such as sugars, sodium chloride, etc., may be included. Absorption of the injectable pharmaceutical form can be delayed by the use of agents delaying absorption (e.g., aluminum monostearate and gelatin).

[0126] 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 inert excipient (or carrier) (e.g., sodium citrate or dicalcium phosphate), which may further include: (a) fillers or fillers (e.g., starch, lactose, sucrose, glucose, mannitol, and silicic acid), (b) binders (e.g., carboxymethylcellulose, alginate esters, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic), (c) humectants (e.g., glycerol), (d) disintegrating agents (e.g., agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain synthetic silicates, sodium carbonate), (e) solution blocking agents (e.g., paraffin), (f) absorption accelerators (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.

[0127] Solid compositions of a similar type may also be employed as fillers in soft-filled and hard-filled gel capsules using, for example, lactose as well as high molecular weight polyethylene glycols and other excipients.

[0128] Solid dosage forms (e.g., tablets, dragees, capsules, pills, and granules) can be prepared with coatings and shells (e.g., enteric coatings and others known in the art). They may contain light-blocking agents, and may further comprise an active compound or compositions of various active compounds that release the active compound or compounds in a delayed manner in a specific part of the intestinal tract. Examples of coating compositions that can be used are polymers and waxes. The active ingredient may also be in microencapsulated form, which may, if appropriate, contain one or more of the above-mentioned excipients.

[0129] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, dispersions, syrups, and elixirs. In addition to the active compound, the liquid dosage forms may contain inert diluents (e.g., water or other solvents), solubilizing agents, 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 of these substances, which are commonly used in the art.

[0130] In addition to these inert diluents, the composition may further contain, for example, wetting agents, emulsifying and suspending agents, flavorings, seasonings, and aromatics.

[0131] In addition to the active compound, suspensions may contain suspending agents such as ethoxylated isooctadecanol, polyoxylated ethylene sorbitol, sorbitan esters, microcrystalline fibers, aluminum metahydroxide, bentonite, agar-agar, and Astragalus gel, or mixtures of these substances.

[0132] Dosage forms for topical administration of the compounds of the present application include ointments, powders, sprays, and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any necessary preservatives, buffers, or propellants. Ophthalmic formulations, eye ointments, powders, and solutions are also included within the scope of this application.

[0133] The amount of the compound of the present application in pharmaceutical compositions and dosage forms can be appropriately determined by those skilled in the art as needed; for example, the compound of the present application may be present in the pharmaceutical composition or dosage form in a therapeutically effective amount.

[0134] In a fourth aspect, the present application relates to the use of a compound of formula (I) or formula (II) of the present application, or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomeric mixture thereof, or a pharmaceutically acceptable salt thereof, a prodrug thereof, or a metabolite thereof, or a pharmaceutical composition as described above, in the manufacture of a medicament for treating a TGF-β (particularly TGF-β1) related disease or condition.

[0135] In a fifth aspect, the present application further provides a method for treating a TGF-β (particularly TGF-β1)-related disease or condition, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I) or Formula (II) of the present application, or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer, or isomeric mixture thereof, or a pharmaceutically acceptable salt thereof, a prodrug thereof, or a metabolite thereof, or the pharmaceutical composition described above. 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.), parenteral gastrointestinal (including subcutaneous, intramuscular, cortical, and intravenous), bronchial, or intranasal administration. The dosage is a therapeutically effective amount, which can be determined by a person skilled in the art according to the actual needs.

[0136] In the present application, the "TGF-β (particularly TGF-β1)-associated disease or condition" may be cancer, viral infection, chronic nephritis, acute nephritis, diabetic nephropathy, osteoporosis, arthritis, wound healing, scarring, ulcers, corneal wounds, valvular cardiac stenosis, congestive cardiac necrosis, neurological dysfunction, Alzheimer's syndrome, peritoneal or subcutaneous adhesions, arteriosclerosis, skin fibrosis and skin aging due to fat loss, bone damage or chondrocyte damage, hypophosphatemic disorders, and organ fibrosis, particularly hepatocellular carcinoma, breast cancer, bladder cancer, colorectal cancer, melanoma, mesothelioma, lung cancer, prostate cancer, membranous adenocarcinoma, testicular cancer, thyroid cancer, squamous cell carcinoma, glioblastoma, neuroblastoma, uterine cancer, rhabdomyosarcoma, renal fibrosis, liver fibrosis, pulmonary fibrosis, skin scarring, skin fibrosis, and skin aging due to fat loss.

[0137] In some embodiments, the TGF-β-related disease or condition is cancer, and the compounds of the present application are used, for example, to inhibit the proliferation, metastasis, etc. of cancer cells.

[0138] Exemplary cancers include bladder cancer, breast cancer, cervical cancer, colorectal cancer, small intestine cancer, colon cancer, rectal cancer, anal cancer, endometrial cancer, head and neck cancer (e.g., cancer of the throat, larynx, nasopharynx, oropharynx, lip and oral cavity), kidney cancer, liver cancer (e.g., hepatocellular carcinoma, cholangiocarcinoma), lung cancer (e.g., adenocarcinoma, small cell and non-small cell lung cancer, small cell and non-small cell carcinoma, bronchial carcinoma, bronchial adenocarcinoma, pleuropulmonary blastoma), ovarian cancer, prostate cancer, testicular cancer, uterine cancer, esophageal cancer, gallbladder cancer, pancreatic cancer (e.g., exocrine pancreatic cancer), thyroid cancer, parathyroid cancer, skin cancer (e.g., squamous cell carcinoma, Kaposi's sarcoma, Merkel cell skin cancer), and brain cancer (e.g., astrocytoma, neural germ cell tumor, subependymoma, neuroectodermal tumor, pineal tumor).

[0139] 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's or non-Hodgkin's lymphoma, myeloproliferative neoplasms (e.g., polycythemia vera, essential thrombocytosis, and essential myelofibrosis), Wattesazone macroglobulinemia, hairy cell lymphoma, chronic myeloid lymphoma, acute lymphoblastic lymphoma, AIDS-related lymphoma, and Burkitt's lymphoma.

[0140] Further exemplary cancers include eye tumors, glioblastoma, melanoma, rhabdomyosarcoma, lymphosarcoma, and osteosarcoma.

[0141] 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, membranous carcinoma, testicular cancer, thyroid cancer, squamous cell carcinoma, glioblastoma, neuroblastoma, uterine cancer, and rhabdomyosarcoma.

[0142] In some other embodiments, the TGF-β-related disease or condition is selected from skeletal and chondrocyte disorders, including, but not limited to, cartilage dysplasia, hypochondroplasia, dwarfism, lethal achondroplasia (TD) (clinical forms TD I and TD II), Apert syndrome, Crouzon syndrome, Jackson-Weiss syndrome, Beare-Stevenson cutis gyrate syndrome, Pfeiffer syndrome, and craniosynostosis.

[0143] In some other embodiments, the TGF-β-related disease or condition is a hypophosphatemic disorder, including, for example, X-linked hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets, and tumor-induced osteromalacia.

[0144] In some other embodiments, the TGF-β-associated disease or condition is selected from a fibrotic disease. Exemplary fibrotic diseases include cirrhosis, glomerulonephritis, pulmonary fibrosis, systemic fibrosis, rheumatoid arthritis, and wound healing.

[0145] In some preferred embodiments, the TGF-β-related disease or condition is a skin disease, particularly skin scarring, skin fibrosis, and skin aging due to fat loss.

