Protein tyrosine kinase inhibitors and their medical uses

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 field of medicine, and specifically to protein tyrosine kinase inhibitors and their use for treating proliferative diseases or conditions mediated by protein tyrosine kinases. [Background technology]

[0002] Age-related macular degeneration (AMD) and diabetic retinopathy (DR) are the most common ocular diseases and the leading cause of blindness in the elderly and working-age population. These lesions are associated with neovascularization and extravasation in the posterior segment of the eye. Exudative AMD is characterized by neovascularization from the choroidal microvascular bed and infiltration into the subretinal space, whereas DR is primarily manifested as 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. Vascular endothelial growth factor-A (VEGF-A) and its corresponding receptor (VEGFR) play a key role in these processes. Furthermore, tumor growth and metastasis depend on sufficient oxygen and nutrients provided by the tumor vascular network. Tumor angiogenesis relies on a highly complex process 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). Overexpression or upregulation of receptor tyrosine kinase (RTK) activity has been shown to be involved in many proliferative disorders, including ocular diseases, tumors, and cancers. Receptor tyrosine kinases are kinase enzymes that modify proteins by chemically adding phosphate groups (phosphorylation). Phosphorylation typically results in functional changes to target proteins, such as altering enzymatic activity, cellular localization, and binding to other proteins. Kinases are known to regulate most cellular pathways, particularly those involved in signal transduction. To date, one approach to inhibiting the VEGF pathway is by inhibiting receptor tyrosine kinase (RTK) activity. The therapeutic goal of protein tyrosine kinase inhibitors in the treatment of ocular diseases such as age-related macular degeneration (AMD) and diabetic retinopathy (DR) is to eliminate pathological angiogenesis and disease progression, thereby preventing visual impairment. Furthermore, VEGFRs, as proangiogenic factors, play an important role in tumor growth, invasion, and exudation, making them excellent therapeutic targets for many cancers. To date, the US FDA has not approved any small molecule tyrosine kinase inhibitors for the treatment of neovascular age-related macular degeneration or diabetic retinopathy. Summary of the Invention

[0003] The present invention provides compounds for treating proliferative diseases or conditions associated with ocular diseases and malignant tumors, such as pathological angiogenesis mediated by protein tyrosine kinases, retinal ischemia, retinal edema, and diabetic retinopathy. The clinical success of VEGF antibody drugs (pegaptanib, ranibizumab, aflibercept, and brolucizumab) supports this concept. For example, the U.S. Food and Drug Administration (FDA) has approved the administration of aflibercept (VEGF Trap-Eye) for the treatment of neovascular age-related macular degeneration. Ziv-aflibercept, which has the same molecular structure, has also been approved by the FDA as a combination therapy for patients with metastatic colorectal cancer. However, these VEGF antibody drugs require intravitreal injection by a retinal specialist. For clinicians and patients, frequent intravitreal injections are inconvenient and involve rare but serious injection-related risks (e.g., endophthalmitis, retinal detachment, cataract, and intraocular inflammation), leading to many patients missing scheduled injections and reduced therapeutic efficacy. Despite the favorable clinical results of VEGF antibody biologics, challenges associated with intravitreal injections remain. Therefore, efforts are underway to develop small molecule antiangiogenic agents, particularly VEGFR tyrosine kinase inhibitors, for ocular administration as a treatment for neovascular age-related macular degeneration. Compared with recombinant proteins, small molecule targeted VEGFR tyrosine kinase inhibitors offer many advantages. They can be formulated as eye drops to avoid intravitreal injection, and they can penetrate the cell membrane and directly interact with the cytoplasmic domain of receptor tyrosine kinases (RTKs). Furthermore, small molecule eye drops are inexpensive. However, to date, no small molecule tyrosine kinase inhibitors have been approved by the US FDA for the treatment of neovascular age-related macular degeneration or diabetic retinopathy.

[0004] Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) are known as the most potent vascular permeability factor and endothelial-specific mitogen, and play important roles in endothelial cell proliferation, migration, and angiogenesis. Angiogenesis is an important mechanism in many physiological and pathological processes, contributing to endothelial cell proliferation, migration, and survival, leading to the formation of renal tubules, and ultimately promoting angiogenesis. Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) play important roles in pathological angiogenesis, including tumor progression and ocular neovascular diseases. For example, VEGF expression levels are significantly positively correlated with the degree of angiogenesis in tumor tissue. VEGF acts on the VEGFR2 receptor, activating phosphorylation of VEGFR receptor tyrosine kinase, leading to aberrant cell signaling, thereby promoting endothelial cell proliferation and angiogenesis. VEGF is a major contributor to many cancers and ocular diseases associated with pathological neovascularization. Compounds of the present invention (e.g., those prepared in Example 1) inhibit antiangiogenic tyrosine kinases and effectively antagonize the activity of all VEGFR receptor (VEGFR1, VEGFR2, VEGFR3) tyrosine kinases, avoiding high selectivity for EGFR inhibition (Example 2).

[0005] VEGFR2 is the primary receptor for VEGF-induced endothelial cell signaling. Upon binding of the ligand VEGF to the receptor during development and / or after tissue injury, VEGFR2 undergoes autophosphorylation and activation, inducing angiogenesis and bypassing blocked blood vessels. The compounds of the present invention significantly inhibit VEGF-induced VEGFR2 autophosphorylation (pVEGFR2) in human endothelial cells, blocking abnormal cell signaling and thereby inhibiting neovascularization (Example 3). The primary function of signaling from the VEGFR receptor is to promote endothelial cell proliferation and neovascularization. The compounds of the present invention demonstrated 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. These novel tyrosine kinase inhibitors can be used in the treatment of neovascular age-related macular degeneration and diabetic retinopathy, as well as in tumor therapy, where inhibition of tumor angiogenesis cuts off the blood and nutrient supply necessary for tumor growth, leading to tumor cell death.

[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 extent to which a therapeutic agent is absorbed from a drug form and becomes available at the site of action. Conventional VEGF tyrosine kinase inhibitors suffer from poor solubility and / or poor kinase inhibitory activity, which significantly impact the bioavailability of such compounds and reduce their therapeutic efficacy. Compounds with low solubility are particularly unsuitable for use in eye drops. For example, axitinib has good inhibitory activity against VEGF tyrosine kinases (VEGFR1, VEGFR2, and VEGFR3), but its solubility is low (less than 2 μg / mL). The present invention provides compounds 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 an IC50 / IC ... 50 ≤100 nM or IC against VEGFR2 50 ≤10 nM or IC against VEGFR2 50The present invention provides a compound (Example 4) that has the advantage of significantly improving solubility and / or has excellent kinase inhibitory activity, such that the solubility is 1 nM or less.

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

[0008] One of the key challenges in developing small-molecule tyrosine kinase inhibitors for clinical use in age-related macular degeneration and diabetic retinopathy is overcoming "on-target" toxicity. Inhibiting VEGFR in healthy vasculature can lead to serious adverse events, such as hypertension, bleeding, and thrombosis. Despite numerous clinical successes in oncology therapy, the safety of oral VEGFR-2 inhibitors may be a major reason why their 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 issue of on-target toxicity.

[0009] While topical ocular administration has proven successful for treating anterior segment-related diseases (e.g., glaucoma), there are currently no FDA-approved topical therapies for posterior segment-related eye diseases (e.g., neovascular AMD, diabetic retinopathy). This is largely due to the anatomical and physiological barriers that the human eye has evolved to protect from foreign substances. The tear film is one of the first barriers that must be overcome. Compounds in the anterior segment are rapidly washed away by the tear film and excreted through the nasolacrimal duct, so compounds must be rapidly absorbed after topical instillation. However, absorption / penetration into ocular tissues can also be challenging. One absorption pathway involves penetration through the cornea, which is composed of tight junctions and an epithelium with alternating lipophilic and hydrophilic layers. Another absorption pathway involves penetration through the conjunctiva and subsequent diffusion into the sclera, a relatively permeable ocular tissue. However, because the conjunctiva is a highly vascularized tissue, drugs that enter the conjunctiva tend to be "lost" to the systemic circulation. Compounds exposed at the sclera can diffuse to the choroid, which is the 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 may be a strong barrier to compound diffusion. Due to this anatomical and physiological barrier, it is estimated that less than 5% of a topical dose reaches posterior ocular tissues. Despite these challenges associated with topical administration, the present invention focuses on the structure-activity relationship (SAR) associated with ocular and blood exposure. Effective delivery to posterior ocular tissues (choroid and retina) can be achieved by compound-containing eye drops (Example 6). Rapid degradation of the compound in plasma may help avoid the problem of systemic on-target toxicity. Axitinib's exposure to the posterior ocular segment is relatively low, below the detection limit in the retina. The present invention provides ophthalmic formulations containing compounds that bind to relevant ocular target receptors, increase bioavailability in the posterior segment of the eye, and maintain sufficient drug concentrations in the posterior segment of the eye (e.g., choroid and retina) to ameliorate problems with ocular delivery of conventional topical therapeutic agents.

[0010] Many eye drops have limited permeability through the corneal and conjunctival barriers, which can require high concentrations of the compound in ophthalmic formulations to achieve therapeutic levels that are effective in posterior segment tissues. This can be a major limitation of eye drops. Depending on the compound (either the molecule itself or at high concentrations), ophthalmic formulations can have side effects on anterior segment tissues (conjunctiva, cornea, and / or lens) and can cause damage to the ocular surface, such as corneal epithelial defects and erosions. In particular, clinical evidence has shown that treatment with EGFR antibody drugs can cause ocular side effects, such as epithelial degeneration and defects, ulcers, corneal epithelial thinning, erosions and / or corneal edema, and keratitis. EGFR is a key factor in wound healing in human corneal epithelial cells. Therefore, it is necessary to select compounds for topical ophthalmic formulations that can avoid inhibiting EGFR activity. The compounds of the present invention not only effectively antagonize VEGFR1, VEGFR2, and VEGFR3 tyrosine kinase activity, but also exhibit high selectivity for inhibiting EGFR tyrosine kinase activity (Example 2).

[0011] Age-related macular degeneration (AMD) is an eye disease that causes vision loss when the macula, the region of the retina responsible for clear, fine vision, degenerates. In exudative AMD, choroidal blood vessels (choroidal neovascularization, CNV) sprout and expand into the submacular space, exuding fluid and blood. 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 patients with diabetes over 15 years of age suffer from diabetic retinopathy. Depending on the stage of progression, diabetic retinopathy can be divided into two phases: a non-proliferative phase (also known as the early phase), characterized by vascular leakage, and a proliferative or late phase, characterized by retinal vascular proliferation 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 diseases. Upregulation of VEGF causes abnormal proliferation and leakage of retinal blood vessels, resulting in visual impairment. Injection of VEGF into the vitreous of Dutch-Belted rabbits induces transient retinal leakage, similar to human exudative AMD and diabetic retinopathy. In this model, compounds of the present invention can demonstrate efficacy in inhibiting retinal leakage. The oxygen-induced retinopathy (OIR) mouse model exhibits reproducible and quantifiable proliferative retinal neovascularization, closely resembling the clusters formed in human vascular pathology (vitreous neovascularization) in mouse OIR. The OIR model is used to evaluate the in vivo efficacy of compounds of the present invention in retinal vasculopathy. A rat model of laser-induced choroidal neovascularization (CNV) involves irradiating rat eyes with photocoagulant green laser pulses, locally destroying Bruch's membrane (the extracellular matrix between the retina and choroid). Destruction of Bruch's membrane induces local inflammatory factors and VEGF production, 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 pathology.Streptozotocin (STZ)-induced diabetic rats are considered a useful preclinical animal model for studying the pathogenesis and treatment of human diabetic retinopathy. Significant increases in retinal vascular permeability were detected in all diabetic rat groups, along with intraretinal hemorrhage and fluorescein exudation, which are considered to be pre-proliferative changes in diabetic retinopathy. However, some rats also exhibited vitreous neovascularization attached to the retina and retinal folds, a hallmark symptom of severe, proliferative diabetic retinopathy, the proliferative phase of diabetic retinopathy. During the progression of diabetic retinopathy, the retinas of streptozotocin (STZ)-induced diabetic mice showed increased expression of the angiogenesis-related growth factor VEGF and its receptors, VEGFR1 and VEGFR2. The in vivo efficacy of the compound-containing ophthalmic formulations of the present invention was evaluated using a rat model of STZ-induced diabetic retinopathy, specifically the inhibition of vascular leakage and angiogenesis, which are 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 pathologies caused or exacerbated by ocular neovascularization, angiogenesis, and / or extravasation, such as 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 due to any pathological mechanism (e.g., sickle cell disease, high myopia, trauma, etc.), traumatic choroidal rupture, ocular histoplasmosis, optic nerve head drusen, angioid streaks, and certain retinal dystrophies, and pathologies caused by any pathological mechanism. Pathological subretinal neovascularization and vascular exudates resulting from (e.g., sickle cell retinopathy, internal carotid artery cavernous fistula, Eales' disease, ocular ischemia syndrome, hyperviscosity syndrome, familial exudative vitreoretinopathy, idiopathic obliterative microarteritis, retinal vasculitis, shatter-like choroidoretinopathy, sarcoidosis, or toxoplasmosis), uveitis, retinal vein occlusion (central or branch), ocular trauma, surgical neovascularization, surgical edema, ocular ischemia, cystoid macular edema, retinopathy of prematurity, sickle cell retinopathy, capsular disease, and / or neovascular glaucoma.

[0013] Furthermore, the development, progression, and metastasis of many tumors, as well as the formation of tumor angiogenesis, 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, vascular endothelial growth factor receptors (VEGFRs) are highly expressed in many tumor cells and tumor vascular endothelial cells. The vascular endothelial growth factor receptor (VEGFR) family is directly involved in tumor development, progression, and angiogenesis. The clinical success of VEGF antibody drugs in the treatment of malignant tumors, as well as ophthalmic diseases associated with pathological neovascularization, substantiates this concept. The present invention is applicable to the treatment of solid tumors and leukemias, such as breast cancer, lung cancer (particularly non-small cell lung cancer), adenocarcinoma, colorectal cancer, renal cancer, liver cancer, pancreatic adenocarcinoma, ovarian cancer, prostate cancer, glioma, glioblastoma, myeloma, acute myeloid leukemia, myeloid metaplasia of unknown etiology, mesothelioma, and myelodysplastic syndrome. The present invention relates to a method for preventing the metastatic spread of tumors and the growth of micrometastases. Illustrative examples of protein tyrosine kinase inhibitors that are anti-angiogenic kinase inhibitors and that can be used to provide beneficial therapeutic results in accordance with embodiments of the present invention include, but are not limited to, receptor tyrosine kinase inhibitors such as VEGFR, Tie-2, and FGFR.

[0014] [ka]

[0015] wherein R1 comprises a substituted cyclic structure, R2 comprises an optionally substituted substituent; R3 comprises an optionally substituted substituent; X1 is an optionally substituted atom; Provided are compounds of formula (I), or pharmaceutically acceptable prodrugs of said compounds, pharmaceutically active metabolites of said compounds, and / or pharmaceutically acceptable salts of said compounds.

[0016] In one aspect, the present invention provides a compound according to 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 aspect, the present invention provides a pharmaceutical composition comprising a compound of 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, and optionally a carrier.

[0018] In one aspect, the present invention provides the use of a compound of 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, and / or a pharmaceutical composition of the present invention in the preparation of a medicament for treating a disease mediated by a protein tyrosine kinase.

[0019] In one aspect, the present invention provides a compound of 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, and / or a pharmaceutical composition of the present invention for treating a disease mediated by a protein tyrosine kinase.

[0020] In one aspect, the present invention provides a method of treating a disease comprising administering a compound of 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, and / or a pharmaceutical composition of the present invention.

[0021] In one aspect, the present invention provides a method of modulating kinase receptor activity comprising administering a compound of 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, and / or a pharmaceutical composition of the present invention.

[0022] Those skilled in the art will readily appreciate other aspects and advantages of the present invention from the following detailed description. In the following detailed description, only exemplary embodiments of the present invention are shown and described. Those skilled in the art will recognize that the teachings of the present invention will enable those skilled in the art to make modifications to the particular embodiments disclosed without departing from the spirit and scope of the present invention. Accordingly, the present specification is intended to be illustrative and not restrictive. DETAILED DESCRIPTION OF THE INVENTION

[0023] Although the following describes embodiments of the present invention using certain specific embodiments, those familiar with the art can easily understand other advantages and effects of the present invention from the disclosure herein.

[0024] Term definition In the present invention, the term "basic nitrogen atom" generally refers to a nitrogen atom having basicity. For example, a basic nitrogen atom may have the ability to donate an unshared electron pair. A basic nitrogen atom is known in the art, for example, when the conjugate acid of the basic nitrogen atom has a pKa of higher than 3 or higher than 5. For example, a non-basic nitrogen atom may be an N atom directly bonded to O, an N atom directly bonded to an aryl ring, or an N atom directly bonded to a carbonyl group.

[0025] In the present invention, the term "methyl group" generally refers to a residue derived by removing a hydrogen atom from a group of one carbon atom. The methyl group may be substituted or unsubstituted, substituted or unsubstituted. The term "alkyl group" generally refers to a saturated, straight-chain or branched-chain aliphatic hydrocarbon group having a residue obtained by removing a hydrogen atom from the same or different carbon atoms of a parent alkane, and may include straight-chain or branched-chain groups of 1 to 20 carbon atoms. For example, alkyl groups containing 1 to 12 carbon atoms, such as 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-), 1,5-butyl (-CH2CH2CH2CH2CH2-), and the like. Alkyl groups can be substituted or unsubstituted, substituted or not, for example, when substituted, the substituents can be substituted at any available point of attachment, preferably the substituents are independently optionally selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, sulfhydryl groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocyclyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, and is substituted by one or more substituents selected from a heterocyclylalkoxy group, a cycloalkylthio group, a heterocyclylalkylthio group, and an oxo group, and is, for example, hydrogen, protium, 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, —SON2NH2, —OC(O)H, —N(H)SO2H, or C 1-6 It may be an aliphatic group.

[0026] In the present invention, the term "aryl group" generally refers to a group having a residue 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- to 14-membered all-carbon monocyclic or fused polycyclic ring (i.e., rings sharing adjacent pairs of carbon atoms) having a conjugated π-electron system, and can be 6- to 10-membered, such as benzene and naphthalene. The aryl ring can be fused to a heteroaryl, heterocyclyl, or cycloalkyl ring, where the ring connected to the parent structure is the aryl ring. The aryl group can be substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocyclylalkoxy, cycloalkylthio, and heterocyclylalkylthio.

[0027] In the present invention, the term "heteroaryl group" generally refers to a group having a residue 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 containing 1 to 4 heteroatoms or 5 to 14 ring atoms, where the heteroatoms may be selected from the group consisting of oxygen, sulfur, and nitrogen. The heteroaryl group may be 5 to 10-membered, 5-membered, or 6-membered, such as 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 fused to an aryl group, heterocyclyl group, or cycloalkyl ring, where the ring connected to the parent structure is a heteroaryl ring. Heteroarylene groups can be optionally substituted or unsubstituted, and when substituted, preferably the substituents are independently one or more groups selected from the group consisting of alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, sulfhydryl groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocyclylalkoxy groups, cycloalkylthio groups, and heterocyclylalkylthio groups.

[0028] In the present invention, the term "aliphatic heterocyclyl group" generally refers to a stable non-aromatic 3- to 7-membered monocyclic ring structure, a fused 7- to 10-membered bicyclic heterocyclyl structure, or a bridged 6- to 10-membered bicyclic heterocyclyl structure, which ring structures may be saturated or partially saturated and, in addition to carbon atoms, contain one or more heteroatoms in the ring structure, which may be selected from the group consisting of oxygen, sulfur, and nitrogen. For example, there may be 1 to 4 heteroatoms as defined above. When referring to an atom in a heterocyclyl ring structure, the term "nitrogen" may include the nitrogen at which a substitution reaction has occurred. A heterocyclylene group may be substituted or unsubstituted.

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

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

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

[0032] In the present invention, the term "aliphatic group" generally refers to a straight-chain hydrocarbon, branched-chain hydrocarbon, or cyclic hydrocarbon having 1 to 12 carbon atoms, or having one or more unsaturated units, but the unsaturated units are not aromatic. For example, the aliphatic group may include substituted or unsubstituted alkyl groups, alkenyl groups, alkynyl groups, and mixtures of these groups, each having a straight-chain, branched-chain, or cyclic structure, such as (cycloalkyl)alkyl groups, (cycloalkenyl)alkyl groups, or (cycloalkyl)alkenyl groups. For example, the aliphatic group may have 1 to 12, 1 to 8, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0033] As used herein, the term "optionally" or "optionally" means that something is possible, but not necessarily occurring, depending on the events or circumstances described below, and the statement includes cases where the events or circumstances 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 the statement includes 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 the present invention, the term "substituted" generally refers to one or more hydrogen atoms in a group, for example, up to 5, for example, 1 to 3 hydrogen atoms, each independently replaced with the corresponding number of substituents. Substituents are only required to be present in chemically feasible positions, and those skilled in the art can easily confirm (experimentally or theoretically) whether the substitution is possible or not. For example, an amino group or a hydroxy group having free hydrogen may be unstable when bonded to a carbon atom having an unsaturated bond (such as an olefinic bond).

[0035] One or more hydrogen atoms in the group, for example, up to 5, for example, 1 to 3 hydrogen atoms, are each independently replaced with the corresponding number of substituents. The substituents are only located in chemically feasible positions, and those skilled in the art can easily confirm (experimentally or theoretically) whether the substitution is possible or not. For example, an amino group or a hydroxy group having free hydrogen may be unstable when bonded to a carbon atom having an unsaturated bond (such as an olefinic bond).

[0036] In the present invention, the term "compound" generally refers to a substance containing two or more different elements. For example, the compound of the present invention may be an organic compound. For example, the compound of the present invention may have a molecular weight of 500 or less, a molecular weight of 1000 or less, a molecular weight of 1000 or more, a molecular weight of 10,000 or more, or a molecular weight of 100,000 or more. In the present invention, the term "compound" may also refer to a compound linked by a chemical bond. For example, the compound may be a compound in which one or more molecules with a molecular weight of 1000 or less are linked to a biopolymer by a chemical bond. The biopolymer may be a polymeric polysaccharide, protein, nucleic acid, polypeptide, or the like. The compound of the present 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 10,000 or less, or a compound obtained by linking a protein to one or more molecules with a molecular weight of 100,000 or less.

[0037] In some embodiments, the compounds of the present invention may be in a "mixture form," and a "mixture form" of a compound may be a composition that includes a compound of the present invention, its tautomers, endo-isomers, racemates, enantiomers, or diastereomers, or more thereof.

[0038] Unless otherwise stated, structures depicted herein may also include compounds that differ only in the presence or absence of one or more isotopically enriched atoms. For example, all compounds that otherwise correspond to the present structures except for the replacement of a hydrogen atom by deuterium or tritium, or the replacement of a carbon atom by carbon-13 or carbon-14 are within the scope of this invention.

[0039] In the present invention, the term "pharmaceutical composition" refers to a mixture of one or more compounds described in the present invention or their physiologically / medicinally acceptable salts or prodrugs with other chemical components, and other components such as physiologically / medicinally acceptable carriers and excipients. Pharmaceutical compositions can facilitate administration to living organisms and contribute to the absorption of active ingredients, thereby exerting biological activity. For the preparation of general pharmaceutical compositions, reference can be made to the Chinese Pharmacopoeia.

[0040] In the present invention, the term "pharmaceutically acceptable salt" or "pharmaceutically usable salt" generally refers to a salt of a compound or ligand-pharmaceutical composition of the present invention, or a salt of a compound described in the present invention, which may be safe and / or effective when administered to a mammal and may have the desired biological activity. The antibody-antibody-drug conjugate compound of the present invention may form a salt with an acid. 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 term "solvate" or "solvate" generally refers to a pharmaceutically acceptable solvate formed by a ligand-drug conjugate compound of the present invention with one or more solvent molecules, non-limiting examples of which include water, ethanol, acetonitrile, isopropyl alcohol, DMSO, and ethyl acetate. A "pharmaceutically acceptable prodrug" refers to a compound that can be converted under physiological conditions or by solvolysis into a specified compound or a pharmaceutically acceptable salt of such a compound. A "pharmaceutically active metabolite" refers to a pharmacologically active product produced by metabolism in the body of a specified compound or its salt. Metabolites of a compound can be identified using conventional techniques known in the art, and their activity can be confirmed using the assays described herein.

