Protein tyrosine kinase inhibitor and medical application thereof

Abstract

The invention relates to a protein tyrosine kinase inhibitor for treating proliferative diseases or symptoms mediated by protein tyrosine kinase, such as eye diseases and malignant tumors accompanied by pathological neovascularization, retinal ischemia, retinal edema, diabetic retinopathy and the like. In particular to a compound with protein tyrosine kinase inhibitory activity and / or solubility and eye bioavailability improvement and application of the compound to treatment of eye diseases and malignant tumors.

Description

Protein tyrosine kinase inhibitor and medical use thereof Technical Field

[0001] The present invention relates to the field of medicine, and in particular to a protein tyrosine kinase inhibitor and its use in treating proliferative diseases or symptoms mediated by protein tyrosine kinase. Background Art

[0002] Age-related macular degeneration (AMD) and diabetic retinopathy (DR) are the most common ocular diseases and the leading causes of blindness in the elderly and working-age populations. These pathologies are associated with neovascularization and extravasation in the posterior segment of the eye. Wet AMD, in particular, is characterized by neovascularization from the choroidal microvascular bed and invasion into the subretinal space, while DR preferentially manifests extravasation and neovascularization at the retinal level. Both AMD and DR are characterized by endothelial cell (EC) proliferation and migration, increased vascular permeability, and inflammation, processes in which vascular endothelial growth factor-A (VEGF-A) and its corresponding receptor (VEGFR) play a key role. Furthermore, tumor growth and metastasis rely on the tumor vascular network for an adequate supply of oxygen and nutrients. Tumor angiogenesis relies on a highly complex process involving growth factor signaling, endothelial cell proliferation, extracellular matrix (ECM) remodeling, and stromal-cell interactions. Among these, vascular endothelial growth factor (VEGF) is the most important pro-angiogenic driver. Overexpression or upregulation of receptor tyrosine kinase (RTK) activity has been implicated in many proliferative disorders, such as ophthalmic diseases, tumors, and cancers. Receptor tyrosine kinases are kinase enzymes that modify proteins by chemically adding phosphate groups (phosphorylation). Phosphorylation typically leads to functional changes in the target protein by altering enzyme activity, cellular localization, or 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 has been to inhibit receptor tyrosine kinase (RTK) activity. In the treatment of ocular diseases such as age-related macular degeneration (AMD) and diabetic retinopathy (DR), the goal of protein tyrosine kinase inhibitor therapy is to counteract pathological neovascularization and disease progression, thereby preventing visual impairment. Furthermore, the importance of VEGFR as an angiogenic inducer in tumor growth, invasion, and extravasation makes it an excellent therapeutic target for a variety of cancers. To date, the US FDA has not approved small molecule tyrosine kinase inhibitors for the treatment of neovascular AMD and diabetic retinopathy.

[0003] Summary of the Invention

[0004] The present invention provides a compound for the treatment of proliferative diseases or symptoms mediated by protein tyrosine kinases, such as ocular diseases and malignant tumors accompanied by pathological neovascularization, retinal ischemia, retinal edema and diabetic retinopathy. The clinical success of VEGF antibody drugs (pegaptanib, ranibizumab, aflibercept and brolucizumab) has verified this concept. For example, the U.S. Food and Drug Administration (FDA) approved aflibercept (VEGF Trap-Eye) is used to treat neovascular age-related macular degeneration. The same molecular structure, ziv-aflibercept, has also been approved by the FDA for systemic use in combination therapy for patients with metastatic colorectal cancer. However, these VEGF antibody drugs need to be administered multiple times by retinal specialists through intravitreal injections. Frequent intravitreal injections are not convenient for clinicians and patients, and there are rare but serious injection-related risks (endophthalmitis, retinal detachment, cataracts, intraocular inflammation, etc.), which leads to many patients not receiving injections on time, resulting in poor drug efficacy. The good clinical results of VEGF antibody biologics, coupled with intravitreal injections, The challenges associated with radiation have led to efforts to develop small molecule anti-angiogenic agents as therapies for neovascular age-related macular degeneration, especially VEGFR tyrosine kinase inhibitors for ocular administration. Compared with recombinant proteins, small molecule targeted VEGFR tyrosine kinase inhibitors have many advantages. They can be made into eye drops to avoid intravitreal injection, can cross the cell membrane and directly interact with the cytoplasmic domain of receptor tyrosine kinase (RTK), and small molecule eye drops are economical and low cost. However, to date, no small molecule tyrosine kinase inhibitors have been approved for marketing by the US FDA for the treatment of neovascular age-related macular degeneration and diabetic retinopathy.

[0005] Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) are known as the most powerful vascular permeability agents and endothelial cell-specific mitogens, playing a key role in endothelial cell proliferation, migration, and angiogenesis. Angiogenesis is a crucial mechanism in many physiological and pathological processes, participating in the proliferation, migration, and survival of endothelial cells, leading to further tubule formation and ultimately promoting blood vessel formation. VEGF and its receptor (VEGFR) play a crucial role in angiogenesis associated with pathologies such as tumor development and ocular neovascularization. For example, VEGF expression levels are significantly positively correlated with the degree of vascularization in tumor tissue. VEGF acts on the VEGFR2 receptor, activating the phosphorylation of the VEGFR receptor tyrosine kinase and leading to aberrant cell signaling, thereby promoting endothelial cell proliferation and neovascularization. It is a key player in many different cancers and ocular diseases accompanied by pathological neovascularization. The compounds of the present invention (eg, those prepared in Example 1) have the ability to inhibit anti-angiogenic tyrosine kinases, effectively antagonize the tyrosine kinase activity of all VEGFR receptors (VEGFR1, VEGFR2, VEGFR3) and avoid being highly selective in inhibiting EGFR (Example 2).

[0006] VEGFR2 is the primary receptor for VEGF-induced endothelial cell signaling. During development and / or after tissue damage, upon binding of the ligand VEGF to the receptor, VEGFR2 undergoes autophosphorylation and becomes activated, inducing angiogenesis and bypassing blocked blood vessels. The compounds of the present invention have a significant inhibitory effect on VEGF-induced VEGFR2 autophosphorylation (pVEGFR2) in human endothelial cells, thereby blocking signal transduction in abnormal cells and thereby inhibiting neovascularization (Example 3). The primary function of VEGFR receptor signaling is to promote endothelial cell proliferation and neovascularization. The compounds of the present invention have been shown to inhibit VEGF-induced human endothelial cell proliferation at nanomolar concentrations. In summary, the compounds of the present invention are novel tyrosine kinase inhibitors. In addition to being used to treat neovascular age-related macular degeneration and diabetic retinopathy, this novel tyrosine kinase inhibitor can also be used in tumor therapy, blocking tumor neovascularization and the blood and nutrient supply required for tumor growth, leading to tumor cell death.

[0007] One of the goals of medicinal chemistry is to improve the bioavailability and stability of compounds to enhance their efficacy. Bioavailability refers to the rate and extent to which a therapeutic agent is absorbed from a pharmaceutical form and becomes available at the site of action. Existing VEGF tyrosine kinase inhibitors have problems with low solubility and / or low kinase inhibitory activity, which greatly affects the bioavailability of such compounds and thus reduces their efficacy. Compounds with low solubility are particularly challenging to formulate as eye drops. For example, although Axitinib has good inhibitory activity against VEGF tyrosine kinases (VEGFR1, VEGFR2, and VEGFR3), it has low solubility (<2 μg / ml). The present invention provides a compound that can have significant solubility, improved advantages, and / or excellent kinase inhibitory activity (Example 4), such as a thermodynamic solubility of 10 μg / ml or more, or a thermodynamic solubility of 100 μg / ml or more, or a thermodynamic solubility of 1000 μg / ml or more, such as an IC of VEGFR2. 50 100 nM or less, or IC for VEGFR2 50 10 nM or less, or IC for VEGFR2 50 1 nM or less.

[0008] Melanocytes in the eye are located in the retinal pigment epithelium, choroid, ciliary body, and iris at the back of the eye. The binding of compounds to melanin may affect ocular pharmacokinetics after topical administration. The present invention provides an eye drop formulation containing a compound for the treatment of age-related macular degeneration and diabetic retinopathy. These are diseases in the posterior segment of the eye, and the eye drop formulation containing the compound is aimed at effective delivery to the tissues at the back of the eye. In these cases, many drugs may be tightly bound to the melanin tissue at the back of the eye (retinal pigment epithelium, choroid) or the front of the eye (ciliary body, iris). Many clinical drugs bind to melanin, thereby affecting their ocular pharmacokinetics. The binding rate of compounds to melanin is an important factor in ocular pharmacokinetics and pharmacodynamics, mainly related to the tissue distribution of the compound inside the eyeball, and this must be taken into account in drug discovery and development. The present invention provides the effect of melanin on compounds (Example 5).

[0009] 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 the risk of “on-target” toxicity. Inhibition of VEGFR in the healthy vasculature has the potential to result in serious adverse events such as hypertension, bleeding, and thrombosis. Despite numerous clinical successes in oncology indications, the safety profile of oral VEGFR-2 inhibitors may be a major reason that has limited their clinical use and / or development in patients with age-related macular degeneration and diabetic retinopathy. In theory, topical eye drops could provide an effective therapy that limits systemic exposure and avoids the issue of on-target toxicity.

[0010] While topical ocular drug delivery has proven to be a successful strategy for treating diseases related to the anterior aspect of the eye, such as glaucoma, there are currently no FDA-approved topical therapies for ocular diseases related to the posterior ocular tissues, such as the retina and choroid, such as neovascular AMD and diabetic retinopathy. This is largely due to the anatomical and physiological barriers that have evolved in the human eye to protect it from exogenous substances. The tear film is one of the first barriers to overcome. Compounds in the anterior aspect of the eye can be rapidly washed away by the tear film, leading to nasolacrimal drainage. Therefore, compounds may need to be rapidly absorbed after topical instillation. However, absorption / penetration into ocular tissues can also be challenging. One absorption pathway involves penetration through the cornea. The cornea is composed of an epithelium with tight junctions and alternating lipophilic and hydrophilic layers. Another absorption pathway involves penetration into the conjunctiva and subsequent diffusion into the sclera. The sclera is a relatively more permeable ocular tissue. However, drugs that enter the conjunctiva tend to be "lost" to the systemic circulation due to the highly vascularized nature of this tissue. Compounds exposed in the sclera have the potential to diffuse into the choroid. The choroid 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 across the blood-retinal barrier (BRB). The BRB has similar functions to the blood-brain barrier and can be a formidable barrier to compound diffusion. Due to these anatomical and physiological barriers, it is estimated that less than 5% of a topically administered dose reaches the posterior ocular tissues. Despite these challenges associated with topical drug delivery, the present invention focuses on developing structure-activity relationships (SARs) related to ocular and blood exposure. Effective delivery to the posterior ocular tissues (choroid and retina) can be achieved through an ocular drop formulation containing the compound (Example 6). Rapid degradation of the compound in plasma is observed, which helps avoid systemic toxicity concerns. Axitinib exposure to posterior ocular tissues is relatively low, with exposure below the limit of detection in the retina. The present invention provides novel ocular formulations containing the compound that maintain sufficient drug concentrations in the posterior ocular segments (such as the choroid and retina) to bind to the relevant receptors targeting the eye, increase posterior ocular bioavailability, and improve the ocular delivery of existing topical therapeutics.

[0011] A major limitation of eye drops may be the need for high concentrations of the compound in the ocular formulation to achieve effective therapeutic drug levels in the posterior ocular tissues, due to the limited penetration of many eye drops through the corneal and conjunctival barriers. Depending on the compound (the molecule itself or its high concentration), the ocular formulation may have side effects on the anterior ocular tissues (including the conjunctiva, cornea, and / or lens), leading to various ocular surface damage, such as corneal epithelial defects and erosions. In particular, it has been observed clinically that treatment with EGFR antibody drugs may cause ocular side effects, such as epithelial degeneration and defects, ulcers, corneal epithelial thinning, erosions, and / or corneal edema, and keratitis. EGFR is a major factor in wound healing in human corneal epithelial cells. Therefore, it is essential to select compounds for topical ocular formulations that avoid inhibiting EGFR activity. The compounds of the present invention, in addition to effectively antagonizing the tyrosine kinase activity of VEGFR1, VEGFR2, and VEGFR3, are highly selective for inhibiting EGFR tyrosine kinase activity (Example 2).

[0012] Age-related macular degeneration (AMD) is an eye disease that causes vision loss due to degeneration of the macula, the area of ​​the retina that enables clear and detailed vision. In the wet form of AMD, choroidal blood vessels (choroidal neovascularization, CNV) sprout and expand into the submacula, leaking fluid and blood. This leads to retinal edema, scar tissue formation, and irreversible damage to the macula. Diabetic retinopathy is a common complication of diabetes, and many structural and functional abnormalities of the retina are associated with the development of diabetes. Almost all patients with diabetes over the age of 15 develop diabetic retinopathy. Diabetic retinopathy is divided into two stages based on the length of time it develops: the non-proliferative phase, also known as the early stage, which is characterized by vascular leakage; and the proliferative phase, or late stage, in which various growth factors induce the proliferation of retinal blood vessels. Based on the properties of the compounds of the present invention as effective VEGF receptor inhibitors, the present invention uses several animal models of choroidal and retinal neovascular diseases to evaluate the in vivo efficacy of the compounds of the present invention. Upregulation of VEGF leads to abnormal growth and leakage of retinal blood vessels, resulting in visual impairment. Intravitreal injection of VEGF in Dutch rabbits results in transient retinal leakage, similar to human wet AMD and diabetic retinopathy. The compounds of the present invention can demonstrate efficacy in inhibiting retinal leakage in this model. The oxygen-induced retinopathy (OIR) mouse model has reproducible and quantifiable proliferative retinal neovascularization, and human vascular pathology (vitreal neovascularization) is very similar to the clusters formed in mouse OIR. The compounds of the present invention are used to evaluate the in vivo efficacy of retinal vascular lesions using the OIR model. The laser-induced choroidal neovascularization (CNV) rat model applies photocoagulation green laser pulses to the rat eye to cause local rupture of Bruch's membrane (Bruch's membrane is the extracellular matrix between the retina and the choroid). The rupture of Bruch's membrane induces the production of local inflammatory factors and VEGF, leading to choroidal neovascularization (CNV). This model has demonstrated the formation of CNV after laser injury in humans, monkeys, pigs and rodents, and is a VEGF-dependent pathology. Streptozotocin (STZ)-induced diabetic rats are considered to be a useful preclinical animal model for studying the pathogenesis and treatment of human diabetic retinopathy. Significantly increased retinal vascular permeability, as evidenced by intraretinal hemorrhages and fluorescein leakage, was detected in all diabetic rat groups, representing preproliferative changes in diabetic retinopathy. However, a subset of these groups exhibited vitreous neovascularization, which adhered to the retina and retinal folds, a prominent manifestation of severe and proliferative diabetic retinopathy and represents the proliferative stage of diabetic retinopathy. During the progression of diabetic retinopathy, altered expression of the angiogenesis-related growth factor VEGF and its receptors VEGFR1 and VEGFR2 was observed in the retinas of streptozotocin (STZ)-induced diabetic mice.The ophthalmic preparation containing the compound of the present invention is used to evaluate the in vivo efficacy of diabetic retinopathy in a rat model of diabetic retinopathy induced by STZ, especially to inhibit vascular leakage and angiogenesis involved in the development of diabetic retinopathy in diabetic mice.

[0013] Based on the properties of the compounds of the present invention as effective VEGF receptor inhibitors, the present invention relates to compounds that can be used to treat pathological conditions caused by or aggravated by ocular angiogenesis, neovascularization and / or vascular leakage, such as in age-related macular degeneration (AMD), including neovascular (wet / exudative) AMD, dry AMD and geographic atrophy); diabetic retinopathy (including proliferative diabetic retinopathy, non-proliferative diabetic retinopathy and diabetic macular edema); pathological choroidal neovascularization (CNV) and vascular leakage caused by any mechanism, such as sickle cell disease, high myopia, trauma; traumatic choroidal rupture, ocular histoplasmosis, Optic nerve drusen, angioid streaks, or some retinal dystrophies; pathological retinal neovascularization and vascular leakage caused by any mechanism, such as sickle cell retinopathy, carotid cavernous fistula, Eales disease, ocular ischemic syndrome, hyperviscosity syndrome, familial exudative vitreoretinopathy, idiopathic occlusive arteritis, retinal vasculitis, avicular retinochoroidopathy, sarcoidosis, or toxoplasmosis; uveitis; retinal vein occlusion (central or branch); ocular trauma; surgically induced neovascularization; surgically induced edema; ocular ischemia; cystoid macular edema; retinopathy of prematurity; sickle cell retinopathy; Coats disease; and / or neovascular glaucoma.

[0014] In addition, the occurrence, development, 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, among which the vascular endothelial growth factor receptor (VEGFR) is highly expressed in many tumor cells and tumor vascular endothelial cells. The vascular endothelial growth factor receptor (VEGFR) family is directly related to the occurrence, development, and formation of tumor angiogenesis. In addition to eye diseases accompanied by pathological neovascularization, the clinical success of VEGF antibody drugs in the treatment of malignant tumor indications has verified this concept. The present invention can be used to treat solid tumors and leukemias, such as breast cancer, lung cancer (particularly non-small cell lung cancer), adenocarcinoma, colorectal cancer, renal cancer, liver cancer, pancreatic cancer, ovarian cancer, prostate cancer, glioma, glioblastoma, myeloma, acute myeloid leukemia, unrelated myeloid metaplasia, mesothelioma, and myelodysplastic syndrome. The present invention relates to drugs used to prevent the metastatic spread of tumors and the growth of micrometastases. According to an embodiment of the present invention, the compound is an anti-angiogenic kinase inhibitor. Examples of protein tyrosine kinase inhibitors that can be used to produce beneficial therapeutic results include receptor tyrosine kinase inhibitors, such as but not limited to VEGFR, Tie-2 and FGFR. In one aspect, the present invention provides a compound represented by formula (I),

[0015] wherein said R1 comprises a substituted cyclic structure;

[0016] R2 contains optionally substituted substituents;

[0017] R3 contains optionally substituted substituents;

[0018] X1 is an optionally substituted atom;

[0019] or a pharmaceutically acceptable prodrug of the compound, a pharmaceutically active metabolite of the compound and / or a pharmaceutically acceptable salt of the compound.

[0020] In one aspect, the present invention provides a compound of the present invention, or a pharmaceutically acceptable prodrug of the compound, a pharmaceutically active metabolite of the compound, and / or a pharmaceutically acceptable salt of the compound.

[0021] In one aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable prodrug, a pharmaceutically active metabolite and / or a pharmaceutically acceptable salt of the compound, and optionally a carrier.

[0022] In one aspect, the present invention provides a compound of the present invention, or a pharmaceutically acceptable prodrug of the compound, a pharmaceutically active metabolite of the compound and / or a pharmaceutically acceptable salt of the compound, and / or a pharmaceutical composition of the present invention, for use in preparing a medicament for treating a protein tyrosine kinase-mediated disease.

[0023] In one aspect, the present invention provides a compound of the present invention or a pharmaceutically acceptable prodrug of the compound, a pharmaceutically active metabolite of the compound and / or a pharmaceutically acceptable salt of the compound, and / or a pharmaceutical composition of the present invention, for use in treating protein tyrosine kinase-mediated diseases.

[0024] In one aspect, the present invention provides a method for treating a disease, comprising administering a compound of the present invention or a pharmaceutically acceptable prodrug, a pharmaceutically active metabolite and / or a pharmaceutically acceptable salt of the compound, and / or a pharmaceutical composition of the present invention.

[0025] In one aspect, the present invention provides a method for modulating kinase receptor activity, comprising administering a compound of the present invention or a pharmaceutically acceptable prodrug, a pharmaceutically active metabolite and / or a pharmaceutically acceptable salt of the compound, and / or a pharmaceutical composition of the present invention.

[0026] Those skilled in the art will readily appreciate other aspects and advantages of the present invention from the detailed description below. The detailed description below only shows and describes exemplary embodiments of the present invention. As will be appreciated by those skilled in the art, the disclosure of the present invention enables those skilled in the art to modify the disclosed embodiments without departing from the spirit and scope of the invention to which the present invention relates. Accordingly, the description in the specification of the present invention is intended to be exemplary only and not restrictive. DETAILED DESCRIPTION

[0027] The following describes the embodiments of the present invention through specific embodiments. People skilled in the art can easily understand other advantages and effects of the present invention from the contents disclosed in this specification.

[0028] Definition of terms

[0029] 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. For example, nitrogen atoms having basicity are known in the art, for example, the conjugate acid of the basic nitrogen atom has a pKa higher than 3 or higher than 5. For example, a nitrogen atom that is not basic may be a nitrogen atom directly connected to an O, a nitrogen atom directly connected to an aromatic ring, or a nitrogen atom directly connected to a carbonyl group.

[0030] In the present invention, the term "methyl" generally refers to a residue derived from a group of 1 carbon atom by removing a hydrogen atom. The methyl group may be substituted or unsubstituted, substituted or unsubstituted. The term "alkyl" generally refers to a saturated straight-chain or branched aliphatic hydrocarbon group having a residue derived from the same or different carbon atoms of the parent alkane by removing a hydrogen atom, which may be a straight-chain or branched group containing 1 to 20 carbon atoms, for example, an alkyl group containing 1 to 12 carbon atoms, for example, an alkyl group containing 1 to 6 carbon atoms. Non-limiting examples of alkyl groups include, but are not limited to, methyl (-CH2-), 1,1-ethyl (-CH(CH3)-), 1,2-ethyl (-CH2CH2)-, 1,1-propyl (-CH(CH2CH3)-), 1,2-propyl (-CH2CH(CH3)-), 1,3-propyl (-CH2CH2CH2-), 1,4-butyl (-CH2CH2CH2CH2-), and 1,5-butyl (-CH2CH2CH2CH2CH2-), and the like. The alkyl group may be substituted or unsubstituted, substituted or unsubstituted, for example, when substituted, the substituent may be substituted at any available point of attachment, and the substituent is preferably independently selected from one or more substituents selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio and oxo, 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, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 Aliphatic group.

[0031] In the present invention, the term "aryl" generally refers to a residue derived from the removal of hydrogen atoms from the same or different carbon atoms of an aromatic ring. The term "aromatic ring" can refer to a 6- to 14-membered all-carbon monocyclic ring or a fused polycyclic ring (i.e., a ring sharing adjacent pairs of carbon atoms) with a conjugated π electron system, which can be 6- to 10-membered, such as benzene and naphthalene. The aromatic ring can be fused to a heteroaryl, heterocyclyl, or cycloalkyl ring, wherein the ring connected to the parent structure is the aryl ring. The aryl group can be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from the following groups: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio.

[0032] In the present invention, the term "heteroaryl" generally refers to a residue derived from the removal of a hydrogen atom from the same or different carbon atoms of a heteroaromatic ring. The term "heteroaromatic ring" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms can be selected from the group consisting of oxygen, sulfur, and nitrogen. Heteroaryl groups can be 5 to 10-membered, and can be 5- or 6-membered, such as furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. The heteroaryl ring can be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring attached to the parent structure is the heteroaryl ring. The heteroarylene group may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio.

[0033] In the present invention, the term "aliphatic heterocyclic group" generally refers to a stable non-aromatic 3- to 7-membered monocyclic ring structure, a fused 7- to 10-membered bicyclic heterocyclic ring structure, or a bridged 6- to 10-membered bicyclic heterocyclic ring structure. These ring structures may be saturated or partially saturated. In addition to carbon atoms, these ring structures may contain one or more heteroatoms, wherein the heteroatoms may be selected from the group consisting of oxygen, sulfur, and nitrogen. For example, the ring structure may contain 1 to 4 heteroatoms as defined above. When used to refer to atoms in a heterocyclic ring structure, the term "nitrogen" may include nitrogen that has undergone substitution reactions. A heterocyclylene group may be substituted or unsubstituted.

[0034] In the present invention, the term "alicyclic group" generally refers to a residue derived from the same carbon atom or different carbon atoms of a carbocyclic ring by removing hydrogen atoms. The term "alicyclic" generally refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon, and the carbocyclic ring contains 3 to 20 carbon atoms, can contain 3 to 12 carbon atoms, can contain 3 to 10 carbon atoms, and can contain 3 to 8 carbon atoms. Non-limiting examples of monocyclic carbocycles include cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, cyclohexadiene, cycloheptane, cycloheptatriene, cyclooctane, etc.; polycyclic carbocycles can include spirocyclic, fused ring and bridged ring carbocycles. Carbocyclylene can be substituted or unsubstituted.

[0035] As used herein, the term "partially unsaturated" generally refers to a cyclic structure containing at least one double or triple bond between the ring molecules. The term "partially unsaturated" encompasses cyclic structures with multiple unsaturations, but is not intended to include aromatic or heteroaromatic rings as defined herein. The term "unsaturated" refers to a moiety having one or more degrees of unsaturation.

[0036] In the present invention, the term "halogen" generally refers to fluorine, chlorine, bromine, and iodine, for example, it can be fluorine or chlorine.

[0037] In the present invention, the term "aliphatic group" generally refers to a straight-chain, branched-chain, or cyclic hydrocarbon having 1-12 carbon atoms, which is either fully saturated or has one or more unsaturated units, provided the unsaturated units are not aromatic. For example, suitable aliphatic groups may include substituted or unsubstituted straight-chain, branched, or cyclic alkyl, alkenyl, alkynyl groups, and mixtures thereof; such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl groups. For example, aliphatic groups have 1-12, 1-8, 1-6, 1-4, or 1-3 carbon atoms.

[0038] In the present invention, the term "optional" or "optionally" generally means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group may but need not be present, and the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[0039] 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, which are independently replaced by a corresponding number of substituents. The substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) whether substitution is possible or not without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

[0040] One or more hydrogen atoms, for example up to 5, for example 1 to 3, in a group are independently replaced by a corresponding number of substituents. The substituents are only in their possible chemical positions, and a person skilled in the art can determine (by experiment or theory) which substitutions are possible or impossible without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

[0041] In the present invention, the term "compound" generally refers to a substance having two or more different elements. For example, the compound of the present invention may be an organic compound, for example, a compound having a molecular weight of 500 or less, a compound having a molecular weight of 1000 or less, a compound having a molecular weight of 1000 or more, or a compound having a molecular weight of 10,000 or more, or a compound having a molecular weight of 10,000 or more or 100,000 or more. In the present invention, a compound may also refer to a compound connected by chemical bonds, for example, a compound in which one or more molecules having a molecular weight of 1000 or less are connected to a biomacromolecule by chemical bonds, and the biomacromolecule may be a polysaccharide, protein, nucleic acid, polypeptide, etc. For example, the compound of the present invention may include a compound in which a protein is connected to one or more molecules having a molecular weight of 1000 or less, a compound in which a protein is connected to one or more molecules having a molecular weight of 10,000 or less, or a compound in which a protein is connected to one or more molecules having a molecular weight of 100,000 or less.

[0042] In some embodiments, the compounds of the present invention may be in the form of a "mixture". The "mixture form" of a compound refers to a composition comprising the compound of the present invention, its tautomers, mesomers, racemates, enantiomers, and diastereomers.

[0043] Unless otherwise indicated, the structures described herein may also include compounds that differ only in the presence or absence of one or more isotopically enriched atoms. For example, compounds identical to the structures described herein 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.

[0044] In the present invention, the term "pharmaceutical composition" generally refers to a mixture containing one or more compounds of the present invention, or their physiologically / pharmaceutically acceptable salts or prodrugs, and other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. Pharmaceutical compositions can facilitate administration to an organism, facilitating the absorption of the active ingredient and thereby exerting its biological activity. The preparation of conventional pharmaceutical compositions can be found in the Chinese Pharmacopoeia.

[0045] In the present invention, the term "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" generally refers to a salt of the compound or ligand-drug conjugate of the present invention, or a salt of the compound described in the present invention. Such salts may be safe and / or effective when used in mammals 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, ethanesulfonate, benzenesulfonate, and p-toluenesulfonate.

[0046] In the present invention, the term "solvate" or "solvate compound" generally refers to a ligand-drug conjugate compound of the present invention that forms a pharmaceutically acceptable solvate with one or more solvent molecules, non-limiting examples of which include water, ethanol, acetonitrile, isopropanol, DMSO, and ethyl acetate. A "pharmaceutically acceptable prodrug" is a compound that can be converted to a specific compound or a pharmaceutically acceptable salt of such a compound under physiological conditions or by solvolysis. A "pharmaceutically active metabolite" is intended to mean a pharmacologically active product produced by the metabolism of a specific compound or its salt in vivo. Metabolites of a compound can be identified using conventional techniques known in the art and their activity can be determined using tests as described herein.

[0047] Pharmaceutical compositions may be in the form of sterile injectable aqueous or oily suspensions for intramuscular and subcutaneous administration. Such suspensions may be formulated using suitable dispersants or wetting agents and suspending agents such as those described above, according to known techniques. Sterile injectable formulations may also be sterile injectable solutions or suspensions prepared in a nontoxic, parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Furthermore, sterile fixed oils may conveniently be used as solvents or suspending media. For example, any blended fixed oil, including synthetic mono- or diglycerides, may be used. Injectable formulations may also be prepared using fatty acids such as oleic acid. For ocular administration, the compounds of the present invention are delivered in a pharmaceutically acceptable ophthalmic carrier such that the compound remains in contact with the ocular surface for a sufficient period of time to allow the compound to penetrate the cornea and internal regions of the eye, including, for example, the anterior chamber, posterior chamber, vitreous body, aqueous humor, vitreous humor, cornea, iris / ciliary body, lens, choroid / retina, and varicose veins. Pharmaceutically acceptable ophthalmic carriers may be ointments, vegetable oils, or encapsulating materials. The compounds of the present invention may also be injected directly into the vitreous and aqueous humor.

[0048] In the present invention, the term "comprising" generally refers to including the features specified but not excluding other elements. The terms "above" and "below" generally refer to including the number.

[0049] In the present invention, the term "about" generally refers to a variation within the range of 0.5%-10% above or below the specified value, for example, a variation within the range of 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, or 10% above or below the specified value.

[0050] Detailed Description of the Invention

[0051] In one aspect, the present invention provides a compound represented by formula (I),

[0052] wherein said R1 comprises a substituted cyclic structure;

[0053] R2 contains optionally substituted substituents;

[0054] R3 contains optionally substituted substituents;

[0055] X1 is an optionally substituted atom;

[0056] or a pharmaceutically acceptable prodrug of the compound, a pharmaceutically active metabolite of the compound and / or a pharmaceutically acceptable salt of the compound.

[0057] For example, the cyclic structure of R1 is substituted with a substituent containing a basic nitrogen atom.

[0058] 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 heterocyclic group.

[0059] In one aspect, the present invention provides a compound represented by formula (I),

[0060] Wherein, the R1 comprises (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 1-5Each independently comprises an optionally substituted substituent, wherein nr0, nr1, nr2, nr3, nr4 and nr5 are each independently selected from 0 or greater; wherein the cyclic structure of R1 is substituted with a substituent comprising a basic nitrogen atom;

[0061] R2 contains optionally substituted substituents;

[0062] R3 contains optionally substituted substituents;

[0063] X1 is an optionally substituted atom;

[0064] or a pharmaceutically acceptable prodrug of the compound, a pharmaceutically active metabolite of the compound and / or a pharmaceutically acceptable salt of the compound.

[0065] In one aspect, the present invention provides a compound represented by formula (I),

[0066] Wherein, the R1 comprises (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 greater; wherein the cyclic structure of R1 is substituted with a substituent comprising a basic nitrogen atom;

[0067] R2 contains optionally substituted substituents;

[0068] R3 contains optionally substituted substituents;

[0069] X1 is an optionally substituted atom;

[0070] or a pharmaceutically acceptable prodrug of the compound, a pharmaceutically active metabolite of the compound and / or a pharmaceutically acceptable salt of the compound.

[0071] In one aspect, the present invention provides a compound represented by formula (I),

[0072] Wherein, the R1 comprises (C=C) nr0 -(R1-1 ) 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 greater;

[0073] Each of the R 1-1 Selected from the following groups: optionally substituted aryl, and optionally substituted heteroaryl; for example, each R 1-1 is selected from the group consisting of an optionally substituted aryl group, an optionally substituted 5-membered heteroaromatic ring group, and an optionally substituted 6-membered heteroaromatic ring group; for example, each R 1-1 is selected from the following group: an optionally substituted aryl group, an optionally substituted 5-membered heteroaromatic ring group containing 1 N atom, a 5-membered heteroaromatic ring group containing 2 N atoms, a 6-membered heteroaromatic ring group containing 1 N atom, and an optionally substituted 6-membered heteroaromatic ring group containing 2 N atoms; for example, each R 1-1 is selected from the group consisting of optionally substituted aryl, optionally substituted pyridinyl, and optionally substituted pyrazolyl;

[0074] Each of the R 1-2 Selected from the group consisting of: chemical bonds and hydroxyl groups; for example, each R 1-2 Can be - or -O-;

[0075] Each of the R 1-3 is selected from optionally substituted alkyl groups; for example, each R 1-3 may be optionally substituted methyl, optionally substituted ethyl, and optionally substituted propyl;

[0076] Each of the R 1-4 is selected from optionally substituted alicyclic groups; for example, each R 1-4 It can be an optionally substituted 5-membered aliphatic heterocyclic group, and an optionally substituted 6-membered aliphatic heterocyclic group; for example, each R 1-4 is selected from the following groups: an optionally substituted 5-membered alicyclic group containing 1 N atom, a 5-membered alicyclic group containing 2 N atoms, a 6-membered alicyclic group containing 1 N atom, and an optionally substituted 6-membered alicyclic group containing 2 N atoms; for example, each R 1-4 selected from the group consisting of optionally substituted pyrrolyl, optionally substituted piperidinyl, and optionally substituted piperazinyl;

[0077] Each of the R 1-5 is selected from optionally substituted alkyl groups; for example, each R 1-5 It may be an optionally substituted methyl group; for example, it may contain two R 1-5 ;

[0078] R2 contains optionally substituted substituents;

[0079] R3 contains optionally substituted substituents;

[0080] X1 is an optionally substituted atom;

[0081] or a pharmaceutically acceptable prodrug of the compound, a pharmaceutically active metabolite of the compound and / or a pharmaceutically acceptable salt of the compound.

[0082] In one aspect, the present invention provides a compound represented by formula (I),

[0083] Wherein, the R1 comprises (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 greater;

[0084] Each of the R 1-1 Selected from the following groups: optionally substituted aryl, and optionally substituted heteroaryl; for example, each R 1-1 is selected from the group consisting of an optionally substituted aryl group, an optionally substituted 5-membered heteroaromatic ring group, and an optionally substituted 6-membered heteroaromatic ring group; for example, each R 1-1 is selected from the following group: an optionally substituted aryl group, an optionally substituted 5-membered heteroaromatic ring group containing 1 N atom, a 5-membered heteroaromatic ring group containing 2 N atoms, a 6-membered heteroaromatic ring group containing 1 N atom, and an optionally substituted 6-membered heteroaromatic ring group containing 2 N atoms; for example, each R 1-1 is selected from the group consisting of optionally substituted aryl, optionally substituted pyridinyl, and optionally substituted pyrazolyl;

[0085] Each of the R 1-2 Selected from the group consisting of: chemical bonds and hydroxyl groups; for example, each R 1-2 Can be - or -O-;

[0086] Each of the R 1-3 is selected from optionally substituted alkyl groups; for example, each R 1-3 may be optionally substituted methyl, optionally substituted ethyl, and optionally substituted propyl;

[0087] Each of the R 1-4is selected from optionally substituted alicyclic groups; for example, each R 1-4 It can be an optionally substituted 5-membered aliphatic heterocyclic group, and an optionally substituted 6-membered aliphatic heterocyclic group; for example, each R 1-4 is selected from the following groups: an optionally substituted 5-membered alicyclic group containing 1 N atom, a 5-membered alicyclic group containing 2 N atoms, a 6-membered alicyclic group containing 1 N atom, and an optionally substituted 6-membered alicyclic group containing 2 N atoms; for example, each R 1-4 selected from the group consisting of optionally substituted pyrrolyl, optionally substituted piperidinyl, and optionally substituted piperazinyl;

[0088] Each of the R 1-5 is selected from optionally substituted alkyl groups; for example, each R 1-5 It may be an optionally substituted methyl group; for example, it may contain two R 1-5 ;

[0089] R2 comprises optionally substituted-S-optionally substituted aryl-optionally substituted amide-optionally substituted alkyl, or-S-optionally substituted aryl-optionally substituted amide-optionally substituted alicyclic; for example, R2 comprises optionally substituted-S-optionally halogen-substituted aryl-optionally substituted amide-optionally substituted methyl, or-S-optionally substituted aryl-optionally substituted amide-optionally substituted cyclopropyl;

[0090] R3 comprises hydrogen or any isotope of hydrogen;

[0091] X1 is optionally substituted CH;

[0092] or a pharmaceutically acceptable prodrug of the compound, a pharmaceutically active metabolite of the compound and / or a pharmaceutically acceptable salt of the compound.