[0146] The present invention will be further described below with reference to specific examples. Example

[0147] The examples described herein below are used 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 the present invention in any way.

[0148] Unless otherwise specified, all reactant materials are commercially available. The equipment used in synthesis experiments and product analysis and detection are all standard equipment and devices commonly used in organic synthesis. Unless otherwise specified, reaction and detection conditions are those commonly used in organic synthesis and pharmaceuticals.

[0149] Example 1: 1-(2-(4-(2-(6-methylpyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)ethan-1-one [ka]

[0150] Synthesis of Compound 1: [ka]

[0151] Synthesis method: Intermediate 1-b: Synthesis of 2-bromo-1-(6-methylpyridin-2-yl)ethan-1-one

[0152] Starting material 1-a (2.0 g, 14.8 mmol) was dissolved in 40 mL of acetonitrile, p-toluenesulfonic acid (3.8 g, 22.2 mmol) was added, and the mixture was heated to 80°C. NBS (2.6 g, 14.8 mmol) was added in portions over 2 hours. After the addition, the mixture was allowed to react at 80°C for 3 hours. After monitoring the completion of the reaction by TLC, the reaction mixture was quenched by adding saturated sodium bicarbonate solution and extracted twice with EA. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified using a silica gel column to obtain 1.8 g of intermediate 1-b in 57.2% yield. LC-MS m / z (ESI) [M+H] + Calculated for C8H9BrNO: 214.1, Found: 214.1.

[0153] Synthesis of Intermediate 1-c: 2-(6-methylpyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole

[0154] 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 mixture was monitored for completion by TLC, quenched by adding water, extracted twice with DCM, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified using a silica gel column to obtain 313.8 mg of intermediate 1-c in 41.9% yield. 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.

[0155] Intermediate 1-d: Synthesis of 3-bromo-2-(6-methylpyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole

[0156] 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 several portions over 5 minutes at room temperature. After immediate TLC monitoring of the complete reaction of the starting material, the reaction mixture was quenched by adding water and extracted twice with DCM. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified using a silica gel column to obtain 289.7 mg of intermediate 1-d in 66.4% yield. LC-MS m / z (ESI) [M+H] + :C 12 H 13 Calculated value for N3Br is 278.0, found value is 278.0.

[0157] Intermediate 1-1: Synthesis of tert-butyl 2-(4-bromopyridin-2-yl)-3a,4,6,6a-tetrahydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

[0158] 2-Aldehyde-4-bromopyridine (0.8 g, 4.3 mmol) was dissolved in 30 mL of tert-butanol, and tert-butyl 3,4-diaminopyrrolidine-1-carboxylate (1.1 g, 5.6 mmol), iodine (1.6 g, 6.5 mmol), and potassium carbonate (1.2 g, 8.6 mmol) were added. The mixture was heated to 70 °C and reacted for 3 hours. After the reaction was completed, the mixture was cooled to room temperature and quenched by adding 5% aqueous sodium thiosulfate. EA was added for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified using a silica gel column to obtain 1.4 g of intermediate 1-1 in 88.9% yield. LC-MS m / z (ESI) [M+H] + :C 15 H 20 The calculated value for BrN4O2 is 367.1 and the measured value is 367.1.

[0159] Intermediate 1-2: Synthesis of tert-butyl 2-(4-bromopyridin-2-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

[0160] Intermediate 1-1 (1.4 g, 3.8 mmol) was dissolved in 20 ml of DMSO, IBX (2.1 g, 7.6 mmol) was added, and the mixture was heated to 50 °C and reacted overnight. After the reaction was completed, the mixture was cooled to room temperature, and 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 using a silica gel column to obtain 1.2 g of intermediate 1-2 in 84.7% yield. LC-MS m / z (ESI) [M+H] + :C 15 H 18 The calculated value for BrN4O2 is 365.1 and the measured value is 365.1.

[0161] Intermediate 1-3: Synthesis of tert-butyl 2-(4-bromopyridin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

[0162] Intermediate 1-2 (1.2 g, 3.2 mmol) was dissolved in 20 mL of THF, cooled to 0°C, and NaH (60%) (0.2 g, 4.9 mmol) was added. The mixture was stirred for 0.5 hours, and then SEMCl (0.8 g, 4.9 mmol) was added. After the addition, the mixture was warmed to room temperature and stirred. After the reaction was complete, water was added to quench the reaction, and EA was added for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified using a silica gel column to obtain 1.2 g of Intermediate 1-3 in 75.2% yield. LC-MS m / z (ESI) [M+H] + :C 21 H 32 The calculated value for BrN4O3Si is 495.1 and the measured value is 495.1.

[0163] Intermediate 1-4: Synthesis of (2-(5-(tert-butoxycarbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)pyridin-4-yl)boronic acid

[0164] Intermediate 1-3 (200.0 mg, 0.4 mmol) was dissolved in 10 ml of dioxane, and bisboronic acid pinacol ester (207.5 mg, 0.8 mmol) and Pd(dppf)Cl (29.7 mg, 0.04 mmol) were added. The mixture was purged with nitrogen gas, potassium acetate (120.5 mg, 1.2 mmol) was added, and the mixture was purged with nitrogen gas again. The mixture was heated to 80 °C and reacted overnight. The reaction mixture was cooled to room temperature to obtain crude intermediate 1-4, which was used directly in the next reaction.

[0165] Intermediate 1-5: Synthesis of tert-butyl 2-(4-(2-(6-methylpyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1-(2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

[0166] To the reaction flask containing intermediate 1-4, 2 ml of water and potassium carbonate (111.6 mg, 0.8 mmol) were added, followed by 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. The mixture was purged with nitrogen gas, heated to 100 °C, and reacted overnight. The reaction mixture was cooled to room temperature, concentrated, and then purified using a silica gel column to obtain 86.5 mg of intermediate 1-5 in a 35.2% yield. LC-MS m / z (ESI) [M+H] + :C 33 H 44 The calculated value for N7O3Si is 614.3 and the measured value is 614.3.

[0167] Synthesis of Intermediate 1-6: 2-(4-(2-(6-methylpyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1-(2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole

[0168] Intermediate 1-5 (60.0 mg, 0.1 mmol) was 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 mixture was allowed to react at room temperature overnight. The reaction mixture was concentrated to remove the solvent, then dissolved in 20 ml of THF, washed once with saturated sodium bicarbonate solution and once with saturated saline, and concentrated to obtain 46.4 mg of crude intermediate 1-6 in 92.8% yield. LC-MS m / z (ESI) [M+H] + :C 28 H 36 The calculated value for N7OSi is 514.3 and the measured value is 514.3.

[0169] Synthesis of Intermediate 1-7: 1-(2-(4-(2-(6-methylpyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1-(2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)ethan-1-one

[0170] 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, and acetyl chloride (14.2 mg, 0.2 mmol) was added. The mixture was stirred at room temperature for 0.5 hours. After the reaction was completed, the mixture was quenched with water and extracted with DCM. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified using a preparative plate to obtain 27.4 mg of intermediate 1-7 in a 54.8% yield. LC-MS m / z (ESI) [M+H] + :C 30 H 38 The calculated value for N7O2Si is 556.3 and the measured value is 556.3.

[0171] Synthesis of Compound 1: 1-(2-(4-(2-(6-methylpyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)ethan-1-one

[0172] 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 incubated 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. The mixture was then purified using a reverse-phase silica gel column to give 6.2 mg of the final product in 29.6% yield. LC-MS m / z (ESI) [M+H] + :C 24 H 24 The calculated value for N7O is 426.2 and the measured value is 426.2.