[0042] Pharmaceutical compositions may be in the form of sterile injectable aqueous or oily suspensions for intramuscular and subcutaneous administration. These may be formulated with suitable dispersing or wetting agents and suspending agents, as described above, according to known techniques. Sterile injectable preparations may also be sterile injectable solutions or suspensions prepared in a non-toxic, parenterally acceptable diluent or solvent, such as a solution prepared in 1,3-butanediol. Additionally, sterile, fixed oils are conveniently used as solvents or suspending media. For example, any mixed fixed oil containing synthetic monoglycerides or diacylglycerols may be used. Additionally, fatty acids such as oleic acid may also be used in the preparation of injectables. For ocular administration, the compounds of the present invention are delivered in a pharmaceutically acceptable ophthalmic carrier that maintains contact with the ocular surface for a time sufficient for the compound to penetrate the cornea and internal regions, including the anterior chamber, posterior chamber, vitreous body, aqueous humor, vitreous humor, cornea, iris / ciliary body, lens, choroid / retina, etc. The pharmaceutically acceptable ophthalmic carrier may be an ointment, vegetable oil, or an encapsulating material. The compounds of the invention may also be injected directly into the vitreous and aqueous humor.

[0043] As used herein, the term "comprising" generally refers to the inclusion of the expressly specified features without the exclusion of other elements. The terms "more than" and "less than" generally refer to an inclusive situation.

[0044] In the present invention, the term "about" generally refers to a variation within a range of 0.5% to 10% above or below the specified numerical value, for example, a variation within a 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 provides a method for producing a medicament for the treatment of a pulmonary arthritis, comprising: [ka] wherein R1 comprises a substituted cyclic structure, R2 comprises an optionally substituted substituent; R3 comprises an optionally substituted substituent; X1 is an optionally substituted atom; Provided are compounds of formula (I), or pharmaceutically acceptable prodrugs of said compounds, pharmaceutically active metabolites of said compounds, and / or pharmaceutically acceptable salts of said compounds.

[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 provides a method for producing a medicament for the treatment of a pulmonary arthritis, comprising: [ka] Here, the 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 where each R 1-0 , R 1-1 , R 1-2 , R 1-3 , R 1-4 , and R 1-5 each independently comprises an optionally substituted substituent, wherein nr0, nr1, nr2, nr3, nr4, and nr5 are each independently selected from 0 or more, and wherein the cyclic structure of R1 is substituted with a substituent containing a basic nitrogen atom; R2 comprises an optionally substituted substituent; R3 comprises an optionally substituted substituent; X1 is an optionally substituted atom; Provided are compounds of formula (I), or pharmaceutically acceptable prodrugs of said compounds, pharmaceutically active metabolites of said compounds, and / or pharmaceutically acceptable salts of said compounds.

[0049] In one aspect, the present invention provides a method for producing a medicament for the treatment of a pulmonary arthritis, comprising: [ka] Here, the 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 where each R 1-1 , R 1-2 , R 1-3 , R 1-4 , and R 1-5 each independently comprises an optionally substituted substituent, wherein nr0, nr1, nr2, nr3, nr4, and nr5 are each independently selected from 0 or more, and wherein the cyclic structure of R1 is substituted with a substituent containing a basic nitrogen atom; R2 comprises an optionally substituted substituent; R3 comprises an optionally substituted substituent; X1 is an optionally substituted atom; Provided are compounds of formula (I), or pharmaceutically acceptable prodrugs of said compounds, pharmaceutically active metabolites of said compounds, and / or pharmaceutically acceptable salts of said compounds.

[0050] In one aspect, the present invention provides a method for producing a medicament for the treatment of a pulmonary arthritis, comprising: [ka] Here, the 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 wherein nr0, nr1, nr2, nr3, nr4, and nr5 are each independently selected from 0 or more; Here, each R 1-1 is selected from the group consisting of optionally substituted aryl groups and optionally substituted heteroaryl ring groups, e.g., each R 1-1 is 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, e.g., each R 1-1 is 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, e.g., each R 1-1 is selected from the group consisting of optionally substituted aryl groups, optionally substituted pyridyl groups, and optionally substituted pyrazolyl groups; Here, each R 1-2is selected from the group consisting of a chemical bond and a hydroxy group, e.g., each R 1-2 may be - or -O-; Here, each R 1-3 is selected from optionally substituted alkyl groups, e.g., each R 1-3 can be an optionally substituted methyl group, an optionally substituted ethyl group, and an optionally substituted propyl group; Here, each R 1-4 is selected from optionally substituted aliphatic heterocyclyl groups, e.g., each R 1-4 can be an optionally substituted 5-membered aliphatic heterocyclyl group, and an optionally substituted 6-membered aliphatic heterocyclyl group, for example, each R 1-4 is selected from the group consisting of an optionally substituted 5-membered aliphatic heterocyclyl group containing one N atom, a 5-membered aliphatic heterocyclyl group containing two N atoms, a 6-membered aliphatic heterocyclyl group containing one N atom, and an optionally substituted 6-membered aliphatic heterocyclyl group containing two N atoms, e.g., each R 1-4 is selected from the group consisting of optionally substituted pyrrolyl groups, optionally substituted piperidinyl groups, and optionally substituted piperazinyl groups; Here, each R 1-5 is selected from optionally substituted alkyl groups, e.g., each R 1-5 can be an optionally substituted methyl group, for example, two R 1-5 may include R2 comprises an optionally substituted substituent; R3 comprises an optionally substituted substituent; X1 is an optionally substituted atom; Provided are compounds of formula (I), or pharmaceutically acceptable prodrugs of said compounds, pharmaceutically active metabolites of said compounds, and / or pharmaceutically acceptable salts of said compounds.

[0051] In one aspect, the present invention provides a method for producing a medicament for the treatment of a pulmonary arthritis, comprising: [ka] Here, the 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 wherein nr0, nr1, nr2, nr3, nr4, and nr5 are each independently selected from 0 or more; Here, each R 1-1 is selected from the group consisting of optionally substituted aryl groups and optionally substituted heteroaryl ring groups, e.g., each R 1-1 is selected from the group consisting of optionally substituted aryl groups, optionally substituted five-membered heteroaryl ring groups, and optionally substituted six-membered heteroaryl ring groups, e.g., each R 1-1 is 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, e.g., each R 1-1 is selected from the group consisting of optionally substituted aryl groups, optionally substituted pyridyl groups, and optionally substituted pyrazolyl groups; Here, each R 1-2 is selected from the group consisting of a chemical bond and a hydroxy group, e.g., each R 1-2 may be - or -O-; Here, each R 1-3 is selected from optionally substituted alkyl groups, e.g., each R 1-3 can be an optionally substituted methyl group, an optionally substituted ethyl group, and an optionally substituted propyl group; Here, each R 1-4 is selected from optionally substituted aliphatic heterocyclyl groups, e.g., each R 1-4can be an optionally substituted 5-membered aliphatic heterocyclyl group, and an optionally substituted 6-membered aliphatic heterocyclyl group, for example, each R 1-4 is selected from the group consisting of an optionally substituted 5-membered aliphatic heterocyclyl group containing one N atom, a 5-membered aliphatic heterocyclyl group containing two N atoms, a 6-membered aliphatic heterocyclyl group containing one N atom, and an optionally substituted 6-membered aliphatic heterocyclyl group containing two N atoms, e.g., each R 1-4 is selected from the group consisting of optionally substituted pyrrolyl groups, optionally substituted piperidinyl groups, and optionally substituted piperazinyl groups; Here, each R 1-5 is selected from optionally substituted alkyl groups, e.g., each R 1-5 can be an optionally substituted methyl group, for example, two R 1-5 may include R2 comprises an optionally substituted -S-optionally substituted aryl-optionally substituted amido-optionally substituted alkyl group, or an -S-optionally substituted aryl-optionally substituted amido-optionally substituted cycloaliphatic group, for example, R2 comprises an optionally substituted -S-optionally halogen substituted aryl-optionally substituted amido-optionally substituted methyl group, or an -S-optionally substituted aryl-optionally substituted amido-optionally substituted cyclopropyl group; R3 comprises hydrogen or any isotope of hydrogen; X1 is optionally substituted CH; Provided are compounds of formula (I), or pharmaceutically acceptable prodrugs of said compounds, pharmaceutically active metabolites of said compounds, and / or pharmaceutically acceptable salts of said compounds.

[0052] For example, the 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 where each R 1-0 , R 1-1 , R 1-2 , R 1-3 , R 1-4 , and R 1-5 each independently comprises an optionally substituted substituent, where nr0, nr1, nr2, nr3, nr4, and nr5 are each independently selected from 0 or more.

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

[0054] For example, the R 1-1 is a chemical bond or is selected from the group consisting of an optionally substituted amide group, an optionally substituted aryl ring group, and an optionally substituted heteroaryl ring group. 1-1 is a chemical bond or is 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 is 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, e.g., each R 1-1is 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, e.g., each R 1-1 is selected from the group consisting of optionally substituted aryl groups, optionally substituted pyridyl groups, and optionally substituted pyrazolyl groups. 1-1 is a chemical bond or is 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 is a chemical bond or is selected from the group consisting of hydrogen, protium, deuterium, tritium, and an optionally substituted hydroxy group. For example, each R 1-2 may 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 is a chemical bond or is selected from the group consisting of hydrogen, protium, deuterium, tritium, and optionally substituted alkyl groups. For example, 1-3 is a chemical bond or is selected from the group consisting of hydrogen, protium, deuterium, tritium, an optionally substituted methyl group, an optionally substituted ethyl group, and an optionally substituted propyl group. For example, each R 1-3 can be an optionally substituted methyl group, an optionally substituted ethyl group, and 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 1-4is a chemical bond or is selected from the group consisting of hydrogen, protium, deuterium, tritium, an optionally substituted amino group, and an optionally substituted aliphatic heterocyclyl group. 1-4 is a chemical bond or is selected from the group consisting of hydrogen, protium, 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 can be an optionally substituted 5-membered aliphatic heterocyclyl group and an optionally substituted 6-membered aliphatic heterocyclyl group, for example, each R 1-4 is selected from the group consisting of an optionally substituted 5-membered aliphatic heterocyclyl group containing one N atom, a 5-membered aliphatic heterocyclyl group containing two N atoms, a 6-membered aliphatic heterocyclyl group containing one N atom, and an optionally substituted 6-membered aliphatic heterocyclyl group containing two N atoms, e.g., 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. For example, said nr4 is 0 or 1. For example, nr4 is 0, 1, 2, or 3.

[0058] For example, the R 1-5 is a chemical bond or is selected from the group consisting of hydrogen, protium, deuterium, tritium, and optionally substituted alkyl groups. For example, 1-5 is a chemical bond or is selected from the group consisting of hydrogen, protium, deuterium, tritium, an optionally substituted methyl group, and an optionally substituted ethyl group. For example, each R 1-5 can be an optionally substituted methyl group, for example, two R 1-5 For example, nr5 is 0, 1, or 2. For example, nr5 is 0, 1, 2, or 3.

[0059] For example, R2 is an optionally substituted sulfhydryl group. For example, R2 is one or more R 2-1and each R is substituted by 2-1 are each independently an optionally substituted substituent. For example, 2-1 is an optionally substituted aryl group. For example, 2-1 is an optionally substituted phenyl group.

[0060] For example, the R 2-1 but one or more R 2-2 and each R is substituted by 2-2 are each independently an optionally substituted substituent. For example, 2-2 is selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, optionally substituted carbonyl group, optionally substituted carboxyl group, optionally substituted amido group, and optionally substituted alkyl group. 2-2 is selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, an optionally substituted carbonyl group, an optionally substituted carboxyl group, an optionally substituted amido group, and an optionally substituted methyl group.

[0061] For example, the R 2-2 but one or more R 2-3 and each R is substituted by 2-3 are each independently an optionally substituted substituent. For example, 2-3 is selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, optionally substituted alkyl groups, optionally substituted alicyclic groups, and optionally substituted amino groups. 2-3 is selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, an optionally substituted methyl group, an optionally substituted ethyl group, an optionally substituted cyclopropyl group, and an optionally substituted amino group.

[0062] For example, the R 2-3 but one or more R 2-4 and each R is substituted by 2-4are each independently an optionally substituted substituent. For example, 2-4 is selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, optionally substituted alkyl groups, and optionally substituted alicyclic groups. 2-4 is selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, an optionally substituted methyl group, an optionally substituted ethyl group, and an optionally substituted cyclopropyl group.

[0063] For example, R2 comprises an optionally substituted -S-optionally substituted aryl group-optionally substituted amido group-optionally substituted alkyl group, or an -S-optionally substituted aryl group-optionally substituted amido group-optionally substituted alicyclic group, e.g., R2 comprises an optionally substituted -S-optionally halogen substituted aryl group-optionally substituted amido group-optionally substituted methyl group, or an -S-optionally substituted aryl group-optionally substituted amido group-optionally substituted cyclopropyl group, e.g., R2 comprises an optionally substituted -SF substituted or unsubstituted aryl group-amido group-methyl group, or -SF substituted or unsubstituted aryl amido group-cyclopropyl group.

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

[0065] For example, said X1 is selected from the group consisting of optionally substituted CH, and N. For example, X1 is optionally substituted CH.

[0066] In some embodiments of the invention, the compound has the following structure: [ka] (II) where: Ring A is a 5- to 7-membered nitrogen-containing heterocyclyl, Ring B is a 5- to 7-membered aryl ring or heterocyclyl; Z is -C(O)NH-, -NHC(O)- or [ka] and Ring E is an aryl ring or a heteroaryl ring; L0 is O, S, N(R La ), a C1-C6 alkylene group, and C(O), and R La is selected from H, a C1-C6 alkyl group, L1 is selected from a single bond, a C1-C6 alkylene group, a C2-C6 alkenylene group, a C2-C6 alkynylene group, and -(C0-C6 alkylene group)-Q1-(C0-C6 alkylene group)-, and Q1 is -O-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -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)—, wherein the H atoms in said alkylene groups are optionally selected from H, C-C 10 Alkyl groups, C2-C 10 Alkenyl groups, C2-C 10 Alkynyl group, halogen, cyano group, nitro group, azide group, C1-C 10 Halogen-substituted alkyl groups, hydroxy groups, C1-C 10 Alkoxy groups, C1-C 10 Halogen-substituted alkoxy groups, amino groups, C1-C 10 may be substituted by an alkylamino group, R Lb But, H, C1-C 10 Alkyl groups, C2-C 10 Alkenyl groups, C2-C 10 Alkynyl groups, C3-C 10Cycloalkyl groups, C3-C 10 Cycloalkylalkyl groups, C6-C 10 Aryl groups, C7-C 12 selected from an arylalkyl group, a 4- to 10-membered heterocyclyl group, and a 4- to 10-membered heterocyclylalkyl group; 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)—, wherein the H atoms in said alkylene groups are optionally selected from H, C-C 10 Alkyl groups, C2-C 10 Alkenyl groups, C2-C 10 Alkynyl group, halogen, cyano group, nitro group, azide group, C1-C 10 Halogen-substituted alkyl groups, hydroxy groups, C1-C 10 Alkoxy groups, C1-C 10 Halogen-substituted alkoxy groups, amino groups, C1-C 10 may be substituted by an alkylamino group, R Lc But, H, C1-C 10 Alkyl groups, C2-C 10 Alkenyl groups, C2-C 10 Alkynyl groups, C3-C 10 Cycloalkyl groups, C3-C 10 Cycloalkylalkyl groups, C6-C 10 Aryl groups, C7-C 12 selected from an arylalkyl group, a 4- to 10-membered heterocyclyl group, and a 4- to 10-membered heterocyclylalkyl group; Y is selected from H, —NR7R8, a nitrogen-containing heterocyclyl group, wherein said nitrogen-containing heterocyclyl group can be optionally substituted by one or more R9 groups, and R9 is selected from halogen, cyano, amino, hydroxy, C1-C 10 Alkyl groups, C1-C 10 Halogen-substituted alkyl groups, C1-C 10 Alkoxy groups, C1-C 10 Halogen-substituted alkoxy groups, C1-C 10 Alkylamino groups, C1-C 10 Cyanoalkyl groups, C1-C 10 Hydroxy-substituted alkyl groups, C1-C 10 Alkoxy-substituted alkyl groups, C1-C 10 Alkylamino-substituted 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 cycloalkyl groups), R7 and R8 are independently H, C1-C 10 Alkyl groups, C2-C 10 Alkenyl groups, C2-C 10 Alkynyl groups, C3-C 10 Cycloalkyl groups, C3-C 10cycloalkylalkyl group, 4- to 10-membered heterocyclyl group, 4- to 10-membered heterocyclylalkyl group, wherein said C1-C 10 Alkyl groups, C2-C 10 Alkenyl groups, C2-C 10 Alkynyl groups, C3-C 10 Cycloalkyl groups, 4-10 membered heterocyclyl groups are optionally H, C-C 10 Alkyl groups, C2-C 10 Alkenyl groups, C2-C 10 Alkynyl groups, C3-C 10 Cycloalkyl groups, C3-C 10 Cycloalkylalkyl groups, C6-C 10 Aryl groups, C7-C 12 may be substituted by a group selected from one or more of an arylalkyl group, a 4- to 10-membered heterocyclyl group, and a 4- to 10-membered heterocyclylalkyl group; R4 is one or more independent substituents on the benzene ring, each R4 independently being H, halogen, C1-C 10 Alkyl group, cyano group, C1-C 10 Halogen-substituted alkyl groups, C1-C 10 Halogen-substituted alkoxy groups, 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 cycloalkyl groups), wherein the C0-C6 alkylene group, C1-C 10 Alkyl groups, C2-C 10 Alkenyl groups, C2-C 10 Alkynyl groups, C3-C 10 Cycloalkyl groups, C6-C 10 The aryl group, the 4- to 10-membered heterocyclyl group, optionally containing halogen, cyano group, amino group, hydroxy group, C1-C 10 Alkyl groups, C1-C 10 Halogen-substituted alkyl groups, C1-C 10 Alkoxy groups, C1-C 10 Halogen-substituted alkoxy groups, C1-C 10 Alkylamino groups, C1-C 10 Cyanoalkyl groups, C1-C 10 Hydroxy-substituted alkyl groups, C1-C 10 Alkoxy-substituted alkyl groups, C1-C 10 Alkylamino-substituted 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 cycloalkyl groups), R 401 and R 402 However, independently, H, C1-C 10 Alkyl groups, C3-C 10 Cycloalkyl groups, C3-C 10 Cycloalkylalkyl groups, C6-C 10 Aryl groups, C6-C 10 selected from an arylalkyl group, a 4- to 10-membered heterocyclyl group, and a 4- to 10-membered heterocyclyl alkyl group; R5, [ka] one or more independent substituents on the ring, each R5 independently being H, halogen, cyano, amino, hydroxy, C1-C 10 Alkyl groups, C1-C 10 Halogen-substituted alkyl groups, C1-C 10 Alkoxy groups, C1-C 10 Halogen-substituted alkoxy groups, C1-C 10 Alkylamino groups, C1-C 10 Cyanoalkyl groups, C1-C 10 Hydroxy-substituted alkyl groups, C1-C 10 Alkoxy-substituted alkyl groups, C1-C 10Alkylamino-substituted 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 cycloalkyl groups), R6 is one or more independent substituents on the E ring, and each R6 is independently H, halogen, cyano, amino, hydroxy, C1-C 10 Alkyl groups, C1-C 10 Halogen-substituted alkyl groups, C1-C 10 Alkoxy groups, C1-C 10 Halogen-substituted alkoxy groups, C1-C 10 Alkylamino groups, C1-C 10 Cyanoalkyl groups, C1-C 10 Hydroxy-substituted alkyl groups, C1-C 10 Alkoxy-substituted alkyl groups, C1-C 10 Alkylamino-substituted 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 cycloalkyl groups).

[0067] In some embodiments of the present invention, the A ring is a 5-membered nitrogen-containing heteroaryl ring, such as [ka] , [ka] , [ka] , [ka] , [ka] is.

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

[0069] In some embodiments of the present invention, [ka] The structure of the part is [ka] , [ka] , [ka] , [ka] , [ka] , [ka] In particular, [ka] , [ka] , [ka] , [ka] , [ka] is.

[0070] In some embodiments of the present invention, [ka] Part [ka] wherein 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 heterocyclyl group, wherein said nitrogen-containing heterocyclyl group can be optionally substituted by one or more R9 groups.

[0071] In some embodiments of the present invention,

[0072] [ka] Part [ka] and Y is selected from H, —NR 7 R 8 , a nitrogen-containing heterocyclyl group, wherein said nitrogen-containing heterocyclyl group can be optionally substituted by one or more R 9 groups.

[0073] In some embodiments of the present invention, [ka] Part [ka] and Y is selected from H, —NR 7 R 8 , a nitrogen-containing heterocyclyl group, wherein said nitrogen-containing heterocyclyl group can be optionally substituted by one or more R 9 groups.

[0074] In some embodiments of the present invention, [ka] Part [ka] and Y is selected from H, —NR 7 R 8 , a nitrogen-containing heterocyclyl group, wherein said nitrogen-containing heterocyclyl group can be optionally substituted by one or more R 9 groups.

[0075] In some embodiments of the present invention, [ka] Part [ka] and Y is selected from H, —NR 7 R 8 , a nitrogen-containing heterocyclyl group, wherein said nitrogen-containing heterocyclyl group can be optionally substituted by one or more R 9 groups.

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

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

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

[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 invention, L is NH, Z is -NHC(O)-, and the compound has the following structure: [ka] (III-1) wherein L2 is selected from a C1-C6 alkylene group, -(C1-C6 alkylene group)-Q2-(C1-C6 alkylene group)-, and Y is -NR7R8 or an optionally substituted nitrogen-containing heterocyclyl group, wherein the nitrogen-containing heterocyclyl group may be optionally substituted by one or more R9 groups.

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

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

[0087] In some embodiments of the present invention, L1 is a C2-C6 alkenylene group, such as: [ka] , [ka] , [ka] ,especially [ka] is.

[0088] In some embodiments of the present invention, L1 is a C2-C6 alkynylene group, such as: [ka] , [ka] , [ka] ,especially [ka] is.

[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 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 invention, the E ring is a benzene ring or a 5- 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 -NR7R8 or an optionally substituted nitrogen-containing heterocyclyl group, where the nitrogen-containing heterocyclyl group can be optionally substituted by one or more R9 groups.

[0094] In some embodiments of the present invention, [ka] The moiety 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, amino, hydroxy, C1-C6 alkyl, and C1-C6 halogen-substituted alkyl.

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

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

[0098] In some embodiments of the invention, L2 is a C1-C6 alkylene group, such as [ka] , [ka] , [ka] is.

[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 )-, and R Lc is selected from H, C1-C3 alkyl groups, especially H.

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

[0102] In some embodiments of the present invention, ring E is a 5- 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, where R7 and R8 are independently selected from H, a C1-C6 alkyl group, or a -(C0-C6 alkylene group)-(C3-C6 cycloalkyl group), e.g., [ka] , [ka] Selected from.

[0104] In some embodiments of the invention, Y is a nitrogen-containing heterocyclyl group, optionally substituted by one or more R9, particularly said nitrogen-containing heterocyclyl group is a 4-8 membered saturated heterocyclyl, such as [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] is.

[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] (wherein the substitution position of R9 can be on any suitable carbon or nitrogen atom), and more specifically, Y is selected from: [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] Selected from.

[0106] In some embodiments of the invention, R9 is H, a C1-C6 alkyl group (e.g., -CH3, [ka] , [ka] , [ka] ), C1-C6 hydroxy-substituted alkyl groups (e.g., [ka] , [ka] ), C1-C6 amino group-substituted alkyl groups (e.g., [ka] , [ka] ), C1-C6 alkoxy-substituted alkyl groups (e.g., [ka] , [ka] ), C1-C6 alkylamino-substituted alkyl groups (e.g., [ka] , [ka] , [ka] , [ka] ), -(C0-C6 alkylene group)-(C3-C6 cycloalkyl group) (e.g., [ka] , [ka] , [ka] , [ka] ) are selected.

