Protein tyrosine kinase inhibitors and their medical use

Abstract

The present invention relates to protein tyrosine kinase (PTK) inhibitors for treating proliferative diseases or conditions mediated by protein tyrosine kinases (PTKs), such as ocular diseases and malignant tumors accompanied by pathological neovascularization, retinal ischemia, retinal edema, diabetic retinopathy, etc. Specifically, the present invention relates to compounds having protein tyrosine kinase inhibitory activity and / or compounds that improve solubility and intraocular bioavailability (BA), and their use in treating ocular diseases and malignant tumors.

Description

[Technical Field]

[0001] The present invention relates to the pharmaceutical field, and more specifically to protein tyrosine kinase inhibitors and their use for treating proliferative disorders or conditions mediated by protein tyrosine kinases. [Background technology]

[0002] Age-related macular degeneration (AMD) and diabetic retinopathy (DR) are the most common eye diseases and are major causes of blindness in the elderly and working-age populations. These lesions are associated with neovascularization and extravascular exudation in the posterior segment of the eye. Exudative AMD is characterized by neovascularization from the choroidal microvascular bed and infiltration into the subretinal space, while DR preferentially manifests as changes in exudation and neovascularization at the retinal level. Both AMD and DR are characterized by endothelial cell (EC) proliferation and migration, increased vascular permeability, and inflammation, in which vascular endothelial growth factor-A (VEGF-A) and its corresponding receptor (VEGFR) play crucial roles. Furthermore, tumor growth and metastasis depend on sufficient oxygen and nutrients provided by the tumor vascular network. Tumor angiogenesis depends on a very complex sequence of growth factor signaling, endothelial cell proliferation, extracellular matrix (ECM) remodeling, and stromal cell interactions. One of the most important pro-angiogenic factors is vascular endothelial growth factor (VEGF). It has become clear that overexpression or upregulation of receptor tyrosine kinase (RTK) activity is involved in many proliferative disorders, including eye diseases, tumors, and cancers. Receptor tyrosine kinases are kinase enzymes that modify proteins by chemically adding phosphate groups (phosphorylation). Phosphorylation usually leads to functional changes in target proteins by altering enzyme activity, cellular localization, and binding to other proteins. Kinases are known to be used to regulate most cellular pathways, especially those involved in signal transduction. Until now, one way to inhibit the VEGF pathway has been to inhibit receptor tyrosine kinase (RTK) activity. The therapeutic goal of protein tyrosine kinase inhibitors in the treatment of eye diseases such as age-related macular degeneration (AMD) and diabetic retinopathy (DR) is to eliminate pathological angiogenesis and disease progression and prevent visual impairment. Furthermore, VEGFR plays an important role as a pro-angiogenic factor in tumor growth, invasion, and exudation, making it an excellent therapeutic target for many cancers. To date, the U.S. FDA has not approved the use of small molecule tyrosine kinase inhibitors in the treatment of neovascular age-related macular degeneration and diabetic retinopathy. [Overview of the project]

[0003] This invention provides compounds for treating ocular diseases such as pathological angiogenesis, retinal ischemia, retinal edema, and diabetic retinopathy, as well as proliferative disorders or symptoms associated with malignant tumors, all mediated by protein tyrosine kinases. The clinical success of VEGF antibody drugs (pegaptanib, ranibizumab, aflibercept, and brolucizumab) has supported this concept. For example, the U.S. Food and Drug Administration (FDA) has approved the administration of aflibercept (VEGF Trap-Eye) in the treatment of neovascular age-related macular degeneration. Ziv-aflibercept, which has the same molecular structure, has also been approved by the FDA as an adjunctive therapy for patients with metastatic colorectal cancer. However, these VEGF antibody drugs require intravitreous injection into the eye by a retinal specialist. For clinicians and patients, frequent intravitreal injections are inconvenient and carry rare but serious injection-related risks (endophthalmitis, retinal detachment, cataracts, intraocular inflammation, etc.), resulting in many patients being unable to receive injections as scheduled and thus reducing treatment effectiveness. Given the promising clinical results of VEGF antibody biologics and the challenges associated with intravitreal injections, we are developing small-molecule anti-angiogenic agents for ocular administration, particularly VEGFR tyrosine kinase inhibitors, as a treatment for neovascular age-related macular degeneration. Compared to recombinant proteins, small-molecule targeted VEGFR tyrosine kinase inhibitors offer several advantages. They can be administered as eye drops to avoid intravitreal injections, and they can permeate the cell membrane and directly interact with the cytoplasmic domain of receptor tyrosine kinase (RTK). Furthermore, small-molecule eye drops are less expensive. However, to date, there are no small-molecule tyrosine kinase inhibitors approved by the US FDA for the treatment of neovascular age-related macular degeneration and diabetic retinopathy.

[0004] Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) are known as the most potent vascular permeability factors and endothelial-specific mitogens, playing crucial roles in endothelial cell proliferation, migration, and angiogenesis. Angiogenesis is a key mechanism in many physiological and pathological processes, involving endothelial cell proliferation, migration, and survival, and ultimately leading to the formation of renal tubules and promoting angiogenesis. Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) play important roles in pathological angiogenesis, such as tumor progression and ocular neovascularization. For example, VEGF expression levels are significantly positively correlated with the degree of angiogenesis in tumor tissue. VEGF acts on the VEGFR2 receptor, activating the phosphorylation of VEGFR receptor tyrosine kinase and triggering the transmission of abnormal cell signals, thereby promoting endothelial cell proliferation and angiogenesis, and is a major contributor to many cancers and ocular diseases involving pathological neovascularization. The compounds of the present invention (for example, those prepared in Example 1) inhibit anti-angiogenic tyrosine kinases and effectively antagonize the activity of all VEGFR receptor (VEGFR1, VEGFR2, VEGFR3) tyrosine kinases, thereby avoiding high selectivity for EGFR inhibition (Example 2).

[0005] VEGFR2 is the primary receptor for VEGF-induced endothelial cell signaling. During development and / or after tissue injury, when the ligand VEGF binds to the receptor, VEGFR2 undergoes autophosphorylation, becomes activated, induces angiogenesis, and bypasses occluded blood vessels. The compounds of the present invention exhibit significant inhibitory activity against VEGF-induced VEGFR2 autophosphorylation (pVEGFR2) in human endothelial cells, inhibiting neovascularization by blocking signaling in abnormal cells (Example 3). The primary function of signaling derived from the VEGFR receptor is to promote endothelial cell proliferation and neovascularization, and the compounds of the present invention suggest the ability to inhibit VEGF-induced human endothelial cell proliferation at nanomolar concentrations. In summary, the compounds of the present invention are novel tyrosine kinase inhibitors. In addition to treating angiogenic age-related macular degeneration and diabetic retinopathy, these novel tyrosine kinase inhibitors can also be applied to oncological adaptation therapies that lead to tumor cell death by inhibiting the formation of neovascularization, thereby blocking the blood and nutrient supply necessary for tumor growth.

[0006] One of the goals of medicinal chemistry is to improve the bioavailability and stability of compounds to enhance therapeutic efficacy. Bioavailability refers to the rate and degree to which a therapeutic agent is absorbed from its drug form and made available at the site of action. Conventional VEGF tyrosine kinase inhibitors have the problem of low solubility and / or low kinase inhibitory activity, which greatly affects the bioavailability of such compounds and thus reduces their therapeutic efficacy. Compounds with low solubility are particularly unsuitable for eye drops. For example, axitinib has good inhibitory activity against VEGF tyrosine kinases (VEGFR1, VEGFR2, and VEGFR3), but has low solubility (less than 2 μg / mL). The present invention provides, for example, a compound with a thermodynamic solubility of 10 μg / mL or more, or a thermodynamic solubility of 100 μg / mL or more, or a thermodynamic solubility of 1,000 μg / mL or more, and IC for VEGFR2. 50 If the impedance is 100nM or less, or the IC for VEGFR2 50 If the impedance is 10nM or less, or if the IC is less than or equal to VEGFR2 50The present invention provides a compound (Example 4) that has the advantage of significantly improving solubility, such as having a concentration of 1 nM or less, and / or possessing excellent kinase inhibitory activity.

[0007] Melanocytes in the eye are located in the retinal pigment epithelium, choroid, ciliary body, and iris of the posterior segment. The binding of compounds to melanin can affect the pharmacokinetics of the eye after topical administration. This invention provides compound-containing eye drops for the treatment of age-related macular degeneration and diabetic retinopathy. These are diseases occurring in the posterior segment, and the compound-containing eye drops are intended for effective delivery to the posterior segment tissues. In such cases, many drugs can strongly bind to melanin tissue in the posterior segment (retinal pigment epithelium, choroid) or the anterior segment (ciliary body, iris). Many clinical drugs bind to melanin, thus affecting the pharmacokinetics of the eye. The binding rate of compounds to melanin is an important factor in ocular pharmacokinetics and pharmacodynamics, and must be considered in drug discovery and drug development, as it is mainly related to the tissue distribution of compounds within the eye. This invention provides the effect of melanin on compounds (Example 5).

[0008] One of the key challenges in the development of small molecule tyrosine kinase inhibitors for clinical use in age-related macular degeneration and diabetic retinopathy is overcoming "on-target" toxicity. Inhibiting VEGFR in a healthy vascular system can lead to serious adverse events such as hypertension, bleeding, and thrombosis. Despite many clinical successes in tumor-specific therapies, the safety of oral VEGFR-2 inhibitors may be the main reason why clinical use and / or development in patients with age-related macular degeneration and diabetic retinopathy has been limited. Theoretically, topical eye drops could provide an effective treatment that limits systemic exposure and avoids the problem of on-target toxicity.

[0009] While topical administration to the eye has proven to be a successful means of treating anterior segment-related diseases (such as glaucoma), there are still no FDA-approved topical therapies for post-ocular tissue-related eye diseases (such as neovascular AMD and diabetic retinopathy). This is largely due to the anatomical and physiological barriers that the human eye has evolved to protect itself from foreign substances. The tear film is one of the first barriers that must be overcome. Compounds from the anterior segment are rapidly washed away by the tear film and drained through the nasolacrimal duct, so the compounds need to be rapidly absorbed after topical instillation. On the other hand, absorption / penetration into ocular tissue can also be difficult. One absorption pathway involves penetration into the cornea. The cornea is composed of epithelium with tight junctions and alternating lipophilic and hydrophilic layers. Another absorption pathway is penetration into the conjunctiva followed by diffusion into the sclera. The sclera is a relatively easily permeable ocular tissue. However, because the conjunctiva is a highly vascular tissue, drugs that enter the conjunctiva tend to be "lost" into the systemic circulation. Compounds exposed in the sclera can diffuse into the choroid, which is a primary target tissue for neovascular AMD. Diffusion from the choroid to the retina (a secondary target tissue for neovascular AMD) is further attenuated through the blood-retinal barrier (BRB). The BRB functions similarly to the blood-brain barrier and can be a strong barrier to compound diffusion. Due to these anatomical and physiological barriers, it is estimated that less than 5% of a locally administered dose reaches the posterior ocular tissues. Despite these challenges associated with local administration, the present invention focuses on structure-activity relationships (SARs) related to ocular and blood exposure. Effective delivery to posterior ocular tissues (choroid and retina) can be achieved by eye drops containing the compound (Example 6). The rapid degradation of the compound in plasma is thought to help avoid systemic on-target toxicity issues. Posterior ocular exposure to axitinib is relatively low, and it is below the detection limit in the retina. The present invention provides an ophthalmic formulation containing a compound that binds to relevant receptors targeting the eye, increases bioavailability in the posterior segment of the eye, and maintains sufficient drug concentration in the posterior segment (such as the choroid and retina) to improve problems in the delivery of conventional topical therapeutic agents to the eye.

[0010] Many eye drops have limited permeability across the corneal and conjunctival barrier, which can be a major limitation of eye drops. Achieving therapeutic efficacy in posterior segment tissues requires high concentrations of the compound in the ophthalmic formulation. Depending on the compound (the molecule itself or its high concentration), ophthalmic formulations can have side effects on anterior segment tissues (conjunctiva, cornea, and / or lens), potentially causing damage to the ocular surface such as corneal epithelial defects and erosion. Clinically, ocular side effects such as epithelial degeneration and defects, ulcers, thinning of the corneal epithelium, erosion, and / or corneal edema, and keratitis have been observed, particularly after treatment with EGFR antibody drugs. EGFR is a major factor in wound healing of human corneal epithelial cells. Therefore, it is necessary to select a compound for a topical ophthalmic formulation that can avoid EGFR activity inhibition. The compound of the present invention effectively antagonizes VEGFR1, VEGFR2, and VEGFR3 tyrosine kinase activity, and also exhibits high selectivity for EGFR tyrosine kinase activity inhibition (Example 2).

[0011] Age-related macular degeneration (AMD) is an eye disease in which degeneration occurs in the macula, the area of ​​the retina responsible for clear and fine vision, leading to vision loss. In exudative AMD, choroidal blood vessels (choroidal neovascularization, CNV) sprout and expand into the submacular space, causing fluid and blood to leak out. This can lead to retinal edema, scar tissue formation, and irreversible damage to the macula. Diabetic retinopathy is a common complication of diabetes, and many of the structural and functional abnormalities of the retina are associated with the progression of diabetes. Most people with diabetes for more than 15 years suffer from diabetic retinopathy. Diabetic retinopathy is divided into two stages depending on the stage of its progression: a non-proliferative stage (also called the early stage) characterized by vascular leakage, and a proliferative or late stage characterized by proliferation of retinal blood vessels induced by various growth factors. Based on the properties of the compounds of the present invention as effective VEGF receptor inhibitors, the present invention evaluates the in vivo efficacy of the compounds of the present invention using several animal models of choroidal and retinal neovascular disease. Upregulation of VEGF causes abnormal proliferation and leakage of retinal blood vessels, leading to visual impairment. Injection of VEGF into the vitreous humor of Dutch-belted rabbits causes transient retinal leakage, similar to exudative AMD and diabetic retinopathy in humans. The compounds of the present invention can demonstrate inhibitory efficacy against retinal leakage in this model. The oxygen-induced retinopathy (OIR) mouse model has reproducible and quantifiable proliferative retinal neovascularization, closely resembling the clusters formed in mouse OIR where human vascular pathology (vitreous neovascularization) is present. The OIR model is used to evaluate the in vivo efficacy of the compounds of the present invention in retinal vascular disease. In the rat model of laser-induced choroidal neovascularization (CNV), the rat eye is irradiated with a photocoagulation green laser pulse to locally destroy Bruch's membrane (Bruch's membrane is the extracellular matrix between the retina and choroid). Destruction of Bruch's membrane induces the production of local inflammatory factors and VEGF, leading to choroidal neovascularization (CNV). In this model, CNV formation after laser injury has already been demonstrated in humans, monkeys, pigs, and rodents, and is a VEGF-dependent pathological condition.Streptozotocin (STZ)-induced diabetic rats are considered a useful preclinical animal model for studying the pathogenesis and treatment of human diabetic retinopathy. A significant increase in retinal vascular permeability was detected in all diabetic rat groups, and these are thought to be preproliferative changes in diabetic retinopathy, such as intraretinal hemorrhage and fluorescein exudation. However, vitreous neovascularization attached to the retina and retinal folds was observed in some cases, which is a prominent symptom of severe, proliferative diabetic retinopathy, the proliferative phase of diabetic retinopathy. During the progression of diabetic retinopathy, altered expression of VEGF, an angiogenesis-related growth factor, and its receptors, VEGFR1 and VEGFR2, increased in the retinas of streptozotocin (STZ)-induced diabetic mice. The ophthalmic formulation containing the compound of the present invention will be evaluated using the STZ-induced diabetic mouse retinopathy rat model to assess the in vivo efficacy of diabetic retinopathy, particularly the inhibition of vascular leakage and neovascularization involved in the progression of diabetic retinopathy in diabetic mice.

[0012] Based on the properties of the compounds of the present invention as effective VEGF receptor inhibitors, the present invention relates to compounds useful for treating conditions caused or exacerbated by ocular neovascularization, neovascularization and / or extravasation. For example, age-related macular degeneration (AMD) (including neovascular (exudative) AMD, non-exudative AMD and geographic atrophy), diabetic retinopathy (including non-proliferative diabetic retinopathy, proliferative diabetic retinopathy and diabetic macular edema), pathological choroidal neovascularization (CNV) and extravasation resulting from some pathological mechanism (e.g., sickle cell anemia, high myopia, trauma, etc.), traumatic choroidal rupture, ocular histoplasmosis, optic disc drusen, retinal pigment streaks, and certain retinal dystrophys, any pathological mechanism Caused by pathological subretinal neovascularization and exudative vascular disease (e.g., sickle cell retinopathy, internal carotid artery cavernous fistula, Eels' disease, ocular ischemic syndrome, hyperviscosity syndrome, familial exudative vitreoretinopathy, idiopathic arteritis occlusion, retinal vasculitis, scatter choroidal retinopathy, sarcoidosis, or toxoplasmosis), uveitis, retinal vein occlusion (central or branched), ocular trauma, surgical neovascularization, surgical edema, ocular ischemia, cystic macular edema, retinopathy of prematurity, sickle cell retinopathy, capsular diseases, and / or neovascular glaucoma.

[0013] In addition, the occurrence, progression, metastasis, and formation of tumor angiogenesis of many tumors are closely related to the abnormal expression of tyrosine kinases. In particular, some tyrosine kinase receptors are abnormally expressed in solid tumor cells, and among them, the vascular endothelial growth factor receptor (VEGFR) is highly expressed in many tumor cells and tumor vascular endothelial cells. The vascular endothelial growth factor receptor (VEGFR) family is directly related to the occurrence, progression, and formation of tumor angiogenesis. In addition to eye diseases with pathological neovascularization, the clinical success of VEGF antibody drugs in the treatment of malignant tumors has proven this concept. The present invention relates to the use in the treatment of solid tumors and leukemias such as breast cancer, lung cancer (especially non-small cell lung cancer), adenocarcinoma, colorectal cancer, renal cancer, liver cancer, pancreatic adenocarcinoma, ovarian cancer, prostate cancer, glioma, glioblastoma, myeloma, acute myeloid leukemia, myelodysplasia of unknown origin, mesothelioma, myelodysplastic syndrome, etc. The present invention relates to a method for preventing the metastatic spread and growth of micrometastases of tumors. According to an embodiment of the present invention, examples of protein tyrosine kinase inhibitors that are anti-angiogenic kinase inhibitors and can be used to bring beneficial treatment results include, but are not limited to, receptor tyrosine kinase inhibitors such as VEGFR, Tie-2, and FGFR. In one aspect, the present invention

[0014]

Chemical formula

[0015] Here, R1 contains a substituted cyclic structure, R2 contains an optionally substituted substituent, R3 contains an optionally substituted substituent, X1 is an optionally substituted atom, There is provided a compound represented by formula (I), or a pharmaceutically acceptable prodrug of the compound, a pharmaceutically active metabolite of the compound, and / or a pharmaceutically acceptable salt of the compound.

[0016] In one embodiment, the present invention provides a compound shown in the present invention, or a pharmaceutically acceptable prodrug of said compound, a pharmaceutically active metabolite of said compound, and / or a pharmaceutically acceptable salt of said compound.

[0017] In one embodiment, the present invention provides a pharmaceutical composition comprising the compound of the present invention or a pharmaceutically acceptable prodrug of the compound, a pharmaceutically active metabolite of the compound and / or a pharmaceutically acceptable salt of the compound, and an optionally selected carrier.

[0018] In one embodiment, the present invention provides the use of the compound of the present invention or a pharmaceutically acceptable prodrug of the compound, a pharmaceutically active metabolite of the compound and / or a pharmaceutically acceptable salt of the compound, and / or a pharmaceutical composition of the present invention in the preparation of a drug for treating a disease mediated by protein tyrosine kinase.

[0019] In one embodiment, the present invention provides compounds of the present invention or pharmaceutically acceptable prodrugs of said compounds, pharmaceutically active metabolites and / or pharmaceutically acceptable salts of said compounds, and / or pharmaceutical compositions of the present invention for treating diseases mediated by protein tyrosine kinases.

[0020] In one embodiment, the present invention provides a method for treating a disease comprising administering a compound of the present invention or a pharmaceutically acceptable prodrug of the said compound, a pharmaceutically active metabolite of the said compound and / or a pharmaceutically acceptable salt of the said compound, and / or a pharmaceutical composition of the present invention.

[0021] In one embodiment, the present invention provides a method for modulating kinase receptor activity, comprising administering a compound of the present invention or a pharmaceutically acceptable prodrug of the said compound, a pharmaceutically active metabolite of the said compound and / or a pharmaceutically acceptable salt of the said compound, and / or a pharmaceutical composition of the present invention.

[0022] Those skilled in the art will readily gain insight into other aspects and advantages of the present invention from the following detailed description. The following detailed description illustrates and describes only exemplary embodiments of the present invention. As those skilled in the art will recognize, the content of the present invention is such that those skilled in the art can modify the specific embodiments disclosed without departing from the spirit and scope of the invention according to the present invention. Accordingly, the description in the specification of the present invention is illustrative and not limiting. [Modes for carrying out the invention]

[0023] The embodiments of the present invention will be described below using specific examples, but those familiar with this art will readily understand other advantages and effects of the present invention as disclosed herein.

[0024] Term definition In this invention, the term "basic nitrogen atom" generally refers to a nitrogen atom that is basic. For example, a basic nitrogen atom may have the ability to donate a lone pair of electrons. Basic nitrogen atoms are known in the art, for example, having a conjugate acid greater than 3 or a pKa greater than 5. For example, a nitrogen atom that is not basic may be a nitrogen atom directly bonded to O, a nitrogen atom directly bonded to an aryl ring, or a nitrogen atom directly bonded to a carbonyl group.

[0025] In this invention, the term "methyl group" generally refers to a residue derived by removing a hydrogen atom from a single carbon atom group. Methyl groups can be substituted or unsubstituted, and can be alternative or non-alternative. The term "alkyl group" generally refers to a saturated linear or branched aliphatic hydrocarbon group having a residue obtained by removing a hydrogen atom from the same or different carbon atoms of the parent alkane, and can include linear or branched groups of 1 to 20 carbon atoms. For example, alkyl groups containing 1 to 12 carbon atoms, for example, alkyl groups containing 1 to 6 carbon atoms. Non-limiting examples of alkyl groups include, but are not limited to, methyl (-CH2-), 1,1-ethyl (-CH(CH3)-), 1,2-ethyl (-CH2CH2)-, 1,1-propyl (-CH(CH2CH3)-), 1,2-propyl (-CH2CH(CH3)-), 1,3-propyl (-CH2CH2CH2-), 1,4-butyl (-CH2CH2CH2CH2-), and 1,5-butyl (-CH2CH2CH2CH2CH2-). Alkyl groups may be substituted or unsubstituted, alternative or non-alternative, for example, if substituted, the substituent may be substituted at any available bond, preferably independently and optionally, alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, sulfhydryl groups, hydroxyl groups, nitro groups, cyano groups, cycloalkyl groups, heterocyclyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, Substituted with one or more substituents selected from heterocyclylalkoxy groups, cycloalkylthio groups, heterocyclylalkylthio groups, and oxo groups, for example, hydrogen, light hydrogen, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 It can be an aliphatic group.

[0026] In the present invention, the term "aryl group" generally refers to a group having residues obtained by removing hydrogen atoms from the same or different carbon atoms of an aryl ring. The term "aryl ring" can refer to a 6-14 member all-carbon monocyclic or fused polycyclic ring (i.e., a ring sharing adjacent pairs of carbon atoms) having a conjugated π-electron system, and can be 6-10 membered, for example, benzene and naphthalene. The aryl ring can be fused to a heteroaryl group, a heterocyclyl group, or a cycloalkyl group, of which the ring bonded to the parent structure is an aryl group ring. The aryl group can be substituted or unsubstituted, and if substituted, preferably the substituent is one or more groups independently selected from the group consisting of alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, sulfhydryl groups, hydroxyl groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocyclylalkoxy groups, cycloalkylthio groups, and heterocyclylalkylthio groups.

[0027] In this invention, the term "heteroaryl group" generally refers to a group having residues obtained by removing hydrogen atoms from the same or different carbon atoms of a heteroaryl ring. The term "heteroaryl ring" refers to a heteroaryl group system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms may be selected from the group consisting of oxygen, sulfur, and nitrogen. Heteroaryl groups can be 5 to 10-membered, 5-membered, or 6-membered, and may include, for example, a furyl group, thienyl group, pyridyl group, pyrrolyl group, N-alkylpyrrolyl group, pyrimidinyl group, pyrazinyl group, imidazolyl group, tetrazole group, etc. The heteroaryl ring may be condensed with an aryl group, a heterocyclyl group, or a cycloalkyl ring, where the ring linked to the parent structure is a heteroaryl ring. The heteroarylene group may be optionally substituted or unsubstituted, and if substituted, preferably the substituent is one or more groups independently selected from the group consisting of alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, sulfhydryl groups, hydroxyl groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocyclylalkoxy groups, cycloalkylthio groups, and heterocyclylalkylthio groups.

[0028] In this invention, the term "aliphatic heterocyclyl group" usually refers to a stable, non-aromatic 3-7 membered monocyclic structure, a condensed 7-10 membered bicyclic heterocyclyl structure, or a bridged 6-10 membered bicyclic heterocyclyl structure, where these cyclic structures may be saturated or partially saturated, and in addition to carbon atoms, the cyclic structure contains one or more heteroatoms, which may be selected from the group consisting of oxygen, sulfur, and nitrogen. For example, there may be one to four heteroatoms as defined above. When referring to atoms in a heterocyclyl cyclic structure, the term "nitrogen" may include nitrogen that has undergone a substitution reaction. Heterocyclylene groups may be substituted or unsubstituted.

[0029] In this invention, the term "alicyclic group" generally refers to a group having residues obtained by removing hydrogen atoms from the same or different carbon atoms of a carbocyclic ring. The term "alicyclic" generally refers to saturated or partially unsaturated monocyclic or polycyclic hydrocarbons, where the carbocyclic ring may contain 3 to 20 carbon atoms, 3 to 12 carbon atoms, 3 to 10 carbon atoms, or 3 to 8 carbon atoms. Non-limiting examples of monocyclic carbocyclic rings include cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, cyclohexadiene, cycloheptane, cycloheptatriene, and cyclooctane, while polycyclic carbocyclic rings may include spirocyclic, fused, and bridging carbocyclic rings. The carbocyclylene group may be substituted or unsubstituted.

[0030] In this invention, the term “partially unsaturated” generally refers to a cyclic structure containing at least one double or triple bond between ring molecules. The term “partially unsaturated” encompasses cyclic structures having multiple unsaturations, but is not intended to include aryl rings or heteroaryl rings as defined in this invention. The term “unsaturated” means that the part has one or more degrees of unsaturation.

[0031] In this invention, the term "halogen" generally refers to fluorine, chlorine, bromine, and iodine, and may be, for example, fluorine or chlorine.

[0032] In this invention, the term "aliphatic group" generally refers to a linear hydrocarbon, branched hydrocarbon, or cyclic hydrocarbon having 1 to 12 carbon atoms, or having one or more unsaturated units, where the unsaturated units are not aromatic groups. For example, applicable aliphatic groups may include substituted or unsubstituted linear, branched, or cyclic alkyl groups, alkenyl groups, alkynyl groups, and mixtures thereof, such as (cycloalkyl)alkyl groups, (cycloalkenyl)alkyl groups, or (cycloalkyl)alkenyl groups. For example, aliphatic groups may have 1 to 12, 1 to 8, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0033] In this invention, the terms "optionally" or "at will" mean that they are possible but not necessarily to occur due to the following circumstances or conditions, and such descriptions include cases where such circumstances or conditions occur or do not occur. For example, "a heterocyclyl group optionally substituted with an alkyl group" means that an alkyl group may be present but is not necessarily present, and such descriptions include cases where the heterocyclyl group is substituted with an alkyl group and cases where the heterocyclyl group is not substituted with an alkyl group.

[0034] In this invention, the term "substitution" generally refers to the substitution of one or more hydrogen atoms in a group, for example, up to five, or for example, one to three hydrogen atoms, independently by a corresponding number of substituents. Substituents are simply located in positions where they are chemically possible, and those skilled in the art can determine whether substitution is possible or impossible (experimentally or theoretically) without special effort. For example, an amino group or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated bond (such as an olefinic bond).

[0035] One or more hydrogen atoms in the group, for example up to five, or 1 to 3 hydrogen atoms, are each independently substituted by a corresponding number of substituents. Substituents are simply located where they are chemically possible, and those skilled in the art can determine whether substitution is possible or impossible (experimentally or theoretically) without special effort. For example, an amino group or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated bond (such as an olefinic bond).

[0036] In this invention, the term "compound" generally refers to a substance having two or more different elements. For example, the compound of this invention may be an organic compound, and may be a compound with a molecular weight of 500 or less, a compound with a molecular weight of 1000 or less, a compound with a molecular weight of 1000 or more, a compound with a molecular weight of 1000 or more, or a compound with a molecular weight of 10000 or more, or a compound with a molecular weight of 100000 or more, or a compound with a molecular weight of 1000000 or more. In this invention, a compound may also refer to a compound linked by chemical bonds, and may be a compound in which one or more molecules with a molecular weight of 1000 or less are linked to a biomacromolecule by chemical bonds, and the biomacromolecule may be a high molecular weight polysaccharide, a protein, a nucleic acid, a polypeptide, etc. The compound of this invention may be a compound obtained by linking a protein to one or more molecules with a molecular weight of 1000 or less, a compound obtained by linking a protein to one or more molecules with a molecular weight of 100000 or less, or a compound obtained by linking a protein to one or more molecules with a molecular weight of 1000000 or less.

[0037] In some embodiments, the compounds of the present invention may be in "mixture form," where the "mixture form" of the compound may be a composition comprising any or more of the compounds of the present invention, their tautomers, endo compounds, racemic compounds, enantiomers, or diastereomers.

[0038] Unless otherwise indicated, the structures described herein may include compounds that differ only in the presence or absence of one or more isotopically enriched atoms. For example, any compound that otherwise matches the structure of the present invention, except that a hydrogen atom is substituted with deuterium or tritium, or a carbon atom is substituted with carbon-13 or carbon-14, is within the scope of the present invention.

[0039] In this invention, the term "pharmaceutical composition" refers to a mixture of one or more compounds described in this invention or their physiologically / medicinal salts or prodrugs with other chemical components, and other components, such as physiologically / medicinal carriers and excipients. A pharmaceutical composition may exert biological activity by facilitating administration to a living organism and contributing to the absorption of the active ingredient. For general information on the preparation of pharmaceutical compositions, the Chinese Pharmacopoeia may be consulted.

[0040] In the present invention, the terms “pharmaceutically acceptable salt” or “pharmaceutically usable salt” generally refer to salts of the compounds or ligand-pharmaceutical compositions of the present invention, or salts of the compounds described in the present invention, which may be safe and / or effective when administered to mammals and may have the desired biological activity. The antibody-antibody drug conjugate compounds of the present invention may form salts with acids. Non-limiting examples of pharmaceutically acceptable salts include hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, citrate, acetate, succinate, ascorbate, oxalate, nitrate, sorbate, hydrogen phosphate, dihydrogen phosphate, salicylate, hydrogen citrate, tartrate, maleate, fumarate, formate, benzoate, methanesulfonate, ethyl sulfonate, benzenesulfonate, and p-toluenesulfonate.

[0041] The terms “solvate” or “solvent compound” generally refer to a pharmaceutically usable solvate formed with one or more solvent molecules of the ligand-drug conjugate compound of the present invention, and non-limiting examples of solvent molecules include water, ethanol, acetonitrile, isopropyl alcohol, DMSO, and ethyl acetate. “Pharmacologically acceptable prodrug” refers to a compound that can be converted to a particular compound or a pharmaceutically acceptable salt of such a compound under physiological conditions or by solvolysis. “Pharmacologically active metabolite” refers to a pharmacologically active product produced by the in vivo metabolism of a particular compound or a salt thereof. Metabolites of compounds can be identified using conventional techniques known in the art, and their activity can be confirmed using the assays described herein.

[0042] The pharmaceutical composition may be in the form of a sterile aqueous or oily suspension for intramuscular and subcutaneous administration. According to known techniques, it can be formulated with suitable dispersants or wetting agents and suspending agents as described above. The sterile injection formulation may also be a sterile injection solution or suspension prepared with a non-toxic, parenterally acceptable diluent or solvent, such as a solution prepared in 1,3-butanediol. Furthermore, sterile fixative oils can be conveniently used as solvents or suspension media. For example, any mixed fixative oil containing synthetic monoglycerides or diacylglycerols can be used. Additionally, fatty acids such as oleic acid can also be used in the preparation of injection formulations. For ocular administration, the compounds of the present invention are delivered in a pharmaceutically acceptable ophthalmic carrier to maintain contact with the ocular surface for a sufficient time to penetrate the cornea and internal regions including the anterior chamber, posterior chamber, vitreous humor, aqueous humor, vitreous fluid, cornea, iris / ciliary body, lens, choroid / retina, etc. The pharmaceutically acceptable ophthalmic carrier may be an ointment, vegetable oil, or encapsulating material. The compounds of the present invention can also be injected directly into the vitreous humor and aqueous humor.

[0043] In this invention, the term "including" generally refers to including the explicitly specified features without excluding other elements. The terms "greater than or equal to" and "less than or equal to" generally refer to a situation that includes that number.

[0044] In the present invention, the term "about" generally refers to a variation within the range of 0.5% to 10% above or below a specified numerical value, for example, within the range of 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, or 10% above or below the specified numerical value.

[0045] Detailed Description of the Invention In one aspect, the present invention [Chemical formula] Here, R1 includes a substituted cyclic structure, R2 includes an optionally substituted substituent, R3 includes an optionally substituted substituent, X1 is an optionally substituted atom, provides a compound represented by formula (I), or a pharmaceutically acceptable prodrug of the compound, a pharmaceutically active metabolite of the compound, and / or a pharmaceutically acceptable salt of the compound.

[0046] For example, the cyclic structure of R1 is substituted with a substituent containing a basic nitrogen atom.

[0047] For example, the cyclic structure of R1 is substituted with a substituent selected from the group consisting of an optionally substituted amino group and an optionally substituted nitrogen-containing aliphatic heterocyclyl group.

[0048] In one aspect, the present invention [Chemical formula] Here, R1 is (R 1-0 ) nr0 -(R 1-1 ) nr1 -(R 1-2 ) nr2 -(R 1-3 ) nr3 -(R1-4 ) nr4 -(R 1-5 ) nr5 This includes, where each R 1-0 , R 1-1 , R 1-2 , R 1-3 , R 1-4 , and R 1-5 However, each comprises a substituent that is independently and arbitrarily substituted, where nr0, nr1, nr2, nr3, nr4, and nr5 are each independently selected from 0 or more numbers, and where the cyclic structure of R1 is substituted by a substituent containing a basic nitrogen atom. R2 includes a substituent that is optionally substituted, R3 includes a substituent that is optionally substituted, X1 is an atom that has been substituted by choice. The present invention provides a compound represented by formula (I), or a pharmaceutically acceptable prodrug of said compound, a pharmaceutically active metabolite of said compound, and / or a pharmaceutically acceptable salt of said compound.

[0049] In one aspect, the present invention is [ka] Here, R1 is (C=C) nr0 -(R 1-1 ) nr1 -(R 1-2 ) nr2 -(R 1-3 ) nr3 -(R 1-4 ) nr4 -(R 1-5 ) nr5 This includes, where each R 1-1 , R 1-2 , R 1-3 , R 1-4 , and R 1-5 Each of these independently contains a substituent that is optionally substituted, where nr0, nr1, nr2, nr3, nr4, and nr5 are each independently selected from 0 or more numbers, where the cyclic structure of R1 is substituted by a substituent containing a basic nitrogen atom. R2 includes a substituent that is optionally substituted, R3 includes a substituent that is optionally substituted, X1 is an atom that has been substituted by choice. The present invention provides a compound represented by formula (I), or a pharmaceutically acceptable prodrug of said compound, a pharmaceutically active metabolite of said compound, and / or a pharmaceutically acceptable salt of said compound.

[0050] In one aspect, the present invention is [ka] Here, R1 is (C=C) nr0 -(R 1-1 ) nr1 -(R 1-2 ) nr2 -(R 1-3 ) nr3 -(R 1-4 ) nr4 -(R 1-5 ) nr5 This includes, where nr0, nr1, nr2, nr3, nr4, and nr5 are each independently selected from 0 or more numbers, Here, each R 1-1 However, selected from the group consisting of optionally substituted aryl groups and optionally substituted heteroaryl ring groups, for example, each R 1-1 However, selected from the group consisting of optionally substituted aryl groups, optionally substituted 5-membered heteroaryl ring groups, and optionally substituted 6-membered heteroaryl ring groups, for example, each R 1-1 However, selected from the group consisting of an optionally substituted aryl group, an optionally substituted 5-membered heteroaryl ring group containing one N atom, a 5-membered heteroaryl ring group containing two N atoms, a 6-membered heteroaryl ring group containing one N atom, and an optionally substituted 6-membered heteroaryl ring group containing two N atoms, for example, each R 1-1 However, selected from the group consisting of an optionally substituted aryl group, an optionally substituted pyridyl group, and an optionally substituted pyrazolyl group, Here, each R 1-2R is selected from the group consisting of chemical bonds and hydroxyl groups, for example, each R 1-2 However, it could be - or -O-, Here, each R 1-3 However, it is selected from optionally substituted alkyl groups, for example, each R 1-3 However, these may be optionally substituted methyl groups, optionally substituted ethyl groups, and optionally substituted propyl groups. Here, each R 1-4 However, it is selected from aliphatic heterocyclyl groups that have been optionally substituted, for example, each R 1-4 R can be an optionally substituted 5-membered aliphatic heterocyclyl group, or an optionally substituted 6-membered aliphatic heterocyclyl group, for example, each R 1-4 However, selected from the group consisting of a 5-membered aliphatic heterocyclyl group containing one optionally substituted N atom, a 5-membered aliphatic heterocyclyl group containing two N atoms, a 6-membered aliphatic heterocyclyl group containing one N atom, and a 6-membered aliphatic heterocyclyl group containing two optionally substituted N atoms, for example, each R 1-4 However, selected from the group consisting of a pyrrolyl group that is optionally substituted, a piperidinyl group that is optionally substituted, and a piperazinyl group that is optionally substituted, Here, each R 1-5 However, it is selected from optionally substituted alkyl groups, for example, each R 1-5 However, it could be a methyl group that is optionally substituted, for example, two R 1-5 May include, R2 includes a substituent that is optionally substituted, R3 includes a substituent that is optionally substituted, X1 is an atom that has been substituted by choice. The present invention provides a compound represented by formula (I), or a pharmaceutically acceptable prodrug of said compound, a pharmaceutically active metabolite of said compound, and / or a pharmaceutically acceptable salt of said compound.