[0173] Example 2: 2-(4-(2-(6-methylpyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole [ka]

[0174] Synthesis of Compound 2: [ka]

[0175] Synthesis method: Synthesis of Compound 2: 2-(4-(2-(6-methylpyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole

[0176] Intermediate 1-5 (36.5 mg, 0.1 mmol) was dissolved in 4 mL of methanol, 2 mL of concentrated hydrochloric acid was added, and the mixture was incubated 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. The mixture was then purified using a reverse-phase silica gel column to give 4.1 mg of the final product in 17.9% yield. LC-MS m / z (ESI) [M+H] + :C 22 H 22 The calculated value for N7 is 384.2 and the measured value is 384.2.

[0177] Example 3: 5-methyl-2-(4-(2-(6-methylpyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole [ka]

[0178] Synthesis of compound 3: [ka]

[0179] Synthesis method: Synthesis of Compound 3: 5-methyl-2-(4-(2-(6-methylpyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1,4,5,6-tetrahydropyrrole[3,4-d]imidazole

[0180] Intermediate 1-6 (50.0 mg, 0.1 mmol) and 30% aqueous formaldehyde (11.7 mg, 0.4 mmol) were dissolved in 5 mL of DCM and stirred at room temperature for 0.5 h. The mixture was cooled to 0 °C and sodium triacetylborohydride (82.8 mg, 0.4 mmol) was added. The mixture was incubated at room temperature for 2 h. The mixture was quenched with water and extracted with DCM. The organic phases were combined, washed with saturated brine, and concentrated. The concentrate was dissolved in 4 mL of methanol, added with 2 mL of concentrated hydrochloric acid, incubated at 50 °C for 2 h, concentrated, dissolved in 5 mL of methanol, added with 0.5 mL of aqueous ammonia, concentrated, and purified using a preparative plate to give 3.2 mg of the final product in 8.3% yield.

[0181] 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).

[0182] Example 4: (4-Methylpiperazin-1-yl)(2-(4-(2-(6-methylpyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)ketone (MDI-980) [ka]

[0183] Synthesis of compound 4: [ka]

[0184] Synthesis method: Synthesis of Compound 4: (4-methylpiperazin-1-yl)(2-(4-(2-(6-methylpyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)ketone

[0185] Intermediate 1-6 (40.0 mg, 0.1 mmol) was dissolved in 10 mL of DCM, triphosgene (23.1 mg, 0.1 mmol) was added, the system was cooled to 0 °C, triethylamine (80.8 mg, 0.8 mmol) was added dropwise, and the reaction was allowed to proceed for 0.5 hours. N-methylpiperidine (8.0 mg, 0.1 mmol) was added, and the system was warmed to room temperature and allowed to react. After the reaction was complete, the mixture was quenched by adding water, extracted with DCM, and the organic phases were combined, washed with saturated brine, and concentrated. The concentrate was dissolved in 4 mL of methanol, added with 2 mL of concentrated hydrochloric acid, and reacted at 50 °C for 2 hours. The concentrate was then concentrated, dissolved in 5 mL of methanol, added with 0.5 mL of aqueous ammonia, concentrated, and purified using a preparative plate to obtain 2.2 mg of the final product in 5.5% yield. LC-MS m / z (ESI) [M+H] + :C 28 H 32 The calculated value for N9O is 510.3 and the measured value is 510.3.

[0186] Example 5: 3-(1H-indazol-5-yl)-2-(6-methylpyridin-2-yl)-5,5a,6,6a-tetrahydrocyclopropane[3,4]pyrrolo[1,2-a]imidazole [ka]

[0187] Synthesis of compound 5: [ka]

[0188] Synthesis method Intermediate 5-2: Synthesis of tert-butyl 3-azabicyclo[3.1.0]hexane-3-carboxylate

[0189] Intermediate 5-1 (5.0 g, 60.1 mmol) was dissolved in 50 ml of DCM, triethylamine (20 ml) was added, and (BOC)2O (15.8 g, 72.2 mmol) was added. The mixture was allowed to react at room temperature for 3 hours. Saturated ammonium chloride solution was added, and the mixture was extracted with DCM, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give 7.6 g of Intermediate 5-2 in a yield of 69.0 g.

[0190] Intermediate 5-3: Synthesis of tert-butyl 2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0191] Rhodium(IV) oxide (64.0 mg, 0.4 mmol) was dissolved in NaIO4 (33.6 g, 10%) and reacted at room temperature for 0.5 hours. A solution of intermediate 5-2 (7.6 g, 44.2 mmol) dissolved in EA (168 ml) was added and reacted at room temperature overnight. Water was added, and the mixture was extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and passed through a column to obtain 9.0 g of intermediate 5-3.

[0192] Intermediate 5-4: Synthesis of 3-azabicyclo[3.1.0]hexan-2-one

[0193] Intermediate 5-3 (9.0 g, 45.6 mmol) was dissolved in 30 ml of DCM, and TFA (8 ml) was added. The mixture was allowed to react at room temperature for 2 hours. The mixture was quenched by adding saturated ammonium chloride solution, extracted with DCM, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel column to obtain 5.0 g of Intermediate 5-4.

[0194] Intermediate 5-5: Synthesis of 2-methoxy-3-azabicyclo[3.1.0]hexan-2-ene

[0195] Intermediate 5-4 (5.0 g, 51.5 mmol) was dissolved in 30 ml of DCM, trimethyloxonium tetrafluoroborate (16.8 g, 113.3 mmol) was added, and the mixture was allowed to react at room temperature for 2 hours. The mixture was quenched by adding saturated sodium carbonate solution, filtered, concentrated, and purified on a silica gel column to obtain 4.0 g of Intermediate 5-5.

[0196] Intermediate 5-6: Synthesis of 3-azabicyclo[3.1.0]hexan-2-en-2-amine hydrochloride

[0197] Intermediate 5-5 (4.0 g, 36.0 mmol) was dissolved in 30 ml of ethanol, and NH4Cl (5.8 g, 108.0 mmol) was added. The mixture was allowed to react at 80°C for 2 hours. The mixture was concentrated to give 2.0 g of Intermediate 5-6. LC-MS m / z (ESI) [M+H] + : Calculated for C5H9N2 is 97.1, Found is 97.1.

[0198] Intermediate 5-7: Synthesis of 2-(6-methylpyridin-2-yl)-5,5a,6,6a-tetrahydrocyclopropane[3,4]pyrrolo[1,2-a]imidazole

[0199] Intermediate 1-b (400.0 mg, 1.9 mmol) was dissolved in 10 ml of toluene, and Intermediate 5-6 (216.0 mg, 2.2 mmol) and sodium bicarbonate (471.0 mg, 5.6 mmol) were added. The mixture was allowed to react overnight at 80°C. After concentration, 120.0 mg was obtained by column chromatography, for a yield of 30.4%. LC-MS m / z (ESI) [M+H] + :C 13 H 14 The calculated value for N3 is 212.1 and the measured value is 212.1.

[0200] Intermediate 5-8: Synthesis of 3-bromo-2-(6-methylpyridin-2-yl)-5,5a,6,6a-tetrahydrocyclopropane[3,4]pyrrolo[1,2-a]imidazole

[0201] Intermediate 5-7 (120.0 mg, 0.6 mmol) was dissolved in 10 mL of DCM, and NBS (101.0 mg, 0.6 mmol) was added in portions. The mixture was allowed to react at room temperature for 0.5 hours. Saturated sodium bicarbonate solution was added, and the mixture was extracted with DCM, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified to give 120.0 mg of the product in 72.9% yield. LC-MS m / z (ESI) [M+H] + :C 13 H 13 Calculated value for BrN3 is 290.0 and measured value is 290.0.