[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 is, [ka] , [ka] or [ka] where: R 4a But -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 are independently selected from H, a C1-C6 alkyl group, and a —(C0-C6 alkylene group)-(C3-C6 cycloalkyl group), wherein the C0-C6 alkylene group, the C1-C6 alkyl group, and the C3-C6 cycloalkyl group are optionally substituted by one or more groups selected from a halogen, a cyano group, an amino group, a hydroxy group, a C1-C6 alkyl group, and a C1-C6 halogen-substituted alkyl group; R 4b are one or more independent substituents on the benzene ring, selected from H, halogen, cyano, amino, hydroxy, C1-C6 alkyl, and C1-C6 halogen-substituted alkyl.

[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 But it's H.

[0111] In some embodiments of the present invention, R 4b 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] is.

[0113] In one aspect, the present invention provides a method for producing a medicament for the treatment of a pulmonary arthritis, comprising: [ka] , [ka] , [ka] , [ka] , [ka] ,

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[0114] In one aspect, the present invention provides a method for producing a medicament for the treatment of a pulmonary arthritis, comprising: [ka] , [ka] , [ka] ,

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[0115] In one aspect, the present invention provides a method for producing a medicament for the treatment of a pulmonary arthritis, comprising: [ka] ,

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[0116] In one aspect, the present invention provides a method for producing a medicament for the treatment of a pulmonary arthritis, comprising: [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] ,

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[0117] In one aspect, the present invention provides a method for producing a medicament for the treatment of a pulmonary arthritis, comprising: [ka] TIFF2025528048000394.tif127170, or a pharmaceutically acceptable prodrug of said compound, a pharmaceutically active metabolite of said compound, and / or a pharmaceutically acceptable salt of said compound.

[0118] Pharmaceutical Composition In one aspect, the present invention provides a pharmaceutical composition comprising a compound of 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, and optionally a 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, excipients, etc. Depending on the method of administration, the composition may contain 0.1 to 99% by weight of the active compound.

[0120] Pharmaceutical compositions containing the active ingredient may be in a form suitable for administration to the eye, such as an aqueous or oily suspension, a dispersible powder or granules, an emulsion or a slurry, etc. Ophthalmic compositions can be prepared according to any method known in the art for preparing pharmaceutical compositions, and the compositions may include adhesives, fillers, lubricants, disintegrants, or pharmaceutically acceptable wetting agents, etc., and the compositions may also contain additives selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives.

[0121] Aqueous suspensions may contain the active substance and excipients that are suitable for mixing with the aqueous suspension. In addition, aqueous suspensions may contain one or more preservatives, such as one or more coloring agents, one or more flavoring agents, and one or more sweetening agents. Oily suspensions may be prepared by suspending the active ingredient in vegetable oil. Oily suspensions may contain thickening agents.

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

[0123] Specifically, the pharmaceutical composition may be in any suitable dosage form, including, but not limited to, gastrointestinal dosage forms, gastrointestinal dosage forms, and parenteral dosage forms, such as injections (e.g., subcutaneous, intravenous, intramuscular, and intraperitoneal), respiratory dosage forms such as sprays, aerosols, and powder mists, dermal dosage forms such as topical solutions, lotions, ointments, plasters, pastes, patches, and patches, mucosal dosage forms such as eye drops, eye ointments, nasal drops, mouthwashes, and sublingual tablets, and intracavity dosage forms such as suppositories, aerosols, effervescent tablets, drops, and drop pills for use in the rectum, vagina, urethra, nose, and ear canal.

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

[0125] In one aspect, the present invention provides the use of a compound of 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, and / or a pharmaceutical composition of the present invention in the preparation of a medicament for the treatment of a disease.

[0126] In one aspect, the present invention provides a compound of 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, and / or a pharmaceutical composition of the present invention for the treatment of a disease.

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

[0128] In some embodiments of the invention, the disease is an ocular disease, including, but not limited to, ocular diseases such as pathological neovascularization, retinal ischemia, retinal edema, diabetic retinopathy, etc., and proliferative diseases associated with malignant tumors.

[0129] In some embodiments of the 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 any pathological mechanism (i.e., high myopia, trauma, sickle cell anemia, ocular histoplasmosis, angioid streaks, traumatic choroidal rupture, optic nerve head drusen, and certain retinal dystrophies ... The ocular diseases include, but are not limited to, pathologic subretinal neovascularization (i.e., sickle cell retinopathy, Eales' disease, ocular ischemia syndrome, internal carotid artery cavernous fistula, familial exudative vitreoretinopathy, hyperviscosity syndrome, idiopathic obliterative microarteritis, birdshot retinochoroidopathy, retinal vasculitis, sarcoidosis, or toxoplasmosis), uveitis, retinal vein occlusion (central or branch), ocular trauma, surgical edema, surgical neovascularization, cystoid macular edema, ocular ischemia, retinopathy of prematurity, Coat's disease, sickle cell retinopathy, and / or neovascular glaucoma.

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

[0131] In some embodiments of the 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 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, particularly a malignant tumor (cancer), including, but not limited to, breast cancer, lung cancer (particularly non-small cell lung cancer), adenocarcinoma, colorectal cancer, renal cancer, liver cancer, pancreatic adenocarcinoma, ovarian cancer, prostate cancer, glioma, glioblastoma, myeloma, acute myeloid leukemia, myeloid metaplasia of unknown cause, mesothelioma, and myelodysplastic syndrome.

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

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

[0136] Specifically, lymphomas include Hodgkin's lymphoma (HL) and non-Hodgkin's 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's lymphoma, lymphoplasmacytic lymphoma, hairy cell leukemia (HCL), immunoblastic leukemia, precursor B-cell lymphoma, and leukemia-associated lymphoma. The tumor may be 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, enteropathic T-cell lymphoma, subcutaneous lipid membrane inflammatory T-cell lymphoma, anaplastic large cell lymphoma, NK / T-cell lymphoma, and, in particular, diffuse large B-cell lymphoma (DLBCL). Specifically, in the use, tumor treatment includes killing tumors and preventing the metastatic spread of tumors and the growth of micrometastases.

[0137] In one aspect, the present invention provides a method of treating a disease comprising administering a compound of 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, 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 various factors, including, but not limited to, the activity of the specific compound used, the patient's age, the patient's weight, the patient's health condition, the patient's behavior, the patient's diet, the administration time, the administration method, the excretion rate, the combination of drugs, etc. Furthermore, for the optimal treatment, such as the treatment mode, the type of the above-mentioned compound of the present invention or its tautomer, endo isomer, racemate, enantiomer, diastereomer or mixed form thereof, or a pharmaceutically acceptable salt thereof, and / or the compound or its tautomer, endo isomer, racemate, enantiomer, diastereomer or mixed form thereof, or a pharmaceutically acceptable daily dose or a pharmaceutically acceptable salt thereof can be verified according to conventional treatment methods.

[0139] In one aspect, the present invention provides a method of modulating kinase receptor activity comprising administering a compound of 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, and / or a pharmaceutical composition of the present invention.

[0140] For example, the method inhibits the activity of a kinase receptor. The compound described in the present invention has inhibitory activity against the in vitro proliferation of a kinase receptor. The inhibitory activity can be a decrease of 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 after addition of the compound of the present invention, compared to a negative control or a control drug. For example, the inhibitory activity can be a decrease of the IC of kinase receptor activity. 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 RI may be 0.5 or less, 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, the inhibition of 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 a functionally active fragment thereof, particularly VEGFR. For example, the method is a non-therapeutic and / or non-diagnostic method. For example, the method is an in vitro and / or ex vivo method.

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

[0143] In one aspect, the present invention provides a method for inhibiting the formation of ocular neovascularization, retinal extravasation, comprising administering a compound of 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, and / or a pharmaceutical composition of the present invention.

[0144] Specifically, the administration may be by any suitable method, particularly intraocular administration, such as eye drops, eye ointment, subconjunctival injection, or intraocular injection, particularly eye drops.

[0145] Without being bound by any theory, the following examples are not intended to limit the scope of the present invention, but are intended only to illustrate the compounds, methods of preparation, and uses of the present invention.

[0146] Example Table 1. Information on compounds of the present invention [Table 1] TIFF2025528048000396.tif255170TIFF2025528048000397.tif255170TIFF2025528048000398.tif23517 0TIFF2025528048000399.tif255170TIFF2025528048000400.tif254170TIFF2025528048000401.tif25317 0TIFF2025528048000402.tif238170TIFF2025528048000403.tif231170TIFF2025528048000404.tif24117 0TIFF2025528048000405.tif245170TIFF2025528048000406.tif250170TIFF2025528048000407.tif58170

[0147] Example 1 [ka]

[0148] Step 1 A solution of 6-bromopyridin-3-ol 1a (10 g, 57.47 mmol) in N,N-dimethylformamide (150 mL) was added with 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) at room temperature under nitrogen gas protection. The mixture was heated to 85 °C and stirred for approximately 16 h. After confirming complete reaction by thin-layer chromatography (petroleum ether / ethyl acetate = 1 / 1), the mixture was poured into water (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate=10 / 1-1 / 1) to give a white solid 6-vinylpyridin-3-ol 1c (4.3 g, 35.50 mmol, yield 61.76%).

[0149] The product was confirmed by LCMS 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 To a solution of N-methyl-2-mercaptobenzamide 1e (13 g, 77.74 mmol) in N,N-dimethylformamide (250 mL), 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 at room temperature. The mixture was heated to 80 °C and stirred for approximately 2 h. After confirming complete reaction by thin-layer chromatography (dichloromethane / methanol = 15 / 1), the mixture was poured into water (1000 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 2 / 1 to 0 / 1) to give a yellow solid, 2-(1H-indazol-6-ylthio)-N-methylbenzamide 1f (8.3 g, yield 37.7%).

[0152] The product was confirmed by LCMS 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 To a solution of 2-(1H-indazol-6-ylthio)-N-methylbenzamide 1f in N,N-dimethylformamide at 0 °C, K2CO3 (6.83 g, 49.4 mmol) and I2 (10.66 g, 42.0 mmol) were added and the mixture was allowed to react at room temperature for approximately 3.5 hours. After confirming complete reaction of the starting materials by thin layer chromatography (dichloromethane / methanol = 15 / 1), the mixture was poured into water (1000 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layer was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product 2-[(3-iodo-1H-indazol-6-yl)thio]-N-methylbenzamide 1g (8.8 g, 87.0%).

[0156] The product was confirmed by LCMS 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 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 2-[(3-iodo-1H-indazol-6-yl)thio]-N-methylbenzamide (1 g, 2.44 mmol) in THF (20 mL) at room temperature, and the mixture was stirred and refluxed for 16 hours. After confirming complete reaction of the starting materials 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, and concentrated to give the crude product. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1- / 5 / 1-3 / 1-1 / 1) to give a white solid, 2-(3-iodo-1-tetrahydropyran-2-yl-indazol-6-yl)thio-N-methyl-benzamide 1h (650 mg, 1.32 mmol, 53.92% yield).

[0160] The product was confirmed by LCMS 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 A solution of 2-(3-iodo-1-tetrahydropyran-2-yl-indazol-6-yl)thio-N-methyl-benzamide 1h (500 mg, 1.01 mmol) in 1,4-dioxane (10 mL) was added to 6-vinylpyridin-3-ol 1c (147.3 mg, 1.22 mmol), triethylamine (307.7 mg, 3.04 mmol), Pd(dba) (464 mg, 506.73 μmol), and P(o-tol) (308.5 mg, 1.01 mmol) at room temperature under nitrogen gas protection. After confirming complete reaction by thin-layer chromatography (20:1 dichloromethane / methanol), the mixture was poured into water (20 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, and concentrated to give the crude product. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 30 / 1-1 / 1) to give a yellow solid, 2-[3-[(E)-2-(5-hydroxy-2-pyridyl)vinyl]-1-tetrahydropyran-2-yl-indazol-6-yl]thio-N-methyl-benzamide 1i (400 mg, 822.06 μmol, yield 81.11%), and the product purity was confirmed to be approximately 30% by LCMS.

[0164] The product was confirmed by LCMS.

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

[0166] Step 6 Trifluoroacetic acid (35.2 mg, 308.27 μmol, 23.75 μL) was added to a solution of 2-[3-[(E)-2-(5-hydroxy-2-pyridyl)vinyl]-1-tetrahydropyran-2-yl-indazol-6-yl]thio-N-methyl-benzamide 1i (150 mg, 308.27 μmol) in dichloromethane (3 mL) at room temperature, and the mixture was stirred at 35 °C for 16 hours. After confirming complete reaction of the starting materials by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (40 mL), adjusted to pH 8-9 with solid sodium carbonate, and extracted with DCM (30 mL x 3). The combined organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by preparative thin layer chromatography to give a white solid, 2-({3-[(E)-2-(5-hydroxypyridin-2-yl)vinyl]-1H-indazol-6-yl}thio)-N-methylbenzamide I-10 (6.1 mg, 15.16 μmol, 4.92% yield).

[0167] The product was confirmed by LCMS 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, 2-[3-[(E)-2-(5-hydroxy-2-pyridyl)vinyl]-1-tetrahydropyran-2-yl-indazol-6-yl]thio-N-methyl-benzamide 1i (400 mg, 822.06 μmol) in tetrahydrofuran (10 mL) was added with 2-(hydroxymethyl)pyrrolidine-1-carboxylic acid 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 the complete reaction of the starting material by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (30 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by preparative thin-layer chromatography (dichloromethane / methanol = 10 / 1) to give a white solid, 2-[[6-[(E)-2-[6-[2-(methylcarbamoyl)phenyl]thio-1-tetrahydropyran-2-yl-indazol-3-yl]vinyl]-3-pyridyl]oxymethyl]pyrrolidine-1-carboxylic acid tert-butyl ester 2b (400 mg, 597.17 μmol, 72.64% yield), which was confirmed to be approximately 29% pure by LCMS.

[0172] The product was confirmed by LCMS.

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

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

[0175] The product was confirmed by LCMS, 1HNMR and 1CNMR.

[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] 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-yl-indazol-6-yl]thio-N-methyl-benzamide 1i (400 mg, 822.06 μmol) in tetrahydrofuran (5 mL) was added with (1-methylpyrrolidin-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 the mixture was stirred at 30°C for about 16 hours. After confirming the complete reaction of the starting material 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, and concentrated to give the crude product. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1 - dichloromethane / methanol = 10 / 1) to give a yellow solid, N-methyl-2-[3-[(E)-2-[5-[(1-methylpyrrolidin-2-yl)methoxy]-2-pyridyl]vinyl]-1-tetrahydropyran-2-ylindol-6-yl]thiobenzamide 3b (240 mg, 411.14 μmol, 50.01% yield).

[0180] The product was confirmed by LCMS.

[0181] MS-ESI calculated value 584.3, actual value 584.3.

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

[0183] The product was confirmed by LCMS, 1HNMR and 1CNMR.

[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 To a solution of 2-[3-[(E)-2-(5-hydroxy-2-pyridyl)vinyl]-1-tetrahydropyran-2-yl-indazol-6-yl]thio-N-methyl-benzamide 1i (400 mg, 822.06 μmol) in tetrahydrofuran (5 mL), 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) were added at room temperature under nitrogen gas protection, and the mixture was allowed to react with stirring at 30°C for approximately 16 hours. After confirming the complete reaction of the starting material by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by preparative thin-layer chromatography (dichloromethane / methanol = 10 / 1) to give a white solid, N-methyl-2-[3-[(E)-2-[5-[2-(1-methyl-4-piperidinyl)ethoxy]-2-pyridyl]vinyl]-1-tetrahydropyran-2-yl-indazol-6-yl]thiobenzamide 4b (120 mg, 196.14 μmol, 23.86% yield).

[0188] The product was confirmed by LCMS.

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

[0190] Step 2 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-indazol-6-yl]thiobenzamide 4b (120 mg, 196.14 μmol) in dichloromethane (5 mL) at room temperature. The mixture was stirred at 40 °C for 16 h. After confirming complete reaction of the starting materials by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (10 mL), adjusted to pH 8-9 with solid sodium carbonate, and extracted with DCM (10 mL × 3). The combined organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by preparative thin layer chromatography to give a white solid, N-methyl-2-({3-[(E)-2-{5-[2-(1-methylpiperidin-4-yl)ethoxy]pyridin-2-yl}vinyl]-1H-indazol-6-yl}thio)benzamide I-5 (17 mg, 32.22 μmol, 16.42% yield).

[0191] The product was confirmed by LCMS, 1HNMR and 1CNMR.

[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 A solution of 2-[3-[(E)-2-(5-hydroxy-2-pyridyl)vinyl]-1-tetrahydropyran-2-yl-indazol-6-yl]thio-N-methyl-benzamide 1i (400 mg, 822.06 μmol) in tetrahydrofuran (5 mL) was added with (1-methylpyrrolidin-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) at room temperature under nitrogen gas protection. The mixture was stirred at 30 °C for approximately 16 hours. After confirming complete reaction by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by preparative thin-layer chromatography (dichloromethane / methanol = 10 / 1) to give a white solid, N-methyl-2-[3-[(E)-2-[5-[(1-methylpyrrolidin-3-yl)methoxy]-2-pyridyl]vinyl]-1-tetrahydropyran-2-ylindol-6-yl]thiobenzamide 5b (170 mg, 291.22 μmol, yield 35.43%).

[0196] The product was confirmed by LCMS.

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

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

[0199] The product was confirmed by LCMS, 1HNMR and 1CNMR.

[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 A solution of 2-[3-[(E)-2-(5-hydroxy-2-pyridyl)vinyl]-1-tetrahydropyran-2-yl-indazol-6-yl]thio-N-methyl-benzamide 1i (500 mg, 1.03 mmol) in tetrahydrofuran (5 mL) was added to 2-(4-methylpiperazin-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) at 0 °C under nitrogen gas protection. The mixture was stirred at 30 °C for approximately 16 h. After confirming complete reaction by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (30 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layer was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by preparative thin-layer chromatography (dichloromethane / methanol = 10 / 1) to give a yellow solid, N-methyl-2-[3-[(E)-2-[5-[2-(4-methylpiperazin-1-yl)ethoxy]-2-pyridyl]vinyl]-1-tetrahydropyran-2-yl-indazol-6-yl]thiobenzamide 6b (400 mg, 652.76 μmol, yield 63.52%).

[0204] The product was confirmed by LCMS.

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

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

[0207] The product was confirmed by LCMS, 1HNMR and 1CNMR.

[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 A solution of 2-[3-[(E)-2-(5-hydroxy-2-pyridyl)vinyl]-1-tetrahydropyran-2-yl-indazol-6-yl]thio-N-methyl-benzamide 1i (750 mg, 1.54 mmol) in tetrahydrofuran (5 mL) was added with 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) at 0 °C under nitrogen gas protection. The mixture was stirred at 40 °C for approximately 16 h. After confirming complete reaction by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (30 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layer was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1 to 0 / 1) to give a white solid, 3-[[6-[(E)-2-[6-[2-(methylcarbamoyl)phenyl]thio-1-tetrahydropyran-2-yl-indazol-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, found 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 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-yl-indazol-3-yl]vinyl]-3-pyridyl]oxymethyl]pyrrolidine-1-carboxylic acid tert-butyl ester 7b (100 mg, 149.29 μmol) in dichloromethane (4 mL) at room temperature. The mixture was stirred at room temperature for approximately 2 hours. After confirming complete reaction of the starting materials by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (10 mL), adjusted to pH 8-9 with solid sodium carbonate, and extracted with ethyl acetate (10 mL × 3). The combined organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by preparative thin layer chromatography to give a white solid, N-methyl-2-(3-[(E)-2-{5-[(pyrrolidin-3-yl)methoxy]pyridin-2-yl}vinyl]-1H-indazol-6-yl}thio)benzamide I-7 (18 mg, 37.07 μmol, 24.83% yield).

[0216] The product was confirmed by LCMS, 1HNMR and 1CNMR.

[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 A solution of 2-[3-[(E)-2-(5-hydroxy-2-pyridyl)vinyl]-1-tetrahydropyran-2-yl-indazol-6-yl]thio-N-methyl-benzamide 1i (400 mg, 822.06 μmol) in tetrahydrofuran (10 mL) was added to [(3S)-1-methylpyrrolidin-3-yl]methanol 8a (114 mg, 986.47 μmol), Ph3P (501 mg, 1.91 mmol), and DIAD (249 mg, 1.23 mmol) at room temperature under nitrogen gas protection. After confirming complete reaction by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (50 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layer was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by preparative thin-layer chromatography to give a white solid, N-methyl-2-[1-methyl-3-[(E)-2-[5-[(3S)-1-methylpyrrolidin-3-yl]methoxy]-2-pyridyl]vinyl]indazol-6-yl]thiobenzamide 8b (300 mg, 513.93 μmol, 62.52% yield).

[0221] The product was confirmed by LCMS.

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

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

[0224] The product was confirmed by LCMS, 1HNMR and 1CNMR.

[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 A solution of 2-[3-[(E)-2-(5-hydroxy-2-pyridyl)vinyl]-1-tetrahydropyran-2-yl-indazol-6-yl]thio-N-methyl-benzamide 1i (500 mg, 1.03 mmol) in tetrahydrofuran (10 mL) was added with [(3R)-1-methylpyrrolidin-3-yl]methanol 9a (142 mg, 1.23 mmol), Ph3P (501 mg, 1.91 mmol), and DIAD (386.5 mg, 1.91 mmol) at 0 °C under nitrogen gas protection. After confirming complete reaction of the starting materials by thin-layer chromatography (petroleum ether / ethyl acetate = 1 / 1), the mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1) to give a yellow solid, N-methyl-2-[1-methyl-3-[(E)-2-[5-[(3R)-1-methylpyrrolidin-3-yl]methoxy]-2-pyridyl]vinyl]indazol-6-yl]thiobenzamide 9b (350 mg, 599.58 μmol, yield 58.35%).

[0229] The product was confirmed by LCMS.

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

[0231] Step 2 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-methylpyrrolidin-3-yl]methoxy]-2-pyridyl]vinyl]indazol-6-yl]thiobenzamide 9b (350 mg, 599.58 μmol) in dichloromethane (6 mL) at room temperature. The mixture was stirred at room temperature for approximately 16 hours. After confirming complete reaction of the starting materials by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (5 mL), adjusted to pH 8-9 with solid sodium carbonate, and extracted with dichloromethane (5 mL × 3). The combined organic layers were washed with water (5 mL × 2), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by preparative thin layer chromatography to give a yellow solid, N-methyl-2-({3-[(E)-2-(5-{[(3R)-1-methylpyrrolidin-3-yl]methoxy}pyridin-2-yl)vinyl]-1H-indazol-6-yl}thio)benzamide I-39 (45 mg, 90.07 μmol, 15.02% yield).

[0232] The product was confirmed by LCMS, 1HNMR and 1CNMR.

[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] Procedure 1 Sodium hydride (1.5 g, 37.15 mmol, 60% purity) was added stepwise to a solution of 6-vinylpyridin-3-ol 1c (1.5 g, 12.38 mmol) in dry N,N-dimethylformamide (20 mL) at low temperature. The mixture was stirred for 1 h at 0 °C. 4-(2-chloroethyl)morpholine hydrochloride 10a (2.8 g, 14.86 mmol) was then slowly added. The mixture was stirred for approximately 4 h at 60 °C. After confirming the complete reaction of the starting material 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 × 3). The combined organic layer was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by preparative thin layer chromatography to give 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 LCMS 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 To a solution of 2-(3-iodo-1-tetrahydropyran-2-yl-indazol-6-yl)thio-N-methyl-benzamide 1h (100 mg, 0.20 mmol) in 1,4-dioxane (5 mL), 4-[2-[(6-vinyl-3-pyridyl)oxy]ethyl]morpholine 10b (57 mg, 0.24 mmol), triethylamine (61.5 mg, 0.61 mmol), Pd(dba) (45.5 mg, 0.20 mmol), and P(o-tol) (61.7 mg, 0.20 mmol) were added at room temperature under nitrogen gas protection, and the mixture was heated to 100 °C and reacted with stirring. After confirming the complete reaction of the starting material by thin-layer chromatography (dichloromethane / methanol = 20 / 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, and concentrated to give the crude product. The crude product was purified by preparative thin-layer chromatography (dichloromethane / methanol = 20 / 1) to give a brown solid, N-methyl-2-[3-[(E)-2-[5-(2-morpholinoethoxy)-2-pyridyl]vinyl]-1-tetrahydropyran-2-yl-indazol-6-yl]thiobenzamide 10c (100 mg, 166.74 μmol, 82.26% yield).