[0051] In one aspect, the present invention is [ka] Here, R1 is (C=C) nr0 -(R 1-1 ) nr1 -(R 1-2 ) nr2 -(R 1-3 ) nr3 -(R 1-4 ) nr4 -(R 1-5 ) nr5 This includes, where nr0, nr1, nr2, nr3, nr4, and nr5 are each independently selected from 0 or more numbers, Here, each R 1-1 However, selected from the group consisting of optionally substituted aryl groups and optionally substituted heteroaryl ring groups, for example, each R 1-1 However, selected from the group consisting of optionally substituted aryl groups, optionally substituted 5-membered heteroaryl ring groups, and optionally substituted 6-membered heteroaryl ring groups, for example, each R 1-1 However, selected from the group consisting of an optionally substituted aryl group, an optionally substituted 5-membered heteroaryl ring group containing one N atom, a 5-membered heteroaryl ring group containing two N atoms, a 6-membered heteroaryl ring group containing one N atom, and an optionally substituted 6-membered heteroaryl ring group containing two N atoms, for example, each R 1-1 However, selected from the group consisting of an optionally substituted aryl group, an optionally substituted pyridyl group, and an optionally substituted pyrazolyl group, Here, each R 1-2 R is selected from the group consisting of chemical bonds and hydroxyl groups, for example, each R 1-2 However, it could be - or -O-, Here, each R 1-3 However, it is selected from optionally substituted alkyl groups, for example, each R 1-3 However, these may be optionally substituted methyl groups, optionally substituted ethyl groups, and optionally substituted propyl groups. Here, each R 1-4 However, it is selected from aliphatic heterocyclyl groups that have been optionally substituted, for example, each R 1-4It may be a 5-membered aliphatic heterocyclyl group optionally substituted, and a 6-membered aliphatic heterocyclyl group optionally substituted. For example, each R 1-4 is selected from the group consisting of a 5-membered aliphatic heterocyclyl group containing one optionally substituted N atom, a 5-membered aliphatic heterocyclyl group containing two N atoms, a 6-membered aliphatic heterocyclyl group containing one N atom, and a 6-membered aliphatic heterocyclyl group containing two optionally substituted N atoms. For example, each R 1-4 is selected from the group consisting of an optionally substituted pyrrolyl group, an optionally substituted piperidinyl group, and an optionally substituted piperazinyl group. Here, each R 1-5 is selected from an optionally substituted alkyl group. For example, each R 1-5 may be an optionally substituted methyl group. For example, two Rs 1-5 may be included. R2 includes an optionally substituted -S- optionally substituted aryl group - optionally substituted amide group - optionally substituted alkyl group, or -S- optionally substituted aryl group - optionally substituted amide group - optionally substituted alicyclic group. For example, R2 includes an optionally substituted -S- aryl group optionally substituted by halogen - optionally substituted amide group - optionally substituted methyl group, or -S- optionally substituted aryl group - optionally substituted amide group - optionally substituted cyclopropyl group. R3 includes hydrogen or an optional isotope of hydrogen. X1 is optionally substituted CH. There is provided a compound represented by formula (I), or a pharmaceutically acceptable prodrug of said compound, a pharmaceutically active metabolite of said compound, and / or a pharmaceutically acceptable salt of said compound.

[0052] For example, said R1 is (R 1-0 ) nr0 -(R 1-1 ) nr1 -(R 1-2 ) nr2 -(R 1-3 )nr3 -(R 1-4 ) nr4 -(R 1-5 ) nr5 This includes, where each R 1-0 , R 1-1 , R 1-2 , R 1-3 , R 1-4 , and R 1-5 However, each independently contains a substituent that is optionally substituted, where nr0, nr1, nr2, nr3, nr4, and nr5 are each independently selected from 0 or more numbers.

[0053] For example, the R 1-0 R is either a chemical bond or selected from the group consisting of an optionally substituted alkenyl group, an optionally substituted alkynyl group, and an optionally substituted amino group. For example, the R 1-0 The group is either a chemical bond or selected from the group consisting of optionally substituted vinyl groups, optionally substituted ethynyl groups, and optionally substituted amino groups. For example, nr0 is 0 or 1. For example, nr0 is 0, 1, 2, or 3.

[0054] For example, the R 1-1 R is either a chemical bond or selected from the group consisting of optionally substituted amide groups, optionally substituted aryl ring groups, and optionally substituted heteroaryl ring groups. For example, the R 1-1 The group is either a chemical bond or selected from the group consisting of an optionally substituted amide group, an optionally substituted phenyl group, and an optionally substituted heteroaryl ring group. For example, each R 1-1 However, selected from the group consisting of optionally substituted aryl groups, optionally substituted 5-membered heteroaryl ring groups, and optionally substituted 6-membered heteroaryl ring groups, for example, each R 1-1However, selected from the group consisting of an optionally substituted aryl group, an optionally substituted 5-membered heteroaryl ring group containing one N atom, a 5-membered heteroaryl ring group containing two N atoms, a 6-membered heteroaryl ring group containing one N atom, and an optionally substituted 6-membered heteroaryl ring group containing two N atoms, for example, each R 1-1 However, it is selected from the group consisting of an optionally substituted aryl group, an optionally substituted pyridyl group, and an optionally substituted pyrazolyl group. For example, the R 1-1 The group is either a chemical bond or selected from the group consisting of an optionally substituted amide group, an optionally substituted phenyl group, an optionally substituted pyridyl group, and an optionally substituted pyrazolyl group. For example, nr1 is 0 or 1. For example, nr1 is 0, 1, 2, or 3.

[0055] For example, the R 1-2 The R is either a chemical bond or selected from the group consisting of hydrogen, light hydrogen, deuterium, tritium, and optionally substituted hydroxyl groups. For example, each R 1-2 However, it can be - or -O-. For example, nr2 is 0 or 1. For example, nr2 is 0, 1, 2, or 3.

[0056] For example, the R 1-3 R is either a chemical bond or selected from the group consisting of hydrogen, light hydrogen, deuterium, tritium, and optionally substituted alkyl groups. For example, the R 1-3 The R is either a chemical bond, or selected from the group consisting of hydrogen, light hydrogen, deuterium, tritium, an optionally substituted methyl group, an optionally substituted ethyl group, and an optionally substituted propyl group. For example, each R 1-3 However, it may be an optionally substituted methyl group, an optionally substituted ethyl group, or an optionally substituted propyl group. For example, nr3 is 0 or 1. For example, nr3 is 0, 1, 2, or 3.

[0057] For example, the R 1-4R is either a chemical bond, or selected from the group consisting of hydrogen, light hydrogen, deuterium, tritium, optionally substituted amino groups, and optionally substituted aliphatic heterocyclyl groups. For example, the R 1-4 R is either a chemical bond, or selected from the group consisting of hydrogen, light hydrogen, deuterium, tritium, an optionally substituted amino group, an optionally substituted pyrrolyl group, an optionally substituted piperidinyl group, an optionally substituted piperazinyl group, and an optionally substituted morpholinyl group. For example, each R 1-4 However, these may be optionally substituted 5-membered aliphatic heterocyclyl groups and optionally substituted 6-membered aliphatic heterocyclyl groups, for example, each R 1-4 However, selected from the group consisting of a 5-membered aliphatic heterocyclyl group containing one optionally substituted N atom, a 5-membered aliphatic heterocyclyl group containing two N atoms, a 6-membered aliphatic heterocyclyl group containing one N atom, and a 6-membered aliphatic heterocyclyl group containing two optionally substituted N atoms, for example, each R 1-4 However, it is selected from the group consisting of a pyrrolyl group that is optionally substituted, a piperidinyl group that is optionally substituted, and a piperazinyl group that is optionally substituted. For example, nr4 is 0 or 1. For example, nr4 is 0, 1, 2, or 3.

[0058] For example, the R 1-5 R is either a chemical bond or selected from the group consisting of hydrogen, light hydrogen, deuterium, tritium, and optionally substituted alkyl groups. For example, the R 1-5 The group is either a chemical bond, or selected from the group consisting of hydrogen, light hydrogen, deuterium, tritium, optionally substituted methyl groups, and optionally substituted ethyl groups. For example, each R 1-5 However, it could be a methyl group that is optionally substituted, for example, two R 1-5 This may include nr5 being 0, 1, or 2. For example, nr5 being 0, 1, 2, or 3.

[0059] For example, R2 is a sulfhydryl group that is optionally substituted. For example, R2 is one or more R 2-1Replaced by, each of the R 2-1 However, each substituent is independently and arbitrarily substituted. For example, the R 2-1 However, it is an aryl group that has been optionally substituted. For example, the R 2-1 However, it is a phenyl group that has been optionally substituted.

[0060] For example, the R 2-1 However, one or more R 2-2 Replaced by, each of the R 2-2 However, each substituent is independently and arbitrarily substituted. For example, the R 2-2 However, it is selected from the group consisting of hydrogen, light hydrogen, deuterium, tritium, halogen, optionally substituted carbonyl group, optionally substituted carboxyl group, optionally substituted amide group, and optionally substituted alkyl group. For example, the R 2-2 However, it is selected from the group consisting of hydrogen, light hydrogen, deuterium, tritium, halogens, optionally substituted carbonyl groups, optionally substituted carboxyl groups, optionally substituted amide groups, and optionally substituted methyl groups.

[0061] For example, the R 2-2 However, one or more R 2-3 Replaced by, each of the R 2-3 However, each substituent is independently and arbitrarily substituted. For example, the R 2-3 However, it is selected from the group consisting of hydrogen, light hydrogen, deuterium, tritium, halogen, optionally substituted alkyl groups, optionally substituted alicyclic groups, and optionally substituted amino groups. For example, the R 2-3 However, it is selected from the group consisting of hydrogen, light hydrogen, deuterium, tritium, halogens, optionally substituted methyl groups, optionally substituted ethyl groups, optionally substituted cyclopropyl groups, and optionally substituted amino groups.

[0062] For example, the R 2-3 However, one or more R 2-4 Replaced by, each of the R 2-4However, each substituent is independently and arbitrarily substituted. For example, the R 2-4 However, it is selected from the group consisting of hydrogen, light hydrogen, deuterium, tritium, halogen, optionally substituted alkyl groups, and optionally substituted alicyclic groups. For example, the R 2-4 The group is selected from the group consisting of hydrogen, light hydrogen, deuterium, tritium, halogens, optionally substituted methyl groups, optionally substituted ethyl groups, and optionally substituted cyclopropyl groups.

[0063] For example, R2 includes an optionally substituted -S-optionally substituted aryl group-optionally substituted amide group-optionally substituted alkyl group, or an optionally substituted -S-optionally substituted aryl group-optionally substituted amide group-optionally substituted alicyclic group, for example, R2 includes an optionally substituted -S-optionally substituted halogen-substituted aryl group-optionally substituted amide group-optionally substituted methyl group, or an optionally substituted -S-optionally substituted aryl group-optionally substituted amide group-optionally substituted cyclopropyl group, for example, R2 includes an optionally substituted -SF-substituted or unsubstituted aryl group-amide group-methyl group, or an -SF-substituted or unsubstituted arylamide group-cyclopropyl group.

[0064] For example, R3 is selected from the group consisting of hydrogen, light hydrogen, deuterium, and tritium.

[0065] For example, X1 is selected from the group consisting of CH and N, which are substituted by any choice. For example, X1 is CH which is substituted by any choice.

[0066] In some embodiments of the present invention, the compound has the following structure: [ka] (II) Here, The A ring is a 5-7 member nitrogen-containing heterocycline. The B ring is a 5-7 membered aryl ring or a heterocyclyl ring. Z is -C(O)NH-, -NHC(O)- or [ka] And, The E ring is an aryl ring or a heteroaryl ring. L0 is O, S, N(R La ), selected from C1-C6 alkylene groups and C(O), R La However, selected from H and C1-C6 alkyl groups, L1 is selected from a single bond, a C1-C6 alkylene group, a C2-C6 alkenylene group, a C2-C6 alkynylene group, and a -(C0-C6 alkylene group)-Q1-(C0-C6 alkylene group)-, and Q1 is selected from -O-, -S-, -C(O)-, -C(O)O-, -OC(O)-, and -C(O)N(R Lb )-,-N(R Lb )C(O)-, -N(R Lb )C(O)O-, -N(R Lb )C(O)N(R Lb )-,-N(R Lb )-, -S(O)2-, -S(O)2N(R Lb )-,-N(R Lb )S(O)2-, -S(O)-, -S(O)N(R Lb )-,-N(R Lb )S(O)- is selected, and the H atom in the alkylene group is optionally H, C1-C 10 Alkyl alkyl group, C2-C 10 Alkenyl group, C2-C 10 Alkynyl group, halogen, cyano group, nitro group, azide group, C1-C 10 Halogen-substituted alkyl group, hydroxyl group, C1-C 10 Alkoxy group, C1-C 10 Halogen-substituted alkoxy group, amino group, C1-C 10 It may be substituted with an alkylamino group, R Lb However, H, C1-C 10 Alkyl alkyl group, C2-C 10 Alkenyl group, C2-C 10 Alkynyl group, C3-C 10Cycloalkyl groups, C3-C 10 Cycloalkylalkyl groups, C6-C 10 Aryl group, C7-C 12 Selected from arylalkyl groups, 4-10 membered heterocyclyl groups, and 4-10 membered heterocyclylalkyl groups, L2 is selected from a single bond, a C1-C6 alkylene group, and -(C0-C6 alkylene group)-Q2-(C0-C6 alkylene group)-, and Q2 is -O-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R Lc )-,-N(R Lc )C(O)-, -N(R Lc )C(O)O-, -N(R Lc )C(O)N(R La )-,-N(R Lc )-, -S(O)2-, -S(O)2N(R Lc )-,-N(R Lc )S(O)2-, -S(O)-, -S(O)N(R Lc )-,-N(R Lc )S(O)- is selected, and the H atom in the alkylene group is optionally H, C1-C 10 Alkyl alkyl group, C2-C 10 Alkenyl group, C2-C 10 Alkynyl group, halogen, cyano group, nitro group, azide group, C1-C 10 Halogen-substituted alkyl group, hydroxyl group, C1-C 10 Alkoxy group, C1-C 10 Halogen-substituted alkoxy group, amino group, C1-C 10 It may be substituted with an alkylamino group, R Lc However, H, C1-C 10 Alkyl alkyl group, C2-C 10 Alkenyl group, C2-C 10 Alkynyl group, C3-C 10 Cycloalkyl groups, C3-C 10 Cycloalkylalkyl groups, C6-C 10 Aryl group, C7-C 12 Selected from arylalkyl groups, 4-10 membered heterocyclyl groups, and 4-10 membered heterocyclylalkyl groups, Y is selected from H, -NR7R8, and nitrogen-containing heterocyclyl groups, where the nitrogen-containing heterocyclyl group may be optionally substituted with one or more R9 groups, where R9 is a halogen, cyano group, amino group, hydroxyl group, or C1-C 10 Alkyl alkyl group, C1-C 10 Halogen-substituted alkyl groups, C1-C 10 Alkoxy group, C1-C 10 Halogen-substituted alkoxy group, C1-C 10 Alkylamino group, C1-C 10 Cyanoalkyl groups, C1-C 10 Hydroxysubstituted alkyl group, C1-C 10 Alkyl substituted alkyl groups, C1-C 10 Alkylaminosubstituted alkyl group, -(C0-C6 alkylene group)-(C6-C 10 Aryl group), -SO2-(C0-C6 alkylene group)-(C6-C 10 Aryl group), -S-(C0-C6 alkylene group)-(C6-C 10 Aryl group), -O-(C0-C6 alkylene group)-(C6-C 10 Aryl group), -(C0-C6 alkylene group)-(4-10 membered heterocyclyl group), -SO2-(C0-C6 alkylene group)-(4-10 membered heterocyclyl group), -S-(C0-C6 alkylene group)-(4-10 membered heterocyclyl group), -O-(C0-C6 alkylene group)-(4-10 membered heterocyclyl group), -(C0-C6 alkylene group)-(C3-C 10 Cycloalkyl group), -SO2-(C0-C6 alkylene group)-(C3-C 10 Cycloalkyl group), -S-(C0-C6 alkylene group)-(C3-C 10 Cycloalkyl group), -O-(C0-C6 alkylene group)-(C3-C 10 Selected from cycloalkyl groups, R7 and R8 are independently H and C1-C 10 Alkyl alkyl group, C2-C 10 Alkenyl group, C2-C 10 Alkynyl group, C3-C 10 Cycloalkyl groups, C3-C 10Selected from cycloalkylalkyl groups, 4-10 membered heterocyclyl groups, and 4-10 membered heterocyclylalkyl groups, where the C1-C 10 Alkyl alkyl group, C2-C 10 Alkenyl group, C2-C 10 Alkynyl group, C3-C 10 Cycloalkyl groups and 4-10 membered heterocyclyl groups are optionally H, C1-C 10 Alkyl alkyl group, C2-C 10 Alkenyl group, C2-C 10 Alkynyl group, C3-C 10 Cycloalkyl groups, C3-C 10 Cycloalkylalkyl groups, C6-C 10 Aryl group, C7-C 12 It may be substituted with any or more groups selected from arylalkyl groups, 4-10 membered heterocyclyl groups, and 4-10 membered heterocyclylalkyl groups. R4 is one or more independent substituents on the benzene ring, and each R4 independently is H, halogen, C1-C 10 Alkyl group, cyano group, C1-C 10 Halogen-substituted alkyl groups, C1-C 10 Halogen-substituted alkoxy group, C1-C 10 Cyanoalkyl group, -OR 401 , -C(O)R 401 -C(O)OR 401 , -NR 402 C(O)OR 401 ,-OC(O)R 401 , -NR 402 SO2R 401 -SO2NR 401 R 402 , -NR 402 C(O)R 401 -C(O)NR 401 R 402 , -NR 401 R 402 -(C0-C6 alkylene group)-NR 401 R 402 , -SR 401 ,-S(O)R 401 -S(O)2R 401 -(C0-C6 alkylene group)-(C6-C10 Aryl group), -SO2-(C0-C6 alkylene group)-(C6-C 10 Aryl group), -S-(C0-C6 alkylene group)-(C6-C 10 Aryl group), -O-(C0-C6 alkylene group)-(C6-C 10 Aryl group), -(C0-C6 alkylene group)-(4-10 membered heterocyclyl group), -SO2-(C0-C6 alkylene group)-(4-10 membered heterocyclyl group), -S-(C0-C6 alkylene group)-(4-10 membered heterocyclyl group), -O-(C0-C6 alkylene group)-(4-10 membered heterocyclyl group), -(C0-C6 alkylene group)-(C3-C 10 Cycloalkyl group), -SO2-(C0-C6 alkylene group)-(C3-C 10 Cycloalkyl group), -S-(C0-C6 alkylene group)-(C3-C 10 Cycloalkyl group), -O-(C0-C6 alkylene group)-(C3-C 10 Selected from cycloalkyl groups, where the C0-C6 alkylene group and the C1-C 10 Alkyl alkyl group, C2-C 10 Alkenyl group, C2-C 10 Alkynyl group, C3-C 10 Cycloalkyl groups, C6-C 10 Aryl groups, 4-10 membered heterocyclyl groups, optionally a halogen, cyano group, amino group, hydroxyl group, C1-C 10 Alkyl alkyl group, C1-C 10 Halogen-substituted alkyl groups, C1-C 10 Alkoxy group, C1-C 10 Halogen-substituted alkoxy group, C1-C 10 Alkylamino group, C1-C 10 Cyanoalkyl groups, C1-C 10 Hydroxysubstituted alkyl group, C1-C 10 Alkyl substituted alkyl groups, C1-C 10 Alkylaminosubstituted alkyl group, -(C0-C6 alkylene group)-(C6-C 10 Aryl group), -SO2-(C0-C6 alkylene group)-(C6-C 10 Aryl group), -S-(C0-C6 alkylene group)-(C6-C10 Aryl group), -O-(C0-C6 alkylene group)-(C6-C 10 Aryl group), -(C0-C6 alkylene group)-(4-10 membered heterocyclyl group), -SO2-(C0-C6 alkylene group)-(4-10 membered heterocyclyl group), -S-(C0-C6 alkylene group)-(4-10 membered heterocyclyl group), -O-(C0-C6 alkylene group)-(4-10 membered heterocyclyl group), -(C0-C6 alkylene group)-(C3-C 10 Cycloalkyl group), -SO2-(C0-C6 alkylene group)-(C3-C 10 Cycloalkyl group), -S-(C0-C6 alkylene group)-(C3-C 10 Cycloalkyl group), -O-(C0-C6 alkylene group)-(C3-C 10 It may be substituted with one or more groups selected from cycloalkyl groups. R 401 and R 402 However, independently, H, C1-C 10 Alkyl, C3-C 10 Cycloalkyl groups, C3-C 10 Cycloalkylalkyl groups, C6-C 10 Aryl group, C6-C 10 Selected from arylalkyl groups, 4-10 membered heterocyclyl groups, and 4-10 membered heterocyclyl group alkyl groups, R5 [ka] One or more independent substituents on the ring, where each R5 is independently H, halogen, cyano group, amino group, hydroxyl group, C1-C 10 Alkyl alkyl group, C1-C 10 Halogen-substituted alkyl groups, C1-C 10 Alkoxy group, C1-C 10 Halogen-substituted alkoxy group, C1-C 10 Alkylamino group, C1-C 10 Cyanoalkyl groups, C1-C 10 Hydroxysubstituted alkyl group, C1-C 10 Alkyl substituted alkyl groups, C1-C 10Alkylaminosubstituted alkyl group, -(C0-C6 alkylene group)-(C6-C 10 Aryl group), -SO2-(C0-C6 alkylene group)-(C6-C 10 Aryl group), -S-(C0-C6 alkylene group)-(C6-C 10 Aryl group), -O-(C0-C6 alkylene group)-(C6-C 10 Aryl group), -(C0-C6 alkylene group)-(4-10 membered heterocyclyl group), -SO2-(C0-C6 alkylene group)-(4-10 membered heterocyclyl group), -S-(C0-C6 alkylene group)-(4-10 membered heterocyclyl group), -O-(C0-C6 alkylene group)-(4-10 membered heterocyclyl group), -(C0-C6 alkylene group)-(C3-C 10 Cycloalkyl group), -SO2-(C0-C6 alkylene group)-(C3-C 10 Cycloalkyl group), -S-(C0-C6 alkylene group)-(C3-C 10 Cycloalkyl group), -O-(C0-C6 alkylene group)-(C3-C 10 Selected from cycloalkyl groups, R6 is one or more independent substituents of the E ring, and each R6 is independently H, halogen, cyano group, amino group, hydroxyl group, C1-C 10 Alkyl alkyl group, C1-C 10 Halogen-substituted alkyl groups, C1-C 10 Alkoxy group, C1-C 10 Halogen-substituted alkoxy group, C1-C 10 Alkylamino group, C1-C 10 Cyanoalkyl groups, C1-C 10 Hydroxysubstituted alkyl group, C1-C 10 Alkyl substituted alkyl groups, C1-C 10 Alkylaminosubstituted alkyl group, -(C0-C6 alkylene group)-(C6-C 10 Aryl group), -SO2-(C0-C6 alkylene group)-(C6-C 10 Aryl group), -S-(C0-C6 alkylene group)-(C6-C 10 Aryl group), -O-(C0-C6 alkylene group)-(C6-C 10Aryl group), -(C0-C6 alkylene group)-(4-10 membered heterocyclyl group), -SO2-(C0-C6 alkylene group)-(4-10 membered heterocyclyl group), -S-(C0-C6 alkylene group)-(4-10 membered heterocyclyl group), -O-(C0-C6 alkylene group)-(4-10 membered heterocyclyl group), -(C0-C6 alkylene group)-(C3-C 10 Cycloalkyl group), -SO2-(C0-C6 alkylene group)-(C3-C 10 Cycloalkyl group), -S-(C0-C6 alkylene group)-(C3-C 10 Cycloalkyl group), -O-(C0-C6 alkylene group)-(C3-C 10 Selected from cycloalkyl groups.

[0067] In some embodiments of the present invention, ring A is a five-membered nitrogen-containing heteroaryl ring, for example, [ka] , [ka] , [ka] , [ka] , [ka] That is the case.

[0068] In some embodiments of the present invention, the B ring is a benzene ring or a 6-membered nitrogen-containing heterocycline, for example, [ka] , [ka] , [ka] , [ka] That is the case.

[0069] In some embodiments of the present invention, [ka] The structure of the part, [ka] , [ka] , [ka] , [ka] , [ka] , [ka] It is one of the following, in particular [ka] , [ka] , [ka] , [ka] , [ka] That is the case.

[0070] In some embodiments of the present invention, [ka] part [ka] Herein, L2 is a C1-C6 alkylene group or -(C0-C6 alkylene group)-Q2-(C0-C6 alkylene group)-, and Y is -NR7R8 or a nitrogen-containing heterocycline group, where the nitrogen-containing heterocycline group may be optionally substituted with one or more R9 groups.

[0071] In some embodiments of the present invention,

[0072] [ka] part [ka] Herein, Y is selected from H, -NR7R8, and a nitrogen-containing heterocycline group, where the nitrogen-containing heterocycline group may be optionally substituted with one or more R9 groups.

[0073] In some embodiments of the present invention, [ka] part [ka] Herein, Y is selected from H, -NR7R8, and a nitrogen-containing heterocycline group, where the nitrogen-containing heterocycline group may be optionally substituted with one or more R9 groups.

[0074] In some embodiments of the present invention, [ka] part [ka] Herein, Y is selected from H, -NR7R8, and a nitrogen-containing heterocycline group, where the nitrogen-containing heterocycline group may be optionally substituted with one or more R9 groups.

[0075] In some embodiments of the present invention, [ka] part [ka] Herein, Y is selected from H, -NR7R8, and a nitrogen-containing heterocycline group, where the nitrogen-containing heterocycline group may be optionally substituted with one or more R9 groups.

[0076] In some embodiments of the present invention, R5 is selected from H, halogen, cyano group, amino group, hydroxyl group, C1-C6 alkyl group, and C1-C6 halogen-substituted alkyl group.

[0077] In some embodiments of the present invention, R5 is H.

[0078] In some embodiments of the present invention, R3 is selected from H and C1-C6 alkyl groups.

[0079] In some embodiments of the present invention, R3 is H.

[0080] In some embodiments of the present invention, L0 is S.

[0081] In some embodiments of the present invention, L0 is O.

[0082] In some embodiments of the present invention, L0 is NH.

[0083] In some embodiments of the present invention, L0 is a methylene group.

[0084] In some embodiments of the present invention, L0 is NH, Z is -NHC(O)-, and the compound has the following structure: [ka] (III-1) Here, L2 is selected from a C1-C6 alkylene group, -(C1-C6 alkylene group)-Q2-(C1-C6 alkylene group)-, and Y is a nitrogen-containing heterocyclyl group that is -NR7R8 or optionally substituted, wherein the nitrogen-containing heterocyclyl group may optionally be substituted with one or more R9 groups.

[0085] In some embodiments of the present invention, Z is [ka] The compound has the following structure [ka] (III-2)

[0086] In some embodiments of the present invention, the compound has the following structure: [ka] (IV)

[0087] In some embodiments of the present invention, L1 is a C2-C6 alkenylene group, for example, [ka] , [ka] , [ka] ,especially [ka] That is the case.

[0088] In some embodiments of the present invention, L1 is a C2-C6 alkynylene group, for example, [ka] , [ka] , [ka] ,especially [ka] That is the case.

[0089] In some embodiments of the present invention, L1 is -Q1-(C0-C6 alkylene group)-.

[0090] In some embodiments of the present invention, L1 is -(C0-C6 alkylene group)-Q1-.

[0091] In some embodiments of the present invention, Q1 is -N(R Lb )- and R Lb However, it is selected from H, C1-C3 alkyl groups, especially H.

[0092] In some embodiments of the present invention, L1 is -NH-.

[0093] In some embodiments of the present invention, the E ring is a benzene ring or a 5-membered or 6-membered nitrogen-containing heteroaryl ring, for example, [ka] , [ka] , [ka] , [ka] , [ka] Specifically, when the E ring is a benzene ring, Y is a nitrogen-containing heterocycline group that is optionally substituted with -NR7R8 or other nitrogen-containing heterocycline groups, where the nitrogen-containing heterocycline group may optionally be substituted with one or more R9 groups.

[0094] In some embodiments of the present invention, [ka] The part has the following structure: [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] .

[0095] In some embodiments of the present invention, R6 is selected from H, halogen, cyano group, amino group, hydroxyl group, C1-C6 alkyl group, and C1-C6 halogen-substituted alkyl group.

[0096] In some embodiments of the present invention, R6 is H.

[0097] In some embodiments of the present invention, L2 is a single bond.

[0098] In some embodiments of the present invention, L2 is a C1-C6 alkylene group, for example, [ka] , [ka] , [ka] That is the case.

[0099] In some embodiments of the present invention, L2 is -Q2-(C0-C6 alkylene group)-.

[0100] In some embodiments of the present invention, Q2 is -O-, -S-, -N(RLc )- Selected from, R Lc However, it is selected from H, C1-C3 alkyl groups, especially H.

[0101] In some embodiments of the present invention, L2 is -O-(C0-C6 alkylene group)-, for example, [ka] , [ka] , [ka] , [ka] That is the case.

[0102] In some embodiments of the present invention, the E ring is a 5-membered or 6-membered nitrogen-containing heteroaryl ring, L2 is a single bond, and Y is H.

[0103] In some embodiments of the present invention, Y is -NR7R8, and R7 and R8 are independently selected from H, C1-C6 alkyl groups, and -(C0-C6 alkylene group)-(C3-C6 cycloalkyl group), for example, [ka] , [ka] They are selected from among them.

[0104] In some embodiments of the present invention, Y is a nitrogen-containing heterocyclyl group, which may be optionally substituted with one or more R9 groups, specifically, the nitrogen-containing heterocyclyl group is a 4-8 member saturated heterocyclyl, for example, [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] That is the case.

[0105] In some embodiments of the present invention, Y is [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] (Here, the substitution position of R9 can be any suitable carbon or nitrogen atom) and more specifically, Y is [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] They are selected from among them.

[0106] In some embodiments of the present invention, R9 is H, C1-C6 alkyl group (e.g., -CH3, [ka] , [ka] , [ka] ), C1-C6 hydroxysubstituted alkyl groups (for example, [ka] , [ka] ), C1-C6 amino group substituted alkyl groups (for example, [ka] , [ka] ), C1-C6 alkoxysubstituted alkyl groups (for example, [ka] , [ka] ), C1-C6 alkylaminosubstituted alkyl groups (for example, [ka] , [ka] , [ka] , [ka] ), -(C0-C6 alkylene group)-(C3-C6 cycloalkyl group)(for example, [ka] , [ka] , [ka] , [ka] ) will be selected from.

[0107] In some embodiments of the present invention, Y is [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] Selected from .

[0108] In some embodiments of the present invention, [ka] The part, [ka] , [ka] or [ka] And here, R 4a However, -C(O)NR 401 R 402 -(C0-C6 alkylene group)-NR 401 R 402 , -C(O)R 401 -C(O)OR 401 Selected from, R 401 and R 402 These are independently selected from H, C1-C6 alkyl groups, and -(C0-C6 alkylene group)-(C3-C6 cycloalkyl group), where the C0-C6 alkylene group, C1-C6 alkyl group, and C3-C6 cycloalkyl group may be optionally substituted with any or more groups selected from halogens, cyano groups, amino groups, hydroxyl groups, C1-C6 alkyl groups, and C1-C6 halogen-substituted alkyl groups. R 4b However, these are one or more independent substituents on the benzene ring, selected from H, halogen, cyano group, amino group, hydroxyl group, C1-C6 alkyl group, and C1-C6 halogen-substituted alkyl group.

[0109] In some embodiments of the present invention, R 4a but, [ka] , [ka] , [ka] , [ka] , [ka] , [ka] ,

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[0110] In some embodiments of the present invention, R 4b However, it is H.

[0111] In some embodiments of the present invention, R 4b However, it is a halogen, for example, F.

[0112] In some embodiments of the present invention, [ka] part [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] That is the case.

[0113] In one aspect, the present invention is [ka] , [ka] , [ka] , [ka] , [ka] ,

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[0114] In one aspect, the present invention is [ka] , [ka] , [ka] ,

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[0115] In one aspect, the present invention is [ka] ,

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[0116] In one aspect, the present invention is [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] ,

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[0117] In one aspect, the present invention is [ka] The present invention provides compounds having a structure selected from the group consisting of TIFF0007911442000394.tif127170, or pharmaceutically acceptable prodrugs of said compounds, pharmaceutically active metabolites of said compounds, and / or pharmaceutically acceptable salts of said compounds.

[0118] Pharmaceutical composition In one embodiment, the present invention provides a pharmaceutical composition comprising the compound of the present invention or a pharmaceutically acceptable prodrug of the compound, a pharmaceutically active metabolite of the compound and / or a pharmaceutically acceptable salt of the compound, and an optionally selected carrier.

[0119] The pharmaceutical composition of the present invention may contain one or more additives in addition to the active compound, and the additives may be selected from the group consisting of fillers (diluents), adhesives, wetting agents, disintegrants, and excipients. Depending on the administration method, the composition may contain 0.1 to 99% by weight of the active compound.

[0120] Pharmaceutical compositions containing active ingredients may be in forms suitable for ophthalmic administration, such as aqueous or oily suspensions, dispersible powders or granules, emulsions or slurries. Ophthalmic compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may include adhesives, fillers, lubricants, disintegrants, or pharmaceutically acceptable wetting agents, and such compositions may also be selected from the group consisting of sweeteners, flavoring agents, colorants, and preservatives.

[0121] The aqueous suspension may contain an active substance and excipients that are appropriately prepared for mixing with the aqueous suspension. Furthermore, the aqueous suspension may contain one or more colorants, one or more flavoring agents, and one or more preservatives such as one or more sweeteners. The oily suspension may be prepared by suspending the active ingredient in vegetable oil. The oily suspension may contain a thickener.

[0122] Specifically, the pharmaceutical composition may employ any suitable route of administration, such as gastrointestinal routes (e.g., oral administration, sublingual administration, rectal administration) or non-gastrointestinal routes (e.g., intravenous administration, intramuscular administration, nasal administration, intraocular administration, intracerebral administration, vaginal administration, intraperitoneal administration, transdermal administration, subcutaneous administration, intradermal administration, respiratory administration, etc.). In some embodiments of the present invention, the pharmaceutical composition may employ an intraocular route of administration (e.g., eye drop administration, eye ointment administration, subconjunctival injection administration, intraocular injection administration).

[0123] Specifically, the pharmaceutical composition may be any suitable dosage form. For example, it may include, but is not limited to, tablets, powders, granules, capsules, ingots, syrups, liquids, emulsions, suspensions, etc., including gastrointestinal dosage forms, enteral dosage forms, and non-enteral dosage forms, such as injectable dosage forms (e.g., for subcutaneous, intravenous, intramuscular, intraperitoneal administration), respiratory dosage forms such as sprays, aerosols, and powder mists, skin dosage forms such as topical solutions, lotions, ointments, plasters, pastes, patches, and seals, mucosal dosage forms such as eye drops, eye ointments, nasal drops, gargles, and sublingual tablets, and sinusal dosage forms such as suppositories, aerosols, effervescent tablets, drops, and pills used in the rectum, vagina, urethra, nose, ear canal, etc.

[0124] In some embodiments of the present invention, the pharmaceutical composition may be an ophthalmic preparation such as eye drops or eye ointment.

[0125] In one embodiment, the present invention provides the use of the compound of the present invention or a pharmaceutically acceptable prodrug of the compound, a pharmaceutically active metabolite of the compound and / or a pharmaceutically acceptable salt of the compound, and / or a pharmaceutical composition of the present invention in the preparation of a drug for the treatment of a disease.

[0126] In one embodiment, the present invention provides compounds of the present invention or pharmaceutically acceptable prodrugs of said compounds for the treatment of diseases, pharmaceutically active metabolites of said compounds and / or pharmaceutically acceptable salts of said compounds, and / or pharmaceutical compositions of the present invention.

[0127] In some embodiments of the present invention, the disease is a proliferative disorder mediated by protein tyrosine kinase.

[0128] In some embodiments of the present invention, the disease is an eye disease that includes, but is not limited to, pathological neovascularization, retinal ischemia, retinal edema, diabetic retinopathy, and other eye diseases, as well as proliferative diseases associated with malignant tumors.

[0129] In some embodiments of the present invention, the disease is diabetic retinopathy (including simple (background) diabetic retinopathy, proliferative diabetic retinopathy, and diabetic macular edema), age-related macular degeneration (AMD) (including neovascular (exudative) AMD, non-exudative AMD, and geographic atrophy), pathological choroidal neovascularization (CNV) resulting from some pathological mechanism (i.e., high myopia, trauma, sickle cell anemia, ocular histoplasmosis, retinal pigment streaks, traumatic choroidal rupture, optic disc drusen, and certain retinal dystrophy), resulting from some pathological mechanism Pathological subretinal neovascularization (i.e., sickle cell retinopathy, Eales disease (periretinal vein inflammation), ocular ischemic syndrome, internal carotid artery cavernous fistula, familial exudative vitreoretinopathy, hyperviscosity syndrome, idiopathic arteritis occlusive, birdshot retinochoroidopathy, retinal vasculitis, sarcoidosis, or toxoplasmosis), uveitis, retinal vein occlusion (central or branched), ocular trauma, surgical edema, surgical neovascularization, cystic macular edema, ocular ischemia, retinopathy of prematurity, Coats' disease, sickle cell retinopathy, and / or neovascular glaucoma.

[0130] In some embodiments of the present invention, the eye disease is a posterior segment disease, i.e., a disease occurring in the vitreous humor, retina, choroid, sclera, or optic nerve.

[0131] In some embodiments of the present invention, the disease is diabetic retinopathy, including simple (background) diabetic retinopathy (non-proliferative diabetic retinopathy), proliferative diabetic retinopathy, diabetic macular edema, and in particular non-proliferative diabetic retinopathy.

[0132] In some other embodiments of the present invention, the disease is age-related macular degeneration (AMD), including neovascular (exudative) AMD, non-exudative AMD, and geographic atrophy.

[0133] In some embodiments of the present invention, the disease is a tumor that includes, but is not limited to, breast cancer, lung cancer (especially non-small cell lung cancer), adenocarcinoma, colorectal cancer, kidney cancer, liver cancer, pancreatic adenocarcinoma, ovarian cancer, prostate cancer, glioma, glioblastoma, myeloma, acute myeloid leukemia, myeloid metaplasia of unknown cause, mesothelioma, and myelodysplastic syndrome, and is particularly a malignant tumor (cancer).

[0134] In some embodiments of the present invention, the disease is a hematopoietic malignancy, including leukemia, lymphoma, gonococcal tumor, and multiple myeloma (MM).

[0135] Specifically, leukemia can be chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), or acute monocytic leukemia.

[0136] Specifically, lymphomas include Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) (e.g., diffuse large cell lymphoma (DLCL) (e.g., diffuse large B cell lymphoma)), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B cell lymphoma, primary mediastinal B cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma, hairy cell leukemia (HCL), immunoblastic leukemia, and precursor B cell lymphoma. Lymphoblastic lymphoma, primary central nervous system (CNS) lymphoma, T-cell NHL, precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteric disease T-cell lymphoma, subcutaneous lipid membrane inflammatory T-cell lymphoma, anaplastic large cell lymphoma, NK / T-cell lymphoma, and especially diffuse large B-cell lymphoma (DLBCL). Specifically, in the above use, tumor treatment includes killing the tumor and preventing the metastasis and spread of the tumor and the proliferation of micrometastases.