[0202] Compound 5: Synthesis of 3-(1H-indazol-5-yl)-2-(6-methylpyridin-yl)-5,5a,6,6a-tetrahydrocyclopropane[3,4]pyrrolo[1,2-a]imidazole

[0203] Intermediate 5-8 (20.0 mg, 0.1 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentanyl-2-yl)-1H-indazole (30.3 mg, 0.1 mmol) were dissolved in 10 ml of 1,4-dioxane and 1 ml of HO. Potassium carbonate (28.6 mg, 0.2 mmol) was added, and the reaction system was protected with nitrogen gas. Pd(dppf)Cl (5.1 mg, 0.01 mmol) was added. The reaction was allowed to proceed at 100 °C for 4 hours. After filtration, concentration, and purification, 4.8 mg of the product was obtained, for a yield of 14.2%. LC-MS m / z (ESI) [M+H] + :C 20 H 18 The calculated value for N5 is 328.2 and the measured value is 328.2.

[0204] Example 6: (2-(4-(4-(6-methylpyridin-2-yl)-1H-imidazol-5-yl)pyridin-2-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(pyrrolidin-1-yl)ketone [ka]

[0205] Synthesis of compound 6: [ka]

[0206] Synthesis method Intermediate 6-1: Synthesis of 2-(1H-imidazol-4-yl)-6-methylpyridine

[0207] Intermediate 1-b (0.8 g, 3.7 mmol) was dissolved in 30 ml of ethylene glycol, and formamidine acetate (2.0 g, 18.7 mmol) was added. The mixture was reacted at 130°C for 2 hours under nitrogen gas protection. After cooling to room temperature, water was added to adjust the pH to 10, and the mixture was extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give 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 160.1.

[0208] Intermediate 6-2: Synthesis of 2-methyl-6-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)pyridine

[0209] 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. The mixture was quenched by adding saturated ammonium chloride solution, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and passed through a column to obtain 140.0 mg of intermediate 6-2. The yield was 19.3%.

[0210] Intermediate 6-3: Synthesis of 2-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-6-methylpyridine

[0211] 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 portions. The mixture was allowed to react at room temperature for 10 minutes. The mixture was quenched by the addition of saturated sodium bicarbonate solution, extracted with DCM, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and passed through a column to obtain 90.0 mg of intermediate 6-3 in a 50.5% yield. LC-MS m / z (ESI) [M+H] + :C 15 H 23 The calculated value for BrN3OSi is 368.1 and the measured value is 368.1.

[0212] Intermediate 6-4: Synthesis of tert-butyl 2-(4-(4-(6-methylpyridin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyridin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

[0213] 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 bisboronic acid pinacol ester (184.0 mg, 0.7 mmol) were added. Under nitrogen gas protection, Pd(dppf)Cl (45.0 mg, 0.1 mmol) was added and the mixture was reacted at 85 °C overnight. Intermediate 6-3 (90.0 mg, 0.2 mmol), potassium acetate (178.0 mg, 1.8 mmol), 1 mL of HO, and Pd(dppf)Cl (45.0 mg, 0.1 mmol) were added and the mixture was reacted at 100 °C for 6 hours. The mixture was filtered, concentrated, and purified to obtain 50.0 mg of intermediate 6-4 in an 11.5% yield.

[0214] Intermediate 6-5: Synthesis of (2-(4-(4-(6-methylpyridin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyridin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(pyrrolidin-1-yl)ketone

[0215] Intermediate 6-4 (50.0 mg, 0.1 mmol) was dissolved in 10 mL of DCM, and under nitrogen gas protection, ZnBr (32.0 mg, 0.1 mmol) was added and the mixture was allowed to react overnight at room temperature. Triethylamine (1 mL) was added and the mixture was allowed to react at room temperature for 0.5 hours. Pyrrolidine-1-carbonyl chloride (10.0 mg, 0.1 mmol) was added and the mixture was allowed to react at room temperature for 2 hours. Water was added, and the mixture was extracted with DCM, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified to give 20.0 mg of intermediate 6-5 in a 42.9% yield. LC-MS m / z (ESI) [M+H] + :C 36 H 53 The calculated value for N8O3Si2 is 701.4 and the measured value is 701.4.

[0216] Synthesis of Compound 6: (2-(4-(4-(6-methylpyridin-2-yl)-1H-imidazol-5-yl)pyridin-2-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(pyrrolidin-1-yl)ketone

[0217] 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 allowed to react at 50°C for 3 hours. The mixture was concentrated, and aqueous ammonia was added to adjust the base. After concentration and purification, 4.7 mg of the product was obtained in 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 441.2.

[0218] Example 7: (4-Methylpiperazin-1-yl)(2-(4-(3-(6-methylpyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)ketone [ka]

[0219] Synthesis of compound 7: [ka]

[0220] Synthesis method: Intermediate 7-1: Synthesis of 2-methyl-6-(1H-pyrazol-3-yl)pyridine

[0221] 1-(6-Methylpyridin-2-yl)ethan-1-one (1.0 g, 7.4 mmol) 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. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a total of 1.1 g of crude intermediate 7-1 in a 90.2% yield.

[0222] Intermediate 7-2: Synthesis of 2-methyl-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)pyridine

[0223] 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 allowed to react for 2 hours. Water was added to the reaction mixture, and the mixture was extracted twice with DCM. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified using a silica gel column to obtain a total of 1.6 g of intermediate 7-2 in 95.5% yield.

[0224] 1H 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).

[0225] Intermediate 7-3: Synthesis of 2-(4-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-methylpyridine

[0226] 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 complete the reaction. Water was added to the reaction mixture, and the mixture was extracted twice with DCM. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified using a silica gel column to obtain a total of 223.2 mg of intermediate 7-3 in 67.4% yield.

[0227] 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).

[0228] Intermediate 7-4: Synthesis of tert-butyl 2-(4-(3-(6-methylpyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)-1-(2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

[0229] tert-Butyl 2-(4-bromopyridin-2-yl)-1-(2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5-(1H)-carboxylate (300.0 mg, 0.6 mmol) and pinacol bisboronate (184.5 mg, 0.7 mmol) were dissolved in 8 mL of dioxane, and 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 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), potassium carbonate (251.1 mg, 1.8 mmol), Pd(dppf)Cl (45.0 mg, 0.1 mmol), 2 ml of water, and the mixture was purged with nitrogen gas. The mixture was then reacted 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 phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified using a silica gel column to give intermediate 7-4 (203.6 mg in total, 50.8% yield).

[0230] 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).

[0231] Intermediate 7-5: Synthesis of 2-(4-(3-(6-methylpyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)-1-(2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole

[0232] Intermediate 7-4 (65.0 mg, 0.1 mmol) was dissolved in 10 ml of DCM, ZnBr (110.9 mg, 0.5 mmol) was added, and the mixture was stirred at room temperature. After the reaction was completed, the mixture was quenched by adding aqueous ammonia, extracted with DCM, and 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 in a 99.7% yield.