[0240] The product was confirmed by LCMS.

[0241] MS-ESI calculated value [M+H] + 600.2, actual value 600.1. Step 3 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-yl-indazol-6-yl]thiobenzamide 10c (400 mg, 0.67 mmol) in dichloromethane (2 mL) at room temperature. The mixture was stirred at 35 °C for 16 h. After confirming complete reaction of the starting materials by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (40 mL), adjusted to pH 8-9 with solid sodium carbonate, and extracted with dichloromethane (30 mL × 3). The combined organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by preparative thin-layer chromatography to give a white solid, N-methyl-2-({3-[(E)-2-{5-[2-(morpholin-4-yl)ethoxy]pyridin-2-yl}vinyl]-1H-indazol-6-yl}thio)benzamide I-3 (53.7 mg, 104.15 μmol, 15.62% yield).

[0242] The product was confirmed by LCMS, 1HNMR and 1CNMR.

[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 To a solution of 5-bromopyridin-2-ol 11b (1 g, 5.75 mmol) in N,N-dimethylformamide (20 mL) was added sodium hydride (689.67 mg, 17.24 mmol, 60% purity) in portions at 0°C under nitrogen gas protection, 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, and the mixture was heated to 60°C and stirred for 16 hours. After confirming the complete reaction of the raw materials by thin layer chromatography (petroleum ether / ethyl acetate = 1 / 1), the mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layer was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product, 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 LCMS 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 To a solution of 5-bromo-2-(2-pyrrolidine-1-methoxy)pyridine 11c (1 g, 3.69 mmol) in dry N,N-dimethylformamide (20 mL), 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 at room temperature. The mixture was heated to 85 °C and stirred for approximately 16 h. After confirming complete reaction by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by preparative thin-layer chromatography (dichloromethane / methanol=10 / 1) to obtain a yellow solid, 2-(2-pyrrolidine-1-ethoxy)-5-vinylpyridine 11d (340 mg, 1.56 mmol, yield 42.23%).

[0250] The product was confirmed by LCMS 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 A solution of 2-(3-iodo-1-tetrahydropyran-2-yl-indazol-6-yl)thio-N-methyl-benzamide 1h (500 mg, 1.01 mmol) in 1,4-dioxane (20 mL) was added with 2-(2-pyrrolidine-1-ethoxy)-5-vinylpyridine 11d (280 mg, 1.28 mmol), triethylamine (300 mg, 2.96 mmol), Pd(dba) (250 mg, 1.11 mmol), and P(o-tol) (250 mg, 821.40 μmol) at room temperature under nitrogen gas protection. The mixture was heated to 100 °C and stirred for approximately 2 hours. After confirming the complete reaction of the starting material by thin-layer chromatography (dichloromethane / methanol = 20 / 1), the mixture was poured into water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by preparative thin-layer chromatography (dichloromethane / methanol = 10 / 1) to give a yellow solid, N-methyl-2-[3-[(E)-2-[6-(2-pyrrolidin-1-ylethoxy)-3-pyridyl]vinyl]-1-tetrahydropyran-2-yl-indazol-6-yl]thiobenzamide 11e (200 mg, 342.62 μmol, 33.81% yield).

[0254] The product was confirmed by LCMS.

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

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

[0257] The product was confirmed by LCMS, 1HNMR and 1CNMR.

[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] [Chemical formula]

[0261] Procedure 1 A solution of 6-bromopyridin-2-ol 12a (500 mg, 2.87 mmol) in N,N-dimethylformamide (10 mL) was heated to 80 °C and stirred for approximately 16 h under nitrogen gas protection. After confirming complete reaction by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (100 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic layer was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate=10 / 1 to 1 / 10) to give a white solid 6-vinylpyridin-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 A solution of 6-vinylpyridin-2-ol 12b (110 mg, 908.07 μmol) in N,N-dimethylformamide (2 mL) was added with 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) at room temperature under nitrogen gas protection. The mixture was heated to 100 °C and stirred for approximately 4 h. After confirming complete reaction of the starting materials by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by preparative thin-layer chromatography (dichloromethane / methanol=10 / 1) to obtain a yellow solid, 2-(2-pyrrolidine-1-ethoxy)-6-vinylpyridine 12c (75 mg, 343.57 μmol, yield 37.84%).

[0264] The product was confirmed by LCMS 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 A solution of 2-(3-iodo-1-tetrahydropyran-2-yl-indazol-6-yl)thio-N-methyl-benzamide 1h (500 mg, 1.01 mmol) in 1,4-dioxane (20 mL) was added with 2-(2-pyrrolidine-1-ethoxy)-6-vinylpyridine 12c (265.5 mg, 1.22 mmol), triethylamine (307.7 mg, 3.04 mmol), Pd(dba) (464 mg, 506.73 μmol), and P(o-tol) (308.5 mg, 1.01 mmol) at room temperature under nitrogen gas protection. The mixture was heated to 100 °C and stirred for approximately 2 h. After confirming the complete reaction of the starting material by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (30 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by preparative thin-layer chromatography (dichloromethane / methanol = 10 / 1) to give a yellow solid, N-methyl-2-[3-[(E)-2-[6-(2-pyrrolidin-1-ylethoxy)-2-pyridyl]vinyl]-1-tetrahydropyran-2-yl-indazol-6-yl]thiobenzamide 12d (370 mg, 633.84 μmol, 62.54% yield).

[0268] The product was confirmed by LCMS.

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

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

[0271] The product was confirmed by LCMS, 1HNMR and 1CNMR.

[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] [Chemical formula]

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

[0276] The product was confirmed by LCMS 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 A solution of 1-[2-(3-bromophenoxy)ethyl]pyrrolidine 13b (800 mg, 2.96 mmol) in N,N-dimethylformamide (8 mL) was heated to 85 °C and stirred for approximately 16 h under nitrogen gas protection. After confirming complete reaction by thin-layer chromatography (dichloromethane / methanol = 10 / 1), 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, and concentrated to give the crude product. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate=10 / 1-dichloromethane / methanol=10 / 1) to give a white solid, 1-[2-(3-vinylphenoxy)ethyl]pyrrolidine 13c (300 mg, 1.38 mmol, yield 46.62%).

[0280] The product was confirmed by LCMS 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 A solution of 2-(3-iodo-1-tetrahydropyran-2-yl-indazol-6-yl)thio-N-methyl-benzamide 1h (200 mg, 405.38 μmol) in 1,4-dioxane (5 mL) was added with 1-[2-(3-vinylphenoxy)ethyl]pyrrolidine 13c (132.14 mg, 608.08 μmol), triethylamine (123.06 mg, 1.22 mmol), Pd(dba) (371.22 mg, 405.38 μmol), and P(o-tol) (123.38 mg, 405.38 μmol) at room temperature under nitrogen gas protection. The mixture was heated to 100 °C and reacted with stirring for approximately 4 hours. After confirming the complete reaction of the starting material by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (20 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, and concentrated to give the crude product. The crude product was purified by preparative thin-layer chromatography (dichloromethane / methanol = 10 / 1) to give a yellow solid, N-methyl-2-[3-[(E)-2-[3-(2-pyrrolidin-1-ethoxy)phenyl]vinyl]-1-tetrahydropyran-2-yl-indazol-6-yl]thiobenzamide 13d (370 mg, 633.84 μmol, 62.54% yield).

[0284] The product was confirmed by LCMS.

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

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

[0287] The product was confirmed by LCMS, 1HNMR and 1CNMR.

[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 A solution of 5-bromopyridin-3-ol 14a (2 g, 11.49 mmol) in N,N-dimethylformamide (20 mL) was heated to 85 °C with stirring for approximately 16 h under nitrogen gas protection. After confirming complete reaction by thin-layer chromatography (dichloromethane / methanol = 10 / 1), 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 (200 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by basic alumina column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 0 / 1) to give a white solid, 5-vinylpyridin-3-ol 14b (600 mg, 4.95 mmol, yield 43.09%).

[0292] The product was confirmed by LCMS 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 To a solution of 5-vinylpyridin-3-ol 14b (300 mg, 2.48 mmol) in N,N-dimethylformamide (4 mL) at 0 °C under nitrogen gas protection, sodium hydride (300.00 mg, 7.50 mmol, 60% purity) was added in portions. The mixture was stirred at 0 °C for 1 h, and then 1-(2-chloroethyl)pyrrolidine hydrochloride 11a (600 mg, 3.53 mmol) was added. The mixture was heated to room temperature and stirred for approximately 2 h. After confirming complete reaction by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by preparative thin-layer chromatography (petroleum ether / ethyl acetate = 5 / 1 to 3 / 1) to obtain a yellow solid, 3-(2-pyrrolidine-1-ethoxy)-5-vinylpyridine 14c (190 mg, 870.39 μmol, yield 35.15%).

[0296] The product was confirmed by LCMS 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 To a solution of 2-(3-iodo-1-tetrahydropyran-2-yl-indazol-6-yl)thio-N-methyl-benzamide 1h (400 mg, 810.77 μmol) in 1,4-dioxane (5 mL), 3-(2-pyrrolidine-1-ethoxy)-5-vinylpyridine 14c (200 mg, 916.20 μmol), triethylamine (300.00 mg, 2.96 mmol), Pd(dba) (320 mg, 1.43 mmol), and P(o-tol) (220 mg, 722.83 μmol) were added at room temperature under nitrogen gas protection. The mixture was heated to 100 °C and stirred for approximately 2 h. After confirming the complete reaction of the starting material 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, and concentrated to give the crude product. The crude product was purified by preparative thin-layer chromatography (dichloromethane / methanol = 10 / 1) to give a yellow oily liquid, N-methyl-2-[3-[(E)-2-[5-(2-pyrrolidin-1-ylethoxy)-3-pyridyl]vinyl]-1-tetrahydropyran-2-yl-indazol-6-yl]thiobenzamide 14d (100 mg, 171.31 μmol, 21.13% yield).

[0300] The product was confirmed by LCMS.

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

[0302] Step 4 To a solution of N-methyl-2-[3-[(E)-2-[5-(2-pyrrolidin-1-ylethoxy)-3-pyridyl]vinyl]-1-tetrahydropyran-2-yl-indazol-6-yl]thiobenzamide 14d (100 mg, 171.31 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (TFA) (1.5 g, 13.16 mmol) at room temperature. The mixture was stirred at room temperature for approximately 2 hours. After confirming complete reaction of the starting materials by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by preparative thin layer chromatography to give a white solid, N-methyl-2-({3-[(E)-2-{5-[2-(pyrrolidin-1-yl)ethoxy]pyridin-3-yl}vinyl]-1H-indazol-6-yl}thio)benzamide I-22 (16.3 mg, 32.62 μmol, 19.04% yield).

[0303] The product was confirmed by LCMS, 1HNMR and 1CNMR.

[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 A solution of 4-bromo-1H-pyrazole 15a (2 g, 13.61 mmol) in DMSO (20 mL) was added with 1-(2-chloroethyl)pyrrolidine hydrochloride 11a (2.8 g, 16.33 mmol) and cesium carbonate (13.3 g, 40.82 mmol) at room temperature under nitrogen gas protection. The mixture was heated to 100 °C and stirred for approximately 2.5 hours. After confirming complete reaction of the starting materials by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (100 mL) and extracted with dichloromethane (40 mL × 3). The combined organic layer was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by silica gel chromatography (dichloromethane / methanol=20 / 1) to give 4-bromo-1-(2-pyrrolidine-1-ethyl)pyrazole 15b (2.5 g, 10.24 mmol, yield 75.25%) as a yellow oily liquid.

[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 A solution of 4-bromo-1-(2-pyrrolidine-1-ethyl)pyrazole 15b (501.4 mg, 2.05 mmol) in N,N-dimethylformamide (10 mL) was heated to 85 °C and stirred for approximately 16 h under nitrogen gas protection. After confirming complete reaction by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (50 mL) and extracted with dichloromethane (50 mL x 3). The combined organic layer was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. 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 LCMS 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 A solution of 2-(3-iodo-1-tetrahydropyran-2-yl-indazol-6-yl)thio-N-methyl-benzamide 1h (500 mg, 1.01 mmol) in 1,4-dioxane (5 mL) was added with 1-(2-pyrrolidine-1-ethyl)-4-vinylpyrazole 15c (213.2 mg, 1.11 mmol), triethylamine (307.7 mg, 3.04 mmol), Pd(dba) (500 mg, 546.04 μmol), and P(o-tol) (500.5 mg, 1.64 mmol) at room temperature under nitrogen gas protection. The mixture was heated to 100 °C and stirred for approximately 2 h. After confirming the complete reaction of the raw materials 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 × 3). The combined organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product, red oily liquid N-methyl-2-[3-[(E)-2-[1-(2-pyrrolidin-1-ylethyl)pyrazol-4-yl]vinyl]-1-tetrahydropyran-2-yl-indazol-6-yl]thiobenzamide 15d (370 mg, 633.84 μmol, yield 62.54%).

[0314] The product was confirmed by LCMS.

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

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

[0317] The product was confirmed by LCMS, 1HNMR and 1CNMR.

[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] Step 1 A solution of 4-bromo-1H-pyrazole 15a (2 g, 13.61 mmol) in DMSO (20 mL) was added with 1-(3-chloropropyl)pyrrolidine hydrochloride 16a (2.4 g, 16.33 mmol) and cesium carbonate (13.3 g, 40.82 mmol) at room temperature under nitrogen gas protection. The mixture was heated to 100 °C and stirred for approximately 4 h. After confirming complete reaction of the starting materials by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (100 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layer was washed with saturated brine (120 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate=20 / 1-0 / 1) to give a yellow solid, 4-bromo-1-(3-pyrrolidin-1-ylpropyl)pyrazole 16b (3 g, 11.62 mmol, yield 85.40%).

[0322] The product was confirmed by LCMS 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 A solution of 4-bromo-1-(3-pyrrolidin-1-ylpropyl)pyrazole 16b (1 g, 3.87 mmol) in N,N-dimethylformamide (10 mL) was heated to 100 °C and stirred for approximately 4 h under nitrogen gas protection. After confirming complete reaction by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine (120 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1 to 0 / 1 and then dichloromethane / methanol = 20 / 1 to 10 / 1) to give a yellow oily liquid, 1-(3-pyrrolidin-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 A solution of 2-(3-iodo-1-tetrahydropyran-2-yl-indazol-6-yl)thio-N-methyl-benzamide 1h (300 mg, 608.08 μmol) in 1,4-dioxane (10 mL) was added with 1-(3-pyrrolidin-1-ylpropyl)-4-vinylpyrazole 16c (124.8 mg, 608.08 μmol), triethylamine (92.3 mg, 912.11 μmol), Pd(dba) (185.1 mg, 608.08 μmol), and P(o-tol) (835.2 mg, 912.11 μmol) at room temperature under nitrogen gas protection. The mixture was heated to 100 °C and stirred for approximately 2 hours. After confirming the complete reaction of the raw materials by thin layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (30 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layer was 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-pyrrolidin-1-ylpropyl)pyrazol-4-yl]vinyl]-1-tetrahydropyran-2-yl-indazol-6-yl]thiobenzamide 16d (300 mg, 525.63 μmol, yield 86.44%).

[0328] The product was confirmed by LCMS.

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

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

[0331] The product was confirmed by LCMS, 1HNMR and 1CNMR.

[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 To a solution of 3-bromo-1H-pyrazole 17a (2 g, 13.61 mmol) in DMSO (20 mL), 1-(2-chloroethyl)pyrrolidine hydrochloride 11a (2.8 g, 16.33 mmol) and cesium carbonate (13.3 g, 40.82 mmol) were added at room temperature under nitrogen gas protection. The mixture was heated to 100 °C and stirred for approximately 4 hours. After confirming complete reaction of the starting materials by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (30 mL) and extracted with dichloromethane (40 mL × 3). The combined organic layer was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to obtain a yellow oily liquid mixture of 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] The identity of 3-bromo-1-(2-pyrrolidine-1-ethyl)pyrazole 17b was confirmed by LCMS 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 LCMS.

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

[0341] Step 2 To a solution 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) 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 at room temperature under nitrogen gas protection. The mixture was heated to 85 °C and reacted with stirring for approximately 16 hours. After confirming the complete reaction of the starting material by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (30 mL) and extracted with dichloromethane (30 mL x 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by preparative thin-layer chromatography (dichloromethane / methanol = 10 / 1) to give a red oily liquid mixture of 1-(2-pyrrolidine-1-ethyl)-3-vinylpyrazole 17c and 1-(2-pyrrolidine-1-ethyl)-5-vinylpyrazole 17c' (0.4 g, 2.09 mmol, 85.09% yield).

[0342] The product mixture was confirmed by LCMS.

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

[0344] Step 3 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), Pd(dba) (464 mg, 506.73 μmol), and P(o-tol) (308.5 mg, 1.01 mmol) was added to a solution of 2-(3-iodo-1-tetrahydropyran-2-yl-indazol-6-yl)thio-N-methyl-benzamide 1h (500 mg, 1.01 mmol) in 1,4-dioxane (10 mL) at room temperature under nitrogen gas protection. The mixture was heated to 100 °C and stirred for approximately 4 hours. After confirming the complete reaction of the raw materials 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 × 3). The combined organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by preparative thin-layer chromatography (dichloromethane / methanol = 10 / 1) to give a yellow solid mixture of N-methyl-2-[3-[(E)-2-[1-(2-pyrrolidin-1-ylethyl)pyrazol-3-yl]vinyl]-1-tetrahydropyran-2-yl-indazol-6-yl]thiobenzamide 17d and N-methyl-2-[3-[(E)-2-[2-(2-pyrrolidin-1-ylethyl)pyrazol-3-yl]vinyl]-1-tetrahydropyran-2-yl-indazol-6-yl]thiobenzamide 17d' (250 mg, 449.06 μmol, yield 44.31%).

[0345] The product was confirmed by LCMS.

[0346] Step 4 To a mixture of N-methyl-2-[3-[(E)-2-[1-(2-pyrrolidin-1-ylethyl)pyrazol-3-yl]vinyl]-1-tetrahydropyran-2-yl-indazol-6-yl]thiobenzamide 17d and N-methyl-2-[3-[(E)-2-[2-(2-pyrrolidin-1-ylethyl)pyrazol-3-yl]vinyl]-1-tetrahydropyran-2-yl-indazol-6-yl]thiobenzamide 17d' (250 mg, 449.06 μmol) in dichloromethane (5 mL) was added trifluoroacetic acid (256 mg, 2.25 mmol) at room temperature. The mixture was stirred at 30 °C for about 16 hours. After confirming the complete reaction of the raw materials by thin layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (40 mL), adjusted to pH = 8-9 with sodium carbonate, extracted with dichloromethane (20 mL × 3), and 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 products were purified by preparative thin-layer chromatography to give yellow solids N-methyl-2-({3-[(E)-2-{1-[2-(pyrrolidin-1-yl)ethyl]-1H-pyrazol-3-yl}vinyl]-1H-indazol-6-yl}thio)benzamide I-13 (4 mg, 8.47 μmol, 1.88% yield) and N-methyl-2-({3-[(E)-2-{1-[2-(pyrrolidin-1-yl)ethyl]-1H-pyrazol-5-yl}vinyl]-1H-indazol-6-yl}thio)benzamide I-25 (7.4 mg, 15.68 μmol, 3.48% yield), respectively.

[0347] The two products obtained were confirmed by LCMS, 1HNMR and 1CNMR.

[0348] N-methyl-2-({3-[(E)-2-{1-[2-(pyrrolidin-1-yl)ethyl]-1H-pyrazol-3-yl}vinyl]-1H-indazol-6-yl}thio)benzamide I-13: MS-ESI calculated [M+H]+ 473.2, found 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 A solution of 4-bromopyridin-2-ol 18a (2 g, 13.61 mmol) in DMSO (20 mL) was added with 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) at room temperature under nitrogen gas protection. The mixture was heated to 85 °C and stirred for approximately 16 h. After confirming complete reaction of the starting materials by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (100 mL) and extracted with dichloromethane (40 mL × 3). The combined organic layer was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by preparative thin-layer chromatography (dichloromethane / methanol=10 / 1) to give a 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 LCMS 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 A solution of 4-bromo-2-(2-pyrrolidine-1-methoxy)pyridine 18b (200 mg, 737.59 μmol) in N,N-dimethylformamide (3 mL) was added 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) at room temperature under nitrogen gas protection. The mixture was heated to 85 °C and stirred for approximately 4 h. After confirming complete reaction by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (50 mL) and extracted with dichloromethane (50 mL x 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by preparative thin-layer chromatography (dichloromethane / methanol=10 / 1) to give a yellow solid, 2-(2-pyrrolidine-1-ethoxy)-4-vinylpyridine 18c (10 mg, 45.81 μmol, yield 6.21%).

[0357] The product was confirmed by LCMS.

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

[0359] Step 3 A solution of 2-(3-iodo-1-tetrahydropyran-2-yl-indazol-6-yl)thio-N-methyl-benzamide 1h (110 mg, 222.96 μmol) in 1,4-dioxane (2 mL) was added with 2-(2-pyrrolidine-1-ethoxy)-4-vinylpyridine 18c (58.4 mg, 267.55 μmol), triethylamine (33.8 mg, 334.44 μmol), Pd(dba) (67.9 mg, 222.96 μmol), and P(o-tol) (306.3 mg, 334.44 μmol) at room temperature under nitrogen gas protection. The mixture was heated to 100 °C and stirred for approximately 2 hours. After confirming the complete reaction of the starting material by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (30 mL) and extracted with ethyl acetate (15 mL × 3). The combined organic layers were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by preparative thin-layer chromatography (dichloromethane / methanol = 10 / 1) to give a yellow solid, N-methyl-2-[3-[(E)-2-[2-(2-pyrrolidine-1-methoxy)-4-pyridyl]vinyl]-1-tetrahydropyran-2-yl-indazol-6-yl]thiobenzamide 18d (37 mg, 63.38 μmol, 28.43% yield).

[0360] The product was confirmed by LCMS 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 Trifluoroacetic acid (78.1 mg, 685.23 μmol) was added to a solution of N-methyl-2-[3-[(E)-2-[2-(2-pyrrolidine-1-methoxy)-4-pyridyl]vinyl]-1-tetrahydropyran-2-yl-indazol-6-yl]thiobenzamide 18d (400 mg, 685.23 μmol) in dichloromethane (10 mL) at room temperature. The mixture was stirred at 40 °C for approximately 16 hours. After confirming complete reaction of the starting materials by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (40 mL), adjusted to pH 8-9 with sodium carbonate, and extracted with dichloromethane (20 mL × 3). The combined organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by preparative thin layer chromatography to give a yellow solid, N-methyl-2-({3-[(E)-2-{2-[2-(pyrrolidin-1-yl)ethoxy]pyridin-4-yl}vinyl]-1H-indazol-6-yl}thio)benzamide I-18 (8 mg, 16.01 μmol, yield 2.34%).

[0364] The product was confirmed by LCMS, 1HNMR and 1CNMR.

[0365] MS-ESI calculated value [M+H]+ 500.2, found 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 1 At 0°C under nitrogen gas protection, sodium hydride (253 mg, 6.32 mmol, 60% purity) was added in portions to a solution of 6-bromopyridin-3-ol 1a (1 g, 5.75 mmol) in N,N-dimethylformamide (20 mL). The mixture was stirred for approximately 1 hour, and then 1-(2-chloroethyl)pyrrolidine hydrochloride 11a (1.08 g, 6.32 mmol) was slowly added at low temperature. The mixture was stirred for 1 hour at low temperature, and then heated to 50°C and stirred for an additional 3 hours. After confirming the complete reaction of the raw materials by thin layer chromatography (petroleum ether / ethyl acetate = 2 / 1), the reaction mixture was cooled to 0 °C and quenched with water (approximately 10 mL). The mixture was poured into water (100 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layer was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product, 2-bromo-5-(2-pyrrolidine-1-methoxy)pyridine 19a (1.5 g, yield 96.3%) as a yellow oily liquid.

[0369] The product was confirmed by LCMS 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, a solution of 2-(3-iodo-1-tetrahydropyran-2-yl-indazol-6-yl)thio-N-methyl-benzamide 1h (300 mg, 608.08 μmol) in 1,4-dioxane (9 mL) was added 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), and the mixture was heated to 110°C and stirred for approximately 6 hours. After confirming the complete reaction of the starting material by thin-layer chromatography (ethyl acetate), the mixture was poured into water (30 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by preparative thin-layer chromatography (ethyl acetate) to give a white solid, 2-(3-acetamido-1-tetrahydropyran-2-yl-indazol-6-yl)thio-N-methyl-benzamide 19b (0.17 g, 400.46 μmol, 65.86% yield).