[0137] In one embodiment, the present invention provides a method for treating a disease comprising administering a compound of the present invention or a pharmaceutically acceptable prodrug of the said compound, a pharmaceutically active metabolite of the said compound and / or a pharmaceutically acceptable salt of the said compound, and / or a pharmaceutical composition of the present invention.

[0138] As is well known to those skilled in the art, the dosage of a drug depends on a variety of factors, including but not limited to the activity of the specific compound used, the patient's age, weight, health status, behavior, diet, administration time, method of administration, excretion rate, and drug combinations. Furthermore, the optimal treatment method, such as the mode of treatment, can be determined according to conventional treatment methods, and the compound of the present invention or its tautomers, endoforms, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, and / or the compound or its tautomers, endoforms, racemates, enantiomers, diastereomers or mixtures thereof, or the pharmaceutically acceptable daily dose or type of pharmaceutically acceptable salt thereof can be determined according to conventional treatment methods.

[0139] In one embodiment, the present invention provides a method for modulating kinase receptor activity, comprising administering a compound of the present invention or a pharmaceutically acceptable prodrug of the said compound, a pharmaceutically active metabolite of the said compound and / or a pharmaceutically acceptable salt of the said compound, and / or a pharmaceutical composition of the present invention.

[0140] For example, the method described above inhibits the activity of the kinase receptor. The compounds described in the present invention have inhibitory activity against the in vitro proliferation of the kinase receptor. The inhibitory activity is such that, after adding the compound of the present invention, the kinase receptor activity decreases by 1% or more, 2% or more, 4% or more, 5% or more, 8% or more, 10% or more, 15% or more, 18% or more, 20% or more, 25% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, or 95% or more compared to a negative control or control drug. For example, the inhibitory activity is such that the IC of kinase receptor activity decreases. 50For value (nM): 10000 or less, 5000 or less, 4000 or less, 3000 or less, 2000 or less, 1000 or less, 500 or less, 400 or less, 300 or less, 200 or less, 150 or less, 120 or less, 110 or less, 100 or less, 99 or less, 98 or less, 97 or less, 95 90 or less, 80 or less, 75 or less, 70 or less, 65 or less, 62 or less, 60 or less, 50 or less, 40 or less, 30 or less, 25 or less, 23 or less, 22 or less, 20 or less, 19 or less, 18 or less, 18.5 or less, 17 or less, 15 or less, 12 or less, 10 or less, 9 or less, 8.5 The following values ​​may be 7 or less, 6.7 or less, 6 or less, 5.9 or less, 5.5 or less, 5.0 or less, 4.8 or less, 4.5 or less, 4.4 or less, 4 or less, 3.5 or less, 3 or less, 2.5 or less, 2 or less, 1.5 or less, 1.0 or less, 0.5 or less, 0.3 or less, 0.29 or less, 0.25 or less, 0.21 or less, 0.20 or less, 0.18 or less, 0.17 or less, 0.15 or less, 0.12 or less, 0.10 or less, 0.09 or less, 0.08 or less, 0.07 or less, 0.06 or less, 0.05 or less, 0.04 or less, 0.03 or less, 0.02 or less, or 0.01 or less. For example, inhibition of the kinase receptor activity can be detected by a mobility shift assay.

[0141] For example, the kinase receptor includes VEGFR (e.g., VEGFR1, VEGFR2, VEGFR3), EGFR or its functionally active fragment, particularly VEGFR. For example, the method is for non-therapeutic and / or non-diagnostic purposes. For example, the method is an in vitro and / or ex vivo method.

[0142] In some embodiments of the present invention, the method selectively inhibits VEGFR (e.g., VEGFR1, VEGFR2, VEGFR3, particularly VEGFR2) relative to EGFR.

[0143] In one embodiment, the present invention provides a method for inhibiting the formation of ocular angiogenesis and extravascular leakage of retina, comprising administering a compound of the present invention or a pharmaceutically acceptable prodrug of the said compound, a pharmaceutically active metabolite of the said compound and / or a pharmaceutically acceptable salt of the said compound, and / or a pharmaceutical composition of the present invention.

[0144] Specifically, the administration can employ any appropriate method of administration, particularly intraocular administration, such as eye drops, eye ointment, subconjunctival injection, intraocular injection, and especially eye drops.

[0145] Regardless of any theories, the following examples are not intended to limit the scope of the present invention, but solely to illustrate the compounds, manufacturing methods, and uses of the present invention.

[0146] Examples Table 1. Compound Information of the Invention [Table 1] TIFF0007911442000396.tif255170TIFF0007911442000397.tif255170TIFF0007911442000398.tif23517 0TIFF0007911442000399.tif255170TIFF0007911442000400.tif254170TIFF0007911442000401.tif25317 0TIFF0007911442000402.tif238170TIFF0007911442000403.tif231170TIFF0007911442000404.tif24117 0TIFF0007911442000405.tif245170TIFF0007911442000406.tif250170TIFF0007911442000407.tif58170

[0147] Example 1 [ka]

[0148] Step 1 At room temperature and under nitrogen gas protection, potassium vinyltrifluoroborate 1b (11.6 g, 86.21 mmol), Pd(dppf)Cl2 (1.3 g, 1.72 mmol), and triethylamine (8.7 g, 86.21 mmol) were added to a solution of 6-bromopyridine-3-ol 1a (10 g, 57.47 mmol) in N,N-dimethylformamide (150 mL) and heated to 85°C, where the mixture was reacted with stirring for approximately 16 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (petroleum ether / ethyl acetate = 1 / 1), the mixture was poured into water (100 mL), extracted with ethyl acetate (50 mL x 3), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was obtained. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1-1 / 1) to obtain a white solid 6-vinylpyridine-3-ol 1c (4.3 g, 35.50 mmol, yield 61.76%).

[0149] The product was confirmed by LC-MS and HNMR.

[0150] MS-ESI calculated value [M+H]+122.1, actual measurement 122.1. 1 H NMR (400 MHz, CDCl3): δ (ppm) 8.17-8.18 (m, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.25-7.28 (m, 1H), 6.80 (dd, J = 11.2 Hz, 11.2 Hz, 1H), 5.93 (d, J = 17.6 Hz, 1H), 5.38 (d, J = 11.2 Hz, 1H).

[0151] Step 2 At room temperature, 6-iodo-1H-indazole 1d (13.3 g, 77.74 mmol), cesium carbonate (50.66 g, 155 mmol), and Pd(dppf)Cl2 (11.38 g, 15.55 mmol) were added to a solution of N-methyl-2-mercaptobenzamide 1e (13 g, 77.74 mmol) in N,N-dimethylformamide (250 mL). The mixture was heated to 80°C and reacted with stirring for approximately 2 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 15 / 1), the mixture was poured into water (1000 mL), extracted with ethyl acetate (100 mL x 3), washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was obtained. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 2 / 1 to 0 / 1) to obtain a yellow solid 2-(1H-indazole-6-ylthio)-N-methylbenzamide 1f (8.3 g, yield 37.7%).

[0152] The product was confirmed by LC-MS and HNMR.

[0153] MS-ESI calculated value [M+H]+ 285.1, actual measurement 285.0.

[0154] 1 H NMR (400 MHz, CDCl3) δ: 8.07 (s, 1H), 7.72 (d, 1H, J=8.4Hz), 7.62-7.65 (m, 2H), 7.26-7.30 (m, 2H), 7.15-7.21 (m, 2H), 6.39 (s, 1H), 2.98 (d, 3H, J=4.8Hz).

[0155] Step 3 At 0°C, K2CO3 (6.83 g, 49.4 mmol) and I2 (10.66 g, 42.0 mmol) were added to a solution of 2-(1H-indazole-6-ylthio)-N-methylbenzamide 1f in N,N-dimethylformamide and reacted at room temperature for approximately 3.5 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 15 / 1), the mixture was poured into water (1000 mL), extracted with ethyl acetate (100 mL x 3), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product 2-[(3-iodo-1H-indazole-6-yl)thio]-N-methylbenzamide 1 g (8.8 g, 87.0%).

[0156] The product was confirmed by LC-MS and HNMR.

[0157] MS-ESI calculated value [M+H]+ 411.0, actual measurement 410.8.

[0158] 1 H NMR (400 MHz, DMSO-d6) δ: 13.59 (s, 1H), 8.40 (d, 1H, J=4.8Hz), 7.58 (s, 1H), 7.44-7.50 (m, 2H), 7.28-7.32 (m, 2H), 7.22-7.27 (m, 1H), 7.14 (dd, 1H, J=8.4, 2.0Hz), 7.02 (dd, 1H, J = 8.0, 2.0Hz), 2.76 (d, 3H, J=4.4Hz).

[0159] Step 4 At room temperature, 3,4-dihydro-2H-pyran (DHP) (1.03 g, 12.22 mmol) and TsOH (63.12 mg, 366.53 μmol) were added to a solution of 1 g (1 g, 2.44 mmol) of 2-[(3-iodo-1H-indazole-6-yl)thio]-N-methylbenzamide in 20 mL of THF, and the mixture was refluxed for 16 hours with stirring. After confirming that the starting materials had reacted completely by thin-layer chromatography (petroleum ether / ethyl acetate = 1 / 2), the mixture was poured into water (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layer was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was obtained. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1- / 5 / 1-3 / 1-1 / 1) to obtain a white solid 2-(3-iodo-1-tetrahydropyran-2-ylindazole-6-yl)thio-N-methylbenzamide 1h (650 mg, 1.32 mmol, yield 53.92%).

[0160] The product was confirmed by LC-MS and HNMR.

[0161] MS-ESI calculated value [M+H]+ 494.0, actual measurement 493.9.

[0162] 1 H NMR (400MHz, CDCl3): δ (ppm) 7.66 (s, 1H), 7.58-7.65 (m, 1H), 7.42 (d, 1H, J = 8.4 Hz), 7.29-7.35 (m, 2H), 7.14-7.22 (m, 2H), 6.27 (s, 1H), 5.64 (dd, 1H, J = 9.4, 2.6 Hz), 4.13 -4.15 (m, 1H), 3.64-3.76 (m, 1H), 2.97 (d, 3H, J = 4.8 Hz), 2.46-2.54 (m, 1H), 2.02-2.18 (m, 2H), 1.66-1.84 (m, 3H).

[0163] Step 5 At room temperature and under nitrogen gas protection, 2-(3-iodo-1-tetrahydropyran-2-ylindazole-6-yl)thio-N-methylbenzamide 1h (500 mg, 1.01 mmol) was dissolved in 1,4-dioxane (10 mL), to which 6-vinylpyridine-3-ol 1c (147.3 mg, 1.22 mmol), triethylamine (307.7 mg, 3.04 mmol), Pd2(dba)3 (464 mg, 506.73 μmol), and P(o-tol)3 (308.5 mg, 1.01 mmol) were added and the mixture was reacted with stirring at room temperature. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 20 / 1), the mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL x 3), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated to obtain the crude product. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 30 / 1-1 / 1) to obtain a yellow solid 2-[3-[(E)-2-(5-hydroxy-2-pyridyl)vinyl]-1-tetrahydropyran-2-ylindazole-6-yl]thio-N-methylbenzamide 1i (400 mg, 822.06 μmol, yield 81.11%), and the product purity was confirmed to be approximately 30% by LC-MS.

[0164] The product was confirmed by LC-MS.

[0165] MS-ESI calculated value [M+H]+ 487.2, actual measurement 487.4.

[0166] Step 6 At room temperature, 2-[3-[(E)-2-(5-hydroxy-2-pyridyl)vinyl]-1-tetrahydropyran-2-ylindazole-6-yl]thio-N-methylbenzamide 1i (150 mg, 308.27 μmol) was dissolved in dichloromethane (3 mL), to which trifluoroacetic acid (35.2 mg, 308.27 μmol, 23.75 μL) was added. The mixture was reacted at 35°C for 16 hours with stirring. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (40 mL), the pH was adjusted to 8-9 with solid sodium carbonate, and the mixture was extracted with DCM (30 mL x 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was obtained. The crude product was purified by preparative thin-layer chromatography to obtain the white solid 2-({3-[(E)-2-(5-hydroxypyridine-2-yl)vinyl]-1H-indazole-6-yl}thio)-N-methylbenzamide I-10 (6.1 mg, 15.16 μmol, yield 4.92%).

[0167] The product was confirmed by LC-MS and HNMR.

[0168] MS-ESI calculated value [M+H]+ 403.1, actual measurement 403.1.

[0169] 1 H NMR (400MHz, CDCl3&CD3OD): δ (ppm) 8.05-8.04 (m, 1H), 7.90 (d, J=8.4Hz, 1H), 7.51-7.42 (m, 3H), 7.39-7.35 (m, 2H), 7.21-7.18 (m, 2H), 7.14-7.07 (m, 3H), 2.82 (s, 3H).

[0170] [ka]

[0171] Step 1 At room temperature and under nitrogen gas protection, a solution of 2-[3-[(E)-2-(5-hydroxy-2-pyridyl)vinyl]-1-tetrahydropyran-2-ylindazole-6-yl]thio-N-methyl-benzamide 1i (400 mg, 822.06 μmol) in tetrahydrofuran (10 mL) was mixed with 2-(hydroxymethyl)pyrrolidine-1-carboxylate tert-butyl ester 2a (198.5 mg, 986.47 μmol), Ph3P (323.4 mg, 1.23 mmol), and DIAD (249.3 mg, 1.23 mmol). The mixture was heated to 40°C and reacted with stirring for approximately 16 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (30 mL), extracted with ethyl acetate (30 mL x 3), washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, concentrated to obtain the crude product. The crude product was purified by preparative thin-layer chromatography (dichloromethane / methanol = 10 / 1) to obtain a white solid 2-[[6-[(E)-2-[6-[2-(methylcarbamoyl)phenyl]thio-1-tetrahydropyran-2-ylindazole-3-yl]vinyl]-3-pyridyl]oxymethyl]pyrrolidine-1-carboxylic acid tert-butyl ester 2b (400 mg, 597.17 μmol, yield 72.64%), and the product purity was confirmed to be approximately 29% by LC-MS.

[0172] The product was confirmed by LC-MS.

[0173] MS-ESI calculated value [M+H]+670.3, actual measurement 670.2.

[0174] Step 2 At room temperature, trifluoroacetic acid (340.4 mg, 2.99 mmol) was added to a solution of 2-[[6-[(E)-2-[6-[2-(methylcarbamoyl)phenyl]thio-1-tetrahydropyran-2-ylindazole-3-yl]vinyl]-3-pyridyl]oxymethyl]pyrrolidine-1-carboxylic acid tert-butyl ester 2b (0.4 g, 597.17 μmol) in dichloromethane (5 mL), and the mixture was heated to 35°C and reacted with stirring for approximately 16 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (40 mL), the pH was adjusted to 8-9 with solid sodium carbonate, and the mixture was extracted with dichloromethane (30 mL x 3). The combined organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was obtained. The crude product was purified by preparative thin-layer chromatography to obtain a white solid N-methyl-2-({3-[(E)-2-{5-[(pyrrolidine-2-yl)methoxy]pyridine-2-yl}vinyl]-1H-indazole-6-yl}thio)benzamide I-14 (13.9 mg, 28.62 μmol, yield 4.79%).

[0175] The product was confirmed by LC-MS, HNMR, and CNMR.

[0176] MS-ESI calculated value [M+H]+486.2, actual measurement 487.0.

[0177] 11H NMR (400 MHz, CDCl3&CD3OD): δ (ppm) 8.24 - 8.23 (m, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.65 - 7.61 (m, 1H), 7.55 - 7.52 (m, 1H), 7.50 - 7.48 (m, 2H), 7.44 - 7.39 (m, 1H), 7.29 - 7.22 (m, 3H), 7.19 - 7.15 (m, 2H), 4.05 - 4.02 (m, 1H), 3.94 (t, J = 8.0 Hz, 1H), 3.53 - 3.50 (m, 1H), 3.04 - 2.91 (m, 2H), 2.88 (s, 1H), 2.02 - 1.95 (m, 1H), 1.89 - 1.79 (m, 2H), 1.64 - 1.57 (m, 1H). 13 13C NMR (100 MHz, CDCl3&CD3OD): δ (ppm) 169.83, 154.32, 148.42, 142.19, 137.25, 136.56, 135.24, 133.46, 131.10, 130.65, 139.35, 128.04, 126.65, 125.39, 122.26, 122.03, 121.83, 121.47, 120.46, 114.42, 70.93, 57.08, 46.10, 46.06, 29.59, 27.64, 26.33, 25.07.

[0178]

Chem.

[0179] [[ID=I5]]Procedure 1 At room temperature and under nitrogen gas protection, a solution of 2-[3-[(E)-2-(5-hydroxy-2-pyridyl)vinyl]-1-tetrahydropyran-2-ylindazole-6-yl]thio-N-methylbenzamide 1i (400 mg, 822.06 μmol) in tetrahydrofuran (5 mL) was mixed with (1-methylpyrrolidine-2-yl)methanol 3a (113.6 mg, 986.47 μmol), Ph3P (215.6 mg, 822.06 μmol), and DIAD (249.3 mg, 1.23 mmol) and reacted with stirring at 30°C for approximately 16 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (30 mL), extracted with ethyl acetate (20 mL x 3), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated to obtain the crude product. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1 - dichloromethane / methanol = 10 / 1) to obtain the yellow solid N-methyl-2-[3-[(E)-2-[5-[(1-methylpyrrolidine-2-yl)methoxy]-2-pyridyl]vinyl]-1-tetrahydropyran-2-ylindole-6-yl]thiobenzamide 3b (240 mg, 411.14 μmol, yield 50.01%).

[0180] The product was confirmed by LC-MS.

[0181] MS-ESI calculated value: 584.3, measured value: 584.3.

[0182] Step 2 At room temperature, trifluoroacetic acid (46.9 mg, 411.14 μmol) was added to a solution of N-methyl-2-[3-[(E)-2-[5-[(1-methylpyrrolidine-2-yl)methoxy]-2-pyridyl]vinyl]-1-tetrahydropyran-2-ylindole-6-yl]thiobenzamide 3b (240 mg, 411.14 μmol) in dichloromethane (5 mL). The mixture was stirred at 30°C for 16 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (10 mL), the pH was adjusted to 8-9 with solid sodium carbonate, and extracted with DCM (10 mL x 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was obtained. The crude product was purified by preparative thin-layer chromatography to obtain a white solid N-methyl-2-({3-[(E)-2-{5-[(1-methylpyrrolidine-2-yl)methoxy]pyridine-2-yl}vinyl]-1H-indazole-6-yl}thio)benzamide I-2 (31.6 mg, 63.25 μmol, yield 7.97%).

[0183] The product was confirmed by LC-MS, HNMR, and CNMR.

[0184] MS-ESI calculated value [M+H]+500.2, actual measurement 500.1.

[0185] 1 H NMR (400MHz, CDCl3&CD3OD): δ (ppm) 8.23 ​​(s, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.63 (s, 1H), 7.47 (dd, J = 39.8, 29.7 Hz, 4H), 7.24 (s, 2H), 4.02 (d, J = 6.4 Hz,2H), 3.08 (s, 3H), 2.85 (s, 1H), 2.70 (s, 3H), 2.28 - 2.32 (m, 1H), 2.63 (s, 1H), 1.98-2.02 (m, 1H), 1.80 (s, 1H), 0.82 (s, 1H). 13C NMR (100MHz, CDCl3&CD3OD): δ (ppm) 169.43, 154.32, 148.32, 137.43, 136.68, 134.67, 133.45, 131.85, 130.74, 129.50, 128.34, 126.93, 125.01, 122.20, 121.86, 121.79, 121.64, 121.49, 120.47, 113.93, 70.84, 64.29, 57.63, 41.61, 29.62, 28.32, 26.44, 22.71, 22.63.

[0186] [ka]

[0187] Step 1 At room temperature and under nitrogen gas protection, a solution of 2-[3-[(E)-2-(5-hydroxy-2-pyridyl)vinyl]-1-tetrahydropyran-2-ylindazole-6-yl]thio-N-methyl-benzamide 1i (400 mg, 822.06 μmol) in tetrahydrofuran (5 mL) was mixed with 2-(1-methyl-4-piperidinyl)ethanol 4a (141.3 mg, 986.47 μmol), Ph3P (323.4 mg, 1.23 mmol), and DIAD (249.3 mg, 1.23 mmol), and the mixture was reacted with stirring at 30°C for approximately 16 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated to obtain the crude product. The crude product was purified by preparative thin-layer chromatography (dichloromethane / methanol = 10 / 1) to obtain the white solid N-methyl-2-[3-[(E)-2-[5-[2-(1-methyl-4-piperidinyl)ethoxy]-2-pyridyl]vinyl]-1-tetrahydropyran-2-yl-indazole-6-yl]thiobenzamide 4b (120 mg, 196.14 μmol, yield 23.86%).

[0188] The product was confirmed by LC-MS.

[0189] MS-ESI calculated value [M+H]+612.3, actual measurement 612.2.

[0190] Step 2 At room temperature, trifluoroacetic acid (22.36 mg, 196.14 μmol) was added to a solution of N-methyl-2-[3-[(E)-2-[5-[2-(1-methyl-4-piperidinyl)ethoxy]-2-pyridyl]vinyl]-1-tetrahydropyran-2-yl-indazole-6-yl]thiobenzamide 4b (120 mg, 196.14 μmol) in dichloromethane (5 mL). The mixture was stirred at 40°C for 16 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (10 mL), the pH was adjusted to 8-9 with solid sodium carbonate, and extracted with DCM (10 mL x 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was obtained. The crude product was purified by preparative thin-layer chromatography to obtain a white solid N-methyl-2-({3-[(E)-2-{5-[2-(1-methylpiperidine-4-yl)ethoxy]pyridine-2-yl}vinyl]-1H-indazole-6-yl}thio)benzamide I-5 (17 mg, 32.22 μmol, yield 16.42%).

[0191] The product was confirmed by LC-MS, HNMR, and CNMR.

[0192] MS-ESI calculated value [M+H]+582.2, actual measurement 528.2.

[0193] 11H NMR (400 MHz, CDCl3&CD3OD): δ 8.24 (d, J = 2.4 Hz, 1H), 8.06 (d, J = 8.6 Hz, 1H), 7.56 - 7.80 (m, 3H), 7.48 - 7.55 (m, 2H), 7.41 - 7.43 (m, 1H), 7.32 (dd, J = 13.0, 6.4 Hz, 2H), 7.21 (d, J = 8.6 Hz, 2H), 4.17 (t, J = 6.2 Hz, 2H), 2.95 (d, J = 11.2 Hz, 2H), 2.88 (s, 3H), 2.34 (s, 3H), 2.16 (dd, J = 26.8, 13.4 Hz, 3H), 1.75 - 1.99 (m, 4H), 1.64 (s, 1H). 13 13C NMR (100 MHz, CDCl3&CD3OD) δ 154.34, 148.14, 137.65, 132.13, 130.84, 129.77, 128.68, 127.18, 124.68, 122.24, 121.58, 121.51, 121.37, 66.12, 55.66, 46.22, 35.50, 31.94, 31.81, 29.66, 26.59.

[0194] [Chemical formula]

[0195] Procedure 1<At room temperature and under nitrogen gas protection, a solution of 2-[3-[(E)-2-(5-hydroxy-2-pyridyl)vinyl]-1-tetrahydropyran-2-ylindazole-6-yl]thio-N-methylbenzamide 1i (400 mg, 822.06 μmol) in tetrahydrofuran (5 mL) was mixed with (1-methylpyrrolidine-3-yl)methanol 5a (113.6 mg, 986.47 μmol), Ph3P (323.4 mg, 1.23 mmol), and DIAD (249.3 mg, 1.23 mmol) and reacted with stirring at 30°C for approximately 16 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated to obtain the crude product. The crude product was purified by preparative thin-layer chromatography (dichloromethane / methanol = 10 / 1) to obtain a white solid N-methyl-2-[3-[(E)-2-[5-[(1-methylpyrrolidine-3-yl)methoxy]-2-pyridyl]vinyl]-1-tetrahydropyran-2-ylindole-6-yl]thiobenzamide 5b (170 mg, 291.22 μmol, yield 35.43%).

[0196] The product was confirmed by LC-MS.

[0197] MS-ESI calculated value [M+H]+584.3, actual measurement 584.2.

[0198] Step 2 At room temperature, trifluoroacetic acid (33.2 mg, 291.22 μmol) was added to a solution of N-methyl-2-[3-[(E)-2-[5-[(1-methylpyrrolidine-3-yl)methoxy]-2-pyridyl]vinyl]-1-tetrahydropyran-2-ylindole-6-yl]thiobenzamide 5b (170 mg, 291.22 μmol) in dichloromethane (5 mL). The mixture was stirred at 40°C for 16 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (10 mL), the pH was adjusted to 8-9 with solid sodium carbonate, and extracted with DCM (10 mL x 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was obtained. The crude product was purified by preparative thin-layer chromatography to obtain a white solid N-methyl-2-({3-[(E)-2-{5-[(1-methylpyrrolidine-3-yl)methoxy]pyridine-2-yl}vinyl]-1H-indazole-6-yl}thio)benzamide I-1 (24.3 mg, 48.64 μmol, yield 16.70%).

[0199] The product was confirmed by LC-MS, HNMR, and CNMR.

[0200] MS-ESI calculated value [M+H]+500.2, actual measurement 500.1.

[0201] 1 H NMR (400 MHz, CD3OD&CDCl3) δ 8.27 (d, J = 2.8 Hz, 1H), 8.07 (d, J = 4.8 Hz, 1H), 7.65-7.77 (m, 2H), 7.43 ― 7.50 (m, 4H), 7.26-7.38 (m, 2H), 7.21-7.26 (m, 2H), 4.03-4.11 (m, 2H), 2.92-2.97 (m, 1H), 2.88 (s, 3H), 2.74-2.86 (m, 3H), 2.63-2.69 (m, 1H), 2.50 (s, 3H), 2.14 ― 2.23 (m, 1H), 1.72 – 1.80 (m, 1H). 13 C NMR (100 MHz, CD3OD&CDCl3) δ: 170.33, 154.69, 148.16, 142.79, 142.73, 142.21, 137.09, 135.42, 133.78, 131.17, 130.33, 129.15, 127.67, 126.43, 125.44, 122.39, 122.02, 121.65, 121.27, 120.29, 114.32, 71.13, 71.08, 58.73, 55.53, 41.15, 37.35, 27.40, 25.66.

[0202] [ka]

[0203] Step 1 Under 0°C and nitrogen gas protection, 2-[3-[(E)-2-(5-hydroxy-2-pyridyl)vinyl]-1-tetrahydropyran-2-ylindazole-6-yl]thio-N-methylbenzamide 1i (500 mg, 1.03 mmol) was dissolved in tetrahydrofuran (5 mL), to which 2-(4-methylpiperazine-1-yl)ethanol 6a (177.8 mg, 1.23 mmol), Ph3P (404.3 mg, 1.54 mmol), and DIAD (311.7 mg, 1.54 mmol) were added and the mixture was reacted with stirring at 30°C for approximately 16 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (30 mL), extracted with ethyl acetate (30 mL x 3), washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, concentrated to obtain the crude product. The crude product was purified by preparative thin-layer chromatography (dichloromethane / methanol = 10 / 1) to obtain the yellow solid N-methyl-2-[3-[(E)-2-[5-[2-(4-methylpiperazine-1-yl)ethoxy]-2-pyridyl]vinyl]-1-tetrahydropyran-2-yl-indazole-6-yl]thiobenzamide 6b (400 mg, 652.76 μmol, yield 63.52%).

[0204] The product was confirmed by LC-MS.

[0205] MS-ESI calculated value [M+H]+613.3, actual measurement 613.2.

[0206] Step 2 At room temperature, trifluoroacetic acid (74.4 mg, 652.76 μmol) was added to a solution of N-methyl-2-[3-[(E)-2-[5-[2-(4-methylpiperazine-1-yl)ethoxy]-2-pyridyl]vinyl]-1-tetrahydropyran-2-yl-indazole-6-yl]thiobenzamide 6b (400 mg, 652.76 μmol) in dichloromethane (10 mL). The mixture was stirred at 30°C for 16 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (10 mL), the pH was adjusted to 8-9 with solid sodium carbonate, and extracted with DCM (10 mL x 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was obtained. The crude product was purified by preparative thin-layer chromatography to obtain a white solid N-methyl-2-({3-[(E)-2-{5-[2-(4-methylpiperazine-1-yl)ethoxy]pyridine-2-yl}vinyl]-1H-indazole-6-yl}thio)benzamide I-4 (27.5 mg, 52.02 μmol, yield 7.97%).

[0207] The product was confirmed by LC-MS, HNMR, and CNMR.

[0208] MS-ESI calculated value [M+H]+529.2, actual measurement 529.2.

[0209] 1 H NMR (400 MHz, CD3OD&CDCl3) δ 8.27 (d, J = 2.4 Hz, 1H), 8.05 (d, J = 11.2 Hz, 1H), 7.81 (s, 1H), 7.61-7.71 (m, 3H), 7.41-7.50 (m, 3H), 7.27-7.32 (m, 2H), 7.21 (d, J = 1.6 Hz, 2H),4.12 (s, 2H), 2.87 (d, J = 15.2 Hz, 4H), 2.50-2.73 (m, 8H), 2.33 (s, 3H). 13C NMR (100 MHz, CD3OD&CDCl3) δ: 170.27, 154.35, 148.36, 137.19, 136.77, 135.58, 133.62, 131.08, 130.43, 129.19, 127.72, 126.39, 125.57, 122.34, 122.18, 121.34, 65.97, 56.72, 54.32, 52.80, 45.07, 25.92.

[0210] [ka]

[0211] Step 1 Under 0°C and nitrogen gas protection, 2-[3-[(E)-2-(5-hydroxy-2-pyridyl)vinyl]-1-tetrahydropyran-2-ylindazole-6-yl]thio-N-methyl-benzamide 1i (750 mg, 1.54 mmol) was dissolved in tetrahydrofuran (5 mL), to which 3-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester 7a (900 mg, 4.47 mmol), Ph3P (972 mg, 3.71 mmol), and DIAD (750 mg, 3.71 mmol) were added and the mixture was reacted with stirring at 40°C for approximately 16 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (30 mL), extracted with ethyl acetate (30 mL x 3), washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, concentrated to obtain the crude product. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1 to 0 / 1) to obtain a white solid 3-[[6-[(E)-2-[6-[2-(methylcarbamoyl)phenyl]thio-1-tetrahydropyran-2-ylindazole-3-yl]vinyl]-3-pyridyl]oxymethyl]pyrrolidine-1-carboxylic acid tert-butyl ester 7b (200 mg, 298.58 μmol, yield 19.37%).

[0212] The product was confirmed by LCMS and HNMR.

[0213] MS-ESI calculated value [M+H]+670.3, actual value 670.2.

[0214] 1 H NMR (400 MHz, CDCl3) δ 8.34 (s, 2H), 8.00 (d, J = 8.4 Hz, 1H), 7.75 (s, 1H), 7.72 ― 7.62 (m, 3H), 7.56 (dd, J = 7.2, 1.6 Hz, 1H), 7.52 - 7.43 (m, 2H), 7.36 - 7.30 (m, 1H), 7.25 - 7.17 (m, 2H), 5.81 - 5.66 (m, 1H), 4.02 (d, J = 11.2 Hz, 3H), 3.70 (m, 3H), 3.42 (s, 1H), 3.23 (s, 1H), 2.98 (dd, J = 4.8, 1.2 Hz, 3H), 2.53 (d, J = 13.2 Hz, 1H), 2.11 (s, 4H), 1.93 - 1.66 (m, 4H), 1.65 - 1.42 (m, 9H).

[0215] Hand 2 At room temperature, trifluoroacetic acid (74.4 mg, 652.76 μmol) was added to a solution of 3-[[6-[(E)-2-[6-[2-(methylcarbamoyl)phenyl]thio-1-tetrahydropyran-2-ylindazole-3-yl]vinyl]-3-pyridyl]oxymethyl]pyrrolidine-1-carboxylic acid tert-butyl ester 7b (100 mg, 149.29 μmol) in dichloromethane (4 mL). The mixture was reacted at room temperature for approximately 2 hours with stirring. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (10 mL), the pH was adjusted to 8-9 with solid sodium carbonate, and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was obtained. The crude product was purified by preparative thin-layer chromatography to obtain a white solid N-methyl-2-(3-[(E)-2-{5-[(pyrrolidine-3-yl)methoxy]pyridine-2-yl}vinyl]-1H-indazole-6-yl}thio)benzamide I-7 (18 mg, 37.07 μmol, yield 24.83%).

[0216] The product was confirmed by LC-MS, HNMR, and CNMR.

[0217] MS-ESI calculated value [M+H]+486.2, actual measurement 486.1.

[0218] 1 H NMR (400 MHz, CD3OD) δ 8.41 (s, 1H), 8.05 (m, 1H), 7.69 - 7.45 (m, 3H), 7.44 - 6.96 (m, 4H), 5.35 (s, 1H), 4.40 - 3.97 (m, 2H), 3.68 - 3.34 (m, 3H), 3.32 - 3.24 (m, 1H), 3.22 - 2.92 (m, 1H), 2.87 (d, J = 12.0 Hz, 3H), 2.42 - 2.18 (m, 1H), 2.08 - 1.84 (m, 1H). 13C NMR (100MHz, CD3OD): δ (ppm) 170.31, 155.28, 142.86, 142.18, 137.76, 134.65, 134.50, 131.60, 130.32, 130.14, 127.72, 126.80, 125.61, 123.74, 120.81, 120.36, 113.83, 69.79, 45.24, 37.89, 26.64, 25.34.

[0219] [ka]

[0220] Step 1 At room temperature and under nitrogen gas protection, a solution of 2-[3-[(E)-2-(5-hydroxy-2-pyridyl)vinyl]-1-tetrahydropyran-2-ylindazole-6-yl]thio-N-methylbenzamide 1i (400 mg, 822.06 μmol) in tetrahydrofuran (10 mL) was mixed with [(3S)-1-methylpyrrolidine-3-yl]methanol 8a (114 mg, 986.47 μmol), Ph3P (501 mg, 1.91 mmol), and DIAD (249 mg, 1.23 mmol) and reacted with stirring at 40°C for approximately 16 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (50 mL), extracted with ethyl acetate (30 mL x 3), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated to obtain the crude product. The crude product was purified by preparative thin-layer chromatography to obtain a white solid N-methyl-2-[1-methyl-3-[(E)-2-[5-[(3S)-1-methylpyrrolidine-3-yl]methoxy]-2-pyridyl]vinyl]indazole-6-yl]thiobenzamide 8b (300 mg, 513.93 μmol, yield 62.52%).

[0221] The product was confirmed by LC-MS.

[0222] MS-ESI calculated value [M+H]+584.3, actual measurement 584.8.

[0223] Step 2 At room temperature, trifluoroacetic acid (3 g, 26.31 mmol) was added to a solution of N-methyl-2-[1-methyl-3-[(E)-2-[5-[(3S)-1-methylpyrrolidine-3-yl]methoxy]-2-pyridyl]vinyl]indazole-6-yl]thiobenzamide 8b (200 mg, 342.62 μmol) in dichloromethane (4 mL). The mixture was reacted at room temperature for approximately 16 hours with stirring. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (20 mL), the pH was adjusted to 8-9 with aqueous sodium carbonate (10 mL), and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was obtained. The crude product was purified by preparative thin-layer chromatography to obtain the white solid N-methyl-2-({3-[(E)-2-(5-{[(3S)-1-methylpyrrolidine-3-yl]methoxy}pyridine-2-yl)vinyl]-1H-indazole-6-yl}thio)benzamide I-37 (43 mg, 86.06 μmol, yield 25.12%).

[0224] The product was confirmed by LC-MS, HNMR, and CNMR.

[0225] MS-ESI calculated value [M+H]+500.2, actual measurement 500.1.

[0226] 11H NMR (400 MHz, CD3OD) δ 8.27 (d, J = 2.8 Hz, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.78 (s, 1H), 7.69 (d, J = 16.4 Hz, 1H), 7.65 - 7.60 (m, 2H), 7.49 (s, 1H), 7.42 (dd, J = 8.8, 2.8 Hz, 1H), 7.29 (dd, J = 13.2, 6.8 Hz, 2H), 7.23 - 7.18 (m, 2H), 4.11 (d, J = 5.2 Hz, 2H), 3.13 (dd, J = 9.2, 4.8 Hz, 1H), 2.88 (s, 3H), 2.82 (s, 1H), 2.54 (s, 3H), 2.45 - 2.38 (m, 1H), 2.16 - 2.08 (m, 1H), 1.90 - 1.82 (m, 2H), 1.77 (dd, J = 13.2, 6.0 Hz, 1H). 13 13C NMR (100 MHz, CDCl3&CD3OD) δ 168.68, 153.46, 147.44, 135.78, 133.95, 132.59, 130.85, 129.82, 128.58, 127.35, 125.96, 124.24, 121.34, 121.02, 120.60, 69.94, 63.40, 56.74, 40.70, 27.41, 25.51, 21.78.

[0227]

Chem.

[0228] Procedure 1 Under 0°C and nitrogen gas protection, a solution of 2-[3-[(E)-2-(5-hydroxy-2-pyridyl)vinyl]-1-tetrahydropyran-2-ylindazole-6-yl]thio-N-methylbenzamide 1i (500 mg, 1.03 mmol) in tetrahydrofuran (10 mL) was mixed with [(3R)-1-methylpyrrolidine-3-yl]methanol 9a (142 mg, 1.23 mmol), Ph3P (501 mg, 1.91 mmol), and DIAD (386.5 mg, 1.91 mmol) and reacted with stirring at 40°C for approximately 16 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (petroleum ether / ethyl acetate = 1 / 1), the mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated to obtain the crude product. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain a yellow solid N-methyl-2-[1-methyl-3-[(E)-2-[5-[(3R)-1-methylpyrrolidine-3-yl]methoxy]-2-pyridyl]vinyl]indazole-6-yl]thiobenzamide 9b (350 mg, 599.58 μmol, yield 58.35%).

[0229] The product was confirmed by LC-MS.

[0230] MS-ESI calculated value [M+H]+ 584.3, actual measurement 584.2.

[0231] Step 2 At room temperature, trifluoroacetic acid (5.3 g, 46.04 mmol) was added to a solution of N-methyl-2-[1-methyl-3-[(E)-2-[5-[(3R)-1-methylpyrrolidine-3-yl]methoxy]-2-pyridyl]vinyl]indazole-6-yl]thiobenzamide 9b (350 mg, 599.58 μmol) in dichloromethane (6 mL). The mixture was reacted at room temperature for approximately 16 hours with stirring. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (5 mL), the pH was adjusted to 8-9 with solid sodium carbonate, and the mixture was extracted with dichloromethane (5 mL x 3). The combined organic layers were washed with water (5 mL x 2), dried over anhydrous sodium sulfate, concentrated, and the crude product was obtained. The crude product was purified by preparative thin-layer chromatography to obtain the yellow solid N-methyl-2-({3-[(E)-2-(5-{ [(3R)-1-methylpyrrolidine-3-yl]methoxy}pyridine-2-yl)vinyl]-1H-indazole-6-yl}thio)benzamide I-39 (45 mg, 90.07 μmol, yield 15.02%).

[0232] The product was confirmed by LC-MS, HNMR, and CNMR.