[0093] For example, the R1 comprises (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 optionally substituted substituents, wherein nr0, nr1, nr2, nr3, nr4 and nr5 are each independently selected from 0 or greater.

[0094] For example, the R 1-0 is a chemical bond or is selected from the following group: optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted amino. 1-0 is a chemical bond or is selected from the following group: 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.

[0095] For example, the R 1-1 is a chemical bond or is selected from the following group: an optionally substituted amide group, an optionally substituted aromatic ring group, and an optionally substituted heteroaromatic ring group. 1-1 is a chemical bond or is selected from the following group: an optionally substituted amide group, an optionally substituted phenyl group, and an optionally substituted heteroaromatic ring group. 1-1 is selected from the group consisting of an optionally substituted aryl group, an optionally substituted 5-membered heteroaromatic ring group, and an optionally substituted 6-membered heteroaromatic ring group; for example, each R 1-1 is selected from the following group: an optionally substituted aryl group, an optionally substituted 5-membered heteroaromatic ring group containing 1 N atom, a 5-membered heteroaromatic ring group containing 2 N atoms, a 6-membered heteroaromatic ring group containing 1 N atom, and an optionally substituted 6-membered heteroaromatic ring group containing 2 N atoms; for example, each R 1-1 is selected from the group consisting of an optionally substituted aryl, an optionally substituted pyridyl, and an optionally substituted pyrazolyl. 1-1 is a chemical bond or is selected from the following group: 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.

[0096] For example, the R 1-2 is a chemical bond or is selected from the following group: hydrogen, protium, deuterium, tritium, and optionally substituted hydroxyl. For example, each R 1-2 For example, nr2 is 0 or 1. For example, nr2 is 0, 1, 2, or 3.

[0097] For example, the R 1-3 is a chemical bond or is selected from the following group: hydrogen, protium, deuterium, tritium, and an optionally substituted alkyl group. 1-3 is a chemical bond or is selected from the following group: 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 It can be an optionally substituted methyl, an optionally substituted ethyl and an optionally substituted propyl. For example, the nr3 is 0 or 1. For example, nr3 is 0, 1, 2, or 3.

[0098] For example, the R 1-4is a chemical bond or is selected from the following group: hydrogen, protium, deuterium, tritium, an optionally substituted amino group and an optionally substituted aliphatic heterocyclic group. 1-4 is a chemical bond or is selected from the following group: 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 It can be an optionally substituted 5-membered aliphatic heterocyclic group, and an optionally substituted 6-membered aliphatic heterocyclic group; for example, each R 1-4 is selected from the following groups: an optionally substituted 5-membered alicyclic group containing 1 N atom, a 5-membered alicyclic group containing 2 N atoms, a 6-membered alicyclic group containing 1 N atom, and an optionally substituted 6-membered alicyclic group containing 2 N atoms; for example, each R 1-4 is selected from the group consisting of an optionally substituted pyrrolyl, an optionally substituted piperidinyl, and an optionally substituted piperazinyl. For example, nr4 is 0 or 1. For example, nr4 is 0, 1, 2, or 3.

[0099] For example, the R 1-5 is a chemical bond or is selected from the following group: hydrogen, protium, deuterium, tritium, and an optionally substituted alkyl group. 1-5 is a chemical bond or is selected from the following group: hydrogen, protium, deuterium, tritium, an optionally substituted methyl group and an optionally substituted ethyl group. For example, each R 1-5 It may be an optionally substituted methyl group; for example, it may contain two R 1-5 For example, nr5 is 0, 1, or 2. For example, nr5 is 0, 1, 2, or 3.

[0100] For example, the R2 is an optionally substituted thiol. 2-1 Substituted, each of the R 2-1 Each independently represents an optionally substituted substituent. 2-1 is an optionally substituted aryl group. 2-1 is an optionally substituted phenyl group.

[0101] For example, the R 2-1 By 1 or more R 2-2 Substituted, each of the R 2-2 Each independently represents an optionally substituted substituent. 2-2 is selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, optionally substituted carbonyl, optionally substituted carboxyl, optionally substituted amide, and optionally substituted alkyl. 2-2 is selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, optionally substituted carbonyl, optionally substituted carboxyl, optionally substituted amido, and optionally substituted methyl.

[0102] For example, the R 2-2By 1 or more R 2-3 Substituted, each of the R 2-3 Each independently represents an optionally substituted substituent. 2-3 is selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, optionally substituted alkyl, optionally substituted alicyclic, and optionally substituted amino. 2-3 is selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, optionally substituted methyl, optionally substituted ethyl, optionally substituted cyclopropyl, and optionally substituted amino.

[0103] For example, the R 2-3 By 1 or more R 2-4 Substituted, each of the R 2-4 Each independently represents an optionally substituted substituent. 2-4 is selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, optionally substituted alkyl, and optionally substituted alicyclic. 2-4 is selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, optionally substituted methyl, optionally substituted ethyl, and optionally substituted cyclopropyl.

[0104] For example, R2 comprises optionally substituted -S-optionally substituted aryl-optionally substituted amide-optionally substituted alkyl, or -S-optionally substituted aryl-optionally substituted amide-optionally substituted alicyclic; for example, R2 comprises optionally substituted -S-optionally halogen-substituted aryl-optionally substituted amide-optionally substituted methyl, or -S-optionally substituted aryl-optionally substituted amide-optionally substituted cyclopropyl; for example, R2 comprises optionally substituted -SF substituted or unsubstituted aryl-amide-methyl, or -SF substituted or unsubstituted arylamide-cyclopropyl.

[0105] For example, the R3 is selected from the group consisting of hydrogen, protium, deuterium, and tritium.

[0106] For example, the X1 is selected from the group consisting of optionally substituted CH, and N. For example, X1 is optionally substituted CH.

[0107] In some embodiments of the present invention, the compound has the following structure:

[0108] in,

[0109] Ring A is a five- to seven-membered nitrogen-containing heterocyclic ring;

[0110] Ring B is a five- to seven-membered aromatic ring or heterocyclic ring;

[0111] Z is -C(O)NH-, -NHC(O)- or

[0112] The E ring is an aromatic ring or a heteroaromatic ring;

[0113] L0 is selected from: O, S, N (R La ), C1-C6 alkylene, C(O); R La Selected from: H, C1-C6 alkyl;

[0114] L1 is selected from: single bond, C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, -(C0-C6 alkylene)-Q1-(C0-C6 alkylene)-, Q1 is selected from: -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)-; the H atoms in the alkylene group may be optionally substituted by the following groups: H, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, halogen, cyano, nitro, azido, C1-C 10 Halogenated alkyl, hydroxyl, C1-C 10 Alkoxy, C1-C 10 Haloalkoxy, amino, C1-C 10 Alkylamino; R Lb Selected from: H, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkylalkyl, C6-C 10 Aryl, C7-C 12 Aralkyl, 4-10 membered heterocyclyl, 4-10 membered heterocyclylalkyl;

[0115] L2 is selected from: single bond, C1-C6 alkylene, -(C0-C6 alkylene)-Q2-(C0-C6 alkylene)-, Q2 is selected from: -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)-; the H atoms in the alkylene group may be optionally substituted by the following groups: H, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, halogen, cyano, nitro, azido, C1-C 10 Halogenated alkyl, hydroxyl, C1-C 10 Alkoxy, C1-C 10 Haloalkoxy, amino, C1-C 10 Alkylamino; R Lc Selected from: H, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkylalkyl, C6-C 10 Aryl, C7-C 12 Aralkyl, 4-10 membered heterocyclyl, 4-10 membered heterocyclylalkyl;

[0116] Y is selected from: H, -NR7R8, nitrogen-containing heterocyclic group, wherein the nitrogen-containing heterocyclic group may be optionally substituted by one or more R9 groups, R9 is selected from: halogen, cyano, amino, hydroxyl, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Alkoxy, C1-C 10 Halogenated alkoxy, C1-C 10 Alkylamino, C1-C 10 Cyanoalkyl, C1-C 10 Hydroxyl substituted alkyl, C1-C 10 Alkoxy-substituted alkyl, C1-C 10 Alkylamino-substituted alkyl, -(C0-C6 alkylene)-(C6-C 10 Aryl), -SO2-(C0-C6 alkylene)-(C6-C 10 Aryl), -S-(C0-C6 alkylene)-(C6-C 10 Aryl), -O-(C0-C6 alkylene)-(C6-C10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclyl), -SO2-(C0-C6 alkylene)-(4-10 membered heterocyclyl), -S-(C0-C6 alkylene)-(4-10 membered heterocyclyl), -O-(C0-C6 alkylene)-(4-10 membered heterocyclyl), -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -SO2-(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -S-(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -O-(C0-C6 alkylene)-(C3-C 10 cycloalkyl);

[0117] R7, R8 are independently selected from: H, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, 4-10 membered heterocyclylalkyl; wherein the C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group may be optionally substituted by one or more groups selected from the following: H, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkylalkyl, C6-C 10 Aryl, C7-C 12 Aralkyl, 4-10 membered heterocyclyl, 4-10 membered heterocyclylalkyl;

[0118] R4 is one or more independent substituents on the benzene ring, each R4 is independently selected from: H, halogen, C1-C 10 Alkyl, cyano, C1-C 10 Halogenated alkyl, C1-C 10 Halogenated alkoxy, C1-C 10 Cyanoalkyl, -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)-NR 401 R 402 、-SR 401 、-S(O)R 401 、-S(O)2R 401 、-(C0-C6 alkylene)-(C6-C 10 Aryl), -SO2-(C0-C6 alkylene)-(C6-C 10 Aryl), -S-(C0-C6 alkylene)-(C6-C 10 Aryl), -O-(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclyl), -SO2-(C0-C6 alkylene)-(4-10 membered heterocyclyl), -S-(C0-C6 alkylene)-(4-10 membered heterocyclyl), -O-(C0-C6 alkylene)-(4-10 membered heterocyclyl), -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -SO2-(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -S-(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -O-(C0-C6 alkylene)-(C3-C 10 Cycloalkyl); wherein the C0-C6 alkylene, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, 4-10 membered heterocyclic group may be optionally substituted by one or more groups selected from the following: halogen, cyano, amino, hydroxyl, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Alkoxy, C1-C 10 Halogenated alkoxy, C1-C 10 Alkylamino, C1-C 10 Cyanoalkyl, C1-C 10 Hydroxyl substituted alkyl, C1-C 10 Alkoxy-substituted alkyl, C1-C 10Alkylamino-substituted alkyl, -(C0-C6 alkylene)-(C6-C 10 Aryl), -SO2-(C0-C6 alkylene)-(C6-C 10 Aryl), -S-(C0-C6 alkylene)-(C6-C 10 Aryl), -O-(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclyl), -SO2-(C0-C6 alkylene)-(4-10 membered heterocyclyl), -S-(C0-C6 alkylene)-(4-10 membered heterocyclyl), -O-(C0-C6 alkylene)-(4-10 membered heterocyclyl), -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -SO2-(C0-C6 alkylene) - (C3-C 10 Cycloalkyl), -S-(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -O-(C0-C6 alkylene)-(C3-C 10 cycloalkyl);

[0119] R 401 and R 402 Independently selected from: H, C1-C 10 Alkyl, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkylalkyl, C6-C 10 Aryl, C6-C 10 Aralkyl, 4-10 membered heterocyclyl, 4-10 membered heterocyclylalkyl;

[0120] R5 is One or more independent substituents on the ring, each R5 is independently selected from: H, halogen, cyano, amino, hydroxyl, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Alkoxy, C1-C 10 Halogenated alkoxy, C1-C 10 Alkylamino, C1-C 10 Cyanoalkyl, C1-C 10 Hydroxyl substituted alkyl, C1-C 10 Alkoxy-substituted alkyl, C1-C 10 Alkylamino-substituted alkyl, -(C0-C6 alkylene)-(C6-C 10 Aryl), -SO2-(C0-C6 alkylene)-(C6-C 10 Aryl), -S-(C0-C6 alkylene)-(C6-C 10Aryl), -O-(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclyl), -SO2-(C0-C6 alkylene)-(4-10 membered heterocyclyl), -S-(C0-C6 alkylene)-(4-10 membered heterocyclyl), -O-(C0-C6 alkylene)-(4-10 membered heterocyclyl), -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -SO2-(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -S-(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -O-(C0-C6 alkylene)-(C3-C 10 cycloalkyl);

[0121] R6 is one or more independent substituents on the E ring, each R6 is independently selected from: H, halogen, cyano, amino, hydroxyl, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Alkoxy, C1-C 10 Halogenated alkoxy, C1-C 10 Alkylamino, C1-C 10 Cyanoalkyl, C1-C 10 Hydroxyl substituted alkyl, C1-C 10 Alkoxy-substituted alkyl, C1-C 10 Alkylamino-substituted alkyl, -(C0-C6 alkylene)-(C6-C 10 Aryl), -SO2-(C0-C6 alkylene)-(C6-C 10 Aryl), -S-(C0-C6 alkylene)-(C6-C 10 Aryl), -O-(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclyl), -SO2-(C0-C6 alkylene)-(4-10 membered heterocyclyl), -S-(C0-C6 alkylene)-(4-10 membered heterocyclyl), -O-(C0-C6 alkylene)-(4-10 membered heterocyclyl), -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -SO2-(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -S-(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -O-(C0-C6 alkylene)-(C3-C 10 cycloalkyl).

[0122] In some embodiments of the present invention, Ring A is a five-membered nitrogen-containing heteroaromatic ring, for example

[0123] In some embodiments of the present invention, ring B is a benzene ring or a six-membered nitrogen-containing heterocycle, for example

[0124] In some embodiments of the present invention, The structure is one of the following: in particular:

[0125] In some embodiments of the present invention, Part of L2 is C1-C6 alkylene or -(C0-C6 alkylene)-Q2-(C0-C6 alkylene)-, Y is -NR7R8 or a nitrogen-containing heterocyclic group, wherein the nitrogen-containing heterocyclic group may be optionally substituted by one or more R9 groups.

[0126] In some embodiments of the present invention, Part of Y is selected from: H, -NR7R8, and a nitrogen-containing heterocyclic group, wherein the nitrogen-containing heterocyclic group may be optionally substituted by one or more R9 groups.

[0127] In some embodiments of the present invention, Part of Y is selected from the group consisting of: H, -NR7R8, and a nitrogen-containing heterocyclic group, wherein the nitrogen-containing heterocyclic group may be optionally substituted by one or more R9 groups.

[0128] In some embodiments of the present invention, Part of Y is selected from: H, -NR7R8, and a nitrogen-containing heterocyclic group, wherein the nitrogen-containing heterocyclic group may be optionally substituted by one or more R9 groups.

[0129] In some embodiments of the present invention, Part of Y is selected from: H, -NR7R8, and a nitrogen-containing heterocyclic group, wherein the nitrogen-containing heterocyclic group may be optionally substituted by one or more R9 groups.

[0130] In some embodiments of the present invention, R5 is selected from the group consisting of: H, halogen, cyano, amino, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl.

[0131] In some embodiments of the present invention, R5 is H.

[0132] In some embodiments of the present invention, R3 is selected from the group consisting of: H, C1-C6 alkyl.

[0133] In some embodiments of the present invention, R3 is H.

[0134] In some embodiments of the present invention, L0 is S.

[0135] In some embodiments of the present invention, L0 is O.

[0136] In some embodiments of the present invention, L0 is NH.

[0137] In some embodiments of the present invention, L0 is methylene.

[0138] In some embodiments of the present invention, L0 is NH, Z is -NHC(O)-, and the compound has the following structure:

[0139] Wherein, L2 is selected from: C1-C6 alkylene, -(C1-C6 alkylene)-Q2-(C1-C6 alkylene)-; Y is -NR7R8 or an optionally substituted nitrogen-containing heterocyclic group, wherein the nitrogen-containing heterocyclic group may be optionally substituted by one or more R9 groups.

[0140] In some embodiments of the present invention, Z is The compound has the following structure:

[0141] In some embodiments of the present invention, the compound has the following structure:

[0142] In some embodiments of the present invention, L1 is C2-C6 alkenylene, for example in particular

[0143] In some embodiments of the present invention, L1 is a C2-C6 alkynylene group, for example in particular

[0144] In some embodiments of the present invention, L1 is -Q1-(C0-C6 alkylene)-.

[0145] In some embodiments of the present invention, L1 is -(C0-C6 alkylene)-Q1-.

[0146] In some embodiments of the present invention, Q1 is -N(R Lb )-,R Lb Selected from: H, C1-C3 alkyl, especially H.

[0147] In some embodiments of the present invention, L1 is -NH-.

[0148] In some embodiments of the present invention, the E ring is a benzene ring or a five-membered or six-membered nitrogen-containing heteroaromatic ring, for example, Specifically, when the E ring is a benzene ring, Y is -NR7R8 or an optionally substituted nitrogen-containing heterocyclic group, wherein the nitrogen-containing heterocyclic group may be optionally substituted by one or more R9 groups.

[0149] In some embodiments of the present invention, The section has the following structure:

[0150] In some embodiments of the present invention, R6 is selected from the group consisting of: H, halogen, cyano, amino, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl.

[0151] In some embodiments of the present invention, R6 is H.

[0152] In some embodiments of the present invention, L2 is a single bond.

[0153] In some embodiments of the present invention, L2 is C1-C6 alkylene, for example,

[0154] In some embodiments of the present invention, L2 is -Q2-(C0-C6 alkylene)-.

[0155] In some embodiments of the present invention, Q2 is selected from: -O-, -S-, -N(R Lc )-,R Lc Selected from: H, C1-C3 alkyl, especially H.

[0156] In some embodiments of the present invention, L2 is -O-(C0-C6 alkylene)-, for example,

[0157] In some embodiments of the present invention, the E ring is a five-membered or six-membered nitrogen-containing heteroaromatic ring, L2 is a single bond, and Y is H.

[0158] In some embodiments of the present invention, Y is -NR7R8, R7, R8 are independently selected from: H, C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C6 cycloalkyl), for example,

[0159] In some embodiments of the present invention, Y is a nitrogen-containing heterocyclic group, which may be optionally substituted by one or more R9. Specifically, the nitrogen-containing heterocyclic group is a 4-8 membered saturated heterocyclic ring, for example,

[0160] In some embodiments of the present invention, Y is selected from the group consisting of: (wherein the substitution position of R9 can be on any suitable carbon atom or nitrogen atom); More specifically, Y is selected from:

[0161] In some embodiments of the present invention, R9 is selected from the group consisting of: H, C1-C6 alkyl (e.g., -CH3, ), C1-C6 hydroxy substituted alkyl (e.g. ), C1-C6 amino substituted alkyl (e.g. ), C1-C6 alkoxy substituted alkyl (e.g. ), C1-C6 alkylamino substituted alkyl (e.g. ), -(C0-C6 alkylene)-(C3-C6 cycloalkyl) (e.g. ).

[0162] In some embodiments of the present invention, Y is selected from the group consisting of:

[0163] In some embodiments of the present invention, Part of in,

[0164] R 4a Selected from: -C(O)NR 401 R 402 、-(C0-C6 alkylene)-NR 401 R 402 、-C(O)R 401 、-C(O)OR 401 , R 401 and R 402 Independently selected from: H, C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C6 cycloalkyl); wherein the C0-C6 alkylene, C1-C6 alkyl, C3-C6 cycloalkyl may be optionally substituted with one or more groups selected from the following: halogen, cyano, amino, hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl;

[0165] R 4bis one or more independent substituents on the phenyl ring selected from the group consisting of: H, halogen, cyano, amino, hydroxyl, C1-C6 alkyl, and C1-C6 haloalkyl.

[0166] In some embodiments of the present invention, R 4a Selected from:

[0167] In some embodiments of the present invention, R 4b For H.

[0168] In some embodiments of the present invention, R 4b is a halogen, such as F.

[0169] In some embodiments of the present invention, Part of

[0170] In one aspect, the present invention provides a compound having a structure selected from the following group:

[0171] or a pharmaceutically acceptable prodrug of the compound, a pharmaceutically active metabolite of the compound and / or a pharmaceutically acceptable salt of the compound.

[0172] In one aspect, the present invention provides a compound having a structure selected from the following group:

[0173] or a pharmaceutically acceptable prodrug of the compound, a pharmaceutically active metabolite of the compound and / or a pharmaceutically acceptable salt of the compound.

[0174] In one aspect, the present invention provides a compound having a structure selected from the following group:

[0175] or a pharmaceutically acceptable prodrug of the compound, a pharmaceutically active metabolite of the compound and / or a pharmaceutically acceptable salt of the compound.

[0176] In one aspect, the present invention provides a compound having a structure selected from the following group:

[0177] or a pharmaceutically acceptable prodrug of the compound, a pharmaceutically active metabolite of the compound and / or a pharmaceutically acceptable salt of the compound.

[0178] In one aspect, the present invention provides a compound having a structure selected from the following group:

[0179] or a pharmaceutically acceptable prodrug of the compound, a pharmaceutically active metabolite of the compound and / or a pharmaceutically acceptable salt of the compound.

[0180] Pharmaceutical composition

[0181] In one aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable prodrug, a pharmaceutically active metabolite and / or a pharmaceutically acceptable salt of the compound, and optionally a carrier.

[0182] The pharmaceutical composition of the present invention may contain, in addition to the active compound, one or more excipients, which may be selected from the following groups: fillers (diluents), binders, wetting agents, disintegrants, and excipients. Depending on the method of administration, the composition may contain 0.1 to 99% by weight of the active compound.

[0183] The pharmaceutical composition containing the active ingredient may be in a form suitable for ophthalmic administration, such as an aqueous or oily suspension, a dispersible powder or granules, an emulsion, or a slurry. The ophthalmic composition may be prepared according to any method known in the art for preparing a pharmaceutical composition. The composition may contain a binder, a filler, a lubricant, a disintegrant, or a pharmaceutically acceptable wetting agent. The composition may also contain one or more ingredients selected from the group consisting of a sweetener, a flavoring agent, a colorant, and a preservative.

[0184] Aqueous suspensions may contain the active ingredient and excipients suitable for preparing aqueous suspensions for mixing. Aqueous suspensions may also contain one or more preservatives, such as one or more colorants, one or more flavorings, and one or more sweeteners. Oil suspensions may be prepared by suspending the active ingredient in a vegetable oil. Oil suspensions may contain a thickening agent.

[0185] Specifically, the pharmaceutical composition can be administered by any suitable route, such as enteral administration (e.g., oral, sublingual, rectal) or parenteral administration (e.g., intravenous, intramuscular, intranasal, intraocular, intracerebral, intravaginal, intraperitoneal, transdermal, subcutaneous, intradermal, respiratory tract administration, etc.). In some embodiments of the present invention, the pharmaceutical composition is administered by intraocular administration (e.g., eye drops, eye ointment, subconjunctival injection, intraocular injection).

[0186] Specifically, the pharmaceutical composition can be in any suitable dosage form, such as a gastrointestinal dosage form, for example, including but not limited to tablets, pills, powders, granules, capsules, lozenges, syrups, liquids, emulsions, suspensions, etc.; parenteral dosage forms, for example, injectable dosage forms: such as injections (for example, for subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection), respiratory tract dosage forms: such as sprays, aerosols, powder mists, etc., skin dosage forms, such as external solutions, lotions, ointments, plasters, pastes, patches, etc., mucosal dosage forms: such as eye drops, eye ointments, nasal drops, gargles, sublingual tablets, etc., cavity dosage forms: such as suppositories, aerosols, effervescent tablets, drops, pills, etc., for rectum, vagina, urethra, nasal cavity, ear canal, etc.

[0187] In some embodiments of the present invention, the pharmaceutical composition is an ophthalmic preparation, such as eye drops or eye ointments.

[0188] In one aspect, the present invention provides a compound of the present invention, or a pharmaceutically acceptable prodrug of the compound, a pharmaceutically active metabolite of the compound and / or a pharmaceutically acceptable salt of the compound, and / or a pharmaceutical composition of the present invention for use in preparing a medicament for treating a disease.

[0189] In one aspect, the present invention provides a compound of the present invention or a pharmaceutically acceptable prodrug of the compound, a pharmaceutically active metabolite of the compound and / or a pharmaceutically acceptable salt of the compound, and / or a pharmaceutical composition of the present invention, for use in treating a disease.

[0190] In some embodiments of the invention, the disease is a proliferative disease mediated by a protein tyrosine kinase.

[0191] In some embodiments of the invention, the disease is an ocular disease, including, but not limited to, diseases associated with pathological neovascularization, retinal ischemia, retinal edema, and diabetic retinopathy.

[0192] In some embodiments of the present invention, the disease is an eye disease, including, but not limited to, diabetic retinopathy (including simple (background) diabetic retinopathy, proliferative diabetic retinopathy and diabetic macular edema); age-related macular degeneration (AMD) (including neovascular (wet / exudative) AMD, dry AMD, and geographic atrophy); pathological choroidal neovascularization (CNV) arising from any pathological mechanism (i.e., high myopia, trauma, sickle cell (anemia) disease; ocular histoplasmosis, angioid streaks, traumatic choroidal rupture, optic nerve drusen, and certain retinal dystrophies); pathological visual atrophy arising from any pathological mechanism. Retinal neovascularization (i.e., sickle cell retinopathy, Eales disease, ocular ischemic syndrome, carotid cavernous fistula, familial exudative vitreoretinopathy, hyperviscosity syndrome, idiopathic occlusive arteritis, 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.

[0193] In some embodiments of the present invention, the ocular disease is a posterior segment disease, ie, a disease occurring in the vitreous, retina, choroid, sclera, or optic nerve.

[0194] In some embodiments of the present invention, the disease is diabetic retinopathy, including simple (background) diabetic retinopathy (non-proliferative diabetic retinopathy), proliferative diabetic retinopathy and diabetic macular edema, in particular non-proliferative diabetic retinopathy.

[0195] In other embodiments of the present invention, the disease is age-related macular degeneration (AMD), including neovascular (wet / exudative) AMD, dry AMD, and geographic atrophy.

[0196] In some embodiments of the present invention, the disease is a tumor, in particular a malignant tumor (cancer), including, but not limited to, solid tumors and leukemias, such as breast cancer, lung cancer (in particular non-small cell lung cancer), adenocarcinoma, colorectal cancer, kidney cancer, liver cancer, pancreatic cancer, ovarian cancer, prostate cancer, glioma, glioblastoma, myeloma, acute myeloid leukemia, unrelated myeloid metaplasia, mesothelioma, myelodysplastic syndrome.

[0197] In some embodiments of the present invention, the disease is a hematological malignancy including leukemia, lymphoma, and multiple myeloma (MM).

[0198] Specifically, the leukemia may be chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), or acute monocytic leukemia.

[0199] Specifically, the lymphoma may be Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) (e.g., diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphoma, primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma, hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, Tumors and primary central nervous system (CNS) lymphomas and T-cell NHL, such as precursor T lymphoblastic lymphoma / leukemia, peripheral T cell lymphoma (PTCL), angioimmunoblastic T cell lymphoma, extranodal natural killer T cell lymphoma, enteropathy-type T cell lymphoma, subcutaneous panniculitis-like T cell lymphoma and anaplastic large cell lymphoma, NK / T cell lymphoma, particularly diffuse large B cell lymphoma (DLBCL). Specifically, in the application, the treatment of the tumor includes killing the tumor, preventing the metastasis and spread of the tumor and the growth of micrometastasis.

[0200] In one aspect, the present invention provides a method for treating a disease, comprising administering a compound of the present invention or a pharmaceutically acceptable prodrug, a pharmaceutically active metabolite and / or a pharmaceutically acceptable salt of the compound, and / or a pharmaceutical composition of the present invention.

[0201] As is well known to those skilled in the art, the dosage of a drug depends on a variety of factors, including but not limited to the following: the activity of the specific compound used, the age of the patient, the weight of the patient, the health status of the patient, the behavior of the patient, the diet of the patient, the time of administration, the route of administration, the rate of excretion, the combination of drugs, etc.; in addition, the optimal treatment mode, such as the mode of treatment, the daily dosage of the compound of the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and / or the compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or the type of pharmaceutically acceptable salt can be verified according to traditional treatment regimens.

[0202] In one aspect, the present invention provides a method for modulating kinase receptor activity, comprising administering a compound of the present invention or a pharmaceutically acceptable prodrug, a pharmaceutically active metabolite and / or a pharmaceutically acceptable salt of the compound, and / or a pharmaceutical composition of the present invention.

[0203] For example, the method inhibits kinase receptor activity. The compound of the present invention may have inhibitory activity against the in vitro proliferation of kinase receptors. The inhibitory activity may be that after the compound of the present invention is added, the kinase receptor activity decreases by more than 1%, more than 2%, more than 4%, more than 5%, more than 8%, more than 10%, more than 15%, more than 18%, more than 20%, more than 25%, more than 40%, more than 50%, more than 60%, more than 70%, more than 80%, more than 90%, or more than 95% compared to the addition of a negative control or a control drug. For example, the inhibitory activity may be an IC for kinase receptor activity. 50 The value (nM) may be 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 or less, 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 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.

[0204] For example, the kinase receptor comprises VEGFR (e.g., VEGFR1, VEGFR2, VEGFR3), EGFR, or a functionally active fragment thereof, in particular 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.

[0205] In some embodiments of the invention, the methods selectively inhibit VEGFR (eg, VEGFR1, VEGFR2, VEGFR3, particularly VEGFR2) relative to EGFR.

[0206] In one aspect, the present invention provides a method for inhibiting ocular neovascularization and retinal vascular leakage, comprising administering a compound of the present invention or a pharmaceutically acceptable prodrug of the compound, a pharmaceutically active metabolite of the compound and / or a pharmaceutically acceptable salt of the compound, and / or a pharmaceutical composition of the present invention.

[0207] Specifically, the administration can be carried out by any suitable administration method, in particular intraocular administration, such as eye drop administration, eye ointment administration, subconjunctival injection administration, intraocular injection administration, in particular eye drop administration.

[0208] Without intending to be bound by any theory, the following examples are merely for illustrating the compounds, preparation methods and uses of the present invention, and are not intended to limit the scope of the present invention.

[0209] Example

[0210] Table 1. Information of compounds of the present invention:

[0211] Example 1

[0212] I-10

[0213] first step

[0214] To a solution of 6-bromopyridin-3-ol 1a (10 g, 57.47 mmol) in N,N-dimethylformamide (150 mL) at room temperature under nitrogen was added potassium vinyl trifluoroborate 1b (11.6 g, 86.21 mmol), Pd(dppf)Cl2 (1.3 g, 1.72 mmol), and triethylamine (8.7 g, 86.21 mmol). The mixture was heated to 85°C and stirred for approximately 16 hours. After thin-layer chromatography (petroleum ether / ethyl acetate = 1 / 1) indicated complete reaction of the starting material, 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 yield the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1-1 / 1) to give 6-vinylpyridin-3-ol 1c (4.3 g, 35.50 mmol, 61.76% yield) as a white solid.

[0215] The product was confirmed by LCMS and HNMR.

[0216] MS-ESI calculated value [M+H]+ 122.1, found 122.1. 1 H NMR (400MHz, CDCl3): δ (ppm) 8.17-8.18 (m, 1H), 7.40 (d, J = 8.4Hz, 1H), 7.25-7.28 (m, 1H), 6.80 (dd, J=11.2Hz, 11.2Hz, 1H), 5.93 (d, J=17.6Hz, 1H), 5.38 (d, J=11.2Hz, 1H).

[0217] Step 2

[0218] To a solution of N-methyl-2-mercaptobenzamide 1e (13 g, 77.74 mmol) in N,N-dimethylformamide (250 mL) were added 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) at room temperature, and the mixture was heated to 80°C and stirred for about 2 hours. After thin layer chromatography (dichloromethane / methanol = 15 / 1) showed that the reaction of the starting material was complete, the mixture was poured into water (1000 mL) and washed with ethyl acetate (100 mL x 100 mL). 3) extraction, and the combined organic layer was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated to give a crude product; the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1 to 0 / 1) to give 2-(1H-indazol-6-ylsulfanyl)-N-methylbenzamide 1f (8.3 g, 37.7% yield) as a yellow solid.

[0219] The product was confirmed by LCMS and HNMR.

[0220] MS-ESI calculated value [M+H]+ 285.1, found 285.0.

[0221] 1 H NMR (400MHz, 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).

[0222] Step 3

[0223] To a solution of 2-(1H-indazol-6-ylthio)-N-methylbenzamide 1f in N,N-dimethylformamide were added K2CO3 (6.83 g, 49.4 mmol) and I2 (10.66 g, 42.0 mmol) at 0°C, and the mixture was allowed to react at room temperature for about 3.5 hours. After thin layer chromatography (dichloromethane / methanol = 15 / 1) showed that the starting material was completely reacted, 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 (100 mL), dried over anhydrous sodium sulfate, and concentrated to give 1 g (8.8 g, 87.0%) of crude 2-[(3-iodo-1H-indazol-6-yl)thio]-N-methylbenzamide.

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

[0225] MS-ESI calculated value [M+H]+ 411.0, found 410.8.

[0226] 1 H NMR (400MHz, 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).

[0227] Step 4

[0228] 3,4-dihydro-2H-pyran (DHP) (1.03 g, 12.22 mmol) and TsOH (63.12 mg, 366.53 μmol) were added to a THF (20 mL) solution of 2-[(3-iodo-1H-indazole-6-yl)thio]-N-methylbenzamide 1 g (1 g, 2.44 mmol) at room temperature, and the mixture was stirred and refluxed for 16 hours. After thin layer chromatography (petroleum ether / ethyl acetate = 1 / 2) showed that the raw material reaction was complete, 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 milliliters), dried over anhydrous sodium sulfate and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1- / 5 / 1-3 / 1-1 / 1) to give 2-(3-iodo-1-tetrahydropyran-2-yl-indole-6-yl)sulfanyl-N-methyl-benzamide 1h (650 mg, 1.32 mmol, 53.92% yield) as a white solid.

[0229] The product was confirmed by LCMS and HNMR.

[0230] MS-ESI calculated value [M+H]+ 494.0, found 493.9.

[0231] 1 H NMR (400MHz, CDCl3): δ (ppm) 7.66 (s, 1H), 7.58-7.65 (m, 1H), 7.42 (d, 1H, J = 8.4Hz), 7.29-7.35 (m, 2H), 7.14-7.22 (m, 2H), 6.27 (s, 1H), 5.64 ( dd,1H,J=9.4,2.6Hz),4.13-4.15(m,1H),3.64-3.76(m,1H),2.97(d,3H,J=4.8Hz),2.46-2.54(m,1H),2.02-2.18(m,2H),1.66-1.84(m,3H).

[0232] Step 5

[0233] Under nitrogen protection, to a solution of 2-(3-iodo-1-tetrahydropyran-2-yl-indole-6-yl)sulfanyl-N-methyl-benzamide 1h (500 mg, 1.01 mmol) in 1,4-dioxane (10 mL) were added 6-vinylpyridine-3-ol 1c (147.3 mg, 1.22 mmol), triethylamine (307.7 mg, 3.04 mmol), Pd2(dba)3 (464 mg, 506.73 μmol) and P(o-tol)3 (308.5 mg, 1.01 mmol) at room temperature and stirred for reaction at room temperature. After thin layer chromatography (dichloromethane / methanol = 20 / 1) showed that the starting material was completely reacted, 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 a crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30 / 1-1 / 1) to give 2-[3-[(E)-2-(5-hydroxy-2-pyridyl)vinyl]-1-tetrahydropyran-2-yl-indole-6-yl]sulfanyl-N-methyl-benzamide 1i (400 mg, 822.06 μmol, 81.11% yield) as a yellow solid. LCMS showed that the product purity was approximately 30%.

[0234] The product was confirmed by LCMS.

[0235] MS-ESI calculated value [M+H]+ 487.2, found 487.4.

[0236] Step 6

[0237] At room temperature, 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-indole-6-yl]thio-N-methyl-benzamide 1i (150 mg, 308.27 μmol) in dichloromethane (3 mL), and the mixture was stirred at 35° C. for 16 hours. After thin layer chromatography (dichloromethane / methanol=10 / 1) showed that the starting material had reacted completely, 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 layers were washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, and concentrated to give a crude product. The crude product was purified by preparative thin layer chromatography to give 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) as a white solid.

[0238] The product was confirmed by LCMS and HNMR.

[0239] MS-ESI calculated value [M+H]+ 403.1, found 403.1.