[0373] The product was confirmed by LCMS.

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

[0375] Step 3 To a solution of 2-(3-acetamido-1-tetrahydropyran-2-yl-indazol-6-yl)thio-N-methyl-benzamide 19b (0.4 g, 942.25 μmol) in 1,4-dioxane (10 mL), NaOH (376.90 mg, 9.42 mmol) and HO (2 mL) were added at room temperature. The mixture was heated to 100 °C and stirred for approximately 16 hours. After confirming complete reaction of the starting materials by thin-layer chromatography (dichloromethane / methanol = 20 / 1), the mixture was poured into water (40 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by preparative thin-layer chromatography (dichloromethane / methanol = 20 / 1, 0.1% NH3·H2O) to give a white solid, 2-(3-amino-1-tetrahydropyran-2-yl-indazol-6-yl)thio-N-methyl-benzamide 19c (0.152 g, 397.41 μmol, 42.18% yield).

[0376] The product was confirmed by LCMS.

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

[0378] Step 4 Xantphos (378.20 mg, 653.63 μmol), Pd(dba) (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) were added to a solution of 2-(3-amino-1-tetrahydropyran-2-yl-indazol-6-yl)thio-N-methyl-benzamide 19c (0.1 g, 261.45 μmol) in 1,4-dioxane (5 mL) at room temperature under nitrogen gas protection. The mixture was heated to 100 °C and stirred for approximately 6 h. After confirming the complete reaction of the starting material by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (30 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, and concentrated to give the crude product as a yellow oil. The crude product was purified by preparative thin-layer chromatography (dichloromethane / methanol = 10 / 1) to give a yellow solid, N-methyl-2-[3-[[5-(2-pyrrolidine-1-methoxy)-2-pyridyl]amino]-1-tetrahydropyran-2-yl-indazol-6-yl]thiobenzamide 19d (0.1 g, 174.61 μmol, 66.78% yield).

[0379] The product was confirmed by LCMS.

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

[0381] Step 5 N-methyl-2-[3-[[5-(2-pyrrolidine-1-methoxy)-2-pyridyl]amino]-1-tetrahydropyran-2-yl-indazol-6-yl]thiobenzamide 19d (86 mg, 150.16 μmol) was added to HCl / MeOH (10 mL) and stirred at room temperature for approximately 4 hours. After confirming complete reaction of the starting materials 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 and extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by preparative thin-layer chromatography (dichloromethane / methanol = 10 / 1, 0.1% NH3·H2O) to give a pale yellow solid, N-methyl-2-{[3-({5-[2-(pyrrolidin-1-yl)ethoxy]pyridin-2-yl}amino)-1H-indazol-6-yl]thio}benzamide I-30 (20.3 mg, 41.55 μmol, 27.67% yield).

[0382] The product was confirmed by LCMS, 1HNMR and 1CNMR.

[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 Acetic acid (55 mg, 915.88 μmol) and KOCN (2.08 g, 24.44 mmol) were added to a mixture of 2-(4-methylpiperazin-1-yl)ethylamine 20a (5 g, 34.91 mmol) and water (50 mL) at room temperature, and the mixture was stirred at 25 °C for approximately 2 h. After confirming the complete reaction of the starting materials by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was directly lyophilized to give a white solid crude product, 2-(4-methylpiperazin-1-yl)ethylurea 20b (6 g, 32.21 mmol, 92.28% yield), of sufficient purity.

[0387] The product was confirmed by LCMS 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 To a solution of 2-(4-methylpiperazin-1-yl)ethyl urea 20b (60.40 mg, 324.31 μmol) in 1,4-dioxane (5 mL) was added 2-(3-iodo-1-tetrahydropyran-2-yl-indazol-6-yl)thio-N-methyl-benzamide 1h (200 mg, 405.38 μmol), potassium tert-butoxide (136.47 mg, 1.22 mmol), and cuprous iodide (15.44 mg, 81.08 μmol) at room temperature under nitrogen gas protection. The mixture was heated to 105°C and reacted with stirring for approximately 16 hours. After confirming the complete reaction of the starting material by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (20 mL) and extracted with dichloromethane (20 mL x 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by preparative thin-layer chromatography (dichloromethane / methanol = 10 / 1) to give a green oily liquid, N-methyl-2-[3-[2-(4-methylpiperazin-1-yl)ethylcarbamoylamino]-1-tetrahydropyran-2-yl-indazol-6-yl]thiobenzamide 20c (30 mg, 54.38 μmol, 13.41% yield).

[0391] The product was confirmed by LCMS.

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

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

[0394] The product was confirmed by LCMS, 1HNMR and 1CNMR.

[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 A solution of 3-bromo-1H-pyrazole 17a (1 g, 6.80 mmol) in DMSO (20 mL) was added to 16a (1 g, 6.80 mmol) and cesium carbonate (3.3 g, 10.21 mmol) at room temperature under nitrogen gas protection. The mixture was heated to 100 °C and stirred for approximately 16 hours. After confirming complete reaction of the starting materials by thin-layer chromatography (dichloromethane / methanol = 20 / 1), the mixture was poured into water (40 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to give a yellow solid, 3-bromo-1-(3-pyrrolidin-1-ylpropyl)pyrazole 21a (1.6 g, 6.20 mmol, 91.09% yield).

[0399] The product was confirmed by LCMS 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 A solution of 3-bromo-1-(3-pyrrolidin-1-ylpropyl)pyrazole 21a (1 g, 3.87 mmol) in N,N-dimethylformamide (10 mL) was heated to 85 °C and stirred for approximately 16 h under nitrogen gas protection. After confirming complete reaction by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (40 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed sequentially with water (40 mL) and brine (40 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by preparative thin layer chromatography to give a yellow oily liquid, 1-(3-pyrrolidin-1-ylpropyl)-3-vinylpyrazole 21b (290 mg, 1.41 mmol, yield 36.47%).

[0403] The product was confirmed by LCMS 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 A solution of 2-(3-iodo-1-tetrahydropyran-2-yl-indazol-6-yl)thio-N-methyl-benzamide 1h (300 mg, 608.08 μmol) in 1,4-dioxane (10 mL) was added with 1-(3-pyrrolidin-1-ylpropyl)-3-vinylpyrazole 21b (187.3 mg, 912.11 μmol), triethylamine (184.6 mg, 1.82 mmol), Pd(dba) (278.4 mg, 304.04 μmol), and P(o-tol) (185.08 mg, 608.08 μmol) at room temperature under nitrogen gas protection. The mixture was heated to 100 °C and stirred for approximately 1 h. After confirming complete reaction by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was concentrated and filtered to give the crude product. The crude product was purified by preparative thin-layer chromatography to give a white solid, N-methyl-2-[3-[(E)-2-[1-(3-pyrrolidin-1-ylpropyl)pyrazol-3-yl]vinyl]-1-tetrahydropyran-2-yl-indazol-6-yl]thiobenzamide 21c (10 mg, 17.52 μmol, yield 2.88%).

[0407] The product was confirmed by LCMS.

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

[0409] Step 4 To a solution of N-methyl-2-[3-[(E)-2-[1-(3-pyrrolidin-1-ylpropyl)pyrazol-3-yl]vinyl]-1-tetrahydropyran-2-yl-indazol-6-yl]thiobenzamide 21c (300 mg, 525.63 μmol) in dichloromethane (5 mL) was added trifluoroacetic acid (599.3 mg, 5.26 mmol) and stirred for approximately 16 hours at room temperature. After confirming complete reaction by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by preparative thin-layer chromatography to give a white solid, N-methyl-2-({3-[(E)-2-{1-[3-(pyrrolidin-1-yl)propyl]-1H-pyrazol-3-yl}vinyl]-1H-indazol-6-yl}thio)benzamide I-11 (16.4 mg, 33.70 μmol, 6.41% yield).

[0410] The product was confirmed by LCMS 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 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 to a solution of 2-bromo-5-(2-pyrrolidine-1-methoxy)pyridine 19a (3.0 g, 11.06 mmol) in N,N-dimethylformamide (60 mL) at room temperature under nitrogen gas protection. The mixture was heated to 50 °C and stirred for 12 h. After confirming the complete reaction of the starting material by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the reaction mixture was poured into water (200 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed sequentially with water (100 mL x 3) and saturated brine (80 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by silica gel chromatography (dichloromethane / methanol = 100 / 1 to 20 / 1) to give trimethyl-[2-[5-(2-pyrrolidine-1-methoxy)-2-pyridyl]ethynyl]silane 22a (1.8 g, 56.4% yield) as a black oil.

[0415] The product was confirmed by LCMS 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 Potassium carbonate (1.03 g, 7.49 mmol) was added to a solution of trimethyl-[2-[5-(2-pyrrolidine-1-methoxy)-2-pyridyl]ethynyl]silane 22a (1.8 g, 6.24 mmol) in methanol (30 mL) at room temperature, and the mixture was stirred for approximately 2 hours. After confirming complete reaction of the starting materials 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 2-ethynyl-5-(2-pyrrolidine-1-ethoxy)pyridine 22b (0.6 g, 44.46% yield) as a brown oily liquid.

[0419] The product was confirmed by LCMS 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, 2-ethynyl-5-(2-pyrrolidine-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 to a solution of 2-[(3-iodo-1H-indazol-6-yl)thio]-N-methylbenzamide 1 g (300 mg, 0.73 mmol) in N,N-dimethylformamide (9 mL). The mixture was heated to 100°C and reacted with stirring for approximately 2 hours. After confirming the complete reaction of the starting material by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (50 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed successively with water (30 mL × 3) and saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by preparative thin-layer chromatography to give a white solid, N-methyl-2-{[3-(2-{5-[2-(pyrrolidin-1-yl)ethoxy]pyridin-2-yl}ethynyl)-1H-indazol-6-yl]thio}benzamide I-16 (15.8 mg, 4.3% yield).

[0423] The product was confirmed by LCMS, 1HNMR and 1CNMR.

[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 portions to a solution of 2-bromopyridin-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 the complete reaction of the raw materials by thin layer chromatography (dichloromethane / methanol = 20 / 1), the mixture was poured into water (10 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layer was 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 LCMS 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 A solution of 2-bromo-4-(2-pyrrolidine-1-methoxy)pyridine 23b (500 mg, 1.84 mmol) in N,N-dimethylformamide (5 mL) was added with potassium vinyltrifluoroborate 1b (370.50 mg, 2.77 mmol), Pd(dppf)Cl2 (50 mg, 0.068 mmol), and triethylamine (280 mg, 2.77 mmol) at room temperature under nitrogen gas protection. The mixture was heated to 85 °C and stirred for approximately 16 h. After confirming complete reaction by thin-layer chromatography (dichloromethane / methanol = 15 / 1), the mixture was poured into water (20 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by preparative thin layer chromatography to give a white solid, 4-(2-pyrrolidine-1-ethoxy)-2-vinylpyridine 23c (50 mg, yield 12.4%).

[0432] The product was confirmed by LCMS 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 To a solution of 2-[(3-iodo-1H-indazol-6-yl)thio]-N-methylbenzamide 1 g (562 mg, 1.37 mmol) in N,N-dimethylformamide (5 mL), 4-(2-pyrrolidine-1-ethoxy)-2-vinylpyridine 23c (100 mg, 0.46 mmol), DIEA (592 mg, 4.58 mmol), Pd(OAc) (100 mg, 0.45 mmol), and P(o-tol) (139 mg, 0.46 mmol) were added at room temperature under nitrogen gas protection. The mixture was heated to 100 °C and reacted with stirring for approximately 16 hours. After confirming the complete reaction of the starting material by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was first purified by preparative thin-layer chromatography (dichloromethane / methanol = 10 / 1) to give a white solid, N-methyl-2-({3-[(E)-2-{4-[2-(pyrrolidin-1-yl)ethoxy]pyridin-2-yl}vinyl]-1H-indazol-6-yl}thio)benzamide I-20 (5 mg, yield 2.18%).

[0436] The product was confirmed by LCMS, 1HNMR and 1CNMR.

[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 A solution of 2-bromo-5-(2-pyrrolidine-1-methoxy)pyridine 19a (0.5 g, 1.84 mmol) in N,N-dimethylformamide (10 mL) was heated to 85 °C and stirred for approximately 16 h under nitrogen gas protection. After confirming complete reaction by thin-layer chromatography (dichloromethane / methanol = 15 / 1), the mixture was poured into water (40 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed sequentially with water (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by preparative thin layer chromatography (dichloromethane / methanol=10 / 1) to give brown oily liquid 5-(2-pyrrolidine-1-ethoxy)-2-vinylpyridine 24a (220 mg, yield 54.7%).

[0441] The product was confirmed by LCMS 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 To a solution of 2-[(3-iodo-1H-indazol-6-yl)thio]-N-methylbenzamide (1 g, 166 mg, 0.41 mmol) in N,N-dimethylformamide (10 mL) was added 5-(2-pyrrolidine-1-ethoxy)-2-vinylpyridine 24a (133 mg, 0.61 mmol), DIEA (157 mg, 1.22 mmol), Pd(OAc) (137 mg, 0.61 mmol), and P(o-tol) (123 mg, 0.41 mmol) at room temperature under nitrogen gas protection. The mixture was heated to 100 °C and reacted with stirring for approximately 16 h. After confirming the complete reaction of the starting material by thin-layer chromatography (dichloromethane / methanol = 20 / 1), the mixture was poured into water (40 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by preparative thin-layer chromatography (dichloromethane / methanol = 10 / 1) three times to give a yellow solid, N-methyl-2-({3-[(E)-2-{5-[2-(pyrrolidin-1-yl)ethoxy]pyridin-2-yl}vinyl]-1H-indazol-6-yl}thio)benzamide I-6 (4.5 mg, 2.2% yield).

[0445] The product was confirmed by LCMS, 1HNMR and 1CNMR.

[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] [Chemical formula]

[0449] Procedure 1 A solution of 2-bromo-4-(2-pyrrolidine-1-methoxy)pyridine 23b (390 mg, 1.44 mmol) in N,N-dimethylformamide (10 mL) was heated to 50 °C and stirred for 12 h under nitrogen gas protection. After confirming complete reaction by thin-layer chromatography (20:1 dichloromethane / methanol), the reaction mixture was poured into water (40 mL) and 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 give the crude product. The crude product was purified by preparative thin layer chromatography (DCM / MeOH=20:1) to give 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 LCMS.

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

[0452] Step 2 Potassium carbonate (138 mg, 1.00 mmol) was added to a solution of trimethyl-[2-[4-(2-pyrrolidine-1-methoxy)-2-pyridyl]ethynyl]silane 25a (240 mg, 0.83 mmol) in methanol (10 mL) at room temperature and stirred for approximately 2 hours. After confirming complete reaction of the starting materials by thin-layer chromatography (dichloromethane / methanol = 20 / 1), the mixture was poured into water (30 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, and concentrated to give the crude product. The crude product was purified by preparative thin-layer chromatography (dichloromethane / methanol = 20 / 1) to give 2-ethynyl-4-(2-pyrrolidine-1-ethoxy)pyridine 25b (107 mg, 59.46% yield) as a red oil.

[0453] The product was confirmed by LCMS.

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

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

[0456] The product was confirmed by LCMS, 1HNMR and 1CNMR.

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

[0461] The product was confirmed by LCMS 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 A solution of 2-bromo-6-(2-pyrrolidine-1-methoxy)pyridine 26a (0.5 g, 1.84 mmol) in N,N-dimethylformamide (20 mL) was heated to 50 °C and stirred for 16 h under nitrogen gas protection. After confirming complete reaction by LCMS, the reaction mixture was poured into water (80 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. 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 LCMS 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 Potassium carbonate (229.98 mg, 1.66 mmol) was added to a solution of trimethyl-[2-[6-(2-pyrrolidine-1-methoxy)-2-pyridyl]ethynyl]silane 26b (400 mg, 1.39 mmol) in methanol (20 mL) at room temperature and stirred for approximately 2 hours. After confirming complete reaction of the starting materials by thin-layer chromatography (dichloromethane / methanol = 20 / 1), the mixture was poured into water (30 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, and concentrated to give the crude product. The crude product was purified by preparative thin-layer chromatography (dichloromethane / methanol = 20 / 1) to give 2-ethynyl-6-(2-pyrrolidine-1-ethoxy)pyridine 26c (50 mg, 231.18 μmol, 16.67% yield) as a red oil.

[0469] The product was confirmed by LCMS 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 A solution of 2-[(3-iodo-1H-indazol-6-yl)thio]-N-methylbenzamide (1 g, 47.31 mg, 115.59 μmol) in N,N-dimethylformamide (10 mL) was added with 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) at room temperature under nitrogen gas protection. The mixture was heated to 50°C and reacted with stirring for approximately 16 hours. After confirming the complete reaction of the starting material by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (40 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by preparative thin-layer chromatography to give a white solid, N-methyl-2-{[3-(2-{6-[2-(pyrrolidin-1-yl)ethoxy]pyridin-2-yl}ethynyl)-1H-indazol-6-yl]thio}benzamide I-24 (17.8 mg, yield 7.23%).

[0473] The product was confirmed by LCMS, 1HNMR and 1CNMR.

[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 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-indazol-6-ylthio)-N-methylbenzamide 1f (4 g, 14.07 mmol) in THF (20 mL) at room temperature, and the mixture was heated to 60 °C and stirred for approximately 16 h. After confirming complete reaction of the starting materials by thin-layer chromatography (petroleum ether / ethyl acetate = 3 / 1), the mixture was concentrated to give the crude product. The crude product was purified by preparative MPLC to give a yellow solid, 2-(1-tetrahydropyran-2-ylindazol-6-yl)thiobenzoic acid methyl ester 27a (2.5 g, 6.79 mmol, 48.23% yield).

[0478] The product was confirmed by LCMS 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 2-(1-tetrahydropyran-2-ylindazol-6-yl)thiobenzoic acid methyl ester 27a (2.5 g, 6.79 mmol) was dissolved in a mixture of HO (8 mL) and THF (20 mL) at room temperature. Lithium hydroxide (1.7 g, 40.71 mmol) was added and the mixture was heated to 40 °C and stirred for approximately 16 h. After confirming complete reaction of the starting materials by thin-layer chromatography (petroleum ether / ethyl acetate = 1 / 1), the reaction mixture was poured into water (20 mL), adjusted to pH 6-7 with 1N hydrochloric acid, and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to give 2-(1-tetrahydropyran-2-ylindazol-6-yl)thiobenzoic acid 27b (2 g, 5.64 mmol, 83.17% yield) as a white solid.

[0482] The product was confirmed by LCMS 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 To a solution of 2-(1-tetrahydropyran-2-ylindazol-6-yl)thiobenzoic acid 27b (900 mg, 2.54 mmol) in N,N-dimethylformamide (10 mL), cyclopropylamine (290 mg, 5.08 mmol), HATU (1.9 g, 5.08 mmol), and DIEA (980 mg, 7.60 mmol) were added at room temperature. After confirming complete reaction by thin-layer chromatography (petroleum ether / ethyl acetate = 1 / 1), the mixture was poured into water (50 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by silica gel chromatography to give a white solid, N-cyclopropyl-2-(1-tetrahydropyran-2-ylindazol-6-yl)thiobenzamide 27c (700 mg, 1.78 mmol, 70.05% yield).

[0486] The product was confirmed by LCMS 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 To a solution of N-cyclopropyl-2-(1-tetrahydropyran-2-ylindazol-6-yl)thiobenzamide 27c (800 mg, 2.03 mmol) in DCM (10 mL) was added trifluoroacetic acid (3 g, 52.62 mmol) at room temperature, and the mixture was stirred at 40 °C for approximately 16 h. After confirming complete reaction of the starting materials by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (20 mL), adjusted to pH 8-9 with sodium carbonate solution, and extracted with dichloromethane (30 mL × 3). The combined organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to give a yellow solid, N-cyclopropyl-2-(1H-indazol-6-ylthio)benzamide 27d (500 mg, 1.62 mmol, 79.49% yield).

[0490] The product was confirmed by LCMS 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 To a solution of N-cyclopropyl-2-(1H-indazol-6-ylthio)benzamide 27d (1.3 g, 4.20 mmol) in N,N-dimethylformamide (10 mL) was added potassium carbonate (2.3 g, 16.81 mmol) and I2 (2.1 g, 8.40 mmol) at room temperature, and the mixture was stirred at 40 °C for approximately 2 h. After confirming the complete reaction of the starting materials by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (100 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layer was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 2 / 1 to 0 / 1) to give a yellow solid, N-cyclopropyl-2-[(3-iodo-1H-indazol-6-yl)thio]benzamide 27e (1 g, 2.30 mmol, 54.67% yield).

[0494] The product was confirmed by LCMS 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 To a solution of N-cyclopropyl-2-[(3-iodo-1H-indazol-6-yl)thio]benzamide 27e (1.3 g, 4.20 mmol) in THF (10 mL), tert-butoxycarbonyl tert-butyl carbonate (250 mg, 1.15 mmol) and triethylamine (232 mg, 2.30 mmol) were added at room temperature. After confirming complete reaction by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (20 mL) and 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 give the crude product. The crude product was purified by preparative thin-layer chromatography (dichloromethane / methanol = 10 / 1) to give 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 LCMS 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 To a solution of 6-[2-(cyclopropylcarbamoyl)phenyl]thio-3-iodoindazole-1-carboxylic acid tert-butyl ester 27f (200 mg, 373.55 μmol) in 1,4-dioxane (5 mL), 5-(2-pyrrolidine-1-ethoxy)-2-vinylpyridine 24a (97 mg, 448.27 μmol), triethylamine (113 mg, 1.12 mmol), Pd(dba) (171 mg, 186.78 μmol), and P(o-tol) (113 mg, 373.55 μmol) were added at room temperature under nitrogen gas protection. The mixture was heated to 100 °C and stirred for approximately 2 h. After confirming complete reaction by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (20 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, and concentrated to give the crude product. The crude product was purified by preparative thin-layer chromatography (dichloromethane / methanol = 10 / 1) to give 27 g (150 mg, 239.70 μmol, 64.17% yield) of yellow oily liquid 6-[2-(cyclopropylcarbamoyl)phenyl]thio-3-[(E)-2-[5-(2-pyrrolidin-1-ylethoxy)-2-pyridyl]vinyl]indazole-1-carboxylic acid tert-butyl ester.

[0502] The product was confirmed by LCMS.

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

[0504] Step 8 To a solution of 27 g (150 mg, 239.70 μmol) of 6-[2-(cyclopropylcarbamoyl)phenyl]thio-3-[(E)-2-[5-(2-pyrrolidin-1-ylethoxy)-2-pyridyl]vinyl]indazole-1-carboxylic acid tert-butyl ester in dichloromethane (5 mL) was added trifluoroacetic acid (1 g, 8.77 mmol) and stirred for approximately 4 hours at room temperature. After confirming complete reaction by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (20 mL), adjusted to pH 8-9 with sodium carbonate solution, 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, and concentrated to give the crude product. The crude product was purified by preparative thin-layer chromatography to give a white solid, N-cyclopropyl-2-({3-[(E)-2-{5-[2-(pyrrolidin-1-yl)ethoxy]pyridin-2-yl}vinyl]-1H-indazol-6-yl}thio)benzamide I-8 (15.4 mg, 29.30 μmol, 12.22% yield).