[0233] MS-ESI calculated value [M+H]+ 500.2, actual measurement 500.1.

[0234] 11H NMR (400 MHz, CD3OD&CDCl3) δ 8.27 (s, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.76 (s, 1H), 7.71-7.67 (m, 1H), 7.64-7.61 (m, 2H), 7.49-7.47 (m, 1H), 7.43-7.41 (m, 1H), 7.33-7.27 (m, 2H), 7.21 (t, J = 8.0 Hz, 2H), 4.11 (d, J = 5.2 Hz, 2H), 3.15 - 3.13 (m, 1H), 2.89 (s, 3H), 2.82 (s, 1H), 2.54 (s, 3H), 2.43-2.39(m, 1H), 2.16-2.11 (m, 1H), 1.88-1.85 (m, 2H), 1.80-1.75 (m, 2H). 13 13C NMR (100 MHz, CDCl3&CD3OD) δ 169.88, 154.17, 148.04, 142.25, 141.19, 136.90, 136.34, 135.28, 133.24, 130.79, 130.20, 128.97, 127.50, 125.29, 122.05, 121.78, 121.54, 121.10, 120.12, 114.30, 70.29, 64.04, 57.23, 41.01, 27.74, 25.77, 22.21.

[0235] [Chemical formula]

[0236] <00,03724>Procedure 1 At low temperature, sodium hydroxypropyl hydride (1.5 g, 37.15 mmol, 60% purity) was added stepwise to a solution of 6-vinylpyridine-3-ol 1c (1.5 g, 12.38 mmol) in dry N,N-dimethylformamide (20 mL). The mixture was then stirred at 0°C for 1 hour. Next, 4-(2-chloroethyl)morpholine hydrochloride 10a (2.8 g, 14.86 mmol) was slowly added. The mixture was stirred at 60°C for approximately 4 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (petroleum ether / ethyl acetate = 3 / 1), the mixture was poured into water (100 mL) and extracted with ethyl acetate (60 mL x 3). The combined organic layer was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was obtained. The crude product was purified by preparative thin-layer chromatography to obtain a yellow oily liquid 4-[2-[(6-vinyl-3-pyridyl)oxy]ethyl]morpholine 10b (1.5 g, 6.40 mmol, yield 51.70%).

[0237] The product was confirmed by LC-MS and HNMR.

[0238] MS-ESI calculated value [M+H]+235.1, actual measurement 235.1. 1 H NMR (400MHz, CDCl3): δ (ppm) 8.29 (d, J = 2.8 Hz, 1H), 7.32-7.30 (m, 1H), 7.20-7.17 (m, 1H), 6.82-6.75 (m, 1H), 6.07-6.02 (m, 1H), 5.39-5.36 (m, 1H), 4.19-4.13 (m, 2H), 3.77-3.75 (m, 4H), 2.85-2.82 (m, 2H), 2.61-2.59 (m, 4H).

[0239] Step 2 At room temperature and under nitrogen gas protection, a solution of 2-(3-iodo-1-tetrahydropyran-2-ylindazole-6-yl)thio-N-methylbenzamide 1h (100 mg, 0.20 mmol) in 1,4-dioxane (5 mL) was mixed with 4-[2-[(6-vinyl-3-pyridyl)oxy]ethyl]morpholine 10b (57 mg, 0.24 mmol), triethylamine (61.5 mg, 0.61 mmol), Pd2(dba)3 (45.5 mg, 0.20 mmol), and P(o-tol)3 (61.7 mg, 0.20 mmol). The mixture was heated to 100°C and reacted with stirring. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 20 / 1), the mixture was poured into water (10 mL), extracted with ethyl acetate (10 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated to obtain the crude product. The crude product was purified by preparative thin-layer chromatography (dichloromethane / methanol = 20 / 1) to obtain the brown solid N-methyl-2-[3-[(E)-2-[5-(2-morpholinoethoxy)-2-pyridyl]vinyl]-1-tetrahydropyran-2-yl-indazole-6-yl]thiobenzamide 10c (100 mg, 166.74 μmol, yield 82.26%).

[0240] The product was confirmed by LC-MS.

[0241] MS-ESI calculated value [M+H] +600.2, measured value 600.1. Step 3 At room temperature, trifluoroacetic acid (380.2 mg, 3.33 mmol) was added to a solution of N-methyl-2-[3-[(E)-2-[5-(2-morpholinoethoxy)-2-pyridyl]vinyl]-1-tetrahydropyran-2-ylindazole-6-yl]thiobenzamide 10c (400 mg, 0.67 mmol) in dichloromethane (2 mL). The mixture was stirred at 35°C for 16 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (40 mL), the pH was adjusted to 8-9 with solid sodium carbonate, and the mixture was extracted with dichloromethane (30 mL x 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was obtained. The crude product was purified by preparative thin-layer chromatography to obtain a white solid N-methyl-2-({3-[(E)-2-{5-[2-(morpholin-4-yl)ethoxy]pyridine-2-yl}vinyl]-1H-indazole-6-yl}thio)benzamide I-3 (53.7 mg, 104.15 μmol, yield 15.62%).

[0242] The product was confirmed by LC-MS, HNMR, and CNMR.

[0243] MS-ESI calculated value [M+H]+516.2, actual measurement 516.2 1 H NMR (400MHz, CDCl3): δ (ppm) 10.28 (s, 1H), 8.38-8.37 (m, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.78-7.74 (m, 1H), 7.68-7.66 (m, 1H), 7.57-7.52 (m, 2H), 7.44 (d, J = 8.8 Hz, 1H), 7.34-7.32 (m, 2H), 7.27-7.22 (m, 3H), 6.37-6.34 (m, 1H), 4.22 (t, J = 5.6 Hz, 2H), 3.78 (t, J = 4.4 Hz, 4H), 2.98 (d, J = 5.2 Hz, 3H), 2.87 (t, J = 5.6 Hz, 2H), 2.63 (s, 4H). 13 C NMR (100 MHz, CDCl3&CD3OD): δ (ppm) 170.16, 154.28, 148.42, 137.19, 136.59, 135.60, 133.54, 131.08, 130.51, 129.24, 127.79, 126.42, 125.60, 122.32, 122.21, 121.99, 121.40, 114.51, 66.52, 65.88, 57.34, 53.82, 26.09.

[0244] [ka]

[0245] Step 1 Under nitrogen gas protection at 0°C, sodium hydride (689.67 mg, 17.24 mmol, 60% purity) was added in fractions to a solution of 5-bromopyridine-2-ol 11b (1 g, 5.75 mmol) in N,N-dimethylformamide (20 mL), and the mixture was stirred at 0°C for 1 hour. Then, 1-(2-chloroethyl)pyrrolidine hydrochloride 11a (1.17 g, 6.90 mmol) was added at 0°C, the mixture was heated to 60°C, and the mixture was stirred for 16 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (petroleum ether / ethyl acetate = 1 / 1), the mixture was poured into water (50 mL), extracted with ethyl acetate (50 mL x 3), washed with saturated saline solution (100 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product, a brown oily liquid 5-bromo-2-(2-pyrrolidine-1-methoxy)pyridine 11c (1 g, 3.69 mmol, yield 64.17%).

[0246] The product was confirmed by LC-MS and HNMR.

[0247] MS-ESI calculated value [M+H]+272.9, actual measurement 272.9.

[0248] 1H NMR (400 MHz, DMSO-d6) δ 8.18 - 8.02 (m, 1H), 7.50 (dt, J = 13.8, 6.9 Hz, 1H), 7.41 - 7.21 (m, 1H), 4.12 (dd, J = 5.5, 2.9 Hz, 2H), 2.76 (dd, J = 5.5, 2.8 Hz, 2H), 2.48 (d, J = 1.7 Hz, 4H), 1.65 (d, J = 3.1 Hz, 4H).

[0249] Step 2 At room temperature, potassium vinyltrifluoroborate 1b (750.0 mg, 5.60 mmol), Pd(dppf)Cl2 (80.1 mg, 109.53 μmol), and triethylamine (560.0 mg, 5.53 mmol) were added to a solution of 5-bromo-2-(2-pyrrolidine-1-methoxy)pyridine 11c (1 g, 3.69 mmol) in dried N,N-dimethylformamide (20 mL). The mixture was heated to 85°C and reacted with stirring for approximately 16 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (50 mL), extracted with ethyl acetate (50 mL x 3), washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was obtained. The crude product was purified by preparative thin-layer chromatography (dichloromethane / methanol = 10 / 1) to obtain the yellow solid 2-(2-pyrrolidine-1-ethoxy)-5-vinylpyridine 11d (340 mg, 1.56 mmol, yield 42.23%).

[0250] The product was confirmed by LC-MS and HNMR.

[0251] MS-ESI calculated value [M+H]+219.1, actual measurement 219.1.

[0252] 1H NMR (400 MHz, CDCl3) δ 7.89 - 7.53 (m, 1H), 7.52 - 7.32 (m, 1H), 6.84 - 6.54 (m, 1H), 6.51 - 6.27 (m, 1H), 5.73 - 5.42 (m, 1H), 5.16 (dt, J = 22.5, 11.2 Hz, 1H), 4.06 (d, J = 17.0 Hz, 2H), 2.83 (d, J = 10.8 Hz, 2H), 2.60 (d, J = 7.4 Hz, 4H), 1.84 - 1.76 (m, 4H).

[0253] Step 3 At room temperature and under nitrogen gas protection, a solution of 2-(3-iodo-1-tetrahydropyran-2-ylindazole-6-yl)thio-N-methylbenzamide 1h (500 mg, 1.01 mmol) in 1,4-dioxane (20 mL) was mixed with 2-(2-pyrrolidine-1-ethoxy)-5-vinylpyridine 11d (280 mg, 1.28 mmol), triethylamine (300 mg, 2.96 mmol), Pd2(dba)3 (250 mg, 1.11 mmol), and P(o-tol)3 (250 mg, 821.40 μmol). The mixture was heated to 100°C and reacted with stirring for approximately 2 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 20 / 1), the mixture was poured into water (30 mL), extracted with ethyl acetate (30 mL x 3), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated to obtain the crude product. The crude product was purified by preparative thin-layer chromatography (dichloromethane / methanol = 10 / 1) to obtain the yellow solid N-methyl-2-[3-[(E)-2-[6-(2-pyrrolinidine-1-ylethoxy)-3-pyridyl]vinyl]-1-tetrahydropyran-2-ylindazole-6-yl]thiobenzamide 11e (200 mg, 342.62 μmol, yield 33.81%).

[0254] The product was confirmed by LC-MS.

[0255] MS-ESI calculated value [M+H]+584.3, actual measurement 584.4.

[0256] Step 4 At room temperature, trifluoroacetic acid (1.20 g, 10.52 mmol) was added to a solution of N-methyl-2-[3-[(E)-2-[6-(2-pyrrolinidine-1-ylethoxy)-3-pyridyl]vinyl]-1-tetrahydropyran-2-ylindazole-6-yl]thiobenzamide 11e (200 mg, 342.62 μmol) in dichloromethane (8 mL). The mixture was stirred at 40°C for 16 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (10 mL), the pH was adjusted to 8-9 with aqueous sodium carbonate solution (10 mL), and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was obtained. The crude product was purified by preparative thin-layer chromatography to obtain a white solid N-methyl-2-({3-[(E)-2-{6-[2-(pyrrolidin-1-yl)ethoxy]pyridine-3-yl}vinyl]-1H-indazole-6-yl}thio)benzamide I-19 (10.4 mg, 20.82 μmol, yield 6.08%).

[0257] The product was confirmed by LC-MS, HNMR, and CNMR.

[0258] MS-ESI calculated value [M+H]+500.2, actual measurement 500.0.

[0259] 11H NMR (400 MHz, CDCl3) δ 11.49 (s, 1H), 7.84 (d, J = 8.5 Hz, 1H), 7.65 (d, J = 5.0 Hz, 1H), 7.43 - 7.28 (m, 6H), 7.22 - 7.08 (m, 2H), 6.94 (dd, J = 41.7, 16.5 Hz, 2H), 6.19 (d, J = 9.4 Hz, 1H), 4.13 (s, 2H), 3.07 - 2.92 (m, 3H), 2.72 (s, 2H), 1.85 (s, 2H), 1.62 (s, 4H), 1.28 (d, J = 10.3 Hz, 2H). 13 13C NMR (100MHz, CDCl3): δ (ppm) 170.29, 162.66, 137.38, 137.19, 136.91, 135.50, 133.68, 131.08, 130.36, 127.70, 126.39, 125.63, 125.28, 121.29, 119.95, 118.46, 54.22, 54.00, 25.76, 23.11.

[0260]

Chem.

[0261] Procedure 1 At room temperature and under nitrogen gas protection, 6-bromopyridine-2-ol 12a (500 mg, 2.87 mmol) was dissolved in N,N-dimethylformamide (10 mL), to which potassium vinyltrifluoroborate 1b (577.4 mg, 4.31 mmol), Pd(dppf)Cl2 (100 mg, 137.81 μmol), and triethylamine (872.4 mg, 8.62 mmol) were added. The mixture was heated to 80°C and reacted with stirring for approximately 16 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (100 mL), extracted with ethyl acetate (40 mL x 3), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was obtained. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1-1 / 10) to obtain a white solid 6-vinylpyridine-2-ol 12b (140 mg, 1.16 mmol, yield 40.22%).

[0262] The product was confirmed by HNMR. 1 H NMR (400 MHz, CDCl3): δ (ppm) 11.84 (s, 1H), 7.42 (s, 1H), 6.46 (m, 2H), 6.14 (m, 2H), 5.55 (d, J = 11.3 Hz, 1H).

[0263] Step 2 At room temperature and under nitrogen gas protection, 1-(2-chloroethyl)pyrrolidine hydrochloride 11a (185.3 mg, 1.09 mmol), NaI (19.1 mg, 127.13 μmol), and silver carbonate (751.2 mg, 2.72 mmol) were added to a solution of 6-vinylpyridine-2-ol 12b (110 mg, 908.07 μmol) in N,N-dimethylformamide (2 mL), and the mixture was heated to 100°C and reacted with stirring for approximately 4 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (10 mL), extracted with ethyl acetate (10 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was obtained. The crude product was purified by preparative thin-layer chromatography (dichloromethane / methanol = 10 / 1) to obtain the yellow solid 2-(2-pyrrolidine-1-ethoxy)-6-vinylpyridine 12c (75 mg, 343.57 μmol, yield 37.84%).

[0264] The product was confirmed by LC-MS and HNMR.

[0265] MS-ESI calculated value [M+H]+219.1, actual measurement 219.1.

[0266] 1 H NMR (400MHz, CDCl3): δ (ppm) 7.53 (t, J=8.0Hz, 1H), 6.84 (d, J=7.2 Hz, 1H), 6.75-6.67 (m, 2H), 6.30-6.25(m, 1H), 5.43-5.40 (m, 1H), 4.58 (t, J=6.0Hz, 2H), 3.01(s, 2H), 2.76 (s, 4H), 1.88 (s, 4H).

[0267] Step 3 At room temperature and under nitrogen gas protection, a solution of 2-(3-iodo-1-tetrahydropyran-2-ylindazole-6-yl)thio-N-methylbenzamide 1h (500 mg, 1.01 mmol) in 1,4-dioxane (20 mL) was mixed with 2-(2-pyrrolidine-1-ethoxy)-6-vinylpyridine 12c (265.5 mg, 1.22 mmol), triethylamine (307.7 mg, 3.04 mmol), Pd2(dba)3 (464 mg, 506.73 μmol), and P(o-tol)3 (308.5 mg, 1.01 mmol). The mixture was heated to 100°C and reacted with stirring for approximately 2 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (30 mL), extracted with ethyl acetate (30 mL x 3), washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, concentrated to obtain the crude product. The crude product was purified by preparative thin-layer chromatography (dichloromethane / methanol = 10 / 1) to obtain the yellow solid N-methyl-2-[3-[(E)-2-[6-(2-pyrrolidine-1-ylethoxy)-2-pyridyl]vinyl]-1-tetrahydropyran-2-ylindazole-6-yl]thiobenzamide 12d (370 mg, 633.84 μmol, yield 62.54%).

[0268] The product was confirmed by LC-MS.

[0269] MS-ESI calculated value [M+H]+584.3, actual measurement 584.1.

[0270] Step 4 At room temperature, trifluoroacetic acid (78.1 mg, 685.23 μmol) was added to a solution of N-methyl-2-[3-[(E)-2-[6-(2-pyrrolinidine-1-ylethoxy)-2-pyridyl]vinyl]-1-tetrahydropyran-2-ylindazole-6-yl]thiobenzamide 12d (0.4 g, 685.23 μmol) in dichloromethane (10 mL). The mixture was stirred at 30°C for 16 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (40 mL), the pH was adjusted to 8-9 with sodium carbonate solid granules, and the mixture was extracted with dichloromethane (20 mL x 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was obtained. The crude product was purified by preparative thin-layer chromatography to obtain the yellow solid N-methyl-2-({3-[(E)-2-{6-[2-(pyrrolidine-1-yl)ethoxy]pyridine-2-yl}vinyl]-1H-indazole-6-yl}thio)benzamide I-17 (27.5 mg, 55.04 μmol, yield 8.03%).

[0271] The product was confirmed by LC-MS, HNMR, and CNMR.

[0272] MS-ESI calculated value [M+H]+500.2, actual measurement 500.1.

[0273] 11H NMR (400 MHz, CDCl3): δ (ppm) 10.61 - 10.42 (m, 1H), 8.02 - 7.97 (m, 2H), 7.65 (s, 1H), 7.56 (t, J = 7.6 Hz, 1H), 7.43 (d, J = 16.1 Hz, 1H), 7.32 (d, J = 3.7 Hz, 1H), 7.24 (d, J = 8.3 Hz, 1H), 6.95 (d, J = 7.1 Hz, 1H), 6.70 (d, J = 8.3 Hz, 1H), 6.36 (s, 1H), 4.62 (t, J = 5.9 Hz, 2H), 2.98 (t, J = 6.1 Hz, 3H), 2.70 (s, 2H), 1.85 (s, 2H). 13 13C NMR (100 MHz, CDCl3): δ (ppm) 168.95, 163.13, 152.66, 143.44, 142.25, 138.96, 136.19, 135.01, 132.77, 130.85, 129.90, 128.59, 126.84, 125.06, 123.37, 121.68, 120.89, 115.98, 114.33, 110.36, 64.19, 55.05, 54.61, 26.88, 23.47.

[0274]

Chem.

[0275] Step 1 At room temperature and under nitrogen gas protection, 1-(2-chloroethyl)pyrrolidine hydrochloride 11a (1.47 g, 8.67 mmol) and cesium carbonate (5.65 g, 17.34 mmol) were added to a DMSO (10 mL) solution of 3-bromophenol 13a (1.00 g, 5.78 mmol) and heated to 50°C, reacting with stirring for approximately 16 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (petroleum ether / ethyl acetate = 1 / 1), the mixture was poured into water (40 mL), extracted with ethyl acetate (20 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated to obtain the crude product. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 5 / 1 to 3 / 1) to obtain a white solid 1-[2-(3-bromophenoxy)ethyl]pyrrolidine 13b (620 mg, 2.29 mmol, yield 39.70%).

[0276] The product was confirmed by LC-MS and HNMR.

[0277] MS-ESI calculated value [M+H]+270.0, actual measurement 270.0.

[0278] 1 H NMR (400 MHz, CDCl3) δ 7.13-7.17 (m, 1H), 7.08-7.10 (m, 2H), 6.86-6.89 (m, 1H), 4.10 (t, J = 6.0 Hz, 2H), 2.91 (t, J = 6.0 Hz, 1H), 2.63-2.66 (m, 4H), 1.81-1.85 (m, 4H).

[0279] Step 2 At room temperature and under nitrogen gas protection, 1-[2-(3-bromophenoxy)ethyl]pyrrolidine 13b (800 mg, 2.96 mmol) was dissolved in N,N-dimethylformamide (8 mL), to which potassium vinyltrifluoroborate 1b (577.4 mg, 4.31 mmol), Pd(dppf)Cl2 (65.00 mg, 88.83 μmol), and triethylamine (898.92 mg, 8.88 mmol) were added. The mixture was heated to 85°C and reacted with stirring for approximately 16 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (100 mL), extracted with ethyl acetate (50 mL x 3), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was obtained. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1 - dichloromethane / methanol = 10 / 1) to obtain a white solid 1-[2-(3-vinylphenoxy)ethyl]pyrrolidine 13c (300 mg, 1.38 mmol, yield 46.62%).

[0280] The product was confirmed by LC-MS and HNMR.

[0281] MS-ESI calculated value [M+H]+218.1, actual measurement 218.1.

[0282] 1 H NMR (400MHz, CDCl3): δ (ppm)7.29-7.15 (m, 1H), 6.98 (m, 2H), 6.83 (m, 1H), 6.68 (dd, J = 17.6, 10.9 Hz, 1H), 5.84-5.60 (m, 1H), 5.24 (d, J = 10.9 Hz, 1H), 4.20-4.03 (m, 2H), 2.90 (t, J = 6.0 Hz, 1H), 2.70-2.54 (m, 4H), 1.87-1.75 (m, 4H).

[0283] Step 3 At room temperature and under nitrogen gas protection, a solution of 2-(3-iodo-1-tetrahydropyran-2-ylindazole-6-yl)thio-N-methylbenzamide 1h (200 mg, 405.38 μmol) in 1,4-dioxane (5 mL) was mixed with 1-[2-(3-vinylphenoxy)ethyl]pyrrolidine 13c (132.14 mg, 608.08 μmol), triethylamine (123.06 mg, 1.22 mmol), Pd2(dba)3 (371.22 mg, 405.38 μmol), and P(o-tol)3 (123.38 mg, 405.38 μmol). The mixture was heated to 100°C and reacted with stirring for approximately 4 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (20 mL), extracted with ethyl acetate (10 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated to obtain the crude product. The crude product was purified by preparative thin-layer chromatography (dichloromethane / methanol = 10 / 1) to obtain the yellow solid N-methyl-2-[3-[(E)-2-[3-(2-pyrrolidine-1-ethoxy)phenyl]vinyl]-1-tetrahydropyran-2-yl-indazole-6-yl]thiobenzamide 13d (370 mg, 633.84 μmol, yield 62.54%).

[0284] The product was confirmed by LC-MS.

[0285] MS-ESI calculated value [M+H]+ 583.3, actual measurement 583.1.

[0286] Step 4 At room temperature, trifluoroacetic acid (0.5 mL) was added to a solution of N-methyl-2-[3-[(E)-2-[3-(2-pyrrolidine-1-ethoxy)phenyl]vinyl]-1-tetrahydropyran-2-ylindazole-6-yl]thiobenzamide 13d (110 mg, 188.76 μmol) in dichloromethane (3 mL). The mixture was reacted with stirring at 40°C for approximately 16 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (30 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was obtained. The crude product was purified by preparative thin-layer chromatography to obtain the white solid N-methyl-2-({3-[(E)-2-{3-[2-(pyrrolidine-1-yl)ethoxy]phenyl}vinyl]-1H-indazole-6-yl}thio)benzamide I-15 (11.8 mg, 23.66 μmol, yield 12.54%).

[0287] The product was confirmed by LC-MS, HNMR, and CNMR.

[0288] MS-ESI calculated value [M+H]+ 499.2, actual measurement 499.1.

[0289] 1 H NMR (400MHz, CD3OD): δ (ppm) 8.07 (d, J = 8.5 Hz, 1H), 7.59 (s, 1H), 7.51-7.49 (m, 3H), 7.35-7.32 (m, 5H), 7.26-7.24 (m, 2H), 6.99 (d, J = 8.0 Hz, 1H), 4.44-4.41 (t, J=9.6 Hz,2H), 3.82-3.74 (m, 2H), 3.72-3.70 (m, 2H), 3.30-3.22 (m, 2H), 2.87 (s, 3H), 2.25-2.17 (m, 2H), 2.11-2.00 (m, 2H). 13C NMR (100 MHz, CD3OD) δ 170.38, 158.23,143.23, 141.95, 139.35, 137.29, 134.97, 134.12, 131.44, 130.58, 130.26, 129.68, 127.67, 126.62, 125.08, 121.26, 120.13,119.19, 119.86, 114.05, 113.80, 111.92, 62.91, 54.34, 53.80, 36.94, 25.32, 22.51, 16.29.

[0290] [ka]

[0291] Step 1 At room temperature and under nitrogen gas protection, potassium vinyltrifluoroborate 1b (2.31 g, 17.24 mmol), Pd(dppf)Cl2 (1 g, 1.37 mmol), and triethylamine (3.00 g, 29.65 mmol) were added to a solution of 5-bromopyridine-3-ol 14a (2 g, 11.49 mmol) in N,N-dimethylformamide (20 mL), and the mixture was heated to 85°C and reacted with stirring for approximately 16 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (100 mL), extracted with ethyl acetate (50 mL x 3), washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was obtained. The crude product was purified by basic alumina column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 0 / 1) to obtain a white solid 5-vinylpyridine-3-ol 14b (600 mg, 4.95 mmol, yield 43.09%).

[0292] The product was confirmed by LC-MS and HNMR.

[0293] MS-ESI calculated value [M+H]+122.1, actual measurement 122.1.

[0294] 1 H NMR (400 MHz, CDCl3) δ 8.12 (t, J = 27.6 Hz, 2H), 7.38 (s, 1H), 6.67 (dd, J = 17.6, 11.0 Hz, 1H), 5.83 (d, J = 17.6 Hz, 1H), 5.41 (d, J = 10.8 Hz, 1H).

[0295] Step 2 Under 0°C and nitrogen gas protection, sodium hydride (300.00 mg, 7.50 mmol, 60% purity) was added in fractions to a solution of 5-vinylpyridine-3-ol 14b (300 mg, 2.48 mmol) in N,N-dimethylformamide (4 mL), and the mixture was stirred at 0°C for 1 hour. Then, 1-(2-chloroethyl)pyrrolidine hydrochloride 11a (600 mg, 3.53 mmol) was added, and the mixture was heated to room temperature and reacted with stirring for about 2 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (10 mL), extracted with ethyl acetate (10 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated to obtain the crude product. The crude product was purified by preparative thin-layer chromatography (petroleum ether / ethyl acetate = 5 / 1 to 3 / 1) to obtain the yellow solid 3-(2-pyrrolidine-1-ethoxy)-5-vinylpyridine 14c (190 mg, 870.39 μmol, yield 35.15%).

[0296] The product was confirmed by LC-MS and HNMR.

[0297] MS-ESI calculated value [M+H]+219.1, actual measurement 219.1.

[0298] 1H NMR (400 MHz, CDCl3) δ 8.33 - 8.06 (m, 2H), 7.61 (dd, J = 12.4, 7.6 Hz, 1H), 6.71 (dd, J = 17.6, 11.2 Hz, 1H), 5.83 (d, J = 17.6 Hz, 1H), 5.41 (d, J = 10.8 Hz, 1H), 4.22 (dd, J = 20.8, 15.2 Hz, 2H), 2.95 (dd, J = 17.2, 11.6 Hz, 2H), 2.54 (d, J = 105.6 Hz, 4H), 1.85 (s, 4H).

[0299] Step 3 At room temperature and under nitrogen gas protection, a solution of 2-(3-iodo-1-tetrahydropyran-2-ylindazole-6-yl)thio-N-methylbenzamide 1h (400 mg, 810.77 μmol) in 1,4-dioxane (5 mL) was mixed with 3-(2-pyrrolidine-1-ethoxy)-5-vinylpyridine 14c (200 mg, 916.20 μmol), triethylamine (300.00 mg, 2.96 mmol), Pd2(dba)3 (320 mg, 1.43 mmol), and P(o-tol)3 (220 mg, 722.83 μmol). The mixture was heated to 100°C and reacted with stirring for approximately 2 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (10 mL), extracted with ethyl acetate (10 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated to obtain the crude product. The crude product was purified by preparative thin-layer chromatography (dichloromethane / methanol = 10 / 1) to obtain a yellow oily liquid N-methyl-2-[3-[(E)-2-[5-(2-pyrrolidine-1-ylethoxy)-3-pyridyl]vinyl]-1-tetrahydropyran-2-ylindazole-6-yl]thiobenzamide 14d (100 mg, 171.31 μmol, yield 21.13%).

[0300] The product was confirmed by LC-MS.

[0301] MS-ESI calculated value [M+H]+ 584.3, actual measurement 584.1.

[0302] Step 4 At room temperature, N-methyl-2-[3-[(E)-2-[5-(2-pyrrolinidine-1-ylethoxy)-3-pyridyl]vinyl]-1-tetrahydropyran-2-ylindazole-6-yl]thiobenzamide 14d (100 mg, 171.31 μmol) was dissolved in dichloromethane (3 mL) and TFA trifluoroacetate (1.5 g, 13.16 mmol) was added. The mixture was reacted at room temperature for approximately 2 hours with stirring. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was obtained. The crude product was purified by preparative thin-layer chromatography to obtain a white solid N-methyl-2-({3-[(E)-2-{5-[2-(pyrrolidine-1-yl)ethoxy]pyridine-3-yl}vinyl]-1H-indazole-6-yl}thio)benzamide I-22 (16.3 mg, 32.62 μmol, yield 19.04%).

[0303] The product was confirmed by LC-MS, HNMR, and CNMR.

[0304] MS-ESI calculated value [M+H]+ 500.2, actual measurement 500.9.

[0305] 11H NMR (400 MHz, CDCl3) δ 8.39 (s, 1H), 8.25 (d, J = 2.6 Hz, 1H), 7.97 (d, J = 8.5 Hz, 1H), 7.70 - 7.65 (m, 1H), 7.52 (s, 1H), 7.43 (d, J = 10.4 Hz, 3H), 7.37 - 7.32 (m, 2H), 7.25 (d, J = 9.7 Hz, 2H), 6.39 (s, 1H), 4.25 (t, J = 5.8 Hz, 2H), 3.00 (dd, J = 10.3, 5.3 Hz, 5H), 2.72 (s, 4H), 1.87 (s, 4H). 13 13C NMR (100MHz, CDCl3): δ (ppm) 168.85, 155.10, 143.18, 142.19, 141.19, 137.13, 136.55, 134.73, 133.23, 131.65, 130.84, 128.62, 126.96, 125.05, 122.39, 121.41, 120.56, 117.33, 113.97, 67.38, 55.00, 54.72, 53.40, 26.87, 23.52.

[0306]

Chem.

[0307] Procedure 1 At room temperature and under nitrogen gas protection, 4-bromo-1H-pyrazole 15a (2 g, 13.61 mmol) was dissolved in DMSO (20 mL), to which 1-(2-chloroethyl)pyrrolidine hydrochloride 11a (2.8 g, 16.33 mmol) and cesium carbonate (13.3 g, 40.82 mmol) were added. The mixture was heated to 100°C and reacted with stirring for approximately 2.5 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (100 mL), extracted with dichloromethane (40 mL x 3), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was obtained. The crude product was purified by silica gel chromatography (dichloromethane / methanol = 20 / 1) to obtain a yellow oily liquid 4-bromo-1-(2-pyrrolidine-1-ethyl)pyrazole 15b (2.5 g, 10.24 mmol, yield 75.25%).

[0308] The product was confirmed by HNMR. 1 H NMR (400MHz, CDCl3): δ (ppm) 7.38 (d, J=2.4Hz, 1H), 6.25 (d, J=2.4Hz, 1H), 4.23 (t, J=6.8Hz, 2H), 2.94-2.91 (m, 2H), 2.57-2.52 (m, 4H), 1.79-1.77 (m, 4H).

[0309] Step 2 At room temperature and under nitrogen gas protection, 4-bromo-1-(2-pyrrolidine-1-ethyl)pyrazole 15b (501.4 mg, 2.05 mmol) was dissolved in N,N-dimethylformamide (10 mL), to which potassium vinyltrifluoroborate 1b (440.8 mg, 3.29 mmol), Pd(dppf)Cl2 (542.9 mg, 742.01 μmol), and triethylamine (668.1 mg, 6.60 mmol) were added. The mixture was heated to 85°C and reacted with stirring for approximately 16 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (50 mL), extracted with dichloromethane (50 mL x 3), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was obtained. The crude product was purified by silica gel chromatography (dichloromethane / methanol = 20 / 1) to obtain a red oily liquid 1-(2-pyrrolidine-1-ethyl)-4-vinylpyrazole 15c (66 mg, 345.06 μmol, yield 16.80%).

[0310] The product was confirmed by LC-MS and HNMR.

[0311] MS-ESI calculated value [M+H]+192.1, actual measurement 192.2.

[0312] 1 H NMR (400MHz, CDCl3): δ (ppm) 7.60(d, J=2.4Hz, 1H), 7.47 (d, J=2.4Hz, 1H), 6.5 (t, J=6.8Hz, 1H), 5.5-5.0(m, 2H), 4.27(m, 2H), 2.98(m, 2H), 2.575(m, 4H), 1.81(m, 5H).

[0313] Step 3 At room temperature and under nitrogen gas protection, a solution of 2-(3-iodo-1-tetrahydropyran-2-ylindazole-6-yl)thio-N-methylbenzamide 1h (500 mg, 1.01 mmol) in 1,4-dioxane (5 mL) was mixed with 1-(2-pyrrolidine-1-ethyl)-4-vinylpyrazole 15c (213.2 mg, 1.11 mmol), triethylamine (307.7 mg, 3.04 mmol), Pd2(dba)3 (500 mg, 546.04 μmol), and P(o-tol)3 (500.5 mg, 1.64 mmol). The mixture was heated to 100°C and reacted with stirring for approximately 2 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (15 mL), filtered, and the filtrate was extracted with dichloromethane (15 mL x 3). The combined organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product, a red oily liquid N-methyl-2-[3-[(E)-2-[1-(2-pyrrolidine-1-ylethyl)pyrazole-4-yl]vinyl]-1-tetrahydropyran-2-ylindazole-6-yl]thiobenzamide 15d (370 mg, 633.84 μmol, yield 62.54%).

[0314] The product was confirmed by LC-MS.

[0315] MS-ESI calculated value [M+H]+557.3, actual measurement 557.3.

[0316] Step 4 At room temperature, trifluoroacetic acid (527.7 mg, 4.63 mmol) was added to a solution of N-methyl-2-[3-[(E)-2-[1-(2-pyrrolidine-1-ylethyl)pyrazole-4-yl]vinyl]-1-tetrahydropyran-2-ylindazole-6-yl]thiobenzamide 15d (360.3 mg, 647.18 μmol) in dichloromethane (10 mL). The mixture was reacted at room temperature for approximately 16 hours with stirring. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (40 mL), the pH was adjusted to 8-9 with sodium carbonate, extracted with dichloromethane (10 mL x 3), the combined organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was obtained. The crude product was purified by preparative thin-layer chromatography to obtain the yellow solid N-methyl-2-({3-[(E)-2-{1-[2-(pyrrolidine-1-yl)ethyl]-1H-pyrazole-4-yl}vinyl]-1H-indazole-6-yl}thio)benzamide I-9 (33.8 mg, 71.52 μmol, yield 11.05%).

[0317] The product was confirmed by LC-MS, HNMR, and CNMR.

[0318] MS-ESI calculated value [M+H]+473.2, actual measurement 473.1.

[0319] 11H NMR (400 MHz, CD3OD): δ (ppm) 10.61 - 10.42 (m, 1H), 8.02 - 7.97 (m, 2H), 7.65 (s, 1H), 7.56 (t, J = 7.6 Hz, 1H), 7.43 (d, J = 16.1 Hz, 1H), 7.32 (d, J = 3.7 Hz, 1H), 7.24 (d, J = 8.3 Hz, 1H), 6.95 (d, J = 7.1 Hz, 1H), 6.70 (d, J = 8.3 Hz, 1H), 6.36 (s, 1H), 4.62 (t, J = 5.9 Hz, 2H), 2.98 (t, J = 6.1 Hz, 3H), 2.70 (s, 2H), 1.85 (s, 2H). 13 13C NMR (100 MHz, CDCl3): δ (ppm) 168.73, 144.24, 142.13, 137.42, 136.63, 134.57, 133.25, 130.85, 128.73, 127.88, 127.08, 124.55, 121.63, 120.57, 120.42, 118.04, 113.50, 55.77, 54.23, 51.40, 31.94, 29.70, 26.84, 23.53, 22.70, 14.13.

[0320]

Chem.

[0321] Procedure 1 At room temperature and under nitrogen gas protection, 1-(3-chloropropyl)pyrrolidine hydrochloride 16a (2.4 g, 16.33 mmol) and cesium carbonate (13.3 g, 40.82 mmol) were added to a DMSO (20 mL) solution of 4-bromo-1H-pyrazole 15a (2 g, 13.61 mmol) and heated to 100°C, and the mixture was reacted with stirring for approximately 4 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (100 mL), extracted with ethyl acetate (50 mL x 3), washed with saturated brine (120 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was obtained. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 20 / 1-0 / 1) to obtain the yellow solid 4-bromo-1-(3-pyrrolidine-1-ylpropyl)pyrazole 16b (3 g, 11.62 mmol, yield 85.40%).

[0322] The product was confirmed by LC-MS and HNMR.

[0323] MS-ESI calculated value [M+H]+259.9, actual measurement 260.1.

[0324] 1 H NMR (400MHz, CDCl3): δ (ppm) 7.43 (d, J = 10.8 Hz, 2H), 4.17 (t, J = 6.8 Hz, 2H), 2.46-2.39 (m, 6H), 2.06-1.99 (m, 2H), 1.82-1.74 (m, 4H).

[0325] Step 2 At room temperature and under nitrogen gas protection, 4-bromo-1-(3-pyrrolidine-1-ylpropyl)pyrazole 16b (1 g, 3.87 mmol) was dissolved in N,N-dimethylformamide (10 mL), to which potassium vinyltrifluoroborate 1b (778.3 mg, 5.81 mmol), Pd(dppf)Cl2 (85 mg, 116.21 μmol), and triethylamine (587.9 mg, 5.81 mmol) were added. The mixture was heated to 100°C and reacted with stirring for approximately 4 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (50 mL), extracted with ethyl acetate (50 mL x 3), washed with saturated brine (120 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was obtained. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1-0 / 1 and then dichloromethane / methanol = 20 / 1-10 / 1) to obtain a yellow oily liquid 1-(3-pyrrolidine-1-ylpropyl)-4-vinylpyrazole 16c (300 mg, 1.46 mmol, yield 37.72%).

[0326] The product was confirmed by HNMR. 1 H NMR (400MHz, CDCl3): δ (ppm) 7.45-7.41 (m, 2H), 6.52 (dd, J = 9.8, 11.2 Hz, 1H), 5.44 (d, J = 16.4 Hz, 1H), 5.05 (d, J = 11.2 Hz, 1H), 4.17 (d, J = 6.8 Hz, 4H), 2.53 (s, 4H), 2.11-1.99 (m, 4H), 1.79 (d, J = 3.2 Hz, 4H).