[0240] 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).

[0241] I-14

[0242] first step

[0243] Under nitrogen protection, to a solution of 2-[3-[(E)-2-(5-hydroxy-2-pyridyl)vinyl]-1-tetrahydropyran-2-yl-indole-6-yl]sulfanyl-N-methyl-benzamide 1i (400 mg, 822.06 μmol) in tetrahydrofuran (10 mL) were added tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate 2a (198.5 mg, 986.47 μmol), Ph3P (323.4 mg, 1.23 mmol) and DIAD (249.3 mg, 1.23 mmol) at room temperature, and the reaction was stirred at 40°C for about 16 hours. After thin layer chromatography (dichloromethane / methanol=10 / 1) showed that the starting material had reacted completely, 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 a crude product. The crude product was purified by preparative thin layer chromatography (dichloromethane / methanol=10 / 1) to give tert-butyl 2-[[6-[(E)-2-[6-[2-(methylcarbamoyl)phenyl]sulfanyl-1-tetrahydropyran-2-yl-indazole-3-yl]vinyl]-3-pyridyl]oxymethyl]pyrrolidine-1-carboxylate 2b (400 mg, 597.17 μmol, 72.64% yield) as a white solid. LCMS showed a product purity of approximately 29%.

[0244] The product was confirmed by LCMS.

[0245] MS-ESI calculated value [M+H]+ 670.3, found 670.2.

[0246] Step 2

[0247] To a solution of tert-butyl 2-[[6-[(E)-2-[6-[2-(methylcarbamoyl)phenyl]sulfanyl-1-tetrahydropyran-2-yl-indolazol-3-yl]vinyl]-3-pyridinyl]oxymethyl]pyrrolidine-1-carboxylate 2b (0.4 g, 597.17 μmol) in dichloromethane (5 mL) was added trifluoroacetic acid (340.4 mg, 2.99 mmol) at room temperature, and the mixture was stirred at 35° C. for approximately 16 hours. After thin layer chromatography (dichloromethane / methanol = 10 / 1) indicated complete reaction of the starting material, the mixture was poured into water (40 mL), adjusted to pH 8-9 with solid sodium carbonate, and extracted with dichloromethane (30 mL x 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to give a crude product. The crude product was purified by preparative thin layer chromatography to give N-methyl-2-({3-[(E)-2-{5-[(pyrrolidin-2-yl)methoxy]pyridin-2-yl}vinyl]-1H-indazol-6-yl}sulfanyl)benzamide I-14 (13.9 mg, 28.62 μmol, 4.79% yield) as a white solid.

[0248] The product was confirmed by LCMS, HNMR and CNMR.

[0249] MS-ESI calculated value [M+H]+ 486.2, found 487.0.

[0250] 1 H NMR (400MHz, CDCl3&CD3OD): δ (ppm) 8.24-8.23 (m, 1H), 7.98 (d, J = 8.8Hz, 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=8.0Hz,1H),3.53-3.50(m,1H),3.0 4-2.91(m,2H),2.88(s,1H),2.02-1.95(m,1H),1.89-1.79(m,2H),1.64-1.57(m,1H).

[0251] 13C NMR (100MHz, 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, 12 8.04,126.65,125.39,122.26,122.03,121.83,121.47,120.46,114.42,70.93,57.08,46.10,46.06,29.59,27.64,26.33,25.07.

[0252] I-2

[0253] first step

[0254] To a solution of 2-[3-[(E)-2-(5-hydroxy-2-pyridyl)vinyl]-1-tetrahydropyran-2-yl-indole-6-yl]thio-N-methyl-benzamide 1i (400 mg, 822.06 μmol) in tetrahydrofuran (5 mL) was added (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) at room temperature under nitrogen. The mixture was stirred at 30°C for approximately 16 hours. After thin-layer chromatography (dichloromethane / methanol = 10 / 1) indicated complete reaction of the starting material, 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 yield the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 - dichloromethane / methanol = 10 / 1) to give N-methyl-2-[3-[(E)-2-[5-[(1-methylpyrrolidin-2-yl)methoxy]-2-pyridinyl]vinyl]-1-tetrahydropyran-2-ylindol-6-yl]sulfanylbenzamide 3b (240 mg, 411.14 μmol, 50.01% yield) as a yellow solid.

[0255] The product was confirmed by LCMS.

[0256] MS-ESI calculated value 584.3, measured 584.3.

[0257] Step 2

[0258] 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]sulfanylbenzamide 3b (240 mg, 411.14 μmol) in dichloromethane (5 mL) was added trifluoroacetic acid (46.9 mg, 411.14 μmol) at room temperature. The mixture was stirred at 30°C for 16 hours. After thin-layer chromatography (dichloromethane / methanol = 10 / 1) indicated complete reaction of the starting material, the mixture was poured into water (10 mL), adjusted to pH 8-9 with solid sodium carbonate, and extracted with DCM (10 mL x 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by preparative thin layer chromatography to give N-methyl-2-({3-[(E)-2-{5-[(1-methylpyrrolidin-2-yl)methoxy]pyridin-2-yl}vinyl]-1H-indazol-6-yl}sulfanyl)benzamide I-2 (31.6 mg, 63.25 μmol, 7.97% yield) as a white solid.

[0259] The product was confirmed by LCMS, HNMR and CNMR.

[0260] MS-ESI calculated value [M+H]+ 500.2, found 500.1.

[0261] 1 H NMR (400MHz, CDCl3&CD3OD): δ (ppm) 8.23 ​​(s, 1H), 7.94 (d, J = 8.0Hz, 1H), 7.63 (s, 1H), 7.47 (dd, J = 39.8, 29.7Hz, 4H), 7.24 (s, 2H), 4.02 (d,J=6.4Hz,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).

[0262] 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, 126.9 3,125.01,122.20,121.86,121.79,121.64,121.49,120.47,113.93,70.84,64.29,57.63,41.61,29.62,28.32,26.44,22.71,22.63.

[0263] I-5

[0264] first step

[0265] To a solution of 2-[3-[(E)-2-(5-hydroxy-2-pyridinyl)vinyl]-1-tetrahydropyran-2-yl-indolazol-6-yl]thio-N-methyl-benzamide 1i (400 mg, 822.06 μmol) in tetrahydrofuran (5 mL) was added 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) at room temperature under nitrogen. The mixture was stirred at 30°C for approximately 16 hours. After thin-layer chromatography (dichloromethane / methanol = 10 / 1) indicated complete reaction of the starting material, 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 yield the crude product. The crude product was purified by preparative thin layer chromatography (dichloromethane / methanol = 10 / 1) to give N-methyl-2-[3-[(E)-2-[5-[2-(1-methyl-4-piperidinyl)ethoxy]-2-pyridinyl]vinyl]-1-tetrahydropyran-2-yl-indazole-6-yl]sulfanylbenzamide 4b (120 mg, 196.14 μmol, 23.86% yield) as a white solid.

[0266] The product was confirmed by LCMS.

[0267] MS-ESI calculated value [M+H]+ 612.3, found 612.2.

[0268] Step 2

[0269] To a solution of N-methyl-2-[3-[(E)-2-[5-[2-(1-methyl-4-piperidinyl)ethoxy]-2-pyridinyl]vinyl]-1-tetrahydropyran-2-yl-indole-6-yl]sulfanylbenzamide 4b (120 mg, 196.14 μmol) in dichloromethane (5 mL) was added trifluoroacetic acid (22.36 mg, 196.14 μmol) at room temperature. The mixture was stirred at 40°C for 16 hours. After thin-layer chromatography (dichloromethane / methanol = 10 / 1) indicated complete reaction of the starting material, the mixture was poured into water (10 mL), adjusted to pH 8-9 with solid sodium carbonate, and extracted with DCM (10 mL x 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by preparative thin layer chromatography to give N-methyl-2-({3-[(E)-2-{5-[2-(1-methylpiperidin-4-yl)ethoxy]pyridin-2-yl}vinyl]-1H-indazol-6-yl}sulfanyl)benzamide I-5 (17 mg, 32.22 μmol, 16.42% yield) as a white solid.

[0270] The product was confirmed by LCMS, HNMR and CNMR.

[0271] MS-ESI calculated value [M+H]+ 582.2, found 528.2.

[0272] 1 H NMR (400MHz, CDCl3&CD3OD): δ8.24(d,J=2.4Hz,1H),8.06(d,J=8.6Hz,1H),7.56 -7.80(m,3H),7.48-7.55(m,2H),7.41-7.43(m,1H),7.32(dd,J=13.0,6.4Hz,2H ),7.21(d,J=8.6Hz,2H),4.17(t,J=6.2Hz,2H),2.95(d,J=11.2Hz,2H),2.88(s, 3H), 2.34 (s, 3H), 2.16 (dd, J = 26.8, 13.4Hz, 3H), 1.75-1.99 (m, 4H), 1.64 (s, 1H).

[0273] 13C NMR (100MHz, CDCl3&CD3OD) δ154.34,148.14,137.65,132.13,130.84,129.77,128.68,127.18,1 24.68,122.24,121.58,121.51,121.37,66.12,55.66,46.22,35.50,31.94,31.81,29.66,26.59.

[0274] I-1

[0275] first step

[0276] To a solution of 2-[3-[(E)-2-(5-hydroxy-2-pyridyl)vinyl]-1-tetrahydropyran-2-yl-indole-6-yl]thio-N-methyl-benzamide 1i (400 mg, 822.06 μmol) in tetrahydrofuran (5 mL) was added (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. The reaction was stirred at 30°C for approximately 16 hours. After thin-layer chromatography (dichloromethane / methanol = 10 / 1) indicated complete reaction of the starting material, 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 yield the crude product. The crude product was purified by preparative thin layer chromatography (dichloromethane / methanol = 10 / 1) to give N-methyl-2-[3-[(E)-2-[5-[(1-methylpyrrolidin-3-yl)methoxy]-2-pyridinyl]vinyl]-1-tetrahydropyran-2-ylindol-6-yl]sulfanylbenzamide 5b (170 mg, 291.22 μmol, 35.43% yield) as a white solid.

[0277] The product was confirmed by LCMS.

[0278] MS-ESI calculated value [M+H]+ 584.3, found 584.2.

[0279] Step 2

[0280] 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]sulfanylbenzamide 5b (170 mg, 291.22 μmol) in dichloromethane (5 mL) was added trifluoroacetic acid (33.2 mg, 291.22 μmol) at room temperature. The mixture was stirred at 40°C for 16 hours. After thin-layer chromatography (dichloromethane / methanol = 10 / 1) indicated complete reaction of the starting material, the mixture was poured into water (10 mL), adjusted to pH 8-9 with solid sodium carbonate, and extracted with DCM (10 mL x 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to yield the crude product. The crude product was purified by preparative thin layer chromatography to give N-methyl-2-({3-[(E)-2-{5-[(1-methylpyrrolidin-3-yl)methoxy]pyridin-2-yl}vinyl]-1H-indazol-6-yl}sulfanyl)benzamide I-1 (24.3 mg, 48.64 μmol, 16.70% yield) as a white solid.

[0281] The product was confirmed by LCMS, HNMR and CNMR.

[0282] MS-ESI calculated value [M+H]+ 500.2, found 500.1.

[0283] 1 H NMR (400MHz, CD3OD&CDCl3)δ8.27(d,J=2.8Hz,1H),8.07(d,J=4.8Hz,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),2.8 8(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).

[0284] 13C NMR(100MHz,CD3OD&CDCl3)δ:170.33,154.69,148.16,142.79,142.73,142.21,137.09,135.42,133.78,131.17,130.33,129.15,1 27.67,126.43,125.44,122.39,122.02,121.65,121.27,120.29,114.32,71.13,71.08,58.73,55.53,41.15,37.35,27.40,25.66.

[0285] I-4

[0286] first step

[0287] To a solution of 2-[3-[(E)-2-(5-hydroxy-2-pyridyl)vinyl]-1-tetrahydropyran-2-yl-indole-6-yl]thio-N-methyl-benzamide 1i (500 mg, 1.03 mmol) in tetrahydrofuran (5 mL) at 0°C under nitrogen was added 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). The mixture was stirred at 30°C for approximately 16 hours. After thin-layer chromatography (dichloromethane / methanol = 10 / 1) indicated complete reaction of the starting material, 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 (40 mL), dried over anhydrous sodium sulfate, and concentrated to yield the crude product. The crude product was purified by preparative thin layer chromatography (dichloromethane / methanol = 10 / 1) to give N-methyl-2-[3-[(E)-2-[5-[2-(4-methylpiperazin-1-yl)ethoxy]-2-pyridinyl]vinyl]-1-tetrahydropyran-2-yl-indole-6-yl]sulfanylbenzamide 6b (400 mg, 652.76 μmol, 63.52% yield) as a yellow solid.

[0288] The product was confirmed by LCMS.

[0289] MS-ESI calculated value [M+H]+ 613.3, found 613.2.

[0290] Step 2

[0291] To a solution of N-methyl-2-[3-[(E)-2-[5-[2-(4-methylpiperazin-1-yl)ethoxy]-2-pyridyl]vinyl]-1-tetrahydropyran-2-yl-indole-6-yl]sulfanylbenzamide 6b (400 mg, 652.76 μmol) in dichloromethane (10 mL) was added trifluoroacetic acid (74.4 mg, 652.76 μmol) at room temperature. The mixture was stirred at 30°C for 16 hours. After thin-layer chromatography (dichloromethane / methanol = 10 / 1) indicated complete reaction of the starting material, the mixture was poured into water (10 mL), adjusted to pH 8-9 with solid sodium carbonate, and extracted with DCM (10 mL x 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to yield the crude product. The crude product was purified by preparative thin layer chromatography to give N-methyl-2-({3-[(E)-2-{5-[2-(4-methylpiperazin-1-yl)ethoxy]pyridin-2-yl}vinyl]-1H-indazol-6-yl}sulfanyl)benzamide I-4 (27.5 mg, 52.02 μmol, 7.97% yield) as a white solid.

[0292] The product was confirmed by LCMS, HNMR and CNMR.

[0293] MS-ESI calculated value [M+H]+ 529.2, found 529.2.

[0294] 1 H NMR(400MHz, CD3OD&CDCl3)δ8.27(d,J=2.4Hz,1H),8.05(d,J=11.2Hz,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=1.6Hz,2H),4.12(s,2H),2.87(d,J=15.2Hz,4H),2.50-2.73(m,8H),2.33(s,3H).

[0295] 13 C NMR(100MHz,CD3OD&CDCl3)δ:170.27,154.35,148.36,137.19,136.77,135.58,133.62,131.08,130.4 3,129.19,127.72,126.39,125.57,122.34,122.18,121.34,65.97,56.72,54.32,52.80,45.07,25.92.

[0296] I-7

[0297] first step

[0298] To a solution of 2-[3-[(E)-2-(5-hydroxy-2-pyridyl)vinyl]-1-tetrahydropyran-2-yl-indole-6-yl]thio-N-methyl-benzamide 1i (750 mg, 1.54 mmol) in tetrahydrofuran (5 mL) at 0°C under nitrogen was added tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate 7a (900 mg, 4.47 mmol), Ph3P (972 mg, 3.71 mmol), and DIAD (750 mg, 3.71 mmol). The mixture was stirred at 40°C for approximately 16 hours. After thin-layer chromatography (dichloromethane / methanol = 10 / 1) indicated complete reaction of the starting material, 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 (40 mL), dried over anhydrous sodium sulfate, and concentrated to yield the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 0 / 1) to give tert-butyl 3-[[6-[(E)-2-[6-[2-(methylcarbamoyl)phenyl]sulfanyl-1-tetrahydropyran-2-yl-indole-3-yl]vinyl]-3-pyridyl]oxymethyl]pyrrolidine-1-carboxylate 7b (200 mg, 298.58 μmol, 19.37% yield) as a white solid.

[0299] The product was confirmed by LCMS and HNMR.

[0300] MS-ESI calculated value [M+H]+ 670.3, found 670.2.

[0301] 1 H NMR(400MHz, CDCl3)δ8.34(s,2H),8.00(d,J=8.4Hz,1H),7.75(s,1H),7.72–7.62(m,3H), 7.56(dd,J=7.2,1.6Hz,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=11.2Hz,3H),3.70(m,3H),3.42(s,1H),3.23(s,1H),2.98(dd,J=4 .8,1.2Hz,3H),2.53(d,J=13.2Hz,1H),2.11(s,4H),1.93–1.66(m,4H),1.65–1.42(m,9H).

[0302] Step 2

[0303] To a solution of tert-butyl 3-[[6-[(E)-2-[6-[2-(methylcarbamoyl)phenyl]thio-1-tetrahydropyran-2-yl-indole-3-yl]vinyl]-3-pyridinyl]oxymethyl]pyrrolidine-1-carboxylate 7b (100 mg, 149.29 μmol) in dichloromethane (4 mL) was added trifluoroacetic acid (74.4 mg, 652.76 μmol) at room temperature. The mixture was stirred at room temperature for approximately 2 hours. After thin layer chromatography (dichloromethane / methanol = 10 / 1) showed complete reaction of the starting material, the mixture was poured into water (10 mL), adjusted to pH 8-9 with solid sodium carbonate, 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 to give N-methyl-2-(3-[(E)-2-{5-[(pyrrolidin-3-yl)methoxy]pyridin-2-yl}vinyl]-1H-indazol-6-yl}sulfanyl)benzamide I-7 (18 mg, 37.07 μmol, 24.83% yield) as a white solid.

[0304] The product was confirmed by LCMS, HNMR and CNMR.

[0305] MS-ESI calculated value [M+H]+ 486.2, found 486.1.

[0306] 1 H NMR(400MHz,CD3OD)δ8.41(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=12.0Hz,3H),2.42–2.18(m,1H),2.08–1.84(m,1H).

[0307] 13 C 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.

[0308] I-37

[0309] first step

[0310] To a solution of 2-[3-[(E)-2-(5-hydroxy-2-pyridyl)vinyl]-1-tetrahydropyran-2-yl-indole-6-yl]thio-N-methyl-benzamide 1i (400 mg, 822.06 μmol) in tetrahydrofuran (10 mL) was added [(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. The mixture was stirred at 40°C for approximately 16 hours. After thin-layer chromatography (dichloromethane / methanol = 10 / 1) indicated complete reaction of the starting material, the mixture was poured into water (50 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 yield the crude product. The crude product was purified by preparative thin layer chromatography to give N-methyl-2-[1-methyl-3-[(E)-2-[5-[(3S)-1-methylpyrrolidin-3-yl]methoxy]-2-pyridinyl]vinyl]indole-6-yl]sulfanylbenzamide 8b (300 mg, 513.93 μmol, 62.52% yield) as a white solid.

[0311] The product was confirmed by LCMS.

[0312] MS-ESI calculated value [M+H]+ 584.3, found 584.8.

[0313] Step 2

[0314] To a solution of N-methyl-2-[1-methyl-3-[(E)-2-[5-[(3S)-1-methylpyrrolidin-3-yl]methoxy]-2-pyridyl]vinyl]indole-6-yl]thiobenzamide 8b (200 mg, 342.62 μmol) in dichloromethane (4 mL) was added trifluoroacetic acid (3 g, 26.31 mmol) at room temperature. The mixture was stirred at room temperature for approximately 16 hours. After thin-layer chromatography (dichloromethane / methanol = 10 / 1) indicated complete reaction of the starting material, 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 x 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to yield the crude product. The crude product was purified by preparative thin layer chromatography to afford 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) as a white solid.

[0315] The product was confirmed by LCMS, HNMR and CNMR.

[0316] MS-ESI calculated value [M+H]+ 500.2, found 500.1.

[0317] 1 H NMR (400MHz, CD3OD) δ8.27(d,J=2.8Hz,1H),8.04(d,J=8.4Hz,1H),7.78(s,1H),7.69(d,J=16.4Hz ,1H),7.65–7.60(m,2H),7.49(s,1H),7.42(dd,J=8.8,2.8Hz,1H),7.29(dd,J=13.2,6.8Hz,2H),7 .23–7.18(m,2H),4.11(d,J=5.2Hz,2H),3.13(dd,J=9.2,4.8Hz,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=13.2,6.0Hz,1H).

[0318] 13C NMR (100MHz, CDCl3&CD3OD) δ168.68,153.46,147.44,135.78,133.95,132.59,130.85,129.82,128.5 8,127.35,125.96,124.24,121.34,121.02,120.60,69.94,63.40,56.74,40.70,27.41,25.51,21.78.

[0319] I-39

[0320] first step

[0321] To a solution of 2-[3-[(E)-2-(5-hydroxy-2-pyridyl)vinyl]-1-tetrahydropyran-2-yl-indole-6-yl]thio-N-methyl-benzamide 1i (500 mg, 1.03 mmol) in tetrahydrofuran (10 mL) at 0°C under nitrogen was added [(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). The mixture was stirred at 40°C for approximately 16 hours. After thin-layer chromatography (petroleum ether / ethyl acetate = 1 / 1) indicated complete reaction of the starting material, 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 yield the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give N-methyl-2-[1-methyl-3-[(E)-2-[5-[(3R)-1-methylpyrrolidin-3-yl]methoxy]-2-pyridyl]vinyl]indazole-6-yl]sulfanylbenzamide 9b (350 mg, 599.58 μmol, 58.35% yield) as a yellow solid.

[0322] The product was confirmed by LCMS.

[0323] MS-ESI calculated value [M+H]+ 584.3, found 584.2.

[0324] Step 2

[0325] To a solution of N-methyl-2-[1-methyl-3-[(E)-2-[5-[(3R)-1-methylpyrrolidin-3-yl]methoxy]-2-pyridyl]vinyl]indole-6-yl]thiobenzamide 9b (350 mg, 599.58 μmol) in dichloromethane (6 mL) was added trifluoroacetic acid (5.3 g, 46.04 mmol) at room temperature. The mixture was stirred at room temperature for approximately 16 hours. After thin-layer chromatography (dichloromethane / methanol = 10 / 1) indicated complete reaction of the starting material, the mixture was poured into water (5 mL), adjusted to pH 8-9 with solid sodium carbonate, and extracted with dichloromethane (5 mL x 3). The combined organic layers were washed with water (5 mL x 2), dried over anhydrous sodium sulfate, and concentrated to yield the crude product. The crude product was purified by preparative thin layer chromatography to afford 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) as a yellow solid.

[0326] The product was confirmed by LCMS, HNMR and CNMR.

[0327] MS-ESI calculated value [M+H]+ 500.2, found 500.1.

[0328] 1 H NMR(400MHz, CD3OD&CDCl3)δ8.27(s,1H),8.04(d,J=8.4Hz,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),7.2 1(t,J=8.0Hz,2H),4.11(d,J=5.2Hz,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).

[0329] 13C NMR (100MHz, CDCl3&CD3OD) δ169.88,154.17,148.04,142.25,141.19,136.90,136.34,135.28,133.24,130.79,130.20,12 8.97,127.50,125.29,122.05,121.78,121.54,121.10,120.12,114.30,70.29,64.04,57.23,41.01,27.74,25.77,22.21.

[0330] I-3

[0331] first step

[0332] At low temperature, sodium hydride (1.5 g, 37.15 mmol, 60% purity) was added stepwise to a solution of 6-vinylpyridine-3-ol 1c (1.5 g, 12.38 mmol) in dry N,N-dimethylformamide (20 mL). The mixture was then stirred at 0 ° C for 1 hour. 4-(2-chloroethyl)morpholine hydrochloride 10a (2.8 g, 14.86 mmol) was then slowly added. The mixture was stirred at 60 ° C for about 4 hours. After thin layer chromatography (petroleum ether / ethyl acetate = 3 / 1) showed that the raw material reaction was complete, the mixture was poured into water (100 mL) and extracted with ethyl acetate (60 mL x 3). The combined organic layer was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate and concentrated to obtain a crude product. The crude product was purified by preparative thin layer chromatography to give 4-[2-[(6-vinyl-3-pyridinyl)oxy]ethyl]morpholine 10b (1.5 g, 6.40 mmol, 51.70% yield) as a yellow oily liquid.

[0333] The product was confirmed by LCMS and HNMR.

[0334] MS-ESI calculated value [M+H]+ 235.1, found 235.1. 1 H NMR (400MHz, CDCl3): δ (ppm) 8.29 (d, J = 2.8Hz, 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).

[0335] Step 2

[0336] Under nitrogen protection, to a solution of 2-(3-iodo-1-tetrahydropyran-2-yl-indole-6-yl)sulfanyl-N-methyl-benzamide 1h (100 mg, 0.20 mmol) in 1,4-dioxane (5 mL) were added 4-[2-[(6-vinyl-3-pyridyl)oxy]ethyl]morpholine 10b (57 mg, 0.24 mmol), triethylamine (61.5 mg, 0.61 mmol), Pd2(dba)3 (45.5 mg, 0.20 mmol) and P(o-tol)3 (61.7 mg, 0.20 mmol) at room temperature and stirred for reaction at 100°C. After thin layer chromatography (dichloromethane / methanol = 20 / 1) showed that the reaction of the starting material was complete, the mixture was poured into water (10 mL) and washed with ethyl acetate (10 mL x 4 ). 3) extraction, the combined organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated to give a crude product; the crude product was purified by preparative thin layer chromatography (dichloromethane / methanol = 20 / 1) to give N-methyl-2-[3-[(E)-2-[5-(2-morpholinethoxy)-2-pyridyl]vinyl]-1-tetrahydropyran-2-yl-indazole-6-yl]sulfanylbenzamide 10c (100 mg, 166.74 μmol, 82.26% yield) as a brown solid.

[0337] The product was confirmed by LCMS.

[0338] MS-ESI calculated value [M+H]+ 600.2, found 600.1. Step 3

[0339] To a solution of N-methyl-2-[3-[(E)-2-[5-(2-morpholinethoxy)-2-pyridyl]vinyl]-1-tetrahydropyran-2-yl-indole-6-yl]thiobenzamide 10c (400 mg, 0.67 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (380.2 mg, 3.33 mmol) at room temperature. The mixture was stirred at 35°C for 16 hours. After thin-layer chromatography (dichloromethane / methanol = 10 / 1) indicated complete reaction of the starting material, the mixture was poured into water (40 mL), adjusted to pH 8-9 with solid sodium carbonate, and extracted with dichloromethane (30 mL x 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to yield the crude product. The crude product was purified by preparative thin layer chromatography to give N-methyl-2-({3-[(E)-2-{5-[2-(morpholin-4-yl)ethoxy]pyridin-2-yl}vinyl]-1H-indazol-6-yl}sulfanyl)benzamide I-3 (53.7 mg, 104.15 μmol, 15.62% yield) as a white solid.

[0340] The product was confirmed by LCMS, HNMR and CNMR.

[0341] MS-ESI calculated value [M+H]+ 516.2, found 516.2

[0342] 1 H NMR (400MHz, CDCl3): δ (ppm) 10.28 (s, 1H), 8.38-8.37 (m, 1H), 8.02 (d, J = 8.4Hz, 1 H),7.78-7.74(m,1H),7.68-7.66(m,1H),7.57-7.52(m,2H),7.44(d,J=8.8Hz,1H ),7.34-7.32(m,2H),7.27-7.22(m,3H),6.37-6.34(m,1H),4.22(t,J=5.6Hz,2H) ,3.78(t,J=4.4Hz,4H),2.98(d,J=5.2Hz,3H),2.87(t,J=5.6Hz,2H),2.63(s,4H).

[0343] 13 C NMR (100MHz, 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.

[0344] I-19

[0345] first step

[0346] 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 protection, and the mixture was stirred at 0°C for 1 h. Then, 1-(2-chloroethyl)pyrrolidine hydrochloride 11a (1.17 g, 6.90 mmol) was added at 0°C, and the temperature was raised to 60°C and the mixture was stirred for 16 h. After thin-layer chromatography (petroleum ether / ethyl acetate = 1 / 1) showed complete reaction of the starting material, 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 (100 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product 5-bromo-2-(2-pyrrolidino-1-methoxy)pyridine 11c (1 g, 3.69 mmol, 64.17% yield) as a brown oily liquid.

[0347] The product was confirmed by LCMS and HNMR.

[0348] MS-ESI calculated value [M+H]+ 272.9, found 272.9.

[0349] 1 H NMR(400MHz, DMSO-d6)δ8.18–8.02(m,1H),7.50(dt,J=13.8,6.9Hz,1H),7.41–7.21(m,1H),4.12 (dd,J=5.5,2.9Hz,2H),2.76(dd,J=5.5,2.8Hz,2H),2.48(d,J=1.7Hz,4H),1.65(d,J=3.1Hz,4H).

[0350] Step 2

[0351] 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) was added potassium vinyl trifluoroborate 1b (750.0 mg, 5.60 mmol), Pd(dppf)Cl2 (80.1 mg, 109.53 μmol), and triethylamine (560.0 mg, 5.53 mmol) at room temperature. The mixture was heated to 85°C and stirred for approximately 16 hours. After thin-layer chromatography (dichloromethane / methanol = 10 / 1) indicated complete reaction of the starting material, 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 yield the crude product. The crude product was purified by preparative thin layer chromatography (dichloromethane / methanol=10 / 1) to give 2-(2-pyrrolidine-1-ethoxy)-5-vinylpyridine 11d (340 mg, 1.56 mmol, 42.23% yield) as a yellow solid.

[0352] The product was confirmed by LCMS and HNMR.

[0353] MS-ESI calculated value [M+H]+ 219.1, found 219.1.

[0354] 1 H NMR (400MHz, CDCl3) δ7.89–7.53(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=22.5,11.2Hz,1H),4.06(d,J=17.0Hz,2H),2.83(d,J=10.8Hz,2H),2.60(d,J=7.4Hz,4H),1.84–1.76(m,4H).

[0355] Step 3

[0356] To a solution of 2-(3-iodo-1-tetrahydropyran-2-yl-indole-6-yl)sulfanyl-N-methyl-benzamide 1h (500 mg, 1.01 mmol) in 1,4-dioxane (20 mL) were added 2-(2-pyrrolidino-1-ethoxy)-5-vinylpyridine 11d (280 mg, 1.28 mmol), triethylamine (300 mg, 2.96 mmol), Pd2(dba)3 (250 mg, 1.11 mmol) and P(o-tol)3 (250 mg, 821.40 μmol) at room temperature under nitrogen protection, and the temperature was raised to 100 ° C and stirred for about 2 hours. After thin-layer chromatography (dichloromethane / methanol = 20 / 1) showed that the starting material had reacted completely, 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 a crude product. The crude product was purified by preparative thin-layer chromatography (dichloromethane / methanol = 10 / 1) to give N-methyl-2-[3-[(E)-2-[6-(2-pyrrolidin-1-ylethoxy)-3-pyridyl]vinyl]-1-tetrahydropyran-2-yl-indole-6-yl]sulfanylbenzamide 11e (200 mg, 342.62 μmol, 33.81% yield) as a yellow solid.

[0357] The product was confirmed by LCMS.

[0358] MS-ESI calculated value [M+H]+ 584.3, found 584.4.

[0359] Step 4

[0360] To a solution of N-methyl-2-[3-[(E)-2-[6-(2-pyrrolidin-1-ylethoxy)-3-pyridyl]vinyl]-1-tetrahydropyran-2-yl-indole-6-yl]sulfanylbenzamide 11e (200 mg, 342.62 μmol) in dichloromethane (8 mL) was added trifluoroacetic acid (1.20 g, 10.52 mmol) at room temperature. The mixture was stirred at 40°C for 16 hours. After thin-layer chromatography (dichloromethane / methanol = 10 / 1) indicated complete reaction of the starting material, 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 x 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to yield the crude product. The crude product was purified by preparative thin layer chromatography to give N-methyl-2-({3-[(E)-2-{6-[2-(pyrrolidin-1-yl)ethoxy]pyridin-3-yl}vinyl]-1H-indazol-6-yl}sulfanyl)benzamide I-19 (10.4 mg, 20.82 μmol, 6.08% yield) as a white solid.

[0361] The product was confirmed by LCMS, HNMR and CNMR.

[0362] MS-ESI calculated value [M+H]+ 500.2, found 500.0.

[0363] 1 H NMR (400MHz, CDCl3) δ11.49(s,1H),7.84(d,J=8.5Hz,1H),7.65(d,J=5.0Hz,1H),7.43–7.28(m,6H),7.22–7.08(m,2H),6.94(dd,J=41 .7,16.5Hz,2H),6.19(d,J=9.4Hz,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=10.3Hz,2H).

[0364] 13 C 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.

[0365] I-17

[0366] first step

[0367] To a solution of 6-bromopyridin-2-ol 12a (500 mg, 2.87 mmol) in N,N-dimethylformamide (10 mL) at room temperature under nitrogen was added potassium vinyl trifluoroborate 1b (577.4 mg, 4.31 mmol), Pd(dppf)Cl2 (100 mg, 137.81 μmol), and triethylamine (872.4 mg, 8.62 mmol). The mixture was heated to 80°C and stirred for approximately 16 hours. After thin-layer chromatography (dichloromethane / methanol = 10 / 1) indicated complete reaction, the mixture was poured into water (100 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to yield the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1-1 / 10) to give 6-vinylpyridin-2-ol 12b (140 mg, 1.16 mmol, 40.22% yield) as a white solid.

[0368] The product was confirmed by HNMR. 1 H NMR (400MHz, CDCl3): δ (ppm) 11.84 (s, 1H), 7.42 (s, 1H), 6.46 (m, 2H), 6.14 (m, 2H), 5.55 (d, J = 11.3Hz, 1H).

[0369] Step 2

[0370] To a solution of 6-vinylpyridin-2-ol 12b (110 mg, 908.07 μmol) in N,N-dimethylformamide (2 mL) at room temperature under nitrogen was added 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). The mixture was heated to 100°C and stirred for approximately 4 hours. After thin-layer chromatography (dichloromethane / methanol = 10 / 1) indicated complete reaction of the starting material, 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 yield the crude product. The crude product was purified by preparative thin layer chromatography (dichloromethane / methanol=10 / 1) to give 2-(2-pyrrolidino-1-ethoxy)-6-vinylpyridine 12c (75 mg, 343.57 μmol, 37.84% yield) as a yellow solid.

[0371] The product was confirmed by LCMS and HNMR.

[0372] MS-ESI calculated value [M+H]+ 219.1, found 219.1.

[0373] 1 H NMR (400MHz, CDCl3): δ (ppm) 7.53 (t, J = 8.0Hz, 1H), 6.84 (d, J = 7.2Hz, 1H), 6.75-6.67 (m, 2H), 6.3 0-6.25(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).

[0374] Step 3

[0375] Under nitrogen protection, to a solution of 2-(3-iodo-1-tetrahydropyran-2-yl-indole-6-yl)sulfanyl-N-methyl-benzamide 1h (500 mg, 1.01 mmol) in 1,4-dioxane (20 mL) were added 2-(2-pyrrolidino-1-ethoxy)-6-vinylpyridine 12c (265.5 mg, 1.22 mmol), triethylamine (307.7 mg, 3.04 mmol), Pd2(dba)3 (464 mg, 506.73 μmol) and P(o-tol)3 (308.5 mg, 1.01 mmol) at room temperature, and the temperature was raised to 100 ° C and stirred for about 2 hours. After thin-layer chromatography (dichloromethane / methanol = 10 / 1) showed that the starting material had reacted completely, 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 a crude product. The crude product was purified by preparative thin-layer chromatography (dichloromethane / methanol = 10 / 1) to give N-methyl-2-[3-[(E)-2-[6-(2-pyrrolidin-1-ylethoxy)-2-pyridyl]vinyl]-1-tetrahydropyran-2-yl-indole-6-yl]sulfanylbenzamide 12d (370 mg, 633.84 μmol, 62.54% yield) as a yellow solid.

[0376] The product was confirmed by LCMS.

[0377] MS-ESI calculated value [M+H]+ 584.3, found 584.1.

[0378] Step 4

[0379] To a solution of N-methyl-2-[3-[(E)-2-[6-(2-pyrrolidin-1-ylethoxy)-2-pyridinyl]vinyl]-1-tetrahydropyran-2-yl-indole-6-yl]thiobenzamide 12d (0.4 g, 685.23 μmol) in dichloromethane (10 mL) was added trifluoroacetic acid (78.1 mg, 685.23 μmol) at room temperature. The mixture was stirred at 30°C for 16 hours. After thin-layer chromatography (dichloromethane / methanol = 10 / 1) indicated complete reaction of the starting material, the mixture was poured into water (40 mL), adjusted to pH 8-9 with solid sodium carbonate pellets, 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 yield the crude product. The crude product was purified by preparative thin layer chromatography to give N-methyl-2-({3-[(E)-2-{6-[2-(pyrrolidin-1-yl)ethoxy]pyridin-2-yl}vinyl]-1H-indazol-6-yl}sulfanyl)benzamide I-17 (27.5 mg, 55.04 μmol, 8.03% yield) as a yellow solid.