[0233] Intermediate 7-6: Synthesis of (4-methylpiperazin-1-yl)(2-(4-(3-(6-methylpyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)ketone

[0234] Intermediate 7-5 (55.0 mg, 0.1 mmol) and triphosgene (29.2 mg, 0.1 mmol) were dissolved in 10 mL of DCM. The temperature was lowered to 0 °C, and triethylamine (99.5 mg, 0.1 mmol) was added to the solution. The reaction was allowed to proceed for 5 minutes. N-methylpiperazine (19.7 mg, 0.2 mmol) was then added to the system, and the mixture was warmed to room temperature and stirred. After the reaction was completed, the mixture was quenched by adding water, extracted with DCM, and the organic phases were combined, washed with saturated brine, and concentrated. The mixture was purified using a silica gel column to obtain a total of 35.2 mg of intermediate 7-6 in a 51.9% yield.

[0235] Synthesis of Compound 7: (4-methylpiperazin-1-yl)(2-(4-(3-(6-methylpyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)ketone

[0236] 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, adjusted to alkaline by adding 0.5 ml of aqueous ammonia, concentrated, and purified to obtain 5.0 mg of the final product in 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 470.2.

[0237] Example 8: 2-(6-methylpyridin-2-yl)-3-(2-(1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)pyridin-4-yl)-5,5a,6,6a-tetrahydrocyclopropane[3,4]pyrrolo[1,2-a]imidazole [ka]

[0238] Synthetic route to compound 8: [ka]

[0239] Synthesis method: Intermediate 8-1: Synthesis of tert-butyl 2-(4-(2-(6-methylpyridin-2-yl)-5,5a,6,6a-tetrahydrocyclopropane[3,4]pyrrolo[1,2-a]imidazo-3-yl)pyridin-2-yl)-1-(2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazo-5(1H)-carboxylate

[0240] Intermediate 1-3 (400 mg, 0.8 mmol) was dissolved in 20 ml of 1,4-dioxane, potassium acetate (238 mg, 2.4 mmol), and bisboronic acid pinacol ester (246 mg, 1.0 mmol) were added, and the mixture was protected with nitrogen gas. Pd(dppf)Cl2 (60.0 mg, 0.1 mmol) was added and the mixture was reacted at 85 °C overnight. Intermediate 5-8 (258.0 mg, 0.9 mmol), potassium acetate (280.0 mg, 2.0 mmol), 2 ml of HO, and Pd(dppf)Cl2 (60.0 mg, 0.1 mmol) were added and the mixture was reacted at 100 °C for 8 hours. The mixture was filtered, concentrated, and purified by column chromatography to obtain 120.0 mg of intermediate 8-1, with a yield of 23.7%. LC-MS m / z (ESI) [M+H]+: C 34 H 44 The calculated value for N7O3Si is 626.3 and the measured value is 626.3.

[0241] Synthesis of Compound 8: 2-(6-methylpyridin-yl)-3-(2-(1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)pyridin-4-yl)-5,5a,6,6a-tetrahydrocyclopropane[3,4]pyrrolo[1,2-a]imidazole

[0242] Intermediate 8-1 (5.0 mg, 0.01 mmol) was dissolved in 5 ml of methanol, 1 ml of concentrated hydrochloric acid was added, and the mixture was allowed to react at room temperature for 10 minutes. The mixture was then concentrated and dissolved in 5 ml of methanol. 0.5 ml of aqueous ammonia was added to make the mixture alkaline. The mixture was then concentrated and purified to give 1.8 mg of the final product, with a yield of 56.9%. LC-MS m / z (ESI) [M+H]:C 23 H 22 The calculated value for N7 is 396.2 and the measured value is 396.2. Examples 9 to 11

[0243] The following examples were prepared according to the synthetic route of Example 1 using the appropriate starting materials.

[0244] [Table 1] TIFF2025526717000025.tif86150

[0245] Examples 12 and 13 The following examples were prepared according to the synthetic route of Example 3 using the appropriate starting materials.

[0246] [Table 2]

[0247] Examples 14 to 15 The following examples were prepared according to the synthetic route of Example 4 using the appropriate starting materials.

[0248] [Table 3]

[0249] Examples 16 to 21 The following examples were prepared according to the synthetic route of Example 5 using the appropriate starting materials.

[0250] [Table 4] TIFF2025526717000029.tif164151

[0251] Examples 22 to 23 The compounds of each of the following examples were prepared according to the synthetic route of Example 7 using the appropriate starting materials.

[0252] [Table 5]

[0253] Examples 25 to 26 The compounds of each of the following examples were prepared according to the synthetic route of Example 3 using the appropriate starting materials.

[0254] [Table 6]

[0255] Examples 27 to 34 The compounds of each of the following examples were prepared according to the synthetic route of Example 4 using the appropriate starting materials.

[0256] [Table 7] TIFF2025526717000033.tif165153TIFF2025526717000034.tif165150TIFF2025526717000035.tif181149

[0257] Examples 35 to 36 The compounds of each of the following examples were prepared according to the synthetic route of Example 5 using the appropriate starting materials.

[0258] [Table 8]

[0259] Examples 37 to 60 The compounds of each of the following examples were prepared according to the synthetic route of Example 7 using the appropriate starting materials.

[0260] [Table 9] TIFF2025526717000038.tif162150TIFF2025526717000039.tif171152TIFF2025526717000040.t if202152TIFF2025526717000041.tif182151TIFF2025526717000042.tif155150TIFF2025526717 000043.tif162150TIFF2025526717000044.tif159152TIFF2025526717000045.tif155150TIFF20 25526717000046.tif171149TIFF2025526717000047.tif157151TIFF2025526717000048.tif89151

[0261] Example 61: (4-methylpiperazin-1-yl)(2-(4-(2-(6-methylpyridin-2-yl)-5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazin-3-yl)pyridin-2-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)ketone [ka]

[0262] Synthesis of compound 61: [ka]

[0263] Synthesis method: Intermediate 61-1: Synthesis of 2-(6-methylpyridin-2-yl)-5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazine

[0264] 2-Bromo-1-(6-methylpyridin-2-yl)ethan-1-one (500.0 mg, 2.3 mmol), morpholin-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 overnight. After completion of the reaction, the mixture was quenched by adding water and extracted twice with EA. The organic phases were combined, washed with saturated brine, concentrated, and purified using a silica gel column to obtain a total of 282.0 mg of intermediate 61-1 in a 56.1% yield. LC-MS m / z (ESI) [M+H]: C 12 H14 The calculated value for N3O is 216.1 and the measured value is 216.1.

[0265] 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).

[0266] Intermediate 61-2: Synthesis of 3-iodo-2-(6-methylpyridin-2-yl)-5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazine

[0267] 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 heated to 60°C for 4 hours. After the reaction was completed, the mixture was quenched by adding water and extracted twice with EA. The organic phases were combined, washed with saturated brine, concentrated, and purified to obtain a total of 23.0 mg of intermediate 61-2 in 72.6% yield. LC-MS m / z (ESI) [M+H]:C 12 H 13 The calculated value for IN3O is 342.0 and the measured value is 342.0.

[0268] 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).

[0269] Intermediate 61-3: Synthesis of tert-butyl 2-(4-(2-(6-methylpyridin-2-yl)-5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazin-3-yl)pyridin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

[0270] tert-Butyl 2-(4-bromopyridin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5-(1H)-carboxylate (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 ester (58.6 mg, 0.2 mmol), and Pd(dppf)Cl (7.5 mg, 0.01 mmol) were added. The mixture was reacted overnight at 100°C under nitrogen gas protection. After cooling to room temperature, intermediate 61-2 (35.0 mg, 0.1 mmol), potassium carbonate (28.4 mg, 0.2 mmol), 2 ml of HO, and Pd-127 (7.8 mg, 0.01 mmol) were added, and the mixture was reacted at 100 °C for 5 hours under nitrogen gas protection. After cooling to room temperature, water was added, and the mixture was extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified to obtain intermediate 61-3 (42.0 mg, 65.0% yield). LC-MS m / z (ESI) [M+H]: C 33 H 44 The calculated value for N7O4Si is 630.3 and the measured value is 630.3.