[0327] Step 3 At room temperature and under nitrogen gas protection, a solution of 2-(3-iodo-1-tetrahydropyran-2-ylindazole-6-yl)thio-N-methylbenzamide 1h (300 mg, 608.08 μmol) in 1,4-dioxane (10 mL) was mixed with 1-(3-pyrrolidine-1-ylpropyl)-4-vinylpyrazole 16c (124.8 mg, 608.08 μmol), triethylamine (92.3 mg, 912.11 μmol), Pd2(dba)3 (185.1 mg, 608.08 μmol), and P(o-tol)3 (835.2 mg, 912.11 μmol). The mixture was heated to 100°C and reacted with stirring for approximately 2 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (30 mL), extracted with ethyl acetate (30 mL x 3), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product, a yellow solid N-methyl-2-[3-[(E)-2-[1-(3-pyrrolidine-1-ylpropyl)pyrazole-4-yl]vinyl]-1-tetrahydropyran-2-ylindazole-6-yl]thiobenzamide 16d (300 mg, 525.63 μmol, yield 86.44%).

[0328] The product was confirmed by LC-MS.

[0329] MS-ESI calculated value [M+H]+571.3, actual measurement 571.3.

[0330] Step 4 At room temperature, a solution of N-methyl-2-[3-[(E)-2-[1-(3-pyrrolinidine-1-ylpropyl)pyrazole-4-yl]vinyl]-1-tetrahydropyran-2-ylindazole-6-yl]thiobenzamide 16d (500 mg, 876.05 μmol) in dichloromethane (10 mL) was mixed with trifluoroacetic acid (100 mg, 876.05 μmol) and reacted with stirring at room temperature for approximately 16 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (40 mL), the pH was adjusted to 8-9 with sodium carbonate, extracted with dichloromethane (30 mL x 3), the combined organic layer was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was obtained. The crude product was purified by preparative thin-layer chromatography to obtain the yellow solid N-methyl-2-({3-[(E)-2-{1-[3-(pyrrolidine-1-yl)propyl]-1H-pyrazole-4-yl}vinyl]-1H-indazole-6-yl}thio)benzamide I-32 (15.4 mg, 31.65 μmol, yield 3.61%).

[0331] The product was confirmed by LC-MS, HNMR, and CNMR.

[0332] MS-ESI calculated value [M+H]+487.2, actual measurement 487.1.

[0333] 1H NMR (400 MHz, CDCl3) δ (ppm) 7.91 (d, J = 8.0 Hz, 1H), 7.74 (s, 1H), 7.66-7.62 (m, 1H), 7.58 (s, 1H), 7.47 (s, 1H), 7.34-7.29 (m, 3H), 7.25-7.21 (m, 2H), 7.20-7.17 (m, 1H), 7.11 (d, J = 16.8 Hz, 1H), 6.33 (s, 1H), 4.22 (t, J = 6.8 Hz, 2H), 2.96 (d, J = 4.8 Hz, 3H), 2.59 (d, J = 19.2 Hz, 5H), 2.18-2.11 (m, 2H), 1.84 (s, 5H). 13 C NMR (100 MHz, CDCl3) δ (ppm) 168.62, 144.36, 142.08, 137.46, 134.46, 131.96, 130.88, 128.81, 127.58, 127.17, 124.62, 121.80, 121.63, 120.49, 117.88, 113.31, 54.06, 53.00, 50.20, 29.71, 29.07, 26.82, 23.46.

[0334] I-13およびI-25

change

[0335] Handy 1 At room temperature and under nitrogen gas protection, 3-bromo-1H-pyrazole 17a (2 g, 13.61 mmol) was dissolved in DMSO (20 mL), to which 1-(2-chloroethyl)pyrrolidine hydrochloride 11a (2.8 g, 16.33 mmol) and cesium carbonate (13.3 g, 40.82 mmol) were added. The mixture was heated to 100°C and reacted with stirring for approximately 4 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (30 mL), extracted with dichloromethane (40 mL x 3), washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was obtained. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to obtain a mixture of the yellow oily liquid 3-bromo-1-(2-pyrrolidine-1-ethyl)pyrazole 17b (major) and 5-bromo-1-(2-pyrrolidine-1-ethyl)pyrazole 17b' (1.2 g, 4.92 mmol, yield 36.12%).

[0336] 3-bromo-1-(2-pyrrolidine-1-ethyl)pyrazole 17b was confirmed by LC-MS and HNMR.

[0337] MS-ESI calculated value [M+H]+245.9, actual measurement 246.0.

[0338] 1 H NMR (400 MHz, CDCl3): δ (ppm) 7.38 (d, J=2.4Hz, 1H), 6.25 (d, J=2.4Hz, 1H), 4.23 (t, J=6.8Hz, 2H), 2.94-2.91 (m, 2H), 2.57-2.52 (m, 4H), 1.79-1.77 (m, 4H).

[0339] 5-Bromo-1-(2-pyrrolidine-1-ethyl)pyrazole 17b' was confirmed by LC-MS.

[0340] MS-ESI calculated value [M+H]+245.9, actual measurement 246.0.

[0341] Step 2 At room temperature and under nitrogen gas protection, a mixture of 3-bromo-1-(2-pyrrolidine-1-ethyl)pyrazole 17b (major) and 5-bromo-1-(2-pyrrolidine-1-ethyl)pyrazole 17b' (600 mg, 2.46 mmol) was dissolved in N,N-dimethylformamide (5 mL). Potassium vinyltrifluoroborate 1b (493.8 mg, 3.69 mmol), Pd(dppf)Cl2 (54 mg, 73.73 μmol), and triethylamine (373 mg, 3.69 mmol) were added, and the mixture was heated to 85°C and stirred for approximately 16 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (30 mL), extracted with dichloromethane (30 mL x 3), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated to obtain the crude product. The crude product was purified by preparative thin-layer chromatography (dichloromethane / methanol = 10 / 1) to obtain a mixture of the red oily liquid 1-(2-pyrrolidine-1-ethyl)-3-vinylpyrazole 17c and 1-(2-pyrrolidine-1-ethyl)-5-vinylpyrazole 17c' (0.4 g, 2.09 mmol, yield 85.09%).

[0342] The mixture of the products was confirmed by LC-MS.

[0343] MS-ESI calculated value [M+H]+192.1, actual measurement 192.1.

[0344] Step 3 At room temperature and under nitrogen gas protection, a solution of 2-(3-iodo-1-tetrahydropyran-2-ylindazole-6-yl)thio-N-methylbenzamide 1h (500 mg, 1.01 mmol) in 1,4-dioxane (10 mL) was mixed with a mixture of 1-(2-pyrrolidine-1-ethyl)-3-vinylpyrazole 17c and 1-(2-pyrrolidine-1-ethyl)-5-vinylpyrazole 17c' (232.6 mg, 1.22 mmol), triethylamine (307.7 mg, 3.04 mmol), Pd2(dba)3 (464 mg, 506.73 μmol), and P(o-tol)3 (308.5 mg, 1.01 mmol). The mixture was heated to 100°C and reacted with stirring for approximately 4 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (30 mL), filtered, and the filtrate was extracted with ethyl acetate (20 mL x 3). The combined organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was obtained. The crude product was purified by preparative thin-layer chromatography (dichloromethane / methanol = 10 / 1) to obtain a mixture of the yellow solid N-methyl-2-[3-[(E)-2-[1-(2-pyrrolidine-1-ylethyl)pyrazole-3-yl]vinyl]-1-tetrahydropyran-2-ylindazole-6-yl]thiobenzamide 17d and N-methyl-2-[3-[(E)-2-[2-(2-pyrrolidine-1-ylethyl)pyrazole-3-yl]vinyl]-1-tetrahydropyran-2-ylindazole-6-yl]thiobenzamide 17d' (250 mg, 449.06 μmol, yield 44.31%).

[0345] The product was confirmed by LC-MS.

[0346] Step 4 At room temperature, a mixture of N-methyl-2-[3-[(E)-2-[1-(2-pyrrolidine-1-ylethyl)pyrazole-3-yl]vinyl]-1-tetrahydropyran-2-ylindazole-6-yl]thiobenzamide 17d and N-methyl-2-[3-[(E)-2-[2-(2-pyrrolidine-1-ylethyl)pyrazole-3-yl]vinyl]-1-tetrahydropyran-2-ylindazole-6-yl]thiobenzamide 17d' (250 mg, 449.06 μmol) was dissolved in dichloromethane (5 mL), to which trifluoroacetic acid (256 mg, 2.25 mmol) was added. The mixture was reacted at 30°C for approximately 16 hours with stirring. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (40 mL), the pH was adjusted to 8-9 with sodium carbonate, and the mixture was extracted with dichloromethane (20 mL x 3). The combined organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was obtained. The crude products were purified by preparative thin-layer chromatography to obtain yellow solid N-methyl-2-({3-[(E)-2-{1-[2-(pyrrolidine-1-yl)ethyl]-1H-pyrazole-3-yl}vinyl]-1H-indazole-6-yl}thio)benzamide I-13 (4 mg, 8.47 μmol, yield 1.88%) and yellow solid N-methyl-2-({3-[(E)-2-{1-[2-(pyrrolidine-1-yl)ethyl]-1H-pyrazole-5-yl}vinyl]-1H-indazole-6-yl}thio)benzamide I-25 (7.4 mg, 15.68 μmol, yield 3.48%).

[0347] The two products obtained were confirmed by LC-MS, HNMR, and CNMR.

[0348] N-methyl-2-({3-[(E)-2-{1-[2-(pyrroridine-1-yl)ethyl]-1H-pyrazole-3-yl}vinyl]-1H-indazole-6-yl}thio)benzamide I-13: MS-ESI calculated value [M+H]+ 473.2, measured value 473.2.

[0349] 1 H NMR (400MHz, CD3OD): δ (ppm) δ 8.02 (d, J = 8.8 Hz, 1H), 7.75 (d, J = 2.0 Hz, 1H), 7.59 (s, 1H), 7.50 - 7.46 (m, 3H), 7.37 - 7.31 (m, 2H), 7.25-7.20 (m, 2H), 6.73 (s, 1H), 4.59 (t, J = 5.6 Hz, 2H), 3.79-3.73 (m, 4H), 3.15 (s, 2H), 2.88 (s, 3H), 2.17 (s, 2H), 2.06 (s, 2H). 13 C NMR (100 MHz, CD3OD): δ (ppm) 170.33, 151.68, 142.74, 142.14, 137.64, 134.90, 134.17, 132.05, 131.46, 130.26, 127.68, 126.65, 125.06, 122.45, 121.15, 121.05, 119.93, 113.79, 103.49, 54.34, 54.29, 25.33, 22.57. N-メチル-2-({3-[(E)-2-{1-[2-(ピロリジン-1-イル)エチル]-1H-ピラゾール-5 -イル}ビニル]-1H-インダゾール-6-イル}チオ)ベンズアミドI-25:MS-ESI calculation value [M+H]+ 473.2, tested 473.1.

[0350] 1 H NMR (400MHz, CD3OD): δ (ppm) δ 8.07 (d, J = 8.4 Hz, 1H), 7.61 - 7.59 (m, 2H), 7.51 - 7.49 (m, 3H), 7.37-7.34 (m, 2H), 7.25-7.21 (m, 2H), 6.81 (d, J = 2.0 Hz, 1H), 4.72 (t, J = 5.6 Hz, 2H), 3.78 (t, J = 5.6 Hz, 4H), 3.15 (s, 2H), 2.88 (s, 3H), 2.17 (s, 1H), 2.05 (s, 1H) 13 C NMR (100 MHz, CD3OD): δ (ppm) 168.95, 163.13, 152.66, 138.96, 135.01, 131.37, 129.90, 126.84, 123.37, 120.89, 115.89, 114.33, 110.36, 64.19, 55.05, 54.61, 26.88, 23.47.

[0351] [ka]

[0352] Step 1 At room temperature and under nitrogen gas protection, 4-bromopyridine-2-ol 18a (2 g, 13.61 mmol) was dissolved in DMSO (20 mL), to which 1-(2-chloroethyl)pyrrolidine hydrochloride 11a (3.1 g, 22.99 mmol), silver carbonate (6.3 g, 22.99 mmol), and NaI (241.2 mg, 1.61 mmol) were added. The mixture was heated to 85°C and reacted with stirring for approximately 16 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (100 mL), extracted with dichloromethane (40 mL x 3), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was obtained. The crude product was purified by preparative thin-layer chromatography (dichloromethane / methanol = 10 / 1) to obtain the yellow solid 4-bromo-2-(2-pyrrolidine-1-methoxy)pyridine 18b (765 mg, 2.82 mmol, yield 24.54%).

[0353] The product was confirmed by LC-MS and HNMR.

[0354] MS-ESI calculated value [M+H]+272.9, actual measurement 273.1.

[0355] 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 5.2 Hz, 1H), 7.00 (d, J = 5.6 Hz, 1H), 6.81 (s, 1H), 4.42 (t, J = 6.0 Hz, 1H), 2.86 (t, J = 6.0 Hz, 2H), 2.59 (d, J = 6.0 Hz, 4H), 1.77-1.81 (m, 4H).

[0356] Step 2 At room temperature and under nitrogen gas protection, 4-bromo-2-(2-pyrrolidine-1-methoxy)pyridine 18b (200 mg, 737.59 μmol) in a solution of N,N-dimethylformamide (3 mL) was mixed with potassium vinyltrifluoroborate 1b (148.2 mg, 1.11 mmol), Pd(dppf)Cl2 (16.2 mg, 22.13 μmol), and triethylamine (112 mg, 1.11 mmol). The mixture was heated to 85°C and reacted with stirring for approximately 4 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (50 mL), extracted with dichloromethane (50 mL x 3), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was obtained. The crude product was purified by preparative thin-layer chromatography (dichloromethane / methanol = 10 / 1) to obtain the yellow solid 2-(2-pyrrolidine-1-ethoxy)-4-vinylpyridine 18c (10 mg, 45.81 μmol, yield 6.21%).

[0357] The product was confirmed by LC-MS.

[0358] MS-ESI calculated value [M+H]+219.1, actual measurement 219.1.

[0359] Step 3 At room temperature and under nitrogen gas protection, a solution of 2-(3-iodo-1-tetrahydropyran-2-ylindazole-6-yl)thio-N-methylbenzamide 1h (110 mg, 222.96 μmol) in 1,4-dioxane (2 mL) was mixed with 2-(2-pyrrolidine-1-ethoxy)-4-vinylpyridine 18c (58.4 mg, 267.55 μmol), triethylamine (33.8 mg, 334.44 μmol), Pd2(dba)3 (67.9 mg, 222.96 μmol), and P(o-tol)3 (306.3 mg, 334.44 μmol). The mixture was heated to 100°C and reacted with stirring for approximately 2 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (30 mL), extracted with ethyl acetate (15 mL x 3), washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, concentrated to obtain the crude product. The crude product was purified by preparative thin-layer chromatography (dichloromethane / methanol = 10 / 1) to obtain the yellow solid N-methyl-2-[3-[(E)-2-[2-(2-pyrrolidine-1-methoxy)-4-pyridyl]vinyl]-1-tetrahydropyran-2-yl-indazole-6-yl]thiobenzamide 18d (37 mg, 63.38 μmol, yield 28.43%).

[0360] The product was confirmed by LC-MS and HNMR.

[0361] MS-ESI calculated value [M+H]+584.3, actual measurement 584.3.

[0362] 1H NMR (400 MHz, CDCl3) δ (ppm) δ 8.48 (d, J = 8.4 Hz, 0H), 7.62 - 7.77 (m, 3H), 7.41 (s, 1H), 7.27-7.28 (m, 3H), 7.20 - 7.23 (m, 3H), 6.29 (s, 1H), 5.75 (d, J = 6.8 Hz, 1H), 4.00 (d, J = 12.0 Hz, 1H), 3.73 (d, J = 8.8 Hz, 1H), 3.21 (s, 1H), 2.96 (d, J = 4.8 Hz, 3H), 2.66 - 2.70 (m, 2H), 2.20-2.49 (m, 4H), 1.58 - 1.73 (m, 8H), 1.22 (d, J = 24.4 Hz, 4H).

[0363] Step 4 At room temperature, trifluoroacetic acid (78.1 mg, 685.23 μmol) was added to a solution of N-methyl-2-[3-[(E)-2-[2-(2-pyrrolinidine-1-methoxy)-4-pyridyl]vinyl]-1-tetrahydropyran-2-ylindazole-6-yl]thiobenzamide 18d (400 mg, 685.23 μmol) in dichloromethane (10 mL). The mixture was reacted with stirring at 40°C for approximately 16 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (40 mL), the pH was adjusted to 8-9 with sodium carbonate, extracted with dichloromethane (20 mL x 3), the combined organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was obtained. The crude product was purified by preparative thin-layer chromatography to obtain the yellow solid N-methyl-2-({3-[(E)-2-{2-[2-(pyrrolidin-1-yl)ethoxy]pyridine-4-yl}vinyl]-1H-indazole-6-yl}thio)benzamide I-18 (8 mg, 16.01 μmol, yield 2.34%).

[0364] The product was confirmed by LC-MS, HNMR, and CNMR.

[0365] MS-ESI calculated value: [M+H]+500.2, measured value: 500.2.

[0366] 1 H NMR (400 MHz, CD3OD&CDCl3) δ 8.01 (d, J = 8.6 Hz, 1H), 7.58 (dd, J = 15.6, 8.4 Hz, 3H), 7.46-7.50 (m, 1H), 7.26-7.33 (m, 3H), 7.23 (d, J = 8.6 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 6.74 (d, J = 7.2 Hz, 1H), 6.62 (s, 1H), 4.13 (t, J = 6.8 Hz, 2H), 2.82 - 2.91 (m, 5H), 2.69 (s, 4H), 1.84 (s, 4H). 13 C NMR (100 MHz, CD3OD&CDCl3) δ 170.27, 163.68, 149.42, 138.06, 136.98, 135.33, 133.98, 131.20, 130.40, 127.73, 127.12, 126.49, 125.82, 120.77, 116.77, 114.49,114.29, 104.30, 99.99, 54.57,54.02, 54.02,53.85, 29.43, 25.81, 23.29,22.96.

[0367]

change

[0368] Hand order 1 At 0°C and under nitrogen gas protection, sodium hydride (253 mg, 6.32 mmol, 60% purity) was added in portions to a solution of 6-bromopyridine-3-ol 1a (1 g, 5.75 mmol) in N,N-dimethylformamide (20 mL), and the mixture was reacted with stirring for about 1 hour. Then, 1-(2-chloroethyl)pyrrolidine hydrochloride 11a (1.08 g, 6.32 mmol) was slowly added at low temperature, and the mixture was reacted with stirring for 1 hour at low temperature. After that, the mixture was heated to 50°C and the reaction was continued with stirring for about 3 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (petroleum ether / ethyl acetate = 2 / 1), the reaction mixture was cooled to 0°C, quenched with water (approximately 10 mL), the mixture was poured into water (100 mL), extracted with ethyl acetate (50 mL x 3), the combined organic layer was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product, a yellow oily liquid 2-bromo-5-(2-pyrrolidine-1-methoxy)pyridine 19a (1.5 g, yield 96.3%).

[0369] The product was confirmed by LC-MS and HNMR.

[0370] MS-ESI calculated value [M+H]+272.9, actual measurement 273.1.

[0371] 1 H NMR (400MHz, CDCl3) δ (ppm) 8.09 (d, 1H, J = 3.2Hz), 7.38 (d, 1H, J = 8.8Hz), 7.16 (dd, 1H, J = 8.8, 2.8Hz), 4.21 (t, 2H, J = 5.6Hz), 3.01 (t, 2H, J = 5.6Hz), 2.75 (s, 4H), 1.87-1.90 (m, 4H).

[0372] Step 2 At room temperature and under nitrogen gas protection, 2-(3-iodo-1-tetrahydropyran-2-ylindazole-6-yl)thio-N-methyl-benzamide 1h (300 mg, 608.08 μmol) in a solution of 1,4-dioxane (9 mL) was mixed with acetamide (71.83 mg, 1.22 mmol), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (86.49 mg, 608.08 μmol), cuprous iodide (115.81 mg, 608.08 μmol), and sodium tert-butoxide (116.88 mg, 1.22 mmol). The mixture was heated to 110°C and reacted with stirring for approximately 6 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (ethyl acetate), the mixture was poured into water (30 mL), extracted with ethyl acetate (20 mL x 3), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated to obtain the crude product. The crude product was purified by preparative thin-layer chromatography (ethyl acetate) to obtain the white solid 2-(3-acetamido-1-tetrahydropyran-2-ylindazole-6-yl)thio-N-methylbenzamide 19b (0.17 g, 400.46 μmol, yield 65.86%).

[0373] The product was confirmed by LC-MS.

[0374] MS-ESI calculated value [M+H]+425.2, actual measurement 425.0.

[0375] Step 3 At room temperature, a solution of 2-(3-acetamido-1-tetrahydropyran-2-ylindazole-6-yl)thio-N-methylbenzamide 19b (0.4 g, 942.25 μmol) in 1,4-dioxane (10 mL) was mixed with NaOH (376.90 mg, 9.42 mmol) and H2O (2 mL). The mixture was heated to 100°C and reacted with stirring for approximately 16 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 20 / 1), the mixture was poured into water (40 mL), extracted with ethyl acetate (20 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was obtained. The crude product was purified by preparative thin-layer chromatography (dichloromethane / methanol = 20 / 1, 0.1% NH3·H2O) to obtain a white solid 2-(3-amino-1-tetrahydropyran-2-ylindazole-6-yl)thio-N-methylbenzamide 19c (0.152 g, 397.41 μmol, yield 42.18%).

[0376] The product was confirmed by LC-MS.

[0377] MS-ESI calculated value [M+H]+383.1, actual measurement 383.1.

[0378] Step 4 At room temperature and under nitrogen gas protection, a solution of 2-(3-amino-1-tetrahydropyran-2-ylindazole-6-yl)thio-N-methylbenzamide 19c (0.1 g, 261.45 μmol) in 1,4-dioxane (5 mL) was mixed with xanthophos (378.20 mg, 653.63 μmol), Pd2(dba)3 (97.72 mg, 169.94 μmol), 2-bromo-5-(2-pyrrolidine-1-methoxy)pyridine 19a (124.8 mg, 608.08 μmol), and cesium carbonate (1.60 g, 4.92 mmol). The mixture was heated to 100°C and reacted with stirring for approximately 6 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (30 mL), extracted with ethyl acetate (10 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product, a yellow oily liquid. The crude product was purified by preparative thin-layer chromatography (dichloromethane / methanol = 10 / 1) to obtain the yellow solid N-methyl-2-[3-[[5-(2-pyrrolidine-1-methoxy)-2-pyridyl]amino]-1-tetrahydropyran-2-yl-indazole-6-yl]thiobenzamide 19d (0.1 g, 174.61 μmol, yield 66.78%).

[0379] The product was confirmed by LC-MS.

[0380] MS-ESI calculated value [M+H]+573.3, actual measurement 573.1.

[0381] Step 5 At low temperature, N-methyl-2-[3-[[5-(2-pyrrolinidine-1-methoxy)-2-pyridyl]amino]-1-tetrahydropyran-2-ylindazole-6-yl]thiobenzamide 19d (86 mg, 150.16 μmol) was mixed with HCl / MeOH (10 mL) and reacted with stirring at room temperature for approximately 4 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was concentrated and poured into water (10 mL). The pH of the aqueous phase was adjusted to neutral with sodium bicarbonate, extracted with ethyl acetate (10 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was obtained. The crude product was purified by preparative thin-layer chromatography (dichloromethane / methanol = 10 / 1, 0.1% NH3·H2O) to obtain a pale yellow solid N-methyl-2-{[3-({5-[2-(pyrrolidin-1-yl)ethoxy]pyridine-2-yl}amino)-1H-indazole-6-yl]thio}benzamide I-30 (20.3 mg, 41.55 μmol, yield 27.67%).

[0382] The product was confirmed by LC-MS, HNMR, and CNMR.

[0383] MS-ESI calculated value [M+H]+489.2, actual measurement 489.1.

[0384] 1 H NMR (400MHz, DMSO-d6): δ 12.18 (s,1H), 9.46 (s,1H), 8.37-8.38 (m,1H), 8.07 (d, 1H, J=8.4Hz), 7.91-7.95 (m, 2H), 7.49 (d, 1H, J=7.6Hz), 7.38-7.42 (m, 2H), 7.24-7.32 (m, 2H), 6.96-7.02 (m, 2H), 4.07-4.09 (m, 2H), 2.77-2.79 (m, 6H), 2.51-2.52 (m, 3H), 1.68 (s, 4H). 13C NMR (100MHz, DMSO-d6): δ 168.36, 149.76, 149.30, 144.53, 141.58, 137.35, 136.32, 134.90, 133.12, 130.69, 130.35, 128.19, 126.48, 125.33, 123.37, 122.35, 114.54, 114.31, 110.61, 68.14, 54.88, 54.47, 26.56, 26.43, 23.62.

[0385] [ka]

[0386] Step 1 At room temperature, a mixture of 2-(4-methylpiperazin-1-yl)ethylamine 20a (5 g, 34.91 mmol) and water (50 mL) was mixed with acetic acid (55 mg, 915.88 μmol) and KOCN (2.08 g, 24.44 mmol), and the mixture was reacted with stirring at 25°C for approximately 2 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was directly freeze-dried to obtain a crude white solid product of sufficient purity, 2-(4-methylpiperazin-1-yl)ethylurea 20b (6 g, 32.21 mmol, yield 92.28%).

[0387] The product was confirmed by LC-MS and HNMR.

[0388] MS-ESI calculated value [M+H]+187.1, actual measurement 187.1.

[0389] 1 H NMR (400MHz, CDCl3): δ (ppm) 5.44 (s, 1H), 4.70 (d, J = 78.3 Hz, 2H), 3.29 (m, J = 10.5, 5.1 Hz, 2H), 2.82 (t, J = 6.1 Hz, 2H), 2.31 (d, J = 1.4 Hz, 8H), 2.01 (s, 3H).

[0390] Step 2 At room temperature and under nitrogen gas protection, a solution of 2-(4-methylpiperazine-1-yl)ethylurea 20b (60.40 mg, 324.31 μmol) in 1,4-dioxane (5 mL) was mixed with 2-(3-iodo-1-tetrahydropyran-2-ylindazole-6-yl)thio-N-methylbenzamide 1h (200 mg, 405.38 μmol), potassium tert-butoxide (136.47 mg, 1.22 mmol), and cuprous iodide (15.44 mg, 81.08 μmol). The mixture was heated to 105°C and reacted with stirring for approximately 16 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (20 mL), extracted with dichloromethane (20 mL x 3), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated to obtain the crude product. The crude product was purified by preparative thin-layer chromatography (dichloromethane / methanol = 10 / 1) to obtain the green oily liquid N-methyl-2-[3-[2-(4-methylpiperazine-1-yl)ethylcarbamoylamino]-1-tetrahydropyran-2-yl-indazole-6-yl]thiobenzamide 20c (30 mg, 54.38 μmol, yield 13.41%).

[0391] The product was confirmed by LC-MS.

[0392] MS-ESI calculated value [M+H]+552.3, actual measurement 552.1.

[0393] Step 3 At 0°C, trifluoroacetic acid (18.60 mg, 163.13 μmol) was added to a solution of N-methyl-2-[3-[2-(4-methylpiperazine-1-yl)ethylcarbamoylamino]-1-tetrahydropyran-2-yl-indazole-6-yl]thiobenzamide 20c (30 mg, 54.38 μmol) in DCM (5 mL) and the mixture was reacted with stirring at room temperature for approximately 16 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (20 mL), the pH was adjusted to 8-9 with solid sodium carbonate, extracted with DCM (20 mL x 3), the combined organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was obtained. The crude product was purified by preparative thin-layer chromatography to obtain the white solid N-methyl-2-{[3-{[2-(4-methylpiperazine-1-yl)ethyl]carbamoyl}amino)-1H-indazole-6-yl]thio}benzamide I-31 (17.4 mg, 37.21 μmol, yield 68.43%).

[0394] The product was confirmed by LC-MS, HNMR, and CNMR.

[0395] MS-ESI calculated value [M+H]+468.2, actual measurement 468.1.

[0396] 1 H NMR (400MHz, CDCl3&CD3OD): δ (ppm)7.74 (s, 1H), 7.46 (d, J = 19.2 Hz, 3H), 7.28 - 7.24 (m, 1H), 7.17 (s, 1H), 7.04 (d, J = 8.5 Hz, 1H), 3.47 (t, J = 6.2 Hz, 2H), 2.89 (s, 3H), 2.83 - 2.35 (m, 10H), 2.31 (s, 3H). 13C NMR (100 MHz, CDCl3&CD3OD) δ 170.12, 156.23, 142.10, 141.37, 131.23, 130.49, 127.83, 126.49, 123.83, 120.50, 113.71, 113.40, 57.02, 54.54, 52.32, 45.20, 37.01, 26.10.

[0397] [ka]

[0398] Step 1 At room temperature and under nitrogen gas protection, 3-bromo-1H pyrazole 17a (1 g, 6.80 mmol) was dissolved in DMSO (20 mL), to which 16a (1 g, 6.80 mmol) and cesium carbonate (3.3 g, 10.21 mmol) were added. The mixture was heated to 100°C and reacted with stirring for approximately 16 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 20 / 1), the mixture was poured into water (40 mL), extracted with ethyl acetate (20 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a yellow solid 3-bromo-1-(3-pyrrolidine-1-ylpropyl)pyrazole 21a (1.6 g, 6.20 mmol, yield 91.09%).

[0399] The product was confirmed by LC-MS and HNMR.

[0400] MS-ESI calculated value [M+H]+259.9, actual measurement 260.1.

[0401] 1H NMR (400 MHz, CDCl3):δ (ppm) δ 7.31 (d, J = 2.4 Hz, 1H), 6.25 (d, J = 2.0 Hz, 1H), 4.18 (t, J = 7.2 Hz, 2H), 2.46-2.52 (m, 4H), 2.41 (t, J = 7.2 Hz, 2H), 2.03 (t, J = 7.2 Hz, 2H), 1.77-1.81 (m, 4H).

[0402] Step 2 At room temperature and under nitrogen gas protection, 3-bromo-1-(3-pyrrolidine-1-ylpropyl)pyrazole 21a (1 g, 3.87 mmol) was dissolved in N,N-dimethylformamide (10 mL), to which potassium vinyltrifluoroborate 1b (778.3 mg, 5.81 mmol), Pd(dppf)Cl2 (85 mg, 116.21 μmol), and triethylamine (778.3 mg, 11.62 mmol) were added. The mixture was heated to 85°C and reacted with stirring for approximately 16 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (40 mL), extracted with ethyl acetate (20 mL x 3), and the combined organic layers were sequentially washed with water (40 mL) and saline solution (40 mL). The mixture was dried over anhydrous sodium sulfate, concentrated, and the crude product was obtained. The crude product was purified by preparative thin-layer chromatography to obtain a yellow oily liquid 1-(3-pyrrolidine-1-ylpropyl)-3-vinylpyrazole 21b (290 mg, 1.41 mmol, yield 36.47%).

[0403] The product was confirmed by LC-MS and HNMR.

[0404] MS-ESI calculated value [M+H]+206.2, actual measurement 206.1.

[0405] 1H NMR (400MHz, CDCl3): δ (ppm) 7.34 (s, 1H), 6.78-6.66 (m, 1H), 6.39-6.37 (m, 1H), 5.74-5.70 (m, 1H), 5.36-5.26 (m, 1H), 4.25-4.16 (m, 2H), 2.50-2.46 (m, 4H), 2.44-2.42 (m, 2H), 2.10-1.99 (m, 2H), 1.83-1.79 (m, 4H).

[0406] Step 3 At room temperature and under nitrogen gas protection, 1-(3-iodo-1-tetrahydropyran-2-ylindazole-6-yl)thio-N-methylbenzamide 1h (300 mg, 608.08 μmol) in a 1,4-dioxane (10 mL) solution was mixed with 1-(3-pyrrolidine-1-ylpropyl)-3-vinylpyrazole 21b (187.3 mg, 912.11 μmol), triethylamine (184.6 mg, 1.82 mmol), Pd2(dba)3 (278.4 mg, 304.04 μmol), and P(o-tol)3 (185.08 mg, 608.08 μmol). The mixture was heated to 100°C and reacted with stirring for approximately 1 hour. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was concentrated and filtered to obtain the crude product. The crude product was purified by preparative thin-layer chromatography to obtain a white solid N-methyl-2-[3-[(E)-2-[1-(3-pyrrolidine-1-ylpropyl)pyrazole-3-yl]vinyl]-1-tetrahydropyran-2-ylindazole-6-yl]thiobenzamide 21c (10 mg, 17.52 μmol, yield 2.88%).

[0407] The product was confirmed by LC-MS.

[0408] MS-ESI calculated value [M+H]+571.3, actual measurement 571.3.

[0409] Step 4 At room temperature, a solution of N-methyl-2-[3-[(E)-2-[1-(3-pyrroridine-1-ylpropyl)pyrazole-3-yl]vinyl]-1-tetrahydropyran-2-ylindazole-6-yl]thiobenzamide 21c (300 mg, 525.63 μmol) in dichloromethane (5 mL) was mixed with trifluoroacetic acid (599.3 mg, 5.26 mmol) and reacted with stirring for approximately 16 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (10 mL), extracted with ethyl acetate (10 mL x 3), washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was obtained. The crude product was purified by preparative thin-layer chromatography to obtain a white solid N-methyl-2-({3-[(E)-2-{1-[3-(pyrrolidine-1-yl)propyl]-1H-pyrazole-3-yl}vinyl]-1H-indazole-6-yl}thio)benzamide I-11 (16.4 mg, 33.70 μmol, yield 6.41%).

[0410] The product was confirmed by LC-MS and HNMR.

[0411] MS-ESI calculated value [M+H]+487.2, actual measurement 487.2.

[0412] 1 H NMR (400MHz, CD3OD): δ (ppm) δ 8.07-8.01 (m, 1H), 7.67-7.60 (m, 2H), 7.50 - 7.42 (m, 3H), 7.36-7.31(m, 2H), 7.22 (dd, J = 14.8, 8.4 Hz, 2H), 6.65 (d, J = 2.0, 1H), 4.24 (t, J = 6.8 Hz, 1H), 2.88 (s, 3H), 2.66-2.58 (m, 6H), 2.14-2.12 (m, 2H), 1.85-1.77 (m, 4H).

[0413] [ka]

[0414] Step 1 At room temperature and under nitrogen gas protection, 2-bromo-5-(2-pyrrolidine-1-methoxy)pyridine 19a (3.0 g, 11.06 mmol) was dissolved in N,N-dimethylformamide (60 mL). Ethynyl(trimethyl)silane (2.17 g, 22.13 mmol, 3.13 mL), Pd(PPh3)2Cl2 (1.55 g, 2.21 mmol), cuprous iodide (421 mg, 2.21 mmol), and triethylamine (3.36 g, 33.19 mmol) were added, and the mixture was heated to 50°C and stirred for 12 hours to allow the reaction to proceed. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the reaction mixture was poured into water (200 mL), extracted with ethyl acetate (100 mL x 3), and the combined organic layers were sequentially washed with water (100 mL x 3) and saturated brine (80 mL). The mixture was dried over anhydrous sodium sulfate, concentrated, and the crude product was obtained. The crude product was purified by silica gel chromatography (dichloromethane / methanol = 100 / 1 to 20 / 1) to obtain a black oily liquid trimethyl-[2-[5-(2-pyrrolidine-1-methoxy)-2-pyridyl]ethynyl]silane 22a (1.8 g, yield 56.4%).

[0415] The product was confirmed by LC-MS and HNMR.

[0416] MS-ESI calculated value [M+H]+ 289.2, actual measurement 289.2.

[0417] 1 H NMR (400 MHz, CDCl3): δ (ppm) 7.28 (d, J = 3.2 Hz, 1H), 7.40 (d, J = 8.8 Hz,1H), 7.13-7.17 (m, 1H), 4.16 (t, J = 6.0 Hz, 2H), 2.89-2.97 (m, 2H), 2.62-2.66 (m, 4H), 1.81-1.84 (m, 4H), 0.26 (s, 9H).

[0418] Step 2 At room temperature, potassium carbonate (1.03 g, 7.49 mmol) was added to a methanol (30 mL) solution of trimethyl-[2-[5-(2-pyrrolidine-1-methoxy)-2-pyridyl]ethynyl]silane 22a (1.8 g, 6.24 mmol) and reacted with stirring for approximately 2 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was directly concentrated to obtain the crude product. The crude product was purified by preparative thin-layer chromatography (dichloromethane / methanol = 10 / 1) to obtain a brown oily liquid 2-ethynyl-5-(2-pyrrolidine-1-ethoxy)pyridine 22b (0.6 g, yield 44.46%).

[0419] The product was confirmed by LC-MS and HNMR.

[0420] MS-ESI calculated value [M+H]+ 217.1, actual measurement 217.2.

[0421] 1 H NMR (400 MHz, CDCl3): δ (ppm) 8.29 (d, J = 2.8 Hz,1H), 7.42 (d, J = 8.4 Hz,1H), 7.15-7.18 (m, 1H), 4.17 (t, J = 5.6 Hz, 2H), 3.08 (s, 1H), 2.93 (t, J = 5.6 Hz, 2H), 2.62-2.65 (m, 4H), 1.80-1.84 (m, 4H).

[0422] Step 3 At room temperature and under nitrogen gas protection, 1 g (300 mg, 0.73 mmol) of 2-[(3-iodo-1H-indazole-6-yl)thio]-N-methylbenzamide was dissolved in 9 mL of N,N-dimethylformamide. To this solution, 2-ethynyl-5-(2-pyrroridine-1-ethoxy)pyridine 22b (159 mg, 0.73 mmol), dichlorobis(triphenylphosphorus)palladium (10 mg, 0.01 mmol), cuprous iodide (28 mg, 0.15 mmol), and triethylamine (184.6 mg, 1.82 mmol) were added, and the mixture was heated to 100°C and stirred for approximately 2 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (50 mL), extracted with ethyl acetate (20 mL x 3), and the combined organic layer was sequentially washed with water (30 mL x 3) and saturated brine (30 mL). The mixture was dried over anhydrous sodium sulfate, concentrated, and the crude product was obtained. The crude product was purified by preparative thin-layer chromatography to obtain the white solid N-methyl-2-{[3-(2-{5-[2-(pyrrolidine-1-yl)ethoxy]pyridine-2-yl}ethynyl)-1H-indazole-6-yl]thio}benzamide I-16 (15.8 mg, yield 4.3%).

[0423] The product was confirmed by LC-MS, HNMR, and CNMR.

[0424] MS-ESI calculated value [M+H]+498.2, actual measurement 498.1.

[0425] 1 H NMR (400 MHz, CDCl3) δ: 11.14 (br s, 1H), 8.39 (d, J=2.4Hz, 1H), 7.88 (d, J=8.4Hz, 1H), 7.59-7.64 (m, 3H), 7.30-7.31 (m, 2H), 7.19-7.27 (m, 3H), 6.37 (d, J=4.4Hz, 1H), 4.22 (t, J =6.0 Hz, 2H), 2.96-2.99 (m, 5H), 2.68 (s, 4H), 1.85 (s, 4H). 13 C NMR (100 MHz, DMSO-d6) δ: 168.30, 155.10, 141.06, 139.36, 137.86, 135.52, 134.19, 134.12, 130.92, 130.80, 128.78, 128.29, 128.02, 126.91, 126.36, 123.99, 121.72, 121.07, 115.10, 92.63, 79.46, 67.92, 54.57, 54.44, 26.56, 23.64.