[0380] The product was confirmed by LCMS, HNMR and CNMR.

[0381] MS-ESI calculated value [M+H]+ 500.2, found 500.1.

[0382] 1 H NMR (400MHz, CDCl3): δ (ppm) 10.61-10.42 (m, 1H), 8.02-7.97 (m, 2H), 7.65 ( s,1H),7.56(t,J=7.6Hz,1H),7.43(d,J=16.1Hz,1H),7.32(d,J=3.7Hz,1H), 7.24(d,J=8.3Hz,1H),6.95(d,J=7.1Hz,1H),6.70(d,J=8.3Hz,1H),6.36(s, 1H),4.62(t,J=5.9Hz,2H),2.98(t,J=6.1Hz,3H),2.70(s,2H),1.85(s,2H).

[0383] 13C NMR (100MHz, 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.

[0384] I-15

[0385] first step

[0386] To a solution of 3-bromophenol 13a (1.00 g, 5.78 mmol) in DMSO (10 mL) at room temperature under nitrogen, 1-(2-chloroethyl)pyrrolidine hydrochloride 11a (1.47 g, 8.67 mmol) and cesium carbonate (5.65 g, 17.34 mmol) were added. The mixture was heated to 50°C and stirred for approximately 16 hours. After thin-layer chromatography (petroleum ether / ethyl acetate = 1 / 1) indicated complete reaction, 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 afford the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1 to 3 / 1) to afford 1-[2-(3-bromophenoxy)ethyl]pyrrolidine 13b (620 mg, 2.29 mmol, 39.70% yield) as a white solid.

[0387] The product was confirmed by LCMS and HNMR.

[0388] MS-ESI calculated value [M+H]+ 270.0, found 270.0.

[0389] 1 H NMR (400MHz, CDCl3) δ7.13-7.17(m,1H),7.08-7.10(m,2H),6.86-6.89(m,1H),4. 10(t,J=6.0Hz,2H),2.91(t,J=6.0Hz,1H),2.63-2.66(m,4H),1.81-1.85(m,4H).

[0390] Step 2

[0391] To a solution of 1-[2-(3-bromophenoxy)ethyl]pyrrolidine 13b (800 mg, 2.96 mmol) in N,N-dimethylformamide (8 mL) at room temperature under nitrogen was added potassium vinyl trifluoroborate 1b (577.4 mg, 4.31 mmol), Pd(dppf)Cl2 (65.00 mg, 88.83 μmol), and triethylamine (898.92 mg, 8.88 mmol). The mixture was stirred at 85°C for approximately 16 hours. After thin-layer chromatography (dichloromethane / methanol = 10 / 1) indicated complete reaction, 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 yield the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 - dichloromethane / methanol = 10 / 1) to give 1-[2-(3-vinylphenoxy)ethyl]pyrrolidine 13c (300 mg, 1.38 mmol, 46.62% yield) as a white solid.

[0392] The product was confirmed by LCMS and HNMR.

[0393] MS-ESI calculated value [M+H]+ 218.1, found 218.1.

[0394] 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, 10.9Hz, 1H), 5.84-5. 60(m,1H),5.24(d,J=10.9Hz,1H),4.20-4.03(m,2H),2.90(t,J=6.0Hz,1H),2.70-2.54(m,4H),1.87-1.75(m,4H).

[0395] Step 3

[0396] To a solution of 2-(3-iodo-1-tetrahydropyran-2-yl-indole-6-yl)thio-N-methyl-benzamide 1h (200 mg, 405.38 μmol) in 1,4-dioxane (5 mL) were added 1-[2-(3-vinylphenoxy)ethyl]pyrrolidine 13c (132.14 mg, 608.08 μmol), triethylamine (123.06 mg, 1.22 mmol), Pd2(dba)3 (371.22 mg, 405.38 μmol) and P(o-tol)3 (123.38 mg, 405.38 μmol) at room temperature under nitrogen protection, and the temperature was raised to 100 ° C and stirred for about 4 hours. After thin-layer chromatography (dichloromethane / methanol = 10 / 1) showed that the starting material had reacted completely, 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 a crude product. The crude product was purified by preparative thin-layer chromatography (dichloromethane / methanol = 10 / 1) to give N-methyl-2-[3-[(E)-2-[3-(2-pyrrolidin-1-ethoxy)phenyl]vinyl]-1-tetrahydropyran-2-yl-indazol-6-yl]sulfanylbenzamide 13d (370 mg, 633.84 μmol, 62.54% yield) as a yellow solid.

[0397] The product was confirmed by LCMS.

[0398] MS-ESI calculated value [M+H]+ 583.3, found 583.1.

[0399] Step 4

[0400] 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) was added trifluoroacetic acid (0.5 mL) at room temperature. The mixture was stirred at 40°C for approximately 16 hours. After thin-layer chromatography (dichloromethane / methanol = 10 / 1) indicated complete reaction of the starting material, 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 yield the crude product. The crude product was purified by preparative thin layer chromatography to give N-methyl-2-({3-[(E)-2-{3-[2-(pyrrolidin-1-yl)ethoxy]phenyl}vinyl]-1H-indazol-6-yl}sulfanyl)benzamide I-15 (11.8 mg, 23.66 μmol, 12.54% yield) as a white solid.

[0401] The product was confirmed by LCMS, HNMR and CNMR.

[0402] MS-ESI calculated value [M+H]+ 499.2, found 499.1.

[0403] 1 H NMR (400MHz, CD3OD): δ (ppm) 8.07 (d, J = 8.5Hz, 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 = 8.0Hz, 1 H),4.44-4.41(t,J=9.6Hz,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).

[0404] 13 C NMR (100MHz, CD3OD) δ170.38,158.23,143.23,141.95,139.35,137.29,134.97,134.12,131.44,130.58,130.26,129.68,127.6 7,126.62,125.08,121.26,120.13,119.19,119.86,114.05,113.80,111.92,62.91,54.34,53.80,36.94,25.32,22.51,16.29.

[0405] I-22

[0406] first step

[0407] To a solution of 5-bromopyridin-3-ol 14a (2 g, 11.49 mmol) in N,N-dimethylformamide (20 mL) at room temperature under nitrogen was added potassium vinyl trifluoroborate 1b (2.31 g, 17.24 mmol), Pd(dppf)Cl2 (1 g, 1.37 mmol), and triethylamine (3.00 g, 29.65 mmol). The mixture was heated to 85°C and stirred for approximately 16 hours. After thin-layer chromatography (dichloromethane / methanol = 10 / 1) indicated complete reaction, 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 (200 mL), dried over anhydrous sodium sulfate, and concentrated to yield the crude product. The crude product was purified by basic alumina column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 0 / 1) to give 5-vinylpyridin-3-ol 14b (600 mg, 4.95 mmol, 43.09% yield) as a white solid.

[0408] The product was confirmed by LCMS and HNMR.

[0409] MS-ESI calculated value [M+H]+ 122.1, found 122.1.

[0410] 1 H NMR (400MHz, CDCl3) δ8.12(t,J=27.6Hz,2H),7.38(s,1H),6.67(dd,J=17.6,11.0Hz,1H),5.83(d,J=17.6Hz,1H),5.41(d,J=10.8Hz,1H).

[0411] Step 2

[0412] 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 was added sodium hydride (300.00 mg, 7.50 mmol, 60% purity) portionwise. The mixture was stirred at 0°C for 1 hour, followed by the addition of 1-(2-chloroethyl)pyrrolidine hydrochloride 11a (600 mg, 3.53 mmol). The mixture was allowed to warm to room temperature and stirred for approximately 2 hours. After thin-layer chromatography (dichloromethane / methanol = 10 / 1) indicated complete reaction of the starting material, 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 yield the crude product. The crude product was purified by preparative thin-layer chromatography (petroleum ether / ethyl acetate = 5 / 1 to 3 / 1) to give 3-(2-pyrrolidino-1-ethoxy)-5-vinylpyridine 14c (190 mg, 870.39 μmol, 35.15% yield) as a yellow solid.

[0413] The product was confirmed by LCMS and HNMR.

[0414] MS-ESI calculated value [M+H]+ 219.1, found 219.1.

[0415] 1 H NMR (400MHz, CDCl3) δ8.33–8.06(m,2H),7.61(dd,J=12.4,7.6Hz,1H),6.71(dd,J=17.6,11.2Hz,1H),5.83(d,J=17.6Hz,1H) ,5.41(d,J=10.8Hz,1H),4.22(dd,J=20.8,15.2Hz,2H),2.95(dd,J=17.2,11.6Hz,2H),2.54(d,J=105.6Hz,4H),1.85(s,4H).

[0416] Step 3

[0417] To a solution of 2-(3-iodo-1-tetrahydropyran-2-yl-indole-6-yl)thio-N-methyl-benzamide 1h (400 mg, 810.77 μmol) in 1,4-dioxane (5 mL) were added 3-(2-pyrrolidino-1-ethoxy)-5-vinylpyridine 14c (200 mg, 916.20 μmol), triethylamine (300.00 mg, 2.96 mmol), Pd2(dba)3 (320 mg, 1.43 mmol) and P(o-tol)3P(o-tol)3 (220 mg, 722.83 μmol) at room temperature under nitrogen protection, and the temperature was raised to 100 ° C and stirred for about 2 hours. After thin-layer chromatography (dichloromethane / methanol = 10 / 1) showed that the starting material had reacted completely, 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 a crude product. The crude product was purified by preparative thin-layer chromatography (dichloromethane / methanol = 10 / 1) to give N-methyl-2-[3-[(E)-2-[5-(2-pyrrolidin-1-ylethoxy)-3-pyridyl]vinyl]-1-tetrahydropyran-2-yl-indole-6-yl]sulfanylbenzamide 14d (100 mg, 171.31 μmol, 21.13% yield) as a yellow oily liquid.

[0418] The product was confirmed by LCMS.

[0419] MS-ESI calculated value [M+H]+ 584.3, found 584.1.

[0420] Step 4

[0421] To a solution of N-methyl-2-[3-[(E)-2-[5-(2-pyrrolidin-1-ylethoxy)-3-pyridyl]vinyl]-1-tetrahydropyran-2-yl-indole-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 thin-layer chromatography (dichloromethane / methanol = 10 / 1) indicated complete reaction of the starting material, 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 yield the crude product. The crude product was purified by preparative thin layer chromatography to give N-methyl-2-({3-[(E)-2-{5-[2-(pyrrolidin-1-yl)ethoxy]pyridin-3-yl}vinyl]-1H-indazol-6-yl}sulfanyl)benzamide I-22 (16.3 mg, 32.62 μmol, 19.04% yield) as a white solid.

[0422] The product was confirmed by LCMS, HNMR and CNMR.

[0423] MS-ESI calculated value [M+H]+ 500.2, found 500.9.

[0424] 1 H NMR (400MHz, CDCl3) δ8.39(s,1H),8.25(d,J=2.6Hz,1H),7.97(d,J=8.5Hz,1H),7.70–7.65(m, 1H),7.52(s,1H),7.43(d,J=10.4Hz,3H),7.37–7.32(m,2H),7.25(d,J=9.7Hz,2H),6.3 9(s,1H),4.25(t,J=5.8Hz,2H),3.00(dd,J=10.3,5.3Hz,5H),2.72(s,4H),1.87(s,4H).

[0425] 13 C 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, 13 0.84,128.62,126.96,125.05,122.39,121.41,120.56,117.33,113.97,67.38,55.00,54.72,53.40,26.87,23.52.

[0426] I-9

[0427] first step

[0428] To a solution of 4-bromo-1H-pyrazole 15a (2 g, 13.61 mmol) in DMSO (20 mL) at room temperature under nitrogen was added 1-(2-chloroethyl)pyrrolidine hydrochloride 11a (2.8 g, 16.33 mmol) and cesium carbonate (13.3 g, 40.82 mmol). The mixture was heated to 100°C and stirred for approximately 2.5 hours. After thin-layer chromatography (dichloromethane / methanol = 10 / 1) indicated complete reaction of the starting material, the mixture was poured into water (100 mL) and extracted with dichloromethane (40 mL x 3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to yield the crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give 4-bromo-1-(2-pyrrolidine-1-ethyl)pyrazole 15b (2.5 g, 10.24 mmol, 75.25% yield) as a yellow oily liquid.

[0429] 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).

[0430] Step 2

[0431] To a solution of 4-bromo-1-(2-pyrrolidine-1-ethyl)pyrazole 15b (501.4 mg, 2.05 mmol) in N,N-dimethylformamide (10 mL) at room temperature under nitrogen was added potassium vinyl trifluoroborate 1b (440.8 mg, 3.29 mmol), Pd(dppf)Cl2 (542.9 mg, 742.01 μmol), and triethylamine (668.1 mg, 6.60 mmol). The mixture was stirred at 85°C for approximately 16 hours. After thin-layer chromatography (dichloromethane / methanol = 10 / 1) indicated complete reaction of the starting material, 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 yield the crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give 1-(2-pyrrolidine-1-ethyl)-4-vinylpyrazole 15c (66 mg, 345.06 μmol, 16.80% yield) as a red oily liquid.

[0432] The product was confirmed by LCMS and HNMR.

[0433] MS-ESI calculated value [M+H]+ 192.1, found 192.2.

[0434] 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).

[0435] Step 3

[0436] To a solution of 2-(3-iodo-1-tetrahydropyran-2-yl-indole-6-yl)thio-N-methyl-benzamide 1h (500 mg, 1.01 mmol) in 1,4-dioxane (5 mL) were added 1-(2-pyrrolidine-1-ethyl)-4-vinylpyrazole 15c (213.2 mg, 1.11 mmol), triethylamine (307.7 mg, 3.04 mmol), Pd2(dba)3 (500 mg, 546.04 μmol) and P(o-tol)3 (500.5 mg, 1.64 mmol) at room temperature under nitrogen protection, and the temperature was raised to 100 ° C and stirred for about 2 hours. After thin-layer chromatography (dichloromethane / methanol = 10 / 1) showed that the starting material was reacted completely, the mixture was poured into water (15 mL) and filtered. The filtrate was extracted with dichloromethane (15 mL × 3), and the combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product N-methyl-2-[3-[(E)-2-[1-(2-pyrrolidin-1-ylethyl)pyrazol-4-yl]vinyl]-1-tetrahydropyran-2-yl-indazol-6-yl]sulfanylbenzamide 15d (370 mg, 633.84 μmol, 62.54% yield) as a red oily liquid.

[0437] The product was confirmed by LCMS.

[0438] MS-ESI calculated value [M+H]+ 557.3, found 557.3.

[0439] Step 4

[0440] 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) was added trifluoroacetic acid (527.7 mg, 4.63 mmol) at room temperature. The mixture was stirred at room temperature for approximately 16 hours. After thin-layer chromatography (dichloromethane / methanol = 10 / 1) indicated complete reaction of the starting material, 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 layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to yield the crude product. The crude product was purified by preparative thin layer chromatography to give 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) as a yellow solid.

[0441] The product was confirmed by LCMS, HNMR and CNMR.

[0442] MS-ESI calculated value [M+H]+ 473.2, found 473.1.

[0443] 1 H NMR (400MHz, CD3OD): δ (ppm) 10.61-10.42 (m, 1H), 8.02-7.97 (m, 2H), 7.65 ( s,1H),7.56(t,J=7.6Hz,1H),7.43(d,J=16.1Hz,1H),7.32(d,J=3.7Hz,1H), 7.24(d,J=8.3Hz,1H),6.95(d,J=7.1Hz,1H),6.70(d,J=8.3Hz,1H),6.36(s, 1H),4.62(t,J=5.9Hz,2H),2.98(t,J=6.1Hz,3H),2.70(s,2H),1.85(s,2H).

[0444] 13C NMR (100MHz, 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.

[0445] I-32

[0446] first step

[0447] To a solution of 4-bromo-1H-pyrazole 15a (2 g, 13.61 mmol) in DMSO (20 mL) at room temperature under nitrogen, 1-(3-chloropropyl)pyrrolidine hydrochloride 16a (2.4 g, 16.33 mmol) and cesium carbonate (13.3 g, 40.82 mmol) were added. The mixture was heated to 100°C and stirred for approximately 4 hours. After thin-layer chromatography (dichloromethane / methanol = 10 / 1) indicated complete reaction of the starting material, 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 (120 mL), dried over anhydrous sodium sulfate, and concentrated to yield the crude product. The crude product was purified by silica gel column 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, 85.40% yield).

[0448] The product was confirmed by LCMS and HNMR.

[0449] MS-ESI calculated value [M+H]+ 259.9, found 260.1.

[0450] 1 H NMR (400MHz, CDCl3): δ (ppm) 7.43 (d, J = 10.8Hz, 2H), 4.17 (t, J = 6.8Hz, 2H), 2.46-2.39 (m, 6H), 2.06-1.99 (m, 2H), 1.82-1.74 (m, 4H).

[0451] Step 2

[0452] To a solution of 4-bromo-1-(3-pyrrolidin-1-ylpropyl)pyrazole 16b (1 g, 3.87 mmol) in N,N-dimethylformamide (10 mL) at room temperature under nitrogen was added potassium vinyl trifluoroborate 1b (778.3 mg, 5.81 mmol), Pd(dppf)Cl2 (85 mg, 116.21 μmol), and triethylamine (587.9 mg, 5.81 mmol). The mixture was heated to 100°C and stirred for approximately 4 hours. After thin-layer chromatography (dichloromethane / methanol = 10 / 1) indicated complete reaction of the starting material, 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 yield the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1-0 / 1 and then dichloromethane / methanol = 20 / 1-10 / 1) to give 1-(3-pyrrolidin-1-ylpropyl)-4-vinylpyrazole 16c (300 mg, 1.46 mmol, 37.72% yield) as a yellow oily liquid.

[0453] 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, 11.2Hz, 1H), 5.44 (d, J = 16.4Hz, 1H), 5.05(d,J=11.2Hz,1H),4.17(d,J=6.8Hz,4H),2.53(s,4H),2.11-1.99(m,4H),1.79(d,J=3.2Hz,4H).

[0454] Step 3

[0455] To a solution of 2-(3-iodo-1-tetrahydropyran-2-yl-indole-6-yl)thio-N-methyl-benzamide 1h (300 mg, 608.08 μmol) in 1,4-dioxane (10 mL) were added 1-(3-pyrrolidin-1-ylpropyl)-4-vinylpyrazole 16c (124.8 mg, 608.08 μmol), triethylamine (92.3 mg, 912.11 μmol), Pd2(dba)3 (185.1 mg, 608.08 μmol) and P(o-tol)3 (835.2 mg, 912.11 μmol) at room temperature under nitrogen protection, and the temperature was raised to 100°C and stirred for about 2 hours. After thin layer chromatography (dichloromethane / methanol = 10 / 1) showed that the starting material was reacted completely, 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 (50 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product N-methyl-2-[3-[(E)-2-[1-(3-pyrrolidin-1-ylpropyl)pyrazol-4-yl]vinyl]-1-tetrahydropyran-2-yl-indazol-6-yl]sulfanylbenzamide 16d (300 mg, 525.63 μmol, 86.44% yield) as a yellow solid.

[0456] The product was confirmed by LCMS.

[0457] MS-ESI calculated value [M+H]+ 571.3, found 571.3.

[0458] Step 4

[0459] 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]sulfanylbenzamide 16d (500 mg, 876.05 μmol) in dichloromethane (10 mL) was added trifluoroacetic acid (100 mg, 876.05 μmol) at room temperature. The reaction was stirred at room temperature for approximately 16 hours. After thin-layer chromatography (dichloromethane / methanol = 10 / 1) indicated complete reaction of the starting material, the mixture was poured into water (40 mL), adjusted to pH 8-9 with sodium carbonate, and extracted with dichloromethane (30 mL x 3). The combined organic layers were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, and concentrated to yield the crude product. The crude product was purified by preparative thin layer chromatography to afford 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) as a yellow solid.

[0460] The product was confirmed by LCMS, HNMR and CNMR.

[0461] MS-ESI calculated value [M+H]+ 487.2, found 487.1.

[0462] 1 H NMR (400MHz, CDCl3) δ (ppm) 7.91 (d, J = 8.0Hz, 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=16.8Hz,1H),6.33(s,1H),4.22(t,J=6.8Hz,2H),2. 96(d,J=4.8Hz,3H),2.59(d,J=19.2Hz,5H),2.18-2.11(m,2H),1.84(s,5H).

[0463] 13 C NMR (100MHz, CDCl3) δ (ppm) 168.62, 144.36, 142.08, 137.46, 134.46, 131.96, 130.88, 128.81, 127.58, 12 7.17,124.62,121.80,121.63,120.49,117.88,113.31,54.06,53.00,50.20,29.71,29.07,26.82,23.46.

[0464] I-13 and I-25

[0465] first step

[0466] To a solution of 3-bromo-1H-pyrazole 17a (2 g, 13.61 mmol) in DMSO (20 mL) at room temperature under nitrogen was added 1-(2-chloroethyl)pyrrolidine hydrochloride 11a (2.8 g, 16.33 mmol) and cesium carbonate (13.3 g, 40.82 mmol). The mixture was heated to 100°C and stirred for approximately 4 hours. After thin-layer chromatography (dichloromethane / methanol = 10 / 1) indicated complete reaction of the starting material, the mixture was poured into water (30 mL) and extracted with dichloromethane (40 mL x 3). The combined organic layers were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, and concentrated to yield the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give a mixture of 3-bromo-1-(2-pyrrolidine-1-ethyl)pyrazole 17b (major) and 5-bromo-1-(2-pyrrolidine-1-ethyl)pyrazole 17b' as a yellow oily liquid (1.2 g, 4.92 mmol, 36.12% yield).

[0467] 3-Bromo-1-(2-pyrrolidine-1-ethyl)pyrazole 17b was confirmed by LCMS and HNMR.

[0468] MS-ESI calculated value [M+H]+ 245.9, found 246.0.

[0469] 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).

[0470] 5-Bromo-1-(2-pyrrolidine-1-ethyl)pyrazole 17b' was confirmed by LCMS.

[0471] MS-ESI calculated value [M+H]+ 245.9, found 246.0.

[0472] Step 2

[0473] To a solution of a mixture of 3-bromo-1-(2-pyrrolidino-1-ethyl)pyrazole 17b (major) and 5-bromo-1-(2-pyrrolidino-1-ethyl)pyrazole 17b' (600 mg, 2.46 mmol) in N,N-dimethylformamide (5 mL) at room temperature under nitrogen was added potassium vinyl trifluoroborate 1b (493.8 mg, 3.69 mmol), Pd(dppf)Cl2 (54 mg, 73.73 μmol), and triethylamine (373 mg, 3.69 mmol). The mixture was stirred at 85°C for approximately 16 hours. After thin-layer chromatography (dichloromethane / methanol = 10 / 1) indicated complete reaction of the starting material, 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 yield the crude product. The crude product was purified by preparative thin layer chromatography (dichloromethane / methanol = 10 / 1) to give a mixture of 1-(2-pyrrolidine-1-ethyl)-3-vinylpyrazole 17c and 1-(2-pyrrolidine-1-ethyl)-5-vinylpyrazole 17c' as a red oily liquid (0.4 g, 2.09 mmol, 85.09% yield).

[0474] The product mixture was confirmed by LCMS.

[0475] MS-ESI calculated value [M+H]+ 192.1, found 192.1.

[0476] Step 3

[0477] To a solution of 2-(3-iodo-1-tetrahydropyran-2-yl-indole-6-yl)thio-N-methyl-benzamide 1h (500 mg, 1.01 mmol) in 1,4-dioxane (10 mL) was added a mixture of 1-(2-pyrrolidin-1-ethyl)-3-vinylpyrazole 17c and 1-(2-pyrrolidin-1-ethyl)-5-vinylpyrazole 17c' (232.6 mg, 1.22 mmol), triethylamine (307.7 mg, 3.04 mmol), Pd2(dba)3 (464 mg, 506.73 μmol), and P(o-tol)3 (308.5 mg, 1.01 mmol) at room temperature under nitrogen. The mixture was heated to 100°C and stirred for approximately 4 h. After thin layer chromatography (dichloromethane / methanol = 10 / 1) showed that the starting material was reacted completely, the mixture was poured into water (30 mL) and filtered. The filtrate was extracted with ethyl acetate (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 a crude product. The crude product was purified by preparative thin layer chromatography (dichloromethane / methanol = 10 / 1) to give 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]sulfanylbenzamide 17d and N-methyl-2-[3-[(E)-2-[2-(2-pyrrolidin-1-ylethyl)pyrazol-3-yl]vinyl]-1-tetrahydropyran-2-yl-indazol-6-yl]sulfanylbenzamide 17d' as a yellow solid (250 mg, 449.06 μmol, 44.31% yield).

[0478] The product was confirmed by LCMS. Step 4

[0479] To a solution of 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]sulfanylbenzamide 17d and N-methyl-2-[3-[(E)-2-[2-(2-pyrrolidin-1-ylethyl)pyrazol-3-yl]vinyl]-1-tetrahydropyran-2-yl-indazol-6-yl]sulfanylbenzamide 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 approximately 16 hours. After thin layer chromatography (dichloromethane / methanol=10 / 1) showed that the starting material was reacted completely, the mixture was poured into water (40 mL), adjusted to pH 8-9 with sodium carbonate, 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 a crude product. The crude product was purified by preparative thin layer chromatography to give yellow solid 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 yellow solid 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.

[0480] The two products were confirmed by LCMS, HNMR and CNMR.

[0481] 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 value [M+H]+ 473.2, found 473.2.

[0482] 1 H NMR (400MHz, CD3OD): δ (ppm) δ8.02 (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=5.6Hz,2H),3.79-3.73(m,4H),3.15(s,2H),2.88(s,3H),2.17(s,2H),2.06(s,2H).

[0483] 13 C NMR (100MHz, 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.

[0484] 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: MS-ESI calculated value [M+H]+ 473.2, found 473.1.

[0485] 1 H NMR (400MHz, CD3OD): δ (ppm) δ8.07 (d, J = 8.4Hz, 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=2.0Hz,1H),4.72(t,J=5.6Hz,2H),3.78(t,J=5.6Hz,4H),3.15(s,2H),2.88(s,3H),2.17(s,1H),2.05(s,1H)

[0486] 13 C NMR (100MHz, 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.

[0487] I-18

[0488] first step

[0489] To a solution of 4-bromopyridin-2-ol 18a (2 g, 13.61 mmol) in DMSO (20 mL) at room temperature under nitrogen was added 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). The mixture was heated to 85°C and stirred for approximately 16 hours. After thin-layer chromatography (dichloromethane / methanol = 10 / 1) indicated complete reaction of the starting material, the mixture was poured into water (100 mL) and extracted with dichloromethane (40 mL x 3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to yield the crude product. The crude product was purified by preparative thin layer chromatography (dichloromethane / methanol=10 / 1) to give 4-bromo-2-(2-pyrrolidine-1-methoxy)pyridine 18b (765 mg, 2.82 mmol, 24.54% yield) as a yellow solid.

[0490] The product was confirmed by LCMS and HNMR.

[0491] MS-ESI calculated value [M+H]+ 272.9, found 273.1.

[0492] 1 H NMR(400MHz, CDCl3) δ7.95(d,J=5.2Hz,1H),7.00(d,J=5.6Hz,1H),6.81(s,1H),4.4 2(t,J=6.0Hz,1H),2.86(t,J=6.0Hz,2H),2.59(d,J=6.0Hz,4H),1.77-1.81(m,4H).

[0493] Step 2

[0494] To a solution of 4-bromo-2-(2-pyrrolidine-1-methoxy)pyridine 18b (200 mg, 737.59 μmol) in N,N-dimethylformamide (3 mL) at room temperature under nitrogen was added potassium vinyl trifluoroborate 1b (148.2 mg, 1.11 mmol), Pd(dppf)Cl2 (16.2 mg, 22.13 μmol), and triethylamine (112 mg, 1.11 mmol). The mixture was heated to 85°C and stirred for approximately 4 hours. After thin-layer chromatography (dichloromethane / methanol = 10 / 1) indicated complete reaction, 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 yield the crude product. The crude product was purified by preparative thin layer chromatography (dichloromethane / methanol=10 / 1) to give 2-(2-pyrrolidine-1-ethoxy)-4-vinylpyridine 18c (10 mg, 45.81 μmol, 6.21% yield) as a yellow solid.

[0495] The product was confirmed by LCMS.

[0496] MS-ESI calculated value [M+H]+ 219.1, found 219.1.

[0497] Step 3

[0498] To a solution of 2-(3-iodo-1-tetrahydropyran-2-yl-indole-6-yl)thio-N-methyl-benzamide 1h (110 mg, 222.96 μmol) in 1,4-dioxane (2 mL) were added 2-(2-pyrrolidine-1-ethoxy)-4-vinylpyridine 18c (58.4 mg, 267.55 μmol), triethylamine (33.8 mg, 334.44 μmol), Pd2(dba)3 (67.9 mg, 222.96 μmol) and P(o-tol)3 (306.3 mg, 334.44 μmol) at room temperature under nitrogen protection, and the temperature was raised to 100°C and the reaction was stirred for about 2 hours. After thin-layer chromatography (dichloromethane / methanol = 10 / 1) indicated complete reaction of the starting material, the mixture was poured into water (30 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, and concentrated to afford the crude product. The crude product was purified by preparative thin-layer chromatography (dichloromethane / methanol = 10 / 1) to afford N-methyl-2-[3-[(E)-2-[2-(2-pyrrolidin-1-methoxy)-4-pyridinyl]vinyl]-1-tetrahydropyran-2-yl-indazol-6-yl]sulfanylbenzamide 18d (37 mg, 63.38 μmol, 28.43% yield) as a yellow solid.

[0499] The product was confirmed by LCMS and HNMR.

[0500] MS-ESI calculated value [M+H]+ 584.3, found 584.3.

[0501] 1 H NMR(400MHz, CDCl3)δ(ppm)δ8.48(d,J=8.4Hz,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=6.8Hz, 1H),4.00(d,J=12.0Hz,1H),3.73(d,J=8.8Hz,1H),3.21(s,1H),2.96(d,J=4 .8Hz,3H),2.66–2.70(m,2H),2.20-2.49(m,4H),1.58–1.73(m,8H),1.22(d,J =24.4Hz,4H).

[0502] Step 4

[0503] To a solution of N-methyl-2-[3-[(E)-2-[2-(2-pyrrolidin-1-methoxy)-4-pyridinyl]vinyl]-1-tetrahydropyran-2-yl-indazol-6-yl]thiobenzamide 18d (400 mg, 685.23 μmol) in dichloromethane (10 mL) was added trifluoroacetic acid (78.1 mg, 685.23 μmol) at room temperature. The mixture was stirred at 40°C for approximately 16 hours. After thin-layer chromatography (dichloromethane / methanol = 10 / 1) indicated complete reaction of the starting material, the mixture was poured into water (40 mL), adjusted to pH 8-9 with sodium carbonate, 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 yield the crude product. The crude product was purified by preparative thin layer chromatography to give N-methyl-2-({3-[(E)-2-{2-[2-(pyrrolidin-1-yl)ethoxy]pyridin-4-yl}vinyl]-1H-indazol-6-yl}sulfanyl)benzamide I-18 (8 mg, 16.01 μmol, 2.34% yield) as a yellow solid.

[0504] The product was confirmed by LCMS, HNMR and CNMR.

[0505] MS-ESI calculated value [M+H]+ 500.2, found 500.2.

[0506] 1H NMR (400MHz, CD3OD&CDCl3) δ8.01(d,J=8.6Hz,1H),7.58(dd,J=15.6,8.4Hz,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=8.0Hz,1H),6.74(d,J=7.2Hz,1H),6.62(s,1H),4.13(t,J=6.8Hz,2H),2.82–2.91(m,5H),2.69(s,4H),1.84(s,4H).

[0507] 13 C NMR(100MHz,CD3OD&CDCl3)δ170.27,163.68,149.42,138.06,136.98,135.33,133.98,131.20,130.40,127.73,127.12,1 26.49,125.82,120.77,116.77,114.49,114.29,104.30,99.99,54.57,54.02,54.02,53.85,29.43,25.81,23.29,22.96.

[0508] I-30

[0509] first step

[0510] To a solution of 6-bromopyridin-3-ol 1a (1 g, 5.75 mmol) in N,N-dimethylformamide (20 mL) was added sodium hydride (253 mg, 6.32 mmol, 60% purity) in portions at 0°C under nitrogen protection. The mixture was stirred for about 1 hour. Then, 1-(2-chloroethyl)pyrrolidine hydrochloride 11a (1.08 g, 6.32 mmol) was slowly added at low temperature. The mixture was stirred at low temperature for 1 hour, then heated to 50°C and stirred for about 3 hours. After thin-layer chromatography (petroleum ether / ethyl acetate = 2 / 1) showed that the starting material had reacted completely, the reaction mixture was cooled to 0°C and quenched with water (about 10 mL). The mixture was then 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 2-bromo-5-(2-pyrrolidino-1-methoxy)pyridine 19a (1.5 g, 96.3% yield) as a yellow oily liquid.

[0511] The product was confirmed by LCMS and HNMR.

[0512] MS-ESI calculated value [M+H]+ 272.9, found 273.1.

[0513] 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).

[0514] Step 2

[0515] Under nitrogen protection, to a solution of 2-(3-iodo-1-tetrahydropyran-2-yl-indole-6-yl)sulfanyl-N-methyl-benzamide 1h (300 mg, 608.08 μmol) in 1,4-dioxane (9 ml) were added 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) at room temperature, and the mixture was heated to 110°C and stirred for about 6 hours. After thin-layer chromatography (ethyl acetate) indicated complete reaction of the starting material, 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 afford the crude product. The crude product was purified by preparative thin-layer chromatography (ethyl acetate) to afford 2-(3-acetylamino-1-tetrahydropyran-2-yl-indazol-6-yl)sulfanyl-N-methyl-benzamide 19b as a white solid (0.17 g, 400.46 μmol, 65.86% yield).

[0516] The product was confirmed by LCMS.

[0517] MS-ESI calculated value [M+H]+ 425.2, found 425.0.

[0518] Step 3

[0519] To a solution of 2-(3-acetylamino-1-tetrahydropyran-2-yl-indazol-6-yl)sulfanyl-N-methyl-benzamide 19b (0.4 g, 942.25 μmol) in 1,4-dioxane (10 mL) was added NaOH (376.90 mg, 9.42 mmol) and H₂O (2 mL) at room temperature. The mixture was heated to 100°C and stirred for approximately 16 hours. After thin-layer chromatography (dichloromethane / methanol = 20 / 1) indicated complete reaction of the starting material, 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 yield the crude product. The crude product was purified by preparative thin layer chromatography (dichloromethane / methanol = 20 / 1, 0.1% NH 3 ·H 2 O) to give 2-(3-amino-1-tetrahydropyran-2-yl-indazol-6-yl)sulfanyl-N-methyl-benzamide 19c (0.152 g, 397.41 μmol, 42.18% yield) as a white solid.

[0520] The product was confirmed by LCMS.

[0521] MS-ESI calculated value [M+H]+ 383.1, found 383.1.

[0522] Step 4

[0523] To a solution of 2-(3-amino-1-tetrahydropyran-2-yl-indazol-6-yl)sulfanyl-N-methyl-benzamide 19c (0.1 g, 261.45 μmol) in 1,4-dioxane (5 mL) was added XantPhos (378.20 mg, 653.63 μmol), Pd2(dba)3 (97.72 mg, 169.94 μmol), 2-bromo-5-(2-pyrrolidino-1-methoxy)pyridine 19a (124.8 mg, 608.08 μmol), and cesium carbonate (1.60 g, 4.92 mmol) at room temperature under nitrogen protection. The reaction was stirred at 100 °C for about 6 hours. After TLC (dichloromethane / methanol = 10 / 1) indicated complete reaction of the starting material, 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 yield the crude product as a yellow oil. The crude product was purified by preparative TLC (dichloromethane / methanol = 10 / 1) to afford N-methyl-2-[3-[[5-(2-pyrrolidin-1-methoxy)-2-pyridinyl]amino]-1-tetrahydropyran-2-yl-indole-6-yl]sulfanylbenzamide 19d (0.1 g, 174.61 μmol, 66.78% yield) as a yellow solid.

[0524] The product was confirmed by LCMS.

[0525] MS-ESI calculated value [M+H]+ 573.3, found 573.1.