[0271] Intermediate 61-4: Synthesis of 2-(6-methylpyridin-2-yl)-3-(2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)pyridin-4-yl)-5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazine

[0272] Intermediate 61-3 (42.0 mg, 0.1 mmol) was dissolved in 10 ml of DCM, and zinc bromide (60.3 mg, 0.3 mmol) was added. The mixture was allowed to react 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 brine, dried over anhydrous sodium sulfate, and concentrated to give 35.0 mg of crude intermediate 61-4 in a 99.1% yield.

[0273] Intermediate 61-5: Synthesis of (4-methylpiperazin-1-yl)(2-(4-(2-(6-methylpyridin-2-yl)-5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazin-3-yl)pyridin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)ketone

[0274] Intermediate 61-4 (35.0 mg, 0.1 mmol) was dissolved in 10 mL of DCM and cooled to 0 °C. Triphosgene (24.5 mg, 0.1 mmol) was added and the mixture was allowed to react for 5 minutes. Triethylamine (66.9 mg, 0.7 mmol) was added dropwise and the mixture was allowed to react for 0.5 hours. N-methylpiperidine (7.9 mg, 0.1 mmol) was added to the mixture and the mixture was allowed to warm to room temperature. After the reaction was completed, the mixture was quenched with water and extracted with DCM. The organic phases were combined, washed with saturated brine, and concentrated and purified to give 31.0 mg of intermediate 61-5 in a 71.5% yield.

[0275] Synthesis of Compound 61: (4-methylpiperazin-1-yl)(2-(4-(2-(6-methylpyridin-2-yl)-5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazin-3-yl)pyridin-2-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)ketone

[0276] 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 incubated at 50 °C for 2 hours. The mixture was concentrated, dissolved in 5 ml of methanol, adjusted to alkaline by adding 0.5 ml of aqueous ammonia, concentrated, and purified using a preparative plate to obtain 4.6 mg of the final product in 18.5% yield. LC-MS m / z (ESI) [M+H]:C 28 H 32 The calculated value for N9O2 is 526.3 and the measured value is 526.3.

[0277] Example 62: (4-methylpiperazin-1-yl)(2-(4-(2-(6-methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)ketone [ka]

[0278] Synthesis of compound 62: [ka]

[0279] Synthesis method: Intermediate 62-1: Synthesis of ethyl 3-(6-methylpyridin-2-yl)-3-oxopropionate

[0280] 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 phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a total of 530.3 mg of crude intermediate 62 in 77.3% yield. 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.

[0281] Intermediate 62-2: Synthesis of ethyl 3-(6-methylpyridin-2-yl)-3-((2-oxopyrrolidin-1-yl)imino)propionate

[0282] 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, at which point the reaction was completed. The reaction mixture was concentrated to remove pyridine, and water was added to the concentrate. The concentrate was extracted twice with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a total of 580.1 mg of crude intermediate 62-2 in 96.6% yield.

[0283] Intermediate 62-3: Synthesis of 2-(6-methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxylic acid

[0284] 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, 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 phases were 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 in 69.4% yield. LC-MS m / z (ESI) [M+H]+: C 13 H 13 The calculated value for N3O2 is 244.1 and the measured value is 244.1.

[0285] Intermediate 62-4: Synthesis of 3-bromo-2-(6-methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole

[0286] 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 complete the reaction. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified using a silica gel column to obtain a total of 350.1 mg of intermediate 62-4 in 90.0% yield. LC-MS m / z (ESI) [M+H]:C 12 H 12 Calculated value for BrN3 is 278.0 and measured value is 278.0.

[0287] Intermediate 62-5: Synthesis of tert-butyl 2-(4-(2-(6-methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydroxypyrrolo[3,4-d]imidazole-5(1H)-carboxylate

[0288] tert-Butyl 2-(4-bromopyridin-2-yl)-1-(2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5-(1H)-carboxylate (106.9 mg, 0.2 mmol) and pinacol bisboronate (109.6 mg, 0.4 mmol) were dissolved in 8 mL of dioxane, and 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 reacted at 90°C for 16 hours. The reaction mixture was cooled to room temperature, and intermediate 62-4 (60.0 mg, 0.2 mmol) was dissolved in 4 mL of dioxane. Potassium carbonate (89.2 mg, 0.6 mmol) and Pd(dppf)Cl (16.0 mg, 0.02 mmol) were added to the reaction mixture. 3 mL of water was added, the mixture was purged with nitrogen gas, and the reaction mixture was allowed to react 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 phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified using a silica gel column to obtain a total of 70.6 mg of intermediate 62-5 in 52.9% yield. LC-MS m / z (ESI) [M+H]: C 33 H 43 The calculated value for N7O3Si is 614.3 and the measured value is 614.5.

[0289] Intermediate 62-6: Synthesis of 2-(4-(2-(6-methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole

[0290] 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, and 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%.

[0291] Intermediate 62-7: Synthesis of (4-methylpiperazin-1-yl)(2-(4-(2-(6-methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydro-pyrrolo[3,4-d]imidazol-5(1H)-yl)ketone

[0292] N-Methylpiperazine (6.2 mg, 0.06 mmol) was dissolved in 5 mL of dichloromethane and 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 allowed to react for 5 minutes. A dichloromethane solution of 62-6 (16.3 mg, 0.03 mmol) was then added to the reaction mixture, and the mixture was warmed to room temperature and stirred. After completion of the reaction, the mixture was quenched by adding water, extracted with dichloromethane, and the organic phases were combined, washed with saturated brine, and concentrated. The mixture was purified using a silica gel column to obtain 15.2 mg of intermediate 62-7 in a yield of 37.7%.

[0293] Synthesis of Compound 62: (4-methylpiperazin-1-yl)(2-(4-(2-(6-methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)-4,6-dihydro-pyrrolo[3,4-d]imidazol-5(1H)-yl)ketone

[0294] 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, adjusted to alkaline by adding 0.5 ml of aqueous ammonia, concentrated, and purified on a silica gel plate to obtain 5.3 mg of the final product in 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 510.3.

[0295] Example 63: 2-(4-(2-(6-methylpyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-5-(methylsulfonyl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine [ka]

[0296] Synthesis of compound 63: [ka]

[0297] Synthesis method: Intermediate 63-2: Synthesis of 3-bromobenzidine methyl ester

[0298] Intermediate 63-1 (5.0 g, 27.5 mmol) was dissolved in 50 ml of methanol, and sodium methoxide (3.0 g, 55.4 mmol) was added to the reaction solution. The mixture was allowed to react at room temperature for 16 hours. The reaction solution was concentrated to remove methanol, and water was added to the concentrate. The mixture was extracted twice with ethyl acetate. The organic phases were 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%.

[0299] Intermediate 63-3: Synthesis of 3-bromobenzimidazole hydrochloride

[0300] 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 thereto, followed by reaction for 2 hours at 80° C. After completion of the reaction, the mixture was concentrated to obtain 3.2 g of Intermediate 63-3, with a yield of 57.1%.