[0426] [ka]

[0427] Step 1 Under low temperature and nitrogen gas protection, sodium hydride (92 mg, 2.30 mmol) was added in fractions to a solution of 2-bromopyridine-4-ol 23a (200 mg, 1.15 mmol) in N,N-dimethylformamide (4 mL), heated to 70°C, and reacted with stirring for about 0.5 hours. After cooling to room temperature, 1-(2-chloroethyl)pyrrolidine hydrochloride 11a (195 mg, 1.15 mmol) was added, heated to 70°C, and reacted with stirring for about 16 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 20 / 1), the mixture was poured into water (10 mL), extracted with ethyl acetate (20 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a yellow oily liquid 2-bromo-4-(2-pyrrolidine-1-methoxy)pyridine 23b (200 mg, yield 64.2%).

[0428] The product was confirmed by LC-MS and HNMR.

[0429] MS-ESI calculated value [M+H]+272.9, actual measurement 272.9.

[0430] 1H NMR (400 MHz, CDCl3) δ: 8.18 (d, 1H, J=6.0Hz), 7.04 (d, 1H, J=2.4Hz), 6.81-6.83 (m, 1H), 4.16-4.19 (m, 2H), 2.93-2.96 (m, 2H), 2.64-2.68 (m, 4H), 1.83-1.86 (m, 4H).

[0431] Step 2 At room temperature and under nitrogen gas protection, 2-bromo-4-(2-pyrrolidine-1-methoxy)pyridine 23b (500 mg, 1.84 mmol) was dissolved in N,N-dimethylformamide (5 mL), to which potassium vinyltrifluoroborate 1b (370.50 mg, 2.77 mmol), Pd(dppf)Cl2 (50 mg, 0.068 mmol), and triethylamine (280 mg, 2.77 mmol) were added. The mixture was heated to 85°C and reacted with stirring for approximately 16 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 15 / 1), the mixture was poured into water (20 mL), extracted with ethyl acetate (10 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was obtained. The crude product was purified by preparative thin-layer chromatography to obtain a white solid 4-(2-pyrrolidine-1-ethoxy)-2-vinylpyridine 23c (50 mg, yield 12.4%).

[0432] The product was confirmed by LC-MS and HNMR.

[0433] MS-ESI calculated value [M+H]+219.1, actual measurement 219.1.

[0434] 1H NMR (400 MHz, CDCl3) δ: 8.38 (d, 1H, J=5.6Hz), 6.88 (d, 1H, J=2.0Hz), 6.71-6.79 (m, 2H), 6.17 (d, 1H, J=17.2Hz), 5.47 (d, 1H, J=10.8Hz), 4.16-4.19 (m, 2H), 2.92-2.95 (m, 2H), 2.65 (s, 4H), 1.83 (s, 4H).

[0435] Step 3 At room temperature and under nitrogen gas protection, 1 g (562 mg, 1.37 mmol) of 2-[(3-iodo-1H-indazole-6-yl)thio]-N-methylbenzamide was mixed with 5 mL of N,N-dimethylformamide. 4-(2-pyrrolidine-1-ethoxy)-2-vinylpyridine 23c (100 mg, 0.46 mmol), DIEA (592 mg, 4.58 mmol), Pd(OAc)2 (100 mg, 0.45 mmol), and P(o-tol)3 (139 mg, 0.46 mmol) were added, and the mixture was heated to 100°C and stirred for approximately 16 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (10 mL), extracted with ethyl acetate (10 mL x 3), washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, concentrated to obtain the crude product. The crude product was first purified by preparative thin-layer chromatography, and then further purified by preparative thin-layer chromatography (dichloromethane / methanol = 10 / 1) to obtain the white solid N-methyl-2-({3-[(E)-2-{4-[2-(pyrrolidine-1-yl)ethoxy]pyridine-2-yl}vinyl]-1H-indazole-6-yl}thio)benzamide I-20 (5 mg, yield 2.18%).

[0436] The product was confirmed by LC-MS, HNMR, and CNMR.

[0437] MS-ESI calculated value [M+H]+500.2, actual measurement 500.1.

[0438] 1 1H NMR (400 MHz, CD3OD) δ: 8.38 (d, 1H, J = 6.0 Hz), 8.09 (d, 1H, J = 8.4 Hz), 7.88 (d, 1H, J = 16.4 Hz), 7.62 (s, 1H), 7.49 - 7.56 (m, 2H), 7.31 - 7.36 (m, 3H), 7.23 - 7.26 (m, 2H), 6.94 (d, 1H, J = 4.0 Hz), 4.34 - 4.37 (m, 2H), 3.13 - 3.14 (m, 2H), 2.86 - 2.88 (m, 7H), 1.92 (s, 4H). 13 13C NMR (100 MHz, CD3OD) δ: 170.38, 165.97, 157.09, 150.09, 142.29, 142.18, 137.59, 134.91, 134.16, 131.46, 130.31, 129.88, 129.25, 127.68, 127.45, 126.68, 125.36, 124.12, 121.14, 120.27, 113.92, 109.19, 108.12, 79.98, 66.15, 54.18, 54.11, 38.16, 29.37, 29.34, 27.39, 27.29, 25.38, 22.82, 20.23.

[0439]

Chem.

[0440] Procedure 1 At room temperature and under nitrogen gas protection, 2-bromo-5-(2-pyrrolidine-1-methoxy)pyridine 19a (0.5 g, 1.84 mmol) was dissolved in N,N-dimethylformamide (10 mL), to which potassium vinyltrifluoroborate 1b (371 mg, 2.77 mmol), Pd(dppf)Cl2 (40 mg, 0.055 mmol), and triethylamine (280 mg, 2.77 mmol) were added. The mixture was heated to 85°C and reacted with stirring for approximately 16 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 15 / 1), the mixture was poured into water (40 mL), extracted with ethyl acetate (10 mL x 3), and the combined organic layers were sequentially washed with water (30 mL) and saturated brine (30 mL). The mixture was dried over anhydrous sodium sulfate, concentrated, and the crude product was obtained. The crude product was purified by preparative thin-layer chromatography (dichloromethane / methanol = 10 / 1) to obtain a brown oily liquid 5-(2-pyrrolidine-1-ethoxy)-2-vinylpyridine 24a (220 mg, yield 54.7%).

[0441] The product was confirmed by LC-MS and HNMR.

[0442] MS-ESI calculated value [M+H]+219.1, actual measurement 219.1.

[0443] 1 H NMR (400 MHz, CDCl3) δ: 8.29 (d, 1H, J=2.8Hz), 7.29 (d, 1H, J=1.2Hz), 7.20 (dd, 1H, J=8.4, 2.8Hz), 6.77 (dd, 1H, J=17.6, 10.8Hz), 6.03 (dd, 1H, J=17.6, 0.8Hz), 5.37 (dd, 1H, J=10.8, 1.2Hz), 4.21 (t, 2H, J=6.0Hz), 2.99 (t, 2H, J=5.6Hz), 2.73 (s, 4H), 1.85-1.88 (m, 4H).

[0444] Step 2 At room temperature and under nitrogen gas protection, 1 g (166 mg, 0.41 mmol) of 2-[(3-iodo-1H-indazole-6-yl)thio]-N-methylbenzamide was dissolved in 10 mL of N,N-dimethylformamide. 5-(2-pyrrolidine-1-ethoxy)-2-vinylpyridine 24a (133 mg, 0.61 mmol), DIEA (157 mg, 1.22 mmol), Pd(OAc)2 (137 mg, 0.61 mmol), and P(o-tol)3 (123 mg, 0.41 mmol) were added, and the mixture was heated to 100°C and stirred for approximately 16 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 20 / 1), the mixture was poured into water (40 mL), extracted with ethyl acetate (20 mL x 3), washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, concentrated to obtain the crude product. The crude product was first purified by preparative thin-layer chromatography, and then purified three times by preparative thin-layer chromatography (dichloromethane / methanol = 10 / 1) to obtain the yellow solid N-methyl-2-({3-[(E)-2-{5-[2-(pyrrolidine-1-yl)ethoxy]pyridine-2-yl}vinyl]-1H-indazole-6-yl}thio)benzamide I-6 (4.5 mg, yield 2.2%).

[0445] The product was confirmed by LC-MS, HNMR, and CNMR.

[0446] MS-ESI calculated value [M+H]+500.2, actual measurement 500.2.

[0447] 11H NMR (400 MHz, CD3OD) δ: 8.28 (d, 1H, J = 2.8 Hz), 8.06 (d, 1H, J = 8.4 Hz), 7.71 (d, 1H, J = 16.4 Hz), 7.65 (d, 1H, J = 8.8 Hz), 7.60 (s, 1H), 7.48 - 7.55 (m, 2H), 7.45 (dd, 1H, J = 8.8, 2.8 Hz), 7.30 - 7.37 (m, 2H), 7.20 - 7.25 (m, 2H), 4.25 (t, 2H, J = 5.6 Hz), 3.00 (t, 2H, J = 5.6 Hz), 2.88 (s, 3H), 2.72 - 2.74 (m, 4H), 1.85 - 1.89 (m, 4H). 13 13C NMR (100 MHz, CD3OD) δ: 170.33, 154.47, 148.22, 137.55, 137.16, 135.04, 134.01, 131.37, 130.28, 129.04, 127.66, 126.59, 125.23, 122.48, 121.94, 121.62, 121.20, 113.95, 66.75, 54.41, 54.16, 38.39, 38.17, 25.37, 22.84.

[0448]

Chem.

[0449] Step 1 At room temperature and under nitrogen gas protection, 2-bromo-4-(2-pyrrolidine-1-methoxy)pyridine 23b (390 mg, 1.44 mmol) was dissolved in N,N-dimethylformamide (10 mL). Ethynyl(trimethyl)silane (283 mg, 2.88 mmol), Pd(PPh3)2Cl2 (202 mg, 0.29 mmol), cuprous iodide (54.78 mg, 0.29 mmol), and triethylamine (436.63 mg, 4.31 mmol) were added, and the mixture was heated to 50°C and stirred for 12 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 20 / 1), the reaction mixture was poured into water (40 mL), extracted with ethyl acetate (10 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was obtained. The crude product was purified by preparative thin-layer chromatography (DCM / MeOH = 20:1) to obtain a black oily liquid trimethyl-[2-[4-(2-pyrrolidine-1-methoxy)-2-pyridyl]ethynyl]silane 25a (240 mg, yield 57.85%).

[0450] The product was confirmed by LC-MS.

[0451] MS-ESI calculated value [M+H]+289.2, actual measurement 289.1.

[0452] Step 2 At room temperature, trimethyl-[2-[4-(2-pyrrolidine-1-methoxy)-2-pyridyl]ethynyl]silane 25a (240 mg, 0.83 mmol) was dissolved in methanol (10 mL), to which potassium carbonate (138 mg, 1.00 mmol) was added and the mixture was reacted with stirring for approximately 2 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 20 / 1), the mixture was poured into water (30 mL), extracted with ethyl acetate (10 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by preparative thin-layer chromatography (dichloromethane / methanol = 20 / 1) to obtain a red oily liquid 2-ethynyl-4-(2-pyrrolidine-1-ethoxy)pyridine 25b (107 mg, yield 59.46%).

[0453] The product was confirmed by LC-MS.

[0454] MS-ESI calculated value [M+H]+217.1, actual measurement 217.1.

[0455] Step 3 At room temperature and under nitrogen gas protection, 1 g (202 mg, 0.49 mmol) of 2-[(3-iodo-1H-indazole-6-yl)thio]-N-methylbenzamide was dissolved in 9 mL of N,N-dimethylformamide. To this, 107 mg (0.49 mmol) of 2-ethynyl-4-(2-pyrrolidine-1-ethoxy)pyridine 25b, 69 mg (0.099 mmol) of dichlorobis(triphenylphosphorus)palladium, 19 mg (0.099 mmol) of cuprous iodide, and 150 mg (1.48 mmol) of triethylamine were added. The mixture was heated to 100°C and stirred for approximately 2 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (40 mL), extracted with ethyl acetate (10 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated to obtain the crude product. The crude product was purified by preparative thin-layer chromatography (dichloromethane / methanol = 10 / 1) to obtain the white solid N-methyl-2-{[3-(2-{4-[2-(pyrrolinidine-1-yl)ethoxy]pyridine-2-yl}ethynyl)-1H-indazole-6-yl]thio}benzamide I-23 (17.8 mg, yield 7.23%).

[0456] The product was confirmed by LC-MS, HNMR, and CNMR.

[0457] MS-ESI calculated value [M+H]+498.2, actual measurement 498.4.

[0458] 1 H NMR (400MHz, CD3OD): δ (ppm) 8.39 (d, J=5.6Hz, 1H), 7.89 (d, J=8.4Hz, 1H), 7.62 (s, 1H), 7.49 (d, J=7.2Hz, 1H), 7.35 (s, 3H), 7.22-7.27 (m, 2H), 7.07 (d, J=4.8Hz, 1H), 4.31 (t, J=5.2Hz, 2H), 3.02 (t, J=5.2Hz, 2H), 2.74 (s, 4H), 1.87 (s, 4H). 13 C NMR (100 MHz, CD3OD) δ 170.30, 165.63, 150.62, 143.38, 140.86, 137.94, 135.11, 134.49, 131.79, 130.31, 127.81, 127.70, 126.86, 125.65, 123.81, 120.42, 113.83, 113.67, 110.49, 90.98, 80.53, 66.76, 54.14, 54.08, 25.31, 22.84.

[0459] [ka]

[0460] Step 1 At room temperature and under nitrogen gas protection, 1-(2-chloroethyl)pyrrolidine hydrochloride 11a (1.54 g, 9.03 mmol) and K2CO3 (4.77 g, 34.48 mmol) were added to a solution of 6-bromopyridine-2-ol 12a (2 g, 11.49 mmol) in N,N-dimethylformamide (50 mL) and heated to 70°C, reacting with stirring for approximately 16 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 15 / 1), the mixture was poured into water (200 mL), extracted with ethyl acetate (50 mL x 3), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated to obtain the crude product. The crude product was purified by preparative thin-layer chromatography to obtain a yellow oily liquid, 2-bromo-6-(2-pyrrolidine-1-methoxy)pyridine 26a (940 mg, 3.47 mmol, yield 30.16%).

[0461] The product was confirmed by LC-MS and HNMR.

[0462] MS-ESI calculated value [M+H]+272.9, actual measurement 273.1.

[0463] 1H NMR (400MHz, CDCl3): δ (ppm) 7.41 (t, J=8.0Hz, 1H), 7.05 (d, J=7.2Hz, 1H), 6.74 (d, J=8.4Hz, 1H), 4.45 (t, J=6.0Hz, 2H), 2.88 (t, J=6.0Hz, 2H), 2.61-2.64 (m, 4H), 1.80-1.84 (m, 4H).

[0464] Step 2 At room temperature and under nitrogen gas protection, 2-bromo-6-(2-pyrrolidine-1-methoxy)pyridine 26a (0.5 g, 1.84 mmol) was dissolved in N,N-dimethylformamide (20 mL). Ethynyl(trimethyl)silane (362.22 mg, 3.69 mmol), Pd(PPh3)2Cl2 (258.86 mg, 368.80 μmol), cuprous iodide (70.24 mg, 368.80 μmol), and triethylamine (559.78 mg, 5.53 mmol) were added, and the mixture was heated to 50°C and stirred for 16 hours. After confirming that the starting materials had reacted completely by LC-MS detection, the reaction mixture was poured into water (80 mL), extracted with ethyl acetate (20 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was obtained. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 1 / 2) to obtain a red oily liquid trimethyl-[2-[6-(2-pyrrolidine-1-methoxy)-2-pyridyl]ethynyl]silane 26b (450 mg, 1.56 mmol, yield 84.60%).

[0465] The product was confirmed by LC-MS and HNMR.

[0466] MS-ESI calculated value [M+H]+289.2, actual measurement 289.2.

[0467] 1H NMR (400MHz, CDCl3): δ (ppm) 7.47-7.51 (m, 1H), 7.12 (d, J=7.2Hz, 1H), 6.76 (d, J=8.4Hz, 1H), 4.48 (t, J=5.6Hz, 2H), 2.89 (t, J=5.6Hz, 2H), 2.61-2.64 (m, 4H), 1.80-1.84 (m, 4H), 0.29 (s, 9H).

[0468] Step 3 At room temperature, trimethyl-[2-[6-(2-pyrrolidine-1-methoxy)-2-pyridyl]ethynyl]silane 26b (400 mg, 1.39 mmol) was dissolved in methanol (20 mL), to which potassium carbonate (229.98 mg, 1.66 mmol) was added and the mixture was reacted with stirring for approximately 2 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 20 / 1), the mixture was poured into water (30 mL), extracted with ethyl acetate (10 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by preparative thin-layer chromatography (dichloromethane / methanol = 20 / 1) to obtain a red oily liquid 2-ethynyl-6-(2-pyrrolidine-1-ethoxy)pyridine 26c (50 mg, 231.18 μmol, yield 16.67%).

[0469] The product was confirmed by LC-MS and HNMR.

[0470] MS-ESI calculated value [M+H]+217.1, actual measurement 217.2.

[0471] 1H NMR (400MHz, CDCl3): δ (ppm) 7.56 (t, J=8.0Hz, 1H), 7.11 (d, J=7.2Hz, 1H), 6.82 (d, J=8.4Hz, 1H), 4.51 (t, J=5.6Hz, 2H), 3.12 (s, 1H), 2.93 (t, J=5.6Hz, 2H), 2.67 (s, 1H), 1.84 (s, 1H).

[0472] Step 4 At room temperature and under nitrogen gas protection, 1 g (47.31 mg, 115.59 μmol) of 2-[(3-iodo-1H-indazole-6-yl)thio]-N-methylbenzamide was dissolved in 10 mL of N,N-dimethylformamide. To this solution, 2-ethynyl-6-(2-pyrrolidine-1-ethoxy)pyridine 26c (25 mg, 115.59 μmol), dichlorobis(triphenylphosphorus)palladium (16.23 mg, 23.12 μmol), cuprous iodide (4.40 mg, 23.12 μmol), and triethylamine (35.09 mg, 346.78 μmol) were added. The mixture was heated to 50°C and reacted with stirring for approximately 16 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (40 mL), extracted with ethyl acetate (10 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated to obtain the crude product. The crude product was purified by preparative thin-layer chromatography to obtain the white solid N-methyl-2-{[3-(2-{6-[2-(pyrrolidine-1-yl)ethoxy]pyridine-2-yl}ethynyl)-1H-indazole-6-yl]thio}benzamide I-24 (17.8 mg, yield 7.23%).

[0473] The product was confirmed by LC-MS, HNMR, and CNMR.

[0474] MS-ESI calculated value [M+H]+498.2, actual measurement 498.0.

[0475] 1H NMR (400MHz, CDCl3+ CD3OD): δ (ppm) 7.83 (d, J=8.4Hz, 1H), 7.79 (s, 1H), 7.73 (t, J=8.0Hz, 1H), 7.63 (s, 1H), 7.48-7.51 (m, 1H), 7.33-7.34 (m, 1H), 7.31-7.32 (m, 1H), 7.22-7.24 (m, 2H), 6.87 (d, J=8.4Hz, 1H), 4.59 (t, J=5.6Hz, 2H), 3.19 (t, J=5.2Hz, 2H), 2.96 (s, 4H), 2.88 (s, 3H), 1.95 (s, 4H).

[0476] [ka]

[0477] Step 1 At room temperature, 3,4-dihydro-2H-pyran (DHP) (1.8 g, 21.62 mmol) and TsOH (2.5 g, 14.78 mmol) were added to a solution of 2-(1H-indazole-6-ylthio)-N-methylbenzamide 1f (4 g, 14.07 mmol) in THF (20 mL), heated to 60°C, and reacted with stirring for approximately 16 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (petroleum ether / ethyl acetate = 3 / 1), the mixture was concentrated to obtain the crude product. The crude product was purified by preparative MPLC to obtain the yellow solid methyl ester 27a (1-tetrahydropyran-2-ylindazole-6-yl)thiobenzoate (2.5 g, 6.79 mmol, yield 48.23%).

[0478] The product was confirmed by LC-MS and HNMR.

[0479] MS-ESI calculated value [M+H]+369.1, actual measurement 369.0.

[0480] 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 5.6 Hz, 1H), 8.02 (d, J = 7.6 Hz, 1H), 7.93 (d, J = 4.0 Hz, 1H), 7.77 (dd, J = 8.4, 4.0 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.25 (t, J = 7.6 Hz, 1H), 7.15 (t, J = 7.6 Hz, 1H), 6.85 (d, J = 8.0 Hz, 1H), 5.72 (dd, J = 9.6, 2.4 Hz, 1H), 4.13 - 4.03 (m, 1H), 3.99 (d, J = 2.0 Hz, 3H), 3.75 (dd, J = 11.2, 8.4 Hz, 1H), 2.59 - 2.39 (m, 1H), 2.13 (t, J = 10.4 Hz, 2H), 1.85 - 1.52 (m, 3H).

[0481] Step 2 At room temperature, 2-(1-tetrahydropyran-2-ylindazole-6-yl)thiobenzoate methyl ester 27a (2.5 g, 6.79 mmol) was dissolved in a mixed solution of H2O (8 mL) and THF (20 mL), lithium hydroxide (1.7 g, 40.71 mmol) was added, and the mixture was heated to 40°C and reacted with stirring for approximately 16 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (petroleum ether / ethyl acetate = 1 / 1), the reaction mixture was poured into water (20 mL), the pH was adjusted to 6-7 with 1N hydrochloric acid solution, extracted with ethyl acetate (20 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a white solid 2-(1-tetrahydropyran-2-ylindazole-6-yl)thiobenzoate 27b (2 g, 5.64 mmol, yield 83.17%).

[0482] The product was confirmed by LC-MS and HNMR.

[0483] MS-ESI calculated value [M+H]+355.1, actual measurement 355.0.

[0484] 1 H NMR (400 MHz, CDCl3) δ 8.21 - 8.07 (m, 2H), 7.97 (s, 1H), 7.79 (dd, J = 8.4, 4.4 Hz, 1H), 7.40 - 7.30 (m, 1H), 7.28 - 7.25 (m, 1H), 7.18 (dd, J = 14.4, 7.2 Hz, 1H), 6.84 (dd, J = 8.0, 4.8 Hz, 1H), 5.74 (dd, J = 9.6, 2.4 Hz, 1H), 4.24 - 3.92 (m, 2H), 2.66 - 2.28 (m, 2H), 2.25 - 2.07 (m, 2H), 1.89 - 1.58 (m, 2H).

[0485] Step 3 At room temperature, cyclopropylamine (290 mg, 5.08 mmol), HATU (1.9 g, 5.08 mmol), and DIEA (980 mg, 7.60 mmol) were added to a solution of 2-(1-tetrahydropyran-2-ylindazole-6-yl)thiobenzoic acid 27b (900 mg, 2.54 mmol) in N,N-dimethylformamide (10 mL), and the mixture was reacted with stirring for approximately 2 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (petroleum ether / ethyl acetate = 1 / 1), the mixture was poured into water (50 mL), extracted with ethyl acetate (20 mL x 3), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was obtained. The crude product was purified by silica gel chromatography to obtain a white solid N-cyclopropyl-2-(1-tetrahydropyran-2-ylindazole-6-yl)thiobenzamide 27c (700 mg, 1.78 mmol, yield 70.05%).

[0486] The product was confirmed by LC-MS and HNMR.

[0487] MS-ESI calculated value [M+H]+394.2, actual measurement 394.2.

[0488] 1 H NMR (400 MHz, CDCl3) δ 8.11 - 7.90 (m, 2H), 7.71 - 7.58 (m, 3H), 7.30 (dd, J = 4.8, 3.6 Hz, 2H), 7.25 - 7.18 (m, 1H), 7.12 (dd, J = 8.4, 1.2 Hz, 1H), 5.66 (dd, J = 9.6, 2.4 Hz, 1H), 4.11 - 3.89 (m, 2H), 2.38 (ddd, J = 17.6, 13.2, 7.6 Hz, 1H), 2.20 - 2.04 (m, 2H), 1.72 (ddd, J = 62.4, 40.0, 27.2 Hz, 4H), 0.82 (dd, J = 12.8, 7.2 Hz, 2H), 0.54 - 0.44 (m, 2H).

[0489] Step 4 At room temperature, trifluoroacetic acid (3 g, 52.62 mmol) was added to a 10 mL solution of N-cyclopropyl-2-(1-tetrahydropyran-2-ylindazole-6-yl)thiobenzamide 27c (800 mg, 2.03 mmol) in dichloromethane (DCM), and the mixture was reacted with stirring at 40°C for approximately 16 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (20 mL), the pH was adjusted to 8-9 with sodium carbonate solution, and the mixture was extracted with dichloromethane (30 mL x 3). The combined organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a yellow solid N-cyclopropyl-2-(1H-indazole-6-ylthio)benzamide 27d (500 mg, 1.62 mmol, yield 79.49%).

[0490] The product was confirmed by LC-MS and HNMR.

[0491] MS-ESI calculated value [M+H]+310.1, actual measurement 310.0.

[0492] 1H NMR (400 MHz, CDCl3) δ 10.99 (s, 1H), 8.05 (s, 1H), 7.77 - 7.53 (m, 3H), 7.32 - 7.20 (m, 3H), 7.12 (d, J = 8.4 Hz, 1H), 6.60 (s, 1H), 2.90 - 2.80 (m, 1H), 0.81 (q, J = 6.4 Hz, 2H), 0.51 (d, J = 6.4 Hz, 2H).

[0493] Step 5 At room temperature, potassium carbonate (2.3 g, 16.81 mmol) and I2 (2.1 g, 8.40 mmol) were added to a solution of N-cyclopropyl-2-(1H-indazole-6-ylthio)benzamide 27d (1.3 g, 4.20 mmol) in N,N-dimethylformamide (10 mL), and the mixture was reacted with stirring at 40°C for about 2 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (100 mL), extracted with ethyl acetate (100 mL x 3), washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was obtained. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 2 / 1 to 0 / 1) to obtain a yellow solid N-cyclopropyl-2-[(3-iodo-1H-indazole-6-yl)thio]benzamide 27e (1 g, 2.30 mmol, yield 54.67%).

[0494] The product was confirmed by LC-MS and HNMR.

[0495] MS-ESI calculated value [M+H]+436.0, actual measurement 435.9.

[0496] 1H NMR (400 MHz, CDCl3) δ 11.17 (s, 1H), 8.04 (s, 1H), 7.68 - 7.55 (m, 2H), 7.46 (d, J = 8.4 Hz, 1H), 7.32 (dd, J = 9.2, 5.6 Hz, 2H), 7.25 - 7.20 (m, 1H), 7.17 (d, J = 8.4 Hz, 1H), 2.88 - 2.80 (m, 1H), 0.85 (q, J = 6.8 Hz, 2H), 0.53 (q, J = 6.8 Hz, 2H).

[0497] Step 6 At room temperature, N-cyclopropyl-2-[(3-iodo-1H-indazole-6-yl)thio]benzamide 27e (1.3 g, 4.20 mmol) was dissolved in THF (10 mL), to which tert-butoxycarbonyl tert-butyl carbonate (250 mg, 1.15 mmol) and triethylamine (232 mg, 2.30 mmol) were added and the mixture was reacted with stirring for approximately 2 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL x 3), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated to obtain the crude product. The crude product was purified by preparative thin-layer chromatography (dichloromethane / methanol = 10 / 1) to obtain a white solid 6-[2-(cyclopropylcarbamoyl)phenyl]thio-3-iodoindazole-1-carboxylic acid tert-butyl ester 27f (280 mg, 522.98 μmol, yield 45.53%).

[0498] The product was confirmed by LC-MS and HNMR.

[0499] MS-ESI calculated value [M-Boc+H]+436.0, actual measurement 435.9.

[0500] 1H NMR (400 MHz, CDCl3) δ 8.04 (s, 1H), 7.75 - 7.62 (m, 1H), 7.40 (dd, J = 13.6, 5.6 Hz, 4H), 7.31 - 7.19 (m, 2H), 2.81 (d, J = 4.4 Hz, 1H), 1.64 (s, 9H), 0.79 (t, J = 6.0 Hz, 2H), 0.47 (d, J = 2.4 Hz, 2H).

[0501] Step 7 At room temperature and under nitrogen gas protection, 6-[2-(cyclopropylcarbamoyl)phenyl]thio-3-iodoindazole-1-carboxylate tert-butyl ester 27f (200 mg, 373.55 μmol) was added to a 1,4-dioxane (5 mL) solution to 5-(2-pyrrolidine-1-ethoxy)-2-vinylpyridine 24a (97 mg, 448.27 μmol), triethylamine (113 mg, 1.12 mmol), Pd2(dba)3 (171 mg, 186.78 μmol), and P(o-tol)3 (113 mg, 373.55 μmol). The mixture was heated to 100°C and reacted with stirring for approximately 2 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (20 mL), extracted with ethyl acetate (10 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated to obtain the crude product. The crude product was purified by preparative thin-layer chromatography (dichloromethane / methanol = 10 / 1) to obtain 27 g (150 mg, 239.70 μmol, yield 64.17%) of the yellow oily liquid 6-[2-(cyclopropylcarbamoyl)phenyl]thio-3-[(E)-2-[5-(2-pyrrolidine-1-ylethoxy)-2-pyridyl]vinyl]indazole-1-carboxylic acid tert-butyl ester.

[0502] The product was confirmed by LC-MS.

[0503] MS-ESI calculated value [M+H]+626.3, actual measurement 626.2.

[0504] Step 8 At room temperature, 27 g (150 mg, 239.70 μmol) of 6-[2-(cyclopropylcarbamoyl)phenyl]thio-3-[(E)-2-[5-(2-pyrrolidine-1-ylethoxy)-2-pyridyl]vinyl]indazole-1-carboxylic acid tert-butyl ester was dissolved in 5 mL of dichloromethane, to which trifluoroacetic acid (1 g, 8.77 mmol) was added, and the mixture was reacted with stirring for approximately 4 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into 20 mL of water, the pH was adjusted to 8-9 with sodium carbonate solution, extracted with ethyl acetate (20 mL x 3), the combined organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was obtained. The crude product was purified by preparative thin-layer chromatography to obtain a white solid N-cyclopropyl-2-({3-[(E)-2-{5-[2-(pyrrolidine-1-yl)ethoxy]pyridine-2-yl}vinyl]-1H-indazole-6-yl}thio)benzamide I-8 (15.4 mg, 29.30 μmol, yield 12.22%).

[0505] The product was confirmed by LC-MS and HNMR.

[0506] MS-ESI calculated value [M+H]+526.2, actual measurement 526.2.

[0507] 11H NMR (400 MHz, CDCl3) δ 8.38 (d, J = 2.8 Hz, 1H), 8.01 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 16.4 Hz, 1H), 7.67 (dd, J = 5.6, 3.2 Hz, 1H), 7.58 - 7.41 (m, 2H), 7.35 (dd, J = 24.0, 19.6 Hz, 2H), 7.25 (dd, J = 8.8, 2.8 Hz, 2H), 7.18 (d, J = 8.4 Hz, 1H), 6.54 (s, 1H), 4.24 (t, J = 5.6 Hz, 2H), 3.00 (t, J = 5.6 Hz, 2H), 2.89 - 2.80 (m, 1H), 2.72 (s, 4H), 1.87 (d, J = 3.2 Hz, 4H), 0.86 - 0.75 (m, 2H), 0.50 (t, J = 8.0 Hz, 2H).

[0508]

Chem.

[0509] Procedure 1 At room temperature and under nitrogen gas protection, 1-methylpiperazine 28b (2.1 g, 21.13 mmol), BuONa (5.1 g, 52.84 mmol), Pd2(dba)3 (806.4 mg, 880.62 μmol), and Xantphos (254.8 mg, 440.31 μmol) were added to a solution of 2-bromo-5-iodopyridine 28a (5 g, 17.61 mmol) in 1,4-dioxane (50 mL) and heated to 60°C, where the mixture was reacted with stirring for approximately 3 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (100 mL), extracted with ethyl acetate (50 mL x 3), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was obtained. The crude product was purified by neutral alumina chromatography column (petroleum ether / ethyl acetate = 10 / 1) to obtain the yellow solid 1-(6-bromo-3-pyridyl)-4-methylpiperazine 28c (2.1 g, 8.20 mmol, yield 46.55%).

[0510] The product was confirmed by LC-MS and HNMR.

[0511] MS-ESI calculated value [M+H]+257.9, actual measurement 258.0.

[0512] 1 H NMR (400 MHz, CDCl3) δ (ppm) 8.01 (d, J = 3.2 Hz, 1H), 7.30 (d, J = 8.8 Hz, 1H), 7.07 (dd, J = 8.8, 3.2 Hz, 1H), 3.21 (t, J = 4.8 Hz, 4H ), 2.57 (t, J = 5.2 Hz, 4H ), 2.35 (s, 3H). Step 2 At room temperature and under nitrogen gas protection, 1-(6-bromo-3-pyridyl)-4-methylpiperazine 28c (2 g, 7.81 mmol) was dissolved in N,N-dimethylformamide (20 mL). Potassium vinyltrifluoroborate 1b (1.3 g, 9.37 mmol), Pd(dppf)Cl2 (571.3 mg, 780.82 μmol), and triethylamine (2.4 g, 23.42 mmol) were added, and the mixture was heated to 85°C and reacted with stirring for approximately 2 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (100 mL), extracted with ethyl acetate (50 mL x 3), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was obtained. The crude product was purified by neutral alumina chromatography column (petroleum ether / ethyl acetate = 10 / 1) to obtain a yellow oily liquid 1-methyl-4-(6-vinyl-3-pyridyl)piperazine 28d (1.2 g, 5.90 mmol, yield 75.60%).

[0513] The product was confirmed by LC-MS and HNMR.

[0514] MS-ESI calculated value [M+H]+204.1, actual measurement 204.1.

[0515] 1 H NMR (400 MHz, CDCl3) δ (ppm) 8.27 (d, J = 3.2 Hz, 1H), 7.24 (s, 1H), 7.16-7.13 (m, 1H), 6.75 (dd, J = 17.5, 10.8 Hz, 1H), 5.98 (d, J = 17.6 Hz, 1H), 5.31 (d, J = 10.8 Hz, 1H), 3.28 - 3.20 (m, 4H), 2.62 - 2.55 (m, 4H), 2.36 (s, 3H).

[0516] Step 3 At room temperature and under nitrogen gas protection, a solution of 6-[2-(cyclopropylcarbamoyl)phenyl]thio-3-iodoindazole-1-carboxylate tert-butyl ester 27f (490 mg, 915.21 μmol) in 1,4-dioxane (10 mL) was mixed with 1-methyl-4-(6-vinyl-3-pyridyl)piperazine 28d (223.3 mg, 1.10 mmol), triethylamine (277.8 mg, 2.75 mmol), Pd2(dba)3 (502.8 mg, 549.13 μmol), and P(o-tol)3 (557.1 mg, 1.83 mmol). The mixture was heated to 85°C and reacted with stirring for approximately 2 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (40 mL), extracted with ethyl acetate (30 mL x 3), washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, concentrated to obtain the crude product. The crude product was purified by preparative MPLC to obtain the white solid 6-[2-(cyclopropylcarbamoyl)phenyl]thio-3-[(E)-2-[5-(4-methylpiperazin-1-yl)-2-pyridyl]vinyl]indazole-1-carboxylic acid tert-butyl ester 28e (110 mg, 180.10 μmol, yield 19.68%).

[0517] The product was confirmed by LC-MS.

[0518] MS-ESI calculated value [M+H]+611.3, actual measurement 611.2.

[0519] Step 4 At room temperature, 100 mg, 163.73 μmol of 6-[2-(cyclopropylcarbamoyl)phenyl]thio-3-[(E)-2-[5-(4-methylpiperazin-1-yl)-2-pyridyl]vinyl]indazole-1-carboxylic acid tert-butyl ester 28e was added to a 2 mL solution of dichloromethane, and the mixture was reacted with stirring for approximately 16 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into 20 mL of water, the pH was adjusted to 8-9 with sodium carbonate solution, and the mixture was extracted with 20 mL of dichloromethane. The combined organic layer was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was obtained. The crude product was purified by preparative thin-layer chromatography to obtain the yellow solid N-cyclopropyl-2-({3-[(E)-2-[5-(4-methylpiperazine-1-yl)pyridine-2-yl]vinyl]-1H-indazole-6-yl}thio)benzamide I-38 (50 mg, 97.91 μmol, yield 59.80%).

[0520] The product was confirmed by LC-MS, HNMR, and CNMR.

[0521] MS-ESI calculated value [M+H]+ 511.2, actual measurement 511.0.

[0522] 1 H NMR (400MHz, CD3OD): δ (ppm) 8.22 (d, J = 2.8 Hz, 1H), 8.02 (d, J = 8.8 Hz, 1H), 7.64 - 7.54 (m, 3H), 7.49-7.43 (m, 2H), 7.40 - 7.29 (m, 3H), 7.25 - 7.23 (m, 1H), 7.17 (d, J = 8.4 Hz, 1H), 3.33 (s, 4H), 2.79-2.75 (m, 1H), 2.65-2.62 (m, 4H), 2.36 (s, 3H), 0.77-0.72 (m, 2H), 0.55 - 0.51 (m, 2H). 13 C NMR (100 MHz, CDCl3& CD3OD) δ: 172.68, 147.59, 147.39, 138.66, 137.99, 135.33, 131.77, 130.85, 128.00, 126.48, 124.48, 123.29, 122.73, 122.17, 121.60, 55.71, 23.95, 6.80.

[0523] [ka]

[0524] Step 1 At room temperature and under nitrogen gas protection, potassium vinyltrifluoroborate 1b (5.4 g, 40.32 mmol), Pd(dppf)Cl2 (975.3 mg, 1.34 mmol), and triethylamine (8.2 g, 80.64 mmol) were added to a solution of 6-bromopyridine-3-carboxyaldehyde 29a (5 g, 26.88 mmol) in N,N-dimethylformamide (50 mL), and the mixture was heated to 85°C and reacted with stirring for approximately 16 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (petroleum ether / ethyl acetate = 10 / 1), the mixture was poured into water (250 mL), extracted with ethyl acetate (100 mL x 3), and the combined organic layers were sequentially washed with water (300 mL) and saturated brine (300 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was obtained. The crude product was purified using a silica gel chromatography column (petroleum ether / ethyl acetate = 10 / 1) to obtain the yellow oily liquid 6-vinylpyridine-3-carboxyaldehyde 29b (1.7 g, 12.77 mmol, yield 47.50%).

[0525] The product was confirmed by LC-MS and HNMR.

[0526] MS-ESI calculated value [M+H]+134.1, actual measurement 134.1.

[0527] 1H NMR (400 MHz, CDCl3): δ 10.08 (s, 1H), 9.01 (s, 1H), 8.13 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 6.88 (dd, J=17.6 Hz, 10.8 Hz, 1H),6.41 (d, J=17.6 Hz, 1H), 5.68 (d, J=10.8 Hz, 1H).