[0526] Step 5

[0527] To N-methyl-2-[3-[[5-(2-pyrrolidin-1-methoxy)-2-pyridinyl]amino]-1-tetrahydropyran-2-yl-indole-6-yl]sulfanylbenzamide 19d (86 mg, 150.16 μmol) was added HCl / MeOH (10 mL) at low temperature and the reaction was stirred at room temperature for approximately 4 hours. After thin-layer chromatography (dichloromethane / methanol = 10 / 1) indicated complete reaction of the starting material, the mixture was concentrated and poured into water (10 mL). The aqueous phase was adjusted to neutral pH with sodium bicarbonate 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 yield the crude product. The crude product was purified by preparative thin layer chromatography (dichloromethane / methanol = 10 / 1, 0.1% NH3·H2O) to give a light yellow solid N-methyl-2-{[3-({5-[2-(pyrrolidin-1-yl)ethoxy]pyridin-2-yl}amino)-1H-indazol-6-yl]sulfanyl}benzamide I-30 (20.3 mg, 41.55 μmol, 27.67% yield).

[0528] The product was confirmed by LCMS, HNMR and CNMR.

[0529] MS-ESI calculated value [M+H]+ 489.2, found 489.1.

[0530] 1 H NMR (400MHz, DMSO-d6): δ12.18(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=7.6 Hz),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).

[0531] 13C NMR (100MHz, DMSO-d6): δ168.36,149.76,149.30,144.53,141.58,137.35,136.32,134.90,133.12,130.69,130. 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.

[0532] I-31

[0533] first step

[0534] To a mixture of 2-(4-methylpiperazin-1-yl)ethanamine 20a (5 g, 34.91 mmol) and water (50 mL) were added acetic acid (55 mg, 915.88 μmol) and KOCN (2.08 g, 24.44 mmol) at room temperature, and the reaction was stirred at 25°C for approximately 2 hours. Thin-layer chromatography (dichloromethane / methanol = 10 / 1) indicated complete reaction of the starting material, which was then lyophilized to afford a sufficiently pure crude white solid of 2-(4-methylpiperazin-1-yl)ethylurea 20b (6 g, 32.21 mmol, 92.28% yield).

[0535] The product was confirmed by LCMS and HNMR.

[0536] MS-ESI calculated value [M+H]+ 187.1, found 187.1.

[0537] 1 H NMR (400MHz, CDCl3): δ (ppm) 5.44 (s, 1H), 4.70 (d, J = 78.3Hz, 2H), 3.29 (m, J = 10.5, 5.1Hz, 2H), 2.82 (t, J = 6.1Hz, 2H), 2.31 (d, J = 1.4Hz, 8H), 2.01 (s, 3H).

[0538] Step 2

[0539] To a solution of 2-(4-methylpiperazin-1-yl)ethylurea 20b (60.40 mg, 324.31 μmol) in 1,4-dioxane (5 mL) were added 2-(3-iodo-1-tetrahydropyran-2-yl-indole-6-yl)sulfanyl-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 protection, and the reaction was stirred at 105 ° C for about 16 hours. After thin layer chromatography (dichloromethane / methanol = 10 / 1) showed that the starting material was reacted completely, the mixture was poured into water (20 mL) and extracted with dichloromethane (20 mL×3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to give a crude product. The crude product was purified by preparative thin layer chromatography (dichloromethane / methanol = 10 / 1) to give N-methyl-2-[3-[2-(4-methylpiperazin-1-yl)ethylcarbamoylamino]-1-tetrahydropyran-2-yl-indole-6-yl]sulfanylbenzamide 20c (30 mg, 54.38 μmol, 13.41% yield) as a green oily liquid.

[0540] The product was confirmed by LCMS.

[0541] MS-ESI calculated value [M+H]+ 552.3, found 552.1.

[0542] Step 3

[0543] To a solution of N-methyl-2-[3-[2-(4-methylpiperazin-1-yl)ethylcarbamoylamino]-1-tetrahydropyran-2-yl-indole-6-yl]sulfanylbenzamide 20c (30 mg, 54.38 μmol) in DCM (5 mL) was added trifluoroacetic acid (18.60 mg, 163.13 μmol) at 0°C, and the reaction was stirred at room temperature for approximately 16 hours. After thin-layer chromatography (dichloromethane / methanol = 10 / 1) indicated complete reaction of the starting material, 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 yield the crude product. The crude product was purified by preparative thin layer chromatography to give N-methyl-2-{[3-{[2-(4-methylpiperazin-1-yl)ethyl]carbamoyl}amino)-1H-indazol-6-yl]sulfanyl}benzamide I-31 (17.4 mg, 37.21 μmol, 68.43% yield) as a white solid.

[0544] The product was confirmed by LCMS, HNMR and CNMR.

[0545] MS-ESI calculated value [M+H]+ 468.2, found 468.1.

[0546] 1 H NMR (400MHz, CDCl3&CD3OD): δ (ppm) 7.74 (s, 1H), 7.46 (d, J = 19.2Hz, 3H), 7.28–7.24 (m, 1H), 7.17 ( s,1H),7.04(d,J=8.5Hz,1H),3.47(t,J=6.2Hz,2H),2.89(s,3H),2.83–2.35(m,10H),2.31(s,3H).

[0547] 13 C NMR (100MHz, CDCl3&CD3OD) δ170.12,156.23,142.10,141.37,131.23,130.49,127.83 ,126.49,123.83,120.50,113.71,113.40,57.02,54.54,52.32,45.20,37.01,26.10.

[0548] I-11

[0549] first step

[0550] To a solution of 3-bromo-1H-pyrazole 17a (1 g, 6.80 mmol) in DMSO (20 mL) at room temperature under nitrogen, 16a (1 g, 6.80 mmol) and cesium carbonate (3.3 g, 10.21 mmol) were added. The mixture was heated to 100°C and stirred for approximately 16 hours. After thin-layer chromatography (dichloromethane / methanol = 20 / 1) indicated complete reaction, 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 afford 3-bromo-1-(3-pyrrolidin-1-ylpropyl)pyrazole 21a (1.6 g, 6.20 mmol, 91.09% yield) as a yellow solid.

[0551] The product was confirmed by LCMS and HNMR.

[0552] MS-ESI calculated value [M+H]+ 259.9, found 260.1.

[0553] 1H NMR (400MHz, CDCl3): δ (ppm) δ7.31 (d, J = 2.4Hz, 1H), 6.25 (d, J = 2.0Hz, 1H), 4.18 (t, J = 7.2H z,2H),2.46-2.52(m,4H),2.41(t,J=7.2Hz,2H),2.03(t,J=7.2Hz,2H),1.77-1.81(m,4H).

[0554] Step 2

[0555] To a solution of 3-bromo-1-(3-pyrrolidin-1-ylpropyl)pyrazole 21a (1 g, 3.87 mmol) in N,N-dimethylformamide (10 mL) at room temperature under nitrogen was added potassium vinyl trifluoroborate 1b (778.3 mg, 5.81 mmol), Pd(dppf)Cl2 (85 mg, 116.21 μmol), and triethylamine (778.3 mg, 11.62 mmol). The mixture was stirred at 85°C for approximately 16 hours. After thin-layer chromatography (dichloromethane / methanol = 10 / 1) indicated complete reaction, 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 yield the crude product. The crude product was purified by preparative thin layer chromatography to give 1-(3-pyrrolidin-1-ylpropyl)-3-vinylpyrazole 21b (290 mg, 1.41 mmol, 36.47% yield) as a yellow oily liquid.

[0556] The product was confirmed by LCMS and HNMR.

[0557] MS-ESI calculated value [M+H]+ 206.2, found 206.1.

[0558] 1 H 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).

[0559] Step 3

[0560] To a solution of 2-(3-iodo-1-tetrahydropyran-2-yl-indole-6-yl)thio-N-methyl-benzamide 1h (300 mg, 608.08 μmol) in 1,4-dioxane (10 mL) was added 1-(3-pyrrolidin-1-ylpropyl)-3-vinylpyrazole 21b (187.3 mg, 912.11 μmol), triethylamine (184.6 mg, 1.82 mmol), Pd2(dba)3 (278.4 mg, 304.04 μmol), and P(o-tol)3 (185.08 mg, 608.08 μmol) at room temperature under nitrogen. The mixture was stirred at 100°C for approximately 1 hour. After complete reaction of the starting material, as indicated by thin-layer chromatography (dichloromethane / methanol = 10 / 1), the mixture was concentrated and filtered to obtain the crude product. The crude product was purified by preparative thin-layer chromatography to afford N-methyl-2-[3-[(E)-2-[1-(3-pyrrolidin-1-ylpropyl)pyrazol-3-yl]vinyl]-1-tetrahydropyran-2-yl-indazol-6-yl]sulfanylbenzamide 21c (10 mg, 17.52 μmol, 2.88% yield) as a white solid.

[0561] The product was confirmed by LCMS.

[0562] MS-ESI calculated value [M+H]+ 571.3, found 571.3.

[0563] Step 4

[0564] 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]sulfanylbenzamide 21c (300 mg, 525.63 μmol) in dichloromethane (5 mL) was added trifluoroacetic acid (599.3 mg, 5.26 mmol) at room temperature, and the reaction was stirred for approximately 16 hours. After thin-layer chromatography (dichloromethane / methanol = 10 / 1) indicated complete reaction of the starting material, 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 (40 mL), dried over anhydrous sodium sulfate, and concentrated to yield the crude product. The crude product was purified by preparative thin layer chromatography to give N-methyl-2-({3-[(E)-2-{1-[3-(pyrrolidin-1-yl)propyl]-1H-pyrazol-3-yl}vinyl]-1H-indazol-6-yl}sulfanyl)benzamide I-11 (16.4 mg, 33.70 μmol, 6.41% yield) as a white solid.

[0565] The product was confirmed by LCMS and HNMR.

[0566] MS-ESI calculated value [M+H]+ 487.2, found 487.2.

[0567] 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, 8.4Hz,2H),6.65(d,J=2.0,1H),4.24(t,J=6.8Hz,1H),2.88(s,3H),2.66-2.58(m,6H),2.14-2.12(m,2H),1.85-1.77(m,4H).

[0568] I-16

[0569] first step

[0570] 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 was added 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). The mixture was heated to 50°C and stirred for 12 hours. After thin-layer chromatography (dichloromethane / methanol = 10 / 1) indicated complete reaction of the starting material, 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 yield the crude product. The crude product was purified by silica gel column 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 oily liquid.

[0571] The product was confirmed by LCMS and HNMR.

[0572] MS-ESI calculated value [M+H]+ 289.2, found 289.2.

[0573] 1H NMR (400MHz, CDCl3): δ (ppm) 7.28 (d, J = 3.2Hz, 1H), 7.40 (d, J = 8.8Hz, 1H), 7.13-7.17 (m, 1H), 4.16(t,J=6.0Hz,2H),2.89-2.97(m,2H),2.62-2.66(m,4H),1.81-1.84(m,4H),0.26(s,9H).

[0574] Step 2

[0575] Potassium carbonate (1.03 g, 7.49 mmol) was added to a solution of trimethyl-[2-[5-(2-pyrrolidin-1-methoxy)-2-pyridyl]ethynyl]silane 22a (1.8 g, 6.24 mmol) in methanol (30 mL) at room temperature, followed by stirring for approximately 2 hours. After TLC (dichloromethane / methanol = 10 / 1) indicated complete reaction, the mixture was concentrated to afford the crude product. The crude product was purified by preparative TLC (dichloromethane / methanol = 10 / 1) to afford 2-ethynyl-5-(2-pyrrolidin-1-ethoxy)pyridine 22b (0.6 g, 44.46% yield) as a brownish-yellow oil.

[0576] The product was confirmed by LCMS and HNMR.

[0577] MS-ESI calculated value [M+H]+ 217.1, found 217.2.

[0578] 1 H NMR (400MHz, CDCl3): δ (ppm) 8.29 (d, J = 2.8Hz, 1H), 7.42 (d, J = 8.4Hz, 1H), 7.15-7.18 (m, 1H), 4 .17(t,J=5.6Hz,2H),3.08(s,1H),2.93(t,J=5.6Hz,2H),2.62-2.65(m,4H),1.80-1.84(m,4H).

[0579] Step 3

[0580] To a solution of 1 g (300 mg, 0.73 mmol) of 2-[(3-iodo-1H-indazol-6-yl)thio]-N-methylbenzamide in N,N-dimethylformamide (9 mL) was added 2-ethynyl-5-(2-pyrrolidin-1-ethoxy)pyridine 22b (159 mg, 0.73 mmol), dichlorobis(triphenylphosphine)palladium (10 mg, 0.01 mmol), cuprous iodide (28 mg, 0.15 mmol), and triethylamine (184.6 mg, 1.82 mmol) at room temperature under nitrogen protection. The mixture was heated to 100 ° C and stirred for about 2 hours. After thin-layer chromatography (dichloromethane / methanol = 10 / 1) indicated complete reaction of the starting material, the mixture was poured into water (50 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed sequentially with water (30 mL x 3) and saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to yield a crude product. Preparative thin-layer chromatography of the crude product afforded N-methyl-2-{[3-(2-{5-[2-(pyrrolidin-1-yl)ethoxy]pyridin-2-yl}ethynyl)-1H-indazol-6-yl]sulfanyl}benzamide I-16 (15.8 mg, 4.3% yield) as a white solid.

[0581] The product was confirmed by LCMS, HNMR and CNMR.

[0582] MS-ESI calculated value [M+H]+ 498.2, found 498.1.

[0583] 1 H NMR(400MHz, 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),7.19-7.2 7(m,3H),6.37(d,J=4.4Hz,1H),4.22(t,J=6.0Hz,2H),2.96-2.99(m,5H),2.68(s,4H),1.85(s,4H).

[0584] 13 C NMR(100MHz,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.

[0585] I-20

[0586] first step

[0587] To a solution of 2-bromopyridin-4-ol 23a (200 mg, 1.15 mmol) in N,N-dimethylformamide (4 mL) was added sodium hydride (92 mg, 2.30 mmol) portionwise under nitrogen at low temperature. The mixture was heated to 70°C and stirred for approximately 0.5 hours. The mixture was then cooled to room temperature and 1-(2-chloroethyl)pyrrolidine hydrochloride 11a (195 mg, 1.15 mmol) was added. The mixture was heated to 70°C and stirred for approximately 16 hours. After thin-layer chromatography (dichloromethane / methanol = 20 / 1) indicated complete reaction, the mixture was poured into water (10 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 afford 2-bromo-4-(2-pyrrolidino-1-methoxy)pyridine 23b (200 mg, 64.2% yield) as a yellow oil.

[0588] The product was confirmed by LCMS and HNMR.

[0589] MS-ESI calculated value [M+H]+ 272.9, found 272.9.

[0590] 1 H NMR (400MHz, 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).

[0591] Step 2

[0592] To a solution of 2-bromo-4-(2-pyrrolidine-1-methoxy)pyridine 23b (500 mg, 1.84 mmol) in N,N-dimethylformamide (5 mL) at room temperature under nitrogen was added potassium vinyl trifluoroborate 1b (370.50 mg, 2.77 mmol), Pd(dppf)Cl2 (50 mg, 0.068 mmol), and triethylamine (280 mg, 2.77 mmol). The mixture was heated to 85°C and stirred for approximately 16 hours. After thin-layer chromatography (dichloromethane / methanol = 15 / 1) indicated complete reaction of the starting material, 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 yield the crude product. The crude product was purified by preparative thin layer chromatography to afford 4-(2-pyrrolidino-1-ethoxy)-2-vinylpyridine 23c as a white solid (50 mg, 12.4% yield).

[0593] The product was confirmed by LCMS and HNMR.

[0594] MS-ESI calculated value [M+H]+ 219.1, found 219.1.

[0595] 1 H NMR (400MHz, 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).

[0596] Step 3

[0597] To a solution of 1 g (562 mg, 1.37 mmol) of 2-[(3-iodo-1H-indazol-6-yl)thio]-N-methylbenzamide in N,N-dimethylformamide (5 mL) at room temperature under nitrogen was added 4-(2-pyrrolidin-1-ethoxy)-2-vinylpyridine 23c (100 mg, 0.46 mmol), DIEA (592 mg, 4.58 mmol), Pd(OAc)2 (100 mg, 0.45 mmol), and P(o-tol)3 (139 mg, 0.46 mmol). The mixture was stirred at 100°C for approximately 16 hours. After TLC (dichloromethane / methanol = 10 / 1) indicated complete reaction of the starting material, 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 (40 mL), dried over anhydrous sodium sulfate, and concentrated to yield the crude product. The crude product was purified by preparative thin layer chromatography and then by preparative thin layer chromatography (dichloromethane / methanol = 10 / 1) to give N-methyl-2-({3-[(E)-2-{4-[2-(pyrrolidin-1-yl)ethoxy]pyridin-2-yl}vinyl]-1H-indazol-6-yl}sulfanyl)benzamide I-20 (5 mg, 2.18% yield) as a white solid.

[0598] The product was confirmed by LCMS, HNMR and CNMR.

[0599] MS-ESI calculated value [M+H]+ 500.2, found 500.1.

[0600] 1 H NMR (400MHz, CD3OD) δ: 8.38 (d, 1H, J = 6.0Hz), 8.09 (d, 1H, J = 8.4Hz), 7.88 (d, 1H, J = 16.4Hz), 7.62 (s, 1H), 7.49-7.56 (m, 2H), 7.3 1-7.36(m,3H),7.23-7.26(m,2H),6.94(d,1H,J=4.0Hz),4.34-4.37(m,2H),3.13-3.14(m,2H),2.86-2.88(m,7H),1.92(s,4H).

[0601] 13C NMR(100MHz,CD3OD)δ:170.38,165.97,157.09,150.09,142.29,142.18,13 7.59,134.91,134.16,131.46,130.31,129.88,129.25,127.68,127.45,12 6.68,125.36,124.12,121.14,120.27,113.92,109.19,108.12,79.98,66.15,54.18,54.11,38.16,29.37,29.34,27.39,27.29,25.38,22.82,20.23.

[0602] I-6

[0603] first step

[0604] To a solution of 2-bromo-5-(2-pyrrolidine-1-methoxy)pyridine 19a (0.5 g, 1.84 mmol) in N,N-dimethylformamide (10 mL) at room temperature under nitrogen was added potassium trifluorovinylborate 1b (371 mg, 2.77 mmol), Pd(dppf)Cl2 (40 mg, 0.055 mmol), and triethylamine (280 mg, 2.77 mmol). The mixture was stirred at 85°C for approximately 16 hours. After thin-layer chromatography (dichloromethane / methanol = 15 / 1) indicated complete reaction, 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 yield the crude product. The crude product was purified by preparative thin layer chromatography (dichloromethane / methanol = 10 / 1) to give 5-(2-pyrrolidino-1-ethoxy)-2-vinylpyridine 24a (220 mg, 54.7% yield) as a brown oily liquid.

[0605] The product was confirmed by LCMS and HNMR.

[0606] MS-ESI calculated value [M+H]+ 219.1, found 219.1.

[0607] 1H NMR (400MHz, 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).

[0608] Step 2

[0609] To a solution of 1 g (166 mg, 0.41 mmol) of 2-[(3-iodo-1H-indazol-6-yl)thio]-N-methylbenzamide in N,N-dimethylformamide (10 mL) at room temperature under nitrogen was added 5-(2-pyrrolidin-1-ethoxy)-2-vinylpyridine 24a (133 mg, 0.61 mmol), DIEA (157 mg, 1.22 mmol), Pd(OAc)2 (137 mg, 0.61 mmol), and P(o-tol)3 (123 mg, 0.41 mmol). The mixture was stirred at 100°C for approximately 16 hours. After TLC (dichloromethane / methanol = 20 / 1) indicated complete reaction of the starting material, 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 (40 mL), dried over anhydrous sodium sulfate, and concentrated to yield the crude product. The crude product was purified three times by preparative thin layer chromatography and then by preparative thin layer chromatography (dichloromethane / methanol = 10 / 1) to give N-methyl-2-({3-[(E)-2-{5-[2-(pyrrolidin-1-yl)ethoxy]pyridin-2-yl}vinyl]-1H-indazol-6-yl}sulfanyl)benzamide I-6 (4.5 mg, 2.2% yield) as a yellow solid.

[0610] The product was confirmed by LCMS, HNMR and CNMR.

[0611] MS-ESI calculated value [M+H]+ 500.2, found 500.2.

[0612] 1H NMR (400MHz, CD3OD) δ: 8.28 (d, 1H, J = 2.8Hz), 8.06 (d, 1H, J = 8.4Hz), 7.71 (d, 1H, J = 16.4Hz), 7.65 (d, 1H, J=8.8Hz),7.60(s,1H),7.48-7.55(m,2H),7.45(dd,1H,J=8.8,2.8Hz),7.30-7.37(m,2H),7.20-7.25(m, 2H), 4.25 (t, 2H, J = 5.6Hz), 3.00 (t, 2H, J = 5.6Hz), 2.88 (s, 3H), 2.72-2.74 (m, 4H), 1.85-1.89 (m, 4H).

[0613] 13 C NMR(100MHz,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.

[0614] I-23

[0615] first step

[0616] To a solution of 2-bromo-4-(2-pyrrolidine-1-methoxy)pyridine 23b (390 mg, 1.44 mmol) in N,N-dimethylformamide (10 mL) at room temperature under nitrogen was added ethynyl(trimethyl)silane (283 mg, 2.88 mmol), Pd(PPh3)2Cl2 (202 mg, 0.29 mmol), cuprous iodide (54.78 mg, 0.29 mmol), and triethylamine (436.63 mg, 4.31 mmol). The mixture was stirred at 50°C for 12 hours. After thin-layer chromatography (dichloromethane / methanol = 20 / 1) indicated complete reaction of the starting material, the reaction mixture was poured into water (40 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 (DCM / MeOH=20:1) to give trimethyl-[2-[4-(2-pyrrolidin-1-methoxy)-2-pyridinyl]ethynyl]silane 25a (240 mg, 57.85% yield) as a black oily liquid.

[0617] The product was confirmed by LCMS.

[0618] MS-ESI calculated value [M+H]+ 289.2, found 289.1.

[0619] Step 2

[0620] To a solution of trimethyl-[2-[4-(2-pyrrolidin-1-methoxy)-2-pyridyl]ethynyl]silane 25a (240 mg, 0.83 mmol) in methanol (10 mL) was added potassium carbonate (138 mg, 1.00 mmol) at room temperature, followed by stirring for approximately 2 hours. After TLC (dichloromethane / methanol = 20 / 1) indicated complete reaction, 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 yield the crude product. The crude product was purified by preparative TLC (dichloromethane / methanol = 20 / 1) to afford 2-ethynyl-4-(2-pyrrolidin-1-ethoxy)pyridine 25b (107 mg, 59.46% yield) as a red oil.

[0621] The product was confirmed by LCMS.

[0622] MS-ESI calculated value [M+H]+ 217.1, found 217.1.

[0623] Step 3

[0624] To a solution of 1 g (202 mg, 0.49 mmol) of 2-[(3-iodo-1H-indazol-6-yl)thio]-N-methylbenzamide in N,N-dimethylformamide (9 mL) at room temperature under nitrogen was added 2-ethynyl-4-(2-pyrrolidin-1-ethoxy)pyridine 25b (107 mg, 0.49 mmol), dichlorobis(triphenylphosphine)palladium (69 mg, 0.099 mmol), cuprous iodide (19 mg, 0.099 mmol), and triethylamine (150 mg, 1.48 mmol). The mixture was stirred at 100°C for approximately 2 hours. After thin-layer chromatography (dichloromethane / methanol = 10 / 1) indicated complete reaction of the starting material, the mixture was poured into water (40 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 yield the crude product. The crude product was purified by preparative thin layer chromatography (dichloromethane / methanol / =10 / 1) to give N-methyl-2-{[3-(2-{4-[2-(pyrrolidin-1-yl)ethoxy]pyridin-2-yl}ethynyl)-1H-indazol-6-yl]sulfanyl}benzamide I-23 (17.8 mg, 7.23% yield) as a white solid.

[0625] The product was confirmed by LCMS, HNMR and CNMR.

[0626] MS-ESI calculated value [M+H]+ 498.2, found 498.4.

[0627] 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).

[0628] 13 C NMR (100MHz, CD3OD) δ170.30,165.63,150.62,143.38,140.86,137.94,135.11,134.49,131.79,130.31,12 7.81,127.70,126.86,125.65,123.81,120.42,113.83,113.67,110.49,90.98,80.53,66.76,54.14,54.08, 25.31,22.84.

[0629] I-24

[0630] first step

[0631] To a solution of 6-bromopyridin-2-ol 12a (2 g, 11.49 mmol) in N,N-dimethylformamide (50 mL) at room temperature under nitrogen was added 1-(2-chloroethyl)pyrrolidine hydrochloride 11a (1.54 g, 9.03 mmol) and KCO (4.77 g, 34.48 mmol). The mixture was heated to 70°C and stirred for approximately 16 hours. After TLC (dichloromethane / methanol = 15 / 1) indicated complete reaction, the mixture was poured into water (200 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to yield the crude product. The crude product was purified by preparative TLC to afford 2-bromo-6-(2-pyrrolidino-1-methoxy)pyridine 26a (940 mg, 3.47 mmol, 30.16% yield) as a yellow oil.

[0632] The product was confirmed by LCMS and HNMR.

[0633] MS-ESI calculated value [M+H]+ 272.9, found 273.1.

[0634] 1 H NMR (400MHz, CDCl3): δ (ppm) 7.41 (t, J = 8.0Hz, 1H), 7.05 (d, J = 7.2Hz, 1H), 6.74 (d, J = 8.4H z,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).

[0635] Step 2

[0636] To a solution of 2-bromo-6-(2-pyrrolidine-1-methoxy)pyridine 26a (0.5 g, 1.84 mmol) in N,N-dimethylformamide (20 mL) at room temperature under nitrogen was added ethynyl(trimethyl)silane (362.22 mg, 3.69 mmol), Pd(PPh3)2Cl2 (258.86 mg, 368.80 μmol), cuprous iodide (70.24 mg, 368.80 μmol), and triethylamine (559.78 mg, 5.53 mmol). The mixture was stirred at 50°C for 16 hours. After LCMS analysis indicated complete reaction of the starting material, the reaction 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 (20 mL), dried over anhydrous sodium sulfate, and concentrated to yield the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 2) to give trimethyl-[2-[6-(2-pyrrolidine-1-methoxy)-2-pyridyl]ethynyl]silane 26b (450 mg, 1.56 mmol, 84.60% yield) as a red oily liquid.

[0637] The product was confirmed by LCMS and HNMR.

[0638] MS-ESI calculated value [M+H]+ 289.2, found 289.2.

[0639] 1 H 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).

[0640] Step 3

[0641] To a solution of trimethyl-[2-[6-(2-pyrrolidin-1-methoxy)-2-pyridinyl]ethynyl]silane 26b (400 mg, 1.39 mmol) in methanol (20 mL) was added potassium carbonate (229.98 mg, 1.66 mmol) at room temperature, followed by stirring for approximately 2 hours. After TLC (dichloromethane / methanol = 20 / 1) indicated complete reaction, 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 yield the crude product. The crude product was purified by preparative TLC (dichloromethane / methanol = 20 / 1) to afford 2-ethynyl-6-(2-pyrrolidin-1-ethoxy)pyridine 26c (50 mg, 231.18 μmol, 16.67% yield) as a red oil.

[0642] The product was confirmed by LCMS and HNMR.

[0643] MS-ESI calculated value [M+H]+ 217.1, found 217.2.

[0644] 1 H 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).

[0645] Step 4

[0646] To a solution of 1 g (47.31 mg, 115.59 μmol) of 2-[(3-iodo-1H-indazol-6-yl)thio]-N-methylbenzamide in N,N-dimethylformamide (10 mL) were added 2-ethynyl-6-(2-pyrrolidin-1-ethoxy)pyridine 26c (25 mg, 115.59 μmol), dichlorobis(triphenylphosphine)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 protection, and the reaction was stirred at 50°C for about 16 hours. After thin-layer chromatography (dichloromethane / methanol = 10 / 1) showed complete reaction of the starting material, the mixture was poured into water (40 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 a crude product. The crude product was purified by preparative thin-layer chromatography to give N-methyl-2-{[3-(2-{6-[2-(pyrrolidin-1-yl)ethoxy]pyridin-2-yl}ethynyl)-1H-indazol-6-yl]sulfanyl}benzamide I-24 (17.8 mg, 7.23% yield) as a white solid.

[0647] The product was confirmed by LCMS, HNMR and CNMR.

[0648] MS-ESI calculated value [M+H]+ 498.2, found 498.0.

[0649] 1 H 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).

[0650] I-8

[0651] first step

[0652] 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. The mixture was heated to 60°C and stirred for approximately 16 hours. After thin-layer chromatography (petroleum ether / ethyl acetate = 3 / 1) indicated complete reaction of the starting materials, the mixture was concentrated to afford the crude product. The crude product was purified by preparative MPLC to afford methyl 2-(1-tetrahydropyran-2-ylindazol-6-yl)thiobenzoate 27a (2.5 g, 6.79 mmol, 48.23% yield) as a yellow solid.

[0653] The product was confirmed by LCMS and HNMR.

[0654] MS-ESI calculated value [M+H]+ 369.1, found 369.0.

[0655] 1 H NMR (400MHz, CDCl3) δ8.07(d,J=5.6Hz,1H),8.02(d,J=7.6Hz,1H),7.93(d,J=4.0Hz,1H),7. 77(dd,J=8.4,4.0Hz,1H),7.31(d,J=8.4Hz,1H),7.25(t,J=7.6Hz,1H),7.15(t,J=7.6Hz,1H) ,6.85(d,J=8.0Hz,1H),5.72(dd,J=9.6,2.4Hz,1H),4.13–4.03(m,1H),3.99(d,J=2.0Hz,3H) ,3.75(dd,J=11.2,8.4Hz,1H),2.59–2.39(m,1H),2.13(t,J=10.4Hz,2H),1.85–1.52(m,3H).

[0656] Step 2

[0657] Methyl 2-(1-tetrahydropyran-2-ylindazol-6-yl)thiobenzoate 27a (2.5 g, 6.79 mmol) was dissolved in a mixture of H₂O (8 mL) and THF (20 mL) at room temperature. Lithium hydroxide (1.7 g, 40.71 mmol) was added, and the mixture was stirred at 40°C for approximately 16 hours. After TLC (petroleum ether / ethyl acetate = 1 / 1) indicated complete reaction, 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 afford 2-(1-tetrahydropyran-2-ylindazol-6-yl)thiobenzoic acid 27b (2 g, 5.64 mmol, 83.17% yield) as a white solid.

[0658] The product was confirmed by LCMS and HNMR.

[0659] MS-ESI calculated value [M+H]+ 355.1, found 355.0.

[0660] 1 H NMR (400MHz, CDCl3) δ8.21–8.07(m,2H),7.97(s,1H),7.79(dd,J=8.4,4.4Hz,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=8.0,4.8Hz,1H),5.74(dd,J=9.6,2.4Hz,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).

[0661] Step 3

[0662] 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) were added cyclopropylamine (290 mg, 5.08 mmol), HATU (1.9 g, 5.08 mmol) and DIEA (980 mg, 7.60 mmol) at room temperature, and the mixture was stirred for about 2 hours. After thin layer chromatography (petroleum ether / ethyl acetate = 1 / 1) showed that the reaction of the starting material was complete, the mixture was poured into water (50 mL) and extracted with ethyl acetate (20 mL x 10 mL). 3), the combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography () to give N-cyclopropyl-2-(1-tetrahydropyran-2-ylindazol-6-yl)thiobenzamide 27c (700 mg, 1.78 mmol, 70.05% yield) as a white solid.

[0663] The product was confirmed by LCMS and HNMR.

[0664] MS-ESI calculated value [M+H]+ 394.2, found 394.2.

[0665] 1 H NMR (400MHz, CDCl3) δ8.11–7.90(m,2H),7.71–7.58(m,3H),7.30(dd,J=4.8,3.6H z,2H),7.25–7.18(m,1H),7.12(dd,J=8.4,1.2Hz,1H),5.66(dd,J=9.6,2.4Hz,1H) ,4.11–3.89(m,2H),2.38(ddd,J=17.6,13.2,7.6Hz,1H),2.20–2.04(m,2H),1.72 (ddd,J=62.4,40.0,27.2Hz,4H),0.82(dd,J=12.8,7.2Hz,2H),0.54–0.44(m,2H).

[0666] Step 4

[0667] 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 hours. After thin-layer chromatography (dichloromethane / methanol = 10 / 1) indicated complete reaction of the starting material, the mixture was poured into water (20 mL), adjusted to pH 8-9 with sodium carbonate solution, and extracted with dichloromethane (30 mL x 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to afford N-cyclopropyl-2-(1H-indazol-6-ylthio)benzamide 27d (500 mg, 1.62 mmol, 79.49% yield) as a yellow solid.

[0668] The product was confirmed by LCMS and HNMR.

[0669] MS-ESI calculated value [M+H]+ 310.1, found 310.0.

[0670] 1 H NMR (400MHz, CDCl3) δ10.99(s,1H),8.05(s,1H),7.77–7.53(m,3H),7.32–7.20(m,3H),7.12( d,J=8.4Hz,1H),6.60(s,1H),2.90–2.80(m,1H),0.81(q,J=6.4Hz,2H),0.51(d,J=6.4Hz,2H).

[0671] Step 5

[0672] 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) were 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 hours. After thin-layer chromatography (dichloromethane / methanol = 10 / 1) indicated complete reaction of the starting material, the mixture was poured into water (100 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 column chromatography (petroleum ether / ethyl acetate = 2 / 1 to 0 / 1) to give N-cyclopropyl-2-[(3-iodo-1H-indazol-6-yl)thio]benzamide 27e (1 g, 2.30 mmol, 54.67% yield) as a yellow solid.

[0673] The product was confirmed by LCMS and HNMR.

[0674] MS-ESI calculated value [M+H]+ 436.0, found 435.9.

[0675] 1 H NMR (400MHz, CDCl3) δ11.17(s,1H),8.04(s,1H),7.68–7.55(m,2H),7.46(d,J=8.4Hz,1H),7.32(dd,J=9.2,5.6H z,2H),7.25–7.20(m,1H),7.17(d,J=8.4Hz,1H),2.88–2.80(m,1H),0.85(q,J=6.8Hz,2H),0.53(q,J=6.8Hz,2H).

[0676] Step 6

[0677] 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) was added tert-butyl tert-butoxycarbonyl carbonate (250 mg, 1.15 mmol) and triethylamine (232 mg, 2.30 mmol) at room temperature, followed by stirring for approximately 2 hours. After thin-layer chromatography (dichloromethane / methanol = 10 / 1) indicated complete reaction of the starting material, 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 yield the crude product. The crude product was purified by preparative thin layer chromatography (dichloromethane / methanol = 10 / 1) to give tert-butyl 6-[2-(cyclopropylcarbamoyl)phenyl]thio-3-iodoindazole-1-carboxylate 27f (280 mg, 522.98 μmol, 45.53% yield) as a white solid.

[0678] The product was confirmed by LCMS and HNMR.

[0679] MS-ESI calculated value [M-Boc+H]+ 436.0, found 435.9.

[0680] 1 H NMR (400MHz, CDCl3) δ8.04 (s, 1H), 7.75–7.62 (m, 1H), 7.40 (dd, J = 13.6, 5.6Hz, 4H), 7.31–7. 19(m,2H),2.81(d,J=4.4Hz,1H),1.64(s,9H),0.79(t,J=6.0Hz,2H),0.47(d,J=2.4Hz,2H).

[0681] Step 7

[0682] To a solution of tert-butyl 6-[2-(cyclopropylcarbamoyl)phenyl]thio-3-iodoindazole-1-carboxylate 27f (200 mg, 373.55 μmol) in 1,4-dioxane (5 mL) were added 5-(2-pyrrolidine-1-ethoxy)-2-vinylpyridine 24a (97 mg, 448.27 μmol), triethylamine (113 mg, 1.12 mmol), Pd2(dba)3 (171 mg, 186.78 μmol) and P(o-tol)3 (113 mg, 373.55 μmol) at room temperature under nitrogen protection, and the temperature was raised to 100 ° C and stirred for about 2 hours. After thin-layer chromatography (dichloromethane / methanol = 10 / 1) showed that the starting material had reacted completely, 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 a 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 tert-butyl 6-[2-(cyclopropylcarbamoyl)phenyl]thio-3-[(E)-2-[5-(2-pyrrolidin-1-ylethoxy)-2-pyridyl]vinyl]indazole-1-carboxylate as a yellow oily liquid.

[0683] The product was confirmed by LCMS.

[0684] MS-ESI calculated value [M+H]+ 626.3, found 626.2.