[0505] The product was confirmed by LCMS 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 A solution of 2-bromo-5-iodopyridine 28a (5 g, 17.61 mmol) in 1,4-dioxane (50 mL) was added with 1-methylpiperazine 28b (2.1 g, 21.13 mmol), BuONa (5.1 g, 52.84 mmol), Pd(dba) (806.4 mg, 880.62 μmol), and Xantphos (254.8 mg, 440.31 μmol) at room temperature under nitrogen gas protection. The mixture was heated to 60 °C and stirred for approximately 3 h. After confirming complete reaction by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (100 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by neutral alumina chromatography column (petroleum ether / ethyl acetate=10 / 1) to give a 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 LCMS 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 A solution of 1-(6-bromo-3-pyridyl)-4-methylpiperazine 28c (2 g, 7.81 mmol) in N,N-dimethylformamide (20 mL) was heated to 85 °C with stirring for approximately 2 h under nitrogen gas protection. After confirming complete reaction by thin-layer chromatography (dichloromethane / methanol = 10 / 1), 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, and concentrated to give the crude product. The crude product was purified by neutral alumina chromatography column (petroleum ether / ethyl acetate=10 / 1) to give 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 LCMS 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 A solution of 6-[2-(cyclopropylcarbamoyl)phenyl]thio-3-iodoindazole-1-carboxylic acid tert-butyl ester 27f (490 mg, 915.21 μmol) in 1,4-dioxane (10 mL) was added with 1-methyl-4-(6-vinyl-3-pyridyl)piperazine 28d (223.3 mg, 1.10 mmol), triethylamine (277.8 mg, 2.75 mmol), Pd(dba) (502.8 mg, 549.13 μmol), and P(o-tol) (557.1 mg, 1.83 mmol) at room temperature under nitrogen gas protection. The mixture was heated to 85 °C and stirred for approximately 2 h. After confirming the complete reaction of the starting material by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (40 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by preparative MPLC to give a 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, 19.68% yield).

[0517] The product was confirmed by LCMS.

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

[0519] Step 4 To a solution 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 (100 mg, 163.73 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (186.7 mg, 1.64 mmol) and stirred for approximately 16 hours at room temperature. After confirming complete reaction by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (20 mL), adjusted to pH 8-9 with sodium carbonate solution, extracted with dichloromethane (20 mL x 3), and the combined organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by preparative thin layer chromatography to give a yellow solid N-cyclopropyl-2-({3-[(E)-2-[5-(4-methylpiperazin-1-yl)pyridin-2-yl]vinyl]-1H-indazol-6-yl}thio)benzamide I-38 (50 mg, 97.91 μmol, 59.80% yield).

[0520] The product was confirmed by LCMS, 1HNMR and 1CNMR.

[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 A solution of 6-bromopyridine-3-carboxaldehyde 29a (5 g, 26.88 mmol) in N,N-dimethylformamide (50 mL) was heated to 85 °C with stirring for approximately 16 h under nitrogen gas protection. After confirming complete reaction by thin-layer chromatography (petroleum ether / ethyl acetate = 10 / 1), the mixture was poured into water (250 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed successively with water (300 mL) and saturated brine (300 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by silica gel chromatography column (petroleum ether / ethyl acetate=10 / 1) to give yellow oily liquid 6-vinylpyridine-3-carboxaldehyde 29b (1.7 g, 12.77 mmol, yield 47.50%).

[0525] The product was confirmed by LCMS 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 To a solution of 6-vinylpyridine-3-carboxaldehyde 29b (500 mg, 3.76 mmol) in THF (20 mL) was added N-methylmethylamine hydrochloride (612.4 mg, 7.51 mmol) and NaBH(OAc)3 (2.4 g, 11.27 mmol) at room temperature. The mixture was stirred for approximately 16 hours. After confirming complete reaction by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (20 mL), adjusted to pH 8-9 with sodium bicarbonate, 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, and concentrated to give the crude product. The crude product was purified by silica gel chromatography (DCM) to give a white solid, N,N-dimethyl-1-(6-vinyl-3-pyridyl)methanamine 29c (400 mg, 2.47 mmol, 65.66% yield).

[0529] The product was confirmed by LCMS 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 A solution of 6-[2-(cyclopropylcarbamoyl)phenyl]thio-3-iodoindazole-1-carboxylic acid tert-butyl ester 27f (500 mg, 933.89 μmol) in 1,4-dioxane (10 mL) was added with N,N-dimethyl-1-(6-vinyl-3-pyridyl)methanamine 29c (303 mg, 1.87 mmol), triethylamine (472.5 mg, 4.67 mmol), Pd(dba) (427.6 mg, 466.94 μmol), and P(o-tol) (426.4 mg, 1.40 mmol) at room temperature under nitrogen gas protection. The mixture was heated to 85 °C and stirred for approximately 2 h. After confirming the complete reaction of the starting material by thin-layer chromatography (petroleum ether / ethyl acetate = 1 / 1), the mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by preparative MPLC to give 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, 29.13% yield).

[0533] The product was confirmed by LCMS.

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

[0535] Step 4 To a solution of 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) in dichloromethane (5 mL) was added trifluoroacetic acid (300.2 mg, 2.63 mmol) and stirred for approximately 16 hours at room temperature. After confirming complete reaction by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (20 mL), adjusted to pH 8-9 with sodium carbonate solution, extracted with dichloromethane (20 mL x 3), and the combined organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by preparative thin layer chromatography to give a white solid, N-cyclopropyl-2-({3-[(E)-2-{5-[(dimethylamino)methyl]pyridin-2-yl}vinyl]-1H-indazol-6-yl}thio)benzamide I-40 (29 mg, 61.75 μmol, 23.46% yield).

[0536] The product was confirmed by LCMS, 1HNMR and 1CNMR.

[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]

Chem.

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

[0541] The product was confirmed by LCMS 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 To a solution of 6-[2-(cyclopropylcarbamoyl)phenyl]thio-3-iodoindazole-1-carboxylic acid tert-butyl ester 27f (500 mg, 933.89 μmol) in 1,4-dioxane (10 mL), 5-(pyrrolidin-1-ylmethyl)-2-vinylpyridine 30a (351.6 mg, 1.87 mmol), triethylamine (472.5 mg, 4.67 mmol), Pd(dba) (427.6 mg, 466.94 μmol), and P(o-tol) (426.4 mg, 1.40 mmol) were added at room temperature under nitrogen gas protection. The mixture was heated to 85 °C and stirred for approximately 2 h. After confirming the complete reaction of the starting material by thin-layer chromatography (petroleum ether / ethyl acetate = 1 / 1), the mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by preparative MPLC to give a yellow oily liquid, 6-[2-(cyclopropylcarbamoyl)phenyl]thio-3-[(E)-2-[5-(pyrrolidin-1-ylmethyl)-2-pyridyl]vinyl]indazole-1-carboxylic acid tert-butyl ester 30b (91 mg, 152.75 μmol, 16.36% yield).

[0545] The product was confirmed by LCMS.

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

[0547] Step 3 To a solution of 6-[2-(cyclopropylcarbamoyl)phenyl]thio-3-[(E)-2-[5-(pyrrolidin-1-ylmethyl)-2-pyridyl]vinyl]indazole-1-carboxylic acid tert-butyl ester 30b (100 mg, 167.85 μmol) in dichloromethane (5 mL) was added trifluoroacetic acid (191.4 mg, 1.68 mmol) and stirred for approximately 16 hours at room temperature. After confirming complete reaction by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (30 mL), adjusted to pH 8-9 with sodium carbonate solution, and extracted with dichloromethane (20 mL x 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by preparative thin layer chromatography to give a white solid N-cyclopropyl-2-({3-[(E)-2-{5-[(pyrrolidin-1-yl)methyl]pyridin-2-yl}vinyl]-1H-indazol-6-yl}thio)benzamide I-41 (15 mg, 30.26 μmol, 18.03% yield).

[0548] The product was confirmed by LCMS, 1HNMR and 1CNMR.

[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]

Chem.

[0552] Procedure 1 In a 250 mL single-neck flask, 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, and then cesium carbonate (18.94 g, 58.2 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered, and the filtrate was collected and diluted with ethyl acetate (200 mL) and washed with water (200 mL × 3). The organic phase was separated and dried over anhydrous sodium sulfate. The solid residue obtained after 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, 50.5% yield), was obtained.

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

[0554] Step 2 In a 250 mL single-neck flask, 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, and water (15 mL) was added. The mixture was heated to 50 °C and stirred for 5 hours. The reaction mixture was filtered, and the filtrate was collected and concentrated under reduced pressure. Dilute hydrochloric acid (1 mol / L) was added to the reaction mixture to adjust the pH to 5. After filtration and drying, a white solid, 3-fluoro-2-[(4-methoxyphenyl)methylthio]benzoic acid 31c (3.80 g, 13.0 mmol, 88.4% yield), was obtained.

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

[0556] Step 3 In a 250 mL single-neck flask, 3-fluoro-2-[(4-methoxyphenyl)methylthio]benzoic acid 31c (3.80 g, 13.0 mmol) was dissolved in N,N-dimethylformamide (38 mL). To the solution were added methanamine (506 mg, 19.5 mmol), N-methylmorpholine (3.943 g, 39.0 mmol), 1-hydroxybenzotriazole (2.64 g, 19.5 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.72 g, 19.5 mmol). The mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate (200 mL) and washed with water (200 mL x 3). The organic phase was separated, collected, and dried over anhydrous sodium sulfate. The solid residue obtained after concentration under reduced pressure was separated by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 4:1) to give a white solid, 3-fluoro-2-[(4-methoxyphenyl)methylthio]-N-methylbenzamide 31d (2.95 g, 9.66 mmol, yield 74.3%).

[0557] Step 4 In a 250 mL three-neck flask, 3-fluoro-2-[(4-methoxyphenyl)methylthio]-N-methylbenzamide 31d (2.95 g, 9.66 mmol) was dissolved in trifluoroacetic acid (32 mL), heated to 70 °C, and stirred for 3 h. The solid residue obtained after 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, 58.8% yield).

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

[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 under nitrogen gas, compound 3-iodo-6-nitro-1-tetrahydropyran-2-ylindazole 31 g (5 g, 13.40 mmol) in dioxane (60 mL) was added compound 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), and the mixture was heated to 100°C and reacted with stirring for 2 hours. After confirming the complete reaction of the starting material 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 give the crude product. The crude product was purified by column chromatography (dichloromethane / methanol = 20 / 1) to give the yellow solid compound 6-nitro-3-[(E)-2-[5-(2-pyrrolidine-1-ethoxy)-2-pyridyl]vinyl]-1-tetrahydropyran-2-ylindazole 31h (2.2 g, 4.64 mmol, 34.62% yield).

[0562] The product was confirmed by LCMS 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 A solution of 6-nitro-3-[(E)-2-[5-(2-pyrrolidine-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 with sodium sulfide nonahydrate (4 g, 16.20 mmol, 98.0% purity) and water (20 mL) at room temperature under nitrogen gas. The mixture was heated to 60 °C and stirred for 2 hours. After confirming complete reaction 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 layer was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by column chromatography (DCM / MeOH = 20 / 1 to 3:1) to obtain a brown oily compound 3-[(E)-2-[5-(2-pyrrolidine-1-ethoxy)-2-pyridyl]vinyl]-1-tetrahydropyran-2-yl-indazol-6-amine 31i (0.9 g, 2.05 mmol, yield 44.36%).

[0566] The product was confirmed by LCMS and HNMR.

[0567] MS-ESI calculated value [M+H]+ 434.2, found 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 To a solution of compound 3-[(E)-2-[5-(2-pyrrolidine-1-ethoxy)-2-pyridyl]vinyl]-1-tetrahydropyran-2-yl-indazol-6-amine 31i (1.3 g, 2.92 mmol) in acetic acid (12 mL) and acetonitrile (15 mL) was added an aqueous solution (6 mL) of sodium nitrite (221.8 mg, 3.21 mmol) and the mixture was stirred at 0-5°C for 1 hour. An aqueous solution (6 mL) of added sodium iodide (884.8 mg, 5.90 mmol) and iodine (370.9 mg, 1.46 mmol) was added and the mixture was stirred at 0°C for 3 hours. After confirming the complete reaction of the starting material by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (50 mL), adjusted to pH 8-9 with sodium carbonate, and extracted with dichloromethane (50 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give the crude product. The crude product was purified by column chromatography (DCM / MeOH = 20 / 1) to give a red solid, 6-iodo-3-[(E)-2-[5-(2-pyrrolidine-1-methoxy)-2-pyridyl]vinyl]-1-tetrahydropyran-2-ylindazole 31j (0.85 g, 1.56 mmol, 53.30% yield).

[0570] The product was confirmed by LCMS 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 Cesium carbonate (418.9 mg, 1.29 mmol), 3-fluoro-N-methyl-2-mercaptobenzamide 31e (142.9 mg, 771.45 μmol), and 1,1′-bisdiphenylphosphineferrocene palladium dichloride (233.3 mg, 321.44 μmol) were added to a solution of 6-iodo-3-[(E)-2-[5-(2-pyrrolidine-1-methoxy)-2-pyridyl]vinyl]-1-tetrahydropyran-2-ylindazole 31j (350 mg, 642.88 μmol) in N,N-dimethylformamide (5 mL) at room temperature under nitrogen gas. The mixture was heated to 80°C and reacted with stirring for 5 hours. After confirming the complete reaction of the starting material 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, and concentrated to give the crude product. The crude product was purified by neutral alumina column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give the yellow solid compound 3-fluoro-N-methyl-2-[3-[(E)-2-[5-(2-pyrrolidin-1-ethoxy)-2-pyridyl]vinyl]-1-tetrahydropyran-2-yl-indazol-6-yl]thiobenzamide 31k (250 mg, 415.47 μmol, 64.63% yield).

[0574] The product was confirmed by LCMS.

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

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

[0577] The product was confirmed by LCMS, 1HNMR and 1CNMR.

[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, 54.6, 54.41, 25.96, 223.06.

[0580]

Chem.

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

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

[0583] Step 2 In a 250 mL single-neck flask, 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, and water (15 mL) was added. The mixture was heated to 50 °C and stirred for 5 hours. The reaction mixture was filtered, and the filtrate was collected and concentrated under reduced pressure. Dilute hydrochloric acid (1 mol / L) was added to the reaction mixture to adjust the pH to 5. After filtration and drying, a white solid, 5-fluoro-2-[(4-methoxyphenyl)methylthio]benzoic acid 32c (3.94 g, 13.5 mmol, 84.38% yield), was obtained.

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

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

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

[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 Cesium carbonate (314.2 mg, 964.32 μmol), 5-fluoro-N-methyl-2-mercaptobenzamide 32e (148.8 mg, 803.60 μmol, obtained by synthesizing 32e from methyl 2,5-difluorobenzoate according to the synthesis method of 31e), and 1,1′-bisdiphenylphosphineferrocenepalladium dichloride (350 mg, 482.32 μmol) were added to a solution of 6-iodo-3-[(E)-2-[5-(2-pyrrolidine-1-methoxy)-2-pyridyl]vinyl]-1-tetrahydropyran-2-ylindazole 31j (350 mg, 642.88 μmol) in N,N-dimethylformamide (5 mL) at room temperature under nitrogen gas. The mixture was heated to 80°C and reacted with stirring for 5 hours. After confirming the complete reaction of the starting material 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, and concentrated to give the crude product. The crude product was purified by neutral alumina column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give the yellow solid compound 5-fluoro-N-methyl-2-[3-[(E)-2-[5-(2-pyrrolidin-1-ethoxy)-2-pyridyl]vinyl]-1-tetrahydropyran-2-yl-indazol-6-yl]thiobenzamide 32f (250 mg, 415.47 μmol, 64.63% yield).

[0589] The product was confirmed by LCMS.

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

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

[0592] The product was confirmed by LCMS, 1HNMR and 1CNMR.

[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 single-neck flask was used, and methyl 2-bromo-4-fluorobenzoate 33a (5.00 g, 21.5 mmol) was dissolved in N,N-dimethylformamide (50 mL). PMMBSH (3.98 g, 25.8 mmol) and cesium carbonate (10.51 g, 32.3 mmol) were added, followed by Pd(dppf)Cl (0.79 g, 1.08 mmol). The mixture was stirred at 120 °C overnight and reacted.

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

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

[0599] Step 2 In a 250 mL single-neck flask, 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, and water (15 mL) was added. The mixture was heated to 50 °C and stirred for 5 hours. The reaction mixture was filtered, and the filtrate was collected and concentrated under reduced pressure. Dilute hydrochloric acid (1 mol / L) was added to the reaction mixture to adjust the pH to 5. After filtration and drying, a white solid, 4-fluoro-2-[(4-methoxyphenyl)methylthio]benzoic acid 33c (3.80 g, 13.0 mmol, 88.4% yield), was obtained.

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

[0601] Step 3 In a 250 mL single-neck flask, 4-fluoro-2-[(4-methoxyphenyl)methylthio]benzoic acid 33c (3.80 g, 13.0 mmol) was dissolved in N,N-dimethylformamide (38 mL). To the solution were added methanamine (506 mg, 19.5 mmol), N-methylmorpholine (3.943 g, 39.0 mmol), 1-hydroxybenzotriazole (2.64 g, 19.5 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.72 g, 19.5 mmol). The mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate (200 mL) and washed with water (200 mL x 3). The organic phase was separated, collected, and dried over anhydrous sodium sulfate. The solid residue obtained after concentration under reduced pressure was separated by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 4:1) to give a white solid, 4-fluoro-2-[(4-methoxyphenyl)methylthio]-N-methylbenzamide 33d (2.95 g, 9.66 mmol, yield 74.3%).

[0602] Step 4 In a 250 mL three-neck flask, 4-fluoro-2-[(4-methoxyphenyl)methylthio]-N-methylbenzamide 33d (2.95 g, 9.66 mmol) was dissolved in trifluoroacetic acid (32 mL), heated to 70 °C, and stirred for 3 h. The solid residue obtained after 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, 58.8% yield).

[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 Cesium carbonate (359.1 mg, 1.10 mmol), 4-fluoro-N-methyl-2-thiobenzamide 33e (122.5 mg, 661.25 μmol), and 1,1′-bisdiphenylphosphineferrocene palladium dichloride (199.9 mg, 275.52 μmol) were added to a solution of 6-iodo-3-[(E)-2-[5-(2-pyrrolidine-1-methoxy)-2-pyridyl]vinyl]-1-tetrahydropyran-2-ylindazole 31j (300 mg, 551.04 μmol) in N,N-dimethylformamide (5 mL) at room temperature under nitrogen gas. The mixture was heated to 80°C and reacted with stirring for 5 hours. After confirming the complete reaction of the starting material 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, and concentrated to give the crude product. The crude product was purified by neutral alumina column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give the yellow solid compound 4-fluoro-N-methyl-2-[3-[(E)-2-[5-(2-pyrrolidin-1-ethoxy)-2-pyridyl]vinyl]-1-tetrahydropyran-2-yl-indazol-6-yl]thiobenzamide 33f (250 mg, 415.47 μmol, 75.40% yield).

[0605] The product was confirmed by LCMS.

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

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

[0608] The product was confirmed by LCMS, 1HNMR and 1CNMR.

[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, 12,3.53, 123.14, 122.40, 117.94, 117.45, 117.21, 114.07, 113.85, 68.36, 56.02, 55.87, 30.93, 27.58, 24.52.

[0611]

Chem.

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

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

[0614] Step 2 In a 250 mL single-neck flask, 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, and water (15 mL) was added. The mixture was heated to 50 °C and stirred for 5 hours. The reaction mixture was filtered, and the filtrate was collected and concentrated under reduced pressure. Dilute hydrochloric acid (1 mol / L) was added to the reaction mixture to adjust the pH to 5. After filtration and drying, a white solid, 2-fluoro-6-[(4-methoxyphenyl)methylthio]benzoic acid 34c (3.80 g, 13.0 mmol, 88.4% yield), was obtained.

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

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

[0617] Step 4 In a 250 mL three-neck flask, 2-fluoro-6-[(4-methoxyphenyl)methylthio]-N-methylbenzamide 34d (2.95 g, 9.66 mmol) was dissolved in trifluoroacetic acid (32 mL), heated to 70 °C, and stirred for 3 h. The solid residue obtained after 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, 58.8% yield).

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

[0620] The product was confirmed by LCMS.

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

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

[0623] The product was confirmed by LCMS, 1HNMR and 1CNMR.

[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 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) was added with cesium carbonate (3.90 g, 11.96 mmol) and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (0.88 g, 1.20 mmol) at room temperature under nitrogen gas. The mixture was heated to 80 °C and stirred for 2 h. After confirming complete reaction by thin-layer chromatography (dichloromethane / methanol = 20 / 1), the mixture was poured into water (30 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate=2 / 1-0 / 1) to give the yellow oily compound 2-(1H-indazol-5-ylthio)-N-methylbenzamide 35b (0.8 g, yield 47.2%).

[0628] The product was confirmed by LCMS.

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

[0630] Step 2 A solution of 2-(1H-indazol-5-ylthio)-N-methylbenzamide 35b (0.5 g, 1.76 mmol) and 2-bromo-5-(2-pyrrolidin-1-ylethoxy)pyridine 19a (478 mg, 1.76 mmol) in dimethyl sulfoxide (20 mL) was added with cesium carbonate (1.15 g, 3.53 mmol), 1,10-phenanthroline (95 mg, 0.53 mmol), and cuprous iodide (101 mg, 0.53 mmol) at room temperature under nitrogen atmosphere. The mixture was heated to 100 °C and stirred for 16 h. Thin-layer chromatography (20 / 1 dichloromethane / methanol) and LCMS confirmed the presence of the product. The mixture was poured into water (80 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, and concentrated to give the crude product. The crude product was purified by preparative high performance liquid chromatography to give a white solid compound N-methyl-2-[(1-{5-[2-(pyrrolidin-1-yl)ethoxy]pyridin-2-yl}-1H-indazol-5-yl)thio]benzamide I-29 (18 mg, yield 2.2%).

[0631] The product was confirmed by LCMS, 1HNMR and 1CNMR.

[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]

Chem.

[0635] Step 1 A solution of 6-bromo-1H-pyrazolo[4,3-b]pyridine 36a (2 g, 10.10 mmol) in N,N-dimethylformamide (20 mL) was added to N-methyl-2-mercaptobenzamide 1e (2.03 g, 12.12 mmol), cesium carbonate (6.58 g, 20.20 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (1.48 g, 2.02 mmol) at room temperature under nitrogen gas. The mixture was heated to 100 °C and stirred for 1 h. After confirming complete reaction by thin-layer chromatography (dichloromethane / methanol = 20 / 1), the mixture was poured into water (40 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by column chromatography (dichloromethane / methanol = 10 / 1) to obtain a brown solid compound N-methyl-2-(1H-pyrazolo[4,3-b]pyridin-6-ylthio)benzamide 36b (1.59 g, 5.59 mmol, yield 55.37%).

[0636] The product was confirmed by LCMS 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 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]pyridin-6-ylthio)benzamide 36b (1.6 g, 5.63 mmol) in N,N-dimethylformamide (5 mL) at room temperature, and the mixture was allowed to react with stirring at 25°C for 3.0 hours. After confirming the complete reaction of the raw materials by thin layer chromatography (dichloromethane / methanol = 20 / 1), the mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to give a crude product of brown solid 2-[(3-iodo-1H-pyrazolyl[4,3-b]pyridin-6-yl)thio]-N-methylbenzamide 36c (2.1 g, 5.12 mmol, yield 90.97%).

[0640] The product was confirmed by LCMS 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 To a solution of 2-[(3-iodo-1H-pyrazolyl[4,3-b]pyridin-6-yl)thio]-N-methylbenzamide 36c (100 mg, 243.76 μmol) in N,N-dimethylformamide (5 mL) were added 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) at room temperature under nitrogen gas protection. The reaction mixture was heated to 100°C and stirred for 16 hours. After confirming the complete reaction of the starting material by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was poured into water (20 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by preparative high-performance liquid chromatography to give the white solid compound N-methyl-2-({3-[(E)-2-(pyridin-2-yl)vinyl]-1H-pyrazolo[4,3-b]pyridin-6-yl}thio)benzamide I-21 (15.8 mg, 40.78 μmol, 16.73% yield).

[0644] The product was confirmed by LCMS, 1HNMR and 1CNMR.

[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 To a solution of 5-bromopyridine-2-nitrile 37a (1 g, 5.46 mmol) in methanol (10 mL) were added di-tert-butyl dicarbonate (2.39 g, 10.93 mmol) and nickel dichloride (129.88 mg, 546.43 μmol) at 0°C. Sodium borohydride (1.45 g, 38.25 mmol) was added portionwise slowly within 2.0 hours, and the mixture was stirred at 25°C for 16 hours. After confirming the complete reaction of the starting materials by thin-layer chromatography (petroleum ether / ethyl acetate = 2 / 1), the mixture was poured into water (50 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to obtain a white solid compound N-[(5-bromo-2-pyridyl)methyl]carbamic acid tert-butyl ester 37b (700 mg, 2.44 mmol, yield 44.61%).