[0528] Step 2 At room temperature, 6-vinylpyridine-3-carboxyaldehyde 29b (500 mg, 3.76 mmol) was dissolved in THF (20 mL) and N-methylmethylamine hydrochloride (612.4 mg, 7.51 mmol) and NaBH(OAc)3 (2.4 g, 11.27 mmol) were added. The mixture was reacted with stirring for approximately 16 hours. After confirming that the starting materials had completely reacted by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (20 mL), the pH was adjusted to 8-9 with sodium bicarbonate, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by silica gel chromatography (DCM) to obtain a white solid N,N-dimethyl-1-(6-vinyl-3-pyridyl)methanamine 29c (400 mg, 2.47 mmol, yield 65.66%).

[0529] The product was confirmed by LC-MS and HNMR.

[0530] MS-ESI calculated value [M+H]+163.1, actual measurement 163.1.

[0531] 1H NMR (400MHz, CDCl3): δ 8.45 (s, 1H), 7.62 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 6.81 (dd, J = 17.6 Hz, 10.8 Hz, 1H), 6.16 (d, J = 17.6 Hz, 1H), 5.46 (dd, J = 10.8 Hz, 4.4 Hz, 1H), 3.41 (s, 2H), 2.23 (s, 6H).

[0532] Step 3 At room temperature and under nitrogen gas protection, 6-[2-(cyclopropylcarbamoyl)phenyl]thio-3-iodoindazole-1-carboxylic acid tert-butyl ester 27f (500 mg, 933.89 μmol) was added to a 1,4-dioxane (10 mL) solution to N,N-dimethyl-1-(6-vinyl-3-pyridyl)methanamine 29c (303 mg, 1.87 mmol), triethylamine (472.5 mg, 4.67 mmol), Pd2(dba)3 (427.6 mg, 466.94 μmol), and P(o-tol)3 (426.4 mg, 1.40 mmol). The mixture was heated to 85°C and reacted with stirring for approximately 2 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (petroleum ether / ethyl acetate = 1 / 1), the mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL x 3), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated to obtain the crude product. The crude product was purified by preparative MPLC to obtain a yellow oily liquid 6-[2-(cyclopropylcarbamoyl)phenyl]thio-3-[(E)-2-[5-[(dimethylamino)methyl]-2-pyridyl]vinyl]indazole-1-carboxylic acid tert-butyl ester 29d (155 mg, 272.07 μmol, yield 29.13%).

[0533] The product was confirmed by LC-MS.

[0534] MS-ESI calculated value [M+H]+570.2, actual measurement 570.2.

[0535] Step 4 At room temperature, 6-[2-(cyclopropylcarbamoyl)phenyl]thio-3-[(E)-2-[5-[(dimethylamino)methyl]-2-pyridyl]vinyl]indazole-1-carboxylic acid tert-butyl ester 29d (150 mg, 263.29 μmol) was dissolved in dichloromethane (5 mL), to which trifluoroacetic acid (300.2 mg, 2.63 mmol) was added, and the mixture was reacted with stirring for approximately 16 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (20 mL), the pH was adjusted to 8-9 with sodium carbonate solution, and the mixture was extracted with dichloromethane (20 mL x 3). The combined organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was obtained. The crude product was purified by preparative thin-layer chromatography to obtain the white solid N-cyclopropyl-2-({3-[(E)-2-{5-[(dimethylamino)methyl]pyridine-2-yl}vinyl]-1H-indazole-6-yl}thio)benzamide I-40 (29 mg, 61.75 μmol, yield 23.46%).

[0536] The product was confirmed by LC-MS, HNMR, and CNMR.

[0537] MS-ESI calculated value [M+H]+ 470.2, actual measurement 470.1.

[0538] 11H NMR (400 MHz, CD3OD): δ 8.49 (s, 1H), 8.05 (d, J = 8.64 Hz, 1H), 7.86 (d, J = 16.8 Hz, 1H), 7.80 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 16.6 Hz, 2H), 7.49 - 7.44 (m, 1H), 7.37 - 7.27 (m, 2H), 7.24 - 7.2 (m, 2H), 3.57 (s, 2H), 2.63 - 2.8 (m, 1H), 2.3 (s, 6H), 0.76 (q, J = 7.0 Hz, 2H), 0.60 - 0.51 (m, 2H). 13C NMR (100 MHz, CD3OD & CDCl3): δ 172.66, 156.23, 151.27, 139.82, 133.39, 132.97, 131.82, 130.51, 129.21, 128.05, 126.72, 122.94, 122.64, 121.78, 61.87, 23.98, 6.88.

[0539]

Chemical formula

[0540] Procedure 1 At room temperature, pyrrolidine (320.5 mg, 4.51 mmol) and NaBH(OAc)3 (2.4 g, 11.27 mmol) were added to a solution of 6-vinylpyridine-3-carboxyaldehyde 29b (500 mg, 3.76 mmol) in tetrahydrofuran (20 mL) and reacted with stirring for approximately 16 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (20 mL), the pH was adjusted to 8-9 with sodium bicarbonate, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic layer was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by silica gel chromatography (DCM) to obtain a white solid 5-(pyrrolidine-1-ylmethyl)-2-vinylpyridine 30a (420 mg, 2.23 mmol, yield 59.41%).

[0541] The product was confirmed by LC-MS and HNMR.

[0542] MS-ESI calculated value [M+H]+189.1, actual measurement 189.1.

[0543] 1 H NMR (400MHz, CDCl3): δ 8.49 (s, 1H), 7.64 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 6.81 (dd, J = 17.5 Hz, 10.8 Hz, 1H), 6.16 (d, J = 17.5 Hz, 1H), 5.45 (d, J = 10.8 Hz, 1H), 3.61 (s, 2H), 2.50 (s, 4H), 1.78 (s, 4H).

[0544] Step 2 At room temperature and under nitrogen gas protection, a solution of 6-[2-(cyclopropylcarbamoyl)phenyl]thio-3-iodoindazole-1-carboxylate tert-butyl ester 27f (500 mg, 933.89 μmol) in 1,4-dioxane (10 mL) was mixed with 5-(pyrrolidine-1-ylmethyl)-2-vinylpyridine 30a (351.6 mg, 1.87 mmol), triethylamine (472.5 mg, 4.67 mmol), Pd2(dba)3 (427.6 mg, 466.94 μmol), and P(o-tol)3 (426.4 mg, 1.40 mmol). The mixture was heated to 85°C and reacted with stirring for approximately 2 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (petroleum ether / ethyl acetate = 1 / 1), the mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL x 3), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated to obtain the crude product. The crude product was purified by preparative MPLC to obtain a yellow oily liquid 6-[2-(cyclopropylcarbamoyl)phenyl]thio-3-[(E)-2-[5-(pyrrolidine-1-ylmethyl)-2-pyridyl]vinyl]indazole-1-carboxylic acid tert-butyl ester 30b (91 mg, 152.75 μmol, yield 16.36%).

[0545] The product was confirmed by LC-MS.

[0546] MS-ESI calculated value [M+H]+596.3, actual measurement 596.3.

[0547] Step 3 At room temperature, 100 mg, 167.85 μmol of 6-[2-(cyclopropylcarbamoyl)phenyl]thio-3-[(E)-2-[5-(pyrrolidine-1-ylmethyl)-2-pyridyl]vinyl]indazole-1-carboxylic acid tert-butyl ester 30b was added to a 5 mL solution of dichloromethane, and the mixture was reacted with stirring for approximately 16 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into 30 mL of water, the pH was adjusted to 8-9 with sodium carbonate solution, and the mixture was extracted with 20 mL x 3 of dichloromethane. The combined organic layers were washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was obtained. The crude product was purified by preparative thin-layer chromatography to obtain the white solid N-cyclopropyl-2-({3-[(E)-2-{5-[(pyrrolidine-1-yl)methyl]pyridine-2-yl}vinyl]-1H-indazole-6-yl}thio)benzamide I-41 (15 mg, 30.26 μmol, yield 18.03%).

[0548] The product was confirmed by LC-MS, HNMR, and CNMR.

[0549] MS-ESI calculated value [M+H]+496.2, actual measurement 496.1.

[0550] 11H NMR (400 MHz, CD3OD): δ 8.53 (d, J = 1.6 Hz, 1H), 8.06 (d, J = 8.5 Hz, 1H), 7.85 (dd, J = 16.7 Hz, 9.3 Hz, 2H), 7.69 (d, J = 8.1 Hz, 1H), 7.60 - 7.53 (m, 2H), 7.45 (dd, J = 7.1 Hz, 1.9 Hz, 1H), 7.34 - 7.32 (m, 2H), 7.28 - 7.24 (m, 1H), 7.20 (dd, J = 8.5 Hz, 1.4 Hz, 1H), 3.75 (s, 2H), 2.78 - 2.64 (m, 1H), 2.64 (s, 4H), 1.86 (s, 4H), 0.78 - 0.71 (m, 2H), 0.56 - 0.50 (m, 2H). 13 13C NMR (100 MHz, CD3OD): δ 172.70, 155.96, 151.03, 143.79, 143.60, 139.59, 139.26, 135.90, 135.76, 133.23, 131.69, 130.39, 128.22, 126.42, 125.30, 122.93, 122.53, 121.60, 144.88, 58.17, 54.93, 24.19, 23.80, 6.49.

[0551] [Chemical formula]

[0552] Procedure 1 A 250 mL necked flask was taken, and methyl 2,3-difluorobenzoate 31a (5.00 g, 29.1 mmol) was dissolved in N,N-dimethylformamide (50 mL). (4-methoxyphenyl)methanethiol (4.564 g, 29.1 mmol) was added, followed by cesium carbonate (18.94 g, 58.2 mmol). The reaction was carried out at room temperature for 2 hours with stirring. The reaction system was filtered, the filtrate was collected, diluted with ethyl acetate (200 mL), and washed with water (200 mL × 3). The organic phase was separated by liquid-liquid separation and dried over anhydrous sodium sulfate. The solid residue obtained by concentration under reduced pressure was separated by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 3:1). After concentration, a white solid methyl 3-fluoro-2-[(4-methoxyphenyl)methylthio]benzoate 31b (4.5 g, 14.7 mmol, yield 50.5%) was obtained.

[0553] MS (ESI) M / Z: 329.1 [M+Na+]

[0554] Step 2 A 250 mL necked flask was taken, and methyl 3-fluoro-2-[(4-methoxyphenyl)methylthio]benzoate 31b (4.50 g, 14.7 mmol) was dissolved in tetrahydrofuran (45 mL). Lithium hydroxide (1.853 g, 44.1 mmol) was added, followed by water (15 mL). The mixture was heated to 50°C and stirred for 5 hours. The reaction system was filtered, the filtrate was collected, concentrated under reduced pressure, and dilute hydrochloric acid (1 mol / L) was added to the reaction system to adjust the pH to 5. After filtration and drying, a white solid 3-fluoro-2-[(4-methoxyphenyl)methylthio]benzoate 31c (3.80 g, 13.0 mmol, yield 88.4%) was obtained.

[0555] MS (ESI) M / Z: 315.2 [M+Na+]

[0556] Step 3 A 250 mL necked flask was taken, and 3-fluoro-2-[(4-methoxyphenyl)methylthio]benzoic acid 31c (3.80 g, 13.0 mmol) was dissolved in N,N-dimethylformamide (38 mL). Methaneamine (506 mg, 19.5 mmol) was added, followed by N-methylmorpholine (3.943 g, 39.0 mmol), and then 1-hydroxybenzotriazole (2.64 g, 19.5 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.72 g, 19.5 mmol). The reaction was carried out at room temperature for 3 hours with stirring. The reaction system was diluted with ethyl acetate (200 mL) and washed with water (200 mL x 3 times). The organic phase was collected by liquid-liquid extraction and dried over anhydrous sodium sulfate. The solid residue obtained by concentration under reduced pressure was separated by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 4:1) and, after concentration, a white solid 3-fluoro-2-[(4-methoxyphenyl)methylthio]-N-methylbenzamide 31d (2.95 g, 9.66 mmol, yield 74.3%) was obtained.

[0557] Step 4 A 250 mL three-necked flask was used to dissolve 3-fluoro-2-[(4-methoxyphenyl)methylthio]-N-methylbenzamide 31d (2.95 g, 9.66 mmol) in trifluoroacetic acid (32 mL). The mixture was heated to 70°C and reacted with stirring for 3 hours. The solid residue obtained by concentration under reduced pressure was separated by silica gel column chromatography (eluent: dichloromethane / methanol = 30:1) to obtain 1.2 g of white solid 3-fluoro-N-methyl-2-thiobenzamide 31e (1.05 g, 5.68 mmol, yield 58.8%) after concentration.

[0558] Step 5 At room temperature, 3,4-dihydro-2H-pyran (2.2 g, 25.95 mmol) and p-toluenesulfonic acid (357.5 mg, 2.08 mmol) were added to a solution of 3-iodo-6-nitro-1H-indazole 31f (5 g, 17.30 mmol) in ethyl acetate (100 mL). The mixture was heated to 75°C and reacted with stirring for 16 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (petroleum ether / ethyl acetate = 10 / 1), the reaction mixture was concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 20 / 1) to obtain the yellow solid compound 3-iodo-6-nitro-1-tetrahydropyran-2-ylindazole 31 g (6.1 g, 16.35 mmol, yield 94.50%).

[0559] The product was confirmed by H-NMR.

[0560] 1 H NMR (400 MHz, CDCl3) δ 8.58 (s, 1H), 8.11 (dd, J = 8.8, 1.2 Hz, 1H), 7.63 (d, J = 8.8 Hz, 1H), 5.81 (dd, J = 9.2, 2.8 Hz, 1H), 4.06 (d, J = 10.4 Hz, 1H), 3.84-3.79 (m, 1H), 2.56-2.53 (m, 1H), 2.18-2.15 (m 2H), 1.81-1.73 (m, 3H).

[0561] Step 6 At room temperature and under nitrogen gas, 31 g (5 g, 13.40 mmol) of compound 3-iodo-6-nitro-1-tetrahydropyran-2-ylindazole was dissolved in 60 mL of dioxane. Compounds 5-(2-pyrrolidine-1-ethoxy)-2-vinylpyridine 24a (3.5 g, 16.08 mmol), tris(dibenzylideneacetone)dipalladium (6.1 g, 6.70 mmol), triethylamine (4.1 g, 40.20 mmol), and tris(o-methylphenyl)phosphorus (4.1 g, 13.40 mmol) were added to this solution. The mixture was heated to 100°C and stirred for 2 hours to allow the reaction to proceed. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (120 mL), filtered, and the filtrate was extracted with dichloromethane (120 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to obtain the crude product. The crude product was purified by column chromatography (dichloromethane / methanol = 20 / 1) to obtain the yellow solid compound 6-nitro-3-[(E)-2-[5-(2-pyrrolinidine-1-ethoxy)-2-pyridyl]vinyl]-1-tetrahydropyran-2-ylindazole 31h (2.2 g, 4.64 mmol, yield 34.62%).

[0562] The product was confirmed by LC-MS and HNMR.

[0563] MS-ESI calculated value [M+H]+464.2, actual measurement 464.1.

[0564] 1H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 8.40 (d, J = 2.8 Hz, 1H), 8.15-8.10 (m, 2H), 7.79-7.74 (m, 1H), 7.62-7.58 (m, 1H), 7.27-7.24 (m, 1H), 7.14-7.10 (m, 1H), 5.84 (dd, J = 9.6, 2.8 Hz, 1H), 4.22 (t, J = 6.0 Hz, 2H), 4.10-4.08 (m, 1H), 3.86-3.81 (m, 1H), 2.98 (t, J = 5.6 Hz, 2H), 2.68-2.59 (m, 4H), 2.22-2.15 (m, 2H), 1.86-1.74 (m, 8H).

[0565] Step 7 At room temperature and under nitrogen gas, a solution of compound 6-nitro-3-[(E)-2-[5-(2-pyrrolinidine-1-ethoxy)-2-pyridyl]vinyl]-1-tetrahydropyran-2-ylindazole 31h (2.2 g, 4.63 mmol) in methanol (20 mL) and tetrahydrofuran (20 mL) was added to sodium sulfide nonahydrate (4 g, 16.20 mmol, 98.0% purity) and water (20 mL). The mixture was heated to 60°C and reacted with stirring for 2 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (80 mL), filtered, and the filtrate was extracted with dichloromethane (80 mL x 3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was obtained. The crude product was purified by column chromatography (DCM / MeOH = 20 / 1 ~ 3:1) to obtain the brown oily compound 3-[(E)-2-[5-(2-pyrroridine-1-ethoxy)-2-pyridyl]vinyl]-1-tetrahydropyran-2-ylindazole-6-amine 31i (0.9 g, 2.05 mmol, yield 44.36%).

[0566] The product was confirmed by LC-MS and HNMR.

[0567] MS-ESI calculated value: [M+H]+434.2, actual value: 434.1.

[0568] 1 H NMR (400 MHz, CDCl3) δ 8.36 (d, J = 2.8 Hz, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.65 (d, J = 16.4 Hz, 1H), 7.52-7.45 (m, 2H), 7.24 (dd, J = 8.4, 2.8 Hz, 1H), 6.76 (d, J = 1.6 Hz, 1H), 6.66 (dd, J = 8.4, 1.6 Hz, 1H), 5.60 (dd, J = 9.6, 2.8 Hz, 1H), 4.20 (t, J = 6.0 Hz, 2H), 4.09-4.07 (m, 1H), 3.78-3.20 (m, 1H), 2.96 (t, J = 5.6 Hz, 2H), 2.66 (s, 4H), 2.20 (s, 1H), 2.09-2.05 (m, 1H), 1.86-1.84 (m, 4H), 1.78-1.63 (m, 4H).

[0569] Hand 8 At 0-5°C, a solution of compound 3-[(E)-2-[5-(2-pyrroridine-1-ethoxy)-2-pyridyl]vinyl]-1-tetrahydropyran-2-ylindazole-6-amine 31i (1.3 g, 2.92 mmol) in acetic acid (12 mL) and acetonitrile (15 mL) was mixed with an aqueous solution of sodium nitrite (221.8 mg, 3.21 mmol) (6 mL) and reacted with stirring at 0-5°C for 1 hour. Then, an aqueous solution of sodium iodide (884.8 mg, 5.90 mmol) and iodine (370.9 mg, 1.46 mmol) (6 mL) was added and reacted with stirring at 0°C for 3 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (50 mL), the pH of the mixture was adjusted to 8-9 with sodium carbonate, and the mixture was extracted with dichloromethane (50 mL x 3). The combined organic layer was dried over anhydrous sodium sulfate, concentrated, and the crude product was obtained. The crude product was purified by column chromatography (DCM / MeOH = 20 / 1) to obtain the red solid compound 6-iodo-3-[(E)-2-[5-(2-pyrrolidine-1-methoxy)-2-pyridyl]vinyl]-1-tetrahydropyran-2-ylindazole 31j (0.85 g, 1.56 mmol, yield 53.30%).

[0570] The product was confirmed by LC-MS and HNMR.

[0571] MS-ESI calculated value [M+H]+545.1, actual measurement 546.0.

[0572] 1H NMR (400 MHz, CDCl3) δ 8.35 (d, J = 3.6 Hz, 1H), 8.02 (s, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.73 (d, J = 16.4 Hz, 1H), 7.55 (d, J = 2.0 Hz, 1H), 7.53-7.51 (m, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.33-7.31 (m, 1H), 5.69 (d, J = 6.8 Hz, 1H), 4.06 (s, 2H), 3.78 (s, 2H), 2.57 (s, 2H), 2.16 (s, 4H), 1.80 (s, 2H), 1.60 (s, 8H).

[0573] Step 9 At room temperature and under nitrogen gas, a solution of compound 6-iodo-3-[(E)-2-[5-(2-pyrroridine-1-methoxy)-2-pyridyl]vinyl]-1-tetrahydropyran-2-ylindazole 31j (350 mg, 642.88 μmol) in N,N-dimethylformamide (5 mL) was mixed with cesium carbonate (418.9 mg, 1.29 mmol), 3-fluoro-N-methyl-2-mercaptobenzamide 31e (142.9 mg, 771.45 μmol), and 1,1'-bisdiphenylphosphineferrocenepalladium dichloride (233.3 mg, 321.44 μmol). The mixture was heated to 80°C and reacted with stirring for 5 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (30 mL), extracted with ethyl acetate (20 mL x 3), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated to obtain the crude product. The crude product was purified by neutral alumina column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain the yellow solid compound 3-fluoro-N-methyl-2-[3-[(E)-2-[5-(2-pyrrolidine-1-ethoxy)-2-pyridyl]vinyl]-1-tetrahydropyran-2-yl-indazole-6-yl]thiobenzamide 31k (250 mg, 415.47 μmol, yield 64.63%).

[0574] The product was confirmed by LC-MS.

[0575] MS-ESI calculated value [M+H]+602.3, actual measurement 602.2.

[0576] Step 10 At room temperature, a solution of compound 3-fluoro-N-methyl-2-[3-[(E)-2-[5-(2-pyrrolinidine-1-ethoxy)-2-pyridyl]vinyl]-1-tetrahydropyran-2-ylindazole-6-yl]thiobenzamide 31k (250 mg, 415.47 μmol) in dichloromethane (5 mL) was mixed with trifluoroacetic acid (473.7 mg, 4.15 mmol) and reacted under a nitrogen atmosphere at 30°C with stirring for 16 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (40 mL), the pH was adjusted to 8-9 with sodium carbonate, extracted with ethyl acetate (30 mL x 3), the combined organic layer was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was obtained. The crude product was purified by preparative high-performance liquid chromatography to obtain the white solid compound 3-fluoro-N-methyl-2-({3-[(E)-2-{5-[2-(pyrrolidine-1-yl)ethoxy]pyridine-2-yl}vinyl]-1H-indazole-6-yl}thio)benzamide I-33 (78 mg, 150.69 μmol, yield 36.27%).

[0577] The product was confirmed by LC-MS, HNMR, and CNMR.

[0578] MS-ESI calculated value [M+H]+518.2, actual measurement 518.1.

[0579] 11H NMR (400 MHz, CDCl3&CD3OD): δ (ppm) 8.26 (d, J = 2.8 Hz, 1H), 8.01 (d, J = 8.4 Hz, 1H), 7.67 (d, J = 16.8 Hz, 1H), 7.61 (d, J = 8.8 Hz, 1H), 7.54 - 7.48 (m, 2H), 7.40 (dd, J = 8.8, 2.8 Hz, 1H), 7.29 - 7.23 (m, 2H), 7.17 (dd, J = 8.4, 1.2 Hz, 1H), 7.11 - 7.06 (m, 1H), 4.23 (t, J = 5.6 Hz, 2H), 2.98 (t, J = 5.2 Hz, 2H), 2.87 (s, 3H), 2.71 (s, 4H), 1.86 (t, J = 3.2 Hz, 4H). 13 13C NMR (100 MHz, CDCl3&CD3OD) δ (ppm) 168.80, 161.97, 160.22, 154.36, 148.28, 137.19, 134.26, 134.19, 130.02, 129.21, 124.79, 122.07, 120.25, 117.44, 115.31, 115.11, 114.88, 113.64, 66.98, 54.61, 54.41, 25.96, 223.06.

[0580]

Chem.

[0581] Step 1 A 250 mL necked flask was taken, and methyl 2,5-difluorobenzoate 32a (5.00 g, 29.1 mmol) was dissolved in N,N-dimethylformamide (50 mL). (4-methoxyphenyl)methanethiol (4.564 g, 29.1 mmol) was added, followed by cesium carbonate (18.94 g, 58.2 mmol). The reaction was carried out at room temperature for 2 hours with stirring. The reaction system was filtered, the filtrate was collected, diluted with ethyl acetate (200 mL), and washed with water (200 mL × 3). The organic phase was separated by liquid-liquid separation and dried over anhydrous sodium sulfate. The solid residue obtained by concentration under reduced pressure was separated by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 3:1) to obtain a white solid methyl 5-fluoro-2-[(4-methoxyphenyl)methylthio]benzoate 32b (4.9 g, 16 mmol, yield 54.9%) after concentration.

[0582] MS (ESI) M / Z: 329.1 [M+Na+]

[0583] Step 2 A 250 mL necked flask was taken, and methyl 5-fluoro-2-[(4-methoxyphenyl)methylthio]benzoate 32b (4.9 g, 16 mmol) was dissolved in tetrahydrofuran (45 mL). Lithium hydroxide (2.017 g, 48 mmol) was added, followed by water (15 mL). The mixture was heated to 50°C and stirred for 5 hours. The reaction system was filtered, the filtrate was collected, and the mixture was concentrated under reduced pressure. Dilute hydrochloric acid (1 mol / L) was added to the reaction system to adjust the pH to 5. After filtration and drying, a white solid 5-fluoro-2-[(4-methoxyphenyl)methylthio]benzoate 32c (3.94 g, 13.5 mmol, yield 84.38%) was obtained.

[0584] MS (ESI) M / Z: 315.2 [M+Na+]

[0585] Step 3 A 250 mL necked flask was taken, and 5-fluoro-2-[(4-methoxyphenyl)methylthio]benzoic acid 32c (3.94 g, 13.5 mmol) was dissolved in N,N-dimethylformamide (38 mL). Methaneamine (532 mg, 20.5 mmol) was added, followed by N-methylmorpholine (4.095 g, 40.5 mmol), and then 1-hydroxybenzotriazole (2.78 g, 20.5 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.91 g, 20.5 mmol). The mixture was reacted at room temperature for 3 hours with stirring. The reaction system was diluted with ethyl acetate (200 mL) and washed with water (200 mL x 3 times). The organic phase was collected by liquid-liquid extraction and dried over anhydrous sodium sulfate. The solid residue obtained by concentration under reduced pressure was separated by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 4:1) and, after concentration, a white solid 5-fluoro-2-[(4-methoxyphenyl)methylthio]-N-methylbenzamide 32d (2.96 g, 9.7 mmol, yield 71.9%) was obtained.

[0586] Step 4 A 250 mL three-necked flask was used, and 5-fluoro-2-[(4-methoxyphenyl)methylthio]-N-methylbenzamide 32d (2.96 g, 9.7 mmol) was dissolved in trifluoroacetic acid (32 mL). The mixture was heated to 70°C and reacted with stirring for 3 hours. The solid residue obtained by concentration under reduced pressure was separated by silica gel column chromatography (eluent: dichloromethane / methanol = 30:1) to obtain 1.2 g of white solid 5-fluoro-N-methyl-2-thiobenzamide 32e (1.1 g, 5.95 mmol, yield 61.3%) after concentration.

[0587] MS (ESI) M / Z: 186.1[M+H+] 1H NMR (400 MHz, MeOD) δ 7.40 (dd, J = 8.8, 5.2 Hz, 1H), 7.23 (dd, J = 8.8, 2.8 Hz, 1H), 7.08 (td, J = 8.4, 2.8 Hz, 1H), 2.89 (s, 3H).

[0588] Step 5 At room temperature and under nitrogen gas, a solution of compound 6-iodo-3-[(E)-2-[5-(2-pyrrolidin-1-methoxy)-2-pyridyl]vinyl]-1-tetrahydropyran-2-ylindazole 31j (350 mg, 642.88 μmol) in N,N-dimethylformamide (5 mL) was mixed with cesium carbonate (314.2 mg, 964.32 μmol), 5-fluoro-N-methyl-2-mercaptobenzamide 32e (148.8 mg, 803.60 μmol, obtained by synthesis using methyl 2,5-difluorobenzoate as a starting material according to the synthesis method of compound 31e), and 1,1'-bisdiphenylphosphineferrocenepalladium dichloride (350 mg, 482.32 μmol). The mixture was heated to 80°C and reacted with stirring for 5 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (30 mL), extracted with ethyl acetate (20 mL x 3), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated to obtain the crude product. The crude product was purified by neutral alumina column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain the yellow solid compound 5-fluoro-N-methyl-2-[3-[(E)-2-[5-(2-pyrrolidine-1-ethoxy)-2-pyridyl]vinyl]-1-tetrahydropyran-2-yl-indazole-6-yl]thiobenzamide 32f (250 mg, 415.47 μmol, yield 64.63%).

[0589] The product was confirmed by LC-MS.

[0590] MS-ESI calculated value [M+H]+602.3, actual measurement 602.2.

[0591] Step 6 At room temperature, a solution of compound 5-fluoro-N-methyl-2-[3-[(E)-2-[5-(2-pyrrolinidine-1-ethoxy)-2-pyridyl]vinyl]-1-tetrahydropyran-2-ylindazole-6-yl]thiobenzamide 32f (250 mg, 415.47 μmol) in dichloromethane (10 mL) was mixed with trifluoroacetic acid (473.7 mg, 4.15 mmol) and reacted under a nitrogen atmosphere at 30°C with stirring for 16 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (40 mL), the pH was adjusted to 8-9 with sodium carbonate, extracted with ethyl acetate (30 mL x 3), the combined organic layer was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was obtained. The crude product was purified by preparative high-performance liquid chromatography to obtain the white solid compound 5-fluoro-N-methyl-2-({3-[(E)-2-{5-[2-(pyrrolidin-1-yl)ethoxy]pyridine-2-yl}vinyl]-1H-indazole-6-yl}thio)benzamide I-34 (33 mg, 63.75 μmol, yield 15.35%).

[0592] The product was confirmed by LC-MS, HNMR, and CNMR.

[0593] MS-ESI calculated value [M+H]+518.2, actual measurement 518.0.

[0594] 1H NMR (400MHz, CDCl3&CD3OD): δ (ppm) 8.28 (d, J = 2.4 Hz, 1H), 8.13 (d, J = 8.4 Hz, 1H), 7.74 - 7.70 (m, 2H), 7.68-7.63 (m, 1H), 7.57 - 7.50 (m, 2H), 7.44 (dd, J = 8.8, 2.8 Hz, 1H), 7.28 (d, J = 9.6 Hz, 1H), 6.97 - 6.93 (m, 1H), 6.70 (dd, J = 10.0, 2.4 Hz, 1H), 4.26 (t, J = 5.2 Hz, 2H), 3.03 (s, 2H), 2.91 (s, 3H), 2.76 (s, 4H), 1.89 (s, 4H). 13 C NMR (100 MHz, CDCl3&CD3OD) δ (ppm) 169.22, 162.37, 154.39, 148.26, 142.24, 137.19, 131.46, 129.35, 126.55, 122.41, 122.07, 121.84, 120.94, 115.97, 115.73, 112.59, 112.37, 67.00, 54.61, 54.40, 26.00, 23.06.

[0595] [ka]

[0596] Step 1 A 250 mL necked flask was taken, methyl 2-bromo-4-fluorobenzoate 33a (5.00 g, 21.5 mmol) was dissolved in N,N-dimethylformamide (50 mL), PMBSH (3.98 g, 25.8 mmol) and cesium carbonate (10.51 g, 32.3 mmol) were added, and then Pd(dppf)Cl2 (0.79 g, 1.08 mmol) was added. The mixture was then reacted overnight at 120°C with stirring.

[0597] Workup: The reaction system was filtered, the filtrate was collected, diluted with ethyl acetate (200 mL), and washed with water (200 mL x 3 times). The organic phase was separated and collected, and dried over anhydrous sodium sulfate. The solid residue obtained by concentration under reduced pressure was separated by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 3:1), and after concentration, 5 g of white solid methyl 4-fluoro-2-[(4-methoxyphenyl)methyl mercapto]benzoate 33b was obtained.

[0598] MS (ESI) M / Z: 329.1[M+Na+]

[0599] Step 2 A 250 mL necked flask was taken, and methyl 4-fluoro-2-[(4-methoxyphenyl)methylthio]benzoate 33b (4.50 g, 14.7 mmol) was dissolved in tetrahydrofuran (45 mL). Lithium hydroxide (1.853 g, 44.1 mmol) was added, followed by water (15 mL). The mixture was heated to 50°C and stirred for 5 hours. The reaction system was filtered, the filtrate was collected, concentrated under reduced pressure, and dilute hydrochloric acid (1 mol / L) was added to adjust the pH to 5. After filtration and drying, a white solid 4-fluoro-2-[(4-methoxyphenyl)methylthio]benzoate 33c (3.80 g, 13.0 mmol, yield 88.4%) was obtained.

[0600] MS (ESI) M / Z: 315.2 [M+Na+]

[0601] Step 3 A 250 mL necked flask was taken, and 4-fluoro-2-[(4-methoxyphenyl)methylthio]benzoic acid 33c (3.80 g, 13.0 mmol) was dissolved in N,N-dimethylformamide (38 mL). Methaneamine (506 mg, 19.5 mmol) was added, followed by N-methylmorpholine (3.943 g, 39.0 mmol), and then 1-hydroxybenzotriazole (2.64 g, 19.5 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.72 g, 19.5 mmol). The reaction was carried out at room temperature for 3 hours with stirring. The reaction system was diluted with ethyl acetate (200 mL) and washed with water (200 mL x 3 times). The organic phase was collected by liquid-liquid extraction and dried over anhydrous sodium sulfate. The solid residue obtained by concentration under reduced pressure was separated by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 4:1), and after concentration, a white solid 4-fluoro-2-[(4-methoxyphenyl)methylthio]-N-methylbenzamide 33d (2.95 g, 9.66 mmol, yield 74.3%) was obtained.

[0602] Step 4 A 250 mL three-necked flask was used to dissolve 4-fluoro-2-[(4-methoxyphenyl)methylthio]-N-methylbenzamide 33d (2.95 g, 9.66 mmol) in trifluoroacetic acid (32 mL). The mixture was heated to 70°C and reacted with stirring for 3 hours. The solid residue obtained by concentration under reduced pressure was separated by silica gel column chromatography (eluent: dichloromethane / methanol = 30:1) to obtain 1.2 g of white solid 4-fluoro-N-methyl-2-thiobenzamide 33e (1.05 g, 5.68 mmol, yield 58.8%) after concentration.

[0603] MS (ESI) M / Z: 186.1[M+H+] 1H NMR (400 MHz, CD3OD) δ 7.50 (dd, J = 8.6, 5.8 Hz, 1H), 7.18 (dd, J = 9.6, 2.5 Hz, 1H), 7.01 - 6.76 (m, 1H), 2.89 (s, 3H).

[0604] Step 5 At room temperature and under nitrogen gas, a solution of compound 6-iodo-3-[(E)-2-[5-(2-pyrrolidin-1-methoxy)-2-pyridyl]vinyl]-1-tetrahydropyran-2-ylindazole 31j (300 mg, 551.04 μmol) in N,N-dimethylformamide (5 mL) was mixed with cesium carbonate (359.1 mg, 1.10 mmol), 4-fluoro-N-methyl-2-thiobenzamide 33e (122.5 mg, 661.25 μmol), and 1,1'-bisdiphenylphosphineferrocenepalladium dichloride (199.9 mg, 275.52 μmol). The mixture was heated to 80°C and reacted with stirring for 5 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (30 mL), extracted with ethyl acetate (20 mL x 3), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated to obtain the crude product. The crude product was purified by neutral alumina column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain the yellow solid compound 4-fluoro-N-methyl-2-[3-[(E)-2-[5-(2-pyrrolidine-1-ethoxy)-2-pyridyl]vinyl]-1-tetrahydropyran-2-yl-indazole-6-yl]thiobenzamide 33f (250 mg, 415.47 μmol, yield 75.40%).

[0605] The product was confirmed by LC-MS.

[0606] MS-ESI calculated value [M+H]+602.3, actual measurement 602.1.

[0607] Step 6 At room temperature, a solution of compound 4-fluoro-N-methyl-2-[3-[(E)-2-[5-(2-pyrrolinidine-1-ethoxy)-2-pyridyl]vinyl]-1-tetrahydropyran-2-ylindazole-6-yl]thiobenzamide 33f (250 mg, 415.47 μmol) in dichloromethane (5 mL) was mixed with trifluoroacetic acid (473.6 mg, 4.15 mmol) and reacted under a nitrogen atmosphere at 30°C with stirring for 16 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (40 mL), the pH was adjusted to 8-9 with sodium carbonate, extracted with ethyl acetate (30 mL x 3), the combined organic layer was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was obtained. The crude product was purified by preparative high-performance liquid chromatography to obtain the yellow solid compound 4-fluoro-N-methyl-2-(3-[(E)-2-{5-[2-(pyrrolidine-1-yl)ethoxy]pyridine-2-yl}vinyl]-1H-indazole-6-yl}thio)benzamide I-35 (20 mg, 38.64 μmol, yield 9.30%).

[0608] The product was confirmed by LC-MS, HNMR, and CNMR.

[0609] MS-ESI calculated value [M+H]+518.2, actual measurement 518.1.

[0610] 11H NMR (400 MHz, CDCl3&CD3OD): δ (ppm) δ 8.29 (d, J = 2.8 Hz, 1H), 8.13 (d, J = 8.4 Hz, 1H), 7.75 - 7.70 (m, 2H), 7.68 - 7.63 (m, 1H), 7.57 - 7.54 (m, 1H), 7.53 - 7.50 (m, 1H), 7.44 (dd, J = 8.8, 2.8 Hz, 1H), 7.28 (d, J = 10.0 Hz, 1H), 6.98 - 6.93 (m, 1H), 6.71 (dd, J = 9.6, 2.4 Hz, 1H), 4.27 (t, J = 5.6 Hz, 2H), 3.05 (t, J = 5.2 Hz, 2H), 2.91 (s, 3H), 2.78 (s, 4H), 1.89 (s, 4H). 13 13C NMR (100 MHz, CDCl3&CD3OD) δ (ppm) 170.59, 166.30, 163.79, 155.74, 149.73, 144.24, 143.69, 14.18, 142.10, 138.66, 136.12, 132.82, 132.34, 131.18, 131.09, 128.00, 125.86, 123.53, 123.14, 122.40, 117.94, 117.45, 117.21, 114.07, 113.85, 68.36, 56.02, 55.87, �0.93, 27.58, 24.52.

[0611]

Chem.

[0612] Procedure 1 A 250 mL necked flask was taken, and methyl 2,6-difluorobenzoate 34a (5.00 g, 29.1 mmol) was dissolved in N,N-dimethylformamide (50 mL). (4-methoxyphenyl)methanethiol (4.564 g, 29.1 mmol) was added, followed by cesium carbonate (18.94 g, 58.2 mmol). The reaction was carried out at room temperature for 2 hours with stirring. The reaction system was filtered, the filtrate was collected, diluted with ethyl acetate (200 mL), and washed with water (200 mL × 3). The organic phase was separated by liquid-liquid separation and dried over anhydrous sodium sulfate. The solid residue obtained by concentration under reduced pressure was separated by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 3:1) to obtain a white solid methyl 2-fluoro-6-[(4-methoxyphenyl)methylthio]benzoate 34b (4.5 g, 14.7 mmol, yield 54.9%) after concentration.

[0613] MS (ESI) M / Z: 329.1 [M+Na+]

[0614] Step 2 A 250 mL necked flask was taken, and methyl 2-fluoro-6-[(4-methoxyphenyl)methylthio]benzoate 34b (4.50 g, 14.7 mmol) was dissolved in tetrahydrofuran (45 mL). Lithium hydroxide (1.853 g, 44.1 mmol) was added, followed by water (15 mL). The mixture was heated to 50°C and stirred for 5 hours. The reaction system was filtered, the filtrate was collected, concentrated under reduced pressure, and dilute hydrochloric acid (1 mol / L) was added to the reaction system to adjust the pH to 5. After filtration and drying, a white solid 2-fluoro-6-[(4-methoxyphenyl)methylthio]benzoate 34c (3.80 g, 13.0 mmol, yield 88.4%) was obtained.