[0685] Step 8

[0686] To a solution of 27 g (150 mg, 239.70 μmol) of tert-butyl 6-[2-(cyclopropylcarbamoyl)phenyl]thio-3-[(E)-2-[5-(2-pyrrolidin-1-ylethoxy)-2-pyridyl]vinyl]indazole-1-carboxylate in dichloromethane (5 mL) at room temperature was added trifluoroacetic acid (1 g, 8.77 mmol), followed by stirring for approximately 4 hours. After thin-layer chromatography (dichloromethane / methanol = 10 / 1) indicated complete reaction of the starting material, 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 yield the crude product. The crude product was purified by preparative thin layer chromatography to give N-cyclopropyl-2-({3-[(E)-2-{5-[2-(pyrrolidin-1-yl)ethoxy]pyridin-2-yl}vinyl]-1H-indazol-6-yl}sulfanyl)benzamide I-8 (15.4 mg, 29.30 μmol, 12.22% yield) as a white solid.

[0687] The product was confirmed by LCMS and HNMR.

[0688] MS-ESI calculated value [M+H]+ 526.2, found 526.2.

[0689] 1 H NMR (400MHz, CDCl3) δ8.38(d,J=2.8Hz,1H),8.01(d,J=8.4Hz,1H),7.75(d,J=16.4Hz,1H),7. 67(dd,J=5.6,3.2Hz,1H),7.58–7.41(m,2H),7.35(dd,J=24.0,19.6Hz,2H),7.25(dd,J=8.8,2 .8Hz,2H),7.18(d,J=8.4Hz,1H),6.54(s,1H),4.24(t,J=5.6Hz,2H),3.00(t,J=5.6Hz,2H),2. 89–2.80(m,1H),2.72(s,4H),1.87(d,J=3.2Hz,4H),0.86–0.75(m,2H),0.50(t,J=8.0Hz,2H).

[0690] I-38

[0691] first step

[0692] To a solution of 2-bromo-5-iodopyridine 28a (5 g, 17.61 mmol) in 1,4-dioxane (50 mL) at room temperature under nitrogen was added 1-methylpiperazine 28b (2.1 g, 21.13 mmol), BuONa (5.1 g, 52.84 mmol), Pd2(dba)3 (806.4 mg, 880.62 μmol), and Xantphos (254.8 mg, 440.31 μmol). The mixture was stirred at 60°C for approximately 3 hours. After thin-layer chromatography (dichloromethane / methanol = 10 / 1) indicated complete reaction of the starting material, 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 yield the crude product. The crude product was purified by neutral alumina column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give 1-(6-bromo-3-pyridyl)-4-methylpiperazine 28c (2.1 g, 8.20 mmol, 46.55% yield) as a yellow solid.

[0693] The product was confirmed by LCMS and HNMR.

[0694] MS-ESI calculated value [M+H]+ 257.9, found 258.0.

[0695] 1 H NMR (400MHz, CDCl3) δ (ppm) 8.01 (d, J = 3.2Hz, 1H), 7.30 (d, J = 8.8Hz, 1H), 7.07 (d d,J=8.8,3.2Hz,1H),3.21(t,J=4.8Hz,4H),2.57(t,J=5.2Hz,4H),2.35(s,3H).

[0696] Step 2

[0697] To a solution of 1-(6-bromo-3-pyridyl)-4-methylpiperazine 28c (2 g, 7.81 mmol) in N,N-dimethylformamide (20 mL) at room temperature under nitrogen was added potassium vinyl trifluoroborate 1b (1.3 g, 9.37 mmol), Pd(dppf)Cl2 (571.3 mg, 780.82 μmol), and triethylamine (2.4 g, 23.42 mmol). The mixture was stirred at 85°C for approximately 2 hours. After thin-layer chromatography (dichloromethane / methanol = 10 / 1) indicated complete reaction, 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 yield the crude product. The crude product was purified by neutral alumina column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give 1-methyl-4-(6-vinyl-3-pyridinyl)piperazine 28d (1.2 g, 5.90 mmol, 75.60% yield) as a yellow oily liquid.

[0698] The product was confirmed by LCMS and HNMR.

[0699] MS-ESI calculated value [M+H]+ 204.1, found 204.1.

[0700] 1 H NMR (400MHz, CDCl3) δ (ppm) 8.27 (d, J = 3.2Hz, 1H), 7.24 (s, 1H), 7.16-7.13 (m, 1H), 6.75 (dd, J = 17.5, 10.8H z,1H),5.98(d,J=17.6Hz,1H),5.31(d,J=10.8Hz,1H),3.28–3.20(m,4H),2.62–2.55(m,4H),2.36(s,3H).

[0701] Step 3

[0702] To a solution of tert-butyl 6-[2-(cyclopropylcarbamoyl)phenyl]thio-3-iodoindazole-1-carboxylate 27f (490 mg, 915.21 μmol) in 1,4-dioxane (10 mL) was added 1-methyl-4-(6-vinyl-3-pyridyl)piperazine 28d (223.3 mg, 1.10 mmol), triethylamine (277.8 mg, 2.75 mmol), Pd2(dba)3 (502.8 mg, 549.13 μmol) and P(o-tol)3 (557.1 mg, 1.83 mmol) at room temperature under nitrogen protection, and the reaction mixture was heated to 85 ° C and stirred for about 2 hours. After thin-layer chromatography (dichloromethane / methanol = 10 / 1) showed complete reaction of the starting material, the mixture was poured into water (40 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, and concentrated to give a crude product. The crude product was purified by preparative MPLC to afford tert-butyl 6-[2-(cyclopropylcarbamoyl)phenyl]thio-3-[(E)-2-[5-(4-methylpiperazin-1-yl)-2-pyridyl]vinyl]indazole-1-carboxylate 28e (110 mg, 180.10 μmol, 19.68% yield) as a white solid.

[0703] The product was confirmed by LCMS.

[0704] MS-ESI calculated value [M+H]+ 611.3, found 611.2.

[0705] Step 4

[0706] To a solution of tert-butyl 6-[2-(cyclopropylcarbamoyl)phenyl]thio-3-[(E)-2-[5-(4-methylpiperazin-1-yl)-2-pyridyl]vinyl]indazole-1-carboxylate 28e (100 mg, 163.73 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (186.7 mg, 1.64 mmol) at room temperature, and the reaction was stirred for approximately 16 hours. After thin-layer chromatography (dichloromethane / methanol = 10 / 1) indicated complete reaction of the starting material, the mixture was poured into water (20 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 (20 mL), dried over anhydrous sodium sulfate, and concentrated to yield the crude product. The crude product was purified by preparative thin layer chromatography to afford 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) as a yellow solid.

[0707] The product was confirmed by LCMS, HNMR and CNMR.

[0708] MS-ESI calculated value [M+H]+ 511.2, found 511.0.

[0709] 1 H NMR (400MHz, CD3OD): δ (ppm) 8.22 (d, J = 2.8Hz, 1H), 8.02 (d, J = 8.8Hz, 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=8.4Hz,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).

[0710] 13 C NMR(100MHz, 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.

[0711] I-40

[0712] first step

[0713] To a solution of 6-bromopyridine-3-carboxaldehyde 29a (5 g, 26.88 mmol) in N,N-dimethylformamide (50 mL) at room temperature under nitrogen was added potassium vinyl trifluoroborate 1b (5.4 g, 40.32 mmol), Pd(dppf)Cl2 (975.3 mg, 1.34 mmol), and triethylamine (8.2 g, 80.64 mmol). The mixture was heated to 85°C and stirred for approximately 16 hours. After thin-layer chromatography (petroleum ether / ethyl acetate = 10 / 1) indicated complete reaction, the mixture was poured into water (250 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed sequentially with water (300 mL) and saturated brine (300 mL), dried over anhydrous sodium sulfate, and concentrated to yield the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give 6-vinylpyridine-3-carboxaldehyde 29b (1.7 g, 12.77 mmol, 47.50% yield) as a yellow oily liquid.

[0714] The product was confirmed by LCMS and HNMR.

[0715] MS-ESI calculated value [M+H]+ 134.1, found 134.1.

[0716] 1 H NMR (400MHz, CDCl3): δ10.08(s,1H),9.01(s,1H),8.13(d,J=8.0Hz,1H),7.48(d,J=8.4H z, 1H), 6.88 (dd, J = 17.6Hz, 10.8Hz, 1H), 6.41 (d, J = 17.6Hz, 1H), 5.68 (d, J = 10.8Hz, 1H).

[0717] Step 2

[0718] To a solution of 6-vinylpyridine-3-carbaldehyde 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, followed by stirring for approximately 16 hours. After thin-layer chromatography (dichloromethane / methanol = 10 / 1) indicated complete reaction, 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 yield the crude product. The crude product was purified by silica gel column chromatography (DCM) to yield N,N-dimethyl-1-(6-vinyl-3-pyridyl)methanamine 29c (400 mg, 2.47 mmol, 65.66% yield) as a white solid.

[0719] The product was confirmed by LCMS and HNMR.

[0720] MS-ESI calculated value [M+H]+ 163.1, found 163.1.

[0721] 1 H NMR (400MHz, CDCl3): δ8.45(s,1H),7.62(dd,J=8.0Hz,1.6Hz,1H),7.32(d,J=8.0Hz,1H),6.81(dd ,J=17.6Hz,10.8Hz,1H),6.16(d,J=17.6Hz,1H),5.46(dd,J=10.8Hz,4.4Hz,1H),3.41(s,2H),2.23 (s,6H).

[0722] Step 3

[0723] Under nitrogen protection, to a solution of tert-butyl 6-[2-(cyclopropylcarbamoyl)phenyl]thio-3-iodoindazole-1-carboxylate 27f (500 mg, 933.89 μmol) in 1,4-dioxane (10 mL) were added N,N-dimethyl-1-(6-vinyl-3-pyridyl)methanamine 29c (303 mg, 1.87 mmol), triethylamine (472.5 mg, 4.67 mmol), Pd2(dba)3 (427.6 mg, 466.94 μmol) and P(o-tol)3 (426.4 mg, 1.40 mmol) at room temperature, and the reaction mixture was stirred at 85 ° C for about 2 hours. After thin-layer chromatography (petroleum ether / ethyl acetate = 1 / 1) showed that the starting material had reacted completely, 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 a crude product. The crude product was purified by preparative MPLC to give tert-butyl 6-[2-(cyclopropylcarbamoyl)phenyl]thio-3-[(E)-2-[5-[(dimethylamino)methyl]-2-pyridyl]vinyl]indazole-1-carboxylate 29d (155 mg, 272.07 μmol, 29.13% yield) as a yellow oily liquid.

[0724] The product was confirmed by LCMS.

[0725] MS-ESI calculated value [M+H]+ 570.2, found 570.2.

[0726] Step 4

[0727] To a solution of tert-butyl 6-[2-(cyclopropylcarbamoyl)phenyl]thio-3-[(E)-2-[5-[(dimethylamino)methyl]-2-pyridyl]vinyl]indazole-1-carboxylate 29d (150 mg, 263.29 μmol) in dichloromethane (5 mL) was added trifluoroacetic acid (300.2 mg, 2.63 mmol) at room temperature, and the reaction was stirred for approximately 16 hours. After thin-layer chromatography (dichloromethane / methanol = 10 / 1) indicated complete reaction of the starting material, the mixture was poured into water (20 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 yield the crude product. The crude product was purified by preparative thin layer chromatography to afford 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) as a white solid.

[0728] The product was confirmed by LCMS, HNMR and CNMR.

[0729] MS-ESI calculated value [M+H]+ 470.2, found 470.1.

[0730] 1 H NMR (400MHz, CD3OD): δ8.49(s,1H),8.05(d,J=8.64Hz,1H),7.86(d,J=16.8Hz,1H),7.80(dd,J=8.0Hz,1.6Hz,1H),7.68(d,J=8.0Hz,1H),7.56(d,J=16 .6Hz,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=7.0Hz,2H),0.60–0.51(m,2H).

[0731] 13CNMR (100MHz, CD3OD&CDCl3): δ172.66,156.23,151.27,139.82,133.39,132.97,1 31.82,130.51,129.21,128.05,126.72,122.94,122.64,121.78,61.87,23.98,6.88.

[0732] I-41

[0733] first step

[0734] To a solution of 6-vinylpyridine-3-carbaldehyde 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, followed by stirring for approximately 16 hours. After thin-layer chromatography (dichloromethane / methanol = 10 / 1) indicated complete reaction, 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 yield the crude product. The crude product was purified by silica gel column chromatography (DCM) to yield 5-(pyrrolidin-1-ylmethyl)-2-vinylpyridine 30a (420 mg, 2.23 mmol, 59.41% yield) as a white solid.

[0735] The product was confirmed by LCMS and HNMR.

[0736] MS-ESI calculated value [M+H]+ 189.1, found 189.1.

[0737] 1 H NMR (400MHz, CDCl3): δ8.49 (s, 1H), 7.64 (dd, J = 8.0Hz, 1.6Hz, 1H), 7.31 (d, J = 8.0Hz, 1H), 6.81 (dd,J=17.5Hz,10.8Hz,1H),6.16(d,J=17.5Hz,1H),5.45(d,J=10.8Hz,1H),3.61(s,2H),2.50(s,4H),1.78(s,4H).

[0738] Step 2

[0739] Under nitrogen protection, to a solution of tert-butyl 6-[2-(cyclopropylcarbamoyl)phenyl]thio-3-iodoindazole-1-carboxylate 27f (500 mg, 933.89 μmol) in 1,4-dioxane (10 mL) were added 5-(pyrrolidin-1-ylmethyl)-2-vinylpyridine 30a (351.6 mg, 1.87 mmol), triethylamine (472.5 mg, 4.67 mmol), Pd2(dba)3 (427.6 mg, 466.94 μmol) and P(o-tol)3 (426.4 mg, 1.40 mmol) at room temperature, and the reaction mixture was stirred at 85 ° C for about 2 hours. After thin-layer chromatography (petroleum ether / ethyl acetate = 1 / 1) showed that the starting material had reacted completely, 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 a crude product. The crude product was purified by preparative MPLC to give tert-butyl 6-[2-(cyclopropylcarbamoyl)phenyl]thio-3-[(E)-2-[5-(pyrrolidin-1-ylmethyl)-2-pyridyl]vinyl]indazole-1-carboxylate 30b (91 mg, 152.75 μmol, 16.36% yield) as a yellow oily liquid.

[0740] The product was confirmed by LCMS.

[0741] MS-ESI calculated value [M+H]+ 596.3, found 596.3.

[0742] Step 3

[0743] To a solution of tert-butyl 6-[2-(cyclopropylcarbamoyl)phenyl]thio-3-[(E)-2-[5-(pyrrolidin-1-ylmethyl)-2-pyridyl]vinyl]indazole-1-carboxylate 30b (100 mg, 167.85 μmol) in dichloromethane (5 mL) was added trifluoroacetic acid (191.4 mg, 1.68 mmol) at room temperature, and the reaction was stirred for approximately 16 hours. After thin-layer chromatography (dichloromethane / methanol = 10 / 1) indicated complete reaction of the starting material, 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 yield the crude product. The crude product was purified by preparative thin layer chromatography to afford 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) as a white solid.

[0744] The product was confirmed by LCMS, HNMR and CNMR.

[0745] MS-ESI calculated value [M+H]+ 496.2, found 496.1.

[0746] 1 H NMR (400MHz, CD3OD): δ8.53(d,J=1.6Hz,1H),8.06(d,J=8.5Hz,1H),7.85(dd,J=16.7 Hz,9.3Hz,2H),7.69(d,J=8.1Hz,1H),7.60–7.53(m,2H),7.45(dd,J=7.1Hz,1.9Hz,1 H),7.34-7.32(m,2H),7.28–7.24(m,1H),7.20(dd,J=8.5Hz,1.4Hz,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).

[0747] 13C NMR (100MHz, CD3OD): δ172.70,155.96,151.03,143.79,143.60,139.59,139.26,135.90,135.76,133.23,1 31.69,130.39,128.22,126.42,125.30,122.93,122.53,121.60,144.88,58.17,54.93,24.19,23.80,6.49.

[0748] I-33

[0749] first step

[0750] In a 250 mL single-necked bottle, 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) and cesium carbonate (18.94 g, 58.2 mmol) were added and stirred at room temperature for two hours. The reaction mixture was filtered, and the filtrate was collected. Ethyl acetate (200 mL) was added to the filtrate and the mixture was washed with water (200 mL x 3). The organic phase was separated and dried over anhydrous sodium sulfate. The solid residue was concentrated under reduced pressure and separated by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 3:1) to afford methyl 3-fluoro-2-[(4-methoxyphenyl)methylthio]benzoate 31b (4.5 g, 14.7 mmol, 50.5% yield) as a white solid.

[0751] MS (ESI) M / Z: 329.1 [M+Na+]

[0752] Step 2

[0753] In a 250 mL single-necked bottle, 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) and water (15 mL) were added. The mixture was heated to 50°C and stirred for 5 hours. The reaction system was filtered, and the filtrate was collected and concentrated under reduced pressure. Dilute hydrochloric acid (1 mol / L) was added to the system to adjust the pH to 5. The mixture was filtered and dried to give 3-fluoro-2-[(4-methoxyphenyl)methylthio]benzoic acid 31c (3.80 g, 13.0 mmol, 88.4% yield) as a white solid.

[0754] MS (ESI) M / Z: 315.2 [M+Na+]

[0755] Step 3

[0756] In a 250 mL single-necked bottle, 3-fluoro-2-[(4-methoxyphenyl)methylthio]benzoic acid 31c (3.80 g, 13.0 mmol) was dissolved in N,N-dimethylformamide (38 mL). Methylamine (506 mg, 19.5 mmol) and N-methylmorpholine (3.943 g, 39.0 mmol) were added. 1-hydroxybenzotriazole (2.64 g, 19.5 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.72 g, 19.5 mmol) were then added. The mixture was stirred at room temperature for 3 hours. Ethyl acetate (200 mL) was added to dilute the reaction system and the mixture was washed with water (200 mL x 3). The mixture was separated and the organic phase was 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 3-fluoro-2-[(4-methoxyphenyl)methylthio]-N-methylbenzamide 31d (2.95 g, 9.66 mmol, 74.3% yield) as a white solid.

[0757] Step 4

[0758] In a 250 mL three-necked flask, 3-fluoro-2-[(4-methoxyphenyl)methylthio]-N-methylbenzamide 31d (2.95 g, 9.66 mmol) was dissolved in trifluoroacetic acid (32 mL). The mixture was heated to 70°C and stirred for three hours. The mixture was concentrated under reduced pressure, and the resulting solid residue was separated by silica gel column chromatography (eluent: dichloromethane / methanol = 30:1). After concentration, 1.2 g of 3-fluoro-N-methyl-2-thiobenzamide 31e (1.05 g, 5.68 mmol, 58.8% yield) was obtained as a white solid.

[0759] Step 5

[0760] To a solution of 3-iodo-6-nitro-1H-indazole 31f (5 g, 17.30 mmol) in ethyl acetate (100 mL) were 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 thin-layer chromatography (petroleum ether / ethyl acetate = 10 / 1) showed complete reaction of the starting materials, the reaction solution was concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 20 / 1) to obtain 3-iodo-6-nitro-1-tetrahydropyran-2-ylindazole 31g (6.1 g, 16.35 mmol, 94.50% yield) as a yellow solid.

[0761] The product was confirmed by H-NMR.

[0762] 1H NMR (400MHz, CDCl3) δ8.58(s,1H),8.11(dd,J=8.8,1.2Hz,1H),7.63(d,J=8.8Hz,1H),5.81(dd ,J=9.2,2.8Hz,1H),4.06(d,J=10.4Hz,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).

[0763] Step 6

[0764] To a solution of 31 g (5 g, 13.40 mmol) of 3-iodo-6-nitro-1-tetrahydropyran-2-yl indazole in dioxane (60 mL) were added 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)phosphine (4.1 g, 13.40 mmol) at room temperature and under nitrogen. The mixture was heated to 100° C. and stirred for 2 hours. After thin layer chromatography (dichloromethane / methanol = 10 / 1) showed that the reaction of the starting materials was complete, the mixture was poured into water (120 mL) and filtered. The filtrate was washed with dichloromethane (120 mL x 10% ethanol). 3) extraction, and the combined organic layers were dried over anhydrous sodium sulfate and concentrated to obtain a crude product; the crude product was purified by column chromatography (dichloromethane / methanol = 20 / 1) to obtain a yellow solid compound 6-nitro-3-[(E)-2-[5-(2-pyrrolidin-1-ethoxy)-2-pyridinyl]vinyl]-1-tetrahydropyran-2-ylindazole 31h (2.2 g, 4.64 mmol, 34.62% yield).

[0765] The product was confirmed by LCMS and HNMR.

[0766] MS-ESI calculated value [M+H]+ 464.2, found 464.1.

[0767] 1H NMR (400MHz, CDCl3) δ8.57 (s, 1H), 8.40 (d, J = 2.8Hz, 1H), 8.15-8.10 (m, 2H), 7.7 9-7.74(m,1H),7.62-7.58(m,1H),7.27-7.24(m,1H),7.14-7.10(m,1H),5.84(dd ,J=9.6,2.8Hz,1H),4.22(t,J=6.0Hz,2H),4.10-4.08(m,1H),3.86-3.81(m,1H) ,2.98(t,J=5.6Hz,2H),2.68-2.59(m,4H),2.22-2.15(m,2H),1.86-1.74(m,8H).

[0768] Step 7

[0769] To a solution of 6-nitro-3-[(E)-2-[5-(2-pyrrolidin-1-ethoxy)-2-pyridinyl]vinyl]-1-tetrahydropyran-2-ylindazole 31h (2.2 g, 4.63 mmol) in methanol (20 mL) and tetrahydrofuran (20 mL) were added sodium sulfide nonahydrate (4 g, 16.20 mmol, 98.0% purity) and water (20 mL) at room temperature under nitrogen. The mixture was heated to 60° C. and stirred for 2 hours. After thin layer chromatography (dichloromethane / methanol = 10 / 1) showed that the reaction of the starting material was complete, the mixture was poured into water (80 mL) and filtered. The filtrate was washed with dichloromethane (80 mL x 10% ethanol). 3) extraction, the combined organic layer was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate and concentrated to give a crude product; the crude product was purified by column chromatography (DCM / MeOH = 20 / 1 to 3:1) to give a brown oily compound 3-[(E)-2-[5-(2-pyrrolidin-1-ethoxy)-2-pyridinyl]vinyl]-1-tetrahydropyran-2-yl-indazol-6-amine 31i (0.9 g, 2.05 mmol, 44.36% yield).

[0770] The product was confirmed by LCMS and HNMR.

[0771] MS-ESI calculated value [M+H]+ 434.2, found 434.1.

[0772] 1H NMR (400MHz, CDCl3) δ8.36(d,J=2.8Hz,1H),7.83(d,J=8.4Hz,1H),7.65(d,J=16.4Hz,1H),7.52 -7.45(m,2H),7.24(dd,J=8.4,2.8Hz,1H),6.76(d,J=1.6Hz,1H),6.66(dd,J=8.4,1.6Hz,1H),5. 60(dd,J=9.6,2.8Hz,1H),4.20(t,J=6.0Hz,2H),4.09-4.07(m,1H),3.78-3.20(m,1H),2.96(t,J =5.6Hz,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).

[0773] Step 8

[0774] To a solution of compound 3-[(E)-2-[5-(2-pyrrolidin-1-ethoxy)-2-pyridinyl]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) at 0-5°C, and the mixture was stirred at 0-5°C for 1 hour. An aqueous solution (6 mL) of 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 thin-layer chromatography (dichloromethane / methanol = 10 / 1) showed complete reaction of the starting material, the mixture was poured into water (50 mL), the pH of the mixture was adjusted to 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 a crude product. The crude product was purified by column chromatography (DCM / MeOH = 20 / 1) to give 6-iodo-3-[(E)-2-[5-(2-pyrrolidin-1-methoxy)-2-pyridyl]vinyl]-1-tetrahydropyran-2-ylindazole 31j (0.85 g, 1.56 mmol, 53.30% yield) as a red solid.

[0775] The product was confirmed by LCMS and HNMR.

[0776] MS-ESI calculated value [M+H]+ 545.1, found 546.0.

[0777] 1H NMR (400MHz, CDCl3) δ8.35(d,J=3.6Hz,1H),8.02(s,1H),7.78(d,J=8.4Hz,1H),7.73(d,J=16.4Hz,1H),7.55(d,J=2.0Hz,1H),7.53-7.51(m,1H) ,7.46(d,J=8.4Hz,1H),7.33-7.31(m,1H),5.69(d,J=6.8Hz,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).

[0778] Step 9

[0779] To a solution of compound 6-iodo-3-[(E)-2-[5-(2-pyrrolidin-1-methoxy)-2-pyridyl]vinyl]-1-tetrahydropyran-2-yl indazole 31j (350 mg, 642.88 μmol) in N,N-dimethylformamide (5 mL) were added cesium carbonate (418.9 mg, 1.29 mmol), 3-fluoro-N-methyl-2-mercaptobenzamide 31e (142.9 mg, 771.45 μmol) and 1,1'-bisdiphenylphosphinoferrocenepalladium dichloride (233.3 mg, 321.44 μmol) at room temperature under nitrogen. The temperature was raised to 80°C and stirred for 5 hours. After thin layer chromatography (dichloromethane / methanol = 10 / 1) showed that the starting material had reacted completely, the mixture was poured into water (30 mL) and washed with ethyl acetate (20 mL x 10). 3) extraction, the combined organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate and concentrated to give a crude product; the crude product was purified by neutral alumina column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give a yellow solid compound 3-fluoro-N-methyl-2-[3-[(E)-2-[5-(2-pyrrolidin-1-ethoxy)-2-pyridinyl]vinyl]-1-tetrahydropyran-2-yl-indazole-6-yl]sulfanylbenzamide 31k (250 mg, 415.47 μmol, 64.63% yield).

[0780] The product was confirmed by LCMS.

[0781] MS-ESI calculated value [M+H]+ 602.3, found 602.2.

[0782] Step 10

[0783] To a solution of compound 3-fluoro-N-methyl-2-[3-[(E)-2-[5-(2-pyrrolidin-1-ethoxy)-2-pyridinyl]vinyl]-1-tetrahydropyran-2-yl-indole-6-yl]thiobenzamide 31k (250 mg, 415.47 μmol) in dichloromethane (5 mL) was added trifluoroacetic acid (473.7 mg, 4.15 mmol) at room temperature. The mixture was stirred at 30°C under a nitrogen atmosphere for 16 hours. After thin layer chromatography (dichloromethane / methanol = 10 / 1) showed that the starting material had reacted completely, the mixture was poured into water (40 mL) and the pH was adjusted to 8-9 with sodium carbonate. Ethyl acetate (30 mL x 10) was added to the resulting mixture. 3) extraction, the combined organic layer was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate and concentrated to give a 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, 36.27% yield).

[0784] The product was confirmed by LCMS, HNMR and CNMR.

[0785] MS-ESI calculated value [M+H]+ 518.2, found 518.1.

[0786] 1 H NMR (400MHz, CDCl3&CD3OD): δ (ppm) 8.26 (d, J = 2.8Hz, 1H), 8.01 (d, J = 8.4Hz, 1H), 7. 67(d,J=16.8Hz,1H),7.61(d,J=8.8Hz,1H),7.54–7.48(m,2H),7.40(dd,J=8.8,2.8H z,1H),7.29-7.23(m,2H),7.17(dd,J=8.4,1.2Hz,1H),7.11-7.06(m,1H),4.23(t,J =5.6Hz,2H),2.98(t,J=5.2Hz,2H),2.87(s,3H),2.71(s,4H),1.86(t,J=3.2Hz,4H).

[0787] 13C NMR(100MHz, CDCl3&CD3OD)δ(ppm)168.80,161.97,160.22,154.36,148.28,137.19,134.26,134.19,130.02,1 29.21,124.79,122.07,120.25,117.44,115.31,115.11,114.88,113.64,66.98,54.61,54.41,25.96,223.06.

[0788] I-34

[0789] first step

[0790] In a 250 mL single-necked bottle, methyl 2,5-difluorobenzoate 32a (5.00 g, 29.1 mmol) was dissolved in N,N-dimethylformamide (50 mL). (4-Methoxyphenyl)methanethiol (4.564 g, 29.1 mmol) and cesium carbonate (18.94 g, 58.2 mmol) were added and stirred at room temperature for two hours. The reaction mixture was filtered, and the filtrate was collected. The filtrate was diluted with ethyl acetate (200 mL) and washed with water (200 mL x 3). The organic phase was separated and dried over anhydrous sodium sulfate. The solid residue was concentrated under reduced pressure and separated by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 3:1) to afford methyl 5-fluoro-2-[(4-methoxyphenyl)methylthio]benzoate 32b (4.9 g, 16 mmol, 54.9% yield) as a white solid.

[0791] MS (ESI) M / Z: 329.1 [M+Na+]

[0792] Step 2

[0793] In a 250 mL single-necked bottle, 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) and water (15 mL) were added, and the mixture was heated to 50°C with stirring for 5 hours. The reaction system was filtered, and the filtrate was collected and concentrated under reduced pressure. Dilute hydrochloric acid (1 mol / L) was added to the system to adjust the pH to 5. The mixture was filtered and dried to afford 5-fluoro-2-[(4-methoxyphenyl)methylthio]benzoic acid 32c (3.94 g, 13.5 mmol, 84.38% yield) as a white solid.

[0794] MS (ESI) M / Z: 315.2 [M+Na+]

[0795] Step 3

[0796] In a 250 mL single-necked bottle, 5-fluoro-2-[(4-methoxyphenyl)methylthio]benzoic acid 32c (3.94 g, 13.5 mmol) was dissolved in N,N-dimethylformamide (38 mL). Methylamine (532 mg, 20.5 mmol) and N-methylmorpholine (4.095 g, 40.5 mmol) were added. 1-Hydroxybenzotriazole (2.78 g, 20.5 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.91 g, 20.5 mmol) were then added. The mixture was stirred at room temperature for 3 hours. Ethyl acetate (200 mL) was added to dilute the reaction system and the mixture was washed with water (200 mL x 3). The mixture was separated and the organic phase was 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 5-fluoro-2-[(4-methoxyphenyl)methylthio]-N-methylbenzamide 32d (2.96 g, 9.7 mmol, 71.9% yield) as a white solid.

[0797] Step 4

[0798] In a 250 mL three-necked flask, 5-fluoro-2-[(4-methoxyphenyl)methylthio]-N-methylbenzamide 32d (2.96 g, 9.7 mmol) was dissolved in trifluoroacetic acid (32 mL). The temperature was raised to 70°C and the reaction was stirred for three hours. The mixture was concentrated under reduced pressure, and the resulting solid residue was separated by silica gel column chromatography (eluent: dichloromethane / methanol = 30:1) to afford 1.2 g of 5-fluoro-N-methyl-2-thiobenzamide 32e as a white solid (1.1 g, 5.95 mmol, 61.3% yield).

[0799] MS (ESI) M / Z: 186.1 [M+H+]

[0800] 1 H NMR (400MHz, MeOD) δ7.40 (dd, J=8.8, 5.2Hz, 1H), 7.23 (dd, J=8.8, 2.8Hz, 1H), 7.08 (td, J=8.4, 2.8Hz, 1H), 2.89 (s, 3H).

[0801] Step 5

[0802] To a solution of compound 6-iodo-3-[(E)-2-[5-(2-pyrrolidin-1-methoxy)-2-pyridinyl]vinyl]-1-tetrahydropyran-2-ylindazole 31j (350 mg, 642.88 μmol) in N,N-dimethylformamide (5 mL) were added cesium carbonate (314.2 mg, 964.32 μmol), 5-fluoro-N-methyl-2-mercaptobenzamide 32e (1 48.8 mg, 803.60 μmol, synthesized according to the synthetic method of compound 31e using methyl 2,5-difluorobenzoate as raw material) and 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium (350 mg, 482.32 μmol), heated to 80°C and stirred for 5 hours; after thin layer chromatography (dichloromethane / methanol = 10 / 1) showed that the raw materials had reacted completely, the mixture was poured into water (30 mL) and washed with ethyl acetate (20 mL) The reaction mixture was stirred for 2 h at 4 ℃ for 30 min (4 ℃ of drying). ...

[0803] The product was confirmed by LCMS.

[0804] MS-ESI calculated value [M+H]+ 602.3, found 602.2.

[0805] Step 6

[0806] To a solution of compound 5-fluoro-N-methyl-2-[3-[(E)-2-[5-(2-pyrrolidin-1-ethoxy)-2-pyridinyl]vinyl]-1-tetrahydropyran-2-yl-indole-6-yl]sulfanylbenzamide 32f (250 mg, 415.47 μmol) in dichloromethane (10 mL) was added trifluoroacetic acid (473.7 mg, 4.15 mmol) at room temperature. The mixture was stirred at 30°C under a nitrogen atmosphere for 16 hours. After thin layer chromatography (dichloromethane / methanol = 10 / 1) showed that the starting material had reacted completely, the mixture was poured into water (40 mL) and the pH was adjusted to 8-9 with sodium carbonate. Ethyl acetate (30 mL x 10) was added to the mixture. 3) extraction, the combined organic layer was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate and concentrated to give a 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}sulfanyl)benzamide I-34 (33 mg, 63.75 μmol, 15.35% yield).

[0807] The product was confirmed by LCMS, HNMR and CNMR.

[0808] MS-ESI calculated value [M+H]+ 518.2, found 518.0.

[0809] 1 H NMR (400MHz, CDCl3&CD3OD): δ (ppm) 8.28 (d, J = 2.4Hz, 1H), 8.13 (d, J = 8.4Hz, 1 H),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 .8Hz,1H),7.28(d,J=9.6Hz,1H),6.97–6.93(m,1H),6.70(dd,J=10.0,2.4Hz,1 H), 4.26 (t, J = 5.2Hz, 2H), 3.03 (s, 2H), 2.91 (s, 3H), 2.76 (s, 4H), 1.89 (s, 4H).

[0810] 13C NMR (100MHz, 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.

[0811] I-35

[0812] first step

[0813] In a 250 mL single-necked bottle, methyl 2-bromo-4-fluorobenzoate 33a (5.00 g, 21.5 mmol) was dissolved in N,N-dimethylformamide (50 mL), and PMBSH (3.98 g, 25.8 mmol) and cesium carbonate (10.51 g, 32.3 mmol) were added, followed by Pd(dppf)Cl2 (0.79 g, 1.08 mmol), and the reaction was stirred at 120 °C overnight.

[0814] Post-treatment: Filter the reaction system, collect the filtrate, dilute it with ethyl acetate (200 mL), and wash it with water (200 mL x 3). Separate the liquid, collect the organic phase, and dry it over anhydrous sodium sulfate. Concentrate under reduced pressure to obtain a solid residue, which was separated by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 3:1). After concentration, 5 g of methyl 4-fluoro-2-[(4-methoxyphenyl)methylmercapto]benzoate 33b was obtained as a white solid.

[0815] MS (ESI) M / Z: 329.1 [M+Na+]

[0816] Step 2

[0817] In a 250 mL single-necked bottle, 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) and water (15 mL) were added. The mixture was heated to 50°C and stirred for 5 hours. The reaction system was filtered, and the filtrate was collected and concentrated under reduced pressure. Dilute hydrochloric acid (1 mol / L) was added to the system to adjust the pH to 5. The mixture was filtered and dried to give 4-fluoro-2-[(4-methoxyphenyl)methylthio]benzoic acid 33c (3.80 g, 13.0 mmol, 88.4% yield) as a white solid.

[0818] MS (ESI) M / Z: 315.2 [M+Na+]

[0819] Step 3

[0820] In a 250 mL single-necked flask, 4-fluoro-2-[(4-methoxyphenyl)methylthio]benzoic acid 33c (3.80 g, 13.0 mmol) was dissolved in N,N-dimethylformamide (38 mL). Methylamine (506 mg, 19.5 mmol) and N-methylmorpholine (3.943 g, 39.0 mmol) were added. 1-Hydroxybenzotriazole (2.64 g, 19.5 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.72 g, 19.5 mmol) were then added. The reaction mixture was stirred at room temperature for 3 hours. Ethyl acetate (200 mL) was added to dilute the reaction mixture and the mixture was washed with water (200 mL x 3). The mixture was separated and the organic phase was 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 4-fluoro-2-[(4-methoxyphenyl)methylthio]-N-methylbenzamide 33d (2.95 g, 9.66 mmol, 74.3% yield) as a white solid.

[0821] Step 4

[0822] In a 250 mL three-necked flask, 4-fluoro-2-[(4-methoxyphenyl)methylthio]-N-methylbenzamide 33d (2.95 g, 9.66 mmol) was dissolved in trifluoroacetic acid (32 mL). The temperature was raised to 70°C and the reaction was stirred for three hours. The mixture was concentrated under reduced pressure, and the resulting solid residue was separated by silica gel column chromatography (eluent: dichloromethane / methanol = 30:1). After concentration, 1.2 g of 4-fluoro-N-methyl-2-thiobenzamide 33e (1.05 g, 5.68 mmol, 58.8% yield) was obtained as a white solid.