[0301] Intermediate 63-4: Synthesis of tert-butyl 2-(4-bromopyridin-2-yl)-3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate

[0302] 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 next day, TLC monitoring showed that the starting materials had reacted completely. The reaction mixture was quenched by adding water and extracted twice with EA. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified using a silica gel column to obtain 2.9 g of intermediate 63-4 in 56.6% yield. 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.

[0303] Intermediate 63-5: Synthesis of tert-butyl 2-(4-bromopyridin-2-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)-3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate

[0304] Intermediate 63-4 (2.9 g, 7.6 mmol) was dissolved in 30 mL of THF, cooled to 0 °C, and NaH (60%) (0.6 g, 15.2 mmol) was added. The mixture was stirred for 0.5 hours, and then SEMCl (1.9 g, 11.4 mmol) was added. After the addition, the mixture was warmed to room temperature and stirred. After the reaction was complete, water was added to quench the reaction, and EA was added for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified using a silica gel column to obtain 2.7 g of intermediate 63-5 in a 68.8% yield. LC-MS m / z (ESI) [M+H] + :C 22 H 34 The calculated value for BrN4O3Si is 509.2 and the measured value is 509.1.

[0305] Intermediate 63-6: Synthesis of (2-(5-(tert-butoxycarbonyl)-3-((2-(trimethylsilyl)ethoxy)methyl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)pyridin-4-yl)boronic acid

[0306] 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 dibromodimethoxyethane (393.3 mg, 0.5 mmol) were added. The mixture was purged with nitrogen gas, and potassium acetate (1.6 g, 15.6 mmol) was added. The mixture was purged with nitrogen gas again, and the temperature was raised to 90 °C and the reaction was carried out overnight. The next day, the reaction mixture was cooled to room temperature, concentrated, and purified using a silica gel column to obtain 1.2 g of intermediate 63-6 in 48.1% yield. LC-MS m / z (ESI) [M+H] + :C 22 H 36 The calculated value for BN4O5Si is 475.3 and the measured value is 475.3.

[0307] Intermediate 63-7: Synthesis of tert-butyl 2-(4-(2-(6-methylpyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)-3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate

[0308] 3-Bromo-2-(6-methylpyridin-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 dibromodimethoxyethane (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 mixture was allowed to react overnight. Water was added, the mixture was extracted, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel column to obtain 89.4 mg of intermediate 63-7 in 39.6% yield. LC-MS m / z (ESI) [M+H] + :C 34 H 46 The calculated value for N7O3Si is 628.3 and the measured value is 628.3.

[0309] Intermediate 63-8: Synthesis of 2-(4-(2-(6-methylpyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine

[0310] 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 atmosphere was purged with nitrogen, and the mixture was allowed to react overnight at room temperature. The next day, after the reaction was complete, 0.5 mL of aqueous ammonia was added to the reaction mixture, followed by water. The mixture was extracted twice with DCM. The organic phases were combined, washed once with saturated sodium bicarbonate solution and once with saturated brine, and concentrated to give 75.0 mg of crude intermediate 63-8 in 100% yield.

[0311] Intermediate 63-9: Synthesis of (2-(4-(2-(6-methylpyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-5-(methylsulfonyl)-3-((2-(trimethylsilyl)ethoxy)methyl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine

[0312] 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, and methanesulfonyl chloride (8.3 mg, 0.1 mmol) was added. The mixture was allowed to react at room temperature for 1 hour, and water was added to the reaction mixture. The mixture was 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%.

[0313] Synthesis of Compound 63: 2-(4-(2-(6-methylpyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-5-(methylsulfonyl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine

[0314] 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 incubated at 50 °C for 2 hours. The mixture was concentrated, dissolved in 5 ml of methanol, 0.5 ml of aqueous ammonia was added, and the mixture was concentrated and purified to give 5.2 mg of the final product in a 20.1% yield. LC-MS m / z (ESI) [M+H]+ :C 24 H 26 The calculated value for N7O2S is 476.2 and the measured value is 476.2. Example 64

[0315] The compounds of the following examples were prepared according to the synthetic route of Example 1 using the appropriate starting materials.

[0316] [Table 10]

[0317] Examples 65 to 74 The compounds in each of the following examples were prepared according to the synthetic route of Example 62 using the appropriate starting materials.

[0318] [Table 11] TIFF2025526717000057.tif165151TIFF2025526717000058.tif178151TIFF2025526717000059.tif173149TIFF2025526717000060.tif176152

[0319] Examples 75 to 76 The compounds in each of the following examples were prepared according to the synthetic route of Example 63 using the appropriate starting materials.

[0320] [Table 12]

[0321] Example 77: Compound activity detection 1. Reagents and Consumables

[0322] [Table 13]

[0323] 2. Experimental Method 2.1 Preparation of 1x kinase reaction buffer

[0324] [Table 14]

[0325] 2.2 Kinase reaction conditions:

[0326] [Table 15]

[0327] 2.3 Activity measurement steps: The activity test is based on the ATP consumption of the TGFβR1 phosphorylation substrate TGFβR1 tide. This experiment uses the ADP-Glo method to measure kinase activity and determine IC50 values to evaluate the inhibitory ability of test compounds against human TGFβR1. DSM was used as the negative control, and LY364947 was used as the positive control. The specific experimental steps were as follows: Compounds were diluted 4-fold with DMSO in a dilution plate, with a final starting compound concentration of 10 μM and 10 concentration gradient points. Compounds were diluted 50-fold with kinase reaction buffer and shaken on a shaker 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 compound diluted in buffer was added to each well. The plate was sealed with a sealing film and centrifuged at 1000 g for 30 seconds and left at room temperature for 10 minutes. TGFβR1 tide and ATP solutions were prepared in enzyme reaction buffer, and 2 μl of the TGFβR1 tide / ATP solution was added to the reaction plate. The plate was sealed with sealing film and centrifuged at 1000 g for 30 seconds, followed by incubation at room temperature for 60 minutes. 4 μL of ADP-Glo was transferred to the 384-well 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 the 384-well reaction plate, centrifuged at 1000 rpm / min for 1 minute, and incubated at 25°C for 40 minutes. Relative luminescence unit (RLU) signals were read using a BMG microplate reader, and the signal intensity was used to represent kinase activity. 3. Data Analysis

[0328] 3.1 The calculation of the inhibition rate is as follows: Compound inhibition rate (%inh) = 100% - (compound - positive control) / (negative control - positive control) * 100%

[0329] 3.2 The IC50 was calculated and the inhibition curve of the compound was constructed. The IC50 (half maximal inhibitory concentration) of the compound was obtained using the following nonlinear fitting equation, and data analysis was performed using Graphpad 7.0 software. Y=Bottom+(Top-Bottom) / (1+10^((LogIC50-X)*Hill Slope)) X: logarithmic value of compound concentration Y: Inhibition rate (%inhibition)

[0330] 3.3 Report Secondary Inspection 3.3.1 After one experimenter has completed the report, the other experimenter will review it again to ensure the accuracy of the data analysis. 3.3.2 Data are derived from BMG and analyzed manually. 3.3.2.1 The ratio is converted to percent inhibition, and IC50 is calculated from the percent inhibition using Prism GraphPad 7.0. 3.3.2.2 The accuracy of the results was verified by recalculating the IC50 ratio.

[0331] 3.4 Quality Control Z factor>0.5, S / B>2. Positive control IC 50 is within three times the historical average.