[0649] The product was confirmed by LCMS 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]carbamic acid tert-butyl ester 37b (500 mg, 1.74 mmol) was added to a hydrochloric acid / methanol solution (15 mL) and reacted with stirring for 2.0 hours at 25° C. After confirming the complete reaction of the raw materials by LCMS, the reaction solution was concentrated under reduced pressure to give white solid compound (5-bromo-2-pyridyl)methylamine dihydrochloride 37c (290 mg, 1.55 mmol, yield 89.05%).

[0653] The product was confirmed by LCMS 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 (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 stirred at 100°C for 16 hours. After confirming complete reaction of the starting materials by thin-layer chromatography (petroleum ether / ethyl acetate = 2 / 1), the reaction mixture was concentrated under reduced pressure, saturated aqueous sodium bicarbonate (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 give 6-bromoimidazo[1,5-a]pyridine 37d (300 mg, 1.52 mmol, 85.07% yield) as a yellow solid.

[0657] The product was confirmed by LCMS 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 To a solution of 6-bromoimidazo[1,5-a]pyridine 37d (0.3 g, 1.52 mmol) in N,N-dimethylformamide (10 mL), N-methyl-2-mercaptobenzamide 1e (254.62 mg, 1.52 mmol), cesium carbonate (992.18 mg, 3.05 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (222.82 mg, 304.52 μmol) were added at room temperature. The mixture was heated to 80 °C and stirred for 2 h. After confirming complete reaction by thin-layer chromatography (dichloromethane / methanol = 15 / 1), the mixture was poured into water (40 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by preparative high performance liquid chromatography to obtain a yellow solid compound 2-imidazo[1,5-a]pyridin-6-ylthio-N-methylbenzamide 37e (87 mg, 307.04 μmol, yield 20.17%).

[0661] The product was confirmed by LCMS 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 To a solution of 2-imidazo[1,5-a]pyridin-6-ylthio-N-methylbenzamide 37e (110 mg, 388.22 μmol) in N,N-dimethylformamide (5 mL) was added iodine (167.50 mg, 659.97 μmol) and potassium carbonate (95.60 mg, 776.43 μmol) at room temperature and stirred for 3.0 hours at 25°C. After confirming complete reaction of the starting materials by thin-layer chromatography (dichloromethane / methanol = 20 / 1), the mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by preparative thin layer chromatography to obtain a yellow solid compound 2-(1-iodoimidazole[1,5-a]pyridin-6-yl)thio-N-methylbenzamide 37f (89 mg, 217.47 μmol, yield 56.02%).

[0665] The product was confirmed by LCMS 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 To a solution of 2-(1-iodoimidazole[1,5-a]pyridin-6-yl)thio-N-methylbenzamide 37f (200 mg, 488.71 μmol) in N,N-dimethylformamide (10 mL) were added 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) at room temperature under nitrogen gas protection. The reaction mixture was heated to 100°C and stirred for 16 hours. After confirming the complete reaction of the starting material by thin-layer chromatography (dichloromethane / methanol = 20 / 1), the mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with water (10 mL × 2) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography, then slurried in methanol (2 mL) and filtered. The filter cake was dried to obtain the yellow solid compound N-methyl-2-({1-[(E)-2-(pyridin-2-yl)vinyl]imidazo[1,5-a]pyridin-6-yl}thio)benzamide I-26 (6.3 mg, 16.30 μmol, 3.34% yield).

[0669] The product was confirmed by LCMS, 1HNMR and 1CNMR.

[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 To a solution of 2-diethoxyphosphoethyl acetate 38b (460.5 mg, 2.05 mmol) in tetrahydrofuran (10 mL) was added sodium hydride (89.6 mg, 3.73 mmol) at 0 °C under nitrogen gas protection. The mixture was stirred at 0 °C for 1.0 h, followed by the slow addition of pyridine-2-carboxaldehyde 38a (0.2 g, 1.87 mmol). The reaction mixture was stirred at 25 °C for 2 h. After confirming complete reaction of the starting materials by thin-layer chromatography (petroleum ether / ethyl acetate = 3 / 1), the mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to give crude (E)-3-(2-pyridyl)prop-2-enoic acid ethyl ester 38c (0.15 g, 846.50 μmol, 45.33% yield) as a yellow oil.

[0674] The product was confirmed by LCMS 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 To a solution of (E)-3-(2-pyridyl)prop-2-enoic acid ethyl ester 38c (0.2 g, 1.13 mmol) in tetrahydrofuran (8 mL) and water (2 mL) at room temperature, lithium hydroxide (81.1 mg, 3.39 mmol) was added and stirred at 30 °C for 16 h. After confirming complete reaction of the starting materials 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, followed by the addition of ethanol (20 mL), stirring for 30 min, and then filtering. The filtrate was concentrated under reduced pressure to give crude (E)-3-(2-pyridyl)prop-2-enoic acid 38d (0.15 g, 1.01 mmol, 89.11% yield) as a yellow solid.

[0678] The product was confirmed by LCMS 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 To a solution of 4-bromopyridine-2-nitrile 38e (0.2 g, 1.09 mmol) and methyl 2-mercaptobenzoate (202.2 mg, 1.20 mmol) in N-methylpyrrolidone (10 mL) was added potassium carbonate (302.1 mg, 2.19 mmol) and cuprous iodide (41.6 mg, 218.57 μmol) at room temperature. The mixture was heated to 100 °C under a nitrogen atmosphere and stirred for approximately 16 hours. After confirming complete reaction by thin-layer chromatography (petroleum ether / ethyl acetate = 5 / 1), the mixture was poured into water (30 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by thin-layer preparative chromatography (petroleum ether / ethyl acetate=5 / 1) to give 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 LCMS 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 To a solution of methyl 2-[(2-cyano-4-pyridyl)thio]benzoate 38f (200 mg, 739.90 μmol) in methanol (5 mL) was added di-tert-butyl dicarbonate (193.8 mg, 887.88 μmol) and Raney nickel (100 mg) at room temperature. The mixture was stirred under hydrogen gas at 25°C for 16 hours. After confirming complete reaction by thin-layer chromatography (ethyl acetate / petroleum ether = 3 / 1), the mixture was filtered and the filtrate was concentrated to give the crude product. The crude product was purified by thin-layer preparative chromatography (ethyl acetate / petroleum ether = 5 / 1-3 / 1) to give methyl 2-[[2-[(tert-butoxycarbonylamino)methyl]-4-pyridyl]thio]benzoate 38g (110 mg, 293.76 μmol, 39.70% yield) as a yellow oil.

[0686] The product was confirmed by LCMS 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 The compound methyl 2-[[2-[(tert-butoxycarbonylamino)methyl]-4-pyridyl]thio]benzoate 38g (140 mg, 373.88 μmol) was dissolved in a solution of hydrochloric acid in 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 LCMS, the reaction solution was concentrated under reduced pressure to obtain a crude product of the compound methyl 2-[[2-(aminomethyl)-4-pyridyl]mercapto]benzoate dihydrochloride 38h.

[0690] The product was confirmed by LCMS.

[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)prop-2-enoic acid 38d (24.0 mg, 160.88 μmol) in N,N-dimethylformamide (5 mL), compound 2-[[2-(aminomethyl)-4-pyridyl]mercapto]benzoate methyl 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 allowed to react at 25°C for 3.0 hours with stirring. After confirming the complete reaction of the starting material by thin-layer chromatography (petroleum ether / ethyl acetate = 3 / 1), the mixture was poured into water (20 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, and concentrated to give the crude product. The crude product was purified by thin-layer preparative chromatography (ethyl acetate / petroleum ether = 3 / 1) to give the yellow oily compound 2-[3-[(E)-2-(2-pyridyl)vinyl]imidazo[1,5-a]pyridin-7-yl]thiobenzoic acid methyl ester 38i (37 mg, 91.25 μmol, 56.72% yield).

[0693] The product was confirmed by LCMS 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 To a solution of 2-[3-[(E)-2-(2-pyridyl)vinyl]imidazo[1,5-a]pyridin-7-yl]thiobenzoic acid methyl ester 38i (13 mg, 32.06 μmol) in 1,2-dichloroethane (1.5 mL) was added phosphorus oxychloride (14.8 mg, 96.18 μmol) at room temperature, and the mixture was stirred at 80 °C for 16 hours. After confirming the complete reaction of the starting materials by LCMS, the mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The residue was purified by thin-layer preparative chromatography (ethyl acetate / petroleum ether = 3 / 1) to obtain a yellow solid compound methyl 2-[[2-[[(E)-3-(2-pyridyl)propa-2-alkenyl]amino]methyl]-4-pyridyl]thio]benzoate 38j (5 mg, 12.90 μmol, yield 40.25%).

[0697] The product was confirmed by LCMS.

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

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

[0700] The product was confirmed by LCMS, 1HNMR and 1CNMR.

[0701] MS-ESI calculated value [M+H]+374.1, actual measurement 374.1.

[0702] 1 H NMR (400 MHz, CDCl3&CD3OD) δ 8.59-8.71 (m, 3H), 8.13 (t, J = 7.2 Hz, 1H), 8.04 (d, J = 7.6 Hz, 1H), 7.83 (d, J = 7.6 Hz, 1H), 7.76 (s, 1H), 7.66 (s, 1H), 7.51-7.55 (m, 2H), 7.34 (t, J = 7.2 Hz, 1H), 7.23 (t, J = 7.2 Hz, 1H), 7.06 (d, J = 8.0 Hz, 1H), 6.82 (d, J = 6.8 Hz, 1H). 13C NMR (100 MHz, CDCl3&CD3OD) δ 168.38, 151.61, 144.03, 142.61, 139.59, 135.70, 132.80, 132.52, 131.63, 128.56, 125.73, 123.67, 123.29, 123.05 (s, 3H), 120.92, 119.86.

[0703] [ka]

[0704] Step 1 To a solution of 2-({3-[(E)-2-(pyridin-2-yl)vinyl]imidazo[1,5-a]pyridin-7-yl}thio)benzoic acid I-28 (23 mg, 61.59 μmol) in N,N-dimethylformamide (2 mL) was added methanamine (8.3 mg, 123.18 μmol), benzotriazol-1-yl-oxytripyrrolidino-phosphonium hexafluorophosphate (48.1 mg, 92.39 μmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (18.8 mg, 123.18 μmol) at room temperature. The mixture was stirred at 25 °C for 16 h. After confirming complete reaction by thin-layer chromatography (dichloromethane / methanol = 15 / 1), the mixture was poured into water (10 mL) and 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 give the crude product, which was purified by preparative high-performance liquid chromatography to give a white solid, N-methyl-2-({3-[(E)-2-(pyridin-2-yl)vinyl]imidazo[1,5-a]pyridin-7-yl}thio)benzamide I-27 (8 mg, 20.70 μmol, 33.61% yield).

[0705] The product was confirmed by LCMS and HNMR.

[0706] MS-ESI calculated value [M+H]+387.1, actual measurement 387.0.

[0707] 1 1H NMR (400 MHz, CD3OD) δ 8.57 (d, J = 4.4 Hz, 1H), 8.42 (d, J = 7.2 Hz, 1H), 7.96 (d, J = 15.6 Hz, 1H), 7.86 - 7.90 (m, 1H), 7.68 (d, J = 7.6 Hz, 1H), 7.63 (s, 1H), 7.51 - 7.56 (m, 3H), 7.92 - 7.44 (m, 3H), 7.32 - 7.35 (m, 1H), 6.67 (dd, J = 7.6, 1.6 Hz, 1H), 2.88 (s, 3H).

[0708]

Chem.

[0709] Procedure 1 6-[2-(Cyclopropylcarbamoyl)phenyl]sulfanyl-3-iodoindazole-1-carboxylic acid tert-butyl ester 27f (500 mg, 933.89 μmol) was dissolved in dioxane (20 mL) at room temperature, and 5-[2-(1-methyl-4-piperidinyl)ethoxy]-2-vinyl-pyridine 39a (230 mg, 933.89 μmol), palladium chloride (83 mg, 466.94 μmol), tris(o-methylphenyl)phosphorus (284 mg, 933.89 μmol), and triethylamine (473 mg, 4.67 mmol) were added. The reaction mixture was stirred at 90 °C under nitrogen gas protection for 1.5 h. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was purified by medium-pressure preparative separation to give a brown solid, 6-[2-(cyclopropylcarbamoyl)phenyl]sulfanyl-3-[(trans)-2-[5-[2-(1-methyl-4-piperidinyl)ethoxy]-2-pyridyl]vinyl]indazole-1-carboxylic acid tert-butyl ester 39b (200 mg, 305.89 μmol, 32.75% yield).

[0710] The product was confirmed by LCMS.

[0711] MS-ESI calculated value [M+H] + 654.3, actual measurement 654.4.

[0712] Step 2 6-[2-(Cyclopropylcarbamoyl)phenyl]sulfanyl-3-[(trans)-2-[5-[2-(1-methyl-4-piperidinyl)ethoxy]-2-pyridyl]vinyl]indazole-1-carboxylic acid tert-butyl ester 39b (800 mg, 1.22 mmol) was dissolved in dichloromethane (9 mL) and trifluoroacetic acid (3 mL) at room temperature, and the reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was poured into water (30 mL), adjusted to pH 8-9 with saturated sodium carbonate solution, and extracted with dichloromethane (20 mL x 3). The combined organic phase was washed with saturated brine (3 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was purified by high-pressure liquid chromatography to give a yellow solid product, N-cyclopropyl-2-({3-[(E)-2-{5-[2-(1-methylpiperidin-4-yl)ethoxy]pyridin-2-yl}vinyl]-1H-indazol-6-yl}thio)benzamide I-42 (69 mg, 124.61 μmol, 10.18% yield).

[0713] The product was confirmed by LCMS, H-NMR and C-NMR.

[0714] MS-ESI calculated value [M+H] + 554.3, actual measurement 554.1.

[0715] 11H NMR (400 MHz, CD3OD): δ (ppm) 8.30 (s, 2H), 8.23 (d, J = 2.8 Hz, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.66 (dd, J = 23.2, 12.6 Hz, 2H), 7.58 - 7.47 (m, 2H), 7.44 - 7.42 (m, 2H), 7.38 - 7.29 (m, 2H), 7.28 - 7.15 (m, 2H), 4.18 (t, J = 6.0 Hz, 2H), 3.49 (d, J = 11.4 Hz, 2H), 3.02 (s, 2H), 2.85 (s, 3H), 2.81 - 2.75 (m, 1H), 2.07 (d, J = 14.6 Hz, 2H), 1.91 (s, 1H), 1.88 - 1.81 (m, 2H), 1.56 (s, 2H), 0.74 (dt, J = 6.8, 3.4 Hz, 2H), 0.61 - 0.48 (m, 2H). 13 13C NMR (100 MHz, CD3OD) δ (ppm) 172.62, 167.55, 155.95, 149.33, 144.07, 143.61, 139.08, 138.44, 136.00, 135.50, 133.05, 131.75, 130.41, 129.17, 128.19, 126.32, 123.89, 123.19, 122.97, 122.63, 121.51, 115.02, 67.15, 55.53, 31.57, 30.67, 23.88, 6.59.

[0716]

Chem.

[0717] Step 1 6-[2-(Cyclopropylcarbamoyl)phenyl]sulfanyl-3-iodoindazole-1-carboxylic acid tert-butyl ester 27f (500 mg, 933.9 μmol) was dissolved in dioxane (5 mL) at room temperature, and 1-(3-pyrrolidin-1-ylpropyl)-4-vinylpyrazole 16c (230 mg, 1.12 mmol), palladium acetate (63 mg, 280.2 μmol), tris(o-methylphenyl)phosphorus (85 mg, 280.2 μmol), and triethylamine (284 mg, 2.80 mmol) were added. The reaction mixture was stirred at 95 °C under nitrogen gas protection for 1.5 hours. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10 / 1) to give a yellow solid, 6-[2-(cyclopropylcarbamoyl)phenyl]sulfanyl-3-[(trans)-2-[1-(3-pyrrolidin-1-ylpropyl)pyrazol-4-yl]vinyl]indazole-1-carboxylic acid tert-butyl ester 40a (300 mg, 489.6 μmol, yield 52.42%).

[0718] The product was confirmed by LCMS.

[0719] MS-ESI calculated value [M+H] + 613.3, measured value 613.3.

[0720] Step 2 6-[2-(Cyclopropylcarbamoyl)phenyl]sulfanyl-3-[(trans)-2-[1-(3-pyrrolidin-1-ylpropyl)pyrazol-4-yl]vinyl]indazole-1-carboxylic acid tert-butyl ester 40a (600 mg, 979.1 μmol) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (5 mL) at room temperature, and the reaction mixture was stirred at 25° C. for 16 hours. The reaction mixture was poured into water (20 mL), adjusted to pH 8-9 with saturated sodium carbonate solution, and extracted with dichloromethane (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by high-pressure liquid chromatography to give a yellow solid product, N-cyclopropyl-2-({3-[(E)-2-{1-[3-(pyrrolidin-1-yl)propyl]-1H-pyrazol-4-yl}vinyl]-1H-indazol-6-yl}thio)benzamide I-43 (29 mg, 56.6 μmol, yield 5.78%).

[0721] The product was confirmed by LCMS, H-NMR and C-NMR.

[0722] MS-ESI calculated value [M+H] + 513.2, actual measurement 513.1.

[0723] 11H NMR (400 MHz, CD3OD): δ (ppm) 8.54 (s, 1H), 7.98 (d, J = 8.6 Hz, 1H), 7.91 (s, 1H), 7.82 (s, 1H), 7.51 (s, 1H), 7.47 - 7.42 (m, 1H), 7.37 - 7.30 (m, 3H), 7.26 - 7.22 (m, 1H), 7.15 (s, 2H), 4.26 (t, J = 6.4 Hz, 2H), 3.07 (s, 4H), 2.99 - 2.92 (m, 2H), 2.82 - 2.73 (m, 1H), 2.27 - 2.18 (m, 2H), 1.98 (dd, J = 8.4, 5.4 Hz, 4H), 0.75 (td, J = 7.2, 5.2 Hz, 2H), 0.58 - 0.48 (m, 2H). 13 13C NMR (100 MHz, CD3OD) δ (ppm) 172.70, 143.55, 139.22, 138.79, 135.94, 135.61, 133.18, 131.67, 129.84, 129.14, 128.19, 125.90, 122.64, 122.38, 121.15, 119.14, 55.17, 53.95, 50.34, 28.74, 24.06, 23.79, 6.48.

[0724]

Chem.

[0725] Procedure 1 N-Cyclopropyl-3-fluoro-2-(3-iodo-1-tetrahydropyran-2-yl-indazol-6-yl)sulfanylbenzamide 41a (2 g, 3.72 mmol) was dissolved in dioxane (20 mL) at room temperature, and 1-(3-pyrrolidin-1-ylpropyl)-4-vinylpyrazole 16c (458 mg, 2.23 mmol), palladium dichloride (198 mg, 1.12 mmol), tris(o-methylphenyl)phosphorus (679 mg, 2.23 mmol), and triethylamine (1.1 g, 11.17 mmol) were added. The reaction mixture was stirred at 90 °C under nitrogen gas protection for 16 h. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was purified by medium pressure preparative separation to give a yellow solid product, N-cyclopropyl-3-fluoro-2-[3-[(trans)-2-[5-(pyrrolidin-1-ylmethyl)-2-pyridyl]vinyl]-1-tetrahydropyran-2-yl-indazol-6-yl]sulfanylbenzamide ...

Claims

1. A compound of formula (I), 【Chemical 1】 Here, the R １ contains a substituted cyclic structure; R ２ contains optionally substituted substituents; R ３ contains optionally substituted substituents; X １ is an optionally substituted atom, Or, a pharmaceutically acceptable prodrug of said compound, a pharmaceutically active metabolite of said compound, and / or a pharmaceutically acceptable salt of said compound.

2. The R １ 2. The compound of claim 1, wherein the ring structure of is substituted with a substituent containing a basic nitrogen atom.

3. The R １ 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.

4. The R １ However, (R １－０ ) ｎｒ０ - (R １－１ ) ｎｒ１ - (R １－２ ) ｎｒ２ - (R １－３ ) ｎｒ３ - (R １－４ ) ｎｒ４ - (R １－５ ) ｎｒ５ Including, among which, each R １－０ , R １－１ , R １－２ , R １－３ , R １－４ , and R １－５ each independently include an optionally substituted substituent, and wherein nr0, nr1, nr2, nr3, nr4m, and nr5 are each independently selected from 0 or more.

5. The R １－０ is a chemical bond or is selected from the group consisting of an optionally substituted alkenyl group, an optionally substituted alkynyl group, and an optionally substituted amino group.

6. The R １－０ is a chemical bond or is selected from the group consisting of an optionally substituted vinyl group, an optionally substituted ethynyl group, and an optionally substituted amino group.

7. The compound according to any one of claims 4 to 6, wherein nr0 is 0 or 1.

8. The R １－１ is a chemical bond or is selected from the group consisting of an optionally substituted amide group, an optionally substituted aryl ring group, and an optionally substituted aromatic heterocyclyl group.

9. The R １－１ is a chemical bond or is selected from the group consisting of an optionally substituted amide group, an optionally substituted phenyl group, and an optionally substituted aromatic heterocyclyl group.

10. The R １－１ is a chemical bond or is 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.

11. The compound according to any one of claims 4 to 10, wherein nr1 is 0 or 1.

12. The R １－２ is a chemical bond or is selected from the group consisting of hydrogen, protium, deuterium, tritium, and an optionally substituted hydroxy group.

13. The compound according to any one of claims 4 to 12, wherein nr2 is 0 or 1.

14. The R １－３ is a chemical bond or is selected from the group consisting of hydrogen, protium, deuterium, tritium, and an optionally substituted alkyl group.

15. The R １－３ is a chemical bond or is selected from the group consisting of hydrogen, protium, deuterium, tritium, an optionally substituted methyl group, an optionally substituted ethyl group, and an optionally substituted propyl group.

16. The compound according to any one of claims 4 to 15, wherein nr3 is 0 or 1.

17. The R １－４ is a chemical bond or is selected from the group consisting of hydrogen, protium, deuterium, tritium, an optionally substituted amino group, or an optionally substituted aliphatic heterocyclyl group.

18. The R １－４ is a chemical bond or is selected from the group consisting of hydrogen, protium, 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.

19. The compound according to any one of claims 4 to 18, wherein nr4 is 0 or 1.

20. The R １－５ is a chemical bond or is selected from the group consisting of hydrogen, protium, deuterium, tritium, and an optionally substituted alkyl group.

21. The R １－５ is a chemical bond or is selected from the group consisting of hydrogen, protium, deuterium, tritium, an optionally substituted methyl group, and an optionally substituted ethyl group.

22. The compound according to any one of claims 4 to 21, wherein nr5 is 0, 1 or 2.

23. The R ２ 23. The compound of any one of claims 1-22, wherein is an optionally substituted sulfhydryl group.

24. The R ２ is one or more R ２－１ and each R ２－１ The compound of any one of claims 1-23, wherein each independently is an optionally substituted substituent.

25. The R ２－１ 25. The compound of claim 24, wherein is an optionally substituted aryl group.

26. The R ２－１ The compound of any one of claims 24-25, wherein is an optionally substituted phenyl group.

27. The R ２－１ is one or more R ２－２ and each R ２－２ The compound of any one of claims 24-26, wherein each independently is an optionally substituted substituent.

28. The R ２－２ is selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, an optionally substituted carbonyl group, an optionally substituted carboxyl group, an optionally substituted amido group, and an optionally substituted alkyl group.

29. The R ２－２ is selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, an optionally substituted carbonyl group, an optionally substituted carboxyl group, an optionally substituted amido group, and an optionally substituted methyl group.

30. The R ２－２ is one or more R ２－３ and each R ２－３ 30. The compound of any one of claims 27-29, wherein each independently is an optionally substituted substituent.

31. The R ２－３ is selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, an optionally substituted alkyl group, an optionally substituted alicyclic group, and an optionally substituted amino group.

32. The R ２－３ is selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, an optionally substituted methyl group, an optionally substituted ethyl group, an optionally substituted cyclopropyl group, and an optionally substituted amino group.

33. The R ２－３ is one or more R ２－４ and each R ２－４ The compound of any one of claims 30-32, wherein each independently is an optionally substituted substituent.

34. The R ２－４ 34. The compound of claim 33, wherein is selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, an optionally substituted alkyl group, and an optionally substituted alicyclic group.