[0823] MS (ESI) M / Z: 186.1 [M+H+]

[0824] 1 H NMR (400MHz, CD3OD) δ7.50 (dd, J=8.6, 5.8Hz, 1H), 7.18 (dd, J=9.6, 2.5Hz, 1H), 7.01–6.76 (m, 1H), 2.89 (s, 3H).

[0825] Step 5

[0826] To a solution of compound 6-iodo-3-[(E)-2-[5-(2-pyrrolidin-1-methoxy)-2-pyridyl]vinyl]-1-tetrahydropyran-2-yl indazole 31j (300 mg, 551.04 μmol) in N,N-dimethylformamide (5 mL) were added cesium carbonate (359.1 mg, 1.10 mmol), 4-fluoro-N-methyl-2-thiobenzamide 33e (122.5 mg, 661.25 μmol) and 1,1'-bis(diphenylphosphinoferrocenepalladium dichloride) (199.9 mg, 275.52 μmol) at room temperature under nitrogen. The mixture was heated to 80°C and stirred for 5 hours. After thin layer chromatography (dichloromethane / methanol = 10 / 1) showed that the reaction of the starting material was complete, the mixture was poured into water (30 mL) and washed with ethyl acetate (20 mL x 10). 3) extraction, and the combined organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to give a crude product; the crude product was purified by neutral alumina column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give a yellow solid compound 4-fluoro-N-methyl-2-[3-[(E)-2-[5-(2-pyrrolidin-1-ethoxy)-2-pyridinyl]vinyl]-1-tetrahydropyran-2-yl-indazole-6-yl]sulfanylbenzamide 33f (250 mg, 415.47 μmol, 75.40% yield).

[0827] The product was confirmed by LCMS.

[0828] MS-ESI calculated value [M+H]+ 602.3, found 602.1.

[0829] Step 6

[0830] To a solution of compound 4-fluoro-N-methyl-2-[3-[(E)-2-[5-(2-pyrrolidin-1-ethoxy)-2-pyridinyl]vinyl]-1-tetrahydropyran-2-yl-indole-6-yl]thiobenzamide 33f (250 mg, 415.47 μmol) in dichloromethane (5 mL) was added trifluoroacetic acid (473.6 mg, 4.15 mmol) at room temperature. The mixture was stirred at 30°C under a nitrogen atmosphere for 16 hours. After thin layer chromatography (dichloromethane / methanol = 10 / 1) showed that the starting material had reacted completely, the mixture was poured into water (40 mL) and the pH was adjusted to 8-9 with sodium carbonate. Ethyl acetate (30 mL x 10) was added to the resulting mixture. 3) extraction, the combined organic layer was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate and concentrated to give a 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}sulfanyl)benzamide I-35 (20 mg, 38.64 μmol, 9.30% yield).

[0831] The product was confirmed by LCMS, HNMR and CNMR.

[0832] MS-ESI calculated value [M+H]+ 518.2, found 518.1.

[0833] 1 H NMR (400MHz, CDCl3&CD3OD): δ (ppm) δ8.29 (d, J = 2.8Hz, 1H), 8.13 (d, J = 8.4Hz, 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=8.8,2.8Hz,1H),7.28(d,J=10.0Hz,1H),6.98-6 .93(m,1H),6.71(dd,J=9.6,2.4Hz,1H),4.27(t,J=5.6Hz,2H),3.05(t,J=5.2Hz,2H),2.91(s,3H),2.78(s,4H),1.89(s,4H).

[0834] 13C NMR(100MHz, CDCl3&CD3OD)δ(ppm)170.59,166.30,163.79,155.74,149.73,144.24,143.69,14.18,142.10,138.66,136.12,132.82,132.34, 131.18,131.09,128.00,125.86,123.53,123.14,122.40,117.94,117. 45,117.21,114.07,113.85,68.36,56.02,55.87,30.93,27.58,24.52.

[0835] I-36

[0836] first step

[0837] In a 250 mL single-necked bottle, methyl 2,6-difluorobenzoate 34a (5.00 g, 29.1 mmol) was dissolved in N,N-dimethylformamide (50 mL). (4-Methoxyphenyl)methanethiol (4.564 g, 29.1 mmol) and cesium carbonate (18.94 g, 58.2 mmol) were added and stirred at room temperature for two hours. The reaction mixture was filtered, and the filtrate was collected. The filtrate was diluted with ethyl acetate (200 mL) and washed with water (200 mL x 3). The organic phase was separated and dried over anhydrous sodium sulfate. The solid residue was concentrated under reduced pressure and separated by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 3:1) to afford methyl 2-fluoro-6-[(4-methoxyphenyl)methylthio]benzoate 34b (4.5 g, 14.7 mmol, 54.9% yield) as a white solid.

[0838] MS (ESI) M / Z: 329.1 [M+Na+]

[0839] Step 2

[0840] In a 250 mL single-necked bottle, 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) and water (15 mL) were added. The mixture was heated to 50°C and stirred for 5 hours. The reaction system was filtered, and the filtrate was collected and concentrated under reduced pressure. Dilute hydrochloric acid (1 mol / L) was added to the system to adjust the pH to 5. The mixture was filtered and dried to afford 2-fluoro-6-[(4-methoxyphenyl)methylthio]benzoic acid 34c (3.80 g, 13.0 mmol, 88.4% yield) as a white solid.

[0841] MS (ESI) M / Z: 315.2 [M+Na+]

[0842] Step 3

[0843] In a 250 mL single-necked bottle, 2-fluoro-6-[(4-methoxyphenyl)methylthio]benzoic acid 34c (3.80 g, 13.0 mmol) was dissolved in N,N-dimethylformamide (38 mL). Methylamine (506 mg, 19.5 mmol) and N-methylmorpholine (3.943 g, 39.0 mmol) were added. 1-Hydroxybenzotriazole (2.64 g, 19.5 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.72 g, 19.5 mmol) were then added. The mixture was stirred at room temperature for 3 hours. Ethyl acetate (200 mL) was added to dilute the reaction mixture and the mixture was washed with water (200 mL x 3). The mixture was separated and the organic phase was 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 2-fluoro-6-[(4-methoxyphenyl)methylthio]-N-methylbenzamide 34d (2.95 g, 9.66 mmol, 74.3% yield) as a white solid.

[0844] Step 4

[0845] In a 250 mL three-necked flask, 2-fluoro-6-[(4-methoxyphenyl)methylthio]-N-methylbenzamide 34d (2.95 g, 9.66 mmol) was dissolved in trifluoroacetic acid (32 mL). The mixture was heated to 70°C and stirred for three hours. The mixture was concentrated under reduced pressure, and the resulting solid residue was separated by silica gel column chromatography (eluent: dichloromethane / methanol = 30:1). After concentration, 1.2 g of 2-fluoro-N-methyl-6-mercaptobenzamide 34e (1.05 g, 5.68 mmol, 58.8% yield) was obtained as a white solid.

[0846] MS (ESI) M / Z: 186.0 [M+H+]

[0847] 1 H NMR (400MHz, CD3OD) δ7.34–7.32(m,1H),7.24–7.20(m,2H),2.92(s,3H).

[0848] Step 5

[0849] To a solution of compound 6-iodo-3-[(E)-2-[5-(2-pyrrolidin-1-methoxy)-2-pyridinyl]vinyl]-1-tetrahydropyran-2-ylindazole 31j (350 mg, 642.88 μmol) in N,N-dimethylformamide (8 mL) were added cesium carbonate (314.2 mg, 964.32 μmol), 2-fluoro-N-methyl-6-mercaptobenzamide 34e (1 48.8 mg, 803.60 μmol, synthesized according to the synthetic method of compound 31e using methyl 2,6-difluorobenzoate as raw material) and 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium (350 mg, 482.32 μmol), heated to 80°C and stirred for 5 hours; after thin layer chromatography (dichloromethane / methanol = 10 / 1) showed that the raw materials were completely reacted, the mixture was poured into water (25 mL) and washed with dichloromethane (25 mL) The mixture was extracted with 4% paraformaldehyde (5-nitropropane) (4-nitropropane) (5-nitropropane) (6-nitropropane) (7-nitropropane) (8-nitropropane) (9-nitropropane) (10-nitropropane) (20-nitropropane) (30-nitropropane) (40-nitropropane) (8-nitropropane) (9-nitropropane) (30-nitropropane) (6-nitropropane) (7-nitropropane) (8-nitropropane) (9-nitropropane) (30-nitropropane) (20-nitropropane) (30-nitropropane) (8-nitropropane) (9-nitropropane) (30-nitropropane) (8-nitropropane) (9-nitropropane) (30-nitropropane) (

[0850] The product was confirmed by LCMS.

[0851] MS-ESI calculated value [M+H]+ 602.3, found 602.2.

[0852] Step 6

[0853] To a solution of 2-fluoro-N-methyl-6-[3-[(E)-2-[5-(2-pyrrolidin-1-ethoxy)-2-pyridinyl]vinyl]-1-tetrahydropyran-2-yl-indazol-6-yl]sulfanylbenzamide 34f (197.9 mg, 328.88 μmol) in dichloromethane (5 mL) was added trifluoroacetic acid (1.2 g, 10.42 mmol) at room temperature. The mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. After thin-layer chromatography (dichloromethane / methanol = 10 / 1) showed that the starting material had reacted completely, the mixture was poured into water (5 mL), and the pH was adjusted to 8-9 with sodium carbonate. The mixture was extracted with dichloromethane (5 mL × 3) and washed with water (5 mL × 10). 2) The combined organic layers were washed, dried over anhydrous sodium sulfate, and concentrated to give a 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, 10.57% yield).

[0854] The product was confirmed by LCMS, HNMR and CNMR.

[0855] MS-ESI calculated value [M+H]+ 518.2, found 518.1.

[0856] 1 H NMR(400MHz, CD3OD)δ8.29(d,J=2.8Hz,1H),8.09(d,J=8.4Hz,1H),7.74–7.64(m,3H),7.56-7.45(m,2H),7.37-7.31(m,1H),7 .26(d,J=8.4Hz,1H),7.12-7.05(m,2H),4.27(t,J=5.2Hz,2H),3.03(t,J=6.0Hz,2H),2.89(s,3H),2.77(s,4H),1.89(s,4H).

[0857] 13 C NMR(100MHz,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.

[0858] I-29

[0859] first step

[0860] To a solution of 5-iodo-1H-indazole 35a (1.02 g, 4.19 mmol) and N-methyl-2-mercaptobenzamide 1e (1 g, 5.98 mmol) in N,N-dimethylformamide (10 mL) were added cesium carbonate (3.90 g, 11.96 mmol) and 1,1'-bis(diphenylphosphinoferrocenepalladium dichloride) (0.88 g, 1.20 mmol) at room temperature under nitrogen. The mixture was heated to 80°C and stirred for 2 hours. After thin layer chromatography (dichloromethane / methanol = 20 / 1) showed that the reaction of the starting materials was complete, the mixture was poured into water (30 mL) and washed with ethyl acetate (10 mL x 10 mL). 3) extraction, and the combined organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to give a crude product; the crude product was purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1 to 0 / 1) to give 2-(1H-indazol-5-ylthio)-N-methylbenzamide 35b (0.8 g, 47.2% yield) as a yellow oil.

[0861] The product was confirmed by LCMS.

[0862] MS-ESI calculated value [M+H]+ 284.1, found 284.1.

[0863] Step 2

[0864] To a solution of compound 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) were added 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. The temperature was raised to 100° C. and the reaction was stirred for 16 hours. Thin layer chromatography (dichloromethane / methanol = 20 / 1) and LCMS showed the presence of a product. The mixture was poured into water (80 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 a crude product. The crude product was purified by preparative high-performance liquid chromatography to give N-methyl-2-[(1-{5-[2-(pyrrolidin-1-yl)ethoxy]pyridin-2-yl}-1H-indazol-5-yl)thio]benzamide I-29 (18 mg, 2.2% yield) as a white solid compound.

[0865] The product was confirmed by LCMS, HNMR and CNMR.

[0866] MS-ESI calculated value [M+H]+ 474.2, found 474.2.

[0867] 1 H NMR (400MHz, CD3OD) δ: 8.73 (d, 1H, J = 8.8Hz), 8.23 ​​(d, 1H, J = 2.8Hz), 8.16 (d, 1H, J = 0.4 Hz),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).

[0868] 13 C NMR(100MHz, CDCl3)δ:168.68,152.93,147.72,138.17,137.07,135.65,135.04,134.32,133.06,130.6 6,129.81,128.41,126.67,126.23,125.95,125.08,115.85,114.51,68.05,55.04,54.77,26.80,23.52.

[0869] I-21

[0870] first step

[0871] To a solution of 6-bromo-1H-pyrazolo[4,3-b]pyridine 36a (2 g, 10.10 mmol) in N,N-dimethylformamide (20 mL) were added N-methyl-2-mercaptobenzamide 1e (2.03 g, 12.12 mmol), cesium carbonate (6.58 g, 20.20 mmol) and 1,1'-bis(diphenylphosphinoferrocenepalladium dichloride) (1.48 g, 2.02 mmol) at room temperature under nitrogen. The mixture was heated to 100°C and stirred for 1 hour. After thin layer chromatography (dichloromethane / methanol = 20 / 1) showed that the reaction of the starting materials was complete, the mixture was poured into water (40 mL) and washed with ethyl acetate (20 mL x 10% ethanol). 3) extraction, the combined organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated to give a crude product; the crude product was purified by column chromatography (dichloromethane / methanol = 10 / 1) to give a brown solid compound N-methyl-2-(1H-pyrazolo[4,3-b]pyridin-6-ylsulfanyl)benzamide 36b (1.59 g, 5.59 mmol, 55.37% yield).

[0872] The product was confirmed by LCMS and HNMR.

[0873] MS-ESI calculated value [M+H]+ 285.1, found 285.0.

[0874] 1 H NMR (400MHz, DMSO-d6): δ (ppm) 13.43 (s, 1H), 8.44 (d, J = 2.0Hz, 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=4.6Hz,3H).

[0875] Step 2

[0876] To a solution of N-methyl-2-(1H-pyrazolo[4,3-b]pyridin-6-ylsulfanyl)benzamide 36b (1.6 g, 5.63 mmol) in N,N-dimethylformamide (5 mL) were added iodine (2.43 g, 9.57 mmol) and potassium carbonate (1.56 g, 11.25 mmol) at room temperature, and the reaction was stirred at 25°C for 3.0 h. After thin layer chromatography (dichloromethane / methanol = 20 / 1) showed that the starting material was reacted completely, 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 of 2-[(3-iodo-1H-pyrazolyl[4,3-b]pyridin-6-yl)thio]-N-methylbenzamide 36c (2.1 g, 5.12 mmol, 90.97% yield) as a brown solid.

[0877] The product was confirmed by LCMS and HNMR.

[0878] MS-ESI calculated value [M+H]+ 411.0, found 410.9.

[0879] 1 H NMR (400MHz, DMSO-d6): δ (ppm) 13.84 (s, 1H), 8.45 (d, J = 1.6Hz, 2H), 8.06 (d, J = 1.6Hz ,1H),7.54-7.49(m,1H),7.42-7.24(m,2H),7.08-6.98(m,1H),2.76(d,J=4.6Hz,3H).

[0880] Step 3

[0881] 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(diphenylphosphino)ferrocene (16.56 mg, 195.01 μmol) at room temperature under nitrogen. The reaction mixture was heated to 100°C and stirred for 16 h. After thin layer chromatography (dichloromethane / methanol = 10 / 1) showed that the starting material was completely reacted, the mixture was poured into water (20 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layer was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to give a crude product. The crude product was purified by preparative high performance liquid chromatography to give 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) as a white solid compound.

[0882] The product was confirmed by LCMS, HNMR and CNMR.

[0883] MS-ESI calculated value [M+H]+ 388.1, found 388.1.

[0884] 1 H NMR (400MHz, DMSO-d6): δ (ppm) 13.55 (s, 1H), 8.62 (d, J = 4.4Hz, 1H), 8.55 (s, 1H), 8.46 (d, J = 4.4Hz, 1H), 8.20-8.07 (m, 2H), 7.93 (d, J = 16.4H z,1H),7.81(t,J=7.6Hz,1H),7.65(d,J=7.6Hz,1H),7.53(d,J=8.4Hz,1H),7.39-7.26(m,3H),7.07(d,J=7.6Hz,1H),2.78(d,J=4.4Hz,3H).

[0885] 13C NMR (100MHz, 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.

[0886] I-26

[0887] first step

[0888] To a solution of 5-bromopyridine-2-carbonitrile 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 slowly added portionwise over 2.0 hours, and the reaction was stirred at 25°C for 16 hours. After thin-layer chromatography (petroleum ether / ethyl acetate = 2 / 1) showed that the starting material had reacted completely, the mixture was poured into water (50 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 a crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to give tert-butyl N-[(5-bromo-2-pyridyl)methyl]carbamate 37b (700 mg, 2.44 mmol, 44.61% yield) as a white solid compound.

[0889] The product was confirmed by LCMS and HNMR.

[0890] MS-ESI calculated value [M+H]+ 287.0, found 286.9.

[0891] 1 H NMR (400MHz, CDCl3) δ8.60(d,J=2.0Hz,1H),7.79(dd,J=8.4,2.4Hz,1H),7.21(d,J=8.4Hz,1H),5.51(s,1H),4.40(d,J=5.4Hz,2H),1.47(s,9H).

[0892] Step 2

[0893] Compound tert-butyl N-[(5-bromo-2-pyridyl)methyl]carbamate 37b (500 mg, 1.74 mmol) was dissolved in a hydrochloric acid / methanol solution (15 mL) and stirred at 25°C for 2 hours. After LCMS showed complete reaction, the reaction solution was concentrated under reduced pressure to afford (5-bromo-2-pyridyl)methanamine dihydrochloride 37c (290 mg, 1.55 mmol, 89.05% yield) as a white solid.

[0894] The product was confirmed by LCMS and HNMR.

[0895] MS-ESI calculated value [M+H]+ 188.9, found 189.0.

[0896] 1 H NMR (400MHz, DMSO-d6): δ8.74(d,J=2.0Hz,1H),8.66(s,3H),8.14(dd,J=8.4,2.4Hz,1H),7.55(d,J=8.4Hz,1H),4.13-4.17(m,2H).

[0897] Step 3

[0898] Compound (5-bromo-2-pyridyl)methylamine dihydrochloride 37c (400 mg, 1.79 mmol) was dissolved in acetic anhydride (2 mL) and formic acid (1.6 mL) and stirred at 100°C for 16 hours. After thin-layer chromatography (petroleum ether / ethyl acetate = 2 / 1) showed complete reaction, the reaction solution 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 layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to afford 6-bromoimidazo[1,5-a]pyridine 37d as a yellow solid (300 mg, 1.52 mmol, 85.07% yield).

[0899] The product was confirmed by LCMS and HNMR.

[0900] MS-ESI calculated value [M+H]+ 197.0, found 197.0.

[0901] 1 H NMR (400MHz, DMSO-d6) δ9.40 (s, 1H), 8.96 (s, 1H), 8.05 (s, 1H), 7.80 (d, J = 9.6Hz, 1H), 7.26 (dd, J = 10.4Hz, 9.6Hz, 1H).

[0902] Step 4

[0903] To a solution of 6-bromoimidazo[1,5-a]pyridine 37d (0.3 g, 1.52 mmol) in N,N-dimethylformamide (10 mL) were added N-methyl-2-mercaptobenzamide 1e (254.62 mg, 1.52 mmol), cesium carbonate (992.18 mg, 3.05 mmol) and 1,1'-bis(diphenylphosphinoferrocenepalladium dichloride) (222.82 mg, 304.52 μmol) at room temperature, and the mixture was stirred at 80°C for 2 hours. After thin layer chromatography (dichloromethane / methanol = 15 / 1) showed that the reaction of the starting materials was complete, the mixture was poured into water (40 mL) and washed with ethyl acetate (20 mL x 10 mL). 3) extraction, and the combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to give a crude product; the crude product was purified by preparative high-performance liquid chromatography to give a yellow solid compound 2-imidazo[1,5-a]pyridin-6-ylsulfanyl-N-methylbenzamide 37e (87 mg, 307.04 μmol, 20.17% yield).

[0904] The product was confirmed by LCMS and HNMR.

[0905] MS-ESI calculated value [M+H]+ 284.1, found 284.1.

[0906] 1 H NMR (400MHz, CDCl3) δ8.20(d,J=0.8Hz,1H),8.13(s,1H),7.54(dd,J=7.6,1.6Hz,1H),7.42–7.45(m,2H),7.29-7.32(m ,1H),7.22-7.26(m,1H),7.14(dd,J=7.6,1.2Hz,1H),6.66(dd,J=9.2,1.2Hz,1H),6.21(s,1H),3.04(d,J=5.2Hz,3H).

[0907] Step 5

[0908] To a solution of 2-imidazo[1,5-a]pyridin-6-ylsulfanyl-N-methylbenzamide 37e (110 mg, 388.22 μmol) in N,N-dimethylformamide (5 mL) were added iodine (167.50 mg, 659.97 μmol) and potassium carbonate (95.60 mg, 776.43 μmol) at room temperature, and the reaction was stirred at 25°C for 3.0 h. After thin-layer chromatography (dichloromethane / methanol = 20 / 1) showed that the starting material had reacted completely, 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 a crude product. The crude product was purified by preparative thin-layer chromatography to give 2-(1-iodoimidazole[1,5-a]pyridin-6-yl)thio-N-methylbenzamide 37f (89 mg, 217.47 μmol, 56.02% yield) as a yellow solid.

[0909] The product was confirmed by LCMS and HNMR.

[0910] MS-ESI calculated value [M+H]+ 410.0, found 410.0.

[0911] 1 H NMR (400MHz, CDCl3) δ8.15 (t, J = 10.8Hz 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=5.2Hz,3H).

[0912] Step 6

[0913] 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(diphenylphosphino)ferrocene (33.22 mg, 390.96 μmol) at room temperature under nitrogen protection. The reaction solution was heated to 100°C and stirred for 16 hours. After thin-layer chromatography (dichloromethane / methanol = 20 / 1) indicated complete reaction of the starting material, the mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with water (10 mL x 2) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to yield a crude product. The crude product was purified by preparative HPLC, slurried with methanol (2 mL), and filtered. After drying the filter cake, a yellow solid, 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), was obtained.

[0914] The product was confirmed by LCMS, HNMR and CNMR.

[0915] MS-ESI calculated value [M+H]+ 387.1, found 387.1.

[0916] 1 H NMR (400MHz, CD3OD+CD3Cl) δ8.47(d,J=3.6Hz,1H),8.20(d,J=16.0Hz,2H),7.77(d,J=15.6Hz,1H)7.64-7.70(m,2H),7 .47(d,J=7.2Hz,1H),7.34-7.40(m,2H),7.20-7.30(m,2H),7.15(d,J=7.2Hz,1H),6.74(d,J=9.6Hz,1H),2.92(s,3H).

[0917] 13C NMR (100MHz, CD3OD+CD3Cl) δ169.50,155.69,148.95,137.23,135.69,135.15,130.76,129.82,128.9 9,127.91,127.83,126.63,126.43,125.64,124.85,122.80,122.20,121.82,120.66,118.12,26.36.

[0918] I-28

[0919] first step

[0920] To a solution of ethyl 2-diethoxyphosphoacetate 38b (460.5 mg, 2.05 mmol) in tetrahydrofuran (10 mL) at 0°C under nitrogen was added sodium hydride (89.6 mg, 3.73 mmol). The mixture was stirred at 0°C for 1.0 hour, 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 hours. After thin-layer chromatography (petroleum ether / ethyl acetate = 3 / 1) indicated complete reaction, 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 afford crude (E)-ethyl 3-(2-pyridyl)prop-2-enoate 38c (0.15 g, 846.50 μmol, 45.33% yield) as a yellow oil.

[0921] The product was confirmed by LCMS and HNMR.

[0922] MS-ESI calculated value [M+H]+ 178.1, found 178.0.

[0923] 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).

[0924] Step 2

[0925] To a solution of ethyl (E)-3-(2-pyridyl)prop-2-enoate 38c (0.2 g, 1.13 mmol) in tetrahydrofuran (8 mL) and water (2 mL) was added lithium hydroxide (81.1 mg, 3.39 mmol) at room temperature, and the mixture was stirred at 30°C for 16 hours. After thin-layer chromatography (dichloromethane / methanol = 10 / 1) indicated complete reaction, the reaction solution was concentrated, followed by the addition of water (10 mL) and the adjustment of pH to 5-6 with aqueous citric acid. The mixture was concentrated under reduced pressure, ethanol (20 mL) was added, and the mixture was stirred for 30 minutes before filtration. The filtrate was concentrated under reduced pressure to yield crude (E)-3-(2-pyridyl)prop-2-enoic acid 38d (0.15 g, 1.01 mmol, 89.11% yield) as a yellow solid.

[0926] The product was confirmed by LCMS and HNMR.

[0927] MS-ESI calculated value [M+H]+150.0, found 150.0.

[0928] 1 H NMR (400MHz, DMSO-d6): δ (ppm) 8.62 (d, J = 4.4Hz, 1H), 7.82-7.86 (m, 1H), 7.6 8-7.70(m,1H),7.50-7.54(m,1H),7.36-7.39(m,1H),6.83(d,J=15.6Hz,1H).

[0929] Step 3

[0930] To a solution of 4-bromopyridine-2-carbonitrile 38e (0.2 g, 1.09 mmol) and methyl 2-mercaptobenzoate (202.2 mg, 1.20 mmol) in N-methylpyrrolidone (10 mL) were 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 nitrogen atmosphere and stirred for about 16 hours. After thin layer chromatography (petroleum ether / ethyl acetate = 5 / 1) showed that the reaction of the starting materials was complete, the mixture was poured into water (30 mL) and washed with ethyl acetate (10 mL x 10 mL). 3) extraction, and the combined organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to give a crude product; the crude product was purified by preparative thin layer chromatography (petroleum ether / ethyl acetate = 5 / 1) to give methyl 2-[(2-cyano-4-pyridyl)thio]benzoate 38f (0.19 g, 702.91 μmol, 64.32% yield) as a white solid.

[0931] The product was confirmed by LCMS and HNMR.

[0932] MS-ESI calculated value [M+H]+ 271.0, found 271.0.

[0933] 1 H NMR (400MHz, CDCl3): δ (ppm) 8.50 (d, J = 8Hz, 1H), 8.00-8.02 (m, 1H), 7.51-7.59 (m, 3H), 7.36 (s, 1H), 7.26-7.28 (m, 1H), 3.87-3.89 (m, 3H).

[0934] Step 4

[0935] To a solution of methyl 2-[(2-cyano-4-pyridyl)thio]benzoate 38f (200 mg, 739.90 μmol) in methanol (5 mL) were added di-tert-butyl dicarbonate (193.8 mg, 887.88 μmol) and Raney nickel (100 mg) at room temperature. The reaction was stirred at 25°C under a hydrogen atmosphere for 16 hours. After thin-layer chromatography (ethyl acetate / petroleum ether = 3 / 1) showed that the starting material had reacted completely, the mixture was filtered and the filtrate was concentrated to give a crude product. The crude product was purified by preparative thin-layer 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.

[0936] The product was confirmed by LCMS and HNMR.

[0937] MS-ESI calculated value [M+H]+ 375.1, found 375.2.

[0938] 1 H NMR(400MHz, CDCl3)δ8.34(d,J=5.6Hz,1H),7.90(dd,J=6.0,1.6Hz,1H),7.26–7.40(m,3H),7.14(s ,1H),7.00(d,J=4.8Hz,1H),5.68(s,1H),4.35(d,J=5.4Hz,2H),3.84(s,3H),1.40(d,J=2.8Hz,9H).

[0939] Step 5

[0940] 38 g (140 mg, 373.88 μmol) of methyl 2-[[2-[(tert-butoxycarbonylamino)methyl]-4-pyridyl]thio]benzoate was dissolved in a solution of hydrochloric acid in dioxane (3 mL, 9 mol / L) and stirred at 25°C for 16 hours. After LCMS indicated complete reaction, the reaction solution was concentrated under reduced pressure to afford methyl 2-[[2-(aminomethyl)-4-pyridyl]thio]benzoate dihydrochloride (38 h of crude product).

[0941] The product was confirmed by LCMS.

[0942] MS-ESI calculated value [M+H]+ 275.1, found 275.0.

[0943] Step 6

[0944] To a solution of (E)-3-(2-pyridyl)prop-2-enoic acid 38d (24.0 mg, 160.88 μmol) in N,N-dimethylformamide (5 mL) were added methyl 2-[[2-(aminomethyl)-4-pyridyl]mercapto]benzoate dihydrochloride 38h (50.0 mg, 160.88 μmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (45.9 mg, 241.31 μmol), 1-hydroxybenzotriazole (32.6 mg, 241.31 μmol) and triethylamine (81.4 mg, 804.38 μmol), and the reaction was stirred at 25°C for 3.0 h. After thin-layer chromatography (petroleum ether / ethyl acetate = 3 / 1) showed that the starting material had reacted completely, 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 a crude product. Purification by preparative thin-layer chromatography (ethyl acetate / petroleum ether = 3 / 1) gave methyl 2-[3-[(E)-2-(2-pyridyl)vinyl]imidazo[1,5-a]pyridin-7-yl]thiobenzoate 38i as a yellow oil (37 mg, 91.25 μmol, 56.72% yield).

[0945] The product was confirmed by LCMS and HNMR.

[0946] MS-ESI calculated value [M+H]+ 406.1, found 406.1.

[0947] 1H NMR (400MHz, CDCl3) δ8.61(d,J=4.0Hz,1H),8.38(d,J=5.6Hz,1H),7.93(dd,J=8.0,1.6Hz,1H), 7.62-7.71(m,2H),7.34-7.44(m,4H),7.08-7.25(m,4H),7.05(dd,J=5.2,1.6Hz,1H),4.63(s,2H),3.87(s,3H).

[0948] Step 7

[0949] To a solution of methyl 2-[3-[(E)-2-(2-pyridyl)vinyl]imidazo[1,5-a]pyridin-7-yl]thiobenzoate 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 h. After LCMS showed that the starting material was reacted completely, 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 a crude product. Purification by preparative thin layer chromatography (ethyl acetate / petroleum ether = 3 / 1) gave methyl 2-[[2-[[(E)-3-(2-pyridyl)prop-2-enyl]amino]methyl]-4-pyridyl]thio]benzoate 38j (5 mg, 12.90 μmol, 40.25% yield) as a yellow solid.

[0950] The product was confirmed by LCMS.

[0951] MS-ESI calculated value [M+H]+ 388.1, found 388.1.

[0952] Step 8

[0953] To a solution of methyl 2-[[2-[[(E)-3-(2-pyridinyl)prop-2-enyl]amino]methyl]-4-pyridinyl]thio]benzoate 38j (80 mg, 206.48 μmol) in methanol (5 mL) was added sodium hydroxide (16.5 mg, 412.95 μmol) at room temperature, and the mixture was stirred at 25°C for 1.0 hour. After thin-layer chromatography (petroleum ether / ethyl acetate = 1 / 1) indicated complete reaction, the mixture was poured into water (10 mL) and the pH was adjusted to 4-5 with 1N aqueous hydrochloric acid. The mixture was filtered, and the filter cake was washed with water and dried to afford 2-({3-[(E)-2-(pyridin-2-yl)vinyl]imidazo[1,5-a]pyridin-7-yl}thio)benzoic acid I-28 as a red solid (48 mg, 128.54 μmol, 62.25% yield).

[0954] The product was confirmed by LCMS, HNMR and CNMR.

[0955] MS-ESI calculated value [M+H]+ 374.1, found 374.1.

[0956] 1 H NMR (400MHz, CDCl3&CD3OD) δ8.59-8.71(m,3H),8.13(t,J=7.2Hz,1H),8.04(d,J=7.6Hz,1H),7.83(d,J=7.6Hz,1H),7.76(s,1 H),7.66(s,1H),7.51-7.55(m,2H),7.34(t,J=7.2Hz,1H),7.23(t,J=7.2Hz,1H),7.06(d,J=8.0Hz,1H),6.82(d,J=6.8Hz,1H).

[0957] 13 C NMR (100MHz, CDCl3&CD3OD) δ168.38,151.61,144.03,142.61,139.59,135.70,132.8 0,132.52,131.63,128.56,125.73,123.67,123.29,123.05(s,3H),120.92,119.86.

[0958] I-27

[0959] first step

[0960] To a solution of compound 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) were added methylamine (8.3 mg, 123.18 μmol), benzotriazol-1-yl-oxytripyrrolidinylphosphine 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 hours. After thin-layer chromatography (dichloromethane / methanol = 15 / 1) indicated complete reaction of the starting material, 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 obtain a crude product. The crude product was purified by preparative HPLC to afford 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) as a white solid.

[0961] The product was confirmed by LCMS and HNMR.

[0962] MS-ESI calculated value [M+H]+ 387.1, found 387.0.

[0963] 1 H NMR (400MHz, CD3OD) δ8.57(d,J=4.4Hz,1H),8.42(d,J=7.2Hz,1H),7.96(d,J=15.6Hz,1H),7.86–7.90(m,1H),7.68(d,J=7 .6Hz,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=7.6,1.6Hz,1H),2.88(s,3H).

[0964] I-42

[0965] first step

[0966] Tert-butyl 6-[2-(cyclopropylcarbamoyl)phenyl]sulfanyl-3-iodoindazole-1-carboxylate 27f (500 mg, 933.89 μmol) was dissolved in dioxane (20 mL) at room temperature. 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)phosphine (284 mg, 933.89 μmol), and triethylamine (473 mg, 4.67 mmol) were added. The reaction system was stirred at 90°C under nitrogen for 1.5 hours. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, 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 using medium pressure to afford tert-butyl 6-[2-(cyclopropylcarbamoyl)phenyl]sulfanyl-3-[(trans)-2-[5-[2-(1-methyl-4-piperidinyl)ethoxy]-2-pyridinyl]vinyl]indazole-1-carboxylate 39b (200 mg, 305.89 μmol, 32.75% yield) as a brown solid.

[0967] The product was confirmed by LCMS.

[0968] MS-ESI calculated value [M+H] + 654.3, measured 654.4.

[0969] Step 2

[0970] Tert-butyl 6-[2-(cyclopropylcarbamoyl)phenyl]sulfanyl-3-[(trans)-2-[5-[2-(1-methyl-4-piperidinyl)ethoxy]-2-pyridinyl]vinyl]indazole-1-carboxylate 39b (800 mg, 1.22 mmol) was dissolved in dichloromethane (9 mL) and trifluoroacetic acid (3 mL) at room temperature. The reaction system was stirred at 25°C for 2 hours. The reaction solution was poured into water (30 mL), the pH was adjusted to 8-9 with saturated sodium carbonate solution, and the mixture was extracted with dichloromethane (20 mL x 3). The organic phases were combined, washed with saturated brine (3 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was prepared 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}sulfanyl)benzamide I-42 (69 mg, 124.61 μmol, 10.18% yield).

[0971] The product was confirmed by LCMS, H-NMR and C-NMR.

[0972] MS-ESI calculated value [M+H] + 554.3, measured 554.1.

[0973] 1 H NMR (400MHz, CD3OD): δ (ppm) 8.30 (s, 2H), 8.23 ​​(d, J = 2.8Hz, 1H), 8.03 (d, J = 8.4Hz, 1H), 7.66 (dd, J = 2 3.2,12.6Hz,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=6.0Hz,2H),3.49(d,J=11.4Hz,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=6.8,3.4Hz,2H),0.61-0.48(m,2H).

[0974] 13 C NMR(100MHz,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.

[0975] I-43

[0976] first step

[0977] Tert-butyl 6-[2-(cyclopropylcarbamoyl)phenyl]sulfanyl-3-iodoindazole-1-carboxylate 27f (500 mg, 933.9 μmol) was dissolved in dioxane (5 mL) at room temperature. 1-(3-pyrrolidin-1-ylpropyl)-4-vinylpyrazole 16c (230 mg, 1.12 mmol), palladium acetate (63 mg, 280.2 μmol), tri(o-methylphenyl)phosphine (85 mg, 280.2 μmol), and triethylamine (284 mg, 2.80 mmol) were added. The reaction system was stirred at 95°C under nitrogen for 1.5 hours. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10 / 1) to give tert-butyl 6-[2-(cyclopropylcarbamoyl)phenyl]sulfanyl-3-[(trans)-2-[1-(3-pyrrolidin-1-ylpropyl)pyrazol-4-yl]vinyl]indazole-1-carboxylate 40a (300 mg, 489.6 μmol, 52.42% yield) as a yellow solid.