[0332] 4. Activity test results

[0333] [Table 16] TIFF2025526717000066.tif110152

[0334] As can be seen from the above results, the compounds of the present application exhibit TGFβR1 inhibitory effects equal to or greater than those of the positive control LY364947, and can therefore be used in the treatment of TGF-β (particularly TGF-β1)-related diseases or conditions.

[0335] While particular embodiments of the present invention have been illustrated and described, it is not intended that these embodiments illustrate and describe all possible forms of the present application. Rather, the words used in the specification of the present invention are descriptive 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 the present disclosure. It is, therefore, intended in the appended claims to cover all such changes and modifications within the scope of the present invention.

Claims

1. A compound of formula (II), 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: 【Chemical 1】 wherein m=0 or 1; R １ is C ５－１６ aryl, 5- to 16-membered heteroaryl, ５－１６ Aryl and 5- to 16-membered heteroaryl are each 1, 2, 3, or 4 R １ｂ each optionally substituted with R １ｂ represents each occurrence of halogen, -OH, -NO ２ , -CN, -SF ５ , -SH, -SC １－４ Alkyl, oxo, C １－４ Alkyl, C １－４ Alkyl halides, C １－４ Alkoxy, C １－４ Halogenated alkoxy, 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 １３ , R １４ and R １５ For each occurrence, H, C １－６ Alkyl, C １－６ Alkyl halides, C ３－７ Alicyclic group, 3- to 10-membered heteroalicyclic group, C ５－８ Aryl, 5- to 7-membered heteroaryl, C ７－１１ dicycloaryl, 7- to 11-membered dicycloheteroaryl, —C １－４ Alkyl-(C ３－７ alicyclic group), -C １－４ alkyl-(3- to 10-membered heteroalicyclic group), —C １－４ Alkyl-(C ６－１２ dicycloaliphatic group), —C １－４ alkyl-(6- to 12-membered dicycloaliphatic group), —C １－４ Alkyl-(C ８－１５ -membered tricycloaliphatic group), —C １－４ alkyl-(8- to 15-membered tricycloaliphatic group), —C １－４ Alkyl-(C ５－８ aryl) and -C １－４ alkyl-(5-10 membered heteroaryl), wherein each member within said group is selected from the group consisting of halogen, —OH, —NH ２ , -NH(CH ３ ), -N(CH ３ ) ２ , -CN, -NO ２ , -SF ５ , -SH, -SC １－４ Alkyl, oxo, C １－４ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－７ Alicyclic group, 3- to 10-membered heteroalicyclic group, C ５－８ Aryl, 5- to 7-membered heteroaryl, C ７－１１ Dicycloaryl, 7- to 11-membered 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 halides, C １－４ Alkoxy and C １－４ optionally substituted with 0, 1, 2, 3, or 4 substituents each independently selected from the group consisting of halogenated alkoxy, or R １３ and R １４ form a 3- to 14-membered ring together with the atoms to which they are attached; R ２ The number of R is 1, 2, 3 or 4, and each R ２ is H, halogen, -CN, -OH, -NO ２ , -NR ７ R ８ , C １－４ Alkyl, C １－４ Alkyl halides, C １－４ Alkoxy, C ３－６ are independently selected from an alicyclic group and a 4- to 6-membered heteroalicyclic group, ７ and R ８ is H, C １－６ Alkyl, C １－４ Alkyl halides, C １－４ alkoxy, or R ７ , R ８ and form a 3- to 6-membered ring together with the N atom connected thereto.)

2. R １ is a substituted or unsubstituted phenyl, naphthyl, anthryl, phenanthryl, azulenyl, biphenyl, thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolyl, isoindolyl, indolizinyl, benzyl, and wherein the substituents are selected from benzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, purine, quinolidinyl, quinolyl, isoquinolyl, cinnolyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, or phenoxazinyl, and when the groups are substituted, the substituents are selected from 1, 2, 3, or 4 R １ｂ where R １ｂ represents each occurrence of halogen, -OH, -NO ２ , -CN, -SF ５ , -SH, -SC １－４ Alkyl, oxo, C １－４ Alkyl, C １－４ Alkyl halides, C １－４ Alkoxy, C １－４ Halogenated alkoxy, C ２－８ Alkenyl, C ２－８ Alkynyl, C ３－７ independently selected from an alicyclic group, a 3- to 10-membered heteroalicyclic group, and preferably R １ is selected from substituted or unsubstituted indazolyl, benzimidazolyl, indolyl, isoindole, triazolopyridyl, imidazopyridyl, benzoxazole, benzothiazole, tetrahydropyrroloimidazole or pyrazolopyridyl; 10. The compound of claim 1, 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.

3. R １ is selected from substituted or unsubstituted indazolyl, benzimidazolyl, indolyl, isoindole, triazolopyridyl, imidazopyridyl, benzoxazole, benzothiazole, tetrahydropyrroloimidazole, or pyrazolopyridyl; R １ When is substituted, the substituents may be 1, 2, 3 or 4 R as defined above. １ｂ and preferably one or two R １ｂ and each R １ｂ is halogen, -OH, -NO ２ , -CN, oxo, C １－４ Alkyl, C １－４ Alkyl halides and C １－４ independently selected from alkoxy; 3. A compound according to claim 1 or 2, 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.

4. R ２ The number of R is 1, 2, 3 or 4, and each R ２ is H, halogen, -CN, -OH, -NO ２ , -NR ７ R ８ , C １－４ Alkyl, C １－４ Alkyl halides, C １－４ alkoxy, where R ７ and R ８ is H, C １－６ Alkyl, C １－４ Alkyl halides, C １－４ alkoxy, or R ７ , R ８ and form a 3- to 6-membered ring together with the N atom to which they are linked, 4. A compound according to any one of claims 1 to 3, 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.

5. R ２ is H, CH ３ , F, Cl and Br; 5. A compound according to any one of claims 1 to 4, 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.

6. The compound according to claim 1, wherein the compound is selected from the following compounds 5, 8, 16 to 21, 35, and 36, 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. 【Chemistry 2】

7. A compound according to any one of claims 1 to 6, 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; one or more pharmaceutically acceptable carriers, adjuvants or excipients; A pharmaceutical composition comprising:

8. Use of a compound according to any one of claims 1 to 6, 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, or a pharmaceutical composition according to claim 7, in the manufacture of a medicament for treating a TGF-β related disease or condition, preferably a TGF-β1 related disease or condition.

9. The use according to claim 8, wherein the TGF-β-related disease or condition is selected from cancer, viral infection, chronic nephritis, acute nephritis, diabetic nephropathy, osteoporosis, arthritis, wound healing, scarring, ulcers, corneal wounds, valvular stenosis, congestive heart necrosis, neurological dysfunction, Alzheimer's syndrome, peritoneal or subcutaneous adhesions, arteriosclerosis, skin fibrosis and skin aging due to fat loss, skeletal or chondrocyte damage, hypophosphatemic disorders, and organ fibrosis.

10. The use according to claim 8, wherein the TGF-β-related disease or condition is selected from hepatocellular carcinoma, breast cancer, bladder cancer, colorectal cancer, melanoma, mesothelioma, lung cancer, prostate cancer, membranous adenocarcinoma, testicular cancer, thyroid cancer, squamous cell carcinoma, glioblastoma, neuroblastoma, uterine cancer, rhabdomyosarcoma, renal fibrosis, liver fibrosis, pulmonary fibrosis, skin scarring, skin fibrosis, and skin aging due to fat loss.

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