[0615] MS (ESI) M / Z: 315.2 [M+Na+]

[0616] Step 3 A 250 mL necked flask was taken, and 2-fluoro-6-[(4-methoxyphenyl)methylthio]benzoic acid 34c (3.80 g, 13.0 mmol) was dissolved in N,N-dimethylformamide (38 mL). Methaneamine (506 mg, 19.5 mmol) was added, followed by N-methylmorpholine (3.943 g, 39.0 mmol), and then 1-hydroxybenzotriazole (2.64 g, 19.5 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.72 g, 19.5 mmol). The mixture was reacted at room temperature for 3 hours with stirring. The reaction system was diluted with ethyl acetate (200 mL) and washed with water (200 mL x 3 times). The organic phase was collected by liquid-liquid extraction and dried over anhydrous sodium sulfate. The solid residue obtained by concentration under reduced pressure was separated by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 4:1) and, after concentration, a white solid 2-fluoro-6-[(4-methoxyphenyl)methylthio]-N-methylbenzamide 34d (2.95 g, 9.66 mmol, yield 74.3%) was obtained.

[0617] Step 4 A 250 mL three-necked flask was used to dissolve 2-fluoro-6-[(4-methoxyphenyl)methylthio]-N-methylbenzamide 34d (2.95 g, 9.66 mmol) in trifluoroacetic acid (32 mL). The mixture was heated to 70°C and reacted with stirring for 3 hours. The solid residue obtained by concentration under reduced pressure was separated by silica gel column chromatography (eluent: dichloromethane / methanol = 30:1) to obtain 1.2 g of white solid 2-fluoro-N-methyl-6-mercaptobenzamide 34e (1.05 g, 5.68 mmol, yield 58.8%) after concentration.

[0618] MS (ESI) M / Z: 186.0[M+H+] 1 H NMR (400 MHz, CD3OD) δ 7.34 - 7.32 (m, 1H), 7.24 - 7.20 (m, 2H), 2.92 (s, 3H).

[0619] Step 5 At room temperature and under nitrogen gas, a solution of compound 6-iodo-3-[(E)-2-[5-(2-pyrrolidin-1-methoxy)-2-pyridyl]vinyl]-1-tetrahydropyran-2-ylindazole 31j (350 mg, 642.88 μmol) in N,N-dimethylformamide (8 mL) was mixed with cesium carbonate (314.2 mg, 964.32 μmol), 2-fluoro-N-methyl-6-mercaptobenzamide 34e (148.8 mg, 803.60 μmol, obtained by synthesis using methyl 2,6-difluorobenzoate as a starting material according to the synthesis method of compound 31e), and 1,1'-bisdiphenylphosphineferrocenepalladium dichloride (350 mg, 482.32 μmol). The mixture was heated to 80°C and reacted with stirring for 5 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (25 mL), extracted with dichloromethane (25 mL x 3), washed with water (20 mL x 2), dried over anhydrous sodium sulfate, concentrated to obtain the crude product. The crude product was purified by preparative thin-layer chromatography (dichloromethane / methanol = 20 / 1) to obtain the red solid compound 2-fluoro-N-methyl-6-[3-[(E)-2-[5-(2-pyrrolidine-1-ethoxy)-2-pyridyl]vinyl]-1-tetrahydropyran-2-yl-indazole-6-yl]thiobenzamide 34f (197.9 mg, 328.88 μmol, yield 51.16%).

[0620] The product was confirmed by LC-MS.

[0621] MS-ESI calculated value [M+H]+602.3, actual measurement 602.2.

[0622] Step 6 At room temperature, trifluoroacetic acid (1.2 g, 10.42 mmol) was added to a solution of compound 2-fluoro-N-methyl-6-[3-[(E)-2-[5-(2-pyrrolinidine-1-ethoxy)-2-pyridyl]vinyl]-1-tetrahydropyran-2-ylindazole-6-yl]thiobenzamide 34f (197.9 mg, 328.88 μmol) in dichloromethane (5 mL), and the mixture was reacted with stirring under a nitrogen atmosphere at room temperature for 16 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (5 mL), the pH was adjusted to 8-9 with sodium carbonate, extracted with dichloromethane (5 mL x 3), the combined organic layer was washed with water (5 mL x 2), dried over anhydrous sodium sulfate, concentrated, and the crude product was obtained. The crude product was purified by preparative high-performance liquid chromatography to obtain the dark yellow solid compound 2-fluoro-N-methyl-6-({3-[(E)-2-{5-[2-(pyrrolidin-1-yl)ethoxy]pyridine-2-yl}vinyl]-1H-indazole-6-yl}thio)benzamide I-36 (18 mg, 34.77 μmol, yield 10.57%).

[0623] The product was confirmed by LC-MS, HNMR, and CNMR.

[0624] MS-ESI calculated value [M+H]+ 518.2, actual measurement 518.1.

[0625] 1 H NMR (400 MHz, CD3OD) δ 8.29 (d, J = 2.8 Hz, 1H), 8.09 (d, J = 8.4 Hz, 1H), 7.74 - 7.64 (m, 3H), 7.56-7.45 (m, 2H), 7.37-7.31 (m, 1H), 7.26 (d, J = 8.4 Hz, 1H), 7.12-7.05 (m, 2H), 4.27 (t, J = 5.2 Hz, 2H), 3.03 (t, J = 6.0 Hz, 2H), 2.89 (s, 3H), 2.77 (s, 4H), 1.89 (s, 4H). 13 C NMR (100 MHz, CD3OD&CDCl3) δ: 165.56, 160.40, 154.46, 148.23, 142.74, 142.13, 137.16, 132.81,130.84, 130.75, 129.19, 126.78, 125.41, 122.41, 122.02, 121.64, 121.39, 120.47, 114.55, 113.84, 113.62, 66.96, 54.54, 54.28, 25.55, 22.96.

[0626] [ka]

[0627] Step 1 At room temperature and under nitrogen gas, cesium carbonate (3.90 g, 11.96 mmol) and 1,1'-bisdiphenylphosphineferrocenepalladium dichloride (0.88 g, 1.20 mmol) were added to a solution of 5-iodo-1H-indazole 35a (1.02 g, 4.19 mmol) and N-methyl-2-mercaptobenzamide 1e (1 g, 5.98 mmol) in N,N-dimethylformamide (10 mL) and heated to 80°C, reacting with stirring for 2 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 20 / 1), the mixture was poured into water (30 mL), extracted with ethyl acetate (10 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1-0 / 1) to obtain the yellow oily compound 2-(1H-indazole-5-ylthio)-N-methylbenzamide 35b (0.8 g, yield 47.2%).

[0628] The product was confirmed by LC-MS.

[0629] MS-ESI calculated value [M+H]+284.1, actual measurement 284.1.

[0630] Step 2 Under room temperature and nitrogen gas, 2-(1H-indazole-5-ylthio)-N-methylbenzamide 35b (0.5 g, 1.76 mmol) and 2-bromo-5-(2-pyrrolidine-1-ylethoxy)pyridine 19a (478 mg, 1.76 mmol) were dissolved in dimethyl sulfoxide (20 mL) and cesium carbonate (1.15 g, 3.53 mmol), 1,10-phenanthroline (95 mg, 0.53 mmol), and cuprous iodide (101 mg, 0.53 mmol) were added. The mixture was heated to 100°C and reacted with stirring for 16 hours. The presence of the product was confirmed by thin-layer chromatography (dichloromethane / methanol = 20 / 1) and LC-MS. The mixture was poured into water (80 mL), extracted with ethyl acetate (20 mL x 3), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was obtained. The crude product was purified by preparative high-performance liquid chromatography to obtain the white solid compound N-methyl-2-[(1-{5-[2-(pyrrolidin-1-yl)ethoxy]pyridine-2-yl}-1H-indazole-5-yl)thio]benzamide I-29 (18 mg, yield 2.2%).

[0631] The product was confirmed by LC-MS, HNMR, and CNMR.

[0632] MS-ESI calculated value [M+H]+474.2, actual measurement 474.2.

[0633] 11H NMR (400 MHz, CD3OD) δ: 8.73 (d, 1H, J=8.8Hz), 8.23 (d, 1H, J=2.8Hz), 8.16 (d, 1H, J= 0.4Hz), 7.93-7.98 (m, 2H), 7.58-7.60 (m, 1H), 7.55 (dd, 1H, J=8.8, 1.6Hz), 7.46 (dd, 1H, J =8.8, 2.8Hz), 7.21-7.23 (m, 2H), 7.01-7.04 (m, 1H), 6.30 (s, 1H), 4.23 (t, 2H, J=6.0Hz), 3.04 (d, 3H, J=4.8Hz), 2.98 (t, 2H, J=6.0Hz), 2.66-2.68 (m, 4H), 1.84-1.88 (m, 4H). 13 13C NMR (100 MHz, CDCl3) δ: 168.68, 152.93, 147.72, 138.17, 137.07, 135.65, 135.04, 134.32, 133.06, 130.66, 129.81, 128.41, 126.67, 126.23, 125.95, 125.08, 115.85, 114.51, 68.05, 55.04, 54.77, 26.80, 23.52.

[0634] [Chemical formula]

[0635] Procedure 1 At room temperature and under nitrogen gas, a solution of 6-bromo-1H-pyrazolo[4,3-b]pyridine 36a (2 g, 10.10 mmol) in N,N-dimethylformamide (20 mL) was mixed with compound N-methyl-2-mercaptobenzamide 1e (2.03 g, 12.12 mmol), cesium carbonate (6.58 g, 20.20 mmol), and 1,1'-bisdiphenylphosphineferrocenepalladium dichloride (1.48 g, 2.02 mmol). The mixture was heated to 100°C and reacted with stirring for 1 hour. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 20 / 1), the mixture was poured into water (40 mL), extracted with ethyl acetate (20 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was obtained. The crude product was purified by column chromatography (dichloromethane / methanol = 10 / 1) to obtain the brown solid compound N-methyl-2-(1H-pyrazolo[4,3-b]pyridine-6-ylthio)benzamide 36b (1.59 g, 5.59 mmol, yield 55.37%).

[0636] The product was confirmed by LC-MS and HNMR.

[0637] MS-ESI calculated value [M+H]+285.1, actual measurement 285.0.

[0638] 1 H NMR (400MHz, DMSO-d6): δ (ppm) 13.43 (s, 1H), 8.44 (d, J = 2.0 Hz, 2H), 8.33 (s, 1H), 8.08 (s, 1H), 7.53-7.50 (m, 1H), 7.37-7.26 (m, 2H), 7.04-6.96 (m, 1H), 2.77 (d, J = 4.6 Hz, 3H).

[0639] Step 2 At room temperature, iodine (2.43 g, 9.57 mmol) and potassium carbonate (1.56 g, 11.25 mmol) were added to a solution of compound N-methyl-2-(1H-pyrazolo[4,3-b]pyridine-6-ylthio)benzamide 36b (1.6 g, 5.63 mmol) in N,N-dimethylformamide (5 mL), and the mixture was reacted at 25°C for 3.0 hours with stirring. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 20 / 1), the mixture was poured into water (10 mL), extracted with ethyl acetate (10 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product 2-[(3-iodo-1H-pyrazolyl[4,3-b]pyridine-6-yl)thio]-N-methylbenzamide 36c (2.1 g, 5.12 mmol, yield 90.97%), a brown solid.

[0640] The product was confirmed by LC-MS and HNMR.

[0641] MS-ESI calculated value [M+H]+411.0, actual measurement 410.9.

[0642] 1 H NMR (400MHz, DMSO-d6): δ (ppm) 13.84 (s, 1H), 8.45 (d, J = 1.6 Hz, 2H), 8.06 (d, J = 1.6 Hz, 1H), 7.54-7.49 (m, 1H), 7.42-7.24 (m, 2H), 7.08-6.98 (m, 1H), 2.76 (d, J = 4.6 Hz, 3H).

[0643] Step 3 At room temperature and under nitrogen gas protection, 2-[(3-iodo-1H-pyrazolyl[4,3-b]pyridine-6-yl)thio]-N-methylbenzamide 36c (100 mg, 243.76 μmol) was dissolved in N,N-dimethylformamide (5 mL), to which 2-vinylpyridine 36d (38.44 mg, 365.65 μmol), diisopropylethylamine (63.03 mg, 487.53 μmol), palladium acetate (21.89 mg, 97.51 μmol), and 1,1'-bis(diphenylphosphine)ferrocene (16.56 mg, 195.01 μmol) were added. The reaction mixture was heated to 100°C and stirred for 16 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (20 mL), extracted with ethyl acetate (10 mL x 3), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography to obtain the white solid compound N-methyl-2-({3-[(E)-2-(pyridine-2-yl)vinyl]-1H-pyrazolo[4,3-b]pyridine-6-yl}thio)benzamide I-21 (15.8 mg, 40.78 μmol, yield 16.73%).

[0644] The product was confirmed by LC-MS, HNMR, and CNMR.

[0645] MS-ESI calculated value [M+H]+388.1, actual measurement 388.1.

[0646] 11H NMR (400 MHz, DMSO-d6): δ (ppm) 13.55 (s, 1H), 8.62 (d, J = 4.4 Hz, 1H), 8.55 (s, 1H), 8.46 (d, J = 4.4 Hz, 1H), 8.20 - 8.07 (m, 2H), 7.93 (d, J = 16.4 Hz, 1H), 7.81 (t, J = 7.6 Hz, 1H), 7.65 (d, J = 7.6 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.39 - 7.26 (m, 3H), 7.07 (d, J = 7.6 Hz, 1H), 2.78 (d, J = 4.4 Hz, 3H). 13 13C NMR (100 MHz, DMSO-d6): δ (ppm) 168.26, 155.29, 150.13, 149.16, 142.32, 138.48, 137.50, 137.42, 135.41, 134.52, 132.05, 131.06, 130.67, 129.41, 128.39, 127.05, 123.41, 123.27, 123.12, 122.84, 26.58.

[0647] [Chemical formula]

[0648] Procedure 1 At 0°C, 5-bromopyridine-2-nitrile 37a (1 g, 5.46 mmol) was dissolved in methanol (10 mL), to which di-tert-butyl dicarbonate (2.39 g, 10.93 mmol) and nickel dichloride (129.88 mg, 546.43 μmol) were added. Within 2.0 hours, sodium borohydride (1.45 g, 38.25 mmol) was added slowly in portions, and the mixture was reacted at 25°C for 16 hours with stirring. After confirming that the starting materials had reacted completely by thin-layer chromatography (petroleum ether / ethyl acetate = 2 / 1), the mixture was poured into water (50 mL), extracted with ethyl acetate (10 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was obtained. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to obtain the white solid compound N-[(5-bromo-2-pyridyl)methyl]carbamate tert-butyl ester 37b (700 mg, 2.44 mmol, yield 44.61%).

[0649] The product was confirmed by LC-MS and HNMR.

[0650] MS-ESI calculated value [M+H]+287.0, actual measurement 286.9.

[0651] 1 H NMR (400 MHz, CDCl3) δ 8.60 (d, J = 2.0 Hz, 1H), 7.79 (dd, J = 8.4, 2.4Hz, 1H), 7.21 (d, J = 8.4 Hz, 1H), 5.51 (s, 1H), 4.40 (d, J = 5.4 Hz, 2H), 1.47 (s, 9H).

[0652] Step 2 Compound N-[(5-bromo-2-pyridyl)methyl]carbamate tert-butyl ester 37b (500 mg, 1.74 mmol) was added to hydrochloric acid / methanol solution (15 mL) and reacted with stirring at 25°C for 2.0 hours. After confirming that the starting materials had reacted completely by LC-MS, the reaction mixture was concentrated under reduced pressure to obtain the white solid compound (5-bromo-2-pyridyl)methylamine dihydrochloride 37c (290 mg, 1.55 mmol, yield 89.05%).

[0653] The product was confirmed by LC-MS and HNMR.

[0654] MS-ESI calculated value [M+H]+188.9, actual measurement 189.0.

[0655] 1 H NMR (400MHz, DMSO-d6): δ 8.74 (d, J = 2.0 Hz, 1H), 8.66 (s, 3H), 8.14 (dd, J = 8.4, 2.4 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 4.13-4.17 (m, 2H).

[0656] Step 3 Compound (5-bromo-2-pyridyl)methylamine dihydrochloride 37c (400 mg, 1.79 mmol) was dissolved in acetic anhydride (2 mL) and formic acid (1.6 mL) and reacted at 100°C with stirring for 16 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (petroleum ether / ethyl acetate = 2 / 1), the reaction mixture was concentrated under reduced pressure, saturated sodium bicarbonate aqueous solution (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the yellow solid compound 6-bromoimidazo[1,5-a]pyridine 37d (300 mg, 1.52 mmol, yield 85.07%).

[0657] The product was confirmed by LC-MS and HNMR.

[0658] MS-ESI calculated value [M+H]+197.0, actual measurement 197.0.

[0659] 1 H NMR (400 MHz, DMSO-d6) δ 9.40 (s, 1H), 8.96 (s, 1H), 8.05 (s, 1H), 7.80 (d, J = 9.6 Hz, 1H), 7.26 (dd, J =10.4Hz ,9.6 Hz, 1H).

[0660] Step 4 At room temperature, a solution of compound 6-bromoimidazo[1,5-a]pyridine 37d (0.3 g, 1.52 mmol) in N,N-dimethylformamide (10 mL) was mixed with compound N-methyl-2-mercaptobenzamide 1e (254.62 mg, 1.52 mmol), cesium carbonate (992.18 mg, 3.05 mmol), and 1,1'-bisdiphenylphosphineferrocenepalladium dichloride (222.82 mg, 304.52 μmol). The mixture was heated to 80°C and reacted with stirring for 2 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 15 / 1), the mixture was poured into water (40 mL), extracted with ethyl acetate (20 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was obtained. The crude product was purified by preparative high-performance liquid chromatography to obtain the yellow solid compound 2-imidazo[1,5-a]pyridine-6-ylthio-N-methylbenzamide 37e (87 mg, 307.04 μmol, yield 20.17%).

[0661] The product was confirmed by LC-MS and HNMR.

[0662] MS-ESI calculated value [M+H]+284.1, actual measurement 284.1.

[0663] 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J = 0.8 Hz, 1H), 8.13 (s, 1H), 7.54 (dd, J = 7.6, 1.6 Hz, 1H), 7.42 - 7.45 (m, 2H), 7.29-7.32 (m, 1H), 7.22-7.26 (m, 1H), 7.14 (dd, J = 7.6, 1.2 Hz, 1H), 6.66 (dd, J = 9.2, 1.2 Hz, 1H), 6.21 (s, 1H), 3.04 (d, J = 5.2 Hz, 3H).

[0664] Step 5 At room temperature, iodine (167.50 mg, 659.97 μmol) and potassium carbonate (95.60 mg, 776.43 μmol) were added to a solution of compound 2-imidazo[1,5-a]pyridine-6-ylthio-N-methylbenzamide 37e (110 mg, 388.22 μmol) in N,N-dimethylformamide (5 mL), and the mixture was reacted with stirring at 25°C for 3.0 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 20 / 1), the mixture was poured into water (10 mL), extracted with ethyl acetate (10 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was obtained. The crude product was purified by preparative thin-layer chromatography to obtain the yellow solid compound 2-(1-iodoimidazole[1,5-a]pyridine-6-yl)thio-N-methylbenzamide 37f (89 mg, 217.47 μmol, yield 56.02%).

[0665] The product was confirmed by LC-MS and HNMR.

[0666] MS-ESI calculated value [M+H]+410.0, actual measurement 410.0.

[0667] 1H NMR (400 MHz, CDCl3) δ 8.15 (t, J = 10.8 Hz 2H), 7.53-7.55 (m, 1H), 7.27 - 7.33 (m, 3H), 7.13-7.15 (m, 1H), 6.72-6.75 (m, 1H), 6.10 (s, 1H), 3.05 (d, J = 5.2 Hz, 3H).

[0668] Step 6 At room temperature and under nitrogen gas protection, a solution of compound 2-(1-iodoimidazole[1,5-a]pyridine-6-yl)thio-N-methylbenzamide 37f (200 mg, 488.71 μmol) in N,N-dimethylformamide (10 mL) was mixed with 2-vinylpyridine 36d (77.07 mg, 733.06 μmol), diisopropylethylamine (126.32 mg, 977.41 μmol), palladium acetate (43.89 mg, 195.48 μmol), and 1,1'-bis(diphenylphosphine)ferrocene (33.22 mg, 390.96 μmol). The reaction mixture was heated to 100°C and stirred for 16 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 20 / 1), the mixture was poured into water (10 mL), extracted with ethyl acetate (10 mL x 3), washed with water (10 mL x 2) and saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography, then slurryed with methanol (2 mL) and filtered. After drying the filtered cake, the yellow solid compound N-methyl-2-({1-[(E)-2-(pyridine-2-yl)vinyl]imidazo[1,5-a]pyridine-6-yl}thio)benzamide I-26 (6.3 mg, 16.30 μmol, yield 3.34%) was obtained.

[0669] The product was confirmed by LC-MS, HNMR, and CNMR.

[0670] MS-ESI calculated value [M+H]+387.1, actual measurement 387.1.

[0671] 1 1H NMR (400 MHz, CD3OD + CD3Cl) δ 8.47 (d, J = 3.6 Hz, 1H), 8.20 (d, J = 16.0 Hz, 2H), 7.77 (d, J = 15.6 Hz, 1H), 7.64 - 7.70 (m, 2H), 7.47 (d, J = 7.2 Hz, 1H), 7.34 - 7.40 (m, 2H), 7.20 - 7.30 (m, 2H), 7.15 (d, J = 7.2 Hz, 1H), 6.74 (d, J = 9.6 Hz, 1H), 2.92 (s, 3H). 13 13C NMR (100 MHz, CD3OD + CD3Cl) δ 169.50, 155.69, 148.95, 137.23, 135.69, 135.15, 130.76, 129.82, 128.99, 127.91, 127.83, 126.63, 126.43, 125.64, 124.85, 122.80, 122.20, 121.82, 120.66, 118.12, 26.36.

[0672]

Chem.

[0673] Procedure 1 Under 0°C and nitrogen gas protection, sodium hydride (89.6 mg, 3.73 mmol) was added to a solution of 2-diethoxyphosphoethyl acetate 38b (460.5 mg, 2.05 mmol) in tetrahydrofuran (10 mL), and the mixture was stirred at 0°C for 1.0 hour. Then, pyridine-2-carboxyaldehyde 38a (0.2 g, 1.87 mmol) was slowly added. The reaction mixture was stirred at 25°C for 2 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (petroleum ether / ethyl acetate = 3 / 1), the mixture was poured into water (10 mL), extracted with ethyl acetate (10 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a yellow oily crude product (E)-3-(2-pyridyl)propa-2-enoate ethyl ester 38c (0.15 g, 846.50 μmol, yield 45.33%).

[0674] The product was confirmed by LC-MS and HNMR.

[0675] MS-ESI calculated value [M+H]+178.1, actual measurement 178.0.

[0676] 1 H NMR (400MHz, CDCl3): δ (ppm) 8.65 (d, J=4.0Hz, 1H), 7.67-7.74 (m, 2H), 7.42 (d, J=8.0Hz, 1H), 7.25-7.29 (m, 1H), 6.90-6.94 (m, 1H), 1.17-1.31 (m, 3H).

[0677] Step 2 At room temperature, lithium hydroxide (81.1 mg, 3.39 mmol) was added to a solution of compound (E)-3-(2-pyridyl)propa-2-enoic acid ethyl ester 38c (0.2 g, 1.13 mmol) in tetrahydrofuran (8 mL) and water (2 mL), and the mixture was stirred at 30°C for 16 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the reaction mixture was concentrated, water (10 mL) was added, and the pH was adjusted to 5-6 with aqueous citric acid. The mixture was concentrated under reduced pressure, ethanol (20 mL) was added, and the mixture was stirred for 30 minutes before being filtered. The filtrate was concentrated under reduced pressure to obtain the yellow solid crude product (E)-3-(2-pyridyl)propa-2-enoic acid 38d (0.15 g, 1.01 mmol, yield 89.11%).

[0678] The product was confirmed by LC-MS and HNMR.

[0679] MS-ESI calculated value [M+H]+150.0, actual measurement 150.0.

[0680] 1 H NMR (400MHz, DMSO-d6): δ (ppm) 8.62 (d, J=4.4Hz, 1H), 7.82-7.86 (m, 1H), 7.68-7.70 (m, 1H), 7.50-7.54 (m, 1H), 7.36-7.39 (m, 1H), 6.83 (d, J=15.6Hz, 1H).

[0681] Step 3 At room temperature, potassium carbonate (302.1 mg, 2.19 mmol) and cuprous iodide (41.6 mg, 218.57 μmol) were added to a solution of 4-bromopyridine-2-nitrile 38e (0.2 g, 1.09 mmol) and 2-mercaptobenzoate (202.2 mg, 1.20 mmol) in N-methylpyrrolidone (10 mL). The mixture was heated to 100°C under a nitrogen atmosphere and reacted with stirring for approximately 16 hours. After confirming that the starting materials had reacted completely by thin-layer chromatography (petroleum ether / ethyl acetate = 5 / 1), the mixture was poured into water (30 mL), extracted with ethyl acetate (10 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was obtained. The crude product was purified by thin-layer preparative chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain a white solid methyl 2-[(2-cyano-4-pyridyl)thio]benzoate 38f (0.19 g, 702.91 μmol, yield 64.32%).

[0682] The product was confirmed by LC-MS and HNMR.

[0683] MS-ESI calculated value [M+H]+271.0, actual measurement 271.0.

[0684] 1 H NMR (400MHz, CDCl3): δ (ppm) 8.50 (d, J=8Hz, 1H), 8.00-8.02 (m, 1H), 7.51-7.59 (m, 3 H), 7.36 (s, 1H), 7.26-7.28 (m, 1H), 3.87-3.89 (m, 3H).

[0685] Step 4 At room temperature, a solution of compound 2-[(2-cyano-4-pyridyl)thio]methyl benzoate 38f (200 mg, 739.90 μmol) in methanol (5 mL) was mixed with di-tert-butyl dicarbonate (193.8 mg, 887.88 μmol) and Raney nickel (100 mg). The mixture was reacted under a hydrogen gas atmosphere at 25°C for 16 hours with stirring. After confirming that the starting materials had reacted completely by thin-layer chromatography (ethyl acetate / petroleum ether = 3 / 1), the mixture was filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by thin-layer preparative chromatography (ethyl acetate / petroleum ether = 5 / 1-3 / 1) to obtain a yellow oily substance, 2-[[2-[(tert-butoxycarbonylamino)methyl]-4-pyridyl]thio]methyl benzoate 38g (110 mg, 293.76 μmol, yield 39.70%).

[0686] The product was confirmed by LC-MS and HNMR.

[0687] MS-ESI calculated value [M+H]+375.1, actual measurement 375.2.

[0688] 1 H NMR (400 MHz, CDCl3) δ 8.34 (d, J = 5.6 Hz, 1H), 7.90 (dd, J = 6.0, 1.6 Hz, 1H), 7.26 - 7.40 (m, 3H), 7.14 (s, 1H), 7.00 (d, J = 4.8 Hz, 1H), 5.68 (s, 1H), 4.35 (d, J = 5.4 Hz, 2H), 3.84 (s, 3H), 1.40 (d, J = 2.8 Hz, 9H).

[0689] Step 5 38 g (140 mg, 373.88 μmol) of compound 2-[[2-[(tert-butoxycarbonylamino)methyl]-4-pyridyl]thio]methyl benzoate was dissolved in a solution of hydrochloric acid and dioxane (3 mL, 9 mol / L) and reacted with stirring at 25°C for 16 hours. After confirming that the starting materials had reacted completely by LC-MS, the reaction mixture was concentrated under reduced pressure to obtain the crude product of compound 2-[[2-(aminomethyl)-4-pyridyl]mercapto]methyl benzoate dihydrochloride 38h.

[0690] The product was confirmed by LC-MS.

[0691] MS-ESI calculated value [M+H]+ 275.1, actual measurement 275.0.

[0692] Step 6 To a solution of compound (E)-3-(2-pyridyl)propa-2-enoic acid 38d (24.0 mg, 160.88 μmol) in N,N-dimethylformamide (5 mL), compound 2-[[2-(aminomethyl)-4-pyridyl]mercapto]methyl benzoate dihydrochloride 38h (50.0 mg, 160.88 μmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (45.9 mg, 241.31 μmol), 1-hydroxybenzotriazole (32.6 mg, 241.31 μmol), and triethylamine (81.4 mg, 804.38 μmol) were added, and the mixture was reacted at 25°C for 3.0 hours with stirring. After confirming that the starting materials had reacted completely by thin-layer chromatography (petroleum ether / ethyl acetate = 3 / 1), the mixture was poured into water (20 mL), extracted with ethyl acetate (10 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated to obtain the crude product. Purification by thin-layer preparative chromatography (ethyl acetate / petroleum ether = 3 / 1) yielded the yellow oily compound 2-[3-[(E)-2-(2-pyridyl)vinyl]imidazo[1,5-a]pyridine-7-yl]thiobenzoate methyl ester 38i (37 mg, 91.25 μmol, yield 56.72%).

[0693] The product was confirmed by LC-MS and HNMR.

[0694] MS-ESI calculated value [M+H]+406.1, actual measurement 406.1.

[0695] 1 H NMR (400 MHz, CDCl3) δ 8.61 (d, J = 4.0 Hz, 1H), 8.38 (d, J = 5.6 Hz, 1H), 7.93 (dd, J = 8.0, 1.6 Hz, 1H), 7.62-7.71 (m, 2H), 7.34 - 7.44 (m, 4H), 7.08 - 7.25 (m, 4H), 7.05 (dd, J = 5.2, 1.6 Hz, 1H), 4.63 (s, 2H), 3.87 (s, 3H).

[0696] Step 7 At room temperature, 13 mg, 32.06 μmol of compound 2-[3-[(E)-2-(2-pyridyl)vinyl]imidazo[1,5-a]pyridine-7-yl]methyl thiobenzoate 38i was added to a solution of 1,2-dichloroethane (1.5 mL) with phosphorus oxychloride (14.8 mg, 96.18 μmol), and the mixture was reacted with stirring at 80°C for 16 hours. After confirming that the starting materials had reacted completely by LC-MS, the mixture was poured into water (10 mL), extracted with ethyl acetate (10 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was obtained. The compound was purified by thin-layer preparative chromatography (ethyl acetate / petroleum ether = 3 / 1) to obtain the yellow solid compound 2-[[2-[[(E)-3-(2-pyridyl)propa-2-alkenyl]amino]methyl]-4-pyridyl]thio]methyl benzoate 38j (5 mg, 12.90 μmol, yield 40.25%).

[0697] The product was confirmed by LC-MS.

[0698] MS-ESI calculated value [M+H]+388.1, actual measurement 388.1.

[0699] Step 8 At room temperature, sodium hydroxide (16.5 mg, 412.95 μmol) was added to a methanol (5 mL) solution of compound 2-[[2-[[(E)-3-(2-pyridyl)propa-2-alkenyl]amino]methyl]-4-pyridyl]thio]methyl benzoate 38j (80 mg, 206.48 μmol) and the mixture was reacted with stirring at 25°C for 1.0 hour. After confirming that the starting materials had reacted completely by thin-layer chromatography (petroleum ether / ethyl acetate = 1 / 1), the mixture was poured into water (10 mL) and the pH was adjusted to 4-5 with 1N hydrochloric acid aqueous solution. The mixture was filtered, the filtered cake was washed with water and dried to obtain the red solid compound 2-({3-[(E)-2-(pyridine-2-yl)vinyl]imidazo[1,5-a]pyridine-7-yl}thio)benzoic acid I-28 (48 mg, 128.54 μmol, yield 62.25%).

[0700] The product was confirmed by LC-MS, HNMR, and CNMR.

[0701] MS-ESI calculated val...

Claims

1. A compound, or a pharmaceutically acceptable salt thereof, stereoisomer, solvate, and deuterated compound thereof, wherein the compound has the following structure: 【Chemistry 1】 (III-2) During the ceremony, 【Chemistry 2】 part 【Transformation 3】 R3 is selected from H, C1-C6 alkyl groups, 【Chemistry 4】 Select from one of the structures, L ０ However, O, S, N(R Ｌａ ) is selected from, R Ｌａ However, it was selected from H, L １ The C2 alkenylene group and the C2 alkynylene group are selected. L ２ is C １ -C ６ an alkylene group, -(C ０ -C ６ alkylene)-Q ２ -(C ０ -C ６ alkylene) - and is selected from Q ２ [[ID=​​​​​​​​ Y is -NR ７ R ８ , selected from nitrogen-containing heterocyclyl groups, where the nitrogen-containing heterocyclyl groups are one or more R ９ It may be optionally substituted by the base, R ９ However, halogens, cyano groups, amino groups, hydroxyl groups, C １ -C １０ alkyl group, C １ -C １０ Halogen-substituted alkyl group, C １ -C １０ Alkoxy group, C １ -C １０ Halogen-substituted alkoxy group, C １ -C １０ Alkylamino group, C １ -C １０ Cyanoalkyl group, C １ -C １０ Hydroxysubstituted alkyl group, C １ -C １０ Alkoxysubstituted alkyl group, C １ -C １０ Alkylaminosubstituted alkyl group, -(C ０ -C ６ (alkylene group) - (C ３ -C １０ Selected from cycloalkyl groups, R ７ , R ８ However, H and C were established independently. １ -C １０ alkyl group, C ３ -C １０ Cycloalkyl groups, C ３ -C １０ Selected from cycloalkylalkyl groups, 【Transformation 5】 part 【Transformation 6】 And here, R 4a is selected from -C(O)NR 401 R 402, -(C0-C6 alkylene group)-NR 401 R 402, -C(O)R 401, and -C(O)OR 401, where R 401 and R 402 are independently selected from H, C1-C6 alkyl group, -(C0-C6 alkylene group)-(C3-C6 cycloalkyl group), where the C0-C6 alkylene group, C1-C6 alkyl group, and C3-C6 cycloalkyl group may be optionally substituted with a group selected from one or more of halogens, cyano groups, amino groups, hydroxyl groups, C1-C6 alkyl groups, and C1-C6 halogen-substituted alkyl groups. R 4b is one or more independent substituents on the benzene ring, selected from H, halogen, cyano group, amino group, hydroxyl group, C1-C6 alkyl group, and C1-C6 halogen-substituted alkyl group. R ５ but, 【Transformation 7】 One or more independent substituents on the ring, each R ５ However, independently, H, halogen, cyano group, amino group, hydroxyl group, C １ -C １０ alkyl group, C １ -C １０ Halogen-substituted alkyl group, C １ -C １０ Alkoxy group, C １ -C １０ Halogen-substituted alkoxy group, C １ -C １０ Alkylamino group, C １ -C １０ Cyanoalkyl group, C １ -C １０ Hydroxysubstituted alkyl group, C １ -C １０ Alkoxysubstituted alkyl group, C １ -C １０ Alkylaminosubstituted alkyl group, -(C ０ -C ６ (alkylene group) - (C ３ -C １０ Selected from cycloalkyl groups, R ６ is one or more independent substituents of the E ring, and each R ６ is independently H, halogen, cyano group, amino group, hydroxy group, C １ -C １０ alkyl group, C １ -C １０ halogen-substituted alkyl group, C １ -C １０ alkoxy group, C １ -C １０ halogen-substituted alkoxy group, C １ -C １０ alkylamino group, C １ -C １０ cyanoalkyl group, C １ -C １０ hydroxy-substituted alkyl group, C １ -C １０ alkoxy-substituted alkyl group, C １ -C １０ alkylamino-substituted alkyl group, -(C ０ -C ６ alkylene group)-(C ３ -C １０ cycloalkyl group), or a pharmaceutically acceptable salt, stereoisomer, solvate and deuterated compound thereof.

2. R ３ The compound according to claim 1, characterized in that it is H.

3. L ０ The compound according to claim 1, characterized in that it is S.

4. L １ but 【Transformation 8】 The compound according to claim 1, characterized in that it is the compound described above. 【Request Item 5】 【Chemistry 9】 The part is, 【Chemistry 10】 The compound according to claim 1, characterized in that it is selected from any of the structures.

6. L ２ However, C １ -C ６ Alkylene group, -Q ２ - (C ０ -C ６ The compound according to claim 1, characterized in that it is selected from an alkylene group.

7. L ２ but 【Chemistry 11】 The compound according to claim 1, characterized by being selected from among.

8. Y is -NR ７ R ８ And R ７ , R ８ However, independently, H, C １ -C ６ Alkyl alkyl group, -(C ０ -C ６ (alkylene group) - (C ３ -C ６ The compound according to claim 1, characterized by being selected from cycloalkyl groups.

9. Y 【Chemistry 12】 The compound according to claim 1, characterized in that it is the compound described above.

10. Y, 【Chemistry 13】 Selected from, R ９ However, H, C １ -C ６ alkyl group, C １ -C ６ Hydroxysubstituted alkyl group, C １ -C ６ Amino group substituted alkyl group, C １ -C ６ Alkoxysubstituted alkyl group, C １ -C ６ Alkylaminosubstituted alkyl group, -(C ０ -C ６ (alkylene group) - (C ３ -C ６ The compound according to claim 1, characterized by being selected from cycloalkyl groups.

11. Y, 【Chemistry 14】 The compound according to claim 1, characterized by being selected from among.

12. R ４ａ but 【Chemistry 15】 Selected from, and / or, R ４ｂ The compound according to claim 1, characterized in that it is H or a halogen. 【Request Item 13】 【Chemistry 16】 part 【Chemistry 17】 The compound according to claim 1, characterized in that it is the compound described above.

14. Compounds having a structure selected from the following group, [Chemistry 18] 【change】 【change】 【change】 【change】 【change】 Alternatively, a pharmaceutically active metabolite of the compound, and / or a pharmaceutically acceptable salt of the compound.

15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14 or a pharmaceutically active metabolite of the compound and / or a pharmaceutically acceptable salt of the compound, and an optionally selected carrier.

16. A drug for the prevention and / or treatment of a disease, comprising a compound or pharmaceutically acceptable salt, stereoisomer, solvate, or deuterated compound according to any one of claims 1 to 14, A drug that causes the aforementioned disease to be a proliferative disorder mediated by protein tyrosine kinase.

17. The drug according to claim 16, characterized in that the disease is an eye disease or a tumor.

18. The disease is selected from diabetic retinopathy, age-related macular degeneration (AMD), pathological choroidal neovascularization (CNV) due to any pathogenesis mechanism, pathological subretinal neovascularization due to any pathogenesis mechanism, uveitis, retinal vein occlusion, ocular trauma, surgical edema, surgical neovascularization, cystoid macular edema (CMO), ocular ischemia, retinopathy of prematurity, Coats' disease, sickle cell retinopathy, and / or neovascular glaucoma. Alternatively, the drug according to claim 16, characterized in that the disease is selected from breast cancer, lung cancer, adenocarcinoma, colorectal cancer, kidney cancer, liver cancer, pancreatic adenocarcinoma, ovarian cancer, prostate cancer, glioma, glioblastoma, myeloma, leukemia, myeloid metaplasia of unknown cause, mesothelioma, and myelodysplastic syndrome.

19. The drug according to claim 16, characterized in that the disease is diabetic retinopathy or retinal vein occlusion, or the disease is a hematopoietic malignancy.

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