[0978] The product was confirmed by LCMS.

[0979] MS-ESI calculated value [M+H] + 613.3, measured 613.3.

[0980] Step 2

[0981] Tert-butyl 6-[2-(cyclopropylcarbamoyl)phenyl]sulfanyl-3-[(trans)-2-[1-(3-pyrrolidin-1-ylpropyl)pyrazol-4-yl]vinyl]indazole-1-carboxylate 40a (600 mg, 979.1 μmol) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (5 mL) at room temperature. The reaction system was stirred at 25°C for 16 hours. The reaction solution was poured into water (20 mL), the pH was adjusted to 8-9 with saturated sodium carbonate solution, and the mixture was extracted with dichloromethane (20 mL x 3). The organic phases were combined, 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 prepared 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, 5.78% yield).

[0982] The product was confirmed by LCMS, H-NMR and C-NMR.

[0983] MS-ESI calculated value [M+H]+ 513.2, measured 513.1.

[0984] 1 H NMR (400MHz, CD3OD): δ (ppm) 8.54 (s, 1H), 7.98 (d, J = 8.6Hz, 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=6.4Hz,2H),3.07(s,4H),2.99-2.92(m,2H),2.82-2.73(m,1H),2.27-2.1 8(m,2H),1.98(dd,J=8.4,5.4Hz,4H),0.75(td,J=7.2,5.2Hz,2H),0.58-0.48(m,2H).

[0985] 13 C NMR(100MHz,CD3OD)δ(ppm)172.70,143.55,139.22,138.79,135.94,135.61,133.18,131.67,129.84,12 9.14,128.19,125.90,122.64,122.38,121.15,119.14,55.17,53.95,50.34,28.74,24.06,23.79,6.48.

[0986] I-44

[0987] first step

[0988] 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. 1-(3-pyrrolidin-1-ylpropyl)-4-vinylpyrazole 16c (458 mg, 2.23 mmol), palladium dichloride (198 mg, 1.12 mmol), tri(o-methylphenyl)phosphine (679 mg, 2.23 mmol), and triethylamine (1.1 g, 11.17 mmol) were added. The reaction system was stirred at 90°C for 16 hours under a nitrogen atmosphere. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified using medium pressure to give N-cyclopropyl-3-fluoro-2-[3-[(trans)-2-[5-(pyrrolidin-1-ylmethyl)-2-pyridinyl]vinyl]-1-tetrahydropyran-2-yl-indazol-6-yl]sulfanylbenzamide 41b (700 mg, 1.14 mmol, 50.99% yield) as a yellow solid.

[0989] The product was confirmed by LCMS.

[0990] MS-ESI calculated value [M+H] + 615.3, measured 615.1

[0991] Step 2

[0992] N-cyclopropyl-3-fluoro-2-[3-[(trans)-2-[5-(pyrrolidin-1-ylmethyl)-2-pyridyl]vinyl]-1-tetrahydropyran-2-yl-indazol-6-yl]sulfanylbenzamide 41b (700 mg, 1.14 mmol) was dissolved in dichloromethane (16 mL) at room temperature, and trifluoroacetic acid (4 mL) was added. The reaction system was stirred at 25°C for 16 hours. The reaction solution was poured into water (50 mL), and the pH was adjusted to 8-9 with saturated aqueous sodium carbonate. The solution was then extracted with dichloromethane (50 mL x 3). The organic phases were combined, washed with saturated brine (30 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-3-fluoro-2-({3-[(E)-2-{1-[3-(pyrrolidin-1-yl)propyl]-1H-pyrazol-4-yl}vinyl]-1H-indazol-6-yl}thio)benzamide I-44 (90.15 mg, 169.88 μmol, 14.92% yield).

[0993] The product was confirmed by LCMS, H-NMR and F-NMR.

[0994] MS-ESI calculated value [M+H] + 531.2, measured 531.1

[0995] 1 H NMR (400MHz, CD3OD): δ (ppm) 7.92-7.89 (m, 2H), 7.78 (s, 1H), 7.54-7.49 (m, 1H), 7.33-7.26 (m, 4H), 7.16-7.05 (m, 2H), 4.11 (t, J = 6.8Hz, 2H),2.78-2.73(m,1H),2.75(s,4H),2.49(t,J=7.6Hz,2H),2.13-2.05(m,2H),1.82-1.80(m,4H),0.75-0.70(m,2H),0.52-0.48(m,2H).

[0996] 19 F NMR (400MHz, CD3OD): δ (ppm)-105.90.

[0997] I-46

[0998] first step

[0999] N-cyclopropyl-5-fluoro-2-(3-iodo-1-tetrahydropyran-2-yl-indazol-6-yl)sulfanylbenzamide 42a (2 g, 3.7 mmol) was dissolved in dioxane (20 mL) at room temperature. 1-(3-pyrrolidin-1-ylpropyl)-4-vinylpyrazole 16c (764 mg, 3.7 mmol), tri(o-methylphenyl)phosphine (1.1 g, 3.7 mmol), triethylamine (1.9 g, 18.6 mmol), and palladium acetate (417 mg, 1.9 mmol) were added. The reaction system was stirred at 90°C under nitrogen for 16 hours. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified using a chromatography column (dichloromethane / methanol = 20 / 1 to 10 / 1) to afford N-cyclopropyl-5-fluoro-2-[3-[(trans)-2-[1-(3-pyrrolidin-1-ylpropyl)pyrazol-4-yl]vinyl]-1-tetrahydropyran-2-yl-indazol-6-yl]sulfanylbenzamide 42b (0.6 g, 975.97 μmol, 26.22% yield) as a yellow oil. The product was confirmed by LCMS.

[1000] MS-ESI calculated value [M+H]+ 615.3, found 615.1.

[1001] Step 2

[1002] N-Cyclopropyl-5-fluoro-2-[3-[(trans)-2-[1-(3-pyrrolidin-1-ylpropyl)pyrazol-4-yl]vinyl]-1-tetrahydropyran-2-yl-indazol-6-yl]sulfanylbenzamide 42b (600 mg, 976.0 μmol) was dissolved in dichloromethane (12 mL) and trifluoroacetic acid (4 mL) at room temperature. The reaction system was stirred at 25°C for 16 hours. The reaction solution was poured into water (30 mL), the pH was adjusted to 8-9 with saturated aqueous sodium carbonate solution, and the mixture was extracted with dichloromethane (30 mL x 3). The organic phases were combined, washed with saturated brine (30 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 N-cyclopropyl-5-fluoro-2-({3-[(E)-2-{1-[3-(pyrrolidin-1-yl)propyl]-1H-pyrazol-4-yl}vinyl]-1H-indazol-6-yl}thio)benzamide I-46 (55 mg, 103.6 μmol, 10.62% yield) as a white solid.

[1003] The product was confirmed by LCMS, F-NMR, H-NMR and C-NMR.

[1004] MS-ESI calculated value [M+H]+ 531.2, found 531.0.

[1005] 1 H NMR (400 MHz CD3OD): δ (ppm) 7.98 (d, J = 8.4Hz, 1H), 7.90 (s, 1H), 7.79 (s, 1H), 7.45 (s, 1H), 7.3 7-7.32(m,2H),7.24(dd,J=8.4,2.8Hz,1H),7.18-7.13(m,2H),7.11(dd,J=8.4,1. 2Hz,1H),4.23(t,J=6.8Hz,2H),2.78-2.75(m,1H),2.61(s,4H),2.53(t,J=7.6Hz ,2H),2.14-2.07(m,2H),1.84-1.81(m,4H),0.76-0.71(m,2H),0.53-0.49(m,2H).

[1006] 13C NMR(100MHz,CD3OD)δ(ppm)171.20,164.43,141.96,138.40,136.55,136.47,136.10,130.65,129.70,1 25.15,122.73,121.04,118.57,116.12,113.86,55.03,54.32,30.77,30.26,24.19,24.19,23.78,6.44.

[1007] 19 F NMR (400MHz, CD3OD): δ (ppm)-115.68.

[1008] I-51

[1009] first step

[1010] 6-Vinylpyridin-3-ol 1c (1 g, 8.26 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL) at room temperature. The temperature was cooled to 0°C and sodium hydride (991 mg, 24.77 mmol, 60%) was added. The reaction system was stirred at 0°C for 0.5 hours. 2-Bromo-N,N-dimethylethanolamine hydrobromide 43a (2.9 g, 12.38 mmol) was added at room temperature. The reaction system was stirred at 50°C for 2 hours. The reaction solution was poured into water (30 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, 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 column chromatography (petroleum ether:ethyl acetate = 10 / 1-3 / 1) to give N,N-dimethyl-2-[(6-vinyl-3-pyridyl)oxy]ethanamine 43b as a white solid (900 mg, 4.68 mmol, 56.71% yield).

[1011] The product was confirmed by LCMS.

[1012] MS-ESI calculated value [M+H] + 193.1, measured 193.1.

[1013] Step 2

[1014] N,N-Dimethyl-2-[(6-vinyl-3-pyridyl)oxy]ethanamine 43b (216 mg, 1.12 mmol) was dissolved in dioxane (10 mL) at room temperature. Tert-butyl 6-[2-(cyclopropylcarbamoyl)phenyl]sulfanyl-3-iodoindazole-1-carboxylate 27f (500 mg, 933.89 μmol), tris(o-methylphenyl)phosphine (500 mg, 1.64 mmol), tris(dibenzylideneacetone)dipalladium (500 mg, 546.02 μmol), and triethylamine (284 mg, 2.80 mmol) were added. The reaction system was stirred at 80°C under nitrogen for 1.5 hours. The reaction solution was poured into water (30 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude yellow solid product, tert-butyl 6-[2-(cyclopropylcarbamoyl)phenyl]sulfanyl-3-[(trans)-2-[5-[2-(dimethylamino)ethoxy]-2-pyridyl]vinyl]indazole-1-carboxylate 43c (300 mg, 500.22 μmol, 53.56% yield).

[1015] The product was confirmed by LCMS.

[1016] MS-ESI calculated value [M+H] + 600.3, measured 600.4.

[1017] Step 3

[1018] Tert-butyl 6-[2-(cyclopropylcarbamoyl)phenyl]sulfanyl-3-[(trans)-2-[5-[2-(dimethylamino)ethoxy]-2-pyridyl]vinyl]indazole-1-carboxylate 43c (300 mg, 500.22 μmol) was dissolved in dichloromethane (4 mL) at room temperature. Trifluoroacetic acid (4 mL) was added, and the reaction solution was stirred at 25°C for 16 hours. The reaction solution was poured into water (30 mL), the pH was adjusted to 9 with saturated sodium carbonate solution, and then extracted with dichloromethane (20 mL x 3). The organic phases were combined, washed with saturated brine (30 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-{5-[2-(dimethylamino)ethoxy]pyridin-2-yl}vinyl]-1H-indazol-6-yl}sulfanyl)benzamide I-51 (2.8 mg, 5.60 μmol, 1.12% yield).

[1019] The product was confirmed by LCMS, H-NMR and C-NMR.

[1020] MS-ESI calculated value [M+H] +500.2, measured 500.2

[1021] 1 H NMR (400MHz, CDCl3): δ (ppm) 8.36 (d, J = 2.8Hz, 1H), 7.99 (d, J = 8.6Hz, 1H), 7.75-7 .63(m,2H),7.73(d,J=16.0Hz,1H),7.68-7.65(m,1H),7.50-7.46(m,1H),7.43-7 .41(m,2H),7.35-7.31(m,3H),7.17(d,J=8.0Hz,1H),6.51(s,1H),4.25(s,2H),2 .92(s,2H),2.85-2.78(m,1H),2.48(s,6H),0.80-0.78(m,2H),0.49-0.45(m,2H).

[1022] 13 C NMR (100MHz, CDCl3): δ (ppm) 169.23, 148.94, 148.78, 142.07, 138.03, 136.79, 133.94, 133.59, 132.75, 132.60, 131.00, 130.53, 1 29.95,129.11,127.54,124.27,122.43,121.69,121.62,121.52,120.80,57.68,45.21,31.93,29.70,23.04,22.69,14.12,6.72.

[1023] I-52

[1024] first step

[1025] 6-Vinylpyridin-3-ol 1c (1 g, 8.26 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL) at room temperature. The temperature was cooled to 0°C and sodium hydride (991 mg, 24.77 mmol, 60%) was added. The reaction system was stirred at 0°C for 0.5 hours. 2-Bromo-N,N-diethylethanolamine hydrobromide 44a (3.2 g, 12.38 mmol) was added at the same temperature. The reaction system was stirred at 50°C for 3 hours. The reaction solution was poured into water (40 mL) and extracted with ethyl acetate (40 mL x 3). The organic phases were combined, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified using medium pressure preparative pressure to obtain N,N-diethyl-2-[(6-vinyl-3-pyridyl)oxy]ethanamine 44b (850 mg, 3.86 mmol, 46.74% yield), a brown liquid.

[1026] The product was confirmed by LCMS and HNMR.

[1027] MS-ESI calculated value [M+H] + 221.2, measured 221.1.

[1028] 1 H NMR (400MHz, CDCl3): δ (ppm) 8.27 (d, J = 2.8 Hz, 1H), 7.27 (s, 1H), 7.17 (dd, J = 8.6, 2.8 Hz, 1H), 6.77 (dd, J = 17.6, 10.8 Hz, 1H), 6.02 (dd, J = 17.6, 1. 2Hz,1H),5.35(dd,J=10.8,1.2Hz,1H),4.10(dd,J=11.8,5.8Hz,2H),2.90(dd,J=8.2,4.0Hz,2H),2.65(dd,J=8.2,6.2Hz,4H),1.10-1.07(m,6H).

[1029] Step 2

[1030] N,N-Diethyl-2-[(6-vinyl-3-pyridyl)oxy]ethanamine 44b (150 mg, 680.86 μmol) was dissolved in dioxane (8 mL) at room temperature. Tert-butyl 6-[2-(cyclopropylcarbamoyl)phenyl]sulfanyl-3-iodoindazole-1-carboxylate 27f (304 mg, 567.38 μmol), tri(o-methylphenyl)phosphine (173 mg, 567.38 μmol), palladium chloride (50 mg, 283.69 μmol), and triethylamine (287 mg, 2.84 mmol) were added. The reaction system was stirred at 95°C under nitrogen for 1.5 hours. The reaction solution was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a brown solid crude product of n-butyl 6-[2-(cyclopropylcarbamoyl)phenyl]aminosulfanyl-3-[(trans)-2-[5-[2-(diethylamino)ethoxy]-2-pyridyl]vinyl]indazole-1-carboxylate 44c (200 mg, 318.58 μmol, 56.15% yield).

[1031] The product was confirmed by LCMS.

[1032] MS-ESI calculated value [M+H] + 628.3, measured 628.2.

[1033] Step 3

[1034] Butyl 6-[2-(cyclopropylcarbamoyl)phenyl]aminosulfanyl-3-[(trans)-2-[5-[2-(diethylamino)ethoxy]-2-pyridyl]vinyl]indazole-1-carboxylate 44c (200 mg, 318.58 μmol) was dissolved in dichloromethane (9 mL) at room temperature. Trifluoroacetic acid (3 mL) was added and the reaction mixture was stirred at 25°C for 2 h. The reaction solution was poured into water (30 mL), and the pH was adjusted to 9 with saturated sodium carbonate solution. The mixture was then extracted with dichloromethane (20 mL x 3). The organic phases were combined and washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a 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-(diethylamino)ethoxy]pyridin-2-yl}vinyl]-1H-indazol-6-yl}sulfanyl)benzoyl I-52 (15 mg, 28.43 μmol, 8.92% yield).

[1035] The product was confirmed by LCMS, H-NMR and C-NMR.

[1036] MS-ESI calculated value [M+H] + 528.2, measured 528.2.

[1037] 1 H NMR (400MHz, CD3OD): δ (ppm) 8.28 (d, J = 2.8Hz, 1H), 8.04 (d, J = 8.4Hz, 1H), 7.68 (dd, J = 24.6, 12.6Hz,2H),7.57-7.42(m,4H),7.34-7.31(m,2H),7.25(dd,J=7.4,1.8Hz,1H),7.18(dd,J=8 .4,1.4Hz,1H),4.29(t,J=5.4Hz,2H),3.18(t,J=5.2Hz,2H),2.92(q,J=7.2Hz,4H),2.78(d,J =3.8Hz,1H),1.20(t,J=7.2Hz,6H),0.75(dd,J=7.2,1.8Hz,2H),0.54(dd,J=3.8,2.2Hz,2H).

[1038] 13C NMR(100MHz,CD3OD)δ(ppm)172.70,155.61,149.97,139.29,138.57,135.73,133.24,131.68,130.37,12 9.14,128.22,126.27,123.87,123.47,122.54,121.49,66.46,52.43,30.75,23.79,14.45,10.69,6.47.

[1039] I-53

[1040] first step

[1041] 6-Vinylpyridin-3-ol 1c (1 g, 8.26 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL) at room temperature. The mixture was cooled to 0°C and sodium hydride (660 mg, 16.51 mmol, 60%) was added. The reaction system was stirred at 0°C for 0.5 hours. 1-(2-chloroethyl)piperidine hydrochloride 45a (2.3 g, 9.91 mmol) was added at the same temperature. The reaction system was stirred at 25°C for 2 hours. The reaction solution was poured into water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:methanol = 1-10 / 1) to obtain 5-[2-(1-piperidinyl)ethoxy]-2-vinylpyridine 45b (800 mg, 3.44 mmol, 41.71% yield) as a yellow liquid.

[1042] The product was confirmed by LCMS and HNMR.

[1043] MS-ESI calculated value [M+H] + 233.2, measured 233.2.

[1044] 1 H NMR (400MHz, CDCl3): δ (ppm) 8.27 (d, J = 2.8Hz, 1H), 8.07 (d, J = 3.2Hz, 1H), 7.36 (d, J = 8.8Hz, 1H), 7.21-7.08 (m, 1H), 6.77 (dd, J = 17.6, 11.2Hz, 1H), 6.0 2(dd,J=17.6,1.2Hz,1H),5.35(dd,J=10.8,1.2Hz,1H),4.18-4.08(m,2H), 2.80-2.75(m,2H),2.51-2.43(m,4H),1.62-1.58(m,4H),1.49-1.38(m,2H)

[1045] Step 2

[1046] 5-[2-(1-piperidinyl)ethoxy]-2-vinylpyridine 45b (260 mg, 1.12 mmol) was dissolved in dioxane (5 mL) at room temperature. Tert-butyl 6-[2-(cyclopropylcarbamoyl)phenyl]sulfanyl-3-iodoindazole-1-carboxylate 27f (500 mg, 933.89 μmol), tris(o-methylphenyl)phosphine (853 mg, 2.80 mmol), tris(dibenzylideneacetone)dipalladium (500 mg, 564.4 mmol), and triethylamine (284 mg, 2.80 mmol) were added. The reaction system was stirred at 85°C under nitrogen for 1.5 hours. The reaction solution was poured into water (20 mL) and extracted with ethyl acetate (20 mL x 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 tert-butyl 6-[2-(cyclopropylcarbamoyl)phenyl]sulfanyl-3-[(trans)-2-[5-[2-(1-piperidinyl)ethoxy]-2-pyridinyl]vinyl]indazole-1-carboxylate 45c (190 mg, 296.97 μmol, 31.80% yield) as a yellow oil.

[1047] The product was confirmed by LCMS.

[1048] MS-ESI calculated value [M+H] + 640.3, measured 640.1.

[1049] Step 3

[1050] Tert-butyl 6-[2-(cyclopropylcarbamoyl)phenyl]sulfanyl-3-[(trans)-2-[5-[2-(1-piperidinyl)ethoxy]-2-pyridinyl]vinyl]indazole-1-carboxylate 45c (60 mg, 93.78 μmol) was dissolved in dichloromethane (5 mL) at room temperature. Trifluoroacetic acid (2 mL) was added, and the reaction solution was stirred at 25°C for 16 hours. The reaction solution was poured into water (30 mL), the pH was adjusted to 9 with saturated sodium carbonate solution, and then extracted with dichloromethane (20 mL x 3). The organic phases were combined and washed with saturated brine (30 mL), dried ...

Claims

1. A compound represented by formula (I), in, Said R1 comprises a substituted cyclic structure; R2 contains optionally substituted substituents; R3 contains optionally substituted substituents; X1 is an optionally substituted atom; or a pharmaceutically acceptable prodrug of the compound, a pharmaceutically active metabolite of the compound and / or a pharmaceutically acceptable salt of the compound. 2 . The compound according to claim 1 , wherein the cyclic structure of R 1 is substituted with a substituent containing a basic nitrogen atom. 3 . The compound according to claim 1 , wherein the cyclic structure of R 1 is substituted by a substituent selected from the group consisting of an optionally substituted amino group and an optionally substituted nitrogen-containing aliphatic heterocyclic group.

4. The compound of any one of claims 1 to 3, wherein R1 comprises (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 optionally substituted substituents, wherein nr0, nr1, nr2, nr3, nr4 and nr5 are each independently selected from 0 or greater.

5. The compound of claim 4, wherein 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 compound according to any one of claims 4 to 5, wherein 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 compound of any one of claims 4 to 7, wherein R 1-1 is a chemical bond or is selected from the following group: an optionally substituted amide group, an optionally substituted aromatic ring group, and an optionally substituted aromatic heterocyclic group.

9. The compound according to any one of claims 4 to 8, wherein R 1-1 is a chemical bond or is selected from the following group: an optionally substituted amide group, an optionally substituted phenyl group, and an optionally substituted aromatic heterocyclic group.

10. The compound according to any one of claims 4 to 9, wherein R 1-1 is a chemical bond or is selected from the following group: an optionally substituted amide group, an optionally substituted phenyl group, an optionally substituted pyridyl group and an optionally substituted pyrazolyl group. The compound according to any one of claims 4 to 10, wherein nr1 is 0 or 1.

12. The compound of any one of claims 4 to 11, wherein R 1-2 is a chemical bond or is selected from the group consisting of hydrogen, protium, deuterium, tritium, and optionally substituted hydroxyl.

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

14. The compound of any one of claims 4 to 13, wherein R 1-3 is a chemical bond or is selected from the group consisting of hydrogen, protium, deuterium, tritium, and optionally substituted alkyl.

15. The compound of any one of claims 4 to 14, wherein R 1-3 is a chemical bond or is selected from the following group: hydrogen, protium, deuterium, tritium, optionally substituted methyl, optionally substituted ethyl and optionally substituted propyl.

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

17. The compound of any one of claims 4 to 16, wherein R 1-4 is a chemical bond or is selected from the following group: hydrogen, protium, deuterium, tritium, an optionally substituted amino group and an optionally substituted aliphatic heterocyclic group.

18. The compound of any one of claims 4 to 17, wherein R 1-4 is a chemical bond or is selected from the following group: hydrogen, protium, deuterium, tritium, optionally substituted amino, optionally substituted pyrrolyl, optionally substituted piperidinyl, optionally substituted piperazinyl and optionally substituted morpholinyl.

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

20. The compound of any one of claims 4 to 19, wherein R 1-5 is a chemical bond or is selected from the group consisting of hydrogen, protium, deuterium, tritium, and optionally substituted alkyl.

21. The compound of any one of claims 4 to 20, wherein 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 of any one of claims 4-21, wherein nr5 is 0, 1 or 2.

23. The compound of any one of claims 1-22, wherein R2 is an optionally substituted thiol.

24. The compound of any one of claims 1 to 23, wherein R2 is replaced by one or more R 2-1 Substituted, each of the R 2-1 Each is independently an optionally substituted substituent.

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

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

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

28. The compound of claim 27, wherein R 2-2 is selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, optionally substituted carbonyl, optionally substituted carboxyl, optionally substituted amide, and optionally substituted alkyl.

29. The compound of any one of claims 27-28, wherein R 2-2 is selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, optionally substituted carbonyl, optionally substituted carboxyl, optionally substituted amido, and optionally substituted methyl.

30. The compound of any one of claims 27-29, wherein R 2-2 By 1 or more R 2-3 Substituted, each of the R 2-3 Each is independently an optionally substituted substituent.

31. The compound of claim 30, wherein R 2-3 is selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, optionally substituted alkyl, optionally substituted alicyclic, and optionally substituted amino.

32. The compound of any one of claims 30-31, wherein R 2-3 is selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, optionally substituted methyl, optionally substituted ethyl, optionally substituted cyclopropyl, and optionally substituted amino.

33. The compound of any one of claims 30-32, wherein R 2-3 By 1 or more R 2-4 Substituted, each of the R 2-4 Each is independently an optionally substituted substituent.

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

35. The compound of any one of claims 33-34, wherein R 2-4 is selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, optionally substituted methyl, optionally substituted ethyl, and optionally substituted cyclopropyl.

36. The compound of any one of claims 1-35, wherein R3 is selected from the group consisting of hydrogen, protium, deuterium, and tritium.

37. The compound of claim 36, wherein X1 is selected from the group consisting of optionally substituted CH, and N.

38. A compound or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, or deuterated compound thereof, wherein the compound has the structure: in, Ring A is a five- to seven-membered nitrogen-containing heterocyclic ring; Ring B is a five- to seven-membered aromatic ring or heterocyclic ring; Z is selected from: -C(O)NH-, -NHC(O)- or The E ring is an aromatic ring or a heteroaromatic ring; L0 is selected from: O, S, N (R La ), C1-C6 alkylene, C(O); R La Selected from: H, C1-C6 alkyl; L1 is selected from: single bond, C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, -(C0-C6 alkylene)-Q1-(C0-C6 alkylene)-, Q1 Selected from: -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)-; the H atoms in the alkylene group may be optionally substituted by the following groups: H, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, halogen, cyano, nitro, azido, C1-C 10 Halogenated alkyl, hydroxyl, C1-C 10 Alkoxy, C1-C 10 Haloalkoxy, amino, C1-C 10 Alkylamino; R Lb Selected from: H, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkylalkyl, C6-C 10 Aryl, C7-C 12 Aralkyl, 4-10 membered heterocyclyl, 4-10 membered heterocyclylalkyl; L2 is selected from: single bond, C1-C6 alkylene, -(C0-C6 alkylene)-Q2-(C0-C6 alkylene)-, Q2 is selected from: -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)-; the H atoms in the alkylene group may be optionally substituted by the following groups: H, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, halogen, cyano, nitro, azido, C1-C 10 Halogenated alkyl, hydroxyl, C1-C 10 Alkoxy, C1-C 10 Haloalkoxy, amino, C1-C 10 Alkylamino; R Lc Selected from: H, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkylalkyl, C6-C 10 Aryl, C7-C 12 Aralkyl, 4-10 membered heterocyclyl, 4-10 membered heterocyclylalkyl; Y is selected from: H, -NR7R8, nitrogen-containing heterocyclic group, wherein the nitrogen-containing heterocyclic group may be optionally substituted by one or more R9 groups, R9 is selected from: halogen, cyano, amino, hydroxyl, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Alkoxy, C1-C 10 Halogenated alkoxy, C1-C 10 Alkylamino, C1-C 10 Cyanoalkyl, C1-C 10 Hydroxyl substituted alkyl, C1-C 10 Alkoxy-substituted alkyl, C1-C 10 Alkylamino-substituted alkyl, -(C0-C6 alkylene)-(C6-C 10 Aryl), -SO2-(C0-C6 alkylene)-(C6-C 10 Aryl), -S-(C0-C6 alkylene)-(C6-C 10 Aryl), -O-(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclyl), -SO2-(C0-C6 alkylene)-(4-10 membered heterocyclyl), -S-(C0-C6 alkylene)-(4-10 membered heterocyclyl), -O-(C0-C6 alkylene)-(4-10 membered heterocyclyl), -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -SO2-(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -S-(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -O-(C0-C6 alkylene)-(C3-C 10 cycloalkyl); R7, R8 are independently selected from: H, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, 4-10 membered heterocyclylalkyl; wherein the C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group may be optionally substituted by one or more groups selected from the following: H, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkylalkyl, C6-C 10 Aryl, C7-C 12 Aralkyl, 4-10 membered heterocyclyl, 4-10 membered heterocyclylalkyl; R4 is one or more independent substituents on the benzene ring, each R4 is independently selected from: H, halogen, C1-C 10 Alkyl, cyano, C1-C 10 Halogenated alkyl, C1-C 10 Halogenated alkoxy, C1-C 10 Cyanoalkyl, -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)-NR 401 R 402 、-SR 401 、-S(O)R 401 、-S(O)2R 401 、-(C0-C6 alkylene)-(C6-C 10 Aryl), -SO2-(C0-C6 alkylene)-(C6-C 10 Aryl), -S-(C0-C6 alkylene)-(C6-C 10 Aryl), -O-(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclyl), -SO2-(C0-C6 alkylene)-(4-10 membered heterocyclyl), -S-(C0-C6 alkylene)-(4-10 membered heterocyclyl), -O-(C0-C6 alkylene)-(4-10 membered heterocyclyl), -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -SO2-(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -S-(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -O-(C0-C6 alkylene)-(C3-C 10 Cycloalkyl); wherein the C0-C6 alkylene, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, 4-10 membered heterocyclic group may be optionally substituted by one or more groups selected from the following: halogen, cyano, amino, hydroxyl, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Alkoxy, C1-C 10 Halogenated alkoxy, C1-C 10 Alkylamino, C1-C 10 Cyanoalkyl, C1-C 10 Hydroxyl substituted alkyl, C1-C 10 Alkoxy-substituted alkyl, C1-C 10 Alkylamino-substituted alkyl, -(C0-C6 alkylene)-(C6-C 10 Aryl), -SO2-(C0-C6 alkylene)-(C6-C 10 Aryl), -S-(C0-C6 alkylene)-(C6-C 10 Aryl), -O-(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclyl), -SO2-(C0-C6 alkylene)-(4-10 membered heterocyclyl), -S-(C0-C6 alkylene)-(4-10 membered heterocyclyl), -O-(C0-C6 alkylene)-(4-10 membered heterocyclyl), -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -SO2-(C0-C6 alkylene) - (C3-C 10 Cycloalkyl), -S-(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -O-(C0-C6 alkylene)-(C3-C 10 cycloalkyl); R 401 and R 402 Independently selected from: H, C1-C 10 Alkyl, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkylalkyl, C6-C 10 Aryl, C6-C 10 Aralkyl, 4-10 membered heterocyclyl, 4-10 membered heterocyclylalkyl; R5 is One or more independent substituents on the ring, each R5 is independently selected from: H, halogen, cyano, amino, hydroxyl, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Alkoxy, C1-C 10 Halogenated alkoxy, C1-C 10 Alkylamino, C1-C 10 Cyanoalkyl, C1-C 10 Hydroxyl substituted alkyl, C1-C 10 Alkoxy-substituted alkyl, C1-C 10 Alkylamino-substituted alkyl, -(C0-C6 alkylene)-(C6-C 10 Aryl), -SO2-(C0-C6 alkylene)-(C6-C 10 Aryl), -S-(C0-C6 alkylene)-(C6-C 10 Aryl), -O-(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclyl), -SO2-(C0-C6 alkylene)-(4-10 membered heterocyclyl), -S-(C0-C6 alkylene)-(4-10 membered heterocyclyl), -O-(C0-C6 alkylene)-(4-10 membered heterocyclyl), -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -SO2-(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -S-(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -O-(C0-C6 alkylene)-(C3-C 10 cycloalkyl); R6 is one or more independent substituents on the E ring, each R6 is independently selected from: H, halogen, cyano, amino, hydroxyl, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Alkoxy, C1-C 10 Halogenated alkoxy, C1-C 10 Alkylamino, C1-C 10 Cyanoalkyl, C1-C 10 Hydroxyl substituted alkyl, C1-C 10 Alkoxy-substituted alkyl, C1-C 10 Alkylamino-substituted alkyl, -(C0-C6 alkylene)-(C6-C 10 Aryl), -SO2-(C0-C6 alkylene)-(C6-C 10 Aryl), -S-(C0-C6 alkylene)-(C6-C 10 Aryl), -O-(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclyl), -SO2-(C0-C6 alkylene)-(4-10 membered heterocyclyl), -S-(C0-C6 alkylene)-(4-10 membered heterocyclyl), -O-(C0-C6 alkylene)-(4-10 membered heterocyclyl), -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -SO2-(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -S-(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -O-(C0-C6 alkylene)-(C3-C 10 cycloalkyl).

39. The compound according to claim 38, wherein The structure is one of the following: Selected from: More preferably Wherein, R3 is selected from: H, C1-C6 alkyl.

40. The compound according to claim 38 or 39, wherein L0 is selected from the group consisting of: S, O, NH, and methylene, preferably S.

41. The compound according to any one of claims 38 to 40, wherein L1 is selected from: C2-C6 alkenylene, C2-C6 alkynylene, -Q1-(C0-C6 alkylene)-, -(C0-C6 alkylene)-Q1-; Preferably, Q1 is -N(R Lb )-,R Lb Selected from: H, C1-C3 alkyl; More preferably, L1 is selected from: -NH-.

42. The compound according to any one of claims 38 to 41, wherein The E ring is a benzene ring or a five-membered or six-membered nitrogen-containing heteroaromatic ring; Preferably, Partially selected from the following structures:

43. The compound according to any one of claims 38 to 42, wherein L2 is selected from: a single bond, C1-C6 alkylene, -Q2-(C0-C6 alkylene)-; Preferably, Q2 is selected from: -O-, -S-, -N(R Lc )-,R Lc Selected from: H, C1-C3 alkyl; More preferably, L2 is selected from:

44. The compound according to any one of claims 38 to 43, wherein Y is -NR7R8, R7 and R8 are independently selected from: H, C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C6 cycloalkyl); Preferably, Y is 45. The compound according to any one of claims 38 to 43, wherein Y is selected from: Preferably, Y is selected from: Preferably, R9 is selected from: H, C1-C6 alkyl (e.g. -CH3, ), C1-C6 hydroxy substituted alkyl (For example ), C1-C6 amino substituted alkyl (e.g. ), C1-C6 alkoxy substituted alkyl (e.g. ), C1-C6 alkylamino substituted alkyl (e.g. ), -(C0-C6 alkylene)-(C3-C6 cycloalkyl) (e.g. )； More preferably, Y is selected from:

46. ​​The compound according to any one of claims 38 to 45, wherein Part of in, R 4a Selected from: -C(O)NR 401 R 402 、-(C0-C6 alkylene)-NR 401 R 402 、-C(O)R 401 、-C(O)OR 401 , R 401 and R 402 Independently selected from: H, C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C6 cycloalkyl); wherein the C0-C6 alkylene, C1-C6 alkyl, C3-C6 cycloalkyl may be optionally substituted with one or more groups selected from the following: halogen, cyano, amino, hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl; R 4b is one or more independent substituents on the phenyl ring selected from: H, halogen, cyano, amino, hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl; Preferably, R 4a Selected from: Preferably, R 4b is H or halogen; More preferably, Part of 47. A compound having a structure selected from the group consisting of: or a pharmaceutically acceptable prodrug of the compound, a pharmaceutically active metabolite of the compound and / or a pharmaceutically acceptable salt of the compound.

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

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

50. The use according to claim 49, wherein The disease is an eye disease, preferably selected from: 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 AMD, and geographic atrophy); pathological choroidal neovascularization (CNV) arising from any pathological mechanism (i.e., high myopia, trauma, sickle cell disease; ocular histoplasmosis, angioid streaks, traumatic choroidal rupture, optic nerve drusen, and certain retinal dystrophies ); pathological retinal neovascularization from any pathological mechanism (i.e., sickle cell retinopathy, Eales disease, ocular ischemic syndrome, carotid cavernous fistula, familial exudative vitreoretinopathy, hyperviscosity syndrome, idiopathic occlusive arteritis, 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; Preferably, the disease is diabetic retinopathy (including non-proliferative and proliferative types and diabetic macular edema) or retinal vein occlusion (central or branch); Or, the disease is a tumor, preferably selected from the group consisting of: breast cancer, lung cancer (especially non-small cell lung cancer), adenocarcinoma, colorectal cancer, renal cancer, liver cancer, pancreatic cancer, ovarian cancer, prostate cancer, glioma, glioblastoma, myeloma, leukemia, unrelated myeloid metaplasia, mesothelioma, and myelodysplastic syndrome; Preferably, the disease is a hematological malignancy, more preferably selected from the group consisting of 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 B-cell lymphoma, primary mediastinal B-cell lymphoma, Burkitt's lymphoma, lymphoplasmacytic lymphoma, hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B lymphoblastic lymphoma and primary central nervous system (CNS) lymphomas and T-cell NHL, such as precursor T lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy-type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma and anaplastic large cell lymphoma, NK / T-cell lymphoma.

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