35. The R ２－４ is selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, an optionally substituted methyl group, an optionally substituted ethyl group, and an optionally substituted cyclopropyl group.

36. The R ３ 36. The compound of any one of claims 1-35, wherein is selected from the group consisting of hydrogen, protium, deuterium, and tritium.

37. The X １ 37. The compound of claim 36, wherein is selected from the group consisting of optionally substituted CH, and N.

38. A compound, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, and deuterated compound thereof, said compound having the structure: 【Chemistry 2】 (II) During the ceremony, Ring A is a 5- to 7-membered nitrogen-containing heterocyclyl; Ring B is a 5- to 7-membered aryl ring or heterocyclyl; Z is —C(O)NH—, —NHC(O)—, or 【Chemistry 3】 is selected from Ring E is an aryl ring or a heteroaryl ring; L ０ But O, S, N (R Ｌａ ), C １ -C ６ alkylene group, C(O), R Ｌａ But H, C １ -C ６ alkyl groups, L １ is a single bond, C １ -C ６ Alkylene group, C ２ -C ６ Alkenylene group, C ２ -C ６ Alkynylene group, -(C ０ -C ６ alkylene)-Q １ -(C ０ -C ６ alkylene)-, and Q １ is -O-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -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) ２ N (R Ｌｂ ) -, -N(R Ｌｂ ) S (O) ２ -, -S(O)-, -S(O)N(R Ｌｂ ) -, -N(R Ｌｂ )S(O)—, and the H atom of the alkylene group is selected from H, C １ -C １０ Alkyl group, C ２ -C １０ Alkenyl group, C ２ -C １０ Alkynyl group, halogen, cyano group, nitro group, azide group, C １ -C １０ Halogen-substituted alkyl group, hydroxy group, C １ -C １０ Alkoxy group, C １ -C １０ Halogen-substituted alkoxy group, amino group, C １ -C １０ optionally substituted with alkylamino groups, R Ｌｂ But H, C １ -C １０ Alkyl group, C ２ -C １０ Alkenyl group, C ２ -C １０ Alkynyl group, C ３ -C １０ Cycloalkyl group, C ３ -C １０ Cycloalkylalkyl group, C ６ -C １０ Aryl group, C ７ -C １２ It is selected from an arylalkyl group, a 4- to 10-membered heterocyclyl group, and a 4- to 10-membered heterocyclylalkyl group. L ２ is a single bond, C １ -C ６ alkylene group, -(C ０ -C ６ alkylene)-Q ２ -(C ０ -C ６ alkylene)-, and Q ２ 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) ２ N (R Ｌｃ ) -, -N(R Ｌｃ ) S (O) ２ -, -S(O)-, -S(O)N(R Ｌｃ ) -, -N(R Ｌｃ )S(O)—, and the H atom of the alkylene group is selected from H, C １ -C １０ Alkyl group, C ２ -C １０ Alkenyl group, C ２ -C １０ Alkynyl group, halogen, cyano group, nitro group, azide group, C １ -C １０ Halogen-substituted alkyl group, hydroxy group, C １ -C １０ Alkoxy group, C １ -C １０ Halogen-substituted alkoxy group, amino group, C １ -C １０ optionally substituted with alkylamino groups, R Ｌｃ But H, C １ -C １０ Alkyl group, C ２ -C １０ Alkenyl group, C ２ -C １０ Alkynyl group, C ３ -C １０ Cycloalkyl group, C ３ -C １０ Cycloalkylalkyl group, C ６ -C １０ Aryl group, C ７ -C １２ It is selected from an arylalkyl group, a 4- to 10-membered heterocyclyl group, and a 4- to 10-membered heterocyclylalkyl group. Y is H, —NR ７ R ８ , a nitrogen-containing heterocyclyl group, wherein the nitrogen-containing heterocyclyl group is selected from one or more R ９ and optionally substituted by R ９ is a halogen, a cyano group, an amino group, a 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 groups, C １ -C １０ Alkoxy-substituted alkyl groups, C １ -C １０ alkylamino-substituted alkyl group, -(C ０ -C ６ alkylene group)-(C ６ -C １０ aryl group), —SO ２ -(C ０ -C ６ alkylene group)-(C ６ -C １０ aryl group), —S—(C ０ -C ６ alkylene group)-(C ６ -C １０ aryl group), —O—(C ０ -C ６ alkylene group)-(C ６ -C １０ aryl group), -(C ０ -C ６ alkylene group)-(4- to 10-membered heterocyclyl group), —SO ２ -(C ０ -C ６ alkylene group)-(4- to 10-membered heterocyclyl group), —S—(C ０ -C ６ alkylene group)-(4- to 10-membered heterocyclyl group), —O—(C ０ -C ６ alkylene group)-(4- to 10-membered heterocyclyl group), -(C ０ -C ６ alkylene group)-(C ３ -C １０ cycloalkyl group), —SO ２ -(C ０ -C ６ alkylene group)-(C ３ -C １０ cycloalkyl group), -S-(C ０ -C ６ alkylene group)-(C ３ -C １０ cycloalkyl group), —O—(C ０ -C ６ alkylene group)-(C ３ -C １０ cycloalkyl groups). R ７ , R ８ However, independently H, C １ -C １０ Alkyl group, C ２ -C １０ Alkenyl group, C ２ -C １０ Alkynyl group, C ３ -C １０ Cycloalkyl group, C ３ -C １０ cycloalkylalkyl group, a 4- to 10-membered heterocyclyl group, a 4- to 10-membered heterocyclylalkyl group, wherein said C １ -C １０ Alkyl group, C ２ -C １０ Alkenyl group, C ２ -C １０ Alkynyl group, C ３ -C １０ Cycloalkyl groups and 4-10 membered heterocyclyl groups are H, C １ -C １０ Alkyl group, C ２ -C １０ Alkenyl group, C ２ -C １０ Alkynyl group, C ３ -C １０ Cycloalkyl group, C ３ -C １０ Cycloalkylalkyl group, C ６ -C １０ Aryl group, C ７ -C １２ It may be optionally substituted with a group selected from one or more of an arylalkyl group, a 4- to 10-membered heterocyclyl group, and a 4- to 10-membered heterocyclylalkyl group. R ４ are one or more independent substituents on the benzene ring, and each R ４ are independently H, halogen, C １ -C １０ Alkyl group, cyano group, C １ -C １０ Halogen-substituted alkyl group, C １ -C １０ Halogen-substituted alkoxy group, C １ -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 SO ２ R ４０１ , -SO ２ NR ４０１ R ４０２ , -NR ４０２ C(O)R ４０１ , —C(O)NR ４０１ R ４０２ , -NR ４０１ R ４０２ , -(C ０ -C ６ alkylene group)-NR ４０１ R ４０２ , -SR ４０１ , -S(O)R ４０１ , -S(O) ２ R ４０１ , -(C ０ -C ６ alkylene group)-(C ６ -C １０ aryl group), —SO ２ -(C ０ -C ６ alkylene group)-(C ６ -C １０ aryl group), —S—(C ０ -C ６ alkylene group)-(C ６ -C １０ aryl group), —O—(C ０ -C ６ alkylene group)-(C ６ -C １０ aryl group), -(C ０ -C ６ alkylene group)-(4- to 10-membered heterocyclyl group), —SO ２ -(C ０ -C ６ alkylene group)-(4- to 10-membered heterocyclyl group), —S—(C ０ -C ６ alkylene group)-(4- to 10-membered heterocyclyl group), —O—(C ０ -C ６ alkylene group)-(4- to 10-membered heterocyclyl group), -(C ０ -C ６ alkylene group)-(C ３ -C １０ cycloalkyl group), —SO ２ -(C ０ -C ６ alkylene group)-(C ３ -C １０ cycloalkyl group), -S-(C ０ -C ６ alkylene group)-(C ３ -C １０ cycloalkyl group), —O—(C ０ -C ６ alkylene group)-(C ３ -C １０ cycloalkyl groups), wherein said C ０ -C ６ Alkylene group, C １ -C １０ Alkyl group, C ２ -C １０ Alkenyl group, C ２ -C １０ Alkynyl group, C ３ -C １０ Cycloalkyl group, C ６ -C １０ The aryl group and the 4- to 10-membered heterocyclyl group are each independently selected from the group consisting of halogen, cyano, amino, hydroxy, 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 groups, C １ -C １０ Alkoxy-substituted alkyl groups, C １ -C １０ alkylamino-substituted alkyl group, -(C ０ -C ６ alkylene group)-(C ６ -C １０ aryl group), —SO ２ -(C ０ -C ６ alkylene group)-(C ６ -C １０ aryl group), —S—(C ０ -C ６ alkylene group)-(C ６ -C １０ aryl group), —O—(C ０ -C ６ alkylene group)-(C ６ -C １０ aryl group), -(C ０ -C ６ alkylene group)-(4- to 10-membered heterocyclyl group), —SO ２ -(C ０ -C ６ alkylene group)-(4- to 10-membered heterocyclyl group), —S—(C ０ -C ６ alkylene group)-(4- to 10-membered heterocyclyl group), —O—(C ０ -C ６ alkylene group)-(4- to 10-membered heterocyclyl group), -(C ０ -C ６ alkylene group)-(C ３ -C １０ cycloalkyl group), —SO ２ -(C ０ -C ６ alkylene group)-(C ３ -C １０ cycloalkyl group), -S-(C ０ -C ６ alkylene group)-(C ３ -C １０ cycloalkyl group), —O—(C ０ -C ６ alkylene group)-(C ３ -C １０ cycloalkyl groups), R ４０１ and R ４０２ However, independently, H, C １ -C １０ Alkyl group, C ３ -C １０ Cycloalkyl group, C ３ -C １０ Cycloalkylalkyl group, C ６ -C １０ Aryl group, C ６ -C １０ selected from an arylalkyl group, a 4- to 10-membered heterocyclyl group, and a 4- to 10-membered heterocyclyl alkyl group; R ５ but, 【Chemistry 4】 one or more independent substituents on the ring, and each R ５ are 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 groups, C １ -C １０ Alkoxy-substituted alkyl groups, C １ -C １０ alkylamino-substituted alkyl group, -(C ０ -C ６ alkylene group)-(C ６ -C １０ aryl group), —SO ２ -(C ０ -C ６ alkylene group)-(C ６ -C １０ aryl group), —S—(C ０ -C ６ alkylene group)-(C ６ -C １０ aryl group), —O—(C ０ -C ６ alkylene group)-(C ６ -C １０ aryl group), -(C ０ -C ６ alkylene group)-(4- to 10-membered heterocyclyl group), —SO ２ -(C ０ -C ６ alkylene group)-(4- to 10-membered heterocyclyl group), —S—(C ０ -C ６ alkylene group)-(4- to 10-membered heterocyclyl group), —O—(C ０ -C ６ alkylene group)-(4- to 10-membered heterocyclyl group), -(C ０ -C ６ alkylene group)-(C ３ -C １０ cycloalkyl group), —SO ２ -(C ０ -C ６ alkylene group)-(C ３ -C １０ cycloalkyl group), -S-(C ０ -C ６ alkylene group)-(C ３ -C １０ cycloalkyl group), —O—(C ０ -C ６ alkylene group)-(C ３ -C １０ cycloalkyl groups), R ６ are one or more independent substituents on the E ring, and each R ６ are 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 groups, C １ -C １０ Alkoxy-substituted alkyl groups, C １ -C １０ alkylamino-substituted alkyl group, -(C ０ -C ６ alkylene group)-(C ６ -C １０ aryl group), —SO ２ -(C ０ -C ６ alkylene group)-(C ６ -C １０ aryl group), —S—(C ０ -C ６ alkylene group)-(C ６ -C １０ aryl group), —O—(C ０ -C ６ alkylene group)-(C ６ -C １０ aryl group), -(C ０ -C ６ alkylene group)-(4- to 10-membered heterocyclyl group), —SO ２ -(C ０ -C ６ alkylene group)-(4- to 10-membered heterocyclyl group), —S—(C ０ -C ６ alkylene group)-(4- to 10-membered heterocyclyl group), —O—(C ０ -C ６ alkylene group)-(4- to 10-membered heterocyclyl group), -(C ０ -C ６ alkylene group)-(C ３ -C １０ cycloalkyl group), —SO ２ -(C ０ -C ６ alkylene group)-(C ３ -C １０ cycloalkyl group), -S-(C ０ -C ６ alkylene group)-(C ３ -C １０ cycloalkyl group), —O—(C ０ -C ６ alkylene group)-(C ３ -C １０ cycloalkyl groups).

39. 【Chemical 5】 Part 【Chemistry 6】 、 【Chemistry 7】 、 【Chemistry 8】 、 【Chemistry 9】 、 【Chemistry 10】 、 【Chemistry 11】 Preferably, 【Chemistry 12】 、 【Chemistry 13】 、 【Chemistry 14】 、 【Chemistry 15】 、 【Chemistry 16】 and more preferably selected from 【Chemistry 17】 where R ３ But H, C １ -C ６ 39. The compound according to claim 38, characterized in that it is selected from alkyl groups.

40. L ０ 40. A compound according to claim 38 or 39, characterized in that is selected from S, O, NH, a methylene group, preferably S.

41. L １ But C ２ -C ６ Alkenylene group, C ２ -C ６ Alkynylene group, -Q １ -(C ０ -C ６ alkylene group)-, -(C ０ -C ６ (alkylene group)-Q １ - is selected from, Preferably, Q １ But -N(R Ｌｂ )- and R Ｌｂ H, C １ -C ３ alkyl groups, More preferably, L １ but 【Chemistry 18】 ， 【Chemistry 19】 ， 【Chemistry 20】 ， 【Chemical 21】 ， 【Chemical 22】 ， 【Chemical 23】 41. Compounds according to any one of claims 38 to 40, characterized in that they are selected from the group consisting of -NH-.

42. Ring E is a benzene ring or a 5- or 6-membered nitrogen-containing heteroaryl ring; Preferably, 【Chemistry 24】 The part is, 【Chemistry 25】 ， 【Chemical 26】 ， 【Chemical 27】 ， 【Chemical 28】 ， 【Chemical Formula 29】 ， 【Chemistry 30】 ， 【Chemical Formula 31】 ， 【Chemical Formula 32】 ， 【Chemical 33】 ， 【Chemical 34】 ， 【Chemical 35】 ， 【Chemical Formula 36】 42. The compound according to any one of claims 38 to 41, characterized in that it is selected from any of the structures

43. L ２ is a single bond, C １ -C ６ alkylene group, -Q ２ -(C ０ -C ６ alkylene group), Preferably, Q ２ However, -O-, -S-, -N(R Ｌｃ )-, and R Ｌｃ But H, C １ -C ３ alkyl groups, More preferably, L ２ but, 【Chemical 37】 ， 【Chemical Formula 38】 ， 【Chemical Formula 39】 ， 【Chemistry 40】 ， 【Chemistry 41】 ， 【Chemistry 42】 ， 【Chemistry 43】 Compounds according to any one of claims 38 to 42, characterized in that they are selected from:

44. Y is -NR ７ R ８ and R ７ , R ８ However, independently, H, C １ -C ６ alkyl group, -(C ０ -C ６ alkylene group)-(C ３ -C ６ cycloalkyl groups), Preferably, Y is 【Chemical 44】 、 【Chemistry 45】 The compound according to any one of claims 38 to 43, characterized in that it is

45. Y is, 【Chemistry 46】 【Chemistry 47】 ， 【Chemistry 48】 ， 【Chemistry 49】 ， 【Chemistry 50】 ， 【Chemistry 51】 ， 【Chemistry 52】 ， 【Chemistry 53】 ， 【Chemical 54】 ， 【Chemistry 55】 ， 【Chemical Formula 56】 ， 【Chemical 57】 ， 【Chemistry 58】 ， 【Chemical 59】 ， 【Chemistry 60】 is selected from Preferably, Y is 【Hua 61】 ， 【Hua 62】 ， 【Chemistry 63】 ， 【Hua 64】 ， 【Chemistry 65】 ， 【Hua 66】 ， 【Chemical Formula 67】 ， 【Chemistry 68】 ， 【Chemical Formula 69】 ， 【Chemistry 70】 ， 【Chemical 71】 ， 【Chemical Formula 72】 ， 【Chemical 73】 ， 【Chemical Formula 74】 ， 【Chemistry 75】 is selected from Preferably, R ９ But H, C １ -C ６ Alkyl groups (e.g., —CH ３ , 【Chemical 76】 、 【Chemical 77】 、 【Chemical 78】 ), C １ -C ６ Hydroxy-substituted alkyl groups (e.g., 【Chemical 79】 、 【Chemistry 80】 ), C １ -C ６ Amino group-replacement alkyl groups (e.g., 【Chemistry 81】 、 【Chemistry 82】 ), C １ -C ６ Alkoxy-substituted alkyl groups, such as 【Chemistry 83】 、 【Chemistry 84】 ), C １ -C ６ Alkylamino-substituted alkyl groups, such as 【Chemistry 85】 、 【Chemistry 86】 、 【Hua 87】 、 【Hua 88】 ), -(C ０ -C ６ alkylene group)-(C ３ -C ６ cycloalkyl groups) (e.g., 【Chemistry 89】 、 【Chemistry 90】 、 【Chemistry 91】 、 【Chemistry 92】 ) are selected from More preferably, Y is 【Chemistry 93】 ， 【Chemistry 94】 ， 【Chemistry 95】 ， 【Chemistry 96】 ， 【Chemistry 97】 ， 【Chemistry 98】 ， 【Hua99】 ， 【Chemistry 100】 ， 【Chemistry 101】 ， 【Chemistry 102】 ， 【Chemistry 103】 ， 【Chemistry 104】 ， 【Chemistry 105】 ， 【Chemistry 106】 ， 【Chemistry 107】 ， 【Chemistry 108】 ， 【Chemistry 109】 ， 【Chemistry 110】 ， 【Chemistry 111】 ， 【Chemistry 112】 ， 【Chemistry 113】 ， 【Chemistry 114】 ， 【Chemistry 115】 Compounds according to any one of claims 38 to 43, characterized in that they are selected from:

46. [Catalog 116] Part 【Chemistry 117】 、 【Chemistry 118】 or 【Chemistry 119】 where: R ４ａ is -C(O)NR ４０１ R ４０２ , -(C ０ -C ６ alkylene group)-NR ４０１ R ４０２ , -C(O)R ４０１ , -C(O)OR ４０１ and R ４０１ and R ４０２ are independent, H, C １ -C ６ alkyl group, -(C ０ -C ６ alkylene group)-(C ３ -C ６ cycloalkyl groups), wherein said C ０ -C ６ Alkylene group, C １ -C ６ Alkyl group, C ３ -C ６ The cycloalkyl group is selected from the group consisting of halogen, cyano, amino, hydroxy, C １ -C ６ Alkyl group, C １ -C ６ It may be optionally substituted with a group selected from one or more halogen-substituted alkyl groups. R ４ｂ are one or more independent substituents on the benzene ring, and are H, halogen, cyano group, amino group, hydroxy group, C １ -C ６ Alkyl group, C １ -C ６ halogen-substituted alkyl groups; Preferably, R ４ａ but, 【Chemistry 120】 ， 【Chemistry 121】 ， 【Chemical Formula 122】 ， 【Chemical 123】 ， 【Chemical 124】 ， 【Chemistry 125】 ， 【126】 ， 【127】 ， 【128】 ， 【129】 ， 【Chemistry 130】 ， 【Chemistry 131】 ， 【132】 ， 【Chemistry 133】 ， 【Chemistry 134】 ， 【Chemistry 135】 ， 【Chemistry 136】 ， 【Chemistry 137】 ， 【Chemistry 138】 ， 【Chemistry 139】 ， 【Chemistry 140】 ， 【Chemistry 141】 ， 【142】 ， 【143】 ， 【Chemical 144】 ， 【Chemistry 145】 is selected from Preferably, R ４ｂ is H or a halogen, More preferably, 【Chemistry 146】 Part 【147】 、 【148】 、 【149】 、 【Chemistry 150】 、 【Chemistry 151】 、 【Chemistry 152】 、 【Chemistry 153】 、 【Chemistry 154】 、 【Chemistry 155】 、 【Chemistry 156】 、 【Chemistry 157】 、 【158】 、 【Chemistry 159】 The compound according to any one of claims 38 to 45, characterized in that it is

47. A compound having a structure selected from the group consisting of: 【Chemistry 160】 【change】 【change】 【change】 【change】 【change】 Or, a pharmaceutically acceptable prodrug of said compound, a pharmaceutically active metabolite of said compound, and / or a pharmaceutically acceptable salt of said compound.

48. 48. A pharmaceutical composition comprising a compound according to any one of claims 1-47 or a pharmaceutically acceptable prodrug of said compound, a pharmaceutically active metabolite of said compound and / or a pharmaceutically acceptable salt of said compound, and optionally a carrier.

49. Use of a compound of any one of claims 1 to 47 or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, deuterated compound, and / or a pharmaceutical composition of claim 48 in the preparation of a pharmaceutical composition for the prevention and / or treatment of a disease. Preferably, the disease is a proliferative disease mediated by a protein tyrosine kinase.

50. The disease is an ocular disease, and is preferably diabetic retinopathy (including non-proliferative diabetic retinopathy, proliferative diabetic retinopathy, and diabetic macular edema), age-related macular degeneration (AMD) (including neovascular (wet / exudative) AMD, dry / non-exudative AMD, and geographic atrophy), pathological choroidal neovascularization (CNV) due to any pathogenic mechanism (i.e., high myopia, trauma, sickle cell anemia, ocular histoplasmosis, angioid streaks (AS), traumatic choroidal rupture, optic nerve head drusen, and certain retinal dystrophies), or any pathogenic mechanism (i.e., high myopia, trauma, sickle cell anemia, ocular histoplasmosis, angioid streaks (AS), traumatic choroidal rupture, optic nerve head drusen, and certain retinal dystrophies). pathologic subretinal neovascularization due to (i.e., sickle cell retinopathy, Eales' disease, ocular ischemia syndrome, carotid-cavernous fistula (CCF), familial exudative vitreoretinopathy (FEVR), hyperviscosity syndrome, polyarteritis nodosa (PAN), bovine choroidal retinopathy (BCR), retinal vasculitis, sarcoidosis, or toxoplasmosis), uveitis, retinal vein occlusion (central or branch), ocular trauma, surgical edema, surgical neovascularization, cystoid macular edema (CMO), ocular ischemia, retinopathy of prematurity, Coat's disease, sickle cell retinopathy, and / or neovascular glaucoma; Preferably, the disease is retinal vein occlusion (central or branch); diabetic retinopathy (including non-proliferative, proliferative and diabetic macular edema) or retinal vein occlusion (central or branch), Alternatively, the disease is a tumor, preferably selected from breast cancer, lung cancer (particularly non-small cell lung cancer), adenocarcinoma, colorectal cancer, renal cancer, liver cancer, pancreatic adenocarcinoma, ovarian cancer, prostate cancer, glioma, glioblastoma, myeloma, leukemia, myeloid metaplasia of unknown cause, mesothelioma, and myelodysplastic syndrome; Preferably, the disease is a hematopoietic malignancy, more preferably, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), acute monocytic leukemia, 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 lymphoma (MZL), primary mediastinal large B-cell lymphoma (PMBCL), Burkitt's lymphoma (BL), lymphoma 50. The use according to claim 49, characterized in that the disease is selected from the group consisting of plasmacytic lymphoma (LPL), hairy cell leukemia (HCL), immunoblastic leukemia cell lymphoma, precursor B-cell lymphoblastic lymphoma, primary central nervous system lymphoma (PCNSL), T-cell NHL, precursor T-cell lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL), angioimmunoblastic T-cell lymphoma, extranodal NK / T-cell lymphoma, enteropathy-associated T-cell lymphoma (EATL), subcutaneous panniculitis-like T-cell lymphoma (SPTCL), anaplastic large cell lymphoma, and NK / T-cell lymphoma.

51. 48. A method of modulating kinase receptor activity comprising administering a compound of any one of claims 1-47, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, or deuterated equivalent thereof, and / or a pharmaceutical composition of claim 48, Preferably, the method selectively inhibits kinase receptor activity; More preferably, the kinase receptor comprises VEGFR, EGFR or a functionally active fragment thereof; Even more preferably, the method selectively inhibits VEGFR (including VEGFR1, VEGFR2, and VEGFR3) receptor activity while avoiding inhibition of EGFR receptor activity